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nord_557_1 | Symptoms of Hemimegalencephaly | HME typically is identified in the neonatal period when the baby develops presents seizures. The seizures usually do not decline in severity or number with medical treatment and in some cases they may exceed 50 or more per day. On physical examination, a child with HME may presents with enlarged head circumference or an asymmetrical head shape. There may be movement or motor deficits on the side opposite to the HME. When these signs are present, the neurologist may suspect the presence of HME and order magnetic resonance imaging (MRI) examination.HME may occur in association with other syndromes, such as Proteus syndrome, epidermal nevus syndrome, tuberous sclerosis complex (TSC), linear sebaceous nevus syndrome, neurofibromatosis, and Sturge-Weber syndrome which are associated with abnormalities of skin pigmentation that can be detected on physical examination. Any child with these skin markings and seizures should be further evaluated for HME as well as other brain malformations. Hemimegalencephaly may also occur in association with Sotos syndrome and Alexander disease. These syndromes arise as a result of complex genetic activities such as single or multiple gene mutations. The mutations causing these disorders can be inherited or occur randomly during fetal development. | Symptoms of Hemimegalencephaly. HME typically is identified in the neonatal period when the baby develops presents seizures. The seizures usually do not decline in severity or number with medical treatment and in some cases they may exceed 50 or more per day. On physical examination, a child with HME may presents with enlarged head circumference or an asymmetrical head shape. There may be movement or motor deficits on the side opposite to the HME. When these signs are present, the neurologist may suspect the presence of HME and order magnetic resonance imaging (MRI) examination.HME may occur in association with other syndromes, such as Proteus syndrome, epidermal nevus syndrome, tuberous sclerosis complex (TSC), linear sebaceous nevus syndrome, neurofibromatosis, and Sturge-Weber syndrome which are associated with abnormalities of skin pigmentation that can be detected on physical examination. Any child with these skin markings and seizures should be further evaluated for HME as well as other brain malformations. Hemimegalencephaly may also occur in association with Sotos syndrome and Alexander disease. These syndromes arise as a result of complex genetic activities such as single or multiple gene mutations. The mutations causing these disorders can be inherited or occur randomly during fetal development. | 557 | Hemimegalencephaly |
nord_557_2 | Causes of Hemimegalencephaly | The basic cause(s) of HME is not well understood. The disorder occurs because the cells of one hemisphere of the brain grow much more rapidly than do the corresponding cells of the other half of the brain (hamartomatous overgrowth of one hemisphere). It is widely believed that a single or multiple gene mutations contribute to this process. As might be expected, the cortex of the enlarged brain is malformed (dysplastic) and the white matter is abnormal. One of the common, empty spaces of the brain (lateral ventricle) in the enlarged hemisphere is enlarged in proportion to the lateral ventricle of the smaller hemisphere. Some clinicians believe that HME occurs as a result of damage to the fetal brain during the first or second trimester of pregnancy that affect the genetically programmed process that establishes symmetry as well as the development of different classes of brain cells. | Causes of Hemimegalencephaly. The basic cause(s) of HME is not well understood. The disorder occurs because the cells of one hemisphere of the brain grow much more rapidly than do the corresponding cells of the other half of the brain (hamartomatous overgrowth of one hemisphere). It is widely believed that a single or multiple gene mutations contribute to this process. As might be expected, the cortex of the enlarged brain is malformed (dysplastic) and the white matter is abnormal. One of the common, empty spaces of the brain (lateral ventricle) in the enlarged hemisphere is enlarged in proportion to the lateral ventricle of the smaller hemisphere. Some clinicians believe that HME occurs as a result of damage to the fetal brain during the first or second trimester of pregnancy that affect the genetically programmed process that establishes symmetry as well as the development of different classes of brain cells. | 557 | Hemimegalencephaly |
nord_557_3 | Affects of Hemimegalencephaly | Hemimegalencephaly is a very rare disorder for which prevalence estimates are not available. | Affects of Hemimegalencephaly. Hemimegalencephaly is a very rare disorder for which prevalence estimates are not available. | 557 | Hemimegalencephaly |
nord_557_4 | Related disorders of Hemimegalencephaly | Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.Megalencephaly is characterized by an abnormally large, heavy, and poorly functioning brain. The head of an infant affected by megalencephaly is abnormally large in the infant’s early years especially. The mechanism that regulates the brain cell reproduction and multiplication is, for reasons that are poorly understood, thrown out of synchronization so that the number, type and location of brain cells are abnormal. This disorder affects more males than females.Hemi-hemimegalencephaly (HHM), or posterior quadrantic dysplasia (PQD), is so rare that only one paper on this subject appears in the literature. That paper reviews the clinical features of 19 patients with epilepsy that doesn’t respond to treatment (intractable). Of these, 14 had confirmed hemi-hemimegalencephaly and 5 were dysplastic in quadrants other than the posterior. Fourteen patients were operated upon and, of these, 6 were seizure free for at least two years; 2 had at least an 85% reduction of seizures; 4 had a reduction of at least 50% in seizures; and 2 patients showed no significant change after surgery. | Related disorders of Hemimegalencephaly. Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.Megalencephaly is characterized by an abnormally large, heavy, and poorly functioning brain. The head of an infant affected by megalencephaly is abnormally large in the infant’s early years especially. The mechanism that regulates the brain cell reproduction and multiplication is, for reasons that are poorly understood, thrown out of synchronization so that the number, type and location of brain cells are abnormal. This disorder affects more males than females.Hemi-hemimegalencephaly (HHM), or posterior quadrantic dysplasia (PQD), is so rare that only one paper on this subject appears in the literature. That paper reviews the clinical features of 19 patients with epilepsy that doesn’t respond to treatment (intractable). Of these, 14 had confirmed hemi-hemimegalencephaly and 5 were dysplastic in quadrants other than the posterior. Fourteen patients were operated upon and, of these, 6 were seizure free for at least two years; 2 had at least an 85% reduction of seizures; 4 had a reduction of at least 50% in seizures; and 2 patients showed no significant change after surgery. | 557 | Hemimegalencephaly |
nord_557_5 | Diagnosis of Hemimegalencephaly | Examination by MRI is usually sufficient to confirm a suspected case of HME. Thus, an MRI examination should be performed as soon as HME is suspected. Seizures are diagnosed and defined by electroencephalography (EEG). | Diagnosis of Hemimegalencephaly. Examination by MRI is usually sufficient to confirm a suspected case of HME. Thus, an MRI examination should be performed as soon as HME is suspected. Seizures are diagnosed and defined by electroencephalography (EEG). | 557 | Hemimegalencephaly |
nord_557_6 | Therapies of Hemimegalencephaly | TreatmentPersistent, intractable seizures are seldom brought under control by means of anti-epileptic medications. Most patients undergo surgery to separate one hemisphere of the brain from the other. The surgical procedure may involve "functional hemispherectomy" in which the nerves and tissue connecting one side of the brain to the other are severed, but the abnormal hemisphere remains within the skull. Complete or anatomic hemispherectomy involves disconnecting one side of the brain from the other and extracting the abnormal hemisphere. These surgeries are typically performed by a neurosurgeon trained in epilepsy surgery. | Therapies of Hemimegalencephaly. TreatmentPersistent, intractable seizures are seldom brought under control by means of anti-epileptic medications. Most patients undergo surgery to separate one hemisphere of the brain from the other. The surgical procedure may involve "functional hemispherectomy" in which the nerves and tissue connecting one side of the brain to the other are severed, but the abnormal hemisphere remains within the skull. Complete or anatomic hemispherectomy involves disconnecting one side of the brain from the other and extracting the abnormal hemisphere. These surgeries are typically performed by a neurosurgeon trained in epilepsy surgery. | 557 | Hemimegalencephaly |
nord_558_0 | Overview of Hemiplegic Migraine | Hemiplegic migraine is a rare disorder in which affected individuals experience a migraine headache along with weakness on one side of the body (hemiplegia). Affected individuals are described as having a migraine with aura. Aura refers to additional neurological symptoms that occur with or sometimes before, the development of migraine headaches. Hemiplegia is an aura symptom. Additional aura symptoms usually affect vision, but also can affect speech, sensation and mental status. In some affected individuals, hemiplegic migraine occurs because of a change (variant or mutation) in a specific gene. This is called familial hemiplegic migraine. Abnormal variants in four genes, CACNA1A, ATP1A2, SCN1A and PRRT2, have all been shown to cause the familial forms. Some affected individuals are thought to develop the disorder because of a variant in an as-yet-unidentified gene. There is usually a family history of hemiplegic migraines in affected individuals. Some individuals may be the first person in their family with hemiplegic migraine; these individuals are described as having sporadic hemiplegic migraine. | Overview of Hemiplegic Migraine. Hemiplegic migraine is a rare disorder in which affected individuals experience a migraine headache along with weakness on one side of the body (hemiplegia). Affected individuals are described as having a migraine with aura. Aura refers to additional neurological symptoms that occur with or sometimes before, the development of migraine headaches. Hemiplegia is an aura symptom. Additional aura symptoms usually affect vision, but also can affect speech, sensation and mental status. In some affected individuals, hemiplegic migraine occurs because of a change (variant or mutation) in a specific gene. This is called familial hemiplegic migraine. Abnormal variants in four genes, CACNA1A, ATP1A2, SCN1A and PRRT2, have all been shown to cause the familial forms. Some affected individuals are thought to develop the disorder because of a variant in an as-yet-unidentified gene. There is usually a family history of hemiplegic migraines in affected individuals. Some individuals may be the first person in their family with hemiplegic migraine; these individuals are described as having sporadic hemiplegic migraine. | 558 | Hemiplegic Migraine |
nord_558_1 | Symptoms of Hemiplegic Migraine | Affected individuals experience hemiplegic migraine attacks. These attacks can range from about one a day to fewer than five in a lifetime. There can often be long episode-free periods during life. Generally, episodes become less frequent as a person ages. Individual episodes can vary in severity and duration. Hemiplegic migraine is a chronic disorder and can be extremely painful and debilitating.Hemiplegic migraine attacks comprise an aura phase and a headache phase. Aura refers to additional neurological symptoms that occur with, or often shortly before, the development of migraine headaches. A migraine aura usually lasts about an hour but can take up to a week to completely resolve. Aura symptoms can often outlast the migraine headache itself.Individuals with hemiplegic migraine experience weakness on one side of the body during the aura (hemiplegia), either just before or during the migraine headache. The degree of weakness can vary from mild to severe. Hemiplegia may affect only part of one side of the body, such as just the hand or the hands and arms, or the face. Weakness of the entire side of the body can occur. Hemiplegia is a distinct aura symptom that characterizes these disorders.In hemiplegic migraine, the weakness is always associated with at least one other aura symptom. Vision is usually affected temporarily, and symptoms can include a sudden appearance of a bright light in the center of the field of vision causing blind spots (scintillating scotoma), double vision, flashing lights (photopsia) and bright, shimmering, jagged lines (fortification spectra). Visual symptoms can also include foggy vision or a loss of vision of one half of the visual field. Additional symptoms include numbness or a prickly sensation of the face or arms and legs (paresthesia), fever, imbalance, drowsiness or lethargy and an inability to understand or express speech (aphasia). The aura rarely involves abnormal movement of one hand or one arm preceding the motor weakness. The specific aura symptoms that develop during a migraine attack can vary from one attack to another. Some individuals with hemiplegic migraine may also have attacks with a so-called typical aura, including visual, sensory and speech troubles but no weakness.During an attack of hemiplegic migraine, headache might start shortly before, during or after the aura. Migraine headaches cause throbbing, intense, sometimes debilitating pain and are notably stronger than regular headaches. The pain can cause nausea or vomiting, and affected individuals may be extremely sensitive to light (photophobia) and to sound (phonophobia).In severe instances, affected individuals may experience prolonged weakness, seizures, confusion, memory loss, and personality or behavioral changes. Although uncommon, hemiplegic migraine attacks can be severe enough to cause coma. During such severe hemiplegic migraine attacks, weakness and speech troubles can last for several days or weeks but usually fully resolve. In rare instances, permanent complications can develop including intellectual disability.A minority of individuals with hemiplegic migraine develop signs or symptoms of involvement of the cerebellum, the area of the brain that controls coordination and balance and is also involved in cognition and behavior. These signs or symptoms can include uncontrolled, repetitive movements of the eyes (nystagmus), slurred speech (dysarthria) and a lack of coordination of voluntary movements (ataxia). These symptoms are permanent and usually slowly progress with ageing.A minority of individuals with hemiplegic migraine may develop epileptic seizures outside of hemiplegic migraine attacks.A minority of individuals with familial hemiplegic migraine may have delayed acquisition of speech and motor features during early childhood, learning difficulties or rarely, cognitive disabilities. | Symptoms of Hemiplegic Migraine. Affected individuals experience hemiplegic migraine attacks. These attacks can range from about one a day to fewer than five in a lifetime. There can often be long episode-free periods during life. Generally, episodes become less frequent as a person ages. Individual episodes can vary in severity and duration. Hemiplegic migraine is a chronic disorder and can be extremely painful and debilitating.Hemiplegic migraine attacks comprise an aura phase and a headache phase. Aura refers to additional neurological symptoms that occur with, or often shortly before, the development of migraine headaches. A migraine aura usually lasts about an hour but can take up to a week to completely resolve. Aura symptoms can often outlast the migraine headache itself.Individuals with hemiplegic migraine experience weakness on one side of the body during the aura (hemiplegia), either just before or during the migraine headache. The degree of weakness can vary from mild to severe. Hemiplegia may affect only part of one side of the body, such as just the hand or the hands and arms, or the face. Weakness of the entire side of the body can occur. Hemiplegia is a distinct aura symptom that characterizes these disorders.In hemiplegic migraine, the weakness is always associated with at least one other aura symptom. Vision is usually affected temporarily, and symptoms can include a sudden appearance of a bright light in the center of the field of vision causing blind spots (scintillating scotoma), double vision, flashing lights (photopsia) and bright, shimmering, jagged lines (fortification spectra). Visual symptoms can also include foggy vision or a loss of vision of one half of the visual field. Additional symptoms include numbness or a prickly sensation of the face or arms and legs (paresthesia), fever, imbalance, drowsiness or lethargy and an inability to understand or express speech (aphasia). The aura rarely involves abnormal movement of one hand or one arm preceding the motor weakness. The specific aura symptoms that develop during a migraine attack can vary from one attack to another. Some individuals with hemiplegic migraine may also have attacks with a so-called typical aura, including visual, sensory and speech troubles but no weakness.During an attack of hemiplegic migraine, headache might start shortly before, during or after the aura. Migraine headaches cause throbbing, intense, sometimes debilitating pain and are notably stronger than regular headaches. The pain can cause nausea or vomiting, and affected individuals may be extremely sensitive to light (photophobia) and to sound (phonophobia).In severe instances, affected individuals may experience prolonged weakness, seizures, confusion, memory loss, and personality or behavioral changes. Although uncommon, hemiplegic migraine attacks can be severe enough to cause coma. During such severe hemiplegic migraine attacks, weakness and speech troubles can last for several days or weeks but usually fully resolve. In rare instances, permanent complications can develop including intellectual disability.A minority of individuals with hemiplegic migraine develop signs or symptoms of involvement of the cerebellum, the area of the brain that controls coordination and balance and is also involved in cognition and behavior. These signs or symptoms can include uncontrolled, repetitive movements of the eyes (nystagmus), slurred speech (dysarthria) and a lack of coordination of voluntary movements (ataxia). These symptoms are permanent and usually slowly progress with ageing.A minority of individuals with hemiplegic migraine may develop epileptic seizures outside of hemiplegic migraine attacks.A minority of individuals with familial hemiplegic migraine may have delayed acquisition of speech and motor features during early childhood, learning difficulties or rarely, cognitive disabilities. | 558 | Hemiplegic Migraine |
nord_558_2 | Causes of Hemiplegic Migraine | Hemiplegic migraine can be classified as either familial or sporadic.Variants in three genes have been identified as causing familial hemiplegic migraine. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.Variants in the CACNA1A gene cause familial hemiplegic migraine type 1. Variants in the ATP1A2 gene cause familial hemiplegic migraine type 2. Variants in the SCN1A gene cause familial hemiplegic migraine type 3. Variants in the PRRT2 gene can also cause familial hemiplegic migraine. Some individuals have familial hemiplegic migraine but do not have variants in these genes. Researchers think that there are additional genes that cause this disorder, but that have yet to be identified.The four genes known to cause hemiplegic migraine produce proteins that are required for the normal function of nerve cells of the brain (neurons). These proteins play a role in the transport of electrically charged particles called ions across a channel that connects nerve cells (neurons), helping to regulate brain activity. Consequently, familial hemiplegic migraine can be classified as channelopathy, a group of disorders characterized by abnormalities in the flow of ions, such as sodium and calcium ions, through pores in cell membranes (ion channels). The proteins produced by these genes may also be involved in other areas or functions of the body as well.Some researchers have shown that nerve cells are overactive (hyperexcitability) in hemiplegic migraine. This hyperexcitability may be associated with a phenomenon called cortical spreading depression that may play a role in the development of hemiplegic migraine. Cortical spreading depression is a slow wave of depolarization of nerve cells that spreads over the hemispheres of the brain. Depolarization refers to a change in the charge between the outside and inside of the membrane of nerve cells, which affects how or if ions can pass through the membrane. These theories are not proven as definitively playing a role in the development of hemiplegic migraine and more research is necessary to determine the complex, underlying factors that cause the signs and symptoms of this disorder.Familial hemiplegic migraine is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Sporadic hemiplegic migraine is the term used to describe individuals with hemiplegic migraine who are the first person in their family with the condition. Some of these individuals may represent a de novo variation of one of the three genes associated with the disorder. Others may have inherited the condition from a parent who did not have any symptoms (asymptomatic).Like common migraines, there are a variety of ‘triggers’ that can cause a migraine attack. Triggers that can cause an episode of hemiplegic migraine include certain foods, certain odors, bright light, too little or too much sleep, physical exertion, stress or minor head trauma. A cerebral angiography can also trigger an episode. This is a type of x-ray exam that is used to assess the health and function of blood vessels in the brain. Sometimes, there are no identifiable triggers when an episode occurs. | Causes of Hemiplegic Migraine. Hemiplegic migraine can be classified as either familial or sporadic.Variants in three genes have been identified as causing familial hemiplegic migraine. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.Variants in the CACNA1A gene cause familial hemiplegic migraine type 1. Variants in the ATP1A2 gene cause familial hemiplegic migraine type 2. Variants in the SCN1A gene cause familial hemiplegic migraine type 3. Variants in the PRRT2 gene can also cause familial hemiplegic migraine. Some individuals have familial hemiplegic migraine but do not have variants in these genes. Researchers think that there are additional genes that cause this disorder, but that have yet to be identified.The four genes known to cause hemiplegic migraine produce proteins that are required for the normal function of nerve cells of the brain (neurons). These proteins play a role in the transport of electrically charged particles called ions across a channel that connects nerve cells (neurons), helping to regulate brain activity. Consequently, familial hemiplegic migraine can be classified as channelopathy, a group of disorders characterized by abnormalities in the flow of ions, such as sodium and calcium ions, through pores in cell membranes (ion channels). The proteins produced by these genes may also be involved in other areas or functions of the body as well.Some researchers have shown that nerve cells are overactive (hyperexcitability) in hemiplegic migraine. This hyperexcitability may be associated with a phenomenon called cortical spreading depression that may play a role in the development of hemiplegic migraine. Cortical spreading depression is a slow wave of depolarization of nerve cells that spreads over the hemispheres of the brain. Depolarization refers to a change in the charge between the outside and inside of the membrane of nerve cells, which affects how or if ions can pass through the membrane. These theories are not proven as definitively playing a role in the development of hemiplegic migraine and more research is necessary to determine the complex, underlying factors that cause the signs and symptoms of this disorder.Familial hemiplegic migraine is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Sporadic hemiplegic migraine is the term used to describe individuals with hemiplegic migraine who are the first person in their family with the condition. Some of these individuals may represent a de novo variation of one of the three genes associated with the disorder. Others may have inherited the condition from a parent who did not have any symptoms (asymptomatic).Like common migraines, there are a variety of ‘triggers’ that can cause a migraine attack. Triggers that can cause an episode of hemiplegic migraine include certain foods, certain odors, bright light, too little or too much sleep, physical exertion, stress or minor head trauma. A cerebral angiography can also trigger an episode. This is a type of x-ray exam that is used to assess the health and function of blood vessels in the brain. Sometimes, there are no identifiable triggers when an episode occurs. | 558 | Hemiplegic Migraine |
nord_558_3 | Affects of Hemiplegic Migraine | The number of newly affected individuals within a year (incidence) and prevalence (the overall number of people with a disorder at a given time (prevalence) of hemiplegic migraine is unknown. Studies in a population of Denmark placed the prevalence at 1 in 10,000 individuals in the general population. The prevalence was the same for the familial and sporadic forms. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency of disorders like hemiplegic migraine in the general population.Hemiplegic migraine affects more females than males. The onset of the disorder is usually within the first or second decade of life but has ranged from early infancy to the elderly. | Affects of Hemiplegic Migraine. The number of newly affected individuals within a year (incidence) and prevalence (the overall number of people with a disorder at a given time (prevalence) of hemiplegic migraine is unknown. Studies in a population of Denmark placed the prevalence at 1 in 10,000 individuals in the general population. The prevalence was the same for the familial and sporadic forms. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency of disorders like hemiplegic migraine in the general population.Hemiplegic migraine affects more females than males. The onset of the disorder is usually within the first or second decade of life but has ranged from early infancy to the elderly. | 558 | Hemiplegic Migraine |
nord_558_4 | Related disorders of Hemiplegic Migraine | Symptoms of the following disorders can be similar to those of hemiplegic migraine. Comparisons may be useful for a differential diagnosis.
Migraines with or without aura must be differentiated from hemiplegic migraine. More common, typical migraines are not associated with the weakness on one side of body that characterized hemiplegic migraine. The cause of typical migraines is unknown.Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia) and in a substantial percentage of patients, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment and persistent issues with balance and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. The first symptoms usually begin before the age of 18 months. AHC is caused by variants in the ATP1A3 gene in most patients. (For more information on this disorder, choose “alternating hemiplegia of childhood” as your search term in the Rare Disease Database.)There are a variety of disorders that can cause migraines symptoms or hemiplegia. MELAS syndrome, MERFF syndrome, CADASIL, hereditary hemorrhagic telangiectasia and retinal vasculopathy with cerebral leukodystrophy may be associated with migraines or hemiplegic. These disorders are distinguished from hemiplegic migraine by the presence of additional clinical symptoms or signs associated with those disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are additional disorders or conditions including multiple sclerosis, brain tumors, transient ischemic attacks (TIA), stroke, metabolic disorders, toxic disorders, functional neurological disorder or epilepsy all of which can cause signs or symptoms similar to those seen in hemiplegic migraine. | Related disorders of Hemiplegic Migraine. Symptoms of the following disorders can be similar to those of hemiplegic migraine. Comparisons may be useful for a differential diagnosis.
Migraines with or without aura must be differentiated from hemiplegic migraine. More common, typical migraines are not associated with the weakness on one side of body that characterized hemiplegic migraine. The cause of typical migraines is unknown.Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia) and in a substantial percentage of patients, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment and persistent issues with balance and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. The first symptoms usually begin before the age of 18 months. AHC is caused by variants in the ATP1A3 gene in most patients. (For more information on this disorder, choose “alternating hemiplegia of childhood” as your search term in the Rare Disease Database.)There are a variety of disorders that can cause migraines symptoms or hemiplegia. MELAS syndrome, MERFF syndrome, CADASIL, hereditary hemorrhagic telangiectasia and retinal vasculopathy with cerebral leukodystrophy may be associated with migraines or hemiplegic. These disorders are distinguished from hemiplegic migraine by the presence of additional clinical symptoms or signs associated with those disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are additional disorders or conditions including multiple sclerosis, brain tumors, transient ischemic attacks (TIA), stroke, metabolic disorders, toxic disorders, functional neurological disorder or epilepsy all of which can cause signs or symptoms similar to those seen in hemiplegic migraine. | 558 | Hemiplegic Migraine |
nord_558_5 | Diagnosis of Hemiplegic Migraine | A diagnosis of hemiplegic migraine is based upon identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests. Two proposed diagnostic criteria have been published (The International Classification of Headache Disorders, 3rd edition and a population-based study of familial hemiplegic migraine suggests revised diagnostic criteria, Thomsen et al. 2002) to help physicians diagnose hemiplegic migraine.Generally, affected individuals must have two episodes of migraine with aura that exhibit specific signs or symptoms. Fully reversible muscle weakness on one side of the body (hemiplegia) that occurs with at least one other type of aura symptom (vision, sensory, speech or brainstem) must be present for a diagnosis. For the familial form, at least one first- or second-degree relative must also have the disorder.Clinical Testing and Workup
Brain imaging is usually normal in individuals with hemiplegic migraine. A minority of individuals affected by hemiplegic migraine associated with permanent cerebellar symptoms have atrophy of the cerebellum.Brain imaging by MRI during a prolonged episode of hemiplegic migraine can show swelling and/or cortical hyperintensity of the affected cerebral hemisphere on T2/FLAIR-weighted MRI. Blood-flow is modified in the affected hemisphere with hypoperfusion followed by persistent hyperperfusion. Brain arteries on angiography may be narrowed at the early phase of the aura and dilated in the second phase. MR angiography may sometimes show diffuse segmental vasoconstriction alternating with vasodilation. All these abnormalities are fully reversible. In very rare patients affected by hemiplegic migraine type 1, severe episodes may be followed by a brain atrophy of the affected hemisphere. An electroencephalogram can show a slowing of brain activity in the affected hemisphere. Usual blood tests are normal. Lumbar puncture is performed in some severe episodes with coma and fever, to rule out an infectious cause. The cerebrospinal fluid can be normal or show an inflammatory reaction with an elevated white blood cell count and an elevated protein level, but the glucose level is always normal and the tests for infectious agents are negative. Molecular genetic testing can confirm a diagnosis of familial hemiplegic migraine in some individuals. Molecular genetic testing can detect variants in the genes known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Hemiplegic Migraine. A diagnosis of hemiplegic migraine is based upon identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests. Two proposed diagnostic criteria have been published (The International Classification of Headache Disorders, 3rd edition and a population-based study of familial hemiplegic migraine suggests revised diagnostic criteria, Thomsen et al. 2002) to help physicians diagnose hemiplegic migraine.Generally, affected individuals must have two episodes of migraine with aura that exhibit specific signs or symptoms. Fully reversible muscle weakness on one side of the body (hemiplegia) that occurs with at least one other type of aura symptom (vision, sensory, speech or brainstem) must be present for a diagnosis. For the familial form, at least one first- or second-degree relative must also have the disorder.Clinical Testing and Workup
Brain imaging is usually normal in individuals with hemiplegic migraine. A minority of individuals affected by hemiplegic migraine associated with permanent cerebellar symptoms have atrophy of the cerebellum.Brain imaging by MRI during a prolonged episode of hemiplegic migraine can show swelling and/or cortical hyperintensity of the affected cerebral hemisphere on T2/FLAIR-weighted MRI. Blood-flow is modified in the affected hemisphere with hypoperfusion followed by persistent hyperperfusion. Brain arteries on angiography may be narrowed at the early phase of the aura and dilated in the second phase. MR angiography may sometimes show diffuse segmental vasoconstriction alternating with vasodilation. All these abnormalities are fully reversible. In very rare patients affected by hemiplegic migraine type 1, severe episodes may be followed by a brain atrophy of the affected hemisphere. An electroencephalogram can show a slowing of brain activity in the affected hemisphere. Usual blood tests are normal. Lumbar puncture is performed in some severe episodes with coma and fever, to rule out an infectious cause. The cerebrospinal fluid can be normal or show an inflammatory reaction with an elevated white blood cell count and an elevated protein level, but the glucose level is always normal and the tests for infectious agents are negative. Molecular genetic testing can confirm a diagnosis of familial hemiplegic migraine in some individuals. Molecular genetic testing can detect variants in the genes known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | 558 | Hemiplegic Migraine |
nord_558_6 | Therapies of Hemiplegic Migraine | The treatment of hemiplegic migraine is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists), neurologists, physicians who specialized in treating headaches or migraines, pain specialists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family may be beneficial as well.Genetic counseling is recommended for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with hemiplegic migraine. As in other common varieties of migraine, treatment is divided in acute treatment taken during the attack to reduce the severity of symptoms and preventive treatment that is taken every day to reduce the frequency of attacks.Various medications may be used to treat an attack of hemiplegic migraine. Analgesics and non-steroid anti-inflammatory drugs can reduce the migraine headache. There are small studies investigating drugs such as verapamil, ketamine and naloxone for the acute treatment of hemiplegic migraine, but no acute treatment has been proven to reduce the intensity and the duration of the aura. For most patients, triptans and ergotamines should be avoided because they tend to cause blood vessels to narrow and there is a risk of stroke. This is based on the theory that there is a vascular cause of migraine. Some physicians think these medications should be reconsidered as a potential treatment. Triptans can be useful in cases with short hemiplegic auras followed by a severe migraine headache; the medication should be taken when the headache starts. Standard preventive medications used to treat regular migraines can be tried for individuals with all types of hemiplegic migraine, to reduce the frequency of attacks. These drugs include tricyclic antidepressants, beta blockers, calcium channel blockers and anti-seizure (anti-convulsant or anti-epileptic) medications. There are small studies investigating drugs such as acetazolamide, verapamil, flunarizine, lamotrigine and botulinium toxin A, for the treatment of hemiplegic migraine. Individuals with hemiplegic migraine were excluded from the trials assessing efficacity and safety of anti-CGRP antibodies in the prevention of migraine. Recently, a small open study reported improvement of hemiplegic migraine in a few individuals with hemiplegic migraine. Further prospective studies are required. Sometimes, in individuals with rare attacks, no preventive treatment is needed.Individuals who experience a severe migraine episode may require hospitalization, particularly for high fever, depressed consciousness or seizures. After alternative diagnoses are excluded, and in case of brain edema on imaging, a course of intravenous steroids may be used. Anti-seizure medications may be used to treat seizures such as those seen in familial hemiplegic type 2. | Therapies of Hemiplegic Migraine. The treatment of hemiplegic migraine is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists), neurologists, physicians who specialized in treating headaches or migraines, pain specialists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family may be beneficial as well.Genetic counseling is recommended for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with hemiplegic migraine. As in other common varieties of migraine, treatment is divided in acute treatment taken during the attack to reduce the severity of symptoms and preventive treatment that is taken every day to reduce the frequency of attacks.Various medications may be used to treat an attack of hemiplegic migraine. Analgesics and non-steroid anti-inflammatory drugs can reduce the migraine headache. There are small studies investigating drugs such as verapamil, ketamine and naloxone for the acute treatment of hemiplegic migraine, but no acute treatment has been proven to reduce the intensity and the duration of the aura. For most patients, triptans and ergotamines should be avoided because they tend to cause blood vessels to narrow and there is a risk of stroke. This is based on the theory that there is a vascular cause of migraine. Some physicians think these medications should be reconsidered as a potential treatment. Triptans can be useful in cases with short hemiplegic auras followed by a severe migraine headache; the medication should be taken when the headache starts. Standard preventive medications used to treat regular migraines can be tried for individuals with all types of hemiplegic migraine, to reduce the frequency of attacks. These drugs include tricyclic antidepressants, beta blockers, calcium channel blockers and anti-seizure (anti-convulsant or anti-epileptic) medications. There are small studies investigating drugs such as acetazolamide, verapamil, flunarizine, lamotrigine and botulinium toxin A, for the treatment of hemiplegic migraine. Individuals with hemiplegic migraine were excluded from the trials assessing efficacity and safety of anti-CGRP antibodies in the prevention of migraine. Recently, a small open study reported improvement of hemiplegic migraine in a few individuals with hemiplegic migraine. Further prospective studies are required. Sometimes, in individuals with rare attacks, no preventive treatment is needed.Individuals who experience a severe migraine episode may require hospitalization, particularly for high fever, depressed consciousness or seizures. After alternative diagnoses are excluded, and in case of brain edema on imaging, a course of intravenous steroids may be used. Anti-seizure medications may be used to treat seizures such as those seen in familial hemiplegic type 2. | 558 | Hemiplegic Migraine |
nord_559_0 | Overview of Hemophagocytic Lymphohistiocytosis | Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by an overactive, abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In hemophagocytic lymphohistiocytosis, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is ineffective and abnormal. This ineffective, abnormal response, causes a variety of signs and symptoms, which, if not treated, can potentially become life-threatening. Some affected individuals may have a genetic predisposition to developing hemophagocytic lymphohistiocytosis. This is known as the primary or familial form. In other individuals, the disorder occurs sporadically usually when there is an underlying predisposing condition or disorder. This is known as the secondary form. The secondary forms are more common than the familial forms. Hemophagocytic lymphohistiocytosis most often affects infants from birth to 18 months, but can affect individuals of any age. Early diagnosis and prompt treatment is essential.Hemophagocytic lymphohistiocytosis (HLH) is a condition with different underlying causes. There are several names used to describe this condition. Familial hemophagocytic lymphohistiocytosis (FHL) refers to genetic forms that are caused by an abnormal variant in a gene. As of April 2018, abnormalities in multiple genes have been identified as causes. Macrophage activation syndrome (MAS) is the term used for hemophagocytic lymphohistiocytosis that occurs in people with an autoimmune or autoinflammatory disease. This is a type of secondary HLH. The diseases most commonly associated with MAS are juvenile systemic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus. | Overview of Hemophagocytic Lymphohistiocytosis. Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by an overactive, abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In hemophagocytic lymphohistiocytosis, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is ineffective and abnormal. This ineffective, abnormal response, causes a variety of signs and symptoms, which, if not treated, can potentially become life-threatening. Some affected individuals may have a genetic predisposition to developing hemophagocytic lymphohistiocytosis. This is known as the primary or familial form. In other individuals, the disorder occurs sporadically usually when there is an underlying predisposing condition or disorder. This is known as the secondary form. The secondary forms are more common than the familial forms. Hemophagocytic lymphohistiocytosis most often affects infants from birth to 18 months, but can affect individuals of any age. Early diagnosis and prompt treatment is essential.Hemophagocytic lymphohistiocytosis (HLH) is a condition with different underlying causes. There are several names used to describe this condition. Familial hemophagocytic lymphohistiocytosis (FHL) refers to genetic forms that are caused by an abnormal variant in a gene. As of April 2018, abnormalities in multiple genes have been identified as causes. Macrophage activation syndrome (MAS) is the term used for hemophagocytic lymphohistiocytosis that occurs in people with an autoimmune or autoinflammatory disease. This is a type of secondary HLH. The diseases most commonly associated with MAS are juvenile systemic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus. | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_1 | Symptoms of Hemophagocytic Lymphohistiocytosis | The onset and severity of hemophagocytic lymphohistiocytosis can vary greatly from one person to another. The specific symptoms that develop can also vary greatly, although the condition often causes multiorgan involvement. Generally, affected individuals develop fevers, a rash, an abnormally large liver (hepatomegaly), and an abnormally large spleen (splenomegaly). Fevers may be prolonged and persistent, often failing to respond to antibiotics. Sometimes, the lymph nodes are also abnormally large (lymphadenopathy). Lymph nodes are part of the lymphatic system, a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich (lymph) and blood cells throughout the body. Lymph nodes are small structures, found in groups throughout the body, that help to filter or drain out harmful substances from the body. These initial sign and symptoms are described as nonspecific. This means that these signs and symptoms are common to many other different disorders or conditions, which can make getting a correct diagnosis difficult. Affected individuals may also have low levels circulating red blood cells (anemia) and low levels of circulating platelets (thrombocytopenia). Red blood cells deliver oxygen to the body and platelets allow the body to form clots to stop bleeding. Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Some affected individuals may develop neurological symptoms including seizures, changes in mental status and irritability, paralysis (palsy) of certain cranial nerves, and problems coordinating voluntary movements (ataxia). Affected individuals are at risk of developing posterior reversible encephalopathy syndrome, which causes a rapid onset of headaches, altered consciousness, seizures, and disturbances in vision. Neurological problems are most common with familial hemophagocytic lymphohistiocytosis. Additional symptoms can occur depending upon the specific organ system involved in an individual. These symptoms can include significant problems breathing (lung dysfunction), severe low blood pressure (hypotension), liver inflammation (hepatitis), kidney dysfunction, yellowing of the skin and whites of the eyes (jaundice), swelling due to fluid accumulation (edema), abdominal swelling due to fluid accumulation (ascites), and a variety of skin problems including widespread, reddening of the skin because of inflammation (erythroderma), rashes, blood spots (purpura), and tiny spots on the skin (petechiae). | Symptoms of Hemophagocytic Lymphohistiocytosis. The onset and severity of hemophagocytic lymphohistiocytosis can vary greatly from one person to another. The specific symptoms that develop can also vary greatly, although the condition often causes multiorgan involvement. Generally, affected individuals develop fevers, a rash, an abnormally large liver (hepatomegaly), and an abnormally large spleen (splenomegaly). Fevers may be prolonged and persistent, often failing to respond to antibiotics. Sometimes, the lymph nodes are also abnormally large (lymphadenopathy). Lymph nodes are part of the lymphatic system, a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich (lymph) and blood cells throughout the body. Lymph nodes are small structures, found in groups throughout the body, that help to filter or drain out harmful substances from the body. These initial sign and symptoms are described as nonspecific. This means that these signs and symptoms are common to many other different disorders or conditions, which can make getting a correct diagnosis difficult. Affected individuals may also have low levels circulating red blood cells (anemia) and low levels of circulating platelets (thrombocytopenia). Red blood cells deliver oxygen to the body and platelets allow the body to form clots to stop bleeding. Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Some affected individuals may develop neurological symptoms including seizures, changes in mental status and irritability, paralysis (palsy) of certain cranial nerves, and problems coordinating voluntary movements (ataxia). Affected individuals are at risk of developing posterior reversible encephalopathy syndrome, which causes a rapid onset of headaches, altered consciousness, seizures, and disturbances in vision. Neurological problems are most common with familial hemophagocytic lymphohistiocytosis. Additional symptoms can occur depending upon the specific organ system involved in an individual. These symptoms can include significant problems breathing (lung dysfunction), severe low blood pressure (hypotension), liver inflammation (hepatitis), kidney dysfunction, yellowing of the skin and whites of the eyes (jaundice), swelling due to fluid accumulation (edema), abdominal swelling due to fluid accumulation (ascites), and a variety of skin problems including widespread, reddening of the skin because of inflammation (erythroderma), rashes, blood spots (purpura), and tiny spots on the skin (petechiae). | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_2 | Causes of Hemophagocytic Lymphohistiocytosis | Hemophagocytic lymphohistiocytosis is broadly broken down into primary and secondary (acquired) forms. The condition results from an ineffective, abnormal response of the immune system to a stimulus or ‘trigger’. The underlying mechanisms that cause signs and symptoms to develop are complex. There is overproduction and overactivity of immune system cells called histiocytes and T cells. These are types of white blood cells, which are the primary cell of the immune system and help the body to fight off infection. Histiocytes (also called macrophages) are large phagocytic cells that normally play a role in responding to infection and injury. A phagocytic cell is any “scavenger” cell that engulfs and destroys invading microorganisms or cellular debris. Macrophages also secrete cytokines, which are proteins that stimulate or inhibit other immune system cells and promote inflammation in response to disease. Excessive cytokine production will eventually cause severe tissue damage. Macrophages may also mistakenly engulf and destroy healthy tissue including healthy blood cells, which is called hemophagocytosis. Cytotoxic lymphocytes, which include T cells and natural killer cells, do not function properly. These cells eliminate other cells that are damaged, stressed, or infected. In HLH, cytotoxic lymphocytes fail to eliminate activated macrophages allowing them to abnormally build up in the organs and tissues of the body, which further activates this ineffective immune response. These immune system abnormalities cause the excessive inflammation and tissue destruction that characterizes the condition. Primary Hemophagocytic Lymphohistiocytosis
The primary form is associated with abnormal variants in certain genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.At least four different genes have been identified that result in a genetic predisposition to developing hemophagocytic lymphohistiocytosis. A genetic predisposition means a person has a gene or genes for a particular disorder, but the disorder will not develop unless other factors help to trigger the disorder. The four genes are PRF1 (familial hemophagocytic lymphocytosis type 2), UNC13D (familial hemophagocytic lymphocytosis type 3), STX11 (familial hemophagocytic lymphocytosis type 4, and STXBP2 (familial hemophagocytic lymphocytosis type 5). The gene for familial hemophagocytic lymphocytosis type 1 has yet to be identified. These genes produce proteins that have an essential role in the immune system. They play a role in turning off or destroying activated immune cells when they are no longer needed. Because of variations (mutations) in these genes, the genes do not produce enough or produce ineffective versions of these proteins. As a result, activated immune cells that should normally be turned off or destroyed persist and continue to work, eventually damaging healthy cells and tissue. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Some individuals may have different variants affecting each copy of the one of the disease genes (compound heterozygotes), while other individuals may have digenic inheritance. Digenic inheritance means they have an abnormal variant in two different genes known to be associated with hemophagocytic lymphohistiocytosis. Some affected individuals have hemophagocytic lymphohistiocytosis as part of a broader genetic disorder. These disorders include Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative disorder, XMEN disease, interleukin-2-inductible T cell kinase deficiency, CD27 deficiency, Hermansky-Pudlak syndrome, lysinuric protein intolerance, and chronic granulomatous disease. In some individuals, hemophagocytic lymphohistiocytosis may be the only clinical problem that individuals with these disorders display. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Secondary Hemophagocytic Lymphohistiocytosis
