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Acute Hepatic Porphyria

ALAD Porphyria

Acute hepatic porphyria is a term encompassing four types of porphyria, in which the production of toxic heme precursors occurs in the liver and causes acute attacks of abdominal pain, nausea, neurological and mental changes, as well as hypertension and pain in the head and neck and/or chest. The diagnosis is made by detecting specific heme precursors in urine or feces. Hematin, symptomatic therapy and liver transplantation are used as therapy.


Presentation

The clinical presentation is quite similar across all types of acute hepatic porphyrias. The "acute attacks" are the hallmark of these disorders, most frequently encountered after puberty in women [5]. Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients [1] [3] [5]. Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions [1] [9]. Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well [5], and a missed diagnosis may lead to severe and irreversible motor neuropathy [2]. In addition to acute attacks, some forms may be accompanied by cutaneous symptoms, such as HCP, in which photosensitivity and blistering skin lesions (vesicles, bullae and erosions with scarring) are constitutive features [1] [5].

Pain
  • All patients used complementary and alternative medicine treatments to avoid hospitalization or manage chronic pain and 81% reported varying degrees of effectiveness.[ncbi.nlm.nih.gov]
  • pain in the head and neck and/or chest.[symptoma.com]
  • Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine.[ncbi.nlm.nih.gov]
  • Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and[orpha.net]
  • If a porphyria patient over 50–60 years of age has persistent upper abdominal pains or debilitation of the general condition, the possibility of liver cancer should be taken into account.[books.google.com]
Weakness
  • Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and[orpha.net]
  • Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy.[symptoma.com]
  • Nerves that control muscles can be affected, leading to weakness, usually beginning in the shoulders and arms. The weakness can progress to virtually all the muscles, including those involved in breathing. Tremors and seizures may develop.[merckmanuals.com]
  • Acute porphyria can also affect the nervous system so that numbness and muscle weakness is felt, even in the chest wall, which can in turn lead to breathing difficulties.[orphan-europe.com]
  • Severe attacks of acute porphyria can sometimes cause nerve damage and muscle weakness that can take months to get better.[webmd.com]
Fatigue
  • RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue.[ncbi.nlm.nih.gov]
  • Natural history studies done both in the US and in Sweden in AIP patients determined that 18 to 22% of AIP patients experience chronic symptoms, most commonly pain (in the abdomen, back or limbs) and fatigue. [6] In 2016, data from an ongoing natural[learnaboutyourpain.com]
  • In the following years, she required weekly hematin infusions, which caused significant fatigue and lethargy, as well as bimonthly phlebotomies to manage the resultant hyperferritinemia from her constant heme infusions.[omicsonline.org]
  • […] defective PBG-D accumulation of porphobilinogen ( PBG ) and δ-aminolevulinic acid ( ALA ) symptoms Clinical features Fever GI symptoms : severe abdominal pain, nausea, vomiting Neurological abnormalities Polyneuropathy : non-specific pain, weakness/fatigue[amboss.com]
  • In some people, symptoms of lesser intensity, such as fatigue, headache, back or thigh pain, insomnia, depression, or anxiety, linger. Attacks are rarely fatal. However, in a few people, attacks are disabling.[merckmanuals.com]
Anemia
  • Four new chapters cover anemias unique to the newborn period, pathology of LHC and other histiocytic disorders, tumors of the spleen, and pathology and classification of myeloproliferative disorders and mast cell disease.[books.google.com]
  • P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias[icd10data.com]
  • Manifestations of porphyria include gastrointestinal, neurologic, and psychologic symptoms, cutaneous photosensitivity, pigmentation of the face (and later of the bones), and anemia with enlargement of the spleen.[medical-dictionary.thefreedictionary.com]
  • ., anemia, alcohol, or chronic heavy metal poisoning ) Porphyria cutanea tarda (PCT) Epidemiology Most common porphyria Peak incidence : 40–70 years Sex: Etiology Defective uroporphyrinogen III decarboxylase ( UROD ) Type I: acquired insufficiency of[amboss.com]
  • Anderson KE, Sassa S, Bishop DF, Desnick RJ: X-Linked sideroblastic anemia and the porphyrias. In Disorders of Heme Biosynthesis. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, 2014. Accessed August 9, 2017.[mayomedicallaboratories.com]
Fever
  • Because the pain is neuropathic, it often is not accompanied by fever or leukocytosis. Patients also may experience nausea, vomiting, constipation, or pain in the chest or back.[hematologyandoncology.net]
