Question 1 of 10

    Acute Intermittent Porphyria (AIP)

    Porphobilinogen[1]

    Acute intermittent porphyria (AIP) belongs to a group of hereditary diseases known as porphyrias which are characterized by defective heme metabolism, leading to excessive cellular secretion of porphyrins and their precursors. Patients with AIP will experience abdominal pain, neuropathies and constipation without the characteristic rash observed in other types of porphyria. Neuro-visceral attacks without cutaneous manifestations are characteristic of AIP. Of the acute hepatic porphyrias, AIP is the most common and most severe.

    Acute Intermittent Porphyria stems from the following process: metabolic.

    Presentation

    Due to hormonal factors, AIP almost always manifests after puberty, especially in women. AIP attacks typically follow a distinct order of events starting with abdominal pain (>95% of attacks), then psychiatric symptoms (eg. hysteria) and finally peripheral and motor neuropathies. Between attacks patients are symptom free. No skin manifestations are observed in patients with AIP during attacks, but neurovisceral signs and symptoms, including abdominal pain associated with lumbago radiating to the thighs, autonomic neuropathies (causing constipation), vomiting, hypertension and tachycardia, may occur. Epigastric and colicky abdominal pain is severe and often lasts for several days but chronic abdominal pain is unusual. Scattered upper body pain may also occur (back, arm and leg pain). Symptoms may also include urinary retention, palpitations and decreased levels of sodium and chloride in the blood. The central nervous system sings of AIP may include seizures, delirium, cortical blindness, irritability, emotionality, anxiety and coma. Peripheral neuropathies may mimic Guillain-Barré syndrome and include weakness that starts in the lower limbs and rises, although any nerve distribution may be observed. A variety of psychiatric symptoms are observed, including depression in most cases, mental changes (confusion and hallucinations) and seizures. Concurrent neurological or abdominal symptoms can be life-threatening and may progress to paralysis and hyponatremia.

    The majority of individuals who inherit the HMBS gene mutation never develop symptoms, however, experts recommend that relatives of AIP patients obtain testing. Individuals who have the trait should be educated on how to avoid attacks. Optimal management should include prevention. AIP attacks are most often triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, fasting and stress), and/or endogenous factors (hormonal).

