Question 1 of 10

    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].

    Liver, Gall & Pancreas
    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]
    • […] 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]
    • Not all porphyrias are genetic, and patients with liver disease who develop porphyria as a result of liver dysfunction may exhibit other signs of their condition, such as jaundice .[house.wikia.com]
    • I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice[porphyriafoundation.com]
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  • Entire body system
    Agitation
    • […] contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes or mental disorders Agitation[webmd.com]
    • 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]
    • Agitation, mania, depression and hallucinations can occur and can persist between attacks.[patient.info]
    • Mental symptoms 40-58 May range from minor behavioral changes to agitation, confusion, hallucinations, and depression.[mdedge.com]
    • Some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases,[porphyriafoundation.com]
    Anemia
    • 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]
    • 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]
    • ., anemia , alcohol, or chronic heavy metal poisoning ) Porphyria cutanea tarda (PTC) Epidemiology Most common porphyria Peak incidence : 40–70 years Sex: Etiology Acquired (type I): insufficiency of uroporphyrinogen -III decarboxylase (UROD) in the context[amboss.com]
    • P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2018 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]
    • Anderson KE, Sassa S, Bishop DF, Desnick RJ: X-Linked sideroblastic anemia and the porphyrias.[mayomedicallaboratories.com]
    Fatigue
    • 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]
    • RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue.[discovery.ucl.ac.uk]
    • Her need for frequent hospitalization, pronounced fatigue, and debilitating abdominal pain prompted the decision to explore LT for a potential cure.[omicsonline.org]
    • […] defective PBG-D accumulation of porphobilinogen (PBG) and δ-aminolevulenic acid (ALA) symptoms Clinical features Fever GI symptoms ; : severe abdominal pain , nausea, vomiting Neurological abnormalities Polyneuropathy : non-specific pain , weakness/fatigue[amboss.com]
    • Robert Desnick told SciBX that during an acute attack, patients often experience a prodromal period with brain fog and fatigue.[nature.com]
    Fever
    • Symptoms often begin after puberty and consist of acute neurovisceral signs, abdominal pain, vomiting, constipation, tachycardia, fever, hypertension and alterations in the central nervous system [7-9].[medcraveonline.com]
    • ., surgery, infection) Pathophysiology : defective PBG-D accumulation of porphobilinogen (PBG) and δ-aminolevulenic acid (ALA) symptoms Clinical features Fever GI symptoms ; : severe abdominal pain , nausea, vomiting Neurological abnormalities Polyneuropathy[amboss.com]
    • In case of acute abdomen with fever, the suspicion of appendicitis is obvious.[lecturio.com]
    • Because the pain is neuropathic, it often is not accompanied by fever or leukocytosis.[hematologyandoncology.net]
    • Not accompanied by peritoneal signs, fever, or leukocytosis.[mdedge.com]
    Limb Pain
    • States and 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[learnaboutyourpain.com]
    Pain
    • Only a small minority of those who carry a mutation for acute porphyria have pain attacks.[ncbi.nlm.nih.gov]
    • […] the United States and 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[learnaboutyourpain.com]
    • The imbalance can contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes[webmd.com]
    • Another aspect of the painfulness of EPP is the painful abdomen, which may manifest as generalized pain, or may imitate an appendicitis .[house.wikia.com]
    • These drugs allay pain and nervousness and apparently allow a period of remission from symptoms.[medical-dictionary.thefreedictionary.com]
    Weakness
    • 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 psychological symptoms[orpha.net]
    • Severe attacks of acute porphyria can cause lasting nerve damage and muscle weakness that can take months to resolve.[webmd.com]
    • This causes weakness of the muscles that are supplied by the damaged nerves.[porphyriafoundation.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]
    • Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.[house.wikia.com]
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  • neurologic
    Confusion
    • […] 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]
    • 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]
    • RESULTS: All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue.[discovery.ucl.ac.uk]
    • […] some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes or mental disorders Agitation, confusion[webmd.com]
    • Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances Porphobilinogen (PBG) and porphyrins are susceptible to degradation at high[mayomedicallaboratories.com]