  • In the case of acute abdomen with fever, the suspicion of appendicitis is obvious. An appendectomy scar is thus often found amongst porphyria patients.[lecturio.com]
  • ., surgery, infection) Pathophysiology : defective PBG-D accumulation of porphobilinogen ( PBG ) and δ-aminolevulinic acid ( ALA ) symptoms Clinical features Fever GI symptoms : severe abdominal pain, nausea, vomiting Neurological abnormalities Polyneuropathy[amboss.com]
  • AIP is the most common form of hepatic porphyria and symptoms are often begin after puberty and consist of acute neurovisceral signs, abdominal pain, vomiting, constipation, tachycardia, fever, hypertension and alterations in the central nervous system[medcraveonline.com]
Abdominal Pain
  • Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine.[ncbi.nlm.nih.gov]
  • Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and[orpha.net]
  • If a porphyria patient over 50–60 years of age has persistent upper abdominal pains or debilitation of the general condition, the possibility of liver cancer should be taken into account.[books.google.com]
  • Patients suffer acute neuro-visceral attacks, which persist for several weeks and manifest as intense abdominal pain, and neurological and psychological symptoms.[orpha.net]
  • Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients.[symptoma.com]
Vomiting
  • Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients.[symptoma.com]
  • MB The most important step is to stabilize patients, and address symptoms such as nausea, vomiting, hypertension, and electrolyte imbalances such as hyponatremia.[hematologyandoncology.net]
  • Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped.[web.archive.org]
  • Symptoms include pain in the chest or abdomen, vomiting, and diarrhea or constipation. During an attack, symptoms can include muscle numbness, tingling, paralysis, cramping, and personality or mental changes.[icd9data.com]
  • Symptoms may include vomiting, abdominal or back pain, weakness in arms or legs, and mental symptoms. Laboratory tests are done on urine samples taken during the attack.[merckmanuals.com]
Nausea
  • Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients.[symptoma.com]
  • MB The most important step is to stabilize patients, and address symptoms such as nausea, vomiting, hypertension, and electrolyte imbalances such as hyponatremia.[hematologyandoncology.net]
  • Medications for pain, nausea and vomiting, and close observation are generally required with monitoring of salt and water balance. Harmful drugs should be stopped.[web.archive.org]
  • Europe, approximately 5,000 people suffer acute attacks annually, and approximately 1,000 of those experience recurrent, debilitating attacks. [5] The most commonly reported symptoms of an acute attack are: [1] Severe abdominal pain Back or limb pain Nausea[learnaboutyourpain.com]
  • Nausea, vomiting, anxiety, and restlessness are treated with a phenothiazine-type drug for a short time. Ondansetron may also be given for nausea. Insomnia may be treated with chloral hydrate or low doses of a benzodiazepine but not a barbiturate.[merckmanuals.com]
Constipation
  • Most important symptoms are related to the gastrointestinal tract and include intense and nonspecific abdominal pain that may be cramping, constipation, nausea, vomiting, decreased bowel sounds and diarrhea in some patients.[symptoma.com]
  • Symptoms include pain in the chest or abdomen, vomiting, and diarrhea or constipation. During an attack, symptoms can include muscle numbness, tingling, paralysis, cramping, and personality or mental changes.[icd9data.com]
  • It is also quite common to have nausea, vomiting and constipation. Acute porphyria can also affect the nervous system so that numbness and muscle weakness is felt, even in the chest wall, which can in turn lead to breathing difficulties.[orphan-europe.com]
  • Patients also may experience nausea, vomiting, constipation, or pain in the chest or back. They also can have significant autonomic dysfunction, including tachycardia and hypertension.[hematologyandoncology.net]
  • Whitehead (North Carolina大学)が再試をし、IBS患者の大腸の感覚閾値が低下していることが広く認識された[Whitehead WF, Engel BT, Schuster MM: Irritable bowel syndrome: Physiological and psychological differences between diarrhea-predominant and constipation-predominant patients.[shiga-med.ac.jp]
Severe Abdominal Pain
  • Depending on the specific type, AHP patients can suffer from a range of symptoms including acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions[clinicaladvisor.com]
  • Patients with AHP can suffer from a range of symptoms that, depending on the specific type, can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous[spjnews.com]
  • Patients with AIP can suffer from acute and/or recurrent life-threatening attacks characterized by severe abdominal pain, neuropathy (affecting the central, peripheral or autonomic nervous system), and neuropsychiatric manifestations.[businesswire.com]