    Entire body system
    Acute Intermittent Porphyria
    Agitation
    • Constipation and/or diarrhea Neurologic symptoms Diffuse musculoskeletal pain headache Sensory loss (40%) An indication of a severe and potentially life-threatening attack Neuropathy can progress to respiratory failure in hours or days Bladder paresis Agitation[wikem.org]
    • 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,[cigna.com]
    • […] 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), neuropsychiatric symptoms ( anxiety , agitation[house.wikia.com]
    Anemia
    • First, they overcome the bodys shortage of heme, relieving anemia.[scientificamerican.com]
    • However, lead poisoning causes a decrease in the number of blood cells (anemia), which is not seen in acute intermittent porphyria.[thinkgenetic.com]
    • The porphyric cats had erythrodontia, porphyrinuria, and mild anemia, but no evidence of acute life-threatening neurovisceral attacks or cutaneous lesions.[bloodjournal.org]
    • 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]
    • 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]
    Dutch
    • NVKC 10 (1985) 223–231 (in Dutch) Google Scholar Beukeveld, G.[link.springer.com]
    • Although original descriptions are attributed to Hippocrates , the disease was first explained biochemically by Felix Hoppe-Seyler in 1871, and acute porphyrias were described by the Dutch physician Barend Joseph Stokvis in 1889.[house.wikia.com]
    Fever
    • […] one acute attack during their lives. acute intermittent porphyria Hematology An AD condition caused by a deficiency of porphobilinogen deaminase, resulting in overproduction of δ-aminolevulinic acid Clinical Recurrent abdominal colic, constipation, fever[medical-dictionary.thefreedictionary.com]
    • In 1999, She was admitted in JK Lone hospital with h/o of severe pain abdomen, convulsions(GCTS type,5 episodes, self aborting),Reddish discoloration of urine & Hypertension after intake of a drug for fever and cough.[slideshare.net]
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  • neurologic
    Confusion
    • The symptoms can be categorized by the 5 Ps of AIP: Painful abdomen (often confused for acute abdomen, leading to a belly full of scars) Port wine–colored urine (urine is colorless initially, but exposure to light causes PBG in urine to oxidize and gives[stepwards.com]
    • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
    • Confusion, convulsions, and muscular weakness, due to neurologic impairment, may lead to paralysis.[sema4genomics.com]
    • […] and/or diarrhea Neurologic symptoms Diffuse musculoskeletal pain headache Sensory loss (40%) An indication of a severe and potentially life-threatening attack Neuropathy can progress to respiratory failure in hours or days Bladder paresis Agitation, confusion[wikem.org]
    • These include areas of reduced or altered sensation, confusion, seizures, palpitations, high blood pressure, and constipation or diarrhea.[labtestsonline.org]
    Convulsions
    • A neurologist’s “back hand” clue fueled an already burning fire in me to find out what was wrong with Jill, whose first presentations were neurological symptoms: tremors, headaches, nauseous and frequent fainting/convulsive spells beginning in sixth grade[globalgenes.org]
    • Neurological manifestations can affect the central nervous system as much as the peripheral nervous system (myalgia, paresis, ascending flaccid paralysis of the limbs, or convulsions) and can lead to severe complications such as motor paralysis.[orpha.net]
    • Confusion, convulsions, and muscular weakness, due to neurologic impairment, may lead to paralysis.[sema4genomics.com]
    • In 1999, She was admitted in JK Lone hospital with h/o of severe pain abdomen, convulsions(GCTS type,5 episodes, self aborting),Reddish discoloration of urine & Hypertension after intake of a drug for fever and cough.[slideshare.net]
    Paresthesia
    • Peripheral neuropathy (patchy numbness and paresthesias) Psychological disturbances (anxiety, confusion, psychosis, dementia ) Precipitated by drugs (drugs that enhance cytochrome P-450 activity, sulfa drugs, barbiturates , some antipsychotics, alcohol[stepwards.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
    • Other symptoms may include: Muscle pain Muscle weakness or paralysis Numbness or tingling Pain in the arms or legs Pain in the back Personality changes Attacks can sometimes be life threatening, producing: Low blood pressure Severe electrolyte imbalances[nytimes.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
    • Seizures often accompany this disease.[en.wikipedia.org]
    • Neurontin : for treatment of seizures.[medical-institution.com]
    • Seizures Edit Seizures often accompany this disease.[house.wikia.com]
    • Management Opioid analgesia Avoid/discontinue offending medications Most seizure medications contraindicated: Benzodiazepines , gabapentin , levetiracetam , and vigabatrin okay Avoid reglan Treat any electrolyte abnormalities beta-blockers can be used[wikem.org]
    • During an attack, you may experience dehydration, breathing problems, seizures and high blood pressure.[mayoclinic.org]
    Tremor
    • A neurologist’s “back hand” clue fueled an already burning fire in me to find out what was wrong with Jill, whose first presentations were neurological symptoms: tremors, headaches, nauseous and frequent fainting/convulsive spells beginning in sixth grade[globalgenes.org]