Individuals with secondary (or acquired) hemophagocytic lymphohistiocytosis develop the disorder because of a heightened, abnormal immune system response that occurs for unknown reasons. There is no family history of the disorder and no known genetic factors can be identified. Conditions that can lead to secondary hemophagocytic lymphohistiocytosis include viral infections especially Epstein-Barr virus, other infections including bacterial, viral and fungal infections, a weakened or depressed immune system, autoimmune diseases, autoinflammatory diseases, rheumatological diseases such as juvenile idiopathic arthritis, metabolic disorders, and cancer such as non-Hodgkin lymphoma.The exact manner that these predisposing conditions cause the signs and symptoms, and specifically how they cause an ineffective, abnormal immune response, in hemophagocytic lymphohistiocytosis are not fully understood. | Causes of Hemophagocytic Lymphohistiocytosis. Hemophagocytic lymphohistiocytosis is broadly broken down into primary and secondary (acquired) forms. The condition results from an ineffective, abnormal response of the immune system to a stimulus or ‘trigger’. The underlying mechanisms that cause signs and symptoms to develop are complex. There is overproduction and overactivity of immune system cells called histiocytes and T cells. These are types of white blood cells, which are the primary cell of the immune system and help the body to fight off infection. Histiocytes (also called macrophages) are large phagocytic cells that normally play a role in responding to infection and injury. A phagocytic cell is any “scavenger” cell that engulfs and destroys invading microorganisms or cellular debris. Macrophages also secrete cytokines, which are proteins that stimulate or inhibit other immune system cells and promote inflammation in response to disease. Excessive cytokine production will eventually cause severe tissue damage. Macrophages may also mistakenly engulf and destroy healthy tissue including healthy blood cells, which is called hemophagocytosis. Cytotoxic lymphocytes, which include T cells and natural killer cells, do not function properly. These cells eliminate other cells that are damaged, stressed, or infected. In HLH, cytotoxic lymphocytes fail to eliminate activated macrophages allowing them to abnormally build up in the organs and tissues of the body, which further activates this ineffective immune response. These immune system abnormalities cause the excessive inflammation and tissue destruction that characterizes the condition. Primary Hemophagocytic Lymphohistiocytosis
The primary form is associated with abnormal variants in certain genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.At least four different genes have been identified that result in a genetic predisposition to developing hemophagocytic lymphohistiocytosis. A genetic predisposition means a person has a gene or genes for a particular disorder, but the disorder will not develop unless other factors help to trigger the disorder. The four genes are PRF1 (familial hemophagocytic lymphocytosis type 2), UNC13D (familial hemophagocytic lymphocytosis type 3), STX11 (familial hemophagocytic lymphocytosis type 4, and STXBP2 (familial hemophagocytic lymphocytosis type 5). The gene for familial hemophagocytic lymphocytosis type 1 has yet to be identified. These genes produce proteins that have an essential role in the immune system. They play a role in turning off or destroying activated immune cells when they are no longer needed. Because of variations (mutations) in these genes, the genes do not produce enough or produce ineffective versions of these proteins. As a result, activated immune cells that should normally be turned off or destroyed persist and continue to work, eventually damaging healthy cells and tissue. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Some individuals may have different variants affecting each copy of the one of the disease genes (compound heterozygotes), while other individuals may have digenic inheritance. Digenic inheritance means they have an abnormal variant in two different genes known to be associated with hemophagocytic lymphohistiocytosis. Some affected individuals have hemophagocytic lymphohistiocytosis as part of a broader genetic disorder. These disorders include Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative disorder, XMEN disease, interleukin-2-inductible T cell kinase deficiency, CD27 deficiency, Hermansky-Pudlak syndrome, lysinuric protein intolerance, and chronic granulomatous disease. In some individuals, hemophagocytic lymphohistiocytosis may be the only clinical problem that individuals with these disorders display. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)Secondary Hemophagocytic Lymphohistiocytosis
Individuals with secondary (or acquired) hemophagocytic lymphohistiocytosis develop the disorder because of a heightened, abnormal immune system response that occurs for unknown reasons. There is no family history of the disorder and no known genetic factors can be identified. Conditions that can lead to secondary hemophagocytic lymphohistiocytosis include viral infections especially Epstein-Barr virus, other infections including bacterial, viral and fungal infections, a weakened or depressed immune system, autoimmune diseases, autoinflammatory diseases, rheumatological diseases such as juvenile idiopathic arthritis, metabolic disorders, and cancer such as non-Hodgkin lymphoma.The exact manner that these predisposing conditions cause the signs and symptoms, and specifically how they cause an ineffective, abnormal immune response, in hemophagocytic lymphohistiocytosis are not fully understood. | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_3 | Affects of Hemophagocytic Lymphohistiocytosis | Hemophagocytic lymphohistiocytosis most often affects infants or young children, but can affect individuals of any age. It affects boys and girls in equal numbers. In adults, it affects men slightly more often than women. The exact incidence and prevalence is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. About 25% of the people with this disorder, have the familial form. | Affects of Hemophagocytic Lymphohistiocytosis. Hemophagocytic lymphohistiocytosis most often affects infants or young children, but can affect individuals of any age. It affects boys and girls in equal numbers. In adults, it affects men slightly more often than women. The exact incidence and prevalence is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. About 25% of the people with this disorder, have the familial form. | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_4 | Related disorders of Hemophagocytic Lymphohistiocytosis | Symptoms of the following disorders can be similar to those of hemophagocytic lymphohistiocytosis and it may be important to distinguish these disorders from it.There are many different conditions that can have signs and symptoms similar to those seen in hemophagocytic lymphohistiocytosis. These include DiGeorge syndrome, Kawasaki disease, tuberculosis, leishmaniasis, multiple organ dysfunction syndrome, encephalitis, drug reaction with eosinophilia and systemic symptoms (DRESS), autoimmune lymphoproliferative syndrome, thrombotic thrombocytopenia purpura, and hemolytic uremic syndrome. Liver disease and certain infections can also resemble hemophagocytic lymphohistiocytosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Hemophagocytic Lymphohistiocytosis. Symptoms of the following disorders can be similar to those of hemophagocytic lymphohistiocytosis and it may be important to distinguish these disorders from it.There are many different conditions that can have signs and symptoms similar to those seen in hemophagocytic lymphohistiocytosis. These include DiGeorge syndrome, Kawasaki disease, tuberculosis, leishmaniasis, multiple organ dysfunction syndrome, encephalitis, drug reaction with eosinophilia and systemic symptoms (DRESS), autoimmune lymphoproliferative syndrome, thrombotic thrombocytopenia purpura, and hemolytic uremic syndrome. Liver disease and certain infections can also resemble hemophagocytic lymphohistiocytosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_5 | Diagnosis of Hemophagocytic Lymphohistiocytosis | A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Guidelines have been published that detail the criteria necessary for a diagnosis of hemophagocytic lymphohistiocytosis. If five of the following eight symptoms are present, then a clinical diagnosis can be made. These eight symptoms are fever; an abnormally large spleen (splenomegaly); low red cell, white cell, or platelet levels (cytopenias); abnormally high levels of a type of fat called a triglyceride in the blood (hypertriglyceridemia) or low levels of a specific blood clotting protein (hypofibrinogenemia); destruction of blood cells by macrophages (hemophagocytosis) in the bone marrow; low or absent natural killer cell activity; abnormal high levels in the blood of a protein that binds to iron (ferritinemia); and elevated soluble interleukin-2 receptor (sCD25), a specialized protein that builds up in the blood when the immune system is stimulated. Because the symptoms of hemophagocytic lymphohistiocytosis are nonspecific, affected individuals may often have been through a prolonged illness and be hospitalized before a diagnosis is made. Clinical Testing and Workup
Physicians may order blood tests to take a complete blood cell count, which will measure the levels of red cells, white cells and platelets. Blood tests can also reveal abnormally high ferritin levels, or abnormal high levels of triglycerides. Physicians may also use blood tests to look for signs of infection in the blood and conduct tests to determine how well the blood clots (coagulation studies). Physicians may also order tests that can assess the health and function of the liver. Sometimes, a bone marrow biopsy (the surgical removal and microscopic examination of a tissue sample) may be taken and studied for signs of hemophagocytosis, signs of infection or infectious organisms, and the accumulation of macrophages.Molecular genetic testing can confirm a diagnosis of hemophagocytic lymphohistiocytosis in certain people. Molecular genetic testing can detect mutations in one of the four specific genes known to cause familial forms of this disorder, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Hemophagocytic Lymphohistiocytosis. A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Guidelines have been published that detail the criteria necessary for a diagnosis of hemophagocytic lymphohistiocytosis. If five of the following eight symptoms are present, then a clinical diagnosis can be made. These eight symptoms are fever; an abnormally large spleen (splenomegaly); low red cell, white cell, or platelet levels (cytopenias); abnormally high levels of a type of fat called a triglyceride in the blood (hypertriglyceridemia) or low levels of a specific blood clotting protein (hypofibrinogenemia); destruction of blood cells by macrophages (hemophagocytosis) in the bone marrow; low or absent natural killer cell activity; abnormal high levels in the blood of a protein that binds to iron (ferritinemia); and elevated soluble interleukin-2 receptor (sCD25), a specialized protein that builds up in the blood when the immune system is stimulated. Because the symptoms of hemophagocytic lymphohistiocytosis are nonspecific, affected individuals may often have been through a prolonged illness and be hospitalized before a diagnosis is made. Clinical Testing and Workup
Physicians may order blood tests to take a complete blood cell count, which will measure the levels of red cells, white cells and platelets. Blood tests can also reveal abnormally high ferritin levels, or abnormal high levels of triglycerides. Physicians may also use blood tests to look for signs of infection in the blood and conduct tests to determine how well the blood clots (coagulation studies). Physicians may also order tests that can assess the health and function of the liver. Sometimes, a bone marrow biopsy (the surgical removal and microscopic examination of a tissue sample) may be taken and studied for signs of hemophagocytosis, signs of infection or infectious organisms, and the accumulation of macrophages.Molecular genetic testing can confirm a diagnosis of hemophagocytic lymphohistiocytosis in certain people. Molecular genetic testing can detect mutations in one of the four specific genes known to cause familial forms of this disorder, but is available only as a diagnostic service at specialized laboratories. | 559 | Hemophagocytic Lymphohistiocytosis |
nord_559_6 | Therapies of Hemophagocytic Lymphohistiocytosis | Treatment
The treatment of hemophagocytic lymphohistiocytosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating blood disorders (hematologists), specialists in diagnosing and treating cancer (oncologists), specialists in diagnosing and treating immune system diseases (immunologists), geneticists (for familial forms), social workers, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause; the presence or absence of certain symptoms; the overall severity of the symptoms and the disorder; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Affected individuals whose overall health is strong enough may undergo treatment for the underlying condition such as medications to treat an underlying infection, or appropriate treatment for autoimmune disorders or cancer. Treating the underlying condition may remove the “trigger” that has led to the abnormal immune system response.Affected individuals who health is deteriorating require treated specific for hemophagocytic lymphohistiocytosis immediately. In 1994, the Histiocyte Society published treatment recommendations for this disorder (HLA-94). There were also published studies from 2004 (HLA-2004) that were slightly different.These treatment regimens include chemotherapy and drugs that suppress the activity of the immune system (immunosuppressive drugs). They target and destroy the hyperactive immune system cells and reduce the life-threatening inflammation that characterizes hemophagocytic lymphohistiocytosis.After initial treatment, which lasts about 8 weeks, affected individuals are gradually weaned off the drugs onto different medications. If affected individuals have not responded well to this treatment, an allogeneic stem cell transplant may be recommended. This treatment is also recommended for individuals with an abnormal variant in a known HLH gene, central nervous system involvement, and blood cancer (hematologic malignancy) that cannot be treated.An allogeneic stem cell transplant is a procedure in which stem cells from an affected individual is replaced with the stem cells from a matched, healthy donor. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g. red blood cells, white blood cells, platelets).Affected individuals undergo high-doses of chemotherapy or radiation to wipe out their stem cells. The stem cells are then replaced with those from a donor. Allogeneic stem cell transplant is a high-risk procedure with the potential for side effects.Some affected individuals may need blood transfusion because they have low levels of circulating red blood cells or platelets. Some physicians may recommend antibiotics to prevent the development of an infection (prophylactic therapy).In 2018, Gamifant (emapalumab) was approved for the treatment of pediatric and adult patients with primary HLH who have refractory, recurrent or progressive disease or cannot tolerate conventional HLH therapy. Gamifant will be marketed by Sobi. | Therapies of Hemophagocytic Lymphohistiocytosis. Treatment
The treatment of hemophagocytic lymphohistiocytosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating blood disorders (hematologists), specialists in diagnosing and treating cancer (oncologists), specialists in diagnosing and treating immune system diseases (immunologists), geneticists (for familial forms), social workers, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause; the presence or absence of certain symptoms; the overall severity of the symptoms and the disorder; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Affected individuals whose overall health is strong enough may undergo treatment for the underlying condition such as medications to treat an underlying infection, or appropriate treatment for autoimmune disorders or cancer. Treating the underlying condition may remove the “trigger” that has led to the abnormal immune system response.Affected individuals who health is deteriorating require treated specific for hemophagocytic lymphohistiocytosis immediately. In 1994, the Histiocyte Society published treatment recommendations for this disorder (HLA-94). There were also published studies from 2004 (HLA-2004) that were slightly different.These treatment regimens include chemotherapy and drugs that suppress the activity of the immune system (immunosuppressive drugs). They target and destroy the hyperactive immune system cells and reduce the life-threatening inflammation that characterizes hemophagocytic lymphohistiocytosis.After initial treatment, which lasts about 8 weeks, affected individuals are gradually weaned off the drugs onto different medications. If affected individuals have not responded well to this treatment, an allogeneic stem cell transplant may be recommended. This treatment is also recommended for individuals with an abnormal variant in a known HLH gene, central nervous system involvement, and blood cancer (hematologic malignancy) that cannot be treated.An allogeneic stem cell transplant is a procedure in which stem cells from an affected individual is replaced with the stem cells from a matched, healthy donor. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g. red blood cells, white blood cells, platelets).Affected individuals undergo high-doses of chemotherapy or radiation to wipe out their stem cells. The stem cells are then replaced with those from a donor. Allogeneic stem cell transplant is a high-risk procedure with the potential for side effects.Some affected individuals may need blood transfusion because they have low levels of circulating red blood cells or platelets. Some physicians may recommend antibiotics to prevent the development of an infection (prophylactic therapy).In 2018, Gamifant (emapalumab) was approved for the treatment of pediatric and adult patients with primary HLH who have refractory, recurrent or progressive disease or cannot tolerate conventional HLH therapy. Gamifant will be marketed by Sobi. | 559 | Hemophagocytic Lymphohistiocytosis |
nord_560_0 | Overview of Hemophilia A | SummaryHemophilia A, also known as classical hemophilia, is a genetic bleeding disorder caused by insufficient levels of a blood protein called factor VIII. Factor VIII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Individuals with hemophilia A do not bleed faster or more profusely than healthy individuals, but because their blood clots poorly, they have difficulty stopping the flow of blood from a wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. Hemophilia A can be mild, moderate or severe, depending on the baseline level of factor VIII made by that individual. In mild cases, prolonged bleeding episodes may only occur after surgery, dental procedures or trauma. In more severely affected individuals, symptoms may include prolonged bleeding from minor wounds, painful swollen bruises, and unexplained (spontaneous) bleeding into vital organs as well as joints and muscles (internal bleeding).Hemophilia A is caused by disruptions or changes (mutations) to the F8 gene located on the X chromosome. This mutation may be inherited or occur randomly with no previous family history of the disorder (spontaneously). Hemophilia A is mostly expressed in males but some females who carry the gene may have mild or, rarely, severe symptoms of bleeding. Although there is no cure for hemophilia, effective therapies have been developed; most affected individuals can lead full, productive lives by maintaining proper treatment and care.IntroductionHemophilia is a general term for a group of rare bleeding disorders caused by congenital deficiency of certain clotting factors. The most common form of hemophilia is hemophilia A. In rare cases, hemophilia A can be acquired during life (acquired hemophilia A) as a result of an auto-antibody to factor VIII. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. This report only deals with the genetic form of hemophilia A. | Overview of Hemophilia A. SummaryHemophilia A, also known as classical hemophilia, is a genetic bleeding disorder caused by insufficient levels of a blood protein called factor VIII. Factor VIII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Individuals with hemophilia A do not bleed faster or more profusely than healthy individuals, but because their blood clots poorly, they have difficulty stopping the flow of blood from a wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. Hemophilia A can be mild, moderate or severe, depending on the baseline level of factor VIII made by that individual. In mild cases, prolonged bleeding episodes may only occur after surgery, dental procedures or trauma. In more severely affected individuals, symptoms may include prolonged bleeding from minor wounds, painful swollen bruises, and unexplained (spontaneous) bleeding into vital organs as well as joints and muscles (internal bleeding).Hemophilia A is caused by disruptions or changes (mutations) to the F8 gene located on the X chromosome. This mutation may be inherited or occur randomly with no previous family history of the disorder (spontaneously). Hemophilia A is mostly expressed in males but some females who carry the gene may have mild or, rarely, severe symptoms of bleeding. Although there is no cure for hemophilia, effective therapies have been developed; most affected individuals can lead full, productive lives by maintaining proper treatment and care.IntroductionHemophilia is a general term for a group of rare bleeding disorders caused by congenital deficiency of certain clotting factors. The most common form of hemophilia is hemophilia A. In rare cases, hemophilia A can be acquired during life (acquired hemophilia A) as a result of an auto-antibody to factor VIII. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. This report only deals with the genetic form of hemophilia A. | 560 | Hemophilia A |
nord_560_1 | Symptoms of Hemophilia A | The severity and symptoms of hemophilia A can vary greatly from one person to another. Hemophilia A can range from mild to moderate to severe. Factor VIII levels in these categories are 5-40% of normal, 1-5%, and less than 1%, respectively. The age of onset and frequency of bleeding episodes depend upon the amount of factor VIII protein and overall clotting ability of the blood. In most individuals, regardless of severity, bleeding episodes tend to be more frequent in childhood and adolescence than in adulthood.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.In mild cases, individuals may experience bruising and bleeding from the mucous membranes such as nosebleeds or bleeding from the gums. More serious, prolonged bleeding episodes may occur only after surgery or dental procedures, injury or trauma. The bleeding in such cases is out of proportion for the procedure or trauma. In many cases, individuals with mild hemophilia A may go undiagnosed until they need a surgical procedure or suffer an injury. In some cases, the first bleeding episode does not occur until well into adulthood. Individuals with a mild form of hemophilia A may go many years without a prolonged bleeding episode. Mild hemophilia A can be associated with anywhere from 5-40% factor VIII clotting activity.Individuals with moderate hemophilia A seldom have spontaneous bleeding episodes. Spontaneous bleeding refers to bleeding episodes that occur without apparent cause. Individuals with moderate hemophilia A are at risk for prolonged bleeding following surgery, dental procedures or trauma. Easy or excessive bruising may also occur. Moderate hemophilia A is often diagnosed by 5 or 6 years of age. By definition, affected individuals have 1-5% of normal factor VIII clotting activity.Severe hemophilia A occurs in individuals with less than 1% of normal factor VIII clotting activity. In contrast to the mild or moderate forms of the disease, severe hemophilia A is associated with spontaneous bleeding episodes. Such episodes often result in bleeding into the deep muscles or joints (hemarthroses), which will acutely cause pain and swelling and early restricted movement of the joint. If not treated in a timely manner or at all, bleeding may result in longer term arthritis (pain and restricted movement) of the affected joint. The joints and muscles are the most common sites for spontaneous bleeding episodes in individuals with severe hemophilia A.Severe cases of hemophilia A usually become apparent early during infancy and a diagnosis is often made by two years of age. Without prophylactic treatment, these infants may experience bleeding from minor mouth injuries. Common symptoms in untreated infants are large swellings or “goose eggs” that form after a bump on the head. In rare cases, infants with severe hemophilia A have extra- or intracranial bleeding following birth. Untreated infants and children may also develop hematomas under the skin. Hematomas are solid swellings or masses of congealed blood. As infants and children grow older, spontaneous joint bleeds may become more frequent.If untreated, infants and children with severe hemophilia A may have approximately two to five spontaneous bleeding episodes per month. Without treatment, affected individuals are at risk for prolonged bleeding from minor injuries, surgery and dental procedures such as tooth extractions.Individuals with the severe form of hemophilia A can experience spontaneous bleeding into any organ system including the kidneys, the gastrointestinal tract, and the brain (intracranial bleeding). Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia). Intracranial bleeding may cause headaches, stiff neck, vomiting, seizures, mental status changes including excessive sleepiness and poor arousability. If untreated, these frequently occurring spontaneous bleeding events can be life-threatening. | Symptoms of Hemophilia A. The severity and symptoms of hemophilia A can vary greatly from one person to another. Hemophilia A can range from mild to moderate to severe. Factor VIII levels in these categories are 5-40% of normal, 1-5%, and less than 1%, respectively. The age of onset and frequency of bleeding episodes depend upon the amount of factor VIII protein and overall clotting ability of the blood. In most individuals, regardless of severity, bleeding episodes tend to be more frequent in childhood and adolescence than in adulthood.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.In mild cases, individuals may experience bruising and bleeding from the mucous membranes such as nosebleeds or bleeding from the gums. More serious, prolonged bleeding episodes may occur only after surgery or dental procedures, injury or trauma. The bleeding in such cases is out of proportion for the procedure or trauma. In many cases, individuals with mild hemophilia A may go undiagnosed until they need a surgical procedure or suffer an injury. In some cases, the first bleeding episode does not occur until well into adulthood. Individuals with a mild form of hemophilia A may go many years without a prolonged bleeding episode. Mild hemophilia A can be associated with anywhere from 5-40% factor VIII clotting activity.Individuals with moderate hemophilia A seldom have spontaneous bleeding episodes. Spontaneous bleeding refers to bleeding episodes that occur without apparent cause. Individuals with moderate hemophilia A are at risk for prolonged bleeding following surgery, dental procedures or trauma. Easy or excessive bruising may also occur. Moderate hemophilia A is often diagnosed by 5 or 6 years of age. By definition, affected individuals have 1-5% of normal factor VIII clotting activity.Severe hemophilia A occurs in individuals with less than 1% of normal factor VIII clotting activity. In contrast to the mild or moderate forms of the disease, severe hemophilia A is associated with spontaneous bleeding episodes. Such episodes often result in bleeding into the deep muscles or joints (hemarthroses), which will acutely cause pain and swelling and early restricted movement of the joint. If not treated in a timely manner or at all, bleeding may result in longer term arthritis (pain and restricted movement) of the affected joint. The joints and muscles are the most common sites for spontaneous bleeding episodes in individuals with severe hemophilia A.Severe cases of hemophilia A usually become apparent early during infancy and a diagnosis is often made by two years of age. Without prophylactic treatment, these infants may experience bleeding from minor mouth injuries. Common symptoms in untreated infants are large swellings or “goose eggs” that form after a bump on the head. In rare cases, infants with severe hemophilia A have extra- or intracranial bleeding following birth. Untreated infants and children may also develop hematomas under the skin. Hematomas are solid swellings or masses of congealed blood. As infants and children grow older, spontaneous joint bleeds may become more frequent.If untreated, infants and children with severe hemophilia A may have approximately two to five spontaneous bleeding episodes per month. Without treatment, affected individuals are at risk for prolonged bleeding from minor injuries, surgery and dental procedures such as tooth extractions.Individuals with the severe form of hemophilia A can experience spontaneous bleeding into any organ system including the kidneys, the gastrointestinal tract, and the brain (intracranial bleeding). Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia). Intracranial bleeding may cause headaches, stiff neck, vomiting, seizures, mental status changes including excessive sleepiness and poor arousability. If untreated, these frequently occurring spontaneous bleeding events can be life-threatening. | 560 | Hemophilia A |
nord_560_2 | Causes of Hemophilia A | Hemophilia A is caused by disruptions or changes (mutations) of the F8 gene. The F8 gene contains instructions for creating (encoding) factor VIII. Factor VIII is one of the essential blood proteins and plays a role in aiding the blood to clot in response to injury. Mutations of the F8 gene result in deficient levels of functional factor VIII. The symptoms of hemophilia A occur due to this deficiency.The F8 gene is located on the X chromosome. Approximately 70% of cases are inherited in an X-linked pattern. In the remaining 30%, cases occur spontaneously (i.e., as a result of a de novo mutation) without a previous family history of the disorder.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes. As such, females who have a disease gene present on only one of their X chromosomes are “carriers” for the disorder, and they usually do not display symptoms of the disorder because they have another normal/healthy copy of the gene to compensate for the copy with the disease-causing change or mutation. Since males have only one X chromosome, if they inherit an X chromosome that contains a disease-causing gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome, not their X chromosome, to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.Females have two X chromosomes, but one of the X chromosomes is “turned off” or inactivated and all of the genes on that chromosome are inactivated. Carrier females, known as heterozygotes, inherit a single copy of the disease-causing gene, such as the gene for hemophilia A, and a normal copy of the F8 gene which compensates for the copy with the hemophilia-causing mutation. If a female has a large proportion of the X chromosome with the unchanged gene inactivated, she may have symptoms of the disorder. Depending on the proportion of the X-chromosome with the disease-causing copy of the gene, a female may exhibit symptoms of the disorder, most commonly appearing to have mild hemophilia. There are other rare mechanisms which can cause a female to have hemophilia or other conditions caused by genes on the X chromosome. | Causes of Hemophilia A. Hemophilia A is caused by disruptions or changes (mutations) of the F8 gene. The F8 gene contains instructions for creating (encoding) factor VIII. Factor VIII is one of the essential blood proteins and plays a role in aiding the blood to clot in response to injury. Mutations of the F8 gene result in deficient levels of functional factor VIII. The symptoms of hemophilia A occur due to this deficiency.The F8 gene is located on the X chromosome. Approximately 70% of cases are inherited in an X-linked pattern. In the remaining 30%, cases occur spontaneously (i.e., as a result of a de novo mutation) without a previous family history of the disorder.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes. As such, females who have a disease gene present on only one of their X chromosomes are “carriers” for the disorder, and they usually do not display symptoms of the disorder because they have another normal/healthy copy of the gene to compensate for the copy with the disease-causing change or mutation. Since males have only one X chromosome, if they inherit an X chromosome that contains a disease-causing gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome, not their X chromosome, to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.Females have two X chromosomes, but one of the X chromosomes is “turned off” or inactivated and all of the genes on that chromosome are inactivated. Carrier females, known as heterozygotes, inherit a single copy of the disease-causing gene, such as the gene for hemophilia A, and a normal copy of the F8 gene which compensates for the copy with the hemophilia-causing mutation. If a female has a large proportion of the X chromosome with the unchanged gene inactivated, she may have symptoms of the disorder. Depending on the proportion of the X-chromosome with the disease-causing copy of the gene, a female may exhibit symptoms of the disorder, most commonly appearing to have mild hemophilia. There are other rare mechanisms which can cause a female to have hemophilia or other conditions caused by genes on the X chromosome. | 560 | Hemophilia A |
nord_560_3 | Affects of Hemophilia A | Hemophilia A is the most common X-linked recessive disorder and the second most common inherited clotting factor deficiency after von Willebrand disease. Hemophilia A mostly affects males but females can also be affected. Approximately 1 in 5,000 newborn males have hemophilia A. Approximately 60% of individuals with hemophilia A have a severe form of the disorder. All racial and ethnic groups are equally affected by hemophilia. | Affects of Hemophilia A. Hemophilia A is the most common X-linked recessive disorder and the second most common inherited clotting factor deficiency after von Willebrand disease. Hemophilia A mostly affects males but females can also be affected. Approximately 1 in 5,000 newborn males have hemophilia A. Approximately 60% of individuals with hemophilia A have a severe form of the disorder. All racial and ethnic groups are equally affected by hemophilia. | 560 | Hemophilia A |
nord_560_4 | Related disorders of Hemophilia A | Symptoms of the following disorders can be similar to those of hemophilia A. Comparisons may be useful for a differential diagnosis.Acquired hemophilia is a rare autoimmune disorder characterized by bleeding that occurs in patients with a personal and family history negative for a bleeding disorder. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy cells or tissue. In acquired hemophilia, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue and during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications. In approximately 50% of cases, there is an identifiable underlying clinical condition; in the other 50% no cause is known (idiopathic). (For more information on this disorder, choose “acquired hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and variable clinical manifestations. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized blood cells that mass together to form the initial clots that stop bleeding. In individuals with VWD, platelets do not stick to the tissue around holes in blood vessels and bleeding is therefore prolonged. Defective VWF can also cause reduced levels of factor VIII. This is because VWF binds to and stabilizes factor VIII so that it is not rapidly broken down within the blood. Most people with VWD have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals have problems during infancy or early childhood such as prolonged bleeding after injury or surgery and/or spontaneous bleeding. Spontaneous bleeding can manifest as gastrointestinal bleeding, nosebleeds, bleeding from the gums and easy bruising. Affected women frequently experience heavy menstrual periods, and may bleed excessively following childbirth. There are three main forms of the disorder. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes.Inherited platelet disorders are characterized by low levels of and/or poorly functioning platelets. Platelets are tiny blood cells that clump together to form plugs at the sites of a wound. Low levels of or dysfunctional platelets result in abnormal bleeding episodes including bruising, recurrent nosebleeds (epistaxis) or mouth bleeding, gastrointestinal bleeding and excessive bleeding following some types of surgery or injury. The bleeding severity and type of symptoms vary depending upon the specific platelet disorder present. Platelet disorders include Bernard-Soulier syndrome and Glanzmann’s thrombasthenia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database). | Related disorders of Hemophilia A. Symptoms of the following disorders can be similar to those of hemophilia A. Comparisons may be useful for a differential diagnosis.Acquired hemophilia is a rare autoimmune disorder characterized by bleeding that occurs in patients with a personal and family history negative for a bleeding disorder. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy cells or tissue. In acquired hemophilia, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue and during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications. In approximately 50% of cases, there is an identifiable underlying clinical condition; in the other 50% no cause is known (idiopathic). (For more information on this disorder, choose “acquired hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease (VWD) is a genetic bleeding disorder resulting in prolonged bleeding and variable clinical manifestations. Individuals with VWD have a defect in or deficiency of a clotting protein known as von Willebrand factor (VWF). Deficient or defective VWF results in improper functioning of platelets, which are specialized blood cells that mass together to form the initial clots that stop bleeding. In individuals with VWD, platelets do not stick to the tissue around holes in blood vessels and bleeding is therefore prolonged. Defective VWF can also cause reduced levels of factor VIII. This is because VWF binds to and stabilizes factor VIII so that it is not rapidly broken down within the blood. Most people with VWD have relatively mild symptoms and are not diagnosed until they are adults. A small percentage of individuals have problems during infancy or early childhood such as prolonged bleeding after injury or surgery and/or spontaneous bleeding. Spontaneous bleeding can manifest as gastrointestinal bleeding, nosebleeds, bleeding from the gums and easy bruising. Affected women frequently experience heavy menstrual periods, and may bleed excessively following childbirth. There are three main forms of the disorder. Most cases are inherited as autosomal dominant disorders; some cases are inherited as autosomal recessive disorders. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Fibrinogen disorders are a group of rare bleeding disorders characterized by deficiency or absence of a certain protein in the blood that is essential in the blood clotting (coagulation) process. This protein is known as fibrinogen or coagulation factor I. Three forms have been identified: congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Individuals with congenital afibrinogenemia may be susceptible to severe bleeding (hemorrhaging) episodes and prolonged bleeding from minor cuts. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms (asymptomatic) or may develop mild bleeding episodes.Inherited platelet disorders are characterized by low levels of and/or poorly functioning platelets. Platelets are tiny blood cells that clump together to form plugs at the sites of a wound. Low levels of or dysfunctional platelets result in abnormal bleeding episodes including bruising, recurrent nosebleeds (epistaxis) or mouth bleeding, gastrointestinal bleeding and excessive bleeding following some types of surgery or injury. The bleeding severity and type of symptoms vary depending upon the specific platelet disorder present. Platelet disorders include Bernard-Soulier syndrome and Glanzmann’s thrombasthenia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database). | 560 | Hemophilia A |
nord_560_5 | Diagnosis of Hemophilia A | A diagnosis of hemophilia A is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized laboratory tests.Clinical Testing and Workup
Laboratory studies should include a complete blood count (CBC), coagulation tests and measurement of the level of specific factors (e.g. factor VIII). Screening coagulation tests that measure how long it takes the blood to clot include the activated partial thromboplastin time (aPTT) and prothrombin time (PT). Typically, the PT is normal, whereas the aPTT is prolonged in hemophilia A when the factor VIII level is less than 30% of normal. In such cases, a diagnosis of hemophilia A must be confirmed through a clotting activity assay. This assay can determine whether the cause of the abnormal aPTT is deficiency of factor VIII (hemophilia A), factor IX (hemophilia B) or another blood clotting factor deficiency. This specific test will also determine the severity of the factor VIII deficiency. Even if an aPTT test is normal this does not rule out mild cases of hemophilia A because of the relative insensitivity of the test.Once the diagnosis of hemophilia A is made, the specific mutation in the F8 gene is often determined to ascertain the affected person’s risk of developing an uncommon but serious complication, i.e., the development of neutralizing anti-factor VIII antibodies, sometimes accompanied by allergic reactions, to the treatment outlined below. This complication is otherwise known as “inhibitor” development, since these antibodies can seriously inhibit the effectiveness of standard replacement treatment (see below).Molecular genetic testing, which can identify mutations in the F8 gene is available on a clinical basis. Understanding the specific F8 gene mutation can also be helpful in identifying female carriers in the family as well as in the prenatal diagnosis of hemophilia A, which is not only feasible, but is also available and encouraged in most Western and developing countries. Importantly, the development of digital PCR now allows analysis of cell-free fetal DNA present in maternal plasma and can diagnose hemophilia A in utero non-invasively as early as 7 weeks of gestation. | Diagnosis of Hemophilia A. A diagnosis of hemophilia A is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized laboratory tests.Clinical Testing and Workup
Laboratory studies should include a complete blood count (CBC), coagulation tests and measurement of the level of specific factors (e.g. factor VIII). Screening coagulation tests that measure how long it takes the blood to clot include the activated partial thromboplastin time (aPTT) and prothrombin time (PT). Typically, the PT is normal, whereas the aPTT is prolonged in hemophilia A when the factor VIII level is less than 30% of normal. In such cases, a diagnosis of hemophilia A must be confirmed through a clotting activity assay. This assay can determine whether the cause of the abnormal aPTT is deficiency of factor VIII (hemophilia A), factor IX (hemophilia B) or another blood clotting factor deficiency. This specific test will also determine the severity of the factor VIII deficiency. Even if an aPTT test is normal this does not rule out mild cases of hemophilia A because of the relative insensitivity of the test.Once the diagnosis of hemophilia A is made, the specific mutation in the F8 gene is often determined to ascertain the affected person’s risk of developing an uncommon but serious complication, i.e., the development of neutralizing anti-factor VIII antibodies, sometimes accompanied by allergic reactions, to the treatment outlined below. This complication is otherwise known as “inhibitor” development, since these antibodies can seriously inhibit the effectiveness of standard replacement treatment (see below).Molecular genetic testing, which can identify mutations in the F8 gene is available on a clinical basis. Understanding the specific F8 gene mutation can also be helpful in identifying female carriers in the family as well as in the prenatal diagnosis of hemophilia A, which is not only feasible, but is also available and encouraged in most Western and developing countries. Importantly, the development of digital PCR now allows analysis of cell-free fetal DNA present in maternal plasma and can diagnose hemophilia A in utero non-invasively as early as 7 weeks of gestation. | 560 | Hemophilia A |