  • abdominal pain Back or limb pain Nausea and vomiting Peripheral and autonomic neuropathy Urine that is reddish in color Neuropsychiatric symptoms, including paralysis, seizures and confusion Elevated heart rate There has also been increasing recognition[learnaboutyourpain.com]
  • The second most common form, acute intermittent porphyria (AIP), is characterized by life-threatening attacks of severe abdominal pain, constipation, tachycardia, and neuropsychiatric abnormalities.[amboss.com]
Hypertension
  • Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine.[ncbi.nlm.nih.gov]
  • Content is provided from medical therapies to surgery on the patient with portal hypertension.[books.google.com]
  • Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions.[symptoma.com]
  • Technical and therapeutic advances have appeared in all areas of hepatology, in particular portal hypertension, liver tumours, genetic diseases and imaging, both diagnostic and therapeutic.[books.google.com]
  • They also can have significant autonomic dysfunction, including tachycardia and hypertension.[hematologyandoncology.net]
Tachycardia
  • Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine.[ncbi.nlm.nih.gov]
  • Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions.[symptoma.com]
  • The second most common form, acute intermittent porphyria (AIP), is characterized by life-threatening attacks of severe abdominal pain, constipation, tachycardia, and neuropsychiatric abnormalities.[amboss.com]
  • Note: In the case of the triad of abdominal pain, neurological-psychiatric symptoms and tachycardia, one should always think about the differential diagnosis of porphyria![lecturio.com]
  • They also can have significant autonomic dysfunction, including tachycardia and hypertension.[hematologyandoncology.net]
Chest Pain
  • Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions.[symptoma.com]
  • The symptoms can include: Belly pain, often severe Chest pain Faster heart rate and higher blood pressure Limb and back pain Muscle weakness Tingling and loss of sensation Cramping Vomiting and constipation You may notice changes in your personality or[webmd.com]
Jaundice
  • Renal tubular disorders and renal stone disease 168 Clinical biochemistry of nutrition 180 Nutritional disorders and their management 200 Clinical biochemistry of the gastrointestinal tract 214 Assessment of hepatic function and investigation of jaundice[books.google.com]
  • A 27-year-old man was admitted to our hospital for evaluation and treatment of liver dysfunction with jaundice and hepatosplenomegaly. The patient had severe photosensitivity from childhood.[ci.nii.ac.jp]
  • […] disease-causing mutation will express symptoms. [2] Individuals who are homozygous for a specific mutation (K404E) or compound heterozygous with a null allele in CPOX have a more severe erythropoietic porphyria, harderoporphyria, [5] characterized by neonatal jaundice[ippn.info]
Muscle Weakness
  • Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy.[symptoma.com]
  • Acute porphyria can also affect the nervous system so that numbness and muscle weakness is felt, even in the chest wall, which can in turn lead to breathing difficulties.[orphan-europe.com]
  • Severe attacks of acute porphyria can sometimes cause nerve damage and muscle weakness that can take months to get better.[webmd.com]
  • Recovery from symptoms may occur within a few days, although complete recovery from severe muscle weakness may take several months or years.[merckmanuals.com]
Myalgia
  • Possibly or definitely related AEs reported in two or more cases were injection site reactions and myalgia; all of these events were mild.[businesswire.com]
  • Four patients were assessed as having AEs possibly related to study drug, including injection site reaction (mild and self-limiting), hypersensitivity, myalgia, headache, moderate renal impairment (in a patient with a history of moderate renal impairment[dddmag.com]
Back Pain
  • The symptoms can include: Belly pain, often severe Chest pain Faster heart rate and higher blood pressure Limb and back pain Muscle weakness Tingling and loss of sensation Cramping Vomiting and constipation You may notice changes in your personality or[webmd.com]
  • Symptoms may include vomiting, abdominal or back pain, weakness in arms or legs, and mental symptoms. Laboratory tests are done on urine samples taken during the attack.[merckmanuals.com]
Photosensitivity
  • Differential diagnoses for variagate porphyria and hereditary coproporphyria also include photosensitivity.[orpha.net]
  • The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions.[symptoma.com]
  • Manifestations of porphyria include gastrointestinal, neurologic, and psychologic symptoms, cutaneous photosensitivity, pigmentation of the face (and later of the bones), and anemia with enlargement of the spleen.[medical-dictionary.thefreedictionary.com]