    • Signs that suggest increased activity of the sympathetic nervous system may be evident including tachycardia, hypertension, palpitations, orthostatic hypotension, sweating, restlessness, and tremor.[en.wikipedia.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
    Hirsutism
    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]
    • The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of type one porphyrins and later hypertrichosis .[house.wikia.com]
    Photosensitivity
    • Photosensitivity may be controlled by avoiding exposure to light.[medical-dictionary.thefreedictionary.com]
    • Photosensitivity is the main feature, neurological involvement is no there.[usmle.biochemistryformedics.com]
    • […] protoporphyria (EPP) Erythropoietic Autosomal recessive [1] Photosensitivity with skin lesions.[house.wikia.com]
    • In this case, the hallmark is photosensitivity (an excessive reaction to light), which causes chronic blistering and even burns on sun-exposed areas.[scientificamerican.com]
    • Another classification system distinguishes porphyrias that cause neurologic symptoms (acute porphyrias) from those that cause photosensitivity (cutaneous porphyrias).[genome.gov]
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  • gastrointestinal
    Abdominal Cramps
    • Increasing dietary fiber intake sometimes causes abdominal cramping, diarrhea and flatulence.[theaipforum.tripod.com]
    • 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
    • The abdominal pain is severe and lasts for several days.[medical-institution.com]
    • Our patient had never experienced similar abdominal pain.[mdedge.com]
    • pain External Links References NR Pimstone, KE.[wikem.org]
    • Severe and poorly localized abdominal pain is a very common symptom (found in 95% of those affected by AIP).[en.wikipedia.org]
    • S endorsed nausea, vomiting, abdominal pain, and homicidal ideations towards his landlord.[hindawi.com]
    Chronic Abdominal Pain
    • Severe abdomen pain of short ( 1 d) duration or chronic abdominal pain is unusual.[medical-institution.com]
    • In Season 6, Episode 15 of Grey's Anatomy, "The Time Warp", Bailey reflects back on her time as an intern when she diagnosed a woman with chronic abdominal pain after numerous surgeries by other doctors.[en.wikipedia.org]
    Colic
    • The liver overproduces a specific acid and the disease is characterized by attacks of high blood pressure, abdominal colic, psychosis, and nervous system disorders.[medical-dictionary.thefreedictionary.com]
    • […] 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
    • […] metabolic stress Carbohydrate deficiency Tobacco, EtOH Porphyrinogenic drugs: sulfonamides, barbiturates, rifampin or metoclopramide Clinical Features Gastrointestinal symptoms Acute abdominal pain (85-90% of attacks) Nausea/vomiting Constipation and/or diarrhea[wikem.org]
    • These include areas of reduced or altered sensation, confusion, seizures, palpitations, high blood pressure, and constipation or diarrhea.[labtestsonline.org]
    • Nausea, vomiting, constipation, and diarrhea can also occur.[en.wikipedia.org]
    • Signs and symptoms of acute porphyria may include: Severe abdominal pain Pain in your chest, legs or back Constipation or diarrhea Nausea and vomiting Muscle pain, tingling, numbness, weakness or paralysis Red or brown urine Mental changes, such as anxiety[mayoclinic.org]
    • Increasing dietary fiber intake sometimes causes abdominal cramping, diarrhea and flatulence.[theaipforum.tripod.com]
    Nausea
    • Nausea, vomiting, constipation, and diarrhea can also occur.[en.wikipedia.org]
    • Acute porphyria is often difficult to diagnose because the symptoms of abdominal pain, nausea, vomiting, etc. are not specific to porphyria.[rarediseasesnetwork.org]
    • If you cannot eat due to nausea, you will get glucose infused directly intravenously.[livestrong.com]
    • Nausea and vomiting can be controlled with olanzapine, lorazepam, or prochlorperazine. [10] Treat seizures with gabapentin (Neurontin).[emedicine.medscape.com]
    • The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and relentless constipation.[orpha.net]
    Recurrent Abdominal Pain
    • To explain other possible causes of minor increases in porphyrin levels in patients with recurrent abdominal pain who have not been diagnosed with porphyria This is a longitudinal study will consist of two parts.[rarediseasesnetwork.org]
    Severe Abdominal Pain
    • The condition is characterized by intermittent and sometimes life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs.[snpedia.com]
    • A partial deficiency in PBGD protein leads to accumulation of neurotoxic intermediates, causing life-threatening acute neurovisceral attacks of severe abdominal pain, often accompanied by nausea, vomiting, tachycardia, and hypertension.[cordis.europa.eu]
    • Patients may have very severe abdominal pain lasting several days.[medical-institution.com]
    • Acute attacks are typically characterized by severe abdominal pain.[sema4genomics.com]
    • Signs and symptoms of acute porphyria may include: Severe abdominal pain Pain in your chest, legs or back Constipation or diarrhea Nausea and vomiting Muscle pain, tingling, numbness, weakness or paralysis Red or brown urine Mental changes, such as anxiety[mayoclinic.org]
    Vomiting
    • The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and relentless constipation.[orpha.net]
    • Frequently, nausea and vomiting are present.[medical-institution.com]