nord_560_6 | Therapies of Hemophilia A | TreatmentIndividuals with hemophilia A will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling is recommended for affected individuals and their families.Although there is no cure for hemophilia A, current treatments are very effective. Treatment consists of replacing the missing clotting protein (factor VIII) and preventing the complications associated with the disorder. Replacement of this protein may be obtained through recombinant factor VIII, which is artificially created in a lab. Many physicians and voluntary health organizations favor the use of recombinant factor VIII because it does not contain components derived from human blood. Factor VIII can also be obtained from frozen plasma (i.e., blood donations). Human blood donations do carry a risk of transmitting viral infection such as hepatitis. However, newer techniques for screening and treating blood donations have made such a risk extremely low.The U.S. Food and Drug Administration (FDA) has approved several recombinant forms of factor VIII for the treatment of hemophilia A including Helixate FS, Recombinate, Kogenate FS, Advate, ReFacto, Eloctate, Nuwiq, Adynovate, Kovaltry, Jivi, and Xyntha. Human plasma-derived preparations include Monarc-M, Monoclate-P, Hemofil M, and Koate-DVI.Individuals with mild or moderate hemophilia A may be treated with replacement therapy as needed (i.e., to treat specific bleeding episodes). This is referred to as ‘on demand’ therapy. Ideally, individuals with severe hemophilia A are treated prophylactically, meaning they receive periodic factor VIII infusions at regular intervals to prevent bleeding episodes and associated complications such as joint damage.Parents and affected individuals can be trained to administer infusions at home. This is especially important for individuals with severe disease because infusion of factor VIII concentrate is most effective within one hour of the onset of a bleeding episode. In general, rapid treatment is important because it reduces pain and damage to the joints, muscle or other affected tissues or organs.Some individuals with mild hemophilia A may be treated with desmopressin (DDAVP), a synthetic agent that is a derivative of the hormone vasopressin. Desmopressin raises the plasma levels of factor VIII. Desmopressin may be administered intravenously or through a nasal spray. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat individuals with mild hemophilia A.InhibitorsIn some cases (approximately 30% of individuals with severe disease), people with hemophilia A may develop “inhibitors” against the replacement factor VIII. Inhibitors are antibodies, which are specialized proteins created by the body’s immune system to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor VIII as “foreign” and create these antibodies (inhibitors), which target and destroy the replacement factor. Inhibitor development can sometimes be accompanied by mild or serious allergic reactions. Inhibitors may also be known as alloantibodies. The reasons a person develops an inhibitor are complex, not fully understood and most likely due to a variety of both genetic and environmental factors. The risk of developing an inhibitor may change during an affected individual’s life. More research is necessary to determine the exact underlying mechanisms that ultimately cause inhibitor development in some individuals with hemophilia A.An inhibitor can seriously “inhibit” the effectiveness of replacement clotting factors, placing the patient at risk of life-threatening bleeding events. In such cases, alternate treatment is used to prevent and/or treat bleeding and additional therapy to eradicate these antibodies is sometimes instituted (immune tolerance induction).The amount of antibody (inhibitor) in an individual can be measured and is referred to as the titer. The inhibitor titer is expressed in a specific measurement called a Bethesda unit. The higher the number of Bethesda units, the more inhibitor that is present. An inhibitor can also be classified as low-responding or high-responding depending on how an individual’s immune system is stimulated based on repeated exposure to factor VIII. If the immune response is strong, inhibitor levels can rise to high levels. This is called high-responding. Alternatively, the immune system response can be weaker; this is classified as low-responding.If the inhibitor titer is very low (i.e., 5 Bethesda units).In individuals with higher titer levels, bypassing agents (concentrates of other coagulation factors that bypass the step in the clotting cascade affected by the factor deficiency) are often used to control bleeding episodes. The bypassing agents that are presently available are recombinant activated factor VII or activated prothrombin complex concentrate. Neither of these therapies is effective in all individuals.The U.S. Food and Drug Administration (FDA) has approved NovoSeven RT, a genetically engineered (recombinant) version of activated coagulation factor VII (factor VIIa), for the treatment of inhibitors in hemophilia A. Because it is artificially created in a lab, it does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with hemophilia.In 2020, FDA approved Sevenfact (recombinant human coagulation factor VIIa expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits’ milk) for treatment and control of bleeding in adults and adolescents age 12 and older with hemophilia A or B with inhibitors (neutralizing antibodies).Activated prothrombin complex concentrate (aPCC) is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA (Factor eight inhibitor bypassing activity).In 2017, the first monoclonal antibody treatment for hemophilia A, Hemlibra (emicizumab-kxwh) was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients who have developed inhibitors. Hemlibra is a bispecific monoclonal antibody that bridges activated coagulation factor 9 and 10 (FIX and FX) to replace the function of activated FVIII and thereby restore blood clotting.While the aforementioned therapies treat bleeding episodes, some individuals with inhibitors may undergo a process known as immune tolerance induction. This type of therapy is designed to eradicate the inhibitor, allowing individuals to be treated with replacement factor VIII. Immune tolerance induction involves exposing an affected individual to high doses of replacement factor VIII over a period of time that can range from months to years. The process is designed to train the immune system to accept therapy with replacement factor VIII without producing more inhibitors. Drawbacks to immune tolerance induction are its very high cost, its inconvenience, and the fact that it is time-consuming. In addition, immune tolerance induction has only proven to be effective in eradicating inhibitors in approximately 70% of patients. | Therapies of Hemophilia A. TreatmentIndividuals with hemophilia A will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling is recommended for affected individuals and their families.Although there is no cure for hemophilia A, current treatments are very effective. Treatment consists of replacing the missing clotting protein (factor VIII) and preventing the complications associated with the disorder. Replacement of this protein may be obtained through recombinant factor VIII, which is artificially created in a lab. Many physicians and voluntary health organizations favor the use of recombinant factor VIII because it does not contain components derived from human blood. Factor VIII can also be obtained from frozen plasma (i.e., blood donations). Human blood donations do carry a risk of transmitting viral infection such as hepatitis. However, newer techniques for screening and treating blood donations have made such a risk extremely low.The U.S. Food and Drug Administration (FDA) has approved several recombinant forms of factor VIII for the treatment of hemophilia A including Helixate FS, Recombinate, Kogenate FS, Advate, ReFacto, Eloctate, Nuwiq, Adynovate, Kovaltry, Jivi, and Xyntha. Human plasma-derived preparations include Monarc-M, Monoclate-P, Hemofil M, and Koate-DVI.Individuals with mild or moderate hemophilia A may be treated with replacement therapy as needed (i.e., to treat specific bleeding episodes). This is referred to as ‘on demand’ therapy. Ideally, individuals with severe hemophilia A are treated prophylactically, meaning they receive periodic factor VIII infusions at regular intervals to prevent bleeding episodes and associated complications such as joint damage.Parents and affected individuals can be trained to administer infusions at home. This is especially important for individuals with severe disease because infusion of factor VIII concentrate is most effective within one hour of the onset of a bleeding episode. In general, rapid treatment is important because it reduces pain and damage to the joints, muscle or other affected tissues or organs.Some individuals with mild hemophilia A may be treated with desmopressin (DDAVP), a synthetic agent that is a derivative of the hormone vasopressin. Desmopressin raises the plasma levels of factor VIII. Desmopressin may be administered intravenously or through a nasal spray. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat individuals with mild hemophilia A.InhibitorsIn some cases (approximately 30% of individuals with severe disease), people with hemophilia A may develop “inhibitors” against the replacement factor VIII. Inhibitors are antibodies, which are specialized proteins created by the body’s immune system to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor VIII as “foreign” and create these antibodies (inhibitors), which target and destroy the replacement factor. Inhibitor development can sometimes be accompanied by mild or serious allergic reactions. Inhibitors may also be known as alloantibodies. The reasons a person develops an inhibitor are complex, not fully understood and most likely due to a variety of both genetic and environmental factors. The risk of developing an inhibitor may change during an affected individual’s life. More research is necessary to determine the exact underlying mechanisms that ultimately cause inhibitor development in some individuals with hemophilia A.An inhibitor can seriously “inhibit” the effectiveness of replacement clotting factors, placing the patient at risk of life-threatening bleeding events. In such cases, alternate treatment is used to prevent and/or treat bleeding and additional therapy to eradicate these antibodies is sometimes instituted (immune tolerance induction).The amount of antibody (inhibitor) in an individual can be measured and is referred to as the titer. The inhibitor titer is expressed in a specific measurement called a Bethesda unit. The higher the number of Bethesda units, the more inhibitor that is present. An inhibitor can also be classified as low-responding or high-responding depending on how an individual’s immune system is stimulated based on repeated exposure to factor VIII. If the immune response is strong, inhibitor levels can rise to high levels. This is called high-responding. Alternatively, the immune system response can be weaker; this is classified as low-responding.If the inhibitor titer is very low (i.e., 5 Bethesda units).In individuals with higher titer levels, bypassing agents (concentrates of other coagulation factors that bypass the step in the clotting cascade affected by the factor deficiency) are often used to control bleeding episodes. The bypassing agents that are presently available are recombinant activated factor VII or activated prothrombin complex concentrate. Neither of these therapies is effective in all individuals.The U.S. Food and Drug Administration (FDA) has approved NovoSeven RT, a genetically engineered (recombinant) version of activated coagulation factor VII (factor VIIa), for the treatment of inhibitors in hemophilia A. Because it is artificially created in a lab, it does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with hemophilia.In 2020, FDA approved Sevenfact (recombinant human coagulation factor VIIa expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits’ milk) for treatment and control of bleeding in adults and adolescents age 12 and older with hemophilia A or B with inhibitors (neutralizing antibodies).Activated prothrombin complex concentrate (aPCC) is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA (Factor eight inhibitor bypassing activity).In 2017, the first monoclonal antibody treatment for hemophilia A, Hemlibra (emicizumab-kxwh) was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients who have developed inhibitors. Hemlibra is a bispecific monoclonal antibody that bridges activated coagulation factor 9 and 10 (FIX and FX) to replace the function of activated FVIII and thereby restore blood clotting.While the aforementioned therapies treat bleeding episodes, some individuals with inhibitors may undergo a process known as immune tolerance induction. This type of therapy is designed to eradicate the inhibitor, allowing individuals to be treated with replacement factor VIII. Immune tolerance induction involves exposing an affected individual to high doses of replacement factor VIII over a period of time that can range from months to years. The process is designed to train the immune system to accept therapy with replacement factor VIII without producing more inhibitors. Drawbacks to immune tolerance induction are its very high cost, its inconvenience, and the fact that it is time-consuming. In addition, immune tolerance induction has only proven to be effective in eradicating inhibitors in approximately 70% of patients. | 560 | Hemophilia A |
nord_561_0 | Overview of Hemophilia B | Summary
Hemophilia B is a rare genetic bleeding disorder in which affected individuals have insufficient levels of a blood protein called factor IX. Factor IX is a clotting factor. Clotting factors are specialized proteins needed for blood clotting, the process by which blood seals a wound to stop bleeding and promote healing. Individuals with hemophilia B do not bleed faster than unaffected individuals, they bleed longer. This is because they are missing or have a decreased amount of a protein involved in blood clotting and are unable to effectively stop the flow of blood from a wound, injury or bleeding site. This is sometimes referred to as prolonged bleeding or a bleeding episode.Hemophilia B is classified as mild, moderate or severe based upon the activity level of factor IX. In mild cases, bleeding symptoms may occur only after surgery, injury or a dental procedure. In some moderate and most severe cases, bleeding symptoms may occur after a minor injury or spontaneously, meaning without an identifiable cause.Hemophilia B is caused by changes (variants or mutations) in the factor IX gene (F9) on the X chromosome. Hemophilia B is most commonly identified in males; however, females who carry the gene may have mild or, rarely, more severe symptoms of bleeding and should have their factor IX level checked.Introduction
Hemophilia B, also known as factor IX deficiency or Christmas disease, is the second most common type of hemophilia. The disorder was first reported in the medical literature in 1952 in a patient with the name of Stephen Christmas. The most well-known family with hemophilia B was that of Queen Victoria of England. Through her descendants, the disorder was passed down to the royal families of Germany, Spain and Russia and thus hemophilia B is also known as the “royal disease.”Although the focus of this report is the genetic, or inherited, form of hemophilia B, it should be noted that another form called acquired hemophilia B can develop, most commonly later in life (see “Related Disorders” section below). An individual with acquired hemophilia B is not born with the condition. Acquired hemophilia B is caused by the body’s production of antibodies against its own factor IX protein. The factor IX antibodies destroy circulating factor IX in the blood causing bleeding symptoms. Acquired hemophilia B is extremely rare; most cases of acquired hemophilia are in those with hemophilia A or factor VIII deficiency. | Overview of Hemophilia B. Summary
Hemophilia B is a rare genetic bleeding disorder in which affected individuals have insufficient levels of a blood protein called factor IX. Factor IX is a clotting factor. Clotting factors are specialized proteins needed for blood clotting, the process by which blood seals a wound to stop bleeding and promote healing. Individuals with hemophilia B do not bleed faster than unaffected individuals, they bleed longer. This is because they are missing or have a decreased amount of a protein involved in blood clotting and are unable to effectively stop the flow of blood from a wound, injury or bleeding site. This is sometimes referred to as prolonged bleeding or a bleeding episode.Hemophilia B is classified as mild, moderate or severe based upon the activity level of factor IX. In mild cases, bleeding symptoms may occur only after surgery, injury or a dental procedure. In some moderate and most severe cases, bleeding symptoms may occur after a minor injury or spontaneously, meaning without an identifiable cause.Hemophilia B is caused by changes (variants or mutations) in the factor IX gene (F9) on the X chromosome. Hemophilia B is most commonly identified in males; however, females who carry the gene may have mild or, rarely, more severe symptoms of bleeding and should have their factor IX level checked.Introduction
Hemophilia B, also known as factor IX deficiency or Christmas disease, is the second most common type of hemophilia. The disorder was first reported in the medical literature in 1952 in a patient with the name of Stephen Christmas. The most well-known family with hemophilia B was that of Queen Victoria of England. Through her descendants, the disorder was passed down to the royal families of Germany, Spain and Russia and thus hemophilia B is also known as the “royal disease.”Although the focus of this report is the genetic, or inherited, form of hemophilia B, it should be noted that another form called acquired hemophilia B can develop, most commonly later in life (see “Related Disorders” section below). An individual with acquired hemophilia B is not born with the condition. Acquired hemophilia B is caused by the body’s production of antibodies against its own factor IX protein. The factor IX antibodies destroy circulating factor IX in the blood causing bleeding symptoms. Acquired hemophilia B is extremely rare; most cases of acquired hemophilia are in those with hemophilia A or factor VIII deficiency. | 561 | Hemophilia B |
nord_561_1 | Symptoms of Hemophilia B | The symptoms and severity of hemophilia B vary greatly based upon the level of factor IX present. Hemophilia B can range from mild to moderate to severe. Individuals with mild hemophilia have factor IX levels between 5 and 40% of normal; those with moderate hemophilia have factor levels from 1 to 5% of normal; and individuals with severe hemophilia have factor levels less than 1% of normal. The age an individual becomes aware that they have hemophilia B, known as age of diagnosis, and the frequency of bleeding episodes depends upon the amount of factor IX present in the blood and the family history.In mild cases of hemophilia B, individuals may experience bruising and bleeding after surgery, dental procedures, injury or trauma. Although some bleeding occurs in individuals without hemophilia after injury or trauma, individuals with hemophilia B often have longer and more severe bleeding episodes with these occurrences. Many individuals with mild hemophilia B may go undiagnosed until a surgical procedure is needed, or an injury occurs. Individuals with mild hemophilia may not experience their first bleeding episode until adulthood. Additionally, individuals with the mild form of hemophilia B may go many years between bleeding episodes.Individuals with moderate hemophilia B may have occasional episodes of spontaneous bleeding from deep tissues such as joints and muscles. Spontaneous bleeding refers to bleeding episodes that occur without an identifiable cause. The individual may not be able to identify an event that may have occurred. Individuals with moderate hemophilia B are also at risk for prolonged bleeding following surgery or trauma. Affected individuals are usually diagnosed by five or six years of age but this may vary as well. The frequency of spontaneous bleeding episodes in individuals with moderate hemophilia B is highly variable.In severe cases of hemophilia B, frequent, spontaneous bleeding episodes are the most common symptom. Spontaneous bleeding episodes may include bleeding into the muscles and joints. This often causes pain and swelling and restricts movement of the joint. Bleeding into a joint is called hemarthrosis. If left untreated, this often results in long-term damage including inflammation of the membrane lining the joints (synovitis) and joint disease (arthropathy) and muscle weakness and/or swelling, tightness and restricted movement around the affected joint. Permanent joint damage may occur. Additional symptoms affecting individuals with severe hemophilia B include easy bruising and bleeding into deep tissues such as the muscles, in addition, nosebleeds, gastrointestinal and central nervous system bleeding.Individuals with a moderate or severe form of hemophilia can potentially experience spontaneous bleeding into other areas including the kidneys, stomach, intestines and brain. Bleeding within the kidneys or stomach and intestines may cause blood in the urine, called hematuria and stomach/intestines, called melena or hematochezia, respectively. Bleeding within the brain may cause headaches, stiff neck, vomiting, seizures and mental status changes including excessive sleepiness and poor arousability, and may result in permanent neurologic damage and/or death if left untreated.Severe cases of hemophilia B usually become apparent early during infancy or childhood. Without preventative treatment, called prophylaxis, a young child may experience two to five spontaneous bleeding episodes per month. Infants are diagnosed with hemophilia B based on a known family history of hemophilia or after they develop bleeding due to a bleeding event which may but not always occur with circumcision, a neonatal procedure; bleeding within the brain or around the head, called an intracranial bleed or extracranial bleed, resulting from delivery may also occur. If an infant is not diagnosed at birth, hemophilia may be suspected if the child develops excessive bruising or deep tissue bleeding in areas such as the buttock muscles from falling while learning to walk; bleeding into the joints; or prolonged bleeding in the mouth due to an injury such as a fall or abnormal bruising or bleeding with immunizations. | Symptoms of Hemophilia B. The symptoms and severity of hemophilia B vary greatly based upon the level of factor IX present. Hemophilia B can range from mild to moderate to severe. Individuals with mild hemophilia have factor IX levels between 5 and 40% of normal; those with moderate hemophilia have factor levels from 1 to 5% of normal; and individuals with severe hemophilia have factor levels less than 1% of normal. The age an individual becomes aware that they have hemophilia B, known as age of diagnosis, and the frequency of bleeding episodes depends upon the amount of factor IX present in the blood and the family history.In mild cases of hemophilia B, individuals may experience bruising and bleeding after surgery, dental procedures, injury or trauma. Although some bleeding occurs in individuals without hemophilia after injury or trauma, individuals with hemophilia B often have longer and more severe bleeding episodes with these occurrences. Many individuals with mild hemophilia B may go undiagnosed until a surgical procedure is needed, or an injury occurs. Individuals with mild hemophilia may not experience their first bleeding episode until adulthood. Additionally, individuals with the mild form of hemophilia B may go many years between bleeding episodes.Individuals with moderate hemophilia B may have occasional episodes of spontaneous bleeding from deep tissues such as joints and muscles. Spontaneous bleeding refers to bleeding episodes that occur without an identifiable cause. The individual may not be able to identify an event that may have occurred. Individuals with moderate hemophilia B are also at risk for prolonged bleeding following surgery or trauma. Affected individuals are usually diagnosed by five or six years of age but this may vary as well. The frequency of spontaneous bleeding episodes in individuals with moderate hemophilia B is highly variable.In severe cases of hemophilia B, frequent, spontaneous bleeding episodes are the most common symptom. Spontaneous bleeding episodes may include bleeding into the muscles and joints. This often causes pain and swelling and restricts movement of the joint. Bleeding into a joint is called hemarthrosis. If left untreated, this often results in long-term damage including inflammation of the membrane lining the joints (synovitis) and joint disease (arthropathy) and muscle weakness and/or swelling, tightness and restricted movement around the affected joint. Permanent joint damage may occur. Additional symptoms affecting individuals with severe hemophilia B include easy bruising and bleeding into deep tissues such as the muscles, in addition, nosebleeds, gastrointestinal and central nervous system bleeding.Individuals with a moderate or severe form of hemophilia can potentially experience spontaneous bleeding into other areas including the kidneys, stomach, intestines and brain. Bleeding within the kidneys or stomach and intestines may cause blood in the urine, called hematuria and stomach/intestines, called melena or hematochezia, respectively. Bleeding within the brain may cause headaches, stiff neck, vomiting, seizures and mental status changes including excessive sleepiness and poor arousability, and may result in permanent neurologic damage and/or death if left untreated.Severe cases of hemophilia B usually become apparent early during infancy or childhood. Without preventative treatment, called prophylaxis, a young child may experience two to five spontaneous bleeding episodes per month. Infants are diagnosed with hemophilia B based on a known family history of hemophilia or after they develop bleeding due to a bleeding event which may but not always occur with circumcision, a neonatal procedure; bleeding within the brain or around the head, called an intracranial bleed or extracranial bleed, resulting from delivery may also occur. If an infant is not diagnosed at birth, hemophilia may be suspected if the child develops excessive bruising or deep tissue bleeding in areas such as the buttock muscles from falling while learning to walk; bleeding into the joints; or prolonged bleeding in the mouth due to an injury such as a fall or abnormal bruising or bleeding with immunizations. | 561 | Hemophilia B |
nord_561_2 | Causes of Hemophilia B | Hemophilia B is caused by a change (variant or mutation) in the F9 gene. The F9 gene is located on the X chromosome and thus is inherited in an X-linked recessive pattern. In about 30% of cases of hemophilia B, the altered gene occurs spontaneously without a previous family history. The F9 gene contains instructions for creating the factor IX protein. Variants in the F9 gene can lead to deficient levels of functional factor IX protein. The bleeding symptoms associated with hemophilia B occur due to this deficiency.X-linked recessive disorders are conditions caused by an altered gene on the X chromosome. Females have two X chromosomes (XX). If only one of their X chromosomes contains a disease-causing variation on a gene, they are called “carriers” of that disorder, and carriers with FIX activity level <40% are now diagnosed as having hemophilia.
Males have one X chromosome and one Y chromosome (XY). Thus, if a male inherits an X chromosome from his mother that contains a disorder-causing gene, he will develop the disorder. Males with an X chromosome containing the disorder-causing gene will pass that gene on to all their daughters. These daughters will be carriers if the X chromosome they inherit from their mother is normal. They will have hemophilia if they inherit another disorder-causing gene from their mother; this is rare. A male cannot pass an X-linked gene on to his sons because males only pass their Y chromosome on to their sons. With each pregnancy, female carriers of an X-linked disorder have a 25% chance for each daughter to be a carrier; a 25% chance of having a non-carrier daughter; a 25% chance of having a son with the disorder; and a 25% chance of having an unaffected son.
Hemophilia B Leyden: There is an unusual form of factor IX deficiency called hemophilia B Leyden. Hemophilia B Leyden is named after the place in the Netherlands where it was first described. Depending upon the particular hemophilia B Leyden variant present, there are undetectable levels of factor IX present early in life that increase over time. By midlife, these patients have factor IX levels at the low end of the normal range and thus may no longer require treatment for bleeding episodes. Hemophilia B Leyden represents approximately 3% of all hemophilia B cases.
| Causes of Hemophilia B. Hemophilia B is caused by a change (variant or mutation) in the F9 gene. The F9 gene is located on the X chromosome and thus is inherited in an X-linked recessive pattern. In about 30% of cases of hemophilia B, the altered gene occurs spontaneously without a previous family history. The F9 gene contains instructions for creating the factor IX protein. Variants in the F9 gene can lead to deficient levels of functional factor IX protein. The bleeding symptoms associated with hemophilia B occur due to this deficiency.X-linked recessive disorders are conditions caused by an altered gene on the X chromosome. Females have two X chromosomes (XX). If only one of their X chromosomes contains a disease-causing variation on a gene, they are called “carriers” of that disorder, and carriers with FIX activity level <40% are now diagnosed as having hemophilia.
Males have one X chromosome and one Y chromosome (XY). Thus, if a male inherits an X chromosome from his mother that contains a disorder-causing gene, he will develop the disorder. Males with an X chromosome containing the disorder-causing gene will pass that gene on to all their daughters. These daughters will be carriers if the X chromosome they inherit from their mother is normal. They will have hemophilia if they inherit another disorder-causing gene from their mother; this is rare. A male cannot pass an X-linked gene on to his sons because males only pass their Y chromosome on to their sons. With each pregnancy, female carriers of an X-linked disorder have a 25% chance for each daughter to be a carrier; a 25% chance of having a non-carrier daughter; a 25% chance of having a son with the disorder; and a 25% chance of having an unaffected son.
Hemophilia B Leyden: There is an unusual form of factor IX deficiency called hemophilia B Leyden. Hemophilia B Leyden is named after the place in the Netherlands where it was first described. Depending upon the particular hemophilia B Leyden variant present, there are undetectable levels of factor IX present early in life that increase over time. By midlife, these patients have factor IX levels at the low end of the normal range and thus may no longer require treatment for bleeding episodes. Hemophilia B Leyden represents approximately 3% of all hemophilia B cases.
| 561 | Hemophilia B |
nord_561_3 | Affects of Hemophilia B | Hemophilia B occurs in approximately 1 in 25,000 male births. It is less prevalent than hemophilia A which occurs in approximately 1 in 5,000 male births. Although many hemophilia B carrier females do not have symptoms, an estimated 10-25% will develop mild symptoms and females have also been reported with moderate and severe symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed around birth or within the first few years of life; those with moderate hemophilia B, five to six years of age; and individuals with mild hemophilia B may not be diagnosed until later in life and even into adulthood. | Affects of Hemophilia B. Hemophilia B occurs in approximately 1 in 25,000 male births. It is less prevalent than hemophilia A which occurs in approximately 1 in 5,000 male births. Although many hemophilia B carrier females do not have symptoms, an estimated 10-25% will develop mild symptoms and females have also been reported with moderate and severe symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed around birth or within the first few years of life; those with moderate hemophilia B, five to six years of age; and individuals with mild hemophilia B may not be diagnosed until later in life and even into adulthood. | 561 | Hemophilia B |
nord_561_4 | Related disorders of Hemophilia B | Symptoms of the following disorders may be similar to those of hemophilia B. Comparisons may be useful for a differential diagnosis.Hemophilia A and C: Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited abnormalities in blood clotting or coagulation, caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A, also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); hemophilia B and hemophilia C, known as factor XI deficiency or Rosenthal’s disease. Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Autosomal disorders are disorders caused by variations in genes located on non-sex chromosomes (sex chromosomes are the X and Y). While hemophilia A and B are most common in males, hemophilia C affects both males and females equally. Hemophilia C does not usually present the same way hemophilia A and B do. People with hemophilia C are usually variable bleeders and may bleed with circumcision but don’t usually have spontaneous joint and muscle bleeds. (For more information on hemophilia A, B and C, choose “hemophilia” as your search term in the Rare Disease Database.)Acquired Hemophilia: Acquired hemophilia is a type of autoimmune disorder. Autoimmune disorders occur when the body’s immune system identifies healthy cells, tissue or proteins as foreign. Acquired hemophilia occurs when individuals without a previous bleeding history develop antibodies against a clotting factor, most commonly factor VIII. This can cause affected individuals to develop symptoms of hemophilia such as nosebleeds, bruising, swelling in tissues due to accumulation of blood called hematomas, blood in the urine, or bleeding from the stomach, intestines or urogenital area. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications. In approximately half of all cases of acquired hemophilia, there is an associated underlying condition (e.g., pregnancy, autoimmune disorders such as lupus or rheumatoid arthritis, myeloproliferative disorders, inflammatory bowel disease, etc.); in the other half, no cause can be identified. (For more information on this disorder, choose “acquired hemophilia” as your search term in the Rare Disease Database.)Von Willebrand Disease: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the general population. It affects males and females equally. There are several types of VWD (VWD type 1, VWD type 2, VWD type 3, and pseudo-VWD) each with differing degrees of severity and inheritance patterns. These categories may be sub-classified into subtypes. The more severe types of VWD such as type 3 may be similar to hemophilia and are characterized by prolonged bleeding.VWD is caused by a defect or deficiency in an individual’s von Willebrand factor (VWF), a large protein made up of multiple subunits called multimers. VWF binds to clotting factor VIII in the circulation and protects it from being broken down. VWF also helps platelets bind to the site of injury in blood vessels. This leads to the formation of a stable blood clot which plugs an injured blood vessel and stops bleeding. If there is an insufficient quantity of VWF or it is defective, an individual may have difficulty forming a blood clot.Most people with VWD have type 1, which can range from relatively mild to more severe; age of diagnosis varies, and it may not be diagnosed until adulthood. Some individuals may have symptoms during infancy or childhood depending on their subtype, level of severity and stressors that are experienced. Symptoms can include nosebleeds, bleeding from the gums, easy bruising and, less commonly, bleeding from the stomach and intestines. Affected individuals may bleed easily after injury, childbirth and/or surgery. Females often have excessive menstrual bleeding or excessive bleeding after delivery. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Congenital Fibrinogen Disorders: Congenital fibrinogen disorders are a group of rare bleeding disorders characterized by an abnormality, deficiency or absence of a certain protein, called fibrinogen or coagulation factor I. This condition is inherited and present at birth. Fibrinogen is essential in the blood clotting process. Two major types of fibrinogen disorders have been identified. Type 1, or quantitative abnormalities, includes afibrinogenemia and hypofibrinogenemia. Quantitative abnormalities result in an absence or reduced amount of fibrinogen protein. Type 2, or qualitative abnormalities, includes dysfibrinogenemia and hypodysfibrinogenemia. Individuals with qualitative abnormalities may have adequate levels of fibrinogen; however, the fibrinogen present does not function properly.Individuals with afibrinogenemia are susceptible to severe bleeding episodes, commonly at birth or following interventions such as circumcision and prolonged bleeding from minor cuts. Individuals with afibrinogenemia may also be predisposed to develop a blood clot called a thrombosis. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms or may develop mild bleeding episodes. (For more information on this disorder, choose “fibrinogen” as your search term in the Rare Disease Database.)Platelet Disorders: Platelets are small, disc-shaped cells that help the blood clot. Platelet disorders are disorders that can predispose an individual to prolonged bleeding. Platelet disorders can be divided into two groups: quantitative and qualitative platelet disorders. Platelets are either not made in sufficient amounts or are defective in their function and therefore may not be adequate to stop bleeding; in addition, some conditions are associated with increased destruction or turnover resulting in an inadequate number when needed.The most common symptoms of platelet disorders include development of petechiae (small red or purple spots on the skin), bruising, recurrent nose bleeds, bleeding of the mouth or gums, heavy menstrual bleeding, excessive postpartum bleeding and bleeding following surgery or other invasive procedure. The severity and symptoms of the disorder vary depending upon the platelet disorder.Other bleeding disorders may also be considered in an individual with symptoms of abnormal bleeding or bruising including deficiencies of other coagulation factors such as factors VII, X, V, II and XIII, etc. | Related disorders of Hemophilia B. Symptoms of the following disorders may be similar to those of hemophilia B. Comparisons may be useful for a differential diagnosis.Hemophilia A and C: Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited abnormalities in blood clotting or coagulation, caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A, also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); hemophilia B and hemophilia C, known as factor XI deficiency or Rosenthal’s disease. Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal recessive genetic disorder. Autosomal disorders are disorders caused by variations in genes located on non-sex chromosomes (sex chromosomes are the X and Y). While hemophilia A and B are most common in males, hemophilia C affects both males and females equally. Hemophilia C does not usually present the same way hemophilia A and B do. People with hemophilia C are usually variable bleeders and may bleed with circumcision but don’t usually have spontaneous joint and muscle bleeds. (For more information on hemophilia A, B and C, choose “hemophilia” as your search term in the Rare Disease Database.)Acquired Hemophilia: Acquired hemophilia is a type of autoimmune disorder. Autoimmune disorders occur when the body’s immune system identifies healthy cells, tissue or proteins as foreign. Acquired hemophilia occurs when individuals without a previous bleeding history develop antibodies against a clotting factor, most commonly factor VIII. This can cause affected individuals to develop symptoms of hemophilia such as nosebleeds, bruising, swelling in tissues due to accumulation of blood called hematomas, blood in the urine, or bleeding from the stomach, intestines or urogenital area. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications. In approximately half of all cases of acquired hemophilia, there is an associated underlying condition (e.g., pregnancy, autoimmune disorders such as lupus or rheumatoid arthritis, myeloproliferative disorders, inflammatory bowel disease, etc.); in the other half, no cause can be identified. (For more information on this disorder, choose “acquired hemophilia” as your search term in the Rare Disease Database.)Von Willebrand Disease: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the general population. It affects males and females equally. There are several types of VWD (VWD type 1, VWD type 2, VWD type 3, and pseudo-VWD) each with differing degrees of severity and inheritance patterns. These categories may be sub-classified into subtypes. The more severe types of VWD such as type 3 may be similar to hemophilia and are characterized by prolonged bleeding.VWD is caused by a defect or deficiency in an individual’s von Willebrand factor (VWF), a large protein made up of multiple subunits called multimers. VWF binds to clotting factor VIII in the circulation and protects it from being broken down. VWF also helps platelets bind to the site of injury in blood vessels. This leads to the formation of a stable blood clot which plugs an injured blood vessel and stops bleeding. If there is an insufficient quantity of VWF or it is defective, an individual may have difficulty forming a blood clot.Most people with VWD have type 1, which can range from relatively mild to more severe; age of diagnosis varies, and it may not be diagnosed until adulthood. Some individuals may have symptoms during infancy or childhood depending on their subtype, level of severity and stressors that are experienced. Symptoms can include nosebleeds, bleeding from the gums, easy bruising and, less commonly, bleeding from the stomach and intestines. Affected individuals may bleed easily after injury, childbirth and/or surgery. Females often have excessive menstrual bleeding or excessive bleeding after delivery. (For more information on this disorder, choose “Von Willebrand” as your search term in the Rare Disease Database.)Congenital Fibrinogen Disorders: Congenital fibrinogen disorders are a group of rare bleeding disorders characterized by an abnormality, deficiency or absence of a certain protein, called fibrinogen or coagulation factor I. This condition is inherited and present at birth. Fibrinogen is essential in the blood clotting process. Two major types of fibrinogen disorders have been identified. Type 1, or quantitative abnormalities, includes afibrinogenemia and hypofibrinogenemia. Quantitative abnormalities result in an absence or reduced amount of fibrinogen protein. Type 2, or qualitative abnormalities, includes dysfibrinogenemia and hypodysfibrinogenemia. Individuals with qualitative abnormalities may have adequate levels of fibrinogen; however, the fibrinogen present does not function properly.Individuals with afibrinogenemia are susceptible to severe bleeding episodes, commonly at birth or following interventions such as circumcision and prolonged bleeding from minor cuts. Individuals with afibrinogenemia may also be predisposed to develop a blood clot called a thrombosis. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms or may develop mild bleeding episodes. (For more information on this disorder, choose “fibrinogen” as your search term in the Rare Disease Database.)Platelet Disorders: Platelets are small, disc-shaped cells that help the blood clot. Platelet disorders are disorders that can predispose an individual to prolonged bleeding. Platelet disorders can be divided into two groups: quantitative and qualitative platelet disorders. Platelets are either not made in sufficient amounts or are defective in their function and therefore may not be adequate to stop bleeding; in addition, some conditions are associated with increased destruction or turnover resulting in an inadequate number when needed.The most common symptoms of platelet disorders include development of petechiae (small red or purple spots on the skin), bruising, recurrent nose bleeds, bleeding of the mouth or gums, heavy menstrual bleeding, excessive postpartum bleeding and bleeding following surgery or other invasive procedure. The severity and symptoms of the disorder vary depending upon the platelet disorder.Other bleeding disorders may also be considered in an individual with symptoms of abnormal bleeding or bruising including deficiencies of other coagulation factors such as factors VII, X, V, II and XIII, etc. | 561 | Hemophilia B |
nord_561_5 | Diagnosis of Hemophilia B | Diagnosis of hemophilia B is made with attention to the following: the patient’s personal history of bleeding, the patient’s family history of bleeding and inheritance and laboratory testing. Several different specialized tests are necessary to confirm a diagnosis of hemophilia B.To determine if an individual has hemophilia B, specialized blood coagulation tests are used that measure how long it takes the blood to clot. The initial test is the activated partial thromboplastin time (aPTT). If the results of the aPTT test are abnormal, more specific blood tests must be used to determine if the cause of the abnormal aPTT is due to a deficiency of factor IX/hemophilia B, factor VIII/hemophilia A or another clotting factor. A specific factor assay also determines the severity level of the factor deficiency. It should be noted that the aPTT is not consistently sensitive to detect mild hemophilia B. If this diagnosis is suspected, a specific factor IX activity level should be performed even in the face of a normal aPTT.Once an individual is diagnosed with hemophilia B, the specific variant in the F9 gene responsible for causing hemophilia may be identified. Identifying the variant may assist in determining an individual’s risk of developing an inhibitor, a serious complication in those with severe hemophilia (see “Complications” section below). Understanding the specific F9 gene variant is important to identify female carriers within a family as factor IX levels are not adequate to determine carrier status. | Diagnosis of Hemophilia B. Diagnosis of hemophilia B is made with attention to the following: the patient’s personal history of bleeding, the patient’s family history of bleeding and inheritance and laboratory testing. Several different specialized tests are necessary to confirm a diagnosis of hemophilia B.To determine if an individual has hemophilia B, specialized blood coagulation tests are used that measure how long it takes the blood to clot. The initial test is the activated partial thromboplastin time (aPTT). If the results of the aPTT test are abnormal, more specific blood tests must be used to determine if the cause of the abnormal aPTT is due to a deficiency of factor IX/hemophilia B, factor VIII/hemophilia A or another clotting factor. A specific factor assay also determines the severity level of the factor deficiency. It should be noted that the aPTT is not consistently sensitive to detect mild hemophilia B. If this diagnosis is suspected, a specific factor IX activity level should be performed even in the face of a normal aPTT.Once an individual is diagnosed with hemophilia B, the specific variant in the F9 gene responsible for causing hemophilia may be identified. Identifying the variant may assist in determining an individual’s risk of developing an inhibitor, a serious complication in those with severe hemophilia (see “Complications” section below). Understanding the specific F9 gene variant is important to identify female carriers within a family as factor IX levels are not adequate to determine carrier status. | 561 | Hemophilia B |
nord_561_6 | Therapies of Hemophilia B | Treatment
The fundamental treatment of hemophilia B is to replace factor IX to achieve adequate blood clotting and to prevent complications associated with the disorder. Currently, replacement of factor IX to achieve a sufficient level is commonly done utilizing recombinant products or with products derived from human blood or plasma. Many physicians and voluntary health organizations favor the use of recombinant factor IX because it does not contain human blood proteins. Human blood donations carry a very small risk of transmitting viral infections such as hepatitis and HIV; however, newer techniques for screening and treating blood donations have this risk extremely low to negligible.Carrier females that have bleeding symptoms may need factor replacement therapy in a variety of circumstances such as for bleeding episodes, following childbirth due to postpartum bleeding or for dental and surgical procedures depending on their factor IX activity level.Federally Recognized Hemophilia Treatment Centers: Evidence has shown that individuals with hemophilia significantly benefit from receiving care from a federally recognized hemophilia treatment center. These specialized centers provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow-up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team including physicians, nurses, physical therapists, social workers and genetic counselors experienced in treating individuals with hemophilia. To locate a hemophilia treatment center, visit the Centers for Disease Control and Prevention website at: https://www.cdc.gov/ncbddd/hemophilia/HTC.htmlCurrent Treatment Options
Recombinant Factor IX: Recombinant factor IX products are manufactured in a laboratory. These genetically engineered products do not contain animal or human protein and are not derived from human blood; they are theoretically considered to be free of the risk of transmitting viruses. Recombinant factor IX therapy is the recommended treatment for individuals with hemophilia B. In the U.S., the currently available recombinant factor IX products are BeneFIX, Rixubis, Ixinity, Alprolix, Idelvion and Rebinyn.Plasma-Derived Factor IX Concentrates: There are two main categories of plasma-derived factor IX concentrates available; highly purified plasma-derived products and intermediate purity plasma-derived products. Plasma-derived products come from human donations of blood or plasma. Highly purified products are essentially free of other clotting factor proteins and are virally inactivated using various methods. There are two high purity products available in the U.S., AlphaNine SD and Mononine. Intermediate purity products contain factor IX and variable amounts of other clotting factor proteins and are virally inactivated; however, they are rarely used in the United States and not recommended for treatment of FIX deficiency.Fresh Frozen Plasma: Fresh frozen plasma is derived from human blood and is used to treat patients with factor IX deficiency only if factor IX concentrate is not available. Fresh frozen plasma contains all the coagulation factors in the blood but is not virally inactivated. In addition, fresh frozen plasma is inefficient in raising factor IX activity to a hemostatic level.In 2020, the FDA approved recombinant coagulation factor VIIa (Sevenfact), another recombinant product that does not contain FIX protein. Sevenfact also has been approved for the treatment and control of bleeding episodes in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors.In 2022, etranacogene dezaparvovec (Hemgenix) was approved by the FDA as the first gene therapy to treat adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.The document in the link below from the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation provides recommendations for the treatment of hemophilia:
https://www.hemophilia.org/sites/default/files/document/files/259_treatment.pdfHistory of Hemophilia Treatment Options
Whole Blood: Until the 1960s, highly reliable treatment for hemophilia did not exist. Patients experiencing bleeding episodes were treated with whole blood transfusions. This was an ineffective treatment option as whole blood does not contain enough clotting factor to increase the level to a hemostatic range to effectively control bleeding. During this time, individuals often had repeated bleeding into the joints or central nervous system which led to permanent joint damage, seizures and a variety of permanent intellectual and movement disorders. The average life expectancy of a male with severe hemophilia during this time was 12 years of age.Cryoprecipitate: In the mid-1960s, Dr. Judith Pool discovered cryoprecipitate, a human plasma-derived material rich in clotting factor VIII, the clotting factor that is deficient in those with hemophilia A. Cryoprecipitate settles to the bottom of containers of frozen plasma when thawed at refrigerator temperature. Upon warming to room temperature, the cryoprecipitate returns to solution. In its frozen form, cryoprecipitate was stored in blood banks and administered to persons with hemophilia A in place of whole blood or plasma. The effect of the more concentrated factor VIII found in cryoprecipitate, compared to whole blood, was more rapid blood clot formation and decreased problems associated with bleeding episodes. Cryoprecipitate does not contain factor IX and is not recommended for use in the United States anymore for treatment of hemophilia A.Plasma-Derived Clotting Factor Concentrates: In the late 1960s and early 1970s clotting factors became available in more concentrated forms that remained stable as powders when stored at refrigerator temperature. This allowed hemophilia patients to store and administer the clotting factor at home without medical supervision. The first available factor IX product was an intermediate purity (PCC) and was approved for use in the U.S. in 1969.One of the main problems with early factor therapy was that the products available came from human plasma from many donors. This carried the risk of transmitting viruses such as hepatitis A, B and C and human immunodeficiency virus (HIV) from the donor to the patient. Until the mid-1980s many individuals receiving factor products became infected with one or more of these viruses due to inability to effectively screen donors or treat the concentrate to inactivate viruses.Recombinant Products: It was not until the late 1980s to the early 1990s, that the efficacy of recombinant factor products was reported, and products made commercially available. In 1992, the first genetically engineered factor VIII concentrate was approved by the U.S. Food and Drug Administration (FDA). It was not until 1997 that the first recombinant factor IX product became available. Use of genetically engineered factor concentrates may eliminate the risk of blood borne infections or transmittable diseases dependent on the method of manufacturing and exposure or use of human or animal proteins in the manufacturing process.Treatment Regimens for Hemophilia
Individuals with mild or moderate hemophilia B may be treated with replacement therapy as needed to treat a bleeding episode. This is called episodic infusion therapy and is used to stop a bleed that has already started. Individuals with severe hemophilia B may receive regular infusions to prevent bleeding episodes. This is called prophylactic therapy and is intended to prevent bleeds before they occur. Prophylactic therapy has been shown to reduce many complications associated with recurrent bleeding such as joint damage and intracranial hemorrhage in patients with severe hemophilia A and B. Parents and affected individuals can be trained to administer factor IX at home. Home therapy is especially important for individuals with severe disease but is also important for moderate and mild hemophilia as infusion of factor IX concentrate is most effective at limiting bleeding when administered within one hour of the onset of a bleeding episode. Some patients with moderate or mild hemophilia B receive prophylaxis for prevention of bleeding during activities either short or longer term (e.g., before a specific activity such as skiing or during basketball or baseball season etc.)Complications
Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, coughing, tight throat or wheezing during or immediately after infusion of replacement with FIX. Infusion reactions are most seen in individuals using fresh frozen plasma where the reaction is typically an allergic-like reaction to some part of the donor’s blood. These reactions can usually be treated with antihistamines and corticosteroids; however, a physician should always be notified of such an event. An important infusion reaction in hemophilia B can occur with the use of factor IX concentrates; these are uncommon but must be recognized promptly for patient safety and monitoring. If symptoms develop or are severe, the infusion should be stopped, and the patient should notify their hemophilia care provider immediately as well as be seen in the emergency room. Infusion reactions in patients with severe factor IX deficiency may be associated with the development of inhibitors.Inhibitors: It is estimated that < 5% of individuals with severe hemophilia B develop “inhibitors” against factor IX replacement therapy. Inhibitors are antibodies, created by the body’s immune system that is usually targeted to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor IX as “foreign” and create antibodies, or “inhibitors”, against it. These antibodies destroy the replacement factor. This complication negatively impacts the effectiveness of standard treatment. In such cases, alternate treatment is used to treat bleeding. In addition, therapy to eradicate these antibodies may be instituted. The therapy is called immune tolerance induction therapy. Immune tolerance induction therapy is less commonly attempted in patients with hemophilia B and inhibitors than in hemophilia A with inhibitors due to the risk of allergic reactions, kidney disease and decreased rate of success. Inhibitor development is considered the most severe problem in hemophilia care today as it affects patient treatment, risk of developing joint disease, cost of hemophilia care, morbidity and mortality. Genetic testing can help determine whether an individual with factor IX deficiency is at a higher risk of developing an inhibitor. NovoSeven RT (recombinant coagulation factor VIIa) is a recombinant product used for treatment and prevention of bleeding in individuals with factor IX deficiency with an inhibitor that does not contain any FIX protein.