  • […] acquired metabolic disorders characterized by defects in the enzymes that are involved in the heme synthesis Autosomal dominant disorder due to partial deficiency of ferrochelatase, characterized by an excess of protoporphyrin and a wide variety of photosensitive[icd9data.com]
  • Photosensitivity is not associated with AIP, but may be present in HCP and VP.[mayomedicallaboratories.com]
Blister
  • The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions.[symptoma.com]
  • These can present with blistering skin lesions or with nonblistering photosensitivity. Hereditary coproporphyria and variegate porphyria also can present with blistering skin lesions similar to those seen in porphyria cutanea tarda.[hematologyandoncology.net]
  • People with the skin type develop blisters, itching, and swelling of their skin when it is exposed to sunlight. The nervous system type is called acute porphyria. Symptoms include pain in the chest or abdomen, vomiting, and diarrhea or constipation.[icd9data.com]
  • Porphyria cutanea tarda (PCT) is the most common form and presents with chronic, blistering cutaneous photosensitivity and tea-colored urine.[amboss.com]
  • People with cutaneous porphyria develop blisters, itching, and swelling of their skin when it is exposed to sunlight. The cutaneous porphyrias include the following types: Also called congenital porphyria.[genome.gov]
Hypertrichosis
  • […] erythropoietic porphyria (CEP) a form of erythropoietic porphyria, with cutaneous photosensitivity leading to mutilating lesions, hemolytic anemia, splenomegaly, excessive urinary excretion of uroporphyrin and coproporphyrin, and invariably erythrodontia and hypertrichosis[medical-dictionary.thefreedictionary.com]
  • HIV Estrogen therapy Sunlight exposure Pathophysiology Clinical findings Cutaneous manifestations Increased fragility of sun-exposed skin blistering and impaired healing ( blistering photosensitivity ) Healing results in scarring and milia formation Hypertrichosis[amboss.com]
  • Other common symptoms may include thickening of the skin, hypo- and hyperpigmentation, hypertrichosis, cutaneous scarring, and deformities of the fingers, eyelids, lips, nose, and ears.[mayomedicallaboratories.com]
  • Fragile, poorly healing skin with pruritus, hyperpigmentation and hypertrichosis are other features. Forehead, cheeks, ears and backs of hands are most commonly affected but all skin exposed to the sun can be affected.[patient.info]
  • Similarly, patients show increased hair growth ( hypertrichosis ) and hyperpigmentation. The skin manifestation of the PCT can be presumed without prophylaxis disfiguring extent.[lecturio.com]
Hyperpigmentation
  • Secondary infections can cause areas of hypo- or hyperpigmentation or sclerodermatous changes and may result in the development of alopecia at sites of repeated skin damage.[mayomedicallaboratories.com]
  • […] therapy Sunlight exposure Pathophysiology Clinical findings Cutaneous manifestations Increased fragility of sun-exposed skin blistering and impaired healing ( blistering photosensitivity ) Healing results in scarring and milia formation Hypertrichosis Hyperpigmentation[amboss.com]
  • Fragile, poorly healing skin with pruritus, hyperpigmentation and hypertrichosis are other features. Forehead, cheeks, ears and backs of hands are most commonly affected but all skin exposed to the sun can be affected.[patient.info]
  • Similarly, patients show increased hair growth ( hypertrichosis ) and hyperpigmentation. The skin manifestation of the PCT can be presumed without prophylaxis disfiguring extent.[lecturio.com]
Cutaneous Manifestation
  • Management includes the prevention of attacks (by avoiding causal factors) and the protection of skin from the light in cases of cutaneous manifestations.[orpha.net]
  • manifestations, notably extreme mechanical fragility of the skin, particularly areas exposed to the sunlight, and by episodes of abdominal pain and neuropathy.[medical-dictionary.thefreedictionary.com]
  • The cutaneous manifestations are similar to those in PCT. They can be the only clinical features of these mixed porphyrias.[patient.info]
  • manifestations Increased fragility of sun-exposed skin blistering and impaired healing ( blistering photosensitivity ) Healing results in scarring and milia formation Hypertrichosis Hyperpigmentation Scleroderma -like changes (especially forehead and[amboss.com]
Dark Urine
  • Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy.[symptoma.com]
  • Signs and Symptoms Diagnosis Treatment Symptoms vary depending on the type of porphyria, but some of the more common include: Dark urine Skin sensitivity, including blistering, of areas exposed to the light, such as the face and back of hands Pain in[ucsfhealth.org]
  • The patient recalled passing dark urine after surgery and was subsequently hospitalized for 3 months.[medicaljournals.se]
Urinary Retention
  • The most typical clinical signs include nausea, vomiting, constipation, diarrhea, urinary retention, tachycardia, hypertension, mental symptoms, and muscle pain and weakness.[revistanefrologia.com]
Dysuria