    • S endorsed nausea, vomiting, abdominal pain, and homicidal ideations towards his landlord.[hindawi.com]
    • Nausea and vomiting can be controlled with olanzapine, lorazepam, or prochlorperazine. [10] Treat seizures with gabapentin (Neurontin).[emedicine.medscape.com]
    • It is also quite common to have nausea , vomiting and constipation .[orphan-europe.com]
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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]
    • Other neurologic signs and symptoms of AIP include seizures, peripheral neuropathy, abnormal sensations, chest pain, leg pain, back pain or headache, and coma.[en.wikipedia.org]
    • They suffered from back pain, difficulty urinating, psychosis, tachycardia and cramps.[house.wikia.com]
    Muscle Weakness
    • Proximal muscle weakness typically beginning in the arms is characteristic; there can be muscle pain, tingling, numbness, weakness or paralysis; muscle weakness seen in AIP can progress to include the muscles of breathing causing respiratory failure and[en.wikipedia.org]
    • 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]
    • Nerve damage and associated muscle weakness from a severe attack improves over time, but such improvement may take many months to resolve fully.[cigna.com]
    • Muscle weakness of the arms and legs may occur and, in severe cases, weakness of the breathing muscles may require the person to be placed on a ventilator.[labtestsonline.org]
    • 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]
    Myalgia
    • Neurological manifestations can affect the central nervous system as much as the peripheral nervous system (myalgia, paresis, ascending flaccid paralysis of the limbs, or convulsions) and can lead to severe complications such as motor paralysis.[orpha.net]
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  • cardiovascular
    Orthostatic Hypotension
    • Signs that suggest increased activity of the sympathetic nervous system may be evident including tachycardia, hypertension, palpitations, orthostatic hypotension, sweating, restlessness, and tremor.[en.wikipedia.org]
    Tachycardia
    • Symptomatic treatment also includes the use of beta-blockers to control tachycardia and prevent arrhythmia; beta- blockers, clonidine, or other recommended antihypertensives can also be used to treat hypertensive crisis.[emedicine.medscape.com]
    • Tachycardia and hyponatremia are common during attacks.[orpha.net]
    • A partial deficiency in PBGD protein leads to accumulation of neurotoxic intermediates, causing life-threatening acute neurovisceral attacks of severe abdominal pain, often accompanied by nausea, vomiting, tachycardia, and hypertension.[cordis.europa.eu]
    • Patients may develop autonomic neuropathies, such as hypertension and tachycardia.[medical-institution.com]
    • Opioid analgesia Avoid/discontinue offending medications Most seizure medications contraindicated: Benzodiazepines , gabapentin , levetiracetam , and vigabatrin okay Avoid reglan Treat any electrolyte abnormalities beta-blockers can be used to treat tachycardia[wikem.org]
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  • urogenital
    Dark Urine
    • Urinary signs and symptoms such as painful urination, urinary retention, urinary incontinence, or dark urine have also been known to occur.[en.wikipedia.org]
    • 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]
    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
    • Her urine was not red at that time (on further questioning, she remembered she had had an episode of “red urine” recently).[mdedge.com]
    • Even a purple hue or red urine may be seen.[house.wikia.com]
    Urinary Incontinence
    • Urinary signs and symptoms such as painful urination, urinary retention, urinary incontinence, or dark urine have also been known to occur.[en.wikipedia.org]
    Urinary Retention
    • Clinical findings Abdominal colic, constipation, fever, leukocytosis, postural hypotension, peripheral neuritis, polyneuropathy, paraplegia, urinary retention, respiratory paralysis, behavioural changes and episodic psychosis (patients are often misdiagnosed[medical-dictionary.thefreedictionary.com]
    • Urinary signs and symptoms such as painful urination, urinary retention, urinary incontinence, or dark urine have also been known to occur.[en.wikipedia.org]
    • Urinary retention can also occur.[cigna.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]
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  • psychiatrical
    Delusion
    • Psychiatric signs and symptoms of AIP may manifest as anxiety, paranoia, irritability, delusions, hallucinations, confusion, and depression.[en.wikipedia.org]
    Hysteria
    • There are three types of hepatic porphyria: (1) In acute intermittent porphyria , also called porphyria hepatica, affected persons have recurrent attacks of abdominal pain and vomiting, weakness or paralysis of the limbs, and psychic changes resembling hysteria[britannica.com]
    • […] impairment and death), autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia , high blood pressure , sweating , restlessness and tremor), neuropsychiatric symptoms ( anxiety , agitation, hallucination, hysteria[house.wikia.com]
    Visual Hallucination
    • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
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  • Eyes
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  • Breast
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  • Workup