| Therapies of Hemophilia B. Treatment
The fundamental treatment of hemophilia B is to replace factor IX to achieve adequate blood clotting and to prevent complications associated with the disorder. Currently, replacement of factor IX to achieve a sufficient level is commonly done utilizing recombinant products or with products derived from human blood or plasma. Many physicians and voluntary health organizations favor the use of recombinant factor IX because it does not contain human blood proteins. Human blood donations carry a very small risk of transmitting viral infections such as hepatitis and HIV; however, newer techniques for screening and treating blood donations have this risk extremely low to negligible.Carrier females that have bleeding symptoms may need factor replacement therapy in a variety of circumstances such as for bleeding episodes, following childbirth due to postpartum bleeding or for dental and surgical procedures depending on their factor IX activity level.Federally Recognized Hemophilia Treatment Centers: Evidence has shown that individuals with hemophilia significantly benefit from receiving care from a federally recognized hemophilia treatment center. These specialized centers provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow-up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team including physicians, nurses, physical therapists, social workers and genetic counselors experienced in treating individuals with hemophilia. To locate a hemophilia treatment center, visit the Centers for Disease Control and Prevention website at: https://www.cdc.gov/ncbddd/hemophilia/HTC.htmlCurrent Treatment Options
Recombinant Factor IX: Recombinant factor IX products are manufactured in a laboratory. These genetically engineered products do not contain animal or human protein and are not derived from human blood; they are theoretically considered to be free of the risk of transmitting viruses. Recombinant factor IX therapy is the recommended treatment for individuals with hemophilia B. In the U.S., the currently available recombinant factor IX products are BeneFIX, Rixubis, Ixinity, Alprolix, Idelvion and Rebinyn.Plasma-Derived Factor IX Concentrates: There are two main categories of plasma-derived factor IX concentrates available; highly purified plasma-derived products and intermediate purity plasma-derived products. Plasma-derived products come from human donations of blood or plasma. Highly purified products are essentially free of other clotting factor proteins and are virally inactivated using various methods. There are two high purity products available in the U.S., AlphaNine SD and Mononine. Intermediate purity products contain factor IX and variable amounts of other clotting factor proteins and are virally inactivated; however, they are rarely used in the United States and not recommended for treatment of FIX deficiency.Fresh Frozen Plasma: Fresh frozen plasma is derived from human blood and is used to treat patients with factor IX deficiency only if factor IX concentrate is not available. Fresh frozen plasma contains all the coagulation factors in the blood but is not virally inactivated. In addition, fresh frozen plasma is inefficient in raising factor IX activity to a hemostatic level.In 2020, the FDA approved recombinant coagulation factor VIIa (Sevenfact), another recombinant product that does not contain FIX protein. Sevenfact also has been approved for the treatment and control of bleeding episodes in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors.In 2022, etranacogene dezaparvovec (Hemgenix) was approved by the FDA as the first gene therapy to treat adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.The document in the link below from the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation provides recommendations for the treatment of hemophilia:
https://www.hemophilia.org/sites/default/files/document/files/259_treatment.pdfHistory of Hemophilia Treatment Options
Whole Blood: Until the 1960s, highly reliable treatment for hemophilia did not exist. Patients experiencing bleeding episodes were treated with whole blood transfusions. This was an ineffective treatment option as whole blood does not contain enough clotting factor to increase the level to a hemostatic range to effectively control bleeding. During this time, individuals often had repeated bleeding into the joints or central nervous system which led to permanent joint damage, seizures and a variety of permanent intellectual and movement disorders. The average life expectancy of a male with severe hemophilia during this time was 12 years of age.Cryoprecipitate: In the mid-1960s, Dr. Judith Pool discovered cryoprecipitate, a human plasma-derived material rich in clotting factor VIII, the clotting factor that is deficient in those with hemophilia A. Cryoprecipitate settles to the bottom of containers of frozen plasma when thawed at refrigerator temperature. Upon warming to room temperature, the cryoprecipitate returns to solution. In its frozen form, cryoprecipitate was stored in blood banks and administered to persons with hemophilia A in place of whole blood or plasma. The effect of the more concentrated factor VIII found in cryoprecipitate, compared to whole blood, was more rapid blood clot formation and decreased problems associated with bleeding episodes. Cryoprecipitate does not contain factor IX and is not recommended for use in the United States anymore for treatment of hemophilia A.Plasma-Derived Clotting Factor Concentrates: In the late 1960s and early 1970s clotting factors became available in more concentrated forms that remained stable as powders when stored at refrigerator temperature. This allowed hemophilia patients to store and administer the clotting factor at home without medical supervision. The first available factor IX product was an intermediate purity (PCC) and was approved for use in the U.S. in 1969.One of the main problems with early factor therapy was that the products available came from human plasma from many donors. This carried the risk of transmitting viruses such as hepatitis A, B and C and human immunodeficiency virus (HIV) from the donor to the patient. Until the mid-1980s many individuals receiving factor products became infected with one or more of these viruses due to inability to effectively screen donors or treat the concentrate to inactivate viruses.Recombinant Products: It was not until the late 1980s to the early 1990s, that the efficacy of recombinant factor products was reported, and products made commercially available. In 1992, the first genetically engineered factor VIII concentrate was approved by the U.S. Food and Drug Administration (FDA). It was not until 1997 that the first recombinant factor IX product became available. Use of genetically engineered factor concentrates may eliminate the risk of blood borne infections or transmittable diseases dependent on the method of manufacturing and exposure or use of human or animal proteins in the manufacturing process.Treatment Regimens for Hemophilia
Individuals with mild or moderate hemophilia B may be treated with replacement therapy as needed to treat a bleeding episode. This is called episodic infusion therapy and is used to stop a bleed that has already started. Individuals with severe hemophilia B may receive regular infusions to prevent bleeding episodes. This is called prophylactic therapy and is intended to prevent bleeds before they occur. Prophylactic therapy has been shown to reduce many complications associated with recurrent bleeding such as joint damage and intracranial hemorrhage in patients with severe hemophilia A and B. Parents and affected individuals can be trained to administer factor IX at home. Home therapy is especially important for individuals with severe disease but is also important for moderate and mild hemophilia as infusion of factor IX concentrate is most effective at limiting bleeding when administered within one hour of the onset of a bleeding episode. Some patients with moderate or mild hemophilia B receive prophylaxis for prevention of bleeding during activities either short or longer term (e.g., before a specific activity such as skiing or during basketball or baseball season etc.)Complications
Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, coughing, tight throat or wheezing during or immediately after infusion of replacement with FIX. Infusion reactions are most seen in individuals using fresh frozen plasma where the reaction is typically an allergic-like reaction to some part of the donor’s blood. These reactions can usually be treated with antihistamines and corticosteroids; however, a physician should always be notified of such an event. An important infusion reaction in hemophilia B can occur with the use of factor IX concentrates; these are uncommon but must be recognized promptly for patient safety and monitoring. If symptoms develop or are severe, the infusion should be stopped, and the patient should notify their hemophilia care provider immediately as well as be seen in the emergency room. Infusion reactions in patients with severe factor IX deficiency may be associated with the development of inhibitors.Inhibitors: It is estimated that < 5% of individuals with severe hemophilia B develop “inhibitors” against factor IX replacement therapy. Inhibitors are antibodies, created by the body’s immune system that is usually targeted to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor IX as “foreign” and create antibodies, or “inhibitors”, against it. These antibodies destroy the replacement factor. This complication negatively impacts the effectiveness of standard treatment. In such cases, alternate treatment is used to treat bleeding. In addition, therapy to eradicate these antibodies may be instituted. The therapy is called immune tolerance induction therapy. Immune tolerance induction therapy is less commonly attempted in patients with hemophilia B and inhibitors than in hemophilia A with inhibitors due to the risk of allergic reactions, kidney disease and decreased rate of success. Inhibitor development is considered the most severe problem in hemophilia care today as it affects patient treatment, risk of developing joint disease, cost of hemophilia care, morbidity and mortality. Genetic testing can help determine whether an individual with factor IX deficiency is at a higher risk of developing an inhibitor. NovoSeven RT (recombinant coagulation factor VIIa) is a recombinant product used for treatment and prevention of bleeding in individuals with factor IX deficiency with an inhibitor that does not contain any FIX protein.
| 561 | Hemophilia B |
nord_562_0 | Overview of Henoch-Schönlein Purpura | Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea, and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system).In one form of the disorder, termed Schönlein's purpura, the skin and joints are affected but the gastrointestinal tract is not. In another form, known as Henoch's purpura, affected individuals have purplish spots on the skin and acute abdominal problems, such as glomerulonephritis (a type of kidney disorder). People with Henoch's purpura are not affected by joint disease.The exact cause of HSP is not fully understood, although research demonstrates that it is related to an abnormal response by the immune system or, in some rare cases, an extreme allergic reaction to certain offending substances (e.g., foods or drugs). | Overview of Henoch-Schönlein Purpura. Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea, and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system).In one form of the disorder, termed Schönlein's purpura, the skin and joints are affected but the gastrointestinal tract is not. In another form, known as Henoch's purpura, affected individuals have purplish spots on the skin and acute abdominal problems, such as glomerulonephritis (a type of kidney disorder). People with Henoch's purpura are not affected by joint disease.The exact cause of HSP is not fully understood, although research demonstrates that it is related to an abnormal response by the immune system or, in some rare cases, an extreme allergic reaction to certain offending substances (e.g., foods or drugs). | 562 | Henoch-Schönlein Purpura |
nord_562_1 | Symptoms of Henoch-Schönlein Purpura | The symptoms of HSP usually begin suddenly. In addition to the characteristic red spotting of the skin (most often on the buttocks and backs of the legs), they may include headache, loss of appetite, and/or fever. The skin typically becomes red (diffuse erythema). Cramping abdominal pain may occur and is usually most severe during the night. Blood may be present in the stool and abnormal bleeding (hemorrhaging) from the gastrointestinal tract can cause bloody diarrhea. Joint pain (arthralgia) may develop in any joint of the body, especially the knees and ankles. Some people with HSP experience vomiting and diarrhea; others may have severe constipation and unusually dark stool (melena).Individuals with HSP typically develop small red or purple spots (petechiae) on the skin, especially on the legs. These purpura spots are caused by small hemorrhages under the skin and are not associated with abnormally low levels of platelets (nonthrombocytopenic) as is common with some other forms of purpura. Other skin lesions associated with HSP include large hives (urticarial wheals) or ulcers (necrotic), especially on the buttocks and legs. Swelling may occur in the face and neck due to abnormal fluid accumulation in the soft tissues of these areas (angioneurotic edema). In rare cases, swelling and edema in the throat can cause breathing difficulties that can lead to life-threatening respiratory problems.Between one-quarter and one-half of people with HSP have problems with kidney function, such as glomerulonephritis, in which the portion of the kidney that separates waste from the blood is damaged. Blood in the urine (hematuria) and inflammatory changes in the kidneys may also develop. Some people may develop severe kidney disease, including IgG nephropathy, chronic inflammation of the kidneys (nephritis), and/or nephrotic syndrome leading to kidney failure.In rare cases, a portion of the affected person’s bowel or intestine may fold in upon itself (intussusception). This can result in substantial pain and, if conservative measures do not resolve the problem, surgery may be required.When the central nervous system is involved, individuals with this disorder may experience severe headaches, perceptual changes, convulsions, visual difficulties (optic atrophy), and/or seizures. | Symptoms of Henoch-Schönlein Purpura. The symptoms of HSP usually begin suddenly. In addition to the characteristic red spotting of the skin (most often on the buttocks and backs of the legs), they may include headache, loss of appetite, and/or fever. The skin typically becomes red (diffuse erythema). Cramping abdominal pain may occur and is usually most severe during the night. Blood may be present in the stool and abnormal bleeding (hemorrhaging) from the gastrointestinal tract can cause bloody diarrhea. Joint pain (arthralgia) may develop in any joint of the body, especially the knees and ankles. Some people with HSP experience vomiting and diarrhea; others may have severe constipation and unusually dark stool (melena).Individuals with HSP typically develop small red or purple spots (petechiae) on the skin, especially on the legs. These purpura spots are caused by small hemorrhages under the skin and are not associated with abnormally low levels of platelets (nonthrombocytopenic) as is common with some other forms of purpura. Other skin lesions associated with HSP include large hives (urticarial wheals) or ulcers (necrotic), especially on the buttocks and legs. Swelling may occur in the face and neck due to abnormal fluid accumulation in the soft tissues of these areas (angioneurotic edema). In rare cases, swelling and edema in the throat can cause breathing difficulties that can lead to life-threatening respiratory problems.Between one-quarter and one-half of people with HSP have problems with kidney function, such as glomerulonephritis, in which the portion of the kidney that separates waste from the blood is damaged. Blood in the urine (hematuria) and inflammatory changes in the kidneys may also develop. Some people may develop severe kidney disease, including IgG nephropathy, chronic inflammation of the kidneys (nephritis), and/or nephrotic syndrome leading to kidney failure.In rare cases, a portion of the affected person’s bowel or intestine may fold in upon itself (intussusception). This can result in substantial pain and, if conservative measures do not resolve the problem, surgery may be required.When the central nervous system is involved, individuals with this disorder may experience severe headaches, perceptual changes, convulsions, visual difficulties (optic atrophy), and/or seizures. | 562 | Henoch-Schönlein Purpura |
nord_562_2 | Causes of Henoch-Schönlein Purpura | The exact cause of HSP is not known, although research suggests that this disease may be caused by immune system dysfunction (i.e., increased IgA immune complexes). Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.In some cases, it has been suggested that this disorder may be an extreme allergic reaction to certain foods, such as chocolate, milk, eggs, or beans. Various drugs (e.g., nifedipine, diltiazem, cefuroxime, diclofenac, etc.), bacteria (e.g., Streptococcus), and insect bites have also been indicated as possible causes in some cases. Rubella precedes the first symptoms of HSP in about 30 percent of cases. In about 66 percent of cases, an upper respiratory infection precedes the onset of symptoms by about 1 to 3 weeks. A definite link to viral infections has not been proven. | Causes of Henoch-Schönlein Purpura. The exact cause of HSP is not known, although research suggests that this disease may be caused by immune system dysfunction (i.e., increased IgA immune complexes). Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.In some cases, it has been suggested that this disorder may be an extreme allergic reaction to certain foods, such as chocolate, milk, eggs, or beans. Various drugs (e.g., nifedipine, diltiazem, cefuroxime, diclofenac, etc.), bacteria (e.g., Streptococcus), and insect bites have also been indicated as possible causes in some cases. Rubella precedes the first symptoms of HSP in about 30 percent of cases. In about 66 percent of cases, an upper respiratory infection precedes the onset of symptoms by about 1 to 3 weeks. A definite link to viral infections has not been proven. | 562 | Henoch-Schönlein Purpura |
nord_562_3 | Affects of Henoch-Schönlein Purpura | HSP is a rare disorder that affects more males than females. The disease may occur in all age groups, although it most commonly affects children.In children, the initial symptoms typically begin after the age of 2 years and usually last for about 4 weeks and the disease usually has a somewhat mild course. About 50 percent of affected children experience one or more recurrences, usually within months. The rate of recurrence seems to be higher among those children whose initial disease was more severe.Most affected children have been between 2 and 11 years of age. In the USA, about 14 cases occur per 100,000 school-aged children. It is generally a benign (non-threatening) disorder appears in most instances to cure itself (self-limiting). | Affects of Henoch-Schönlein Purpura. HSP is a rare disorder that affects more males than females. The disease may occur in all age groups, although it most commonly affects children.In children, the initial symptoms typically begin after the age of 2 years and usually last for about 4 weeks and the disease usually has a somewhat mild course. About 50 percent of affected children experience one or more recurrences, usually within months. The rate of recurrence seems to be higher among those children whose initial disease was more severe.Most affected children have been between 2 and 11 years of age. In the USA, about 14 cases occur per 100,000 school-aged children. It is generally a benign (non-threatening) disorder appears in most instances to cure itself (self-limiting). | 562 | Henoch-Schönlein Purpura |
nord_562_4 | Related disorders of Henoch-Schönlein Purpura | Common purpura is the most prevalent type of purpura, occurring most often in women over age 50. When there has been no injury, purpura lesions occur more often than subcutaneous bleeding. However, following surgery or even minor injuries, blood vessel fragility results in excessive bleeding. The bleeding may be reduced by short-term corticosteroid therapy and/or, in postmenopausal women, the administration of estrogen.Scurvy, a type of purpura, results from a deficiency of vitamin C in the diet. Symptoms may include experience generalized weakness, anemia, spongy gums, and a tendency to bleed (hemorrhage) under the skin (subcutaneous) and from the delicate mucous membranes that line the mouth and the gastrointestinal tract. Scurvy rarely occurs in modern civilizations due to improvement of diet and availability of foods that contain Vitamin C.Gardener-Diamond syndrome (Autoerytrocyte Sensitization) is a rare disorder that is sometimes called painful bruising syndrome. It is characterized by purpura spots, mainly in young women. Gardener-Diamond syndrome is thought to be an autoimmune disorder.Vasculitis (angiitis) is a vascular inflammatory disease that may occur alone or in association with other allergic or rheumatic diseases. Inflammation of the vascular walls constricts the blood vessels and may cause a lack of blood supply to certain areas of the body (ischemia), tissue loss (necrosis), and/or blood clots (thrombosis). Any size vessel or any part of the vascular system may be affected, and symptoms are relative to the system involved. Symptoms may include fever, headache, profound loss of appetite, weight loss, weakness, abdominal pain, diarrhea, and/or muscle and joint pain. Since there are many forms of Vasculitis, there are many causes. Some types may be caused by allergic reactions or hypersensitivity to certain medications such as sulfur drugs, penicillin, propylthiouracil, other drugs, toxins, and other inhaled environmental irritants. Other forms may occur because of a fungal infection, parasites or viral infections, while in some cases there may be no apparent cause. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Cutaneous necrotizing vasculitis is a relatively common inflammatory disease of the blood vessels, including the veins, arteries, and smaller blood vessels (capillaries). This disorder typically affects the skin and may occur alone or in conjunction with allergic, infectious, or rheumatic diseases. Symptoms may include skin nodules, small hemorrhages under the skin, and/or skin lesions that may be red and flat (macules). These may develop on many parts of the body, especially the back, hands, buttocks, and/or legs. In some cases, hives that are intensely itchy (urticaria) or ring-shaped ulcers may also be present. Fever, generalized discomfort (malaise), and/or muscle or joint pain may also occur. The exact cause of cutaneous necrotizing vasculitis is unknown. Some lesions may be caused by an allergic reaction or hypersensitivity to certain medications such as sulfa or penicillin, other drugs, toxins, and inhaled environmental irritants.Kawasaki disease is an inflammatory disease of childhood characterized by fever, skin rashs, swollen lymph nodes (lymphadenopathy), inflammation of the arteries (polyarteritis), and inflammation of blood vessels (vasculitis). Inflammatory changes cause destructive lesions in the blood vessels that can lead to complications involving the liver, gall bladder, and heart. The symptoms may include an abnormally high fever that begins suddenly and lasts for approximately two weeks. Other symptoms may include redness in the lining of the eyelids of both eyes (bilateral conjunctivitis), irritability, fatigue, redness (inflammation) of the mouth and tongue (stomatitis), cracking of the lips, swelling of the lymph nodes in the neck (cervical adenopathy), and/or skin rashs. The exact cause of Kawasaki disease is not fully understood. It may be related to two previously unknown strains of staphylococcus and streptococcus bacteria and/or a possible immunological abnormality. (For more information on this disorder, choose “Kawasaki” as your search term in the Rare Disease Database.)Immune thrombocytopenia is a rare platelet disorder characterized by unexplained low levels of platelets in the circulating blood. Symptoms may include nosebleeds (epistaxis), small red or purple spots on the skin that represent small hemorrhages under the skin (petechiae), and/or bleeding from the rectum and/or urinary tract. Anemia may follow and produce weakness and fatigue. Other people with this disorder may experience episodes of elevated fever and abnormal enlargement of the spleen. No specific cause for Immune thrombocyopenia has been identified. Current evidence supports an immunologic basis, since most patients have antiplatelet antibodies that are identifiable. (For more information on this disorder, choose “Immune Thrombocytopenia” as your search term in the Rare Disease Database.)Thrombotic thrombocytopenic purpura (TTP) is a rare blood disease characterized by abnormally low levels of circulating platelets in the blood, abnormal destruction of red blood cells, kidney dysfunction, and disturbances of the nervous system. Symptoms of this disorder, which begin suddenly, may include fever, headache, purpura spots on the skin and mucous membranes, joint pain (arthralgias), partial loss of feeling in the arms or legs (paresis), changes in mental status, and/or seizures. The exact cause of TTP is not known. It may be due to an infectious agent or to an autoimmune reaction. (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.) | Related disorders of Henoch-Schönlein Purpura. Common purpura is the most prevalent type of purpura, occurring most often in women over age 50. When there has been no injury, purpura lesions occur more often than subcutaneous bleeding. However, following surgery or even minor injuries, blood vessel fragility results in excessive bleeding. The bleeding may be reduced by short-term corticosteroid therapy and/or, in postmenopausal women, the administration of estrogen.Scurvy, a type of purpura, results from a deficiency of vitamin C in the diet. Symptoms may include experience generalized weakness, anemia, spongy gums, and a tendency to bleed (hemorrhage) under the skin (subcutaneous) and from the delicate mucous membranes that line the mouth and the gastrointestinal tract. Scurvy rarely occurs in modern civilizations due to improvement of diet and availability of foods that contain Vitamin C.Gardener-Diamond syndrome (Autoerytrocyte Sensitization) is a rare disorder that is sometimes called painful bruising syndrome. It is characterized by purpura spots, mainly in young women. Gardener-Diamond syndrome is thought to be an autoimmune disorder.Vasculitis (angiitis) is a vascular inflammatory disease that may occur alone or in association with other allergic or rheumatic diseases. Inflammation of the vascular walls constricts the blood vessels and may cause a lack of blood supply to certain areas of the body (ischemia), tissue loss (necrosis), and/or blood clots (thrombosis). Any size vessel or any part of the vascular system may be affected, and symptoms are relative to the system involved. Symptoms may include fever, headache, profound loss of appetite, weight loss, weakness, abdominal pain, diarrhea, and/or muscle and joint pain. Since there are many forms of Vasculitis, there are many causes. Some types may be caused by allergic reactions or hypersensitivity to certain medications such as sulfur drugs, penicillin, propylthiouracil, other drugs, toxins, and other inhaled environmental irritants. Other forms may occur because of a fungal infection, parasites or viral infections, while in some cases there may be no apparent cause. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Cutaneous necrotizing vasculitis is a relatively common inflammatory disease of the blood vessels, including the veins, arteries, and smaller blood vessels (capillaries). This disorder typically affects the skin and may occur alone or in conjunction with allergic, infectious, or rheumatic diseases. Symptoms may include skin nodules, small hemorrhages under the skin, and/or skin lesions that may be red and flat (macules). These may develop on many parts of the body, especially the back, hands, buttocks, and/or legs. In some cases, hives that are intensely itchy (urticaria) or ring-shaped ulcers may also be present. Fever, generalized discomfort (malaise), and/or muscle or joint pain may also occur. The exact cause of cutaneous necrotizing vasculitis is unknown. Some lesions may be caused by an allergic reaction or hypersensitivity to certain medications such as sulfa or penicillin, other drugs, toxins, and inhaled environmental irritants.Kawasaki disease is an inflammatory disease of childhood characterized by fever, skin rashs, swollen lymph nodes (lymphadenopathy), inflammation of the arteries (polyarteritis), and inflammation of blood vessels (vasculitis). Inflammatory changes cause destructive lesions in the blood vessels that can lead to complications involving the liver, gall bladder, and heart. The symptoms may include an abnormally high fever that begins suddenly and lasts for approximately two weeks. Other symptoms may include redness in the lining of the eyelids of both eyes (bilateral conjunctivitis), irritability, fatigue, redness (inflammation) of the mouth and tongue (stomatitis), cracking of the lips, swelling of the lymph nodes in the neck (cervical adenopathy), and/or skin rashs. The exact cause of Kawasaki disease is not fully understood. It may be related to two previously unknown strains of staphylococcus and streptococcus bacteria and/or a possible immunological abnormality. (For more information on this disorder, choose “Kawasaki” as your search term in the Rare Disease Database.)Immune thrombocytopenia is a rare platelet disorder characterized by unexplained low levels of platelets in the circulating blood. Symptoms may include nosebleeds (epistaxis), small red or purple spots on the skin that represent small hemorrhages under the skin (petechiae), and/or bleeding from the rectum and/or urinary tract. Anemia may follow and produce weakness and fatigue. Other people with this disorder may experience episodes of elevated fever and abnormal enlargement of the spleen. No specific cause for Immune thrombocyopenia has been identified. Current evidence supports an immunologic basis, since most patients have antiplatelet antibodies that are identifiable. (For more information on this disorder, choose “Immune Thrombocytopenia” as your search term in the Rare Disease Database.)Thrombotic thrombocytopenic purpura (TTP) is a rare blood disease characterized by abnormally low levels of circulating platelets in the blood, abnormal destruction of red blood cells, kidney dysfunction, and disturbances of the nervous system. Symptoms of this disorder, which begin suddenly, may include fever, headache, purpura spots on the skin and mucous membranes, joint pain (arthralgias), partial loss of feeling in the arms or legs (paresis), changes in mental status, and/or seizures. The exact cause of TTP is not known. It may be due to an infectious agent or to an autoimmune reaction. (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.) | 562 | Henoch-Schönlein Purpura |
nord_562_5 | Diagnosis of Henoch-Schönlein Purpura | The diagnosis of HSP may be difficult, especially in adults. The disease is frequently confused with other forms of vascular inflammation (see Related Disorders section of this report). Routine laboratory tests are usually not definitive for the disorder. The platelet count is typically normal although white blood cell and sedimentation rates may be elevated.The disorder is diagnosed by a combination of the presence of skin lesions and/or joint tenderness, combined with a confirmed test for blood in the urine (urinalysis), and a skin biopsy that shows inflammation of the arterial and venous capillaries. | Diagnosis of Henoch-Schönlein Purpura. The diagnosis of HSP may be difficult, especially in adults. The disease is frequently confused with other forms of vascular inflammation (see Related Disorders section of this report). Routine laboratory tests are usually not definitive for the disorder. The platelet count is typically normal although white blood cell and sedimentation rates may be elevated.The disorder is diagnosed by a combination of the presence of skin lesions and/or joint tenderness, combined with a confirmed test for blood in the urine (urinalysis), and a skin biopsy that shows inflammation of the arterial and venous capillaries. | 562 | Henoch-Schönlein Purpura |
nord_562_6 | Therapies of Henoch-Schönlein Purpura | TherapyIf individuals are thought to have HSP as the result of an allergic reaction, they must strictly avoid the offending substance (e.g., food or drug). When evidence of streptococcal infection is present, antibiotic therapy is prescribed. Mild childhood cases of the disease often improve spontaneously with advancing age. There is no specific treatment, however, in most patients, the disease has a limited course and the outlook for recovery is good.If non-steroid anti-inflammatories fail to relieve symptoms, some patients may be treated with glucocorticoids (steroid) drugs such as prednisone. These drugs may be useful to help control acute abdominal and joint pain. In some cases, swelling of soft tissues (angioedema) may be helped with steroid drugs. Dapsone may be prescribed when prednisone is contra-indicated or fails to relieve symptoms. The use of steroids to treat this disorder remains a matter of controversy in the medical literature. Some research indicates that steroids do not shorten the length of the illness or reduce the frequency or recurrence of symptoms. Other studies indicate that early steroid treatment may help to reduce the risk of kidney damage.Patients with HSP who have advanced kidney disease and renal failure will probably benefit from mechanical cleansing of the waste products from the blood (hemodialysis). Aggressive and supportive care may be necessary during acute kidney crisis. Some patients with severe kidney disease have undergone kidney transplantation. However, the disease can recur in the transplanted kidney. Other treatment is symptomatic and supportive. | Therapies of Henoch-Schönlein Purpura. TherapyIf individuals are thought to have HSP as the result of an allergic reaction, they must strictly avoid the offending substance (e.g., food or drug). When evidence of streptococcal infection is present, antibiotic therapy is prescribed. Mild childhood cases of the disease often improve spontaneously with advancing age. There is no specific treatment, however, in most patients, the disease has a limited course and the outlook for recovery is good.If non-steroid anti-inflammatories fail to relieve symptoms, some patients may be treated with glucocorticoids (steroid) drugs such as prednisone. These drugs may be useful to help control acute abdominal and joint pain. In some cases, swelling of soft tissues (angioedema) may be helped with steroid drugs. Dapsone may be prescribed when prednisone is contra-indicated or fails to relieve symptoms. The use of steroids to treat this disorder remains a matter of controversy in the medical literature. Some research indicates that steroids do not shorten the length of the illness or reduce the frequency or recurrence of symptoms. Other studies indicate that early steroid treatment may help to reduce the risk of kidney damage.Patients with HSP who have advanced kidney disease and renal failure will probably benefit from mechanical cleansing of the waste products from the blood (hemodialysis). Aggressive and supportive care may be necessary during acute kidney crisis. Some patients with severe kidney disease have undergone kidney transplantation. However, the disease can recur in the transplanted kidney. Other treatment is symptomatic and supportive. | 562 | Henoch-Schönlein Purpura |
nord_563_0 | Overview of Hepatic Encephalopathy | Hepatic encephalopathy is a brain disorder that develops in some individuals with liver disease. Hepatic encephalopathy is a complex disorder that encompasses a spectrum or continuum of disease that ranges from a subtle condition with no outward signs or symptoms to a severe form that can cause serious, life-threatening complications. Symptoms are related to progressive dysfunction of the brain and may include personality changes, intellectual impairment, impaired memory and loss of consciousness (coma). Hepatic encephalopathy can occur in individuals with acute or chronic liver (hepatic) disease or in individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present). A portosystemic shunt is an abnormal passageway that allows blood from the gastrointestinal tract to bypass the liver. They can be present at birth (congenital) or acquired during life. Hepatic encephalopathy is caused when toxins that are normally cleared from the body by the liver accumulate in the blood, eventually traveling to the brain. Many of the symptoms of hepatic encephalopathy are reversible when promptly detected and treated. | Overview of Hepatic Encephalopathy. Hepatic encephalopathy is a brain disorder that develops in some individuals with liver disease. Hepatic encephalopathy is a complex disorder that encompasses a spectrum or continuum of disease that ranges from a subtle condition with no outward signs or symptoms to a severe form that can cause serious, life-threatening complications. Symptoms are related to progressive dysfunction of the brain and may include personality changes, intellectual impairment, impaired memory and loss of consciousness (coma). Hepatic encephalopathy can occur in individuals with acute or chronic liver (hepatic) disease or in individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present). A portosystemic shunt is an abnormal passageway that allows blood from the gastrointestinal tract to bypass the liver. They can be present at birth (congenital) or acquired during life. Hepatic encephalopathy is caused when toxins that are normally cleared from the body by the liver accumulate in the blood, eventually traveling to the brain. Many of the symptoms of hepatic encephalopathy are reversible when promptly detected and treated. | 563 | Hepatic Encephalopathy |
nord_563_1 | Symptoms of Hepatic Encephalopathy | Hepatic encephalopathy encompasses a spectrum or continuum of disease and, consequently, the symptoms and severity of the disorder can vary widely from one person to another. The severity of hepatic encephalopathy can range from mild, barely discernable symptoms to serious, life-threatening complications. Hepatic encephalopathy may develop slowly over time in individuals with chronic liver disease or may occur episodically, worsening and then improving only to recur. An episode of hepatic encephalopathy is often triggered by certain conditions such as infection, gastrointestinal bleeding, constipation, certain drugs, surgery or an alcohol binge. Episodes of hepatic encephalopathy can develop rapidly and without warning, often necessitating hospitalization. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Many of the symptoms of hepatic encephalopathy are reversible when promptly identified and treated. Hepatic encephalopathy is sometimes broken down into three subtypes: Type A, which is associated with acute liver failure; Type B, which is associated a portosystemic shunt (a shunt that bypasses the liver) with no existing liver disease present; and Type C, which is associated with scarring and poor function of the liver (cirrhosis), which often occurs with chronic liver disease. While the symptoms are similar among these different subtypes of hepatic encephalopathy, individuals with acute liver failure are more likely to have swelling (edema) in the brain and increased pressure within the skull (intracranial hypertension), which can potentially cause life-threatening complications. Researchers now believe that as many as 70 percent of individuals with cirrhosis development symptoms of hepatic encephalopathy. Many individuals only develop mild symptoms, so-called minimal hepatic encephalopathy (MHE). MHE may not be associated with any obvious or outwardly noticeable signs or symptoms. However, there may be subtle or minimal changes in memory, concentration, and intellectual function. Coordination may also be affected and some affected individuals may take longer to respond to situations (increased reaction time). These symptoms, although termed “subtle”, can still have significant consequences on daily life such as impairing a person's ability to drive a car. Hepatic encephalopathy can be associated with more severe symptoms including reduced alertness, shortened attention span, disruptions in sleep patterns, mild confusion, slowing of the ability to perform mental tasks and mood or personality changes. More noticeable changes in memory, concentration or intellectual function than occur in MHE may also be seen. When affected individuals have obvious, outward signs and symptoms, the disorder may be referred to as overt hepatic encephalopathy. Eventually, affected individuals may develop lethargy, slurred speech, confusion, significant delays in performing mental tasks, and regression of skills requiring the coordination of mental and physical activities (psychomotor retardation). Affected individuals may also develop obvious personality changes including inappropriate behavior or lack of restraint. Some individuals may slowly flap their hands up and down when attempting to hold their arms out, a condition known as asterixis. In the most severe form of hepatic encephalopathy, affected individuals may develop marked confusion or disorientation, amnesia, greatly dulled or reduced consciousness (stupor) or loss of consciousness (coma). Additional severe and potentially life-threatening complications of cirrhosis include permanent nervous system damage, heart failure, kidney abnormalities including kidney failure, breathing (respiratory) abnormalities and blood poisoning (sepsis). | Symptoms of Hepatic Encephalopathy. Hepatic encephalopathy encompasses a spectrum or continuum of disease and, consequently, the symptoms and severity of the disorder can vary widely from one person to another. The severity of hepatic encephalopathy can range from mild, barely discernable symptoms to serious, life-threatening complications. Hepatic encephalopathy may develop slowly over time in individuals with chronic liver disease or may occur episodically, worsening and then improving only to recur. An episode of hepatic encephalopathy is often triggered by certain conditions such as infection, gastrointestinal bleeding, constipation, certain drugs, surgery or an alcohol binge. Episodes of hepatic encephalopathy can develop rapidly and without warning, often necessitating hospitalization. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Many of the symptoms of hepatic encephalopathy are reversible when promptly identified and treated. Hepatic encephalopathy is sometimes broken down into three subtypes: Type A, which is associated with acute liver failure; Type B, which is associated a portosystemic shunt (a shunt that bypasses the liver) with no existing liver disease present; and Type C, which is associated with scarring and poor function of the liver (cirrhosis), which often occurs with chronic liver disease. While the symptoms are similar among these different subtypes of hepatic encephalopathy, individuals with acute liver failure are more likely to have swelling (edema) in the brain and increased pressure within the skull (intracranial hypertension), which can potentially cause life-threatening complications. Researchers now believe that as many as 70 percent of individuals with cirrhosis development symptoms of hepatic encephalopathy. Many individuals only develop mild symptoms, so-called minimal hepatic encephalopathy (MHE). MHE may not be associated with any obvious or outwardly noticeable signs or symptoms. However, there may be subtle or minimal changes in memory, concentration, and intellectual function. Coordination may also be affected and some affected individuals may take longer to respond to situations (increased reaction time). These symptoms, although termed “subtle”, can still have significant consequences on daily life such as impairing a person's ability to drive a car. Hepatic encephalopathy can be associated with more severe symptoms including reduced alertness, shortened attention span, disruptions in sleep patterns, mild confusion, slowing of the ability to perform mental tasks and mood or personality changes. More noticeable changes in memory, concentration or intellectual function than occur in MHE may also be seen. When affected individuals have obvious, outward signs and symptoms, the disorder may be referred to as overt hepatic encephalopathy. Eventually, affected individuals may develop lethargy, slurred speech, confusion, significant delays in performing mental tasks, and regression of skills requiring the coordination of mental and physical activities (psychomotor retardation). Affected individuals may also develop obvious personality changes including inappropriate behavior or lack of restraint. Some individuals may slowly flap their hands up and down when attempting to hold their arms out, a condition known as asterixis. In the most severe form of hepatic encephalopathy, affected individuals may develop marked confusion or disorientation, amnesia, greatly dulled or reduced consciousness (stupor) or loss of consciousness (coma). Additional severe and potentially life-threatening complications of cirrhosis include permanent nervous system damage, heart failure, kidney abnormalities including kidney failure, breathing (respiratory) abnormalities and blood poisoning (sepsis). | 563 | Hepatic Encephalopathy |