  • Muscle weakness, tremor, diaphoresis, dysuria, dark urine, bladder distension and severe neuropathy may be encountered as well, and a missed diagnosis may lead to severe and irreversible motor neuropathy.[symptoma.com]
Red Urine
  • Red urine that fluoresces in nappies can allow an easy bedside diagnosis. [ 3 ] There is severe photosensitivity. Pruritus and erythema followed by vesicle and bullous formation occur on exposure to sunlight.[patient.info]
Seizure
  • We studied one patient with major motor seizures and acute intermittent porphyria. The seizure disorder was exacerbated by phenytoin and did not respond to a high-carbohydrate diet or to intravenous hematin.[ncbi.nlm.nih.gov]
  • Subsequently neurological symptoms with seizures developed leading to a status epilepticus with continuing seizures at week 14.[ncbi.nlm.nih.gov]
  • Despite intravenous glucose infusions and appropriate medication no reduction in seizure-frequency and neuropsychiatric syndromes was observed. An abortion was induced.[ncbi.nlm.nih.gov]
  • Phenytoin or valproic acid should be avoided in management of seizures, as they may cause more severe symptoms. Instead, benzodiazepines, gabapentin, magnesium and propofol (in the setting of refractory seizures) are used.[symptoma.com]
Confusion
  • RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue.[ncbi.nlm.nih.gov]
  • […] attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and psychological symptoms (irritability, anxiety, auditory or visual hallucinations, mental confusion[orpha.net]
  • Additional signs include head, neck and chest pain, hypertension, seizures, mental changes (restlessness, anxiety, confusion, insomnia, disorientation), and neuropathies that can induce severe muscle weakness.[symptoma.com]
  • The most commonly reported symptoms of an acute attack are: [1] Severe abdominal pain Back or limb pain Nausea and vomiting Peripheral and autonomic neuropathy Urine that is reddish in color Neuropsychiatric symptoms, including paralysis, seizures and confusion[learnaboutyourpain.com]
  • H&O Does porphyria often get confused with other diseases? MB The most common presenting symptoms of this disorder—abdominal pain, nausea, and vomiting—are common, nonspecific symptoms.[hematologyandoncology.net]
Convulsions
  • In its rare neurological manifestation it can lead to untreatable convulsions which leave no option but to terminate the pregnancy.[ncbi.nlm.nih.gov]
  • Clinical description All acute hepatic porphyrias can be accompanied by neuro-visceral attacks that appear as intense abdominal pain (in 85-95% of cases) over one to two weeks, neurological symptoms (muscular weakness, sensory loss or convulsions) and[orpha.net]
  • Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions.[symptoma.com]
  • In its rare neurological manifestation it can lead to untreatable convulsions which leave no option but to terminate the pregnancy. 2007 S. Karger AG, Basel References Heydy L, González-Arriaza MD: Acute porphyrias: a case report and review.[karger.com]
  • Complication management Treatment of convulsions: the most commonly used anticonvulsants are porphyrogenic. Gabapentin and probably vigabatrin can be used to treat convulsions.[patient.info]
Insomnia
  • Head, neck and chest pain are seen in approximately 50% of cases, as are hypertension, tachycardia, mental changes (restlessness, anxiety, insomnia, disorientation, paranoia and hallucinations) and convulsions.[symptoma.com]
  • Mental symptoms, such as irritability, restlessness, insomnia, agitation, tiredness, and depression, are common. Nervous system symptoms are numerous.[merckmanuals.com]
  • […] features Fever GI symptoms : severe abdominal pain, nausea, vomiting Neurological abnormalities Polyneuropathy : non-specific pain, weakness/fatigue, paresthesia, paresis Seizures Psychiatric abnormalities ; : hallucinations, disorientation, anxiety, insomnia[amboss.com]
  • However, they should be considered, particularly in female patients with unexplained abdominal pain and associated neurological or psychiatric features or hyponatraemia. [ 6 ] Attacks can start with anxiety, restlessness and insomnia in 20-30% of patients[patient.info]
Agitation
  • Patients also may develop paresis or acute motor neuropathy, and may experience changes in mental status, such as behavioral changes, agitation, or hallucinations.[hematologyandoncology.net]
  • You could also feel agitated, confused, or get seizures. Some complications you could get are: Long-term pain Kidney damage Liver cancer Symptoms of Cutaneous Porphyria Symptoms of cutaneous porphyria happen when your skin is in sunlight.[webmd.com]
  • Mental symptoms, such as irritability, restlessness, insomnia, agitation, tiredness, and depression, are common. Nervous system symptoms are numerous.[merckmanuals.com]
  • Agitation, mania, depression and hallucinations can occur and can persist between attacks. Urine may be dark or reddish due to the excessive excretion of haem precursors.[patient.info]