    Convulsions
    • 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 psychological symptoms[orpha.net]
    • Gabapentin and probably vigabatrin can be used to treat convulsions.[patient.info]
    • 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[symptoma.com]
    • The most common symptom is intense abdominal pain, but some people also suffer muscular weakness, sensory disturbances or convulsions, and as a group the diseases are "devastating for patients" with attacks lasting for days and often requiring admission[fiercebiotech.com]
    • In its rare neurological manifestation it can lead to untreatable convulsions which leave no option but to terminate the pregnancy. 2007 S.[karger.com]
    Headache
    • AEs in three or more patients included: abdominal pain, headache, nasopharyngitis, nausea and vomiting.[dddmag.com]
    • Other general symptoms often accompanying acute attacks are tiredness, restlessness and headaches.[signavitae.com]
    Insomnia
    • 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]
    • Chloral hydrate may be used for insomnia.[mdedge.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]
    • Some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases,[porphyriafoundation.com]
    • Insomnia and anxiety are usually mild and do not require additional medications but can be treated with benzodiazepines, such as lorazepam. 49 Hallucinations are also signs of acute encephalopathy and should be treated with phenothiazine or olanzapine[dovepress.com]
    Paresthesia
    • […] defective PBG-D accumulation of porphobilinogen (PBG) and δ-aminolevulenic acid (ALA) symptoms Clinical features Fever GI symptoms ; : severe abdominal pain , nausea, vomiting Neurological abnormalities Polyneuropathy : non-specific pain , weakness/fatigue, paresthesia[amboss.com]
    • Neurological-psychiatric symptoms of an acute intermittent porphyria are diverse and can occur in the form of peripheral nerve palsies, neuralgic pains, paresthesias, epilepsies, resentment and psychoses.[lecturio.com]
    • They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor[house.wikia.com]
    Personality Change
    • The imbalance can contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes[webmd.com]
    • Acute hepatic porphyria can be triggered by pregnancy and usually presents with gastrointestinal symptoms and personality changes.[karger.com]
    • Symptoms of acute porphyria include pain in the chest, abdomen, limbs, or back; muscle numbness, tingling, paralysis, or cramping; vomiting; constipation; and personality changes or mental disorders.[genome.gov]
    Seizure
    • Subsequently neurological symptoms with seizures developed leading to a status epilepticus with continuing seizures at week 14.[karger.com]
    • The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures.[ncbi.nlm.nih.gov]
    • Seizures Edit Seizures often accompany this disease.[house.wikia.com]
    • […] porphyria often is "silent," meaning that the genetic change causes symptoms only in the presence of certain environmental triggers, such as alcohol consumption, inadequate diet and certain medications — especially sedatives related to barbiturates, anti-seizure[ucsfhealth.org]
    • […] that can accompany HCP, as most anti-seizure medications can make the symptoms worse.[ippn.info]
    Tremor
    • Attacks are characterized by abdominal pain, sympathetic over-activity resulting in tachycardia, hypertension , tremors, diaphoresis, arrhythmias, and acute neurologic manifestations (confusion, hallucinations, neuropathy, and seizures) [ 1 ].[omicsonline.org]
    • […] starting in upper extremities which can progress to include respiratory impairment and death), autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia , high blood pressure , sweating , restlessness and tremor[house.wikia.com]
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  • Skin
    Blister
    • Porphyria cutanea tarda ( PCT ) is the most common form and presents with chronic, blistering cutaneous photosensitivity and tea-colored urine.[amboss.com]
    • The majority of patients exhibit acute attacks, while 20% can also present with skin-related symptoms, such as photosensitivity and blistering skin lesions [1].[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]
    • VP is an autosomal dominant genetic disorder with severe neurovisceral symptoms or chronic blistering skin lesions.[medcraveonline.com]
    • Haemorrhagic blisters, erosions, crusts and milia on the back of the hands and the distal forearms of patient 1.[medicaljournals.se]
    Cutaneous Manifestation
    • Some types have both acute and cutaneous manifestations.[ncbi.nlm.nih.gov]
    • 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.[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 scalp[amboss.com]
    • Variegate porphyria presents with cutaneous manifestations about 60% of the time; hereditary coproporphyria does so only rarely ( 5%).[mdedge.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]