    To diagnose AIP it is essential to identify increased porphobilinogen and ALA (sometimes erythrocyte hydroxymethylbilane synthase enzyme) in patients’ freshly voided urine. If levels of porphobilinogen are within the normal levels (0-4 mg/L) during acute neurovisceral symptoms, porphyria can be eliminated as the cause [9] [10]. Spot urine tests are commonly used and can rapidly detect levels of porphobilinogen greater than 6 mg/L. Porphobilinogen levels in AIP patients remain elevated between attacks, however, the levels of porphobilinogen in some patients that have been symptom free for years may return to normal.

    Coporphobilinogen, which arises from spontaneous polymerization of porphobilinogen, is the primary porphyrin detected in urine. Nonspecific elevation of porphyrins in urine is common and does not indicate AIP. Levels of porphyrins in stool are typically within the reference range or mildly elevated in AIP. Helpful screening tools include the Watson-Schwartz test (with Ehrlich’s aldehyde reagent), observing burgundy red discoloration in long stored urine and observation of pink colored urine after exposure to light, however, quantitative tests of porphobilinogen and ALA must be performed to verify AIP. Identification of the underlying mutation of the HMBS gene may be performed.

    Test Results

    EEG
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  • Laboratory

    Serum
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  • Urine
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  • Cerebrospinal Fluid
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  • Imaging

    X-ray
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  • Treatment

    The goal for treatment of AIP attacks is to decrease heme synthesis and reduce levels of porphyrin precursors. Patients should stop taking any medications or drugs that may worsen their attack. Heme synthesis is inhibited by high doses of glucose, therefore, 400 grams of glucose per day may be administered for one to two days to treat mild attacks. For severe attacks that include neurologic dysfunction or attacks that don’t resolve within 36 hours, 4 mg/kg/day of hematin should be administered for 4 days. Severe pain may be treated with narcotics along with laxatives and stool softeners to prevent further constipation. Patients experiencing seizures should be given gabapentin (Neurontin) and classic antiseizure medication should be avoided because they have been shown to cause acute porphyria attacks. During attacks, patients should be placed on a carbohydrate rich diet and IV glucose should be administered to patients who cannot eat. Other medications to treat anxiety, hypertension, nausea, vomiting, tachycardia or restlessness may also be used as needed. Fluid and electrolyte levels should be monitored and balanced during attacks. Between attacks a balanced diet, rather than a carbohydrate rich diet, is recommended.

    In summary, when an AIP attack is confirmed, treatment with an injection of glucose in mild cases or hematin in severe cases along with administration of carbohydrates is recommended. Triggering factors should be suppressed and symptom management, including pain, vomiting and neurological disorders should be addressed. In patients with recurrent attacks, hematin administration may be repeated. In severe cases hepatic transplant may be required although this is rare.

    Prognosis

    Approximately 60-80% of patients that have an AIP attack, do not experience subsequent attacks. However, improperly diagnosing AIP may be dangerous, particularly when treatment involves precipitating factors, such as certain medications. Patients treated for AIP, before severe nerve damage occurs, have a good prognosis and most symptoms resolve after an attack. Some patients develop chronic pain and although nerve damage and muscle weakness from attacks improve over time, this may take several months or longer to fully resolve. Avoiding precipitating factors is the best way to prevent future attacks from occurring.