Workup

To make the diagnosis of acute hepatic porphyrias, a thorough patient history that will reveal presence of any of the mentioned porphyrias (having in mind the autosomal dominant pattern of inheritance), recent use of drugs or habits that may have precipitated the attacks, as well as history of similar symptoms, is essential. Together with a thorough physical examination, sufficient information can be gathered to suspect porphyria as an underlying cause. To confirm the diagnosis, urine and fecal testing for heme precursors and toxic metabolites should be performed. A distinction between subtypes can be made based on the obtained findings. AIP is suspected when markedly higher levels (20-100x higher) of ALA, PBG and uroporphyrin are found in urine, whereas detection of high coproporphyrin III levels in urine and stool, in addition to ALA and PBG in urine, is highly specific for HCP [5]. VP, on the other hand, is distinguished from HCP by confirming the presence of protoporphyrin in stool [5]. Urine and stool samples should be obtain during or right after the acute attacks [2]. A definite diagnosis is made through genetic tests, specifically polymerase chain reaction (PCR), which will detect the exact type of mutation [1].

Hyponatremia
  • It is very important to monitor patients with hyponatremia because they can develop seizures.[hematologyandoncology.net]
  • Seizures may occur in 20% of cases, particularly in patients with hyponatremia.[revistanefrologia.com]
  • Hyponatremia Hyponatremia is a relatively common metabolic manifestation accompanying acute attack. It is usually mild and easily corrected.[signavitae.com]
  • Initial therapeutic measures of acute hepatic porphyrias are focused on symptom alleviation - management of tachycardia, electrolyte dysbalance (hyponatremia is common, and often the cause of seizures) and gastrointestinal irritation.[symptoma.com]

Treatment

Initial therapeutic measures of acute hepatic porphyrias are focused on symptom alleviation - management of tachycardia, electrolyte dysbalance (hyponatremia is common, and often the cause of seizures) and gastrointestinal irritation [8]. Phenytoin or valproic acid should be avoided in management of seizures, as they may cause more severe symptoms [2]. Instead, benzodiazepines, gabapentin, magnesium and propofol (in the setting of refractory seizures) are used. Intravenous administration of hemin (a synthetic form of heme), however, is the mainstay of treatment, especially when dealing with acute attacks [2] [10]. Hemin is able to expand the pool of heme in hepatocytes, which produces a negative feedback mechanism that will reduce the production of heme precursors, most notably ALA [2]. Intravenous infusions will lead to resolution of symptoms within 3-4 days, and the lipophilic form (hematin), or heme arginate, is given in doses of 3 mg/kg per 24 hours as a single dose for 4 days [9]. For more severe enzyme deficiencies that cause recurrent life-threatening attacks and predispose patients to progressive motor neuropathies, liver transplantation may be indicated, but proper follow-up and rigorous anticoagulant therapy is mandatory, since a very high risk for hepatic artery thrombosis has been noted [9].

Prognosis

Before the introduction of modern critical care and directed therapy, mortality rates exceeded 35%, but with early identification and increased awareness of the disorder, patients achieve a good prognosis through long-term monitoring and avoidance of factors that are known to induce acute attacks [2]. However, numerous complications may arise, especially if the diagnosis is made late, most important being irreversible nerve degeneration (characteristic for AIP), renal insufficiency, chronic hypertension and hepatocellular carcinoma, which seems to be age-related and more commonly encountered among patients suffering from ongoing liver disease [2] [6].

Etiology

Acute hepatic porphyrias are all caused by genetic deficiencies of enzymes involved in one of the steps of heme synthesis, many of which occur in the liver. Although only 15% of total heme is synthesized in the liver, genetic mutations reduce enzymatic activity by 50% in AIP, HCP and VP, whereas 95% reduction is seen in ADP [5]. Apart from an autosomal recessive pattern of inheritance seen in ADP, all hepatic porphyrias are caused by autosomal dominant mutations, leading to accumulation of neurotoxic substances in the liver, presumably γ-aminobutyric acid analogs and/or porphobilinogen (PBG) [5].