nord_563_2 | Causes of Hepatic Encephalopathy | Hepatic encephalopathy occurs in individuals with liver disease when toxins that are normally cleared in the liver accumulate in the blood eventually traveling to and damaging the brain. The exact underlying mechanisms by which hepatic encephalopathy develops in individuals with liver disease are not fully understood. Researchers believe that high blood pressure of the main vein of the liver (portal hypertension) results in blood bypassing the liver. Normally, blood travels through the portal vein and enters the liver where toxins are removed or filtered from the blood (detoxification). By bypassing the liver, unfiltered blood ends up circulating throughout the body eventually reaching the brain where certain toxics damage brain tissue. Although the exact underlying process by which hepatic encephalopathy develops is unknown, high levels of substances produced by the digestive breakdown of proteins, such as ammonia, are believed to play a major role. Ammonia is elevated in individuals with acute and chronic liver disease and is known to affect the brain in other disorders such as Reye syndrome and certain metabolic disorders. Ammonia is normally converted to urea in the liver and cleared out of the body through the urine. Ammonia is highly toxic to the brain. Although ammonia is generally accepted to a play a role in hepatic encephalopathy, some individuals with elevated ammonia levels do not develop symptoms, suggesting that additional factors play a role in the development of the disorder. Additional factors that have been explored as potentially playing a role in the development of hepatic encephalopathy include manganese toxicity and impaired function of certain central nervous system cells called astrocytes, which play a role in regulating the blood-brain barrier and also help to detoxify certain chemicals including ammonia; dysfunction of the blood-brain barrier, which prevents dangerous substances from reaching the brain; amino acid imbalances; short chain fatty acids; infection; inflammation; and increased activity of GABA, an inhibitory neurotransmitter in the central nervous system. More research is necessary to determine the exact, underlying factors that ultimately cause the development of hepatic encephalopathy and its associated symptoms. As briefly discussed above, in individuals with chronic liver disease, episodes of hepatic encephalopathy may be triggered by certain events or occurrences such as low levels of oxygen in the body, dehydration, constipation, gastrointestinal bleeding, an alcohol binge, infection, kidney abnormalities and the use of certain drugs especially those that act on the central nervous system such as tranquilizers and other sleep medications, antidepressants, and antipsychotics. In some cases, surgery can precipitate an episode of hepatic encephalopathy. Gastrointestinal bleeding is the most common precipitating event associated with hepatic encephalopathy, most likely because individuals with cirrhosis are at a greater risk of gastrointestinal bleeding than the general population. | Causes of Hepatic Encephalopathy. Hepatic encephalopathy occurs in individuals with liver disease when toxins that are normally cleared in the liver accumulate in the blood eventually traveling to and damaging the brain. The exact underlying mechanisms by which hepatic encephalopathy develops in individuals with liver disease are not fully understood. Researchers believe that high blood pressure of the main vein of the liver (portal hypertension) results in blood bypassing the liver. Normally, blood travels through the portal vein and enters the liver where toxins are removed or filtered from the blood (detoxification). By bypassing the liver, unfiltered blood ends up circulating throughout the body eventually reaching the brain where certain toxics damage brain tissue. Although the exact underlying process by which hepatic encephalopathy develops is unknown, high levels of substances produced by the digestive breakdown of proteins, such as ammonia, are believed to play a major role. Ammonia is elevated in individuals with acute and chronic liver disease and is known to affect the brain in other disorders such as Reye syndrome and certain metabolic disorders. Ammonia is normally converted to urea in the liver and cleared out of the body through the urine. Ammonia is highly toxic to the brain. Although ammonia is generally accepted to a play a role in hepatic encephalopathy, some individuals with elevated ammonia levels do not develop symptoms, suggesting that additional factors play a role in the development of the disorder. Additional factors that have been explored as potentially playing a role in the development of hepatic encephalopathy include manganese toxicity and impaired function of certain central nervous system cells called astrocytes, which play a role in regulating the blood-brain barrier and also help to detoxify certain chemicals including ammonia; dysfunction of the blood-brain barrier, which prevents dangerous substances from reaching the brain; amino acid imbalances; short chain fatty acids; infection; inflammation; and increased activity of GABA, an inhibitory neurotransmitter in the central nervous system. More research is necessary to determine the exact, underlying factors that ultimately cause the development of hepatic encephalopathy and its associated symptoms. As briefly discussed above, in individuals with chronic liver disease, episodes of hepatic encephalopathy may be triggered by certain events or occurrences such as low levels of oxygen in the body, dehydration, constipation, gastrointestinal bleeding, an alcohol binge, infection, kidney abnormalities and the use of certain drugs especially those that act on the central nervous system such as tranquilizers and other sleep medications, antidepressants, and antipsychotics. In some cases, surgery can precipitate an episode of hepatic encephalopathy. Gastrointestinal bleeding is the most common precipitating event associated with hepatic encephalopathy, most likely because individuals with cirrhosis are at a greater risk of gastrointestinal bleeding than the general population. | 563 | Hepatic Encephalopathy |
nord_563_3 | Affects of Hepatic Encephalopathy | The exact incidence of hepatic encephalopathy in the general population is unknown. It affects males and females in equal numbers and can occur in individuals of any age who have acute or chronic liver disease. Approximately 24-53 percent of individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present) develop hepatic encephalopathy. Hepatic encephalopathy is most often associated with cirrhosis, which is estimated to affect 5.5 million people in the United States. Approximately 70 percent of individuals with cirrhosis may develop symptoms of hepatic encephalopathy. Because some mild cases of hepatic encephalopathy may go undiagnosed, it is difficult to determine the true frequency in the general population. | Affects of Hepatic Encephalopathy. The exact incidence of hepatic encephalopathy in the general population is unknown. It affects males and females in equal numbers and can occur in individuals of any age who have acute or chronic liver disease. Approximately 24-53 percent of individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present) develop hepatic encephalopathy. Hepatic encephalopathy is most often associated with cirrhosis, which is estimated to affect 5.5 million people in the United States. Approximately 70 percent of individuals with cirrhosis may develop symptoms of hepatic encephalopathy. Because some mild cases of hepatic encephalopathy may go undiagnosed, it is difficult to determine the true frequency in the general population. | 563 | Hepatic Encephalopathy |
nord_563_4 | Related disorders of Hepatic Encephalopathy | Symptoms of the following disorders can be similar to those of hepatic encephalopathy. Comparisons may be useful for a differential diagnosis.There are a wide variety of disorders and conditions that can cause altered mental status similar to that seen in individuals with hepatic encephalopathy. Such disorders and conditions can include intracranial tumors or lesions, infections of the brain including meningitis or encephalitis, psychiatric illnesses, metabolic disorders, toxic encephalopathy such as from excessive alcohol intake, Wernicke-Korsakoff syndrome, Reye syndrome, and other disorders such as the urea cycle disorders that cause high levels of ammonia in the blood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Hepatic Encephalopathy. Symptoms of the following disorders can be similar to those of hepatic encephalopathy. Comparisons may be useful for a differential diagnosis.There are a wide variety of disorders and conditions that can cause altered mental status similar to that seen in individuals with hepatic encephalopathy. Such disorders and conditions can include intracranial tumors or lesions, infections of the brain including meningitis or encephalitis, psychiatric illnesses, metabolic disorders, toxic encephalopathy such as from excessive alcohol intake, Wernicke-Korsakoff syndrome, Reye syndrome, and other disorders such as the urea cycle disorders that cause high levels of ammonia in the blood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 563 | Hepatic Encephalopathy |
nord_563_5 | Diagnosis of Hepatic Encephalopathy | A diagnosis of hepatic encephalopathy may be suspected in some individuals with liver disease based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests that are used to rule out other conditions. Such tests may include a complete blood count, liver function tests, tests that evaluate serum ammonia levels, and an electroencephalogram, which is a test that measures the electrical activity of the brain, may be useful in detecting encephalopathy. Specialized imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans may be used to rule out other conditions affecting the brain such as tumors. | Diagnosis of Hepatic Encephalopathy. A diagnosis of hepatic encephalopathy may be suspected in some individuals with liver disease based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests that are used to rule out other conditions. Such tests may include a complete blood count, liver function tests, tests that evaluate serum ammonia levels, and an electroencephalogram, which is a test that measures the electrical activity of the brain, may be useful in detecting encephalopathy. Specialized imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans may be used to rule out other conditions affecting the brain such as tumors. | 563 | Hepatic Encephalopathy |
nord_563_6 | Therapies of Hepatic Encephalopathy | TreatmentThe specific therapies used to treat hepatic encephalopathy may vary depending upon numerous factors including whether there is a triggering event, the presence or absence of certain symptoms, the severity of the disorder and the severity of the underlying liver disease, an individual's age and general health and other factors. An episode of hepatic encephalopathy can be a medical emergency that requires an emergency room visit or hospitalization.Initial therapies may be aimed at identifying and removing a triggering event such as infection, gastrointestinal bleeding, certain drugs or kidney dysfunction. Such therapies may include medications to treat infections, medications or procedures to alleviate or control bleeding, stopping the use of medications that can trigger an episode and any appropriate therapy for kidney issues.Additional treatment for individuals with hepatic encephalopathy is usually aimed at lowering the levels of ammonia and other toxins in the blood. Since such toxins originally arise in the gut, therapies are directed toward the gastrointestinal system. Such therapies may include, using synthetic sugars such as lactulose, which speeds up the passage of food through the gastrointestinal tract and inhibits the absorption of toxins by the intestines and antibiotics, which act on bacteria in the colon. Lactulose and antibiotics may be used in conjunction.In 2010, the Food and Drug Administration (FDA) approved the use of rifaximin (Xifaxan®) to reduce the risk of overt hepatic encephalopathy in individuals 18 and older. Xifaxan reduces the risk of overt hepatic encephalopathy and reduces the number of hospitalizations due to hepatic encephalopathy. Xifaxan is thought to act on microorganisms found in the digestive tracts of humans (gut flora). For more information on Xifaxan, contact:Salix Pharmaceuticals Corporate Headquarters1700 Perimeter Park DriveMorrisville, NC 27560-8404Phone: 919-862-1000Fax: 919-862-1095For product information, adverse event reports, and product complaint reports, please contact:Salix Product Information Call CenterPhone: 800-508-0024Fax: 510-595-8183Email: [email protected]The symptoms of hepatic encephalopathy are often reversible when promptly identified and treated. However, individuals with chronic liver disease are at risk for a recurrence of hepatic encephalopathy and should be periodically monitored by a physician. | Therapies of Hepatic Encephalopathy. TreatmentThe specific therapies used to treat hepatic encephalopathy may vary depending upon numerous factors including whether there is a triggering event, the presence or absence of certain symptoms, the severity of the disorder and the severity of the underlying liver disease, an individual's age and general health and other factors. An episode of hepatic encephalopathy can be a medical emergency that requires an emergency room visit or hospitalization.Initial therapies may be aimed at identifying and removing a triggering event such as infection, gastrointestinal bleeding, certain drugs or kidney dysfunction. Such therapies may include medications to treat infections, medications or procedures to alleviate or control bleeding, stopping the use of medications that can trigger an episode and any appropriate therapy for kidney issues.Additional treatment for individuals with hepatic encephalopathy is usually aimed at lowering the levels of ammonia and other toxins in the blood. Since such toxins originally arise in the gut, therapies are directed toward the gastrointestinal system. Such therapies may include, using synthetic sugars such as lactulose, which speeds up the passage of food through the gastrointestinal tract and inhibits the absorption of toxins by the intestines and antibiotics, which act on bacteria in the colon. Lactulose and antibiotics may be used in conjunction.In 2010, the Food and Drug Administration (FDA) approved the use of rifaximin (Xifaxan®) to reduce the risk of overt hepatic encephalopathy in individuals 18 and older. Xifaxan reduces the risk of overt hepatic encephalopathy and reduces the number of hospitalizations due to hepatic encephalopathy. Xifaxan is thought to act on microorganisms found in the digestive tracts of humans (gut flora). For more information on Xifaxan, contact:Salix Pharmaceuticals Corporate Headquarters1700 Perimeter Park DriveMorrisville, NC 27560-8404Phone: 919-862-1000Fax: 919-862-1095For product information, adverse event reports, and product complaint reports, please contact:Salix Product Information Call CenterPhone: 800-508-0024Fax: 510-595-8183Email: [email protected]The symptoms of hepatic encephalopathy are often reversible when promptly identified and treated. However, individuals with chronic liver disease are at risk for a recurrence of hepatic encephalopathy and should be periodically monitored by a physician. | 563 | Hepatic Encephalopathy |
nord_564_0 | Overview of Hepatitis D | SummaryHepatitis D is a liver disease caused by the hepatitis delta virus (HDV). HDV is known as a “satellite virus” or an “incomplete virus” because it can only infect people who are also infected with the hepatitis B virus (HBV). Patients with an HDV infection may have an acute co-infection (an infection discovered at the same time as HBV) or a new or “superinfection” (when a patient already infected with HBV later acquires HDV). Both forms of infection can cause a chronic, long-term illness. Age of onset can occur at birth through mother to child transmission (rare), and more importantly, can occur through infection as an adult. Chronic HDV is one of the most severe forms of viral hepatitis (liver inflammation due to a viral infection) and causes more severe liver disease than having chronic HBV infection alone. Chronic HDV is also associated with a more accelerated progression of liver disease, a higher risk of liver cancer and early development of liver complications in patients who have already developed cirrhosis (end stage liver disease), liver failure, liver transplant, and death. An accurate prevalence of HDV is unknown given there is suboptimal awareness and testing for this disease both domestically and globally. However, recent studies estimate that the prevalence of HDV ranges from 12 to 74 million individuals affected worldwide, and it likely affects 5-10% of patients with chronic HBV infection. This emphasizes the need for further research and data in order to formulate an accurate estimate of HDV prevalence and to understand which individuals are at greatest risk of HDV infection. Despite the severity of this disease and how quickly it can lead to liver damage and deterioration, there are no current recommendations from the Centers for Disease Control (CDC) or World Health Organization (WHO) to make this a reportable disease, and there are no FDA-approved therapies available for HDV treatment. One medication called bulevirtide (Hepcludex, Myr/Gilead Sciences) is approved in Europe. In addition, there are many promising therapies for HDV on the horizon.IntroductionOne of the first physicians to describe HDV was Dr. Mario Rizzetto in the 1970s. Dr. Rizzetto detected a new antigen-antibody complex in the liver cell nuclei of patients with chronic HBV infection. Antigens are molecules capable of stimulating an immune response, and antibodies (immunoglobins) are Y-shaped proteins produced by B cells of the immune system in response to exposure to antigens. He used direct immunofluorescence (a technique for determining the location of an antigen/antibody in tissues by reaction with an antibody/antigen labeled with a fluorescent dye) to find this new antigen-antibody and he named this antigen delta. He observed that there was a higher prevalence of the delta antigen in chronic HBV patients with more severe liver damage. This delta antigen was ultimately confirmed by others and became what we know today as HDV. While the presence of HDV has been known for many years, the prevalence of HDV remains unclear, primarily due to suboptimal awareness and testing for this disease. There are many factors that contribute to suboptimal testing, including the need for wider availability of improved HDV diagnostic tests, the need for greater awareness of risks of this disease among patients and providers, more clear guidelines and recommendations about which populations to target for HDV testing, and lack of effective therapies to manage HDV. Given the aforementioned risks of HDV in contributing to more aggressive disease progression, including the higher risk of cirrhosis and liver cancer, early detection is critical. Emerging HDV therapeutics on the horizon should dramatically expand the treatment landscape in the future. | Overview of Hepatitis D. SummaryHepatitis D is a liver disease caused by the hepatitis delta virus (HDV). HDV is known as a “satellite virus” or an “incomplete virus” because it can only infect people who are also infected with the hepatitis B virus (HBV). Patients with an HDV infection may have an acute co-infection (an infection discovered at the same time as HBV) or a new or “superinfection” (when a patient already infected with HBV later acquires HDV). Both forms of infection can cause a chronic, long-term illness. Age of onset can occur at birth through mother to child transmission (rare), and more importantly, can occur through infection as an adult. Chronic HDV is one of the most severe forms of viral hepatitis (liver inflammation due to a viral infection) and causes more severe liver disease than having chronic HBV infection alone. Chronic HDV is also associated with a more accelerated progression of liver disease, a higher risk of liver cancer and early development of liver complications in patients who have already developed cirrhosis (end stage liver disease), liver failure, liver transplant, and death. An accurate prevalence of HDV is unknown given there is suboptimal awareness and testing for this disease both domestically and globally. However, recent studies estimate that the prevalence of HDV ranges from 12 to 74 million individuals affected worldwide, and it likely affects 5-10% of patients with chronic HBV infection. This emphasizes the need for further research and data in order to formulate an accurate estimate of HDV prevalence and to understand which individuals are at greatest risk of HDV infection. Despite the severity of this disease and how quickly it can lead to liver damage and deterioration, there are no current recommendations from the Centers for Disease Control (CDC) or World Health Organization (WHO) to make this a reportable disease, and there are no FDA-approved therapies available for HDV treatment. One medication called bulevirtide (Hepcludex, Myr/Gilead Sciences) is approved in Europe. In addition, there are many promising therapies for HDV on the horizon.IntroductionOne of the first physicians to describe HDV was Dr. Mario Rizzetto in the 1970s. Dr. Rizzetto detected a new antigen-antibody complex in the liver cell nuclei of patients with chronic HBV infection. Antigens are molecules capable of stimulating an immune response, and antibodies (immunoglobins) are Y-shaped proteins produced by B cells of the immune system in response to exposure to antigens. He used direct immunofluorescence (a technique for determining the location of an antigen/antibody in tissues by reaction with an antibody/antigen labeled with a fluorescent dye) to find this new antigen-antibody and he named this antigen delta. He observed that there was a higher prevalence of the delta antigen in chronic HBV patients with more severe liver damage. This delta antigen was ultimately confirmed by others and became what we know today as HDV. While the presence of HDV has been known for many years, the prevalence of HDV remains unclear, primarily due to suboptimal awareness and testing for this disease. There are many factors that contribute to suboptimal testing, including the need for wider availability of improved HDV diagnostic tests, the need for greater awareness of risks of this disease among patients and providers, more clear guidelines and recommendations about which populations to target for HDV testing, and lack of effective therapies to manage HDV. Given the aforementioned risks of HDV in contributing to more aggressive disease progression, including the higher risk of cirrhosis and liver cancer, early detection is critical. Emerging HDV therapeutics on the horizon should dramatically expand the treatment landscape in the future. | 564 | Hepatitis D |
nord_564_1 | Symptoms of Hepatitis D | As previously noted, HDV can present as a co-infection or as a superinfection. Co-infection occurs when a person is simultaneously infected with both HBV and HDV, which is generally less common than superinfection. Superinfection occurs when a person who is already infected with HBV acquires HDV infection. Age of onset can vary from acquiring infection at birth via mother to child transmission to acquiring as an adult through different routes of infection detailed below.HDV infection can occur and resolve suddenly (acute disease) or develop into a long-term illness (chronic disease). Signs and symptoms of acute HDV infection typically appear 3-7 weeks after initial infection and are indistinguishable from symptoms seen in other types of acute viral hepatitis infection. Some of these symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark-colored urine, clay-colored bowel movements, joint pain and jaundice. These symptoms can progress to liver failure and death in some instances or can resolve and develop into a chronic infection. Chronic HDV infection, on the other hand, accelerates disease progression in patients with chronic HBV, which leads to earlier development of cirrhosis, liver cancer and liver decompensation. A person with chronic HBV who acquires HDV infection has a very low chance of clearing the virus spontaneously, and over 80% of patients infected with HDV will develop chronic HDV infection as superinfection. | Symptoms of Hepatitis D. As previously noted, HDV can present as a co-infection or as a superinfection. Co-infection occurs when a person is simultaneously infected with both HBV and HDV, which is generally less common than superinfection. Superinfection occurs when a person who is already infected with HBV acquires HDV infection. Age of onset can vary from acquiring infection at birth via mother to child transmission to acquiring as an adult through different routes of infection detailed below.HDV infection can occur and resolve suddenly (acute disease) or develop into a long-term illness (chronic disease). Signs and symptoms of acute HDV infection typically appear 3-7 weeks after initial infection and are indistinguishable from symptoms seen in other types of acute viral hepatitis infection. Some of these symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark-colored urine, clay-colored bowel movements, joint pain and jaundice. These symptoms can progress to liver failure and death in some instances or can resolve and develop into a chronic infection. Chronic HDV infection, on the other hand, accelerates disease progression in patients with chronic HBV, which leads to earlier development of cirrhosis, liver cancer and liver decompensation. A person with chronic HBV who acquires HDV infection has a very low chance of clearing the virus spontaneously, and over 80% of patients infected with HDV will develop chronic HDV infection as superinfection. | 564 | Hepatitis D |
nord_564_2 | Causes of Hepatitis D | Hepatitis D is caused by the HDV, which is a unique virus with defective replication processes. Because it cannot replicate like other viruses, it requires co-infection with chronic HBV in order to survive and replicate. HDV is a single-stranded RNA virus and only codes for 2 proteins (HDV large and small antigen). As previously noted, it can present as simultaneous HBV-HDV co-infection or more commonly as a HDV superinfection in patients with underlying chronic HBV. HDV has 8 distinct genetic profiles (genotypes), each with 2-4 subtypes. Genotype 1 is the most prevalent worldwide and is seen predominantly in Europe and North America. Genotype 2 is seen more commonly in Asia and the Middle East. Genotype 3 is mostly seen in the Amazon Basin. Genotype 4 is seen in Taiwan, China, and Japan. Genotypes 5-8 are mostly seen in Africa, although some studies have reported presence of genotypes 5-7 in European regions with newer immigration patterns. | Causes of Hepatitis D. Hepatitis D is caused by the HDV, which is a unique virus with defective replication processes. Because it cannot replicate like other viruses, it requires co-infection with chronic HBV in order to survive and replicate. HDV is a single-stranded RNA virus and only codes for 2 proteins (HDV large and small antigen). As previously noted, it can present as simultaneous HBV-HDV co-infection or more commonly as a HDV superinfection in patients with underlying chronic HBV. HDV has 8 distinct genetic profiles (genotypes), each with 2-4 subtypes. Genotype 1 is the most prevalent worldwide and is seen predominantly in Europe and North America. Genotype 2 is seen more commonly in Asia and the Middle East. Genotype 3 is mostly seen in the Amazon Basin. Genotype 4 is seen in Taiwan, China, and Japan. Genotypes 5-8 are mostly seen in Africa, although some studies have reported presence of genotypes 5-7 in European regions with newer immigration patterns. | 564 | Hepatitis D |
nord_564_3 | Affects of Hepatitis D | Existing studies vary in their estimates of global prevalence of HDV, estimating from 12 to 74 million, but many believe that the true prevalence is between 15 and 20 million. The variation in prevalence estimates is due to lack of high-quality data, which is further compounded by suboptimal awareness of testing, contributing to significant under-diagnosis of this disease. Existing studies estimate that prevalence of HDV in the US ranges from 100,000 to 150,000 individuals affected. While HDV is found globally, certain regions and countries have observed higher prevalence. For example, some of the highest reported prevalence has been observed in Mongolia, Somalia, the Punjab region of India and the Amazon Basin. HDV is mainly transmitted through activities that involve percutaneous contact (for example, a puncture through the skin) and to a lesser extent through mucosal contact (through the digestive, genital, and urinary tracts) with infectious blood or bodily fluids. Examples of potential routes of infection include: sexual contact with an infected individual; injection drug use that involves sharing needles, syringes or drug preparation equipment; contact with blood or open sores with blood from an infected person; needle sticks or exposures to sharp, contaminated instruments; sharing items such as razors or toothbrushes with an infected person; and mother to child via birth from an infected mother. | Affects of Hepatitis D. Existing studies vary in their estimates of global prevalence of HDV, estimating from 12 to 74 million, but many believe that the true prevalence is between 15 and 20 million. The variation in prevalence estimates is due to lack of high-quality data, which is further compounded by suboptimal awareness of testing, contributing to significant under-diagnosis of this disease. Existing studies estimate that prevalence of HDV in the US ranges from 100,000 to 150,000 individuals affected. While HDV is found globally, certain regions and countries have observed higher prevalence. For example, some of the highest reported prevalence has been observed in Mongolia, Somalia, the Punjab region of India and the Amazon Basin. HDV is mainly transmitted through activities that involve percutaneous contact (for example, a puncture through the skin) and to a lesser extent through mucosal contact (through the digestive, genital, and urinary tracts) with infectious blood or bodily fluids. Examples of potential routes of infection include: sexual contact with an infected individual; injection drug use that involves sharing needles, syringes or drug preparation equipment; contact with blood or open sores with blood from an infected person; needle sticks or exposures to sharp, contaminated instruments; sharing items such as razors or toothbrushes with an infected person; and mother to child via birth from an infected mother. | 564 | Hepatitis D |
nord_564_4 | Related disorders of Hepatitis D | HDV only occurs in the setting of HBV infection in humans. However, there are other disorders that may present with signs and symptoms similar to HDV. As previously mentioned, the clinical presentation of HDV can be fairly non-specific and can be seen in patients with other liver diseases. For example, other viral hepatitis infections may present similarly. There are 5 main types of viral hepatitis: A, B, C, D, E. Hepatitis A is usually transmitted via contaminated food and can present similarly to an acute HDV infection. HBV reactivation or flare can also occur in patients with underlying chronic HBV and can mimic the signs and symptoms seen in acute HDV infection. Hepatitis C can be acquired through blood (e.g., blood transfusion, shared needles, etc.) as well as via sexual contact. While it is more common for hepatitis C to progress without symptoms initially then become a chronic infection, acute hepatitis C infection can occur and present very similarly to acute HDV infection. Hepatitis E infection is commonly acquired through contaminated food and water especially among travelers to regions with high prevalence of viral hepatitis. The clinical presentation of hepatitis E can also be very similar to HDV infection. | Related disorders of Hepatitis D. HDV only occurs in the setting of HBV infection in humans. However, there are other disorders that may present with signs and symptoms similar to HDV. As previously mentioned, the clinical presentation of HDV can be fairly non-specific and can be seen in patients with other liver diseases. For example, other viral hepatitis infections may present similarly. There are 5 main types of viral hepatitis: A, B, C, D, E. Hepatitis A is usually transmitted via contaminated food and can present similarly to an acute HDV infection. HBV reactivation or flare can also occur in patients with underlying chronic HBV and can mimic the signs and symptoms seen in acute HDV infection. Hepatitis C can be acquired through blood (e.g., blood transfusion, shared needles, etc.) as well as via sexual contact. While it is more common for hepatitis C to progress without symptoms initially then become a chronic infection, acute hepatitis C infection can occur and present very similarly to acute HDV infection. Hepatitis E infection is commonly acquired through contaminated food and water especially among travelers to regions with high prevalence of viral hepatitis. The clinical presentation of hepatitis E can also be very similar to HDV infection. | 564 | Hepatitis D |
nord_564_5 | Diagnosis of Hepatitis D | The detection and diagnosis of HDV is based on laboratory testing of blood samples. Recommendations from the American Association for the Study of Liver Diseases (AASLD) suggest testing for HDV with a total antibody test in patients with chronic HBV who are at high risk. One element of high risk is location, including individuals born in regions with high prevalence of viral hepatitis such as West Africa, the horn of Africa, Central and Northern Asia, Mongolia, Pakistan, Japan, Taiwan, Kiribati, Nauru, the Middle East region, Eastern Mediterranean regions, Turkey, the Amazon Basin and Greenland. Other high-risk individuals are persons who inject drugs, men who have sex with men, persons with HIV or hepatitis C co-infection, individuals at risk for sexually transmitted diseases and patients with elevated liver enzymes despite low HBV DNA levels. The Hepatitis B Foundation recommends testing for HDV in all HBsAg+ patients since risk based testing has been a failure and there are no peer reviewed references that support risk based testing will aid in viral hepatitis elimination.Clinical Testing and Work-UpInitial assessment for HDV includes laboratory testing of blood samples for anti-HDV total immunoglobulin G (IgG) and IgM antibodies. If anti-HDV total (including IgG) antibodies are detected, quantitative testing with polymerase chain reaction (PCR) should follow. The PCR test looks for evidence of active HDV infection, specifically HDV RNA, which provides evidence of active HDV replication that is present. Given that all patients with HDV will have chronic HBV infection, a comprehensive assessment of HBV should already have been performed. This includes qualitative testing for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe) and quantitative HBV DNA PCR, as well as quantitative testing for hepatitis B surface antigen, if available. All individuals should also be evaluated for immunity to hepatitis A virus, with a test that detects hepatitis A virus total antibody (includes IgG) antibodies. If negative, appropriate vaccination should be provided. All patients should also be tested for hepatitis C virus and HIV.In order to track progression of disease, all individuals being evaluated for HDV infection should also have routine testing to establish a baseline and measure against that baseline over time. Evaluation of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, is needed. Liver function tests, including bilirubin (direct bilirubin), albumin, and prothrombin time (PT)/international normalized ratio (INR), should also be conducted. Platelet count should be included as an indirect assessment of portal hypertension, as that is an indication of cirrhosis. Assessment of liver scarring (hepatic fibrosis) should also be performed. This can be done in a number of ways: using non-invasive serology-based fibrosis prediction scores (such as fibrosis-4 {FIB-4} score), using an aspartate aminotransferase-to-platelet ratio index (APRI), using proprietary tests (such as Fibrosure) or enhanced liver fibrosis tests. Non-invasive imaging-based assessment of hepatic fibrosis can also be performed with options like Fibroscan transient elastography, ultrasound-based shear-wave elastography or magnetic resonance elastography. Given the availability of several non-invasive options of assessing hepatic fibrosis, liver biopsy is less commonly used for staging degree of hepatic fibrosis, but may still be useful when the diagnosis is not clear or to evaluate for other liver diseases that may also be present, such as nonalcoholic steatohepatitis (NASH) and alcohol associated liver disease (AALD). | Diagnosis of Hepatitis D. The detection and diagnosis of HDV is based on laboratory testing of blood samples. Recommendations from the American Association for the Study of Liver Diseases (AASLD) suggest testing for HDV with a total antibody test in patients with chronic HBV who are at high risk. One element of high risk is location, including individuals born in regions with high prevalence of viral hepatitis such as West Africa, the horn of Africa, Central and Northern Asia, Mongolia, Pakistan, Japan, Taiwan, Kiribati, Nauru, the Middle East region, Eastern Mediterranean regions, Turkey, the Amazon Basin and Greenland. Other high-risk individuals are persons who inject drugs, men who have sex with men, persons with HIV or hepatitis C co-infection, individuals at risk for sexually transmitted diseases and patients with elevated liver enzymes despite low HBV DNA levels. The Hepatitis B Foundation recommends testing for HDV in all HBsAg+ patients since risk based testing has been a failure and there are no peer reviewed references that support risk based testing will aid in viral hepatitis elimination.Clinical Testing and Work-UpInitial assessment for HDV includes laboratory testing of blood samples for anti-HDV total immunoglobulin G (IgG) and IgM antibodies. If anti-HDV total (including IgG) antibodies are detected, quantitative testing with polymerase chain reaction (PCR) should follow. The PCR test looks for evidence of active HDV infection, specifically HDV RNA, which provides evidence of active HDV replication that is present. Given that all patients with HDV will have chronic HBV infection, a comprehensive assessment of HBV should already have been performed. This includes qualitative testing for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe) and quantitative HBV DNA PCR, as well as quantitative testing for hepatitis B surface antigen, if available. All individuals should also be evaluated for immunity to hepatitis A virus, with a test that detects hepatitis A virus total antibody (includes IgG) antibodies. If negative, appropriate vaccination should be provided. All patients should also be tested for hepatitis C virus and HIV.In order to track progression of disease, all individuals being evaluated for HDV infection should also have routine testing to establish a baseline and measure against that baseline over time. Evaluation of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, is needed. Liver function tests, including bilirubin (direct bilirubin), albumin, and prothrombin time (PT)/international normalized ratio (INR), should also be conducted. Platelet count should be included as an indirect assessment of portal hypertension, as that is an indication of cirrhosis. Assessment of liver scarring (hepatic fibrosis) should also be performed. This can be done in a number of ways: using non-invasive serology-based fibrosis prediction scores (such as fibrosis-4 {FIB-4} score), using an aspartate aminotransferase-to-platelet ratio index (APRI), using proprietary tests (such as Fibrosure) or enhanced liver fibrosis tests. Non-invasive imaging-based assessment of hepatic fibrosis can also be performed with options like Fibroscan transient elastography, ultrasound-based shear-wave elastography or magnetic resonance elastography. Given the availability of several non-invasive options of assessing hepatic fibrosis, liver biopsy is less commonly used for staging degree of hepatic fibrosis, but may still be useful when the diagnosis is not clear or to evaluate for other liver diseases that may also be present, such as nonalcoholic steatohepatitis (NASH) and alcohol associated liver disease (AALD). | 564 | Hepatitis D |
nord_564_6 | Therapies of Hepatitis D | TreatmentThe goal of HDV treatment is to suppress HDV replication and normalize alanine aminotransferase levels, which helps reduce risks of disease progression, cirrhosis and liver cancer. While there are no currently FDA-approved therapies for the treatment of HDV, interferon-based therapies (which use signaling proteins to cause nearby cells to heighten their anti-viral defenses) have been used. Peginterferon-alfa-2a (PEGASYS) is the most commonly used interferon treatment for HDV. However, the effectiveness of this therapy is limited, with only approximately 40% of treated patients achieving undetectable HDV RNA at 24 weeks following completion of treatment. Follow-up data demonstrated that only 12% of treated patients have sustained suppression of HDV 4 years after treatment. Achieving suppression of HDV RNA is associated with greater likelihood of normalizing alanine aminotransferase. The European Medicines Agency (EMA) has approved bulevirtide (Hepcludex), an entry inhibitor, to treat HDV and is available in in multiple countries in the European Union and Russia. There is an urgent unmet need for newer and more effective therapies for HDV. Given that all HDV patients have underlying chronic HBV infection, treatment with HBV therapies should also be implemented to suppress HBV DNA | Therapies of Hepatitis D. TreatmentThe goal of HDV treatment is to suppress HDV replication and normalize alanine aminotransferase levels, which helps reduce risks of disease progression, cirrhosis and liver cancer. While there are no currently FDA-approved therapies for the treatment of HDV, interferon-based therapies (which use signaling proteins to cause nearby cells to heighten their anti-viral defenses) have been used. Peginterferon-alfa-2a (PEGASYS) is the most commonly used interferon treatment for HDV. However, the effectiveness of this therapy is limited, with only approximately 40% of treated patients achieving undetectable HDV RNA at 24 weeks following completion of treatment. Follow-up data demonstrated that only 12% of treated patients have sustained suppression of HDV 4 years after treatment. Achieving suppression of HDV RNA is associated with greater likelihood of normalizing alanine aminotransferase. The European Medicines Agency (EMA) has approved bulevirtide (Hepcludex), an entry inhibitor, to treat HDV and is available in in multiple countries in the European Union and Russia. There is an urgent unmet need for newer and more effective therapies for HDV. Given that all HDV patients have underlying chronic HBV infection, treatment with HBV therapies should also be implemented to suppress HBV DNA | 564 | Hepatitis D |
nord_565_0 | Overview of Hepatocellular Carcinoma | SummaryHepatocellular carcinoma (HCC) is a rare disorder in the United States, but the most common primary tumor of the liver. Most people have an underlying liver disease such as infection with hepatitis B or C virus, or non-alcoholic fatty liver disease. Most people have cirrhosis, which is scarring of the liver that can occur as a result of chronic liver diseases. If HCC is found early, there may be curative treatments offered. However, HCC often does not cause any symptoms, especially early in the disease course. If HCC is diagnosed at a late stage, patients may not be able to receive curative treatments, and care is then geared toward helping people have a better quality of life. Although HCC does not necessarily cause symptoms, many individuals will have symptoms caused by the underlying liver disease. The exact cause of HCC is not fully understood. | Overview of Hepatocellular Carcinoma. SummaryHepatocellular carcinoma (HCC) is a rare disorder in the United States, but the most common primary tumor of the liver. Most people have an underlying liver disease such as infection with hepatitis B or C virus, or non-alcoholic fatty liver disease. Most people have cirrhosis, which is scarring of the liver that can occur as a result of chronic liver diseases. If HCC is found early, there may be curative treatments offered. However, HCC often does not cause any symptoms, especially early in the disease course. If HCC is diagnosed at a late stage, patients may not be able to receive curative treatments, and care is then geared toward helping people have a better quality of life. Although HCC does not necessarily cause symptoms, many individuals will have symptoms caused by the underlying liver disease. The exact cause of HCC is not fully understood. | 565 | Hepatocellular Carcinoma |
nord_565_1 | Symptoms of Hepatocellular Carcinoma | Most people do not have any noticeable symptoms associated with hepatocellular carcinoma. They may have symptoms related liver cirrhosis that may become more difficult to control.Because of the underlying liver disease and HCC, the liver may become decompensated. This means that an organ, in this instance the liver, is having trouble compensating for the effects of disease. Symptoms of liver decompensation can include fluid buildup in the abdomen (ascites), an abnormally enlarged spleen (splenomegaly), high pressure in the main vein that supplies the liver (portal hypertension), yellowing of the skin, eyes and mucous membranes because of the buildup of bile in the body (jaundice), and hepatic encephalopathy, a condition in which toxins that are normally cleared by the liver are not cleared and instead travel through the bloodstream to the brain. Hepatic encephalopathy is a spectrum of disease that can cause very subtle symptoms or severe, life-threatening complications. When symptoms do occur, they can include personality changes, intellectual impairment, impaired memory or loss of consciousness (coma). Although HCC often does not cause symptoms, some people will develop mild to moderate pain in the upper abdomen and may feel full despite eating less food than usual (early satiety). Some may experience fatigue, unintended weight loss or have a mass that can be felt (palpable) in the upper abdomen. Less commonly, fever or diarrhea may be present. Usually, such symptoms occur later in the diseases course and indicate advanced disease.Some symptoms may occur if the cancer has spread to other areas (metastasized). For example, bone pain may occur if the cancer has spread to the bones, or a person may have difficulty breathing (dyspnea) if the cancer has spread to the lungs. Some people with HCC may develop a paraneoplastic syndrome. Paraneoplastic syndromes are a group of disorders that occur when the immune system’s response to cancer also damages the central nervous system. There is also a risk of a tumor rupturing, leading to bleeding into the peritoneum, which is the membrane that lines the abdomen and covers the abdominal organs (intraperitoneal hemorrhage). | Symptoms of Hepatocellular Carcinoma. Most people do not have any noticeable symptoms associated with hepatocellular carcinoma. They may have symptoms related liver cirrhosis that may become more difficult to control.Because of the underlying liver disease and HCC, the liver may become decompensated. This means that an organ, in this instance the liver, is having trouble compensating for the effects of disease. Symptoms of liver decompensation can include fluid buildup in the abdomen (ascites), an abnormally enlarged spleen (splenomegaly), high pressure in the main vein that supplies the liver (portal hypertension), yellowing of the skin, eyes and mucous membranes because of the buildup of bile in the body (jaundice), and hepatic encephalopathy, a condition in which toxins that are normally cleared by the liver are not cleared and instead travel through the bloodstream to the brain. Hepatic encephalopathy is a spectrum of disease that can cause very subtle symptoms or severe, life-threatening complications. When symptoms do occur, they can include personality changes, intellectual impairment, impaired memory or loss of consciousness (coma). Although HCC often does not cause symptoms, some people will develop mild to moderate pain in the upper abdomen and may feel full despite eating less food than usual (early satiety). Some may experience fatigue, unintended weight loss or have a mass that can be felt (palpable) in the upper abdomen. Less commonly, fever or diarrhea may be present. Usually, such symptoms occur later in the diseases course and indicate advanced disease.Some symptoms may occur if the cancer has spread to other areas (metastasized). For example, bone pain may occur if the cancer has spread to the bones, or a person may have difficulty breathing (dyspnea) if the cancer has spread to the lungs. Some people with HCC may develop a paraneoplastic syndrome. Paraneoplastic syndromes are a group of disorders that occur when the immune system’s response to cancer also damages the central nervous system. There is also a risk of a tumor rupturing, leading to bleeding into the peritoneum, which is the membrane that lines the abdomen and covers the abdominal organs (intraperitoneal hemorrhage). | 565 | Hepatocellular Carcinoma |