    • […] sunlight-dependent skin damage (chronic photosensitivity) 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]
    • Similarly, patients show increased hair growth ( hypertrichosis ) and hyperpigmentation .[lecturio.com]
    • Fragile, poorly healing skin with pruritus, hyperpigmentation and hypertrichosis are other features.[patient.info]
    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]
    • 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]
    • […] sunlight-dependent skin damage (chronic photosensitivity) 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]
    • Similarly, patients show increased hair growth ( hypertrichosis ) and hyperpigmentation .[lecturio.com]
    • Fragile, poorly healing skin with pruritus, hyperpigmentation and hypertrichosis are other features.[patient.info]
    Photosensitivity
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  • respiratoric
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  • gastrointestinal
    Abdominal Cramps
    • Masters suggested Ryan's abdominal bleeding might be caused by acute intermittent porphyria, but there were no abdominal cramps to go along with it.[house.wikia.com]
    Abdominal Pain
    • 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 psychological symptoms[orpha.net]
    • Acute intermittent porphyria, porphyria variegata, and to a lesser degree hereditary coproporphyria can cause acute symptoms: abdominal pains and general symptoms.[books.google.com]
    • The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures.[ncbi.nlm.nih.gov]
    • Often there is no abdominal pain, distinguishing it from other porphyrias.[house.wikia.com]
    Colic
    • AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy.[uniprot.org]
    • […] decarboxylase Porphyria cutanea tarda (PCT) Hepatic Autosomal dominant Photosensitivity with vesicles and bullae 1 in 10,000 Coproporphyrinogen (COPRO) oxidase Hereditary coproporphyria (HCP) Hepatic Autosomal dominant Photosensitivity, neurologic symptoms, colic[house.wikia.com]
    Diarrhea
    • This includes the acute attacks of abdominal pain, nausea , vomiting, diarrhea , tachycardia , hypertension and seizures , as well as the cutaneous findings seen in porphyria cutanea tarda (PCT), namely increased skin fragility, bullous lesions after[ippn.info]
    • Constipation is frequently present, as the nervous system of the gut is affected, but diarrhea can also occur.[house.wikia.com]
    • Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention).[porphyriafoundation.com]
    • Diarrhea Loperamide may be administered. ). [mdedge.com]
    Nausea
    • The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures.[ncbi.nlm.nih.gov]
    • 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]
    • Although some patients receive timely treatment, half of them suffer through attacks, receiving only supportive care (medication for nausea and pain) in Emergency or as an inpatient as they are not able to receive Normosang and/or Panhematin treatment[canadianassociationforporphyria.ca]
    • 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 the abdomen Nausea[ucsfhealth.org]
    • It is also quite common to have nausea , vomiting and constipation .[orphan-europe.com]
    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]
    • 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]
    • AHP patients have been known to suffer from an array of symptoms that can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and potentially[raredr.com]
    • These inherited disorders are characterized by life-threatening acute attacks that include severe abdominal pain, muscle weakness, seizures and paralysis.[nature.com]
    Vomiting
    • Patients may be given medicine for pain, nausea, and vomiting .[webmd.com]
    • […] 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 and vomiting[learnaboutyourpain.com]
    • Unlike acute intermittent porphyria , individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of[ippn.info]
    • It is also quite common to have nausea , vomiting and constipation .[orphan-europe.com]
    • Patients also may experience nausea, vomiting, constipation, or pain in the chest or back.[hematologyandoncology.net]
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  • musculoskeletal
    Back Pain
    • Symptoms may include vomiting, abdominal or back pain, weakness in arms or legs, and mental symptoms.[merckmanuals.com]
    • The imbalance can contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes[webmd.com]
    • They suffered from back pain, difficulty urinating, psychosis, tachycardia and cramps.[house.wikia.com]
    • […] precipitate acute attacks by the central mechanism making AIP a central nervous system disorder in addition to a liver disease. 27 Diagnosis of AIP The clinical criteria of an acute attack include the paroxysmal nature of the symptoms with abdominal or back[dovepress.com]
    Muscle Weakness
    • Severe attacks of acute porphyria can cause lasting nerve damage and muscle weakness that can take months to resolve.[webmd.com]