Epidemiology

Prevalence rates of acute hepatic porphyrias significantly vary across different types and geographical regions. Overall prevalence rate of AIP in Europe is estimated at 1 in 75,000 individuals, ranging from 1 in 1,000 in northern Sweden to 2 in 100,000 in Finland, while Argentina reports rates of 1 in 125,000 individuals [1]. On the other hand, valegriate porphyria (VP) is most commonly encountered in South Africa, where 1 in 300 individuals suffer from this type of porphyria due to founder effect [6]. Other countries report much lower rates (2 per 100,000 in Finland and 1 per 600,000 in Argentina) [1]. Up to 2015, only 6 cases of ADP are reported [6]. Numerous precipitating factors or events are well-established inducers of acute attacks: lipophilic drugs (rifampicin, sulfonamide antibiotics, barbiturates and hydantoins) [6], corticosteroids, androgens, alcohol, organic solvents, pesticides, but also profound emotional stress, caloric deprivation that leads to severe fasting and physical effort [1] [6]. It must be noted that some types of hepatic porphyria, such as AIP, are more prevalent among women [6].

Sex distribution
Age distribution

Pathophysiology

Heme formation is a complex metabolic pathway involving eight different enzymes, all being potential targets for genetic mutations and the occurrence of porphyrias [7]. 85% of heme is formed in erythrocytes, and only 15% in the liver, but about 80% of heme synthesized in this organ is necessary for activity of cytochromal P450 enzymes and the electron transport chain in the TCA cycle, which are essential for degradation of toxic chemical and energy formation, respectively [1]. In the setting of genetic mutations that cause deficiencies of enzymes involved in heme synthesis, the pathogenesis of porphyrias stems from insufficient heme production and consequent hepatic accumulation of its precursors, in the attempt to accelerate the production of heme. As enzyme deficiencies impair the ability of the liver to produce heme, these precursors accumulate and become toxic (presumably γ-aminobutyric acid analogs, ALA, and/or porphobilinogen) and their deleterious effects develop through interaction with γ-aminobutyric acid (GABA) or glutamate receptors, the sites where main neuronal transmitters exert their effects [2] [5]. For symptoms to appear, however, the accumulation of these metabolites is not sufficient, but intake of certain drugs, stress, or severe caloric deprivation causes further saturation of cytochromal enzymes and even larger accumulation of toxic metabolites, eventually breaching the threshold of tolerance by the body resulting in the onset of symptoms.

Prevention

Genetic counselling may be highly recommended for families with a positive history for porphyrias. For those in whom the diagnosis is confirmed, several preventive measures may be of significant benefit [2] [8]:

  • Avoiding use of hazardous drugs and exposure to substances that are known inducers of acute attacks.
  • Avoid periods of starvation and profound fasting.
  • Prophylactic therapy with hematin.
  • Regular screening - Abdominal ultrasonography and serum alpha-fetoprotein levels performed on an annual basis after 50 years of age is recommended, primarily to identify early signs of liver disease and hepatocellular carcinoma.

Summary

Porphyrias are a group of genetic disorders that arise as a result of deficiency of enzymes involved in the formation of heme, a vital constituent of hemoglobin and cytochromal enzymes that participate in metabolism of numerous drugs in the liver and in the tricyclic acid cycle (TCA), where they are necessary cofactors in the electron transport chain [1]. Based on the onset of symptoms, porphyrias are generally divided into acute and non-acute, and a further classification according to the type of symptoms (neurovisceral and/or cutaneous) can be made as well [1] [2]. Additionally, porphyrias can be classified into hepatic and erythropoietic, depending the site of overproduction of toxic metabolites [3], and four hepatic porphyrias are recognized in literature [4] [5] [6]:

  • δ-aminolevulinic acid dehydratase deficiency (ADP) porphyria - Only a six cases of ADP have been described in literature up to today, in which the second step of heme synthesis (condensation of two molecules of δ-aminolevulinic acid - ALA into porphobilinogen) is affected by autosomal recessive mutations [2].
  • Acute intermittent porphyria (AIP) - Considered as one of the most common forms of porphyria, AIP is inherited through autosomal dominant patterns, and is caused by mutations in hydroxymethylbilane synthase (HMB-synthase) gene, responsible for the third step of heme synthesis - conversion of porphobilinogen (PBG) into uroporphyrinogen [2]. The clinical presentation appears in only 10% of mutation carriers and comprises typical acute attack consisting of nonspecific abdominal pain, nausea, tachycardia, vomiting, constipation, mental changes, convulsions, hypertension and pain in the head, neck and/or thorax [1].
  • Hereditary coproporphyria (HCP) - Deficiency of coproporphyrinogen oxidase (CPOX), necessary for the sixth step of heme formation - conversion of coproporphyrinogen III to protoporphyrinogen IX, through autosomal dominant mutations of the CPOX gene is the mechanism of disease in this type of porphyria [1]. The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions [1].
  • Variegate porphyria (VP) - Like AIP and HCP, variegate porphyria (VP) is inherited by autosomal dominant transfer of mutated genes that code for protoporphyrinogen oxidase (PPOX), which is necessary for the conversion of protoporphyrinogen to protoporphyrin, the seventh and second-last step in heme synthesis [6]. Adult-onset of cutaneous blistering lesions (subepidermal vesicles, erosions, bullae) of the sun-exposed skin and acute attacks of abdominal and chest pain, constipation, muscle weakness that can be severe enough to cause paralysis of the limbs and respiratory muscles, as well as psychiatric disturbances are main symptoms of VP [7].