nord_565_2 | Causes of Hepatocellular Carcinoma | The exact reasons why hepatocellular carcinoma develops is not fully understood. It is a multifactorial disorder, which means that there are multiple factors that must occur before the disorder develops. There are risk factors that increase the chances of a person developing HCC. Most people have an underlying liver disorder including infection with hepatitis B or C viruses, scarring of the liver (cirrhosis), a condition in which fat builds up in the liver (non-alcoholic fatty liver disease), and a condition in which fat builds up in the liver along with inflammation and liver cell damage (nonalcoholic steatohepatitis or NASH). Heavy drinking is also a risk factor for HCC; excessive drinking is one of the main causes of cirrhosis and can also cause alcoholic fatty liver disease. Cigarette smoking is also a potential risk factor for HCC. Obesity and diabetes are modest risk factors, but the absolute risk is considered to be very low. Foods contaminated with aflatoxin also increase the risk of HCC; this is even true for people without an underlying liver disorder. Aflatoxins are a type of toxin produced by fungi and may contaminate certain agricultural products. There are also several metabolic and genetic disorders that may increase the risk of developing HCC. These disorders include Wilson disease, hemochromatosis, autoimmune hepatitis, alpha-1 antitrypsin deficiency, and primary biliary cholangitis (For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.). | Causes of Hepatocellular Carcinoma. The exact reasons why hepatocellular carcinoma develops is not fully understood. It is a multifactorial disorder, which means that there are multiple factors that must occur before the disorder develops. There are risk factors that increase the chances of a person developing HCC. Most people have an underlying liver disorder including infection with hepatitis B or C viruses, scarring of the liver (cirrhosis), a condition in which fat builds up in the liver (non-alcoholic fatty liver disease), and a condition in which fat builds up in the liver along with inflammation and liver cell damage (nonalcoholic steatohepatitis or NASH). Heavy drinking is also a risk factor for HCC; excessive drinking is one of the main causes of cirrhosis and can also cause alcoholic fatty liver disease. Cigarette smoking is also a potential risk factor for HCC. Obesity and diabetes are modest risk factors, but the absolute risk is considered to be very low. Foods contaminated with aflatoxin also increase the risk of HCC; this is even true for people without an underlying liver disorder. Aflatoxins are a type of toxin produced by fungi and may contaminate certain agricultural products. There are also several metabolic and genetic disorders that may increase the risk of developing HCC. These disorders include Wilson disease, hemochromatosis, autoimmune hepatitis, alpha-1 antitrypsin deficiency, and primary biliary cholangitis (For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.). | 565 | Hepatocellular Carcinoma |
nord_565_3 | Affects of Hepatocellular Carcinoma | Hepatocellular carcinoma is one of the most prevalent cancers in the world, but relatively rare in the United States. There are approximately six new cases of HCC per every 100,000 people in the general population of the U.S. The number of people who develop HCC in the U.S. has risen in the last four decades. In certain geographic regions in the world, HCC is much more common most likely due to increased frequency of hepatitis B infection or exposure to aflatoxins. One estimate places HCC as the fifth most common cancer that leads to death in the world. HCC accounts for about 85%-90% of all primary liver cancers. Primary means that the cancer started in the liver as opposed to secondary, in which cancer has spread to the liver from another area of the body. | Affects of Hepatocellular Carcinoma. Hepatocellular carcinoma is one of the most prevalent cancers in the world, but relatively rare in the United States. There are approximately six new cases of HCC per every 100,000 people in the general population of the U.S. The number of people who develop HCC in the U.S. has risen in the last four decades. In certain geographic regions in the world, HCC is much more common most likely due to increased frequency of hepatitis B infection or exposure to aflatoxins. One estimate places HCC as the fifth most common cancer that leads to death in the world. HCC accounts for about 85%-90% of all primary liver cancers. Primary means that the cancer started in the liver as opposed to secondary, in which cancer has spread to the liver from another area of the body. | 565 | Hepatocellular Carcinoma |
nord_565_4 | Related disorders of Hepatocellular Carcinoma | Symptoms of the following disorders can be similar to those of hepatocellular carcinoma. Comparisons may be useful for a differential diagnosis.Certain other tumors such as a hepatoblastoma or hemangioma of the liver can be mistaken for HCC. A hepatoblastoma is a malignant form of cancer that most commonly affects infants and children. A hemangioma is a non-cancerous (benign) tumor that consists of an overgrowth of blood vessels. Another benign tumor that can occur in the liver is focal nodular hyperplasia. A liver hemangioma and focal nodular hyperplasia are the two most common tumors of the liver. | Related disorders of Hepatocellular Carcinoma. Symptoms of the following disorders can be similar to those of hepatocellular carcinoma. Comparisons may be useful for a differential diagnosis.Certain other tumors such as a hepatoblastoma or hemangioma of the liver can be mistaken for HCC. A hepatoblastoma is a malignant form of cancer that most commonly affects infants and children. A hemangioma is a non-cancerous (benign) tumor that consists of an overgrowth of blood vessels. Another benign tumor that can occur in the liver is focal nodular hyperplasia. A liver hemangioma and focal nodular hyperplasia are the two most common tumors of the liver. | 565 | Hepatocellular Carcinoma |
nord_565_5 | Diagnosis of Hepatocellular Carcinoma | Because hepatocellular carcinoma does not cause symptoms early in the disease, getting a prompt diagnosis is difficult. Since there are more effective treatment options the earlier the disease is identified, early diagnosis is very important. People who have a high risk of developing HCC should enter into a surveillance program. This program involves studying the liver through an ultrasound examination every six months. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures such as the liver. Such a program is the only effective way to detect and diagnose HCC in a timely fashion, so that curative treatment options can still be used. People with hepatitis B or cirrhosis from any cause should be enrolled in such a surveillance program. (Patients with hepatitis C who do not have cirrhosis are not typically screened for liver cancer).Doctors may then recommend advanced imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to try and confirm a diagnosis of HCC. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of specific organs and bodily tissues.People who are not in a surveillance program may be diagnosed because they have liver disease and doctors discover that they have rising alpha-fetoprotein levels. This protein occurs in high levels in developing fetuses, but is usually not seen in high levels in children or adults. High levels of this protein might indicate liver cancer, especially in people who have underlying liver disease. Doctors will usually order a CT scan or MRI to try and detect the presence of liver cancer. Sometimes, doctors may need to take a tiny sample of liver tissue to be studied under a microscope to confirm a diagnosis of HCC. This is called a liver biopsy. During a biopsy, a needed is passed through the skin to take a tiny sample of affected liver tissue. There is a risk of false negatives, so careful surveillance with imaging tests is still recommended even if the biopsy is negative. There is also a risk of “tumor seeding” during a biopsy, where cancer cells spread to neighboring tissues, in this instance, along the path the biopsy needle travels. Because of these risks, liver biopsy is not routinely performed for people with typical imaging features of HCC. | Diagnosis of Hepatocellular Carcinoma. Because hepatocellular carcinoma does not cause symptoms early in the disease, getting a prompt diagnosis is difficult. Since there are more effective treatment options the earlier the disease is identified, early diagnosis is very important. People who have a high risk of developing HCC should enter into a surveillance program. This program involves studying the liver through an ultrasound examination every six months. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures such as the liver. Such a program is the only effective way to detect and diagnose HCC in a timely fashion, so that curative treatment options can still be used. People with hepatitis B or cirrhosis from any cause should be enrolled in such a surveillance program. (Patients with hepatitis C who do not have cirrhosis are not typically screened for liver cancer).Doctors may then recommend advanced imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to try and confirm a diagnosis of HCC. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of specific organs and bodily tissues.People who are not in a surveillance program may be diagnosed because they have liver disease and doctors discover that they have rising alpha-fetoprotein levels. This protein occurs in high levels in developing fetuses, but is usually not seen in high levels in children or adults. High levels of this protein might indicate liver cancer, especially in people who have underlying liver disease. Doctors will usually order a CT scan or MRI to try and detect the presence of liver cancer. Sometimes, doctors may need to take a tiny sample of liver tissue to be studied under a microscope to confirm a diagnosis of HCC. This is called a liver biopsy. During a biopsy, a needed is passed through the skin to take a tiny sample of affected liver tissue. There is a risk of false negatives, so careful surveillance with imaging tests is still recommended even if the biopsy is negative. There is also a risk of “tumor seeding” during a biopsy, where cancer cells spread to neighboring tissues, in this instance, along the path the biopsy needle travels. Because of these risks, liver biopsy is not routinely performed for people with typical imaging features of HCC. | 565 | Hepatocellular Carcinoma |
nord_565_6 | Therapies of Hepatocellular Carcinoma | TreatmentHepatocellular carcinoma usually occurs in people who have an underlying liver disease or liver dysfunction. Treatment may require the coordinated efforts of a team of specialists. Specialists who diagnose and treat cancer (oncologists), specialists who diagnose and treat liver disorders (hepatologists), specialists who use ionizing radiation to treat cancer (radiation oncologists), specialists who use minimally-invasive, image-guide technologies to diagnose and treat cancer (interventional radiologists), transplant surgeons, and surgeons who specialize in the liver and gall bladder and bile ducts (hepatobiliary surgeon), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; the presence or absence of certain symptoms; whether the disease has spread (metastasized) to other areas of the body; how well or poorly the liver is functioning overall; an individual’s age and general health; and/or other elements. Decisions concerning the use of surgery, radiation, specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Because people with HCC usually have an underlying liver condition, that condition needs to be monitored and treated as well. The underlying liver condition will greatly impact the longer-term survival of an affected individual. Physicians will stage HCC as part of developing a treatment plan. Cancer staging is used to determine how far cancer has progressed in a person and where it is located within the body. The most commonly used staging system is the Barcelona Cancer of the Liver staging system which takes into consideration liver function, daily performance ability and the size and number of liver tumors.If HCC is found early enough and the underlying liver condition hasn’t compromised liver function, a patient may be eligible for surgical removal (resection) of the tumor. Surgical resection is best undertaken by a hepatobiliary surgeon because they are experienced with liver surgery. Additionally, some people with small tumors may be candidates for a liver transplant. If surgery or a transplant is not possible, affected individuals may undergo radiofrequency ablation or microwave ablation. Radiofrequency ablation is a procedure in which a small needle is inserted into the tumor and used to deliver high-frequency alternating current (radiofrequency waves) that destroys (ablates) affected tissue. Microwave ablation is a procedure that destroys tumors in the liver by using heat generated f by microwave energy. Some people may undergo transarterial chemoembolization or TACE. This procedure involves injecting a chemotherapeutic drug into the main artery of the liver to cut of the blood supply to the tumor or tumors. Generally, TACE is used for people with multifocal disease (cancer in many areas of the liver), preserved liver function, and good performance status without of cancer outside the liver (extra-hepatic) or in the portal vein, the large veins that carries blood from the intestines to the liver. Performance status refers to a person’s ability to perform normal daily activities.Some people who have cancer that has spread outside of the liver or affects the portal or hepatic veins, have good performance status and preserved liver function, have benefited with treatment with a drug called sorafenib. In 2007, the U.S. Food and Drug Administration (FDA) approved sorafenib for hepatocellular carcinoma that could not be treated by surgery (unresectable). | Therapies of Hepatocellular Carcinoma. TreatmentHepatocellular carcinoma usually occurs in people who have an underlying liver disease or liver dysfunction. Treatment may require the coordinated efforts of a team of specialists. Specialists who diagnose and treat cancer (oncologists), specialists who diagnose and treat liver disorders (hepatologists), specialists who use ionizing radiation to treat cancer (radiation oncologists), specialists who use minimally-invasive, image-guide technologies to diagnose and treat cancer (interventional radiologists), transplant surgeons, and surgeons who specialize in the liver and gall bladder and bile ducts (hepatobiliary surgeon), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; the presence or absence of certain symptoms; whether the disease has spread (metastasized) to other areas of the body; how well or poorly the liver is functioning overall; an individual’s age and general health; and/or other elements. Decisions concerning the use of surgery, radiation, specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Because people with HCC usually have an underlying liver condition, that condition needs to be monitored and treated as well. The underlying liver condition will greatly impact the longer-term survival of an affected individual. Physicians will stage HCC as part of developing a treatment plan. Cancer staging is used to determine how far cancer has progressed in a person and where it is located within the body. The most commonly used staging system is the Barcelona Cancer of the Liver staging system which takes into consideration liver function, daily performance ability and the size and number of liver tumors.If HCC is found early enough and the underlying liver condition hasn’t compromised liver function, a patient may be eligible for surgical removal (resection) of the tumor. Surgical resection is best undertaken by a hepatobiliary surgeon because they are experienced with liver surgery. Additionally, some people with small tumors may be candidates for a liver transplant. If surgery or a transplant is not possible, affected individuals may undergo radiofrequency ablation or microwave ablation. Radiofrequency ablation is a procedure in which a small needle is inserted into the tumor and used to deliver high-frequency alternating current (radiofrequency waves) that destroys (ablates) affected tissue. Microwave ablation is a procedure that destroys tumors in the liver by using heat generated f by microwave energy. Some people may undergo transarterial chemoembolization or TACE. This procedure involves injecting a chemotherapeutic drug into the main artery of the liver to cut of the blood supply to the tumor or tumors. Generally, TACE is used for people with multifocal disease (cancer in many areas of the liver), preserved liver function, and good performance status without of cancer outside the liver (extra-hepatic) or in the portal vein, the large veins that carries blood from the intestines to the liver. Performance status refers to a person’s ability to perform normal daily activities.Some people who have cancer that has spread outside of the liver or affects the portal or hepatic veins, have good performance status and preserved liver function, have benefited with treatment with a drug called sorafenib. In 2007, the U.S. Food and Drug Administration (FDA) approved sorafenib for hepatocellular carcinoma that could not be treated by surgery (unresectable). | 565 | Hepatocellular Carcinoma |
nord_566_0 | Overview of Hepatoerythropoietic Porphyria | SummaryHepatoerythropoietic porphyria (HEP) is an extremely rare genetic disorder characterized by deficiency of the enzyme, uroporphyrinogen decarboxylase. This deficiency is caused by mutations of both copies of a person’s UROD gene, which means that the disorder is inherited as an autosomal recessive trait. Most affected individuals have a profound deficiency of this enzyme and onset of the disorder is usually during infancy or early childhood. However, some individuals may have a mild form that can go undiagnosed until adulthood. The childhood form of HEP is often associated with painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Affected areas of skin can scar and become discolored. There may be risk of bacterial infection. Abnormal, excessive hair (hypertrichosis) on affected skin is also common. Mild anemia and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) have also been reported. Mild cases of HEP may go unrecognized until adulthood and can be clinically indistinguishable from porphyria cutanea tarda (PCT), a related disorder that may be acquired or occur in individuals with a mutation of one UROD gene (autosomal dominant inheritance). Cutaneous photosensitivity is generally much more severe in HEP than in PCT. NORD has a separate report on porphyria cutanea tarda.IntroductionHEP belongs to a group of disorders known as the porphyrias. This group of at least seven disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias”. The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. HEP is a hepatic and cutaneous porphyria. | Overview of Hepatoerythropoietic Porphyria. SummaryHepatoerythropoietic porphyria (HEP) is an extremely rare genetic disorder characterized by deficiency of the enzyme, uroporphyrinogen decarboxylase. This deficiency is caused by mutations of both copies of a person’s UROD gene, which means that the disorder is inherited as an autosomal recessive trait. Most affected individuals have a profound deficiency of this enzyme and onset of the disorder is usually during infancy or early childhood. However, some individuals may have a mild form that can go undiagnosed until adulthood. The childhood form of HEP is often associated with painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Affected areas of skin can scar and become discolored. There may be risk of bacterial infection. Abnormal, excessive hair (hypertrichosis) on affected skin is also common. Mild anemia and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) have also been reported. Mild cases of HEP may go unrecognized until adulthood and can be clinically indistinguishable from porphyria cutanea tarda (PCT), a related disorder that may be acquired or occur in individuals with a mutation of one UROD gene (autosomal dominant inheritance). Cutaneous photosensitivity is generally much more severe in HEP than in PCT. NORD has a separate report on porphyria cutanea tarda.IntroductionHEP belongs to a group of disorders known as the porphyrias. This group of at least seven disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias”. The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. HEP is a hepatic and cutaneous porphyria. | 566 | Hepatoerythropoietic Porphyria |
nord_566_1 | Symptoms of Hepatoerythropoietic Porphyria | The symptoms and severity of HEP can vary from one person to another. Onset is usually within the first two years of life, but mild cases that go undiagnosed until adulthood have been reported. Although HEP is associated with specific, characteristic symptoms, several factors, including the small number of identified cases, make it difficult to establish the full range of associated symptoms of the disorder.Severe cutaneous photosensitivity is usually the first sign. Affected infants may have extremely fragile skin that that can peel or blister on minimal impact is common. Reddening of the skin is common (erythema). Blistering skin lesions can develop on sun-exposed skin such as the hands and face. Photosensitivity can be severe and can cause scarring, erosion, and disfigurement. Bacterial infection of skin lesions can occur.Abnormal, excessive hair growth (hypertrichosis) may also occur on sun-exposed skin. Affected skin may darken or lose color (hyper- or hypopigmentation). Small bumps with a distinct white head (milia) may also develop. Some affected individuals have teeth that are reddish-brown colored (erythrodontia).Low levels of circulating red blood cells (anemia) may also occur. Anemia may be due to the premature destruction of red blood cells (hemolysis). Anemia associated with HEP may be mild or severe. Severe anemia may be associated with fatigue, pale skin, irregular heartbeat, chest pain, dizziness, and abnormally cold hands and feet. Some individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly).Mild cases of HEP can go undiagnosed until adulthood. Overt photosensitivity may not be seen and mild skin damage can be mistaken for other conditions during childhood. | Symptoms of Hepatoerythropoietic Porphyria. The symptoms and severity of HEP can vary from one person to another. Onset is usually within the first two years of life, but mild cases that go undiagnosed until adulthood have been reported. Although HEP is associated with specific, characteristic symptoms, several factors, including the small number of identified cases, make it difficult to establish the full range of associated symptoms of the disorder.Severe cutaneous photosensitivity is usually the first sign. Affected infants may have extremely fragile skin that that can peel or blister on minimal impact is common. Reddening of the skin is common (erythema). Blistering skin lesions can develop on sun-exposed skin such as the hands and face. Photosensitivity can be severe and can cause scarring, erosion, and disfigurement. Bacterial infection of skin lesions can occur.Abnormal, excessive hair growth (hypertrichosis) may also occur on sun-exposed skin. Affected skin may darken or lose color (hyper- or hypopigmentation). Small bumps with a distinct white head (milia) may also develop. Some affected individuals have teeth that are reddish-brown colored (erythrodontia).Low levels of circulating red blood cells (anemia) may also occur. Anemia may be due to the premature destruction of red blood cells (hemolysis). Anemia associated with HEP may be mild or severe. Severe anemia may be associated with fatigue, pale skin, irregular heartbeat, chest pain, dizziness, and abnormally cold hands and feet. Some individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly).Mild cases of HEP can go undiagnosed until adulthood. Overt photosensitivity may not be seen and mild skin damage can be mistaken for other conditions during childhood. | 566 | Hepatoerythropoietic Porphyria |
nord_566_2 | Causes of Hepatoerythropoietic Porphyria | HEP is caused by mutations of both alleles of the UROD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.HEP is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Investigators have determined that the UROD gene is located on the short arm (p) of chromosome 1 (1p34.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p34.1” refers to band 34.1 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The UROD gene creates (encodes) an enzyme known as uroporphyrinogen decarboxylase (UROD), which is the fifth enzyme in the heme biosynthetic pathway. In HEP, UROD enzyme activity is usually less than 10% its normal levels. Such low enzyme activity results in the abnormal accumulation of specific porphyrins and related chemicals in body, especially within the bone marrow, red blood cells, liver and skin. Symptoms develop because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with HEP. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver. | Causes of Hepatoerythropoietic Porphyria. HEP is caused by mutations of both alleles of the UROD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.HEP is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Investigators have determined that the UROD gene is located on the short arm (p) of chromosome 1 (1p34.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p34.1” refers to band 34.1 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The UROD gene creates (encodes) an enzyme known as uroporphyrinogen decarboxylase (UROD), which is the fifth enzyme in the heme biosynthetic pathway. In HEP, UROD enzyme activity is usually less than 10% its normal levels. Such low enzyme activity results in the abnormal accumulation of specific porphyrins and related chemicals in body, especially within the bone marrow, red blood cells, liver and skin. Symptoms develop because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with HEP. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver. | 566 | Hepatoerythropoietic Porphyria |
nord_566_3 | Affects of Hepatoerythropoietic Porphyria | HEP is an extremely rare disorder that affects males and females in equal numbers. Approximately 40 cases have been reported in the medical literature. The exact incidence or prevalence of HEP in the general population is unknown. | Affects of Hepatoerythropoietic Porphyria. HEP is an extremely rare disorder that affects males and females in equal numbers. Approximately 40 cases have been reported in the medical literature. The exact incidence or prevalence of HEP in the general population is unknown. | 566 | Hepatoerythropoietic Porphyria |
nord_566_4 | Related disorders of Hepatoerythropoietic Porphyria | Symptoms of the following disorders can be similar to those of HEP. Comparisons may be useful for a differential diagnosis.Congenital erythropoietic porphyria (CEP) is a rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III cosynthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Both parents are usually healthy, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent. (For more information on this disorder, choose “congenital erythropoietic porphyria” as your search term in the Rare Disease Database.)There are other conditions that may cause signs and symptoms that are similar to those seen in HEP. Such conditions include other cutaneous porphyrias, drug-induced photosensitivity, epidermolysis bullosa, various forms of lupus, and solar urticarial. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Hepatoerythropoietic Porphyria. Symptoms of the following disorders can be similar to those of HEP. Comparisons may be useful for a differential diagnosis.Congenital erythropoietic porphyria (CEP) is a rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III cosynthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Both parents are usually healthy, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent. (For more information on this disorder, choose “congenital erythropoietic porphyria” as your search term in the Rare Disease Database.)There are other conditions that may cause signs and symptoms that are similar to those seen in HEP. Such conditions include other cutaneous porphyrias, drug-induced photosensitivity, epidermolysis bullosa, various forms of lupus, and solar urticarial. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 566 | Hepatoerythropoietic Porphyria |
nord_566_5 | Diagnosis of Hepatoerythropoietic Porphyria | A diagnosis of HEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. HEP may be considered in infants and children with chronic, blistering photosensitivity.Clinical Testing and WorkupScreening tests can help diagnose HEP by measuring the levels of certain porphyrins in blood plasma, urine and red blood cells. These tests can help to differentiate the disorder from congenital erythropoietic porphyria by the different patterns of individual porphyrins and/or by demonstrating markedly decreased activity of the UROD enzyme. There is elevation of porphyrins in plasma, urine, and feces. Porphyrin patterns in HEP are similar to those seen in PCT with elevation of highly carboxylated porphyrins and isocoproporphyrins. In contrast to PCT, there are markedly increased levels of zinc protoporphyrin in red blood cells in HEP patients which is due to accumulation of pathway intermediates being metabolized to protoporphyrins.Molecular genetic testing can confirm a diagnosis of HEP by detecting mutations in both UROD genes, but is available only on a clinical basis. | Diagnosis of Hepatoerythropoietic Porphyria. A diagnosis of HEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. HEP may be considered in infants and children with chronic, blistering photosensitivity.Clinical Testing and WorkupScreening tests can help diagnose HEP by measuring the levels of certain porphyrins in blood plasma, urine and red blood cells. These tests can help to differentiate the disorder from congenital erythropoietic porphyria by the different patterns of individual porphyrins and/or by demonstrating markedly decreased activity of the UROD enzyme. There is elevation of porphyrins in plasma, urine, and feces. Porphyrin patterns in HEP are similar to those seen in PCT with elevation of highly carboxylated porphyrins and isocoproporphyrins. In contrast to PCT, there are markedly increased levels of zinc protoporphyrin in red blood cells in HEP patients which is due to accumulation of pathway intermediates being metabolized to protoporphyrins.Molecular genetic testing can confirm a diagnosis of HEP by detecting mutations in both UROD genes, but is available only on a clinical basis. | 566 | Hepatoerythropoietic Porphyria |
nord_566_6 | Therapies of Hepatoerythropoietic Porphyria | TreatmentThe treatment of HEP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.There is no specific, FDA-approved therapy for individuals with HEP. Because the disorder is so rare, most treatment information is based other forms of porphyria.Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, but certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.Phlebotomies, which are used to treat individuals with PCT, are generally ineffective in individuals with HEP since elevated iron levels are not a feature of the disorder. Another treatment for PCT, the antimalarial drug chloroquine, was effective in at least one case reported in the medical literature.Anemia may require treatment in some cases. Blood transfusions have been used to treat some individuals. Recombinant erythropoietin, which helps the body produce more red blood cells, was successfully used to treat severe anemia in an individual with HEP whose anemia was not associated with increased red cell destruction. | Therapies of Hepatoerythropoietic Porphyria. TreatmentThe treatment of HEP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.There is no specific, FDA-approved therapy for individuals with HEP. Because the disorder is so rare, most treatment information is based other forms of porphyria.Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, but certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.Phlebotomies, which are used to treat individuals with PCT, are generally ineffective in individuals with HEP since elevated iron levels are not a feature of the disorder. Another treatment for PCT, the antimalarial drug chloroquine, was effective in at least one case reported in the medical literature.Anemia may require treatment in some cases. Blood transfusions have been used to treat some individuals. Recombinant erythropoietin, which helps the body produce more red blood cells, was successfully used to treat severe anemia in an individual with HEP whose anemia was not associated with increased red cell destruction. | 566 | Hepatoerythropoietic Porphyria |
nord_567_0 | Overview of Hepatopulmonary Syndrome | SummaryThe hepatopulmonary syndrome (HPS) is a rare lung complication of liver disease.
When the liver is not functioning properly, blood vessels in the lungs may dilate. If this is severe enough, the lungs can lose their ability to effectively transfer oxygen to the body. This is called hepatopulmonary syndrome (HPS) and it occurs in approximately 5-32% of patients with scarring of the liver (cirrhosis)1.The most prominent symptom of HPS is usually a severe shortness of breath and low blood oxygen levels. Patients may also notice that their fingertips turn blue or that their fingers take on a club-like appearance2. Supplemental oxygen is often required to manage the symptoms of HPS, but this may not be necessary in milder cases.Currently, the only known cure for HPS is a liver transplant. After replacing the diseased liver in HPS patients, the lungs return to normal within approximately one year3.Introduction The first recorded description of a low level of oxygen in the blood (hypoxemia) with liver dysfunction was by Flückiger in 1884. It was not until nearly a century later, in 1977, that Kennedy and Knudson described a patient with these classic findings, and coined the term “hepatopulmonary syndrome” 5.Today, HPS is a well-recognized and relatively common complication of liver disease of varying causes (though overall it remains a rare disease, as only patients with liver disease can get it). HPS is defined by a triad of features: (1) liver disease (liver dysfunction or abnormally high blood pressure in the large vein that brings blood from the intestine to the liver and its branches (called portal hypertension), (2) widening of blood vessels entering the lungs (called intrapulmonary vascular dilatations or IPVDs; and (3) abnormal oxygenation. Although there is some variability in the reported literature, and some debate as to the correct oxygenation threshold to identify “clinically relevant” HPS, a consensus group has defined this by an alveolar-arterial gradient (AaDO2) ≥ 15 mm Hg (> 20 mm Hg in patients > 64 years of age).6It is important to note that portopulmonary hypertension is often confused with hepatopulmonary syndrome, but these are entirely different diseases (see “Related Disorders” below). | Overview of Hepatopulmonary Syndrome. SummaryThe hepatopulmonary syndrome (HPS) is a rare lung complication of liver disease.
When the liver is not functioning properly, blood vessels in the lungs may dilate. If this is severe enough, the lungs can lose their ability to effectively transfer oxygen to the body. This is called hepatopulmonary syndrome (HPS) and it occurs in approximately 5-32% of patients with scarring of the liver (cirrhosis)1.The most prominent symptom of HPS is usually a severe shortness of breath and low blood oxygen levels. Patients may also notice that their fingertips turn blue or that their fingers take on a club-like appearance2. Supplemental oxygen is often required to manage the symptoms of HPS, but this may not be necessary in milder cases.Currently, the only known cure for HPS is a liver transplant. After replacing the diseased liver in HPS patients, the lungs return to normal within approximately one year3.Introduction The first recorded description of a low level of oxygen in the blood (hypoxemia) with liver dysfunction was by Flückiger in 1884. It was not until nearly a century later, in 1977, that Kennedy and Knudson described a patient with these classic findings, and coined the term “hepatopulmonary syndrome” 5.Today, HPS is a well-recognized and relatively common complication of liver disease of varying causes (though overall it remains a rare disease, as only patients with liver disease can get it). HPS is defined by a triad of features: (1) liver disease (liver dysfunction or abnormally high blood pressure in the large vein that brings blood from the intestine to the liver and its branches (called portal hypertension), (2) widening of blood vessels entering the lungs (called intrapulmonary vascular dilatations or IPVDs; and (3) abnormal oxygenation. Although there is some variability in the reported literature, and some debate as to the correct oxygenation threshold to identify “clinically relevant” HPS, a consensus group has defined this by an alveolar-arterial gradient (AaDO2) ≥ 15 mm Hg (> 20 mm Hg in patients > 64 years of age).6It is important to note that portopulmonary hypertension is often confused with hepatopulmonary syndrome, but these are entirely different diseases (see “Related Disorders” below). | 567 | Hepatopulmonary Syndrome |
nord_567_1 | Symptoms of Hepatopulmonary Syndrome | The vast majority of HPS patients (82%) initially present with features of their liver disease, while a minority (18%) present with lung (pulmonary) complaints first. Overall, the most common complaint is an insidiously progressive shortness of breath (dyspnea) at rest or upon exertion, reported in 95% of patients and usually developing after years of liver disease2. However, given the high prevalence and often multifactorial nature of dyspnea in cirrhotic patients, this complaint is easily overlooked, and HPS patients reportedly have respiratory symptoms for a mean of 4.8 years before diagnosis 7. In a majority of patients, dyspnea and hypoxemia progress over time 8. Furthermore, this progressive decline often occurs despite stable liver function 9. A more specific complaint is that of platypnea – breathlessness experienced in the upright position which is improved when lying down (supine position)7. This in turn correlates to the objective finding of orthodeoxia, a drop of 4mmHg in PaO2 or 5% in saturation when moving from the supine to the standing position, occurring in as many as 88% of HPS patients7.Other clinical manifestations of HPS include:
• Spider angiomata (small, dilated blood vessels clustered very close to the surface of the skin. (likelihood of HPS 21%)
• Clubbing of fingers or toes (likelihood of HPS 78%)
• Cyanosis (abnormal bluish discoloration of skin or mucous membranes due to tissues near the skin surface having low oxygen saturation) (likelihood of HPS 100%)2It is important to note that chest x-ray and thoracic CT scanning are often unremarkable in HPS; a lack of radiographic abnormalities is not sufficient evidence to rule out HPS.It should also be noted that HPS is not limited to patients with severe liver dysfunction; in fact, many patients with moderate to severe HPS have comparatively well preserved hepatic function1. | Symptoms of Hepatopulmonary Syndrome. The vast majority of HPS patients (82%) initially present with features of their liver disease, while a minority (18%) present with lung (pulmonary) complaints first. Overall, the most common complaint is an insidiously progressive shortness of breath (dyspnea) at rest or upon exertion, reported in 95% of patients and usually developing after years of liver disease2. However, given the high prevalence and often multifactorial nature of dyspnea in cirrhotic patients, this complaint is easily overlooked, and HPS patients reportedly have respiratory symptoms for a mean of 4.8 years before diagnosis 7. In a majority of patients, dyspnea and hypoxemia progress over time 8. Furthermore, this progressive decline often occurs despite stable liver function 9. A more specific complaint is that of platypnea – breathlessness experienced in the upright position which is improved when lying down (supine position)7. This in turn correlates to the objective finding of orthodeoxia, a drop of 4mmHg in PaO2 or 5% in saturation when moving from the supine to the standing position, occurring in as many as 88% of HPS patients7.Other clinical manifestations of HPS include:
• Spider angiomata (small, dilated blood vessels clustered very close to the surface of the skin. (likelihood of HPS 21%)
• Clubbing of fingers or toes (likelihood of HPS 78%)
• Cyanosis (abnormal bluish discoloration of skin or mucous membranes due to tissues near the skin surface having low oxygen saturation) (likelihood of HPS 100%)2It is important to note that chest x-ray and thoracic CT scanning are often unremarkable in HPS; a lack of radiographic abnormalities is not sufficient evidence to rule out HPS.It should also be noted that HPS is not limited to patients with severe liver dysfunction; in fact, many patients with moderate to severe HPS have comparatively well preserved hepatic function1. | 567 | Hepatopulmonary Syndrome |
nord_567_2 | Causes of Hepatopulmonary Syndrome | The cause of HPS remains unclear and it is unknown why some patients with liver disease develop IPVDs while others do not. Hypoxemia in HPS is primarily due to limitations to the movement of oxygen from the lungs into the bloodstream (diffusion limitation), and mismatching between air moving through the lungs and blood moving through the lungs (ventilation-perfusion mismatch), caused by the presence of IPVDs1.Accordingly, efforts to decipher the cause of HPS have focused on the cause of the IPVDs that underlie the hypoxemia of HPS. Autopsies in HPS patients have confirmed that small blood vessels (capillaries) in the lungs are severely enlarged (dilated).10. These enlargements may result from increased production or impaired liver clearance of chemicals that cause blood vessels to relax (vasodilators), or from decreased production or lack of sensitivity to a chemical normally coming from a healthy liver that causes blood vessels to contract (vasoconstrictor). Though the nature of this underlying “liver factor” remains unclear, it is clear that at the level of the pulmonary blood vessels, nitric oxide (NO) has emerged as an important cause of this dilatation of blood vessels (vasodilation). The NO may be released through several pathways, including by inflammation caused by bacteria and bacterial material escaping from the gut into the blood circulation in patients with cirrhosis (gut bacterial translocation), which causes recruitment of cells called macrophages to the pulmonary blood vessels, where they produce and release NO14. In addition, rats with HPS demonstrate liver overproduction of a chemical called endothelin-1, with causes local NO production and release in the lungs 15,16. As our understanding of the cause of HPS evolves, it is more and more evident that these NO-mediated changes in pulmonary blood vessel size likely result in a more chronic change in the structure of the blood vessels themselves, which is called vascular remodeling. In turn, this may result from an imbalance of liver-released factors stimulating and preventing pulmonary blood vessel cell (endothelial cell) growth, that have yet to be identified17. | Causes of Hepatopulmonary Syndrome. The cause of HPS remains unclear and it is unknown why some patients with liver disease develop IPVDs while others do not. Hypoxemia in HPS is primarily due to limitations to the movement of oxygen from the lungs into the bloodstream (diffusion limitation), and mismatching between air moving through the lungs and blood moving through the lungs (ventilation-perfusion mismatch), caused by the presence of IPVDs1.Accordingly, efforts to decipher the cause of HPS have focused on the cause of the IPVDs that underlie the hypoxemia of HPS. Autopsies in HPS patients have confirmed that small blood vessels (capillaries) in the lungs are severely enlarged (dilated).10. These enlargements may result from increased production or impaired liver clearance of chemicals that cause blood vessels to relax (vasodilators), or from decreased production or lack of sensitivity to a chemical normally coming from a healthy liver that causes blood vessels to contract (vasoconstrictor). Though the nature of this underlying “liver factor” remains unclear, it is clear that at the level of the pulmonary blood vessels, nitric oxide (NO) has emerged as an important cause of this dilatation of blood vessels (vasodilation). The NO may be released through several pathways, including by inflammation caused by bacteria and bacterial material escaping from the gut into the blood circulation in patients with cirrhosis (gut bacterial translocation), which causes recruitment of cells called macrophages to the pulmonary blood vessels, where they produce and release NO14. In addition, rats with HPS demonstrate liver overproduction of a chemical called endothelin-1, with causes local NO production and release in the lungs 15,16. As our understanding of the cause of HPS evolves, it is more and more evident that these NO-mediated changes in pulmonary blood vessel size likely result in a more chronic change in the structure of the blood vessels themselves, which is called vascular remodeling. In turn, this may result from an imbalance of liver-released factors stimulating and preventing pulmonary blood vessel cell (endothelial cell) growth, that have yet to be identified17. | 567 | Hepatopulmonary Syndrome |
nord_567_3 | Affects of Hepatopulmonary Syndrome | Among cirrhotic subjects awaiting orthotopic liver transplantation (replacing the recipient liver with the donor liver), approximately 70% complain of dyspnea, 34-47% have intrapulmonary vascular dilatations (IPVDs), and 5-32% have HPS 6,18-23. HPS occurs in children and adults, in both males and females, and in people of all ethnic backgrounds. Though HPS has been reported in people with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia), the most common cause remains cirrhosis, though no specific etiology nor severity of cirrhosis has been found to be correlated with the incidence or severity of HPS. | Affects of Hepatopulmonary Syndrome. Among cirrhotic subjects awaiting orthotopic liver transplantation (replacing the recipient liver with the donor liver), approximately 70% complain of dyspnea, 34-47% have intrapulmonary vascular dilatations (IPVDs), and 5-32% have HPS 6,18-23. HPS occurs in children and adults, in both males and females, and in people of all ethnic backgrounds. Though HPS has been reported in people with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia), the most common cause remains cirrhosis, though no specific etiology nor severity of cirrhosis has been found to be correlated with the incidence or severity of HPS. | 567 | Hepatopulmonary Syndrome |
nord_567_4 | Related disorders of Hepatopulmonary Syndrome | Portopulmonary hypertension is another vascular complication of liver disease, which is often confused with HPS. However, hepatopulmonary syndrome and portopulmonary hypertension are not the same disease. Although both are abnormalities of the pulmonary vasculature resulting from liver disease, HPS is characterized by vasodilatation and hypoxemia whereas portopulmonary hypertension is characterized by obstruction or narrowing (vasoconstriction) of blood vessels with resulting pulmonary arterial hypertension6. | Related disorders of Hepatopulmonary Syndrome. Portopulmonary hypertension is another vascular complication of liver disease, which is often confused with HPS. However, hepatopulmonary syndrome and portopulmonary hypertension are not the same disease. Although both are abnormalities of the pulmonary vasculature resulting from liver disease, HPS is characterized by vasodilatation and hypoxemia whereas portopulmonary hypertension is characterized by obstruction or narrowing (vasoconstriction) of blood vessels with resulting pulmonary arterial hypertension6. | 567 | Hepatopulmonary Syndrome |
nord_567_5 | Diagnosis of Hepatopulmonary Syndrome | Because dyspnea is common in liver disease, HPS is often missed or diagnosed late. In the absence of an alternative explanation, a saturation of < 96% is suggestive of HPS.24 Worsening dyspnea in the upright compared to supine position (platypnea) and orthodeoxia (PaO2 drop by more than 5% or 4 mmHg in the upright position) occur in only 25% of patients6 but are highly specific for HPS (thought to be from gravitational re-distribution of blood flow to basilar parts of the lungs, where vascular dilatations are more severe), as are clubbing or cyanosis (in any patient with liver disease).21 Accordingly, clinicians should think of HPS in patients with liver disease and an unexplained oxygen saturation of < 96%, or any of: platypnea, orthodeoxia, clubbing, or cyanosis. After pulmonary evaluation, any patient with a PaO2 < 80 mmHg or alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg that cannot be fully explained by other diagnoses should be referred for a diagnostic workup for possible HPS25.