    • Nerve damage and associated muscle weakness can improve over a period of months or longer after a severe attack.[porphyriafoundation.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]
    • 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[symptoma.com]
    • Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.[house.wikia.com]
    Myalgia
    • 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]
    • 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]
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  • cardiovascular
    Chest Pain
    • The imbalance can contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes[webmd.com]
    • 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[symptoma.com]
    Tachycardia
    • The triad of cardiovascular symptoms , especially tachycardia and hypertension is completed.[lecturio.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]
    • 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[symptoma.com]
    • Cardiovascular Tachycardia 28, 64-85 May warrant treatment to control rate, if symptomatic.[mdedge.com]
    • Beta-blockers can reduce tachycardia and hypertension.[patient.info]
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  • urogenital
    Dark Urine
    • 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]
    • They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor[house.wikia.com]
    • Other useful clues are a history of dark urine, especially reddish urine, tachycardia, and systemic arterial hypertension during attacks.[mdedge.com]
    Dysuria
    • They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor[house.wikia.com]
    Red Urine
    • Red urine that fluoresces in nappies can allow an easy bedside diagnosis. [ 3 ] There is severe photosensitivity.[patient.info]
    • Even a purple hue or red urine may be seen.[house.wikia.com]
    Urinary Retention
    • Difficulty passing urine (urinary retention) can also occur.[porphyriafoundation.com]
    • They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor[house.wikia.com]
    • Metoclopramide has been associated with neuropathy and encephalopathy during a few acute attacks, 70 but some patients have used it without complications. 66 Urinary retention is quite common and can be treated with catheterization.[dovepress.com]
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  • psychiatrical
    Psychiatric Manifestation
    • Much the same way as previously diagnosed patients with MCSS showed similarities with somatization disorders, the psychiatric manifestations of acute porphyria may also be confused with various psychiatric disorders (especially when combined with an isolated[mdedge.com]
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  • Eyes
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  • Breast
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  • 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].

    Test Results

    EEG
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  • Laboratory

    Serum
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  • Urine
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  • Stool
    Coproporphyrin Increased
    • ) increase only with hepatopathy Protoporphyrin* X-EPP Free and zinc protoporphyrin Protoporphyrin ( 634 nm)** Urine porphyrins (especially coproporphyrin) increase only with hepatopathy Protoporphyrin* *Porphyrin levels normal or slightly increased.[mdedge.com]
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  • Cerebrospinal Fluid
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  • Imaging

    X-ray
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  • 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].

    Complications

    Acute Pancreatitis
    • In the third dose cohort, which remains blinded, one death was reported after the data transfer date due to acute pancreatitis complicated by a pulmonary embolism and following an earlier hospitalization for bacteremia; the death was considered to be[businesswire.com]
    • In the third dose cohort, which remains blinded, one death due to acute pancreatitis, considered unlikely related to givosiran or placebo, was reported after the data transfer date.[spjnews.com]
    • The pancreas was slightly fibrotic and displayed a peripancreatic fat necrosis as the result of acute pancreatitis.[medicaljournals.se]
    Anxiety
    • […] 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 psychological symptoms (irritability, anxiety[orpha.net]
    • Phenothiazines can be used for nausea, vomiting, anxiety and restlessness.[patient.info]
    • Clinical 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[amboss.com]
    • During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations.[house.wikia.com]
    • Treatment for AIP also includes drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness.[porphyriafoundation.com]
    Appendicitis
    • In case of acute abdomen with fever, the suspicion of appendicitis is obvious.[lecturio.com]