Two main features are shared by all porphyrias. Firstly, the onset of symptoms stems from accumulation of toxic substances of the heme pathway due to enzyme deficiencies; and secondly, these metabolites are not sufficient by themselves to cause symptoms [4]. Acute attacks are precipitated by various factors and events, including alcohol, pesticides, organic solvents, caloric deficiency, corticosteroids, and numerous lipophilic drugs (barbiturates, rifampicin, sulfonamide antimicrobials etc.) [1] [6]. For this reason, the diagnosis of hepatic porphyrias can be made by detecting heme precursor metabolites in urine or feces after use of certain drugs, substances or nutritional-related effects. Treatment principles comprise discontinuation of potentially hazardous drugs, administration of hematin (a synthetic form of heme that inhibits production of toxic metabolites), dextrose, symptomatic care, and in most severe cases, liver transplantation [8].

Patient Information

Porphyrias are a group of inherited disorders that cause insufficient formation of heme, a precursor of hemoglobin and a vital constituent of various liver enzymes involved in metabolism of numerous drugs and toxic substances. Based on their clinical features and site of occurrence, they can be divided into acute or non-acute, hepatic or erythropoietic (originating from the liver or red blood cells, respectively) and neurovisceral or cutaneous, implying that symptoms may be related either to the nervous system and internal organs or the skin. Acute hepatic porphyrias are a group of disorders in which enzyme deficiencies cause insufficient formation of heme in the liver and subsequent accumulation of toxic metabolites of this pathway in the same organ. Delta-aminolevulinic acid dehydratase deficiency (ADP) porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP) are representatives of this group. For symptoms to appear, enzyme deficiencies are not sufficient by themselves, but additional factors are necessary to trigger their onset. Examples are use of drugs metabolized by enzymes that use heme as its substrate, such as rifampicin, barbiturates, and sulfonamide antibiotics, whereas corticosteroids and androgens, profound fasting due to starvation, emotional stress, exposure to organic solvents, pesticides, and alcohol are other notable examples. The hallmark of hepatic porphyrias are "acute attacks" of nonspecific and intense abdominal pain accompanied by nausea, vomiting, cramping, constipation and deceased bowel sounds, hence the term acute hepatic porphyria. Additional signs include head, neck and chest pain, hypertension, seizures, mental changes (restlessness, anxiety, confusion, insomnia, disorientation), and neuropathies that can induce severe muscle weakness. The diagnosis can be made by detecting toxic metabolites in urine or feces and genetic testing may be performed as a confirmation. Treatment initially focuses on alleviation of symptoms through stabilizing blood pressure and seizures, as well as gastrointestinal complaints. The mainstay of therapy, however, is administration of synthetic heme (known as hematin or heme arginate), which increases the pool of heme in the liver, thus reducing the production of toxic metabolites. Because acute attacks may be recurrent and severe, and even life-threatening, liver transplantation may be considered. For the same reason, a late diagnosis is detrimental, as current therapeutic modalities and preventive strategies (avoiding use of drugs or other factors that can precipitate the onset of symptoms) can successfully treat the condition and prevent long-term sequelae.

References

Article

  1. Szlendak U, Bykowska K, Lipniacka A. Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria. Adv Clin Exp Med. 2016;25(2):361-368.
  2. Bissell DM, Wang B. Acute Hepatic Porphyria. J Clin Transl Hepatol. 2015;3(1):17-26.
  3. Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: A 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
  4. Siegesmund M, van Tuyll van Serooskerken AM, Poblete-Gutiérrez P, Frank J. The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol. 2010;24(5):593-605.
  5. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120(23):4496-4504. .
  6. Ramanujam V-MS, Anderson KE. Porphyria Diagnostics – Part 1: A brief overview of the porphyrias. Curr Protoc Hum Genet. 2015;86:17.20.1-17.20.26.
  7. Singal AK, Anderson KE. Variegate Porphyria. 2013 Feb 14. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
  8. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  9. Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver Transplantation in the Management of Porphyria. Hepatology (Baltimore, Md). 2014;60(3):1082-1089
  10. Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8:201-214.

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Last updated: 2018-06-21 23:28