    Complications

    Anxiety
    • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
    • Psychological evaluation of patients [ Time Frame: up to 24 months ] The presence and level of anxiety and depression will be assessed by using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) rating scales.[clinicaltrials.gov]
    • Peripheral neuropathy (patchy numbness and paresthesias) Psychological disturbances (anxiety, confusion, psychosis, dementia ) Precipitated by drugs (drugs that enhance cytochrome P-450 activity, sulfa drugs, barbiturates , some antipsychotics, alcohol[stepwards.com]
    • Psychiatric signs and symptoms of AIP may manifest as anxiety, paranoia, irritability, delusions, hallucinations, confusion, and depression.[en.wikipedia.org]
    • Signs and symptoms of acute porphyria may include: Severe abdominal pain Pain in your chest, legs or back Constipation or diarrhea Nausea and vomiting Muscle pain, tingling, numbness, weakness or paralysis Red or brown urine Mental changes, such as anxiety[mayoclinic.org]
    Appendicitis
    • Neuropathy can progress to respiratory failure in hours or days Bladder paresis Agitation, confusion, combativeness, seizure Differential Diagnosis Diffuse Abdominal pain Abdominal aortic aneurysm Aortocaval fistula Acute gastroenteritis Aortoenteric fisulta Appendicitis[wikem.org]
    • 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
    • Patients may develop autonomic neuropathies, such as hypertension and tachycardia.[medical-institution.com]
    • Acute presentationsCharacterized by severe abdominal pain, autonomic instability, electrolyte disturbance and neuropsychiatric manifestations.Features of the Acute Porphyric Attack1)Nervous system dysfunction Autonomic neuropathy Abdominal pain, Vomiting[slideshare.net]
    Coma
    • Acute hepatitis A without hepatic coma / with hepatic coma [ gastr/hepat ] trafność: 12.7pkt. zaloguj się 6. acute hepatic encephalopathy [ med. ] [ neur. ] [ gastr/hepat ] trafność: 12.5pkt. zaloguj się 7.[verba-medica.pl]
    • AIP patients may have central nervous system signs consisting of seizures, mental status changes, cortical blindness, and coma.[medical-institution.com]
    • Other neurologic signs and symptoms of AIP include seizures, peripheral neuropathy, abnormal sensations, chest pain, leg pain, back pain or headache, and coma.[en.wikipedia.org]
    • Other effects can include tachycardia, hypertension, hyponatremia, peripheral neuropathy, and organic brain dysfunction marked by seizures, coma, hallucinations, and respiratory paralysis.[medical-dictionary.thefreedictionary.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, coma[cigna.com]
    Constipation
    • Constipation is common and can be very severe.[medical-institution.com]
    • Nausea, vomiting, constipation, and diarrhea can also occur.[en.wikipedia.org]
    • Laxatives and stool softeners should be administered with the narcotics to avert exacerbating existing constipation.[emedicine.medscape.com]
    • Clinical findings Abdominal colic, constipation, fever, leukocytosis, postural hypotension, peripheral neuritis, polyneuropathy, paraplegia, urinary retention, respiratory paralysis, behavioural changes and episodic psychosis (patients are often misdiagnosed[medical-dictionary.thefreedictionary.com]
    • The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and relentless constipation.[orpha.net]
    Cortical Blindness
    • AIP patients may have central nervous system signs consisting of seizures, mental status changes, cortical blindness, and coma.[medical-institution.com]
    Delirium
    • The neurovisceral symptoms consist of autonomic neuropathies (eg, constipation, colicky abdominal pain, vomiting, hypertension), peripheral neuropathy, seizures, delirium, coma, and depression.[medical-institution.com]
    • […] death), autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia , high blood pressure , sweating , restlessness and tremor), neuropsychiatric symptoms ( anxiety , agitation, hallucination, hysteria, delirium[house.wikia.com]
    Depression
    • Depression is very common.[medical-institution.com]
    • Psychological evaluation of patients [ Time Frame: up to 24 months ] The presence and level of anxiety and depression will be assessed by using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) rating scales.[clinicaltrials.gov]
    • We ask about general symptoms (anxious mood, depressed mood, insomnia, fatigue, and pain) regardless of condition.[patientslikeme.com]
    • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
    • 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]
    Hallucinations
    • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
    • Psychiatric signs and symptoms of AIP may manifest as anxiety, paranoia, irritability, delusions, hallucinations, confusion, and depression.[en.wikipedia.org]
    • […] of acute porphyria may include: Severe abdominal pain Pain in your chest, legs or back Constipation or diarrhea Nausea and vomiting Muscle pain, tingling, numbness, weakness or paralysis Red or brown urine Mental changes, such as anxiety, confusion, hallucinations[mayoclinic.org]
    • QUESTION OF THE DAY A 21-year-old young woman, who recently began taking birth control pills, presents to the emergency room with cramping abdominal pain, anxiety, paranoia, and hallucinations.[usmle.biochemistryformedics.com]
    • Other effects can include tachycardia, hypertension, hyponatremia, peripheral neuropathy, and organic brain dysfunction marked by seizures, coma, hallucinations, and respiratory paralysis.[medical-dictionary.thefreedictionary.com]
    Hereditary Coproporphyria
    • Other acute porphyrias include Variegate porphyria Hereditary coproporphyria Delta-aminolevulinic acid dehydratase-deficiency porphyria, which is extremely rare Variegate porphyria and hereditary coproporphyria also cause skin (cutaneous) symptoms.[merckmanuals.com]
    • These other porphyrias are: hereditary coproporphyria, variegate porphyria, and ALAD deficiency porphyria.[thinkgenetic.com]
    • […] porphyria Hereditary coproporphyria Porphyria cutanea tarda Variegate porphyria GeneReviews acute intermittent porphyria [genetests.org] Top of page Last Reviewed: April 18, 2013[genome.gov]
    • Substantial PBG elevation (which occurs only in AIP, hereditary coproporphyria [HCP], and variegate porphyria [VP]) should be established, or have been established in the past, before treatment is started, particularly with hemin.[uptodate.com]
    • Acute intermittent porphyria Variegate porphyria Hereditary coproporphyria Aminolevulinate dehydratase deficiency porphyria Most people with an acute porphyria never experience any health problems, however, about one in five people with will experience[orphan-europe.com]
    Hypertension
    • Patients may develop autonomic neuropathies, such as hypertension and tachycardia.[medical-institution.com]