    • However, the disease is often undiagnosed or misdiagnosed in the emergency room and mistaken for appendicitis because of the severe abdominal pain and a general lack of awareness about the condition.[nature.com]
    • Some of the more common misdiagnoses are appendicitis and cholecystitis; other patients are told they have a urinary tract infection, colitis, or another common condition.[hematologyandoncology.net]
    • Another aspect of the painfulness of EPP is the painful abdomen, which may manifest as generalized pain, or may imitate an appendicitis .[house.wikia.com]
    Autonomic Neuropathy
    • 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]
    • neuropathy Urine that is reddish in color Neuropsychiatric symptoms, including paralysis, seizures and confusion Elevated heart rate There has also been increasing recognition that AHP patients have significant chronic disease manifestations. [learnaboutyourpain.com]
    • AHP patients have been known to suffer from an array of symptoms that can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and potentially[raredr.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]
    Constipation
    • 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[symptoma.com]
    • It is also quite common to have nausea , vomiting and constipation .[orphan-europe.com]
    • The imbalance can contribute to some of these symptoms: Abdominal pain , often severe Chest pain Increased heart rate and blood pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes[webmd.com]
    • Symptoms often begin after puberty and consist of acute neurovisceral signs, abdominal pain, vomiting, constipation, tachycardia, fever, hypertension and alterations in the central nervous system [7-9].[medcraveonline.com]
    • Lead toxicity can cause symptoms that mimic acute porphyria (acute abdominal pain, constipation, and neuropathy).[porphyriafoundation.com]
    Depression
    • Depression often accompanies the disease and is best dealt with by treating the offending symptoms and, if needed, the judicious use of anti-depressants.[house.wikia.com]
    • […] pressure Limb and back pain Muscle weakness Tingling Loss of sensation Cramping Vomiting and constipation Personality changes or mental disorders Agitation, confusion, and seizures Long-term complications in some patients have included: Chronic pain Depression[webmd.com]
    • Mental symptoms 40-58 May range from minor behavioral changes to agitation, confusion, hallucinations, and depression.[mdedge.com]
    • Agitation, mania, depression and hallucinations can occur and can persist between attacks.[patient.info]
    • Some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases,[porphyriafoundation.com]
    Hallucinations
    • […] 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 psychological symptoms (irritability, anxiety, auditory or visual hallucinations[orpha.net]
    • […] δ-aminolevulenic acid (ALA) symptoms Clinical features Fever GI symptoms ; : severe abdominal pain , nausea, vomiting Neurological abnormalities Polyneuropathy : non-specific pain , weakness/fatigue, paresthesia , paresis Seizures Psychiatric abnormalities ; : hallucinations[amboss.com]
    • During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations.[house.wikia.com]
    • Attacks are characterized by abdominal pain, sympathetic over-activity resulting in tachycardia, hypertension , tremors, diaphoresis, arrhythmias, and acute neurologic manifestations (confusion, hallucinations, neuropathy, and seizures) [ 1 ].[omicsonline.org]
    • 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]
    Hypertension
    • Content is provided from medical therapies to surgery on the patient with portal hypertension.[books.google.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]
    • Beta-blockers can reduce tachycardia and hypertension.[patient.info]
    • Other long-term complications include chronic arterial hypertension and subsequent renal impairment.[mdedge.com]
    • Review of hepatocellular cancer, hypertension, and renal impairment as late complications of acute porphyria and recommendations for patient follow-up.[rarediseases.org]
    Hypomagnesemia
    • Seizures can be a consequence of hyponatremia or hypomagnesemia, or be secondary to CNS involvement.[signavitae.com]
    • Increased risks for hyponatremia and hypomagnesemia.[mdedge.com]
    Hyponatremia
    • Hyponatremia Hyponatremia is a relatively common metabolic manifestation accompanying acute attack.[signavitae.com]
    • Another important early sign of this disorder is hyponatremia.[hematologyandoncology.net]
    • Increased risks for hyponatremia and hypomagnesemia.[mdedge.com]
    • The clinical criteria of an acute attack include the paroxysmal nature and various combinations of symptoms, such as abdominal pain, autonomic dysfunction, hyponatremia, muscle weakness, or mental symptoms, in the absence of other obvious causes.[dovepress.com]
    • For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion.[porphyriafoundation.com]
    Ileus
    • A painful blockage or obstruction (ileus) of part of the small intestines may also occur.[porphyriafoundation.com]