The diagnostic approach to HPS involves objective testing for each of the three components of its definition (see above). To begin with, evidence for (1) liver disease is sought through abdominal imaging for liver abnormalities including cirrhosis, as well as ancillary signs of portal hypertension, such as enlarged veins (varices) and/or enlarged spleen (splenomegaly). Furthermore, blood tests that show biochemical evidence of synthetic liver dysfunction, including albumin, bilirubin and international normalized ratio (INR) provide evidence for cirrhosis. Next, evidence for (2) IPVDs is sought through contrast echocardiography (or macroaggregated albumin shunt testing), and the presence of (3) an elevated alveolar-arterial oxygen gradient is determined by analysis of arterial blood gasses (ABG). Due to the important effect of orthodeoxia, in cases of suspected HPS, it is recommended that ABGs be performed only after 15 to 20 minutes at rest in the standing position.Clinical Testing and Work-Up All of the tests used to evaluate possible HPS are non-invasive. Initial workup should include some or all of the following tests:Pulmonary Function Tests
Pulmonary function tests in HPS patients usually reveal normal flows and lung volumes, though patients may have reduced lung volumes from accumulation of fluid in the abdomen (tense ascites) or excess fluid around the lungs (pleural effusions)26. Reduced movement of oxygen from the lungs into the bloodstream (diffusion impairment) is a frequent finding in HPS, occurring in up to 83% of patients in one series 7, however this finding is frequent in people with cirrhosis who do not have HPS as well, occurring in 50-70% of cirrhotic patients 20,27. Still, HPS subjects have been noted to have more profound reductions in diffusion capacity, with a mean DLCO of 55% predicted versus a mean of 72% predicted in people with cirrhosis who do not have HPS 20. Six Minute Walk Test, and if required, an Oxygen Titration
A six-minute walk test allows for objective assessment of exercise capacity and any low blood oxygen level (desaturation) with exercise. If patients do desaturate to below 88% with exertion, an oxygen titration study should then be performed to identify and match oxygen requirements.Liver Function Tests
Includes imaging with abdominal ultrasound and/or CT scan and some blood tests to determine the severity of a patient’s liver disease.Arterial Blood Gas
For this test, a small amount of blood is drawn from an artery in the wrist. The oxygen and carbon dioxide levels in the blood are then analyzed to help determine if a patient’s lungs are functioning properly.Echocardiogram
An echocardiogram, also known as a cardiac ultrasound, is a technique that uses sound waves to take images of the heart. In HPS patients, a small amount of salt water (agitated saline solution) is injected into a vein in the arm during the echocardiogram. This test helps determine whether or not the blood vessels in the lungs are dilated–a hallmark symptom of HPS.2-D transthoracic agitated saline contrast echocardiography (CE) has become the test of choice for identifying IPVDs. Saline microbubbles ranging from 15-180 um in size are created by mixing 10 ml of normal saline with 10 ml air, and are injected intravenously during normal transthoracic echocardiography. Within seconds, these bubbles appear in the right-sided heart chambers, and in the absence of IPVDs, become trapped in the pulmonary capillary bed, and are eventually absorbed. However, in HPS, IPVDs allow bubbles to pass through the pulmonary vascular bed, resulting in detectable bubbles in the left-sided heart chambers. Since an intracardiac shunt could have the same effect, the timing of left-sided bubble appearance is closely monitored, and the shunt is likely to be intracardiac if bubbles appear within 1-3 beats, and intrapulmonary if they appear after 3 beats (usually within 4-6 heartbeats)23.
Macroaggregated Albumin Lung Perfusion Scan
Sometimes a technetium-99 labeled macroaggregated albumin total body scan (MAA scan) will be ordered to determine the extent to which HPS is contributing to a patient’s oxygenation abnormalities. For this test, a small amount of safe, radioactive particles called Tc99m-MAA are injected into the patient’s arm and then a specialized camera is used to detect where in the body these particles end up. This is a more specific technique to test for the presence and severity of dilated blood vessels in the lungs.Especially in patients with evidence of coexisting cardiorespiratory disease, an MAA scan may be used to help establish the contribution of HPS to gas exchange abnormalities. In this technique, radioisotope labeled aggregates of albumin ranging between 20-60 um in diameter are injected into the venous circulation. In healthy people, these albumin aggregates are trapped in the pulmonary blood vessels, and nuclear scintigraphy reveals majority pulmonary uptake of the radioisotope. However, in the presence of IPVDs or an intracardiac shunt, these aggregates escape the filtering pulmonary capillaries and enter the body (systemic) circulation, becoming trapped primarily in brain, kidney and liver capillary beds. The amount of this anatomically shunted radioisotope can then be measured, enabling a calculation of the shunted fraction of the total blood pulmonary blood flow26,28,29. CT Scan of the Chest
This test is done to evaluate for other abnormalities that may be contributing to abnormal oxygenation. Although pulmonary blood vessels are generally dilated, the CT scan itself does not distinguish HPS from liver disease without HPS.30Follow-up visits will often include pulmonary function tests, a six-minute walk test, an oxygen titration study, and an arterial blood gas to monitor disease progression. | Diagnosis of Hepatopulmonary Syndrome. Because dyspnea is common in liver disease, HPS is often missed or diagnosed late. In the absence of an alternative explanation, a saturation of < 96% is suggestive of HPS.24 Worsening dyspnea in the upright compared to supine position (platypnea) and orthodeoxia (PaO2 drop by more than 5% or 4 mmHg in the upright position) occur in only 25% of patients6 but are highly specific for HPS (thought to be from gravitational re-distribution of blood flow to basilar parts of the lungs, where vascular dilatations are more severe), as are clubbing or cyanosis (in any patient with liver disease).21 Accordingly, clinicians should think of HPS in patients with liver disease and an unexplained oxygen saturation of < 96%, or any of: platypnea, orthodeoxia, clubbing, or cyanosis. After pulmonary evaluation, any patient with a PaO2 < 80 mmHg or alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg that cannot be fully explained by other diagnoses should be referred for a diagnostic workup for possible HPS25.
The diagnostic approach to HPS involves objective testing for each of the three components of its definition (see above). To begin with, evidence for (1) liver disease is sought through abdominal imaging for liver abnormalities including cirrhosis, as well as ancillary signs of portal hypertension, such as enlarged veins (varices) and/or enlarged spleen (splenomegaly). Furthermore, blood tests that show biochemical evidence of synthetic liver dysfunction, including albumin, bilirubin and international normalized ratio (INR) provide evidence for cirrhosis. Next, evidence for (2) IPVDs is sought through contrast echocardiography (or macroaggregated albumin shunt testing), and the presence of (3) an elevated alveolar-arterial oxygen gradient is determined by analysis of arterial blood gasses (ABG). Due to the important effect of orthodeoxia, in cases of suspected HPS, it is recommended that ABGs be performed only after 15 to 20 minutes at rest in the standing position.Clinical Testing and Work-Up All of the tests used to evaluate possible HPS are non-invasive. Initial workup should include some or all of the following tests:Pulmonary Function Tests
Pulmonary function tests in HPS patients usually reveal normal flows and lung volumes, though patients may have reduced lung volumes from accumulation of fluid in the abdomen (tense ascites) or excess fluid around the lungs (pleural effusions)26. Reduced movement of oxygen from the lungs into the bloodstream (diffusion impairment) is a frequent finding in HPS, occurring in up to 83% of patients in one series 7, however this finding is frequent in people with cirrhosis who do not have HPS as well, occurring in 50-70% of cirrhotic patients 20,27. Still, HPS subjects have been noted to have more profound reductions in diffusion capacity, with a mean DLCO of 55% predicted versus a mean of 72% predicted in people with cirrhosis who do not have HPS 20. Six Minute Walk Test, and if required, an Oxygen Titration
A six-minute walk test allows for objective assessment of exercise capacity and any low blood oxygen level (desaturation) with exercise. If patients do desaturate to below 88% with exertion, an oxygen titration study should then be performed to identify and match oxygen requirements.Liver Function Tests
Includes imaging with abdominal ultrasound and/or CT scan and some blood tests to determine the severity of a patient’s liver disease.Arterial Blood Gas
For this test, a small amount of blood is drawn from an artery in the wrist. The oxygen and carbon dioxide levels in the blood are then analyzed to help determine if a patient’s lungs are functioning properly.Echocardiogram
An echocardiogram, also known as a cardiac ultrasound, is a technique that uses sound waves to take images of the heart. In HPS patients, a small amount of salt water (agitated saline solution) is injected into a vein in the arm during the echocardiogram. This test helps determine whether or not the blood vessels in the lungs are dilated–a hallmark symptom of HPS.2-D transthoracic agitated saline contrast echocardiography (CE) has become the test of choice for identifying IPVDs. Saline microbubbles ranging from 15-180 um in size are created by mixing 10 ml of normal saline with 10 ml air, and are injected intravenously during normal transthoracic echocardiography. Within seconds, these bubbles appear in the right-sided heart chambers, and in the absence of IPVDs, become trapped in the pulmonary capillary bed, and are eventually absorbed. However, in HPS, IPVDs allow bubbles to pass through the pulmonary vascular bed, resulting in detectable bubbles in the left-sided heart chambers. Since an intracardiac shunt could have the same effect, the timing of left-sided bubble appearance is closely monitored, and the shunt is likely to be intracardiac if bubbles appear within 1-3 beats, and intrapulmonary if they appear after 3 beats (usually within 4-6 heartbeats)23.
Macroaggregated Albumin Lung Perfusion Scan
Sometimes a technetium-99 labeled macroaggregated albumin total body scan (MAA scan) will be ordered to determine the extent to which HPS is contributing to a patient’s oxygenation abnormalities. For this test, a small amount of safe, radioactive particles called Tc99m-MAA are injected into the patient’s arm and then a specialized camera is used to detect where in the body these particles end up. This is a more specific technique to test for the presence and severity of dilated blood vessels in the lungs.Especially in patients with evidence of coexisting cardiorespiratory disease, an MAA scan may be used to help establish the contribution of HPS to gas exchange abnormalities. In this technique, radioisotope labeled aggregates of albumin ranging between 20-60 um in diameter are injected into the venous circulation. In healthy people, these albumin aggregates are trapped in the pulmonary blood vessels, and nuclear scintigraphy reveals majority pulmonary uptake of the radioisotope. However, in the presence of IPVDs or an intracardiac shunt, these aggregates escape the filtering pulmonary capillaries and enter the body (systemic) circulation, becoming trapped primarily in brain, kidney and liver capillary beds. The amount of this anatomically shunted radioisotope can then be measured, enabling a calculation of the shunted fraction of the total blood pulmonary blood flow26,28,29. CT Scan of the Chest
This test is done to evaluate for other abnormalities that may be contributing to abnormal oxygenation. Although pulmonary blood vessels are generally dilated, the CT scan itself does not distinguish HPS from liver disease without HPS.30Follow-up visits will often include pulmonary function tests, a six-minute walk test, an oxygen titration study, and an arterial blood gas to monitor disease progression. | 567 | Hepatopulmonary Syndrome |
nord_567_6 | Therapies of Hepatopulmonary Syndrome | TreatmentLiver transplantation is the only known effective therapy for HPS, with significant improvement in oxygenation observed in the majority of patients within one year of transplantation3. Patients require close assessment and follow-up by lung and liver experts before and after transplant. Long-term oxygen therapy is the mainstay of supportive therapy for HPS, and there may also be a role for pre-and post-operative pulmonary rehabilitation.It has been clearly shown that HPS patients with a paO2 60 mmHg have significantly better 5-year survival rates with liver transplantation, when compared to supportive therapy 8. As a result, the United Network for Organ Sharing (UNOS) has recommended the allocation of additional points in the MELD (model for end-stage liver disease) organ-allocation prioritization system, for HPS subjects with paO2 < 60 mm Hg, with a goal of transplantation within 3 months of listing 31.Since hypoxemia is progressive in HPS, and pre-operative prognosis and surgical outcomes are closely linked to the severity of hypoxemia, HPS patients should be listed for transplantation as early as possible. Also, it is of note that within the last decade, increasing interest and expertise has evolved in living-related liver transplantation as well, and it appears as though this procedure has a similar effect on HPS to that of transplantation with a liver from a person who has died. There are a number of important complications regarding liver transplantation for HPS. Firstly, there have been numerous reports of severe post-transplant hypoxemia32 requiring prolonged mechanical ventilation and innovative techniques to manage hypoxemia33. Also, a number of centers have noted increased post-operative infections and leaks of bile from the connections between bile ducts (anastomotic bile duct leaks), suspected to be the result of delayed wound healing due to hypoxemia. Also, numerous early post-operative blood clots including portal vein and hepatic artery blot clots have been reported, possibly in the context of overproduction of red blood cells (polycythemia) from chronic hypoxemia 34,35. Furthermore, there are reports of post-transplant recurrence of HPS as a result of graft dysfunction from liver inflammation and damage caused by a buildup of fat in the liver (non-alcoholic steatohepatitis or NASH), or recurrent hepatitis C. Also, there has been a report of post-transplant resolution of hypoxemia followed by development progressive pulmonary hypertension. Finally, numerous reports have shown that decreased diffusing capacity of the lungs (DLCO) in HPS does not improve post-transplant, despite an improvement in oxygenation. | Therapies of Hepatopulmonary Syndrome. TreatmentLiver transplantation is the only known effective therapy for HPS, with significant improvement in oxygenation observed in the majority of patients within one year of transplantation3. Patients require close assessment and follow-up by lung and liver experts before and after transplant. Long-term oxygen therapy is the mainstay of supportive therapy for HPS, and there may also be a role for pre-and post-operative pulmonary rehabilitation.It has been clearly shown that HPS patients with a paO2 60 mmHg have significantly better 5-year survival rates with liver transplantation, when compared to supportive therapy 8. As a result, the United Network for Organ Sharing (UNOS) has recommended the allocation of additional points in the MELD (model for end-stage liver disease) organ-allocation prioritization system, for HPS subjects with paO2 < 60 mm Hg, with a goal of transplantation within 3 months of listing 31.Since hypoxemia is progressive in HPS, and pre-operative prognosis and surgical outcomes are closely linked to the severity of hypoxemia, HPS patients should be listed for transplantation as early as possible. Also, it is of note that within the last decade, increasing interest and expertise has evolved in living-related liver transplantation as well, and it appears as though this procedure has a similar effect on HPS to that of transplantation with a liver from a person who has died. There are a number of important complications regarding liver transplantation for HPS. Firstly, there have been numerous reports of severe post-transplant hypoxemia32 requiring prolonged mechanical ventilation and innovative techniques to manage hypoxemia33. Also, a number of centers have noted increased post-operative infections and leaks of bile from the connections between bile ducts (anastomotic bile duct leaks), suspected to be the result of delayed wound healing due to hypoxemia. Also, numerous early post-operative blood clots including portal vein and hepatic artery blot clots have been reported, possibly in the context of overproduction of red blood cells (polycythemia) from chronic hypoxemia 34,35. Furthermore, there are reports of post-transplant recurrence of HPS as a result of graft dysfunction from liver inflammation and damage caused by a buildup of fat in the liver (non-alcoholic steatohepatitis or NASH), or recurrent hepatitis C. Also, there has been a report of post-transplant resolution of hypoxemia followed by development progressive pulmonary hypertension. Finally, numerous reports have shown that decreased diffusing capacity of the lungs (DLCO) in HPS does not improve post-transplant, despite an improvement in oxygenation. | 567 | Hepatopulmonary Syndrome |
nord_568_0 | Overview of Hepatorenal Syndrome | Hepatorenal syndrome (HRS) is a form of impaired kidney function that occurs in individuals with advanced liver disease. Individuals with hepatorenal syndrome do not have any identifiable cause of kidney dysfunction and the kidneys themselves are not structural damaged. Therefore, hepatorenal syndrome may be referred as a “functional” form of kidney impairment. In fact, if the kidney of an individual with hepatorenal syndrome were to be transplanted into an otherwise healthy individual, it would function normally. Hepatorenal syndrome is classified into to two distinct types. Type I is a rapidly progressive condition that leads to renal failure; type II does not have a rapid course and progresses slowly over weeks to months.Although the hepatorenal syndrome occurs in individuals with liver disease, the exact cause of the condition is unknown. Researchers have noted that blood circulation is abnormal in individuals with hepatorenal syndrome. The arteries that circulate oxygenated blood from the lungs to the rest of the body (systemic circulation) widen in contrast to the arteries of the kidney, which narrow causing a decrease in the blood flow through the kidney. Many affected individuals also have high blood pressure of the branches of the portal vein (portal hypertension), the main vein that carries blood from the intestines to the liver. | Overview of Hepatorenal Syndrome. Hepatorenal syndrome (HRS) is a form of impaired kidney function that occurs in individuals with advanced liver disease. Individuals with hepatorenal syndrome do not have any identifiable cause of kidney dysfunction and the kidneys themselves are not structural damaged. Therefore, hepatorenal syndrome may be referred as a “functional” form of kidney impairment. In fact, if the kidney of an individual with hepatorenal syndrome were to be transplanted into an otherwise healthy individual, it would function normally. Hepatorenal syndrome is classified into to two distinct types. Type I is a rapidly progressive condition that leads to renal failure; type II does not have a rapid course and progresses slowly over weeks to months.Although the hepatorenal syndrome occurs in individuals with liver disease, the exact cause of the condition is unknown. Researchers have noted that blood circulation is abnormal in individuals with hepatorenal syndrome. The arteries that circulate oxygenated blood from the lungs to the rest of the body (systemic circulation) widen in contrast to the arteries of the kidney, which narrow causing a decrease in the blood flow through the kidney. Many affected individuals also have high blood pressure of the branches of the portal vein (portal hypertension), the main vein that carries blood from the intestines to the liver. | 568 | Hepatorenal Syndrome |
nord_568_1 | Symptoms of Hepatorenal Syndrome | Individuals with hepatorenal syndrome will have a variety of nonspecific symptoms including fatigue, abdominal pain, and a general feeling of ill health (malaise). Affected individuals also have symptoms related to advanced liver disease including the accumulation of fluid in the abdomen (ascites), yellowing of the skin and the whites of the eyes (jaundice), an enlarged spleen (splenomegaly) and an enlarged, extremely tender liver (hepatomegaly).Hepatorenal syndrome type I is characterized by a rapid decrease in kidney function. The kidneys act as a filtration system removing unwanted substances and excess fluid from the body. Symptoms of decreasing renal function include the accumulation of excess watery fluid in the spaces between the tissues and organs causing swelling of these areas (edema), dramatically decreased urination, and the presence of increased nitrogenous waste products such as creatinine and BUN in the blood (azotemia). Hepatorenal syndrome type I can progress to life-threatening renal failure within days.Individuals with hepatorenal syndrome type I are more likely to suffer from hepatic encephalopathy, a condition that occurs when the liver fails to breakdown (metabolize) certain substances in the body. These substances travel through the bloodstream to the brain with toxic effects. Hepatic encephalopathy may cause confusion, drowsiness, recognizable changes in judgment and other intellectual processes, and other psychological alterations. It also is more likely to occur with acute liver failure due to any cause.Hepatorenal syndrome type II causes renal dysfunction that generally progresses much slower than it does in type I. Affected individuals are less likely to develop jaundice and usually do not develop hepatic encephalopathy. Individuals with hepatorenal syndrome type II often develop accumulation of fluid in the abdomen (ascites) does not respond to treatment with diuretics, which are drugs that help remove excess fluid from the body. This finding is referred to as diuretic-resistant ascites. It can occur over weeks to months with a slow rise of BUN and Creatinine. | Symptoms of Hepatorenal Syndrome. Individuals with hepatorenal syndrome will have a variety of nonspecific symptoms including fatigue, abdominal pain, and a general feeling of ill health (malaise). Affected individuals also have symptoms related to advanced liver disease including the accumulation of fluid in the abdomen (ascites), yellowing of the skin and the whites of the eyes (jaundice), an enlarged spleen (splenomegaly) and an enlarged, extremely tender liver (hepatomegaly).Hepatorenal syndrome type I is characterized by a rapid decrease in kidney function. The kidneys act as a filtration system removing unwanted substances and excess fluid from the body. Symptoms of decreasing renal function include the accumulation of excess watery fluid in the spaces between the tissues and organs causing swelling of these areas (edema), dramatically decreased urination, and the presence of increased nitrogenous waste products such as creatinine and BUN in the blood (azotemia). Hepatorenal syndrome type I can progress to life-threatening renal failure within days.Individuals with hepatorenal syndrome type I are more likely to suffer from hepatic encephalopathy, a condition that occurs when the liver fails to breakdown (metabolize) certain substances in the body. These substances travel through the bloodstream to the brain with toxic effects. Hepatic encephalopathy may cause confusion, drowsiness, recognizable changes in judgment and other intellectual processes, and other psychological alterations. It also is more likely to occur with acute liver failure due to any cause.Hepatorenal syndrome type II causes renal dysfunction that generally progresses much slower than it does in type I. Affected individuals are less likely to develop jaundice and usually do not develop hepatic encephalopathy. Individuals with hepatorenal syndrome type II often develop accumulation of fluid in the abdomen (ascites) does not respond to treatment with diuretics, which are drugs that help remove excess fluid from the body. This finding is referred to as diuretic-resistant ascites. It can occur over weeks to months with a slow rise of BUN and Creatinine. | 568 | Hepatorenal Syndrome |
nord_568_2 | Causes of Hepatorenal Syndrome | The exact cause of hepatorenal syndrome is unknown. It occurs in individuals with advanced liver disease, especially individuals who have scarring and dysfunction of the liver (cirrhosis). The characteristic finding in individuals with hepatorenal syndrome is narrowing (constriction) of the blood vessels that feed the kidneys (renal vasoconstriction), which results in decreased blood flow to the kidneys, eventually impairing kidney function.The reason that renal vasoconstriction occurs is unknown. Researchers believe that the complex interaction of several different factors is involved including high blood pressure of the main blood vessels of the liver (portal hypertension), abnormalities in the physical factors that govern blood flow (systemic hemodynamics), the activation of substances that cause blood vessels to narrow (vasoconstrictors) and suppression of substances that cause blood vessels to widen (vasodilators).Researchers have also determined that cirrhotic cardiomyopathy may also contribute to the development of hepatorenal syndrome in some individuals. Cirrhotic cardiomyopathy refers to the abnormal functioning of the heart in individuals with scarring of the liver (cirrhosis). Cirrhotic cardiomyopathy results in decreased cardiac outflow (heart failure) and abnormal widening of certain arteries in the body.In some individuals with hepatorenal syndrome, certain ‘triggers' can be identified that make it more likely for individuals with liver disease to developed impaired kidney function (hepatorenal syndrome). There triggers are called precipitating factors. The most common precipitating factor is spontaneous bacterial peritonitis (SBP), an infection of the thin membrane (peritoneum) that lines the abdominal cavity. SBP is a known complication in individuals with ascites and cirrhosis. Other common triggers are acute blood loss from the gastrointestinal tract (GI bleeding), low blood pressure and infection from any cause. | Causes of Hepatorenal Syndrome. The exact cause of hepatorenal syndrome is unknown. It occurs in individuals with advanced liver disease, especially individuals who have scarring and dysfunction of the liver (cirrhosis). The characteristic finding in individuals with hepatorenal syndrome is narrowing (constriction) of the blood vessels that feed the kidneys (renal vasoconstriction), which results in decreased blood flow to the kidneys, eventually impairing kidney function.The reason that renal vasoconstriction occurs is unknown. Researchers believe that the complex interaction of several different factors is involved including high blood pressure of the main blood vessels of the liver (portal hypertension), abnormalities in the physical factors that govern blood flow (systemic hemodynamics), the activation of substances that cause blood vessels to narrow (vasoconstrictors) and suppression of substances that cause blood vessels to widen (vasodilators).Researchers have also determined that cirrhotic cardiomyopathy may also contribute to the development of hepatorenal syndrome in some individuals. Cirrhotic cardiomyopathy refers to the abnormal functioning of the heart in individuals with scarring of the liver (cirrhosis). Cirrhotic cardiomyopathy results in decreased cardiac outflow (heart failure) and abnormal widening of certain arteries in the body.In some individuals with hepatorenal syndrome, certain ‘triggers' can be identified that make it more likely for individuals with liver disease to developed impaired kidney function (hepatorenal syndrome). There triggers are called precipitating factors. The most common precipitating factor is spontaneous bacterial peritonitis (SBP), an infection of the thin membrane (peritoneum) that lines the abdominal cavity. SBP is a known complication in individuals with ascites and cirrhosis. Other common triggers are acute blood loss from the gastrointestinal tract (GI bleeding), low blood pressure and infection from any cause. | 568 | Hepatorenal Syndrome |
nord_568_3 | Affects of Hepatorenal Syndrome | Hepatorenal syndrome affects males and females in equal numbers. The exact incidence of hepatorenal syndrome is unknown. It is estimated to occur in approximately 8-10 percent of individuals with the accumulation of fluid in the abdomen (ascites) and cirrhosis. Although it is most common in individuals with advanced cirrhosis and ascites, hepatorenal syndrome has also occurs in individuals with other forms of liver disease including fulminant hepatic failure. | Affects of Hepatorenal Syndrome. Hepatorenal syndrome affects males and females in equal numbers. The exact incidence of hepatorenal syndrome is unknown. It is estimated to occur in approximately 8-10 percent of individuals with the accumulation of fluid in the abdomen (ascites) and cirrhosis. Although it is most common in individuals with advanced cirrhosis and ascites, hepatorenal syndrome has also occurs in individuals with other forms of liver disease including fulminant hepatic failure. | 568 | Hepatorenal Syndrome |
nord_568_4 | Related disorders of Hepatorenal Syndrome | Symptoms of the following disorders can be similar to those of hepatorenal syndrome. Comparisons may be useful for a differential diagnosis.There are many causes of acute kidney failure: abnormalities of the blood vessels of or leading to the kidney; abnormalities of the glomeruli of the kidneys due to infections or diseases such as Goodpasture syndrome, polycystic kidney disease, or Wegener’s granulomatosis; acute interstitial nephritis (inflammation of the kidney) commonly related to drugs or infections; intratubular obstruction; or acute tubular necrosis. An underlying problem in the kidney distinguishes these disorders from the hepatorenal syndrome. (For more information on these disorders, choose ‘Goodpasture', ‘Polycystic Kidney', or ‘Wegener' as your search terms in the Rare Disease Database.) | Related disorders of Hepatorenal Syndrome. Symptoms of the following disorders can be similar to those of hepatorenal syndrome. Comparisons may be useful for a differential diagnosis.There are many causes of acute kidney failure: abnormalities of the blood vessels of or leading to the kidney; abnormalities of the glomeruli of the kidneys due to infections or diseases such as Goodpasture syndrome, polycystic kidney disease, or Wegener’s granulomatosis; acute interstitial nephritis (inflammation of the kidney) commonly related to drugs or infections; intratubular obstruction; or acute tubular necrosis. An underlying problem in the kidney distinguishes these disorders from the hepatorenal syndrome. (For more information on these disorders, choose ‘Goodpasture', ‘Polycystic Kidney', or ‘Wegener' as your search terms in the Rare Disease Database.) | 568 | Hepatorenal Syndrome |
nord_568_5 | Diagnosis of Hepatorenal Syndrome | A diagnosis of hepatorenal syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The International Ascites Club, an organization dedicated to encouraging scientific research into advanced cirrhosis, has established criteria for a diagnosis of hepatorenal syndrome.The major criteria are: the presence advanced liver failure with portal hypertension; high levels of creatine (an organic acid); the absence of other causes of renal failure such as bacterial infection, shock, and the use of drugs that are toxic to the kidneys; no improvement in renal function with the withdrawal of diuretics and expansion of plasma with albumin (a protein made in the liver which is low in patients with liver disease); and low levels of protein in the urine with no evidence of a disease of the urinary disease (uropathy) or parenchymal renal disease. | Diagnosis of Hepatorenal Syndrome. A diagnosis of hepatorenal syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The International Ascites Club, an organization dedicated to encouraging scientific research into advanced cirrhosis, has established criteria for a diagnosis of hepatorenal syndrome.The major criteria are: the presence advanced liver failure with portal hypertension; high levels of creatine (an organic acid); the absence of other causes of renal failure such as bacterial infection, shock, and the use of drugs that are toxic to the kidneys; no improvement in renal function with the withdrawal of diuretics and expansion of plasma with albumin (a protein made in the liver which is low in patients with liver disease); and low levels of protein in the urine with no evidence of a disease of the urinary disease (uropathy) or parenchymal renal disease. | 568 | Hepatorenal Syndrome |
nord_568_6 | Therapies of Hepatorenal Syndrome | TreatmentThe only curative therapy for individuals with hepatorenal syndrome is a liver transplant, which corrects both liver disease and associated impaired renal function. Even after successful liver transplantation, patients who had hepatorenal syndrome beforehand may not fully recover their kidney function. A small percentage may go on to permanent damage requiring dialysis. Much research is ongoing to determine which patients will recover and which may not. Those who may not recover may need a kidney transplant with their liver transplant. However, due to a limited number of donors and long waiting lists, a liver transplant is not always feasible. For patients who develop hepatorenal syndrome with acute liver failure and not cirrhosis, recovery from hepatorenal syndrome can occur if the liver recovers. However, individuals with hepatorenal syndrome requiring dialysis or suffering from advanced kidney failure for 6-8 weeks before receiving a liver transplant, may require a kidney transplant with their liver transplant, as kidney function may not recover. Individuals with liver disease and the hepatorenal syndrome who receive a liver transplant have a lower success rate than in individuals with liver disease and normal kidney function who receive a liver transplant. Therefore, many of the therapies used to treat hepatorenal syndrome are done to improve kidney function in individuals eligible for a liver transplant. For individuals awaiting a transplant, several therapies to maintain kidney function may be used. Paracentesis is a surgical procedure that removes the excess fluid from the abdomen (ascites). Under carefully controlled conditions, this procedure may benefit some affected individuals. In addition, avoiding diuretics (which can worsen kidney function), maintaining electrolyte balance, and promptly treating infection may also be necessary. In 2022, terlipressin (Terlivaz) was approved by the U.S. Food and Drug Administration (FDA) as a treatment option to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney failure. Terlipressin is in the class of drugs known as systemic vasoconstrictors (drugs that cause the blood vessels to narrow). | Therapies of Hepatorenal Syndrome. TreatmentThe only curative therapy for individuals with hepatorenal syndrome is a liver transplant, which corrects both liver disease and associated impaired renal function. Even after successful liver transplantation, patients who had hepatorenal syndrome beforehand may not fully recover their kidney function. A small percentage may go on to permanent damage requiring dialysis. Much research is ongoing to determine which patients will recover and which may not. Those who may not recover may need a kidney transplant with their liver transplant. However, due to a limited number of donors and long waiting lists, a liver transplant is not always feasible. For patients who develop hepatorenal syndrome with acute liver failure and not cirrhosis, recovery from hepatorenal syndrome can occur if the liver recovers. However, individuals with hepatorenal syndrome requiring dialysis or suffering from advanced kidney failure for 6-8 weeks before receiving a liver transplant, may require a kidney transplant with their liver transplant, as kidney function may not recover. Individuals with liver disease and the hepatorenal syndrome who receive a liver transplant have a lower success rate than in individuals with liver disease and normal kidney function who receive a liver transplant. Therefore, many of the therapies used to treat hepatorenal syndrome are done to improve kidney function in individuals eligible for a liver transplant. For individuals awaiting a transplant, several therapies to maintain kidney function may be used. Paracentesis is a surgical procedure that removes the excess fluid from the abdomen (ascites). Under carefully controlled conditions, this procedure may benefit some affected individuals. In addition, avoiding diuretics (which can worsen kidney function), maintaining electrolyte balance, and promptly treating infection may also be necessary. In 2022, terlipressin (Terlivaz) was approved by the U.S. Food and Drug Administration (FDA) as a treatment option to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney failure. Terlipressin is in the class of drugs known as systemic vasoconstrictors (drugs that cause the blood vessels to narrow). | 568 | Hepatorenal Syndrome |
nord_569_0 | Overview of Hereditary Angioedema | Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries). In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals.The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions (e.g., flow of body fluids in and out of cells). Hereditary angioedema type II, a more uncommon form of the disorder, occurs as the result of the production of abnormal complement proteins. | Overview of Hereditary Angioedema. Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries). In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals.The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions (e.g., flow of body fluids in and out of cells). Hereditary angioedema type II, a more uncommon form of the disorder, occurs as the result of the production of abnormal complement proteins. | 569 | Hereditary Angioedema |
nord_569_1 | Symptoms of Hereditary Angioedema | The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid (edema). The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.The symptoms of hereditary angioedema may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen the recurring symptoms.Symptoms associated with swelling in the digestive system (gastrointestinal tract) include nausea, vomiting, acute abdominal pain, and/or other signs of obstruction. Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation. | Symptoms of Hereditary Angioedema. The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid (edema). The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.The symptoms of hereditary angioedema may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen the recurring symptoms.Symptoms associated with swelling in the digestive system (gastrointestinal tract) include nausea, vomiting, acute abdominal pain, and/or other signs of obstruction. Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation. | 569 | Hereditary Angioedema |
nord_569_2 | Causes of Hereditary Angioedema | Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a spontaneous new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.The symptoms of hereditary angioedema type I develop due to a deficiency of a protein known as complement component C1 esterase inhibitor. Hereditary angioedema type II is a more uncommon form of the disorder and may occur because of abnormal C1 esterase proteins that do not function properly.The gene that causes hereditary angioedema is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q12-q13.1” refers to bands 12-13.1 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | Causes of Hereditary Angioedema. Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a spontaneous new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.The symptoms of hereditary angioedema type I develop due to a deficiency of a protein known as complement component C1 esterase inhibitor. Hereditary angioedema type II is a more uncommon form of the disorder and may occur because of abnormal C1 esterase proteins that do not function properly.The gene that causes hereditary angioedema is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q12-q13.1” refers to bands 12-13.1 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | 569 | Hereditary Angioedema |
nord_569_3 | Affects of Hereditary Angioedema | Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide. | Affects of Hereditary Angioedema. Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide. | 569 | Hereditary Angioedema |
nord_569_4 | Related disorders of Hereditary Angioedema | Symptoms of the following disorders can be similar to those of hereditary angioedema. Comparisons may be useful for a differential diagnosis:Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoproliferative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusitis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disorders, choose “Anaphylaxis,” “Leukemia,” “Myeloma,” “Lupus,” and “Cryoglobulinemia” as your search term in the Rare Disease Database.)Cutis laxa is a rare congenital or acquired connective tissue disorder characterized by limp or slack skin. The affected areas of the skin may be thickened and dark. This disorder is usually diagnosed at birth or early in infancy. The initial symptom is usually an episode of swelling on the face and may be confused with hereditary angioedema. Cutis laxa progresses causing skin changes and damage to blood vessels. (For more information on this disorder, choose “Cutis Laxa” as your search term in the Rare Disease Database.) | Related disorders of Hereditary Angioedema. Symptoms of the following disorders can be similar to those of hereditary angioedema. Comparisons may be useful for a differential diagnosis:Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoproliferative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusitis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disorders, choose “Anaphylaxis,” “Leukemia,” “Myeloma,” “Lupus,” and “Cryoglobulinemia” as your search term in the Rare Disease Database.)Cutis laxa is a rare congenital or acquired connective tissue disorder characterized by limp or slack skin. The affected areas of the skin may be thickened and dark. This disorder is usually diagnosed at birth or early in infancy. The initial symptom is usually an episode of swelling on the face and may be confused with hereditary angioedema. Cutis laxa progresses causing skin changes and damage to blood vessels. (For more information on this disorder, choose “Cutis Laxa” as your search term in the Rare Disease Database.) | 569 | Hereditary Angioedema |
nord_569_5 | Diagnosis of Hereditary Angioedema | The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests that detect decreased levels of complement proteins. In instances of high clinical suspicion and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated. | Diagnosis of Hereditary Angioedema. The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests that detect decreased levels of complement proteins. In instances of high clinical suspicion and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated. | 569 | Hereditary Angioedema |
nord_569_6 | Therapies of Hereditary Angioedema | Treatment
In 2008, the Food and Drug Administration (FDA) approved Cinryze, a C1 inhibitor therapy, for routine prevention (prophylaxis) of attacks of spontaneous swelling (angioedema) in adolescents and adults with HAE. This is the first drug approved for this purpose in the U.S. In 2009, FDA approved Berinert, to treat acute abdominal attacks and facial swelling associated with HAE in adults and adolescents. It is a protein product derived from human plasma. In 2016, FDA approved Berinert, as the first and only pediatric treatment for HAE. Also in 2009, FDA approved Kalbitor (ecallantide) to treat sudden and potentially life-threatening fluid buildup related to HAE. Kalbitor is a liquid that is intended to be injected under the skin of people age 16 and older with HAE.In 2014, FDA approved Ruconest, a recombinant C1-esterase inhibitor for the treatment of acute attacks in adult and adolescent patients with HAE. In 2017, FDA approved Haegarda (C1-esterase inhibitor) for administration under the skin to prevent HAE attacks. Most recently, in 2020, FDA approved Orladeyo (berotralstat) to prevent attacks in patients 12 years of age and older with HAE. Orladeyo is an oral capsule taken one time per day. To avoid episodes of angioedema associated with surgery, dental work, and similar stresses, short-term treatment is suggested before surgery or dental procedures. Patients should discuss options with their physicians.In acute attacks with the danger of severe airway swelling and obstruction, it is essential to maintain or establish an airway. A temporary surgical opening in the throat (tracheotomy) may be created and oxygen may have to be supplied. | Therapies of Hereditary Angioedema. Treatment
In 2008, the Food and Drug Administration (FDA) approved Cinryze, a C1 inhibitor therapy, for routine prevention (prophylaxis) of attacks of spontaneous swelling (angioedema) in adolescents and adults with HAE. This is the first drug approved for this purpose in the U.S. In 2009, FDA approved Berinert, to treat acute abdominal attacks and facial swelling associated with HAE in adults and adolescents. It is a protein product derived from human plasma. In 2016, FDA approved Berinert, as the first and only pediatric treatment for HAE. Also in 2009, FDA approved Kalbitor (ecallantide) to treat sudden and potentially life-threatening fluid buildup related to HAE. Kalbitor is a liquid that is intended to be injected under the skin of people age 16 and older with HAE.In 2014, FDA approved Ruconest, a recombinant C1-esterase inhibitor for the treatment of acute attacks in adult and adolescent patients with HAE. In 2017, FDA approved Haegarda (C1-esterase inhibitor) for administration under the skin to prevent HAE attacks. Most recently, in 2020, FDA approved Orladeyo (berotralstat) to prevent attacks in patients 12 years of age and older with HAE. Orladeyo is an oral capsule taken one time per day. To avoid episodes of angioedema associated with surgery, dental work, and similar stresses, short-term treatment is suggested before surgery or dental procedures. Patients should discuss options with their physicians.In acute attacks with the danger of severe airway swelling and obstruction, it is essential to maintain or establish an airway. A temporary surgical opening in the throat (tracheotomy) may be created and oxygen may have to be supplied. | 569 | Hereditary Angioedema |