    • AIP patients have an increased risk of developing hepatocellular carcinoma, melanoma, lymphoma, chronic hypertension, chronic kidney disease, and chronic pain.[en.wikipedia.org]
    • Other effects can include tachycardia, hypertension, hyponatremia, peripheral neuropathy, and organic brain dysfunction marked by seizures, coma, hallucinations, and respiratory paralysis.[medical-dictionary.thefreedictionary.com]
    • (The management of hypertension (high blood pressure) may include salt restriction.[theaipforum.tripod.com]
    • Propranolol (which may decrease enzyme activity as well as control hypertension, tachycardia & anxiety)4.[slideshare.net]
    Hypomagnesemia
    • […] neuropathy Paresis, flaccid quadriplegia, Respiratory Paralysis Bulbar Involment Vagal CN involvment-Dysphagia,Dysphonia, Cerebral Involment Mental status changes,Anxiety,Seizures,Coma2)Lab Changes Dark colour(Reddish) urine,Hyponatremia,Hypokalemia,Hypomagnesemia[slideshare.net]
    Hyponatremia
    • The patient was admitted to the intensive care unit (ICU) for treatment of hyponatremia.[mdedge.com]
    • Intravenous glucose in water solutions (eg, dextrose 5% or 10% [D5W, D10W]), should be avoided as they may aggravate hyponatremia. [9] Patients experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with hematin[emedicine.medscape.com]
    • Other nonspecific signs in an attack of AIP include the following: Hyponatremia Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Mild leukocytosis Although a defective enzyme causes AIP, measuring the activity of porphobilinogen deaminase[emedicine.medscape.com]
    • Tachycardia and hyponatremia are common during attacks.[orpha.net]
    • This excruciating pain is often associated with nausea, vomiting, hyponatremia, tachycardia, and hypertension [ 4 ].[hindawi.com]
    Ileus
    • A painful blockage or obstruction (ileus) of part of the intestines such as the third segment of the small intestines (ileum) may also occur.[cigna.com]
    • Gut dysmotility, ileus , intussusception , hypoganglionosis , encopresis in children and intestinal pseudo-obstruction have been associated with porphyrias.[house.wikia.com]
    Lead Poisoning
    • Lead poisoning can also have similar symptoms to acute intermittent porphyria.[thinkgenetic.com]
    Leukocytosis
    • Other nonspecific signs in an attack of AIP include the following: Hyponatremia Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Mild leukocytosis Although a defective enzyme causes AIP, measuring the activity of porphobilinogen deaminase[emedicine.medscape.com]
    • Clinical findings Abdominal colic, constipation, fever, leukocytosis, postural hypotension, peripheral neuritis, polyneuropathy, paraplegia, urinary retention, respiratory paralysis, behavioural changes and episodic psychosis (patients are often misdiagnosed[medical-dictionary.thefreedictionary.com]
    Paralysis
    • In cases with cardiac arrhythmia and respiratory paralysis (rare), attacks can be fatal.[orpha.net]
    • Recovery from severe paralysis is generally slow.[sema4genomics.com]
    • Other effects can include tachycardia, hypertension, hyponatremia, peripheral neuropathy, and organic brain dysfunction marked by seizures, coma, hallucinations, and respiratory paralysis.[medical-dictionary.thefreedictionary.com]
    • Paraesthesias and paralysis also occur, and death may result from respiratory paralysis.[clinicaltrials.gov]
    • Then moved onto severe abdominal (liver) pain, respiratory difficulty and paralysis–all of which resolved with heme treatments.[globalgenes.org]
    Paraplegia
    • Clinical findings Abdominal colic, constipation, fever, leukocytosis, postural hypotension, peripheral neuritis, polyneuropathy, paraplegia, urinary retention, respiratory paralysis, behavioural changes and episodic psychosis (patients are often misdiagnosed[medical-dictionary.thefreedictionary.com]
    Peripheral Neuropathy
    • Patients often experience peripheral neuropathies that are predominantly motor and can mimic Guillain-Barré syndrome.[medical-institution.com]
    • Any part of the nervous system may be involved, with evidence for autonomic and peripheral neuropathy.[usmle.biochemistryformedics.com]
    • Peripheral neuropathy (patchy numbness and paresthesias) Psychological disturbances (anxiety, confusion, psychosis, dementia ) Precipitated by drugs (drugs that enhance cytochrome P-450 activity, sulfa drugs, barbiturates , some antipsychotics, alcohol[stepwards.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]
    • Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy).[cigna.com]
    Porphyria Cutanea Tarda
    • An estimated 80 percent of porphyria cutanea tarda cases are sporadic.[genome.gov]
    • Porphyria cutanea tarda D.[usmle.biochemistryformedics.com]
    • Abstract: Literature has been surveyed on the involvement of oral contraceptives in the contraction of porphyria cutanea tarda.[popline.org]
    • Porphyria cutanea tarda (PCT) is the most common type of all the porphyrias.[mayoclinic.org]
    Psychosis
    • The liver overproduces a specific acid and the disease is characterized by attacks of high blood pressure, abdominal colic, psychosis, and nervous system disorders.[medical-dictionary.thefreedictionary.com]
    • Peripheral neuropathy (patchy numbness and paresthesias) Psychological disturbances (anxiety, confusion, psychosis, dementia ) Precipitated by drugs (drugs that enhance cytochrome P-450 activity, sulfa drugs, barbiturates , some antipsychotics, alcohol[stepwards.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]
    • Women tend to experience flares during the luteal (progesterone) phase of the menstrual cycle. 1 Acute intermittent porphyria can mimic Guillain-Barré syndrome and psychosis. 2 Delayed diagnosis may lead to irreversible neurological damage or death. 2[mdedge.com]
    • This can lead to acute AIP attacks, characterized by severe abdominal pain, nausea and vomiting, psychosis and, in severe cases, paralysis and heart arrhythmia.[livestrong.com]
    Tyrosinemia
    • Succinylacetone, a substrate analogue of ALA found in patients with hereditary tyrosinemia, is the most potent inhibitor of ALAD.[emedicine.medscape.com]
    • In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I .[house.wikia.com]
    Variegate Porphyria
    • Variegate porphyria (See Variegate porphyria ) is by far the commonest.[porphyria-professionals.uct.ac.za]
    • Genetics Edit Mutations in the PPOX gene cause variegate porphyria.[house.wikia.com]
    • Other acute porphyrias include Variegate porphyria Hereditary coproporphyria Delta-aminolevulinic acid dehydratase-deficiency porphyria, which is extremely rare Variegate porphyria and hereditary coproporphyria also cause skin (cutaneous) symptoms.[merckmanuals.com]
    • We are interested in all three types of acute porphyria: Acute Intermittent Porphyria (AIP), Hereditary Corproporphyria (HCP) or Variegate Porphyria (VP).[rarediseasesnetwork.org]
  • more...
  • Etiology