    • Gut dysmotility, ileus , intussusception , hypoganglionosis , encopresis in children and intestinal pseudo-obstruction have been associated with porphyrias.[house.wikia.com]
    • Bowel paresis (ileus) Neostigmine can be administered.[mdedge.com]
    Iron Deficiency Anemia
    • Furthermore, iron deficiency anemia, lead toxicity, and increased erythropoiesis lead to increased erythrocyte zinc protoporphyrin, which may be reported erroneously by some reference laboratories as "free protoporphyrin."[mdedge.com]
    Leukocytosis
    • Because the pain is neuropathic, it often is not accompanied by fever or leukocytosis.[hematologyandoncology.net]
    • Not accompanied by peritoneal signs, fever, or leukocytosis.[mdedge.com]
    • Other nonspecific signs in an attack of AIP include hyponatremia, syndrome of inappropriate secretion of antidiuretic hormone, and mild leukocytosis.[ddtjournal.org]
    Neuropathy
    • Coverage encompasses both inherited and acquired diseases, including neuropathies arisingfrom physical injury, diabetes, alcoholism, toxins, autoimmune responses, nutritional deficiencies, vascularand metabolic disorders, medication-induced neuropathies[books.google.com]
    • AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy.[uniprot.org]
    • The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy.[porphyriafoundation.com]
    • 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]
    • […] 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 and vomiting Peripheral and autonomic neuropathy[learnaboutyourpain.com]
    Paralysis
    • […] 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 and possibly paralysis[clinicaladvisor.com]
    • […] debilitating attacks. [5] 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[learnaboutyourpain.com]
    • […] have been known to suffer from an array of symptoms that can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and potentially paralysis[raredr.com]
    • 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[symptoma.com]
    • Proximal myopathy affecting the arms can progress to quadraparesis, respiratory muscle paralysis and respiratory arrest.[patient.info]
    Peripheral Motor Neuropathy
    • Respiratory paralysis 9-20 Preceded by progressive peripheral motor neuropathy and paresis.[mdedge.com]
    Peripheral Neuropathy
    • Features of Textbook of Peripheral Neuropathy Include : ̈ Practical yet comprehensive an accessible go-to reference for clinicians ̈ Covers all clinically relevant peripheral neuropathies ̈ Clinical Pearls and Key Points are set off from the text for[books.google.com]
    • AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy.[uniprot.org]
    • Common symptoms include severe abdominal pain, peripheral neuropathy, and psychiatric symptoms.[mayomedicallaboratories.com]
    • Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy).[porphyriafoundation.com]
    • Symptomatically, acute porphyrias primarily present with nervous system involvement, often with severe abdominal pain , vomiting , peripheral neuropathy and mental disturbances.[house.wikia.com]
    Psychosis
    • They suffered from back pain, difficulty urinating, psychosis, tachycardia and cramps.[house.wikia.com]
    • Mental illness, especially psychosis. [ 10 ] Neurological deficits.[patient.info]
    • Nausea/Vomiting Phenothiazines, chlorpromazine, droperidol, prochlorperazine, or ondansetron Agitation, insomnia, anxiety, confusion, and psychosis Chlorpromazine, fluphenazine, or lorazepam.[mdedge.com]
    • Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria.[dovepress.com]
    Respiratory Muscle Paralysis
    • Proximal myopathy affecting the arms can progress to quadraparesis, respiratory muscle paralysis and respiratory arrest.[patient.info]
    Sudden Death
    • Sudden death can occur during an acute attack and is thought to be due to cardiac arrhythmia.[patient.info]
    • In a few cases, acute attacks of AIP have been documented to cause sudden death, presumably due to cardiac arrhythmias.[mdedge.com]
    Syndrome of Inappropriate Antidiuretic Hormone Secretion
    • We describe a patient with VP who received class Ic antiarrhythmic agents for paroxysmal atrial fibrillation (AF) and presented with an acute episode of porphyria, which consisted of acute abdomen and syndrome of inappropriate antidiuretic hormone secretion[revespcardiol.org]
    • Hyponatremia presumably occurs because of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or because of loss of sodium in the gastrointestinal tract or kidneys.[hematologyandoncology.net]
    • […] of inappropriate antidiuretic hormone secretion.[dovepress.com]
    Vegetative State
    • Ceccaldi PF, Bazin A, Gomis P, Ducarme G, Chaufer AL, Gabriel R: Persistent vegetative state with encephalitis in a pregnant woman with successful fetal outcome.[karger.com]
  • more...
  • 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.

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    References

    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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