nord_570_0 | Overview of Hereditary Breast and Ovarian Cancer Syndrome | Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. Additionally, to a lesser degree, there is also an increased risk of developing other types of cancer including prostrate cancer, melanoma, and pancreatic cancer. HBOC syndrome is most commonly associated with variations (mutations) in the either the BRCA1 gene or the BRCA2 gene. In HBOC syndrome, there is usually a family history of cancer and the variant gene is inherited. The underlying causes of cancer are not completely understood and while inheriting a variation in the BRCA1 or BRCA2 gene greatly increases a person’s risk of developing certain cancers, it does not mean that the people will definitely develop cancer. Some people with variations in these genes never develop cancer. How these gene variants affect individuals and families will be different. Most likely, there are additional genetic (e.g. variations in other genes) or environmental factors (e.g. smoking) that influence whether and how cancer develops.Most forms of cancer develop sporadically. When cancer occurs sporadically, it is usually because of aging and other factors besides genetics. With sporadic cancer, there is a single occurrence of that form of cancer in the family and the affected person is usually older (often more than 60 years old). Sometimes, cancer is familial. This means that two or more first-degree relatives have the same type of cancer. Cancer usually develops after the age of 50 and there are several, moderate-to-minor genetic factors involved. In addition, there is often an environment factor or factors as well. HBOC syndrome is a genetic disorder in which multiple members in multiple generations are affected. Cancer often develops before the age of 50. The affected family members have a variation in a single major cancer susceptibility gene, most often the BRCA1 or BRCA2 gene. | Overview of Hereditary Breast and Ovarian Cancer Syndrome. Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. Additionally, to a lesser degree, there is also an increased risk of developing other types of cancer including prostrate cancer, melanoma, and pancreatic cancer. HBOC syndrome is most commonly associated with variations (mutations) in the either the BRCA1 gene or the BRCA2 gene. In HBOC syndrome, there is usually a family history of cancer and the variant gene is inherited. The underlying causes of cancer are not completely understood and while inheriting a variation in the BRCA1 or BRCA2 gene greatly increases a person’s risk of developing certain cancers, it does not mean that the people will definitely develop cancer. Some people with variations in these genes never develop cancer. How these gene variants affect individuals and families will be different. Most likely, there are additional genetic (e.g. variations in other genes) or environmental factors (e.g. smoking) that influence whether and how cancer develops.Most forms of cancer develop sporadically. When cancer occurs sporadically, it is usually because of aging and other factors besides genetics. With sporadic cancer, there is a single occurrence of that form of cancer in the family and the affected person is usually older (often more than 60 years old). Sometimes, cancer is familial. This means that two or more first-degree relatives have the same type of cancer. Cancer usually develops after the age of 50 and there are several, moderate-to-minor genetic factors involved. In addition, there is often an environment factor or factors as well. HBOC syndrome is a genetic disorder in which multiple members in multiple generations are affected. Cancer often develops before the age of 50. The affected family members have a variation in a single major cancer susceptibility gene, most often the BRCA1 or BRCA2 gene. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_1 | Symptoms of Hereditary Breast and Ovarian Cancer Syndrome | HBOC syndrome is a cancer predisposition syndrome in which individuals are at a greater risk of developing certain cancers, particularly breast or ovarian cancer. Signs and symptoms are associated with the development of cancer, and depend upon the type and location of cancer. HBOC syndrome can cause cancer in multiple family members over several generations in one family. It can also be associated with more than one cancer in the same person. The exact percentage of risk for specific types of cancer in HBOC syndrome varies greatly depending on the specific gene that is altered and the specific alteration (i.e. mutation). Some people with a variation in these genes will never develop cancer. Female breast cancer is the most common type of cancer associated with a variation in the BRCA1 or BRCA2 genes. The risk for breast in the general population is about 12%, but for women with a BRCA1 gene variation it can be between 46%-87%, and between 38%-84% for women with a BRCA2 variation. There is also an increased risk of having a second primary breast cancer. In HBOC syndrome, ovarian cancer includes cancer of the fallopian tubes. Primary peritoneal cancers can also occur. These are cancers that develop in the thin layer of tissue that lines the abdomen (peritoneum). The risk for ovarian cancer in the general population is about 1%-2%, but about 39%-63% with BRCA1 gene variations and 16.5%-27% with BRCA2 variations. There is an increased risk for male breast cancer, which affects about .1% of the population. In men with a BRCA1 gene variation, there is a 1.2% risk and an 8.9% risk in men with a BRCA2 gene variation. In general, the relative risk for male breast cancer is greatest in men in their 30s and 40s and decreases with advancing age. There is a risk of prostate cancer of 6% before the age of 69 in the general population. There is an 8.9% by 65 years of age in men with a BRCA1 variation and a 15% risk by age 65 in men with a BRCA2 variation. The lifetime risk for prostate cancer is about 20%-25%. The risk of pancreatic cancer in the general population is about .5%. With a BRCA1 variation the risk is about 1%-3%, and with a BRCA2 variation the risk is about 2%-7%. Other cancers including melanoma, cervical and uterine cancer have all been reported as having higher rates in affected individuals. Further studies are needed to confirm which additional cancers are definitively associated with variations in these genes. | Symptoms of Hereditary Breast and Ovarian Cancer Syndrome. HBOC syndrome is a cancer predisposition syndrome in which individuals are at a greater risk of developing certain cancers, particularly breast or ovarian cancer. Signs and symptoms are associated with the development of cancer, and depend upon the type and location of cancer. HBOC syndrome can cause cancer in multiple family members over several generations in one family. It can also be associated with more than one cancer in the same person. The exact percentage of risk for specific types of cancer in HBOC syndrome varies greatly depending on the specific gene that is altered and the specific alteration (i.e. mutation). Some people with a variation in these genes will never develop cancer. Female breast cancer is the most common type of cancer associated with a variation in the BRCA1 or BRCA2 genes. The risk for breast in the general population is about 12%, but for women with a BRCA1 gene variation it can be between 46%-87%, and between 38%-84% for women with a BRCA2 variation. There is also an increased risk of having a second primary breast cancer. In HBOC syndrome, ovarian cancer includes cancer of the fallopian tubes. Primary peritoneal cancers can also occur. These are cancers that develop in the thin layer of tissue that lines the abdomen (peritoneum). The risk for ovarian cancer in the general population is about 1%-2%, but about 39%-63% with BRCA1 gene variations and 16.5%-27% with BRCA2 variations. There is an increased risk for male breast cancer, which affects about .1% of the population. In men with a BRCA1 gene variation, there is a 1.2% risk and an 8.9% risk in men with a BRCA2 gene variation. In general, the relative risk for male breast cancer is greatest in men in their 30s and 40s and decreases with advancing age. There is a risk of prostate cancer of 6% before the age of 69 in the general population. There is an 8.9% by 65 years of age in men with a BRCA1 variation and a 15% risk by age 65 in men with a BRCA2 variation. The lifetime risk for prostate cancer is about 20%-25%. The risk of pancreatic cancer in the general population is about .5%. With a BRCA1 variation the risk is about 1%-3%, and with a BRCA2 variation the risk is about 2%-7%. Other cancers including melanoma, cervical and uterine cancer have all been reported as having higher rates in affected individuals. Further studies are needed to confirm which additional cancers are definitively associated with variations in these genes. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_2 | Causes of Hereditary Breast and Ovarian Cancer Syndrome | HBOC syndrome is caused by a variation in a single major cancer-causing gene, most often the breast cancer susceptibility gene 1 (BRCA1) or the breast cancer susceptibility gene 2 (BRCA2). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The gene variation in HBOC syndrome is a germline mutation (as opposed to a sporadic mutation). A germline mutation is a genetic change that occurs in the body’s reproductive cells, either the egg or the sperm. Germline mutations can be passed on from parents to children. A sporadic mutation is one that occurs after fertilization at some other point in life. Most likely, the gene is somehow damaged or changed due to many different factors. When a change (variation) in a gene causes a disease, it is called a pathogenic (or disease causing) variant. However, some variations in a gene do not cause problems. Sometimes, doctors discover a variation in a gene and they do not know whether or not it causes disease. This is called a variation of unknown significance. Having a pathogenic variation in one of these two genes greatly increases a person’s risk of developing cancer, but how these variations affect every person in a family can be very different. Most families with a pathogenic variation have higher cancer incidence rates, while others do not. Not every person who has a pathogenic variation will definitely develop cancer. Whether cancer develops, the type of cancer that develops, and the age that cancer develops can be different in people in the same family with the same variation in one of these genes. Whether and to what degree a BRCA1 or BRCA2 gene variation causes cancer in an individual or family is called “penetrance.” This means that other factors, most likely additional genetic factors or environmental ones play a role in the development of cancer in people with variations in their BRCA1 or BRCA2 genes. The BRCA1 and BRCA2 genes are tumor suppressor genes. These genes help to regulate cell growth. They normally limit or stop the growth of cells. When the tumor suppressor genes are altered, cells can multiply (proliferate) wildly, causing cancer. When the normal versions of these genes are present, they appear to prevent cancer from developing. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Sometimes de novo variations of the BRCA1 or BRCA2 gene have been reported. However, this is rare. This type of gene variation occurs as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The variation can then be passed on by the affected person in an autosomal dominant pattern. | Causes of Hereditary Breast and Ovarian Cancer Syndrome. HBOC syndrome is caused by a variation in a single major cancer-causing gene, most often the breast cancer susceptibility gene 1 (BRCA1) or the breast cancer susceptibility gene 2 (BRCA2). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The gene variation in HBOC syndrome is a germline mutation (as opposed to a sporadic mutation). A germline mutation is a genetic change that occurs in the body’s reproductive cells, either the egg or the sperm. Germline mutations can be passed on from parents to children. A sporadic mutation is one that occurs after fertilization at some other point in life. Most likely, the gene is somehow damaged or changed due to many different factors. When a change (variation) in a gene causes a disease, it is called a pathogenic (or disease causing) variant. However, some variations in a gene do not cause problems. Sometimes, doctors discover a variation in a gene and they do not know whether or not it causes disease. This is called a variation of unknown significance. Having a pathogenic variation in one of these two genes greatly increases a person’s risk of developing cancer, but how these variations affect every person in a family can be very different. Most families with a pathogenic variation have higher cancer incidence rates, while others do not. Not every person who has a pathogenic variation will definitely develop cancer. Whether cancer develops, the type of cancer that develops, and the age that cancer develops can be different in people in the same family with the same variation in one of these genes. Whether and to what degree a BRCA1 or BRCA2 gene variation causes cancer in an individual or family is called “penetrance.” This means that other factors, most likely additional genetic factors or environmental ones play a role in the development of cancer in people with variations in their BRCA1 or BRCA2 genes. The BRCA1 and BRCA2 genes are tumor suppressor genes. These genes help to regulate cell growth. They normally limit or stop the growth of cells. When the tumor suppressor genes are altered, cells can multiply (proliferate) wildly, causing cancer. When the normal versions of these genes are present, they appear to prevent cancer from developing. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Sometimes de novo variations of the BRCA1 or BRCA2 gene have been reported. However, this is rare. This type of gene variation occurs as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The variation can then be passed on by the affected person in an autosomal dominant pattern. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_3 | Affects of Hereditary Breast and Ovarian Cancer Syndrome | HBOC syndrome can affect both men and women and occurs in people from all ethnic and racial backgrounds. In fact, HBOC syndrome is the most common cause of hereditary breast and ovarian cancer in all ethnic and racial backgrounds. The prevalence, which is the number of people with a disorder at a given time, is not known, but estimated to be somewhere between 1 in 200 to 1 in 800 people in the general population. In certain populations, the prevalence is higher. In individuals of Ashkenazi Jewish descent, HBOC syndrome affects about 1 in 40 people. Sometimes, this is due to a founder effect. A founder effect is when a small, isolated population of people expands over several generations leading to a high prevalence of a genetic trait. | Affects of Hereditary Breast and Ovarian Cancer Syndrome. HBOC syndrome can affect both men and women and occurs in people from all ethnic and racial backgrounds. In fact, HBOC syndrome is the most common cause of hereditary breast and ovarian cancer in all ethnic and racial backgrounds. The prevalence, which is the number of people with a disorder at a given time, is not known, but estimated to be somewhere between 1 in 200 to 1 in 800 people in the general population. In certain populations, the prevalence is higher. In individuals of Ashkenazi Jewish descent, HBOC syndrome affects about 1 in 40 people. Sometimes, this is due to a founder effect. A founder effect is when a small, isolated population of people expands over several generations leading to a high prevalence of a genetic trait. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_4 | Related disorders of Hereditary Breast and Ovarian Cancer Syndrome | Symptoms of the following disorders can be similar to those of HBOC syndrome. Comparisons may be useful for a differential diagnosis.HBOC syndrome needs to be differentiated from other forms of hereditary cancer including hereditary diffuse gastric cancer or Lynch syndrome and other syndromes in which hereditary forms of cancer are present including Peutz-Jeghers syndrome, Li-Fraumeni syndrome, hereditary diffuse gastric cancer, and PTEN hamartoma syndrome. Werner syndrome and Bloom syndrome are rare, multisystem disorders in which hereditary cancer development is a symptom. These syndromes are all caused by changes (variations) in specific genes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are specific genes that cause inherited forms of cancer including the CHEK2, ATM, PALB2, RAD51C, and BARD1 genes. These diseases all convey some degree of increased risk for breast and/or ovarian cancer, although that risk is often less than that associated with the BRCA1 or BRCA2 genes. | Related disorders of Hereditary Breast and Ovarian Cancer Syndrome. Symptoms of the following disorders can be similar to those of HBOC syndrome. Comparisons may be useful for a differential diagnosis.HBOC syndrome needs to be differentiated from other forms of hereditary cancer including hereditary diffuse gastric cancer or Lynch syndrome and other syndromes in which hereditary forms of cancer are present including Peutz-Jeghers syndrome, Li-Fraumeni syndrome, hereditary diffuse gastric cancer, and PTEN hamartoma syndrome. Werner syndrome and Bloom syndrome are rare, multisystem disorders in which hereditary cancer development is a symptom. These syndromes are all caused by changes (variations) in specific genes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are specific genes that cause inherited forms of cancer including the CHEK2, ATM, PALB2, RAD51C, and BARD1 genes. These diseases all convey some degree of increased risk for breast and/or ovarian cancer, although that risk is often less than that associated with the BRCA1 or BRCA2 genes. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_5 | Diagnosis of Hereditary Breast and Ovarian Cancer Syndrome | Several different groups have put out guidelines for screening and diagnostic criteria for HBOC. These guidelines help to identify individuals who would most benefit from screening for variations in the BRCA1 or BRCA2 genes. One of the most commonly referenced guidelines was created by the National Comprehensive Cancer Network (NCCN). Information on these guidelines can be found at: https://www.nccn.org/professionals/physician_gls/default.aspxGenerally, HBOC syndrome may be suspected in women with breast cancer before 50 years of age, in men with breast cancer, in women with ovarian cancer, in people with multiple primary breast cancers in one or both breasts, and the association of pancreatic or prostate cancer or both with breast or ovarian cancer or both. Additionally, HBOC syndrome may be suspected when two or more relatives have breast cancer before the age of 50, when three or more relatives develop breast cancer, or if there is a previously identified variation in the BRCA1 or BRCA2 gene in the family. HBOC syndrome should be considered in anyone of Ashkenazi Jewish heritage who develops breast cancer. Specific breast cancer subtypes may have different indications for testing. For example, triple negative breast cancer may be suspected in individuals who develop the disorder before age 60. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. This involves taking a blood or saliva sample and testing it for variations in the BRCA1 and BRCA2 genes known to cause HBOC syndrome. However, molecular genetic testing is available only as a diagnostic service at specialized laboratories. Additionally, if someone tests negative for BRCA1 or BRCA2 gene variations, they can still develop sporadic forms of cancer, or cancer because of a different hereditary cause. In people who have an identified variation in the BRCA1 or BRCA2 genes periodic screening tests may be performed. Women may routinely undergo magnetic resonance imaging (MRI) and/or mammography. Data suggests that the use of both imaging techniques is more sensitive. An MRI can also be used to help to determine the extent and exact location of cancer associated with HBOC syndrome. Mammography is a different, specialized imaging technique that uses low-dose x-rays to see inside the breasts to find any tumors. | Diagnosis of Hereditary Breast and Ovarian Cancer Syndrome. Several different groups have put out guidelines for screening and diagnostic criteria for HBOC. These guidelines help to identify individuals who would most benefit from screening for variations in the BRCA1 or BRCA2 genes. One of the most commonly referenced guidelines was created by the National Comprehensive Cancer Network (NCCN). Information on these guidelines can be found at: https://www.nccn.org/professionals/physician_gls/default.aspxGenerally, HBOC syndrome may be suspected in women with breast cancer before 50 years of age, in men with breast cancer, in women with ovarian cancer, in people with multiple primary breast cancers in one or both breasts, and the association of pancreatic or prostate cancer or both with breast or ovarian cancer or both. Additionally, HBOC syndrome may be suspected when two or more relatives have breast cancer before the age of 50, when three or more relatives develop breast cancer, or if there is a previously identified variation in the BRCA1 or BRCA2 gene in the family. HBOC syndrome should be considered in anyone of Ashkenazi Jewish heritage who develops breast cancer. Specific breast cancer subtypes may have different indications for testing. For example, triple negative breast cancer may be suspected in individuals who develop the disorder before age 60. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. This involves taking a blood or saliva sample and testing it for variations in the BRCA1 and BRCA2 genes known to cause HBOC syndrome. However, molecular genetic testing is available only as a diagnostic service at specialized laboratories. Additionally, if someone tests negative for BRCA1 or BRCA2 gene variations, they can still develop sporadic forms of cancer, or cancer because of a different hereditary cause. In people who have an identified variation in the BRCA1 or BRCA2 genes periodic screening tests may be performed. Women may routinely undergo magnetic resonance imaging (MRI) and/or mammography. Data suggests that the use of both imaging techniques is more sensitive. An MRI can also be used to help to determine the extent and exact location of cancer associated with HBOC syndrome. Mammography is a different, specialized imaging technique that uses low-dose x-rays to see inside the breasts to find any tumors. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_570_6 | Therapies of Hereditary Breast and Ovarian Cancer Syndrome | Treatment
The treatment of HBOC syndrome is highly individualized, which means that the specific treatment options and recommendations will vary among affected individuals. The therapeutic management may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), oncology nurses, psychiatrists, and other healthcare specialists. Psychosocial support for the entire family is essential as well.Genetic counseling is extremely important in HBOC syndrome. Understanding the risk of cancer based on variations in the BRCA1 and BRCA2 is critical to allow affected individuals, along with their medical team, to make the best decisions concerning their health. Genetic counseling by appropriately trained medical personnel including genetic counselors is recommended by multiple organizations that deal with cancer.Several organizations have released guidelines for the surveillance, screening and treatment of HBOC syndrome. Information on the guidelines published by the National Comprehensive Cancer Network (NCCN) can be found at: https://www.nccn.org/professionals/physician_gls/default.aspx.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the type of cancer; disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgery, and/or other treatments should be made by physicians, genetic counselors, and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Specific surveillance recommendations have been made for women with intact breast tissue and a known hereditary risk of breast cancer. Other women, especially those with a confirmed disease-causing variation in the BRCA1 and BRCA2 gene may choose to have the breasts surgically removed as a preventive measure. This is called prophylactic mastectomy. This surgery may be recommended after counseling involving the specific cancer risk, degree of protection, and issues involving breast reconstruction. Doctors estimate that the cancer risk in unaffected women is reduced 90-95% following preventive mastectomy.Another treatment option is chemoprevention. Chemoprevention involves using certain drugs such as tamoxifen to lower the risk of developing breast cancer. One large, clinical trial demonstrated an almost 50% decrease in the risk of breast cancer in unaffected women.In 2018, the U.S. Food and Drug Administration (FDA) approved the drug olaparib (Lynparza®) for the treatment of BRCA-associated breast cancer that has spread (metastasized) to other areas of the body. Lynparza is a PARP, or poly (ADP-ribose) polymerase, is an enzyme that helps the body to repair DNA when it becomes damaged. Researchers believe that medications that stop or hinder (inhibit) the activity of PARP will prevent cancer cells from repairing themselves, and continuing to grow and spread. This is a targeted therapy, which means that it is targeting a specific molecule or substance (e.g. PARP) that contributes to cancer growth. Targeted therapies act by blocking the growth and spread of cancer rather than destroying cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy and are less likely to damage healthy cells.Lynparza has also been approved by the FDA for women who have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have responded to treatment with a platinum-based chemotherapy medication (see Investigational Therapies below), but in whom the cancer has returned. Lynparza is also approved for advanced ovarian cancer in women who have received treatment with three or more prior chemotherapy medications.In 2018, Talazoparib (talzenna) was approved to treat patients with deleterious or suspected deleterious germline BRCA gene mutations and HER2 negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on a companion diagnostic for talazoparib. FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients who are eligible for talazoparib. Talzenna is manufactured by Pfizer.In 2018, the FDA approved the drug rucaparib (RuBRCAa®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.In 2017, the FDA approved the drug niraparib (Zejula®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.A procedure called risk-reducing salpino-oophorectomy may be recommended for women with ovarian cancer. And for mutation carriers who do not have cancer. This is the surgical removal of the ovaries and the fallopian tubes. This is procedure significantly reduces the risk of ovarian cancer as well as somewhat reducing the risk of breast cancer. Women will not be able to have children after this procedure. Premenopausal women who undergo this surgery will begin to have menopausal symptoms. This surgery may be recommendation in women after counseling on reproductive issues, degree of protection, and hormonal and menopausal issues.Some studies have shown that oral contraceptives have a duration-dependent protective effect against ovarian cancer. Duration-dependent means this protective effect exists while the contraceptive is being taken, but stops once women stop taking the medication. Oral contraceptive use may be associated with a slightly increased risk of breast cancer, however.The use of hormonal therapy to treat menopausal symptoms is controversial and should be discussed in an individual setting based on personal history of cancer, prophylactic surgeries, etc. This therapy is used to help manage common symptoms of menopause and to protect bone health. However, long-term hormonal therapy is associated with an increased risk of breast cancer in women who have undergone normal menopause. Studies have also shown that short-term therapy with estrogen plus progestin increased breast cancer risk. Women who have gone through menopause because of surgery experience an abrupt rather gradual loss of hormones. Some studies have shown that short-term therapy has been used effectively in treating these abrupt symptoms and has not shown an increase in breasts cancer risk.The treatment of other forms of cancer associated with HBOC syndrome generally follows the standard guidelines for individuals without BRCA1 or BRCA2 gene variations. | Therapies of Hereditary Breast and Ovarian Cancer Syndrome. Treatment
The treatment of HBOC syndrome is highly individualized, which means that the specific treatment options and recommendations will vary among affected individuals. The therapeutic management may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), oncology nurses, psychiatrists, and other healthcare specialists. Psychosocial support for the entire family is essential as well.Genetic counseling is extremely important in HBOC syndrome. Understanding the risk of cancer based on variations in the BRCA1 and BRCA2 is critical to allow affected individuals, along with their medical team, to make the best decisions concerning their health. Genetic counseling by appropriately trained medical personnel including genetic counselors is recommended by multiple organizations that deal with cancer.Several organizations have released guidelines for the surveillance, screening and treatment of HBOC syndrome. Information on the guidelines published by the National Comprehensive Cancer Network (NCCN) can be found at: https://www.nccn.org/professionals/physician_gls/default.aspx.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the type of cancer; disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgery, and/or other treatments should be made by physicians, genetic counselors, and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Specific surveillance recommendations have been made for women with intact breast tissue and a known hereditary risk of breast cancer. Other women, especially those with a confirmed disease-causing variation in the BRCA1 and BRCA2 gene may choose to have the breasts surgically removed as a preventive measure. This is called prophylactic mastectomy. This surgery may be recommended after counseling involving the specific cancer risk, degree of protection, and issues involving breast reconstruction. Doctors estimate that the cancer risk in unaffected women is reduced 90-95% following preventive mastectomy.Another treatment option is chemoprevention. Chemoprevention involves using certain drugs such as tamoxifen to lower the risk of developing breast cancer. One large, clinical trial demonstrated an almost 50% decrease in the risk of breast cancer in unaffected women.In 2018, the U.S. Food and Drug Administration (FDA) approved the drug olaparib (Lynparza®) for the treatment of BRCA-associated breast cancer that has spread (metastasized) to other areas of the body. Lynparza is a PARP, or poly (ADP-ribose) polymerase, is an enzyme that helps the body to repair DNA when it becomes damaged. Researchers believe that medications that stop or hinder (inhibit) the activity of PARP will prevent cancer cells from repairing themselves, and continuing to grow and spread. This is a targeted therapy, which means that it is targeting a specific molecule or substance (e.g. PARP) that contributes to cancer growth. Targeted therapies act by blocking the growth and spread of cancer rather than destroying cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy and are less likely to damage healthy cells.Lynparza has also been approved by the FDA for women who have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have responded to treatment with a platinum-based chemotherapy medication (see Investigational Therapies below), but in whom the cancer has returned. Lynparza is also approved for advanced ovarian cancer in women who have received treatment with three or more prior chemotherapy medications.In 2018, Talazoparib (talzenna) was approved to treat patients with deleterious or suspected deleterious germline BRCA gene mutations and HER2 negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on a companion diagnostic for talazoparib. FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients who are eligible for talazoparib. Talzenna is manufactured by Pfizer.In 2018, the FDA approved the drug rucaparib (RuBRCAa®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.In 2017, the FDA approved the drug niraparib (Zejula®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.A procedure called risk-reducing salpino-oophorectomy may be recommended for women with ovarian cancer. And for mutation carriers who do not have cancer. This is the surgical removal of the ovaries and the fallopian tubes. This is procedure significantly reduces the risk of ovarian cancer as well as somewhat reducing the risk of breast cancer. Women will not be able to have children after this procedure. Premenopausal women who undergo this surgery will begin to have menopausal symptoms. This surgery may be recommendation in women after counseling on reproductive issues, degree of protection, and hormonal and menopausal issues.Some studies have shown that oral contraceptives have a duration-dependent protective effect against ovarian cancer. Duration-dependent means this protective effect exists while the contraceptive is being taken, but stops once women stop taking the medication. Oral contraceptive use may be associated with a slightly increased risk of breast cancer, however.The use of hormonal therapy to treat menopausal symptoms is controversial and should be discussed in an individual setting based on personal history of cancer, prophylactic surgeries, etc. This therapy is used to help manage common symptoms of menopause and to protect bone health. However, long-term hormonal therapy is associated with an increased risk of breast cancer in women who have undergone normal menopause. Studies have also shown that short-term therapy with estrogen plus progestin increased breast cancer risk. Women who have gone through menopause because of surgery experience an abrupt rather gradual loss of hormones. Some studies have shown that short-term therapy has been used effectively in treating these abrupt symptoms and has not shown an increase in breasts cancer risk.The treatment of other forms of cancer associated with HBOC syndrome generally follows the standard guidelines for individuals without BRCA1 or BRCA2 gene variations. | 570 | Hereditary Breast and Ovarian Cancer Syndrome |
nord_571_0 | Overview of Hereditary Coproporphyria | Hereditary coproporphyria (HCP) is a rare metabolic disorder characterized by deficiency of the enzyme coproporphyrinogen oxidase. This enzyme deficiency results in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the CPOX gene. However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a CPOX gene mutation do not develop symptoms of HCP. Additional factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Some affected individuals experience acute attacks or episodes that develop over a period of days. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can cause life-threatening complications. The CPOX mutation is inherited as an autosomal dominant trait.HCP belongs to a group of disorders known as the porphyrias. This group is characterized by abnormally high levels of porphyrin precursors and, in many cases, porphyrins, due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the hepatic and erythropoietic types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as cutaneous porphyrias. The term acute porphyria is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Most forms of porphyria are genetic inborn errors of metabolism. HCP is an acute, hepatic form of porphyria. | Overview of Hereditary Coproporphyria. Hereditary coproporphyria (HCP) is a rare metabolic disorder characterized by deficiency of the enzyme coproporphyrinogen oxidase. This enzyme deficiency results in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the CPOX gene. However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a CPOX gene mutation do not develop symptoms of HCP. Additional factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Some affected individuals experience acute attacks or episodes that develop over a period of days. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can cause life-threatening complications. The CPOX mutation is inherited as an autosomal dominant trait.HCP belongs to a group of disorders known as the porphyrias. This group is characterized by abnormally high levels of porphyrin precursors and, in many cases, porphyrins, due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the hepatic and erythropoietic types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as cutaneous porphyrias. The term acute porphyria is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Most forms of porphyria are genetic inborn errors of metabolism. HCP is an acute, hepatic form of porphyria. | 571 | Hereditary Coproporphyria |
nord_571_1 | Symptoms of Hereditary Coproporphyria | The episodes or “attacks” that characterize HCP usually develop over the course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are more common in women than men. Intermittent, recurrent body pain, usually affecting the abdomen and the lower back may occur chronically. Pain in these areas is often the initial sign of an attack. Pain usually begins as low-grade, vague pain in the abdomen and slowly over a few days worsens eventually causing severe abdominal pain. Pain may radiate to affect the lower back, neck, buttocks, or arms and legs. Pain is usually not well localized, but in some cases can be mistaken for inflammation of the gallbladder, appendix or another intra-abdominal organ. In a minority of cases, pain primarily affects the back and the arms and legs and is usually described as deep and aching. Abdominal pain is often described as colicky and is usually associated with nausea and vomiting. Vomiting may be severe enough that affected individuals vomit after eating or drinking any food or liquid. The absence of bowel sounds (ileus), which indicates a lack of intestinal activity may be noted. Constipation may also occur and can be severe (obstipation). Affected individuals may also experience a faster than normal heart rate (tachycardia), high blood pressure (hypertension), irregular heartbeats (cardiac arrhythmias), and a sudden fall in blood pressure upon standing (orthostatic hypotension). Hypertension may persist in between acute attacks. Neurologic symptoms, including seizures, may be associated with HCP. In some cases, new-onset seizures may be the initial sign of the disorder. Abnormally low sodium levels in the blood (hyponatremia) may occur during an attack and contribute to the onset of seizures. Affected individuals may also develop damage to the nerves in the extremities (peripheral neuropathy). Peripheral neuropathy may be preceded by the loss of deep tendon reflexes. Peripheral neuropathy is characterized by numbness or tingling and burning sensations that, in HCP, usually begin in the upper legs and arms. Affected individuals may develop muscle weakness initially in the feet and legs that progresses to affect and paralyze all extremities and the body trunk (motor paralysis) and the respiratory muscles (respiratory paralysis and failure). This ascending paralysis in HCP can mimic the ascending paralysis seen in Guillain-Barré syndrome (GBS), a disorder in which the body’s immune system attacks the nerves. Differentiating HCP from GBS is extremely important to ensure prompt treatment of HCP and the avoidance of medications that can precipitate or worsen an acute attack. (For more information on GBS, see the Related Disorders section of this report.)Some individuals develop psychological symptoms, although such symptoms are highly variable. Such symptoms can include irritability, depression, anxiety, and insomnia. Less often, more acute psychiatric symptoms can develop including hallucinations, paranoia, disorientation, mental confusion, delirium, and psychosis. In some cases, affected individuals may develop skin (cutaneous) lesions affecting the sun-exposed areas of skin such as the hands and face. Affected individuals may develop severe pain, burning, and itching of such areas (photosensitivity). Eventually, the skin may become fragile and develop fluid-filled blisters (bullae). Affected areas may also exhibit darkly discolored (hyperpigmented) scars and excessive hair growth. | Symptoms of Hereditary Coproporphyria. The episodes or “attacks” that characterize HCP usually develop over the course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are more common in women than men. Intermittent, recurrent body pain, usually affecting the abdomen and the lower back may occur chronically. Pain in these areas is often the initial sign of an attack. Pain usually begins as low-grade, vague pain in the abdomen and slowly over a few days worsens eventually causing severe abdominal pain. Pain may radiate to affect the lower back, neck, buttocks, or arms and legs. Pain is usually not well localized, but in some cases can be mistaken for inflammation of the gallbladder, appendix or another intra-abdominal organ. In a minority of cases, pain primarily affects the back and the arms and legs and is usually described as deep and aching. Abdominal pain is often described as colicky and is usually associated with nausea and vomiting. Vomiting may be severe enough that affected individuals vomit after eating or drinking any food or liquid. The absence of bowel sounds (ileus), which indicates a lack of intestinal activity may be noted. Constipation may also occur and can be severe (obstipation). Affected individuals may also experience a faster than normal heart rate (tachycardia), high blood pressure (hypertension), irregular heartbeats (cardiac arrhythmias), and a sudden fall in blood pressure upon standing (orthostatic hypotension). Hypertension may persist in between acute attacks. Neurologic symptoms, including seizures, may be associated with HCP. In some cases, new-onset seizures may be the initial sign of the disorder. Abnormally low sodium levels in the blood (hyponatremia) may occur during an attack and contribute to the onset of seizures. Affected individuals may also develop damage to the nerves in the extremities (peripheral neuropathy). Peripheral neuropathy may be preceded by the loss of deep tendon reflexes. Peripheral neuropathy is characterized by numbness or tingling and burning sensations that, in HCP, usually begin in the upper legs and arms. Affected individuals may develop muscle weakness initially in the feet and legs that progresses to affect and paralyze all extremities and the body trunk (motor paralysis) and the respiratory muscles (respiratory paralysis and failure). This ascending paralysis in HCP can mimic the ascending paralysis seen in Guillain-Barré syndrome (GBS), a disorder in which the body’s immune system attacks the nerves. Differentiating HCP from GBS is extremely important to ensure prompt treatment of HCP and the avoidance of medications that can precipitate or worsen an acute attack. (For more information on GBS, see the Related Disorders section of this report.)Some individuals develop psychological symptoms, although such symptoms are highly variable. Such symptoms can include irritability, depression, anxiety, and insomnia. Less often, more acute psychiatric symptoms can develop including hallucinations, paranoia, disorientation, mental confusion, delirium, and psychosis. In some cases, affected individuals may develop skin (cutaneous) lesions affecting the sun-exposed areas of skin such as the hands and face. Affected individuals may develop severe pain, burning, and itching of such areas (photosensitivity). Eventually, the skin may become fragile and develop fluid-filled blisters (bullae). Affected areas may also exhibit darkly discolored (hyperpigmented) scars and excessive hair growth. | 571 | Hereditary Coproporphyria |
nord_571_2 | Causes of Hereditary Coproporphyria | The CPOX gene mutation that predisposes individuals to developing HCP is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The CPOX gene creates (encodes) the enzyme coproporphyrinogen-III oxidase (CPO). This enzyme is the sixth enzyme is process of heme biosynthesis. Mutations in the CPOX gene lead to deficient activity of CPO in the body (approximately 50% reduced), which in turn leads to insufficient heme production and occasionally to the accumulation of CPO precursors in the liver. Many of the triggers of an acute attack act by increasing the demand for heme, which makes the CPO deficiency more significant. For example, heme synthesis is required to metabolize specific medications. However, the underlying genetic mutation in HCP limits the production of heme and increases the accumulation of porphyrin precursors in the body. Additionally, the offending medication is not metabolized and eliminated from the body, thereby precipitating an acute attack. The exact, underlying reasons why symptoms develop in some affected individuals and not others are not fully understood. More research is necessary to determine the specific underlying mechanisms that are involved in the development of symptomatic episodes. | Causes of Hereditary Coproporphyria. The CPOX gene mutation that predisposes individuals to developing HCP is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The CPOX gene creates (encodes) the enzyme coproporphyrinogen-III oxidase (CPO). This enzyme is the sixth enzyme is process of heme biosynthesis. Mutations in the CPOX gene lead to deficient activity of CPO in the body (approximately 50% reduced), which in turn leads to insufficient heme production and occasionally to the accumulation of CPO precursors in the liver. Many of the triggers of an acute attack act by increasing the demand for heme, which makes the CPO deficiency more significant. For example, heme synthesis is required to metabolize specific medications. However, the underlying genetic mutation in HCP limits the production of heme and increases the accumulation of porphyrin precursors in the body. Additionally, the offending medication is not metabolized and eliminated from the body, thereby precipitating an acute attack. The exact, underlying reasons why symptoms develop in some affected individuals and not others are not fully understood. More research is necessary to determine the specific underlying mechanisms that are involved in the development of symptomatic episodes. | 571 | Hereditary Coproporphyria |
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