    AIP may be caused by a combination of a genetic defects coding for the PBGD enzyme and acquired causes that produce symptoms in some patients. The genetic cause of PBGD enzyme deficiency is an autosomal dominant mutation in the hydroxymethylbilane synthase (HMBS) gene (11q23.3) which codes for PBGD [1]. Penetrance of this mutation is very weak. Genetic causes of AIP are more common and patients with an enzyme mutation experience significantly diminished activity of PBGD by 40-60% of normal, leading to excessive porphyrins production. Chemicals that boost heme synthesis along with fasting, stress, infections or surgery are inducers of porphyria. Additionally, drugs such as phenobarbital, sulfonamides, estrogens, anti-seizure drugs, rifampin, metoclopramide and alcohol, which may increase the hepatic P450 system, are associated with porphyria. High levels of progesterone, observed in women after ovulation or during the end of the menstrual cycle, may lead to an acute attack. In some cases, no activating factors are identified. Patients with AIP have an increased risk for developing renal disease and hepatocellular carcinoma.

    Epidemiology

    Most studies indicate a higher prevalence of AIP in women compared to men (ratio of 1.5-2:1 or about 80% of cases are in females). Symptoms appear in most patients after puberty and between the ages of 18 and 40 years of age. Attacks occurring outside of this timeframe are usually caused by a major provocation, such as use of phenobarbital or estrogens. In the general adult population prevalence of AIP is fairly low, ranging between 1 and 8 per 100,000 (1 per 75,000 in Europe) [1] [3], however, incidences have been reported to be much higher in psychiatric populations (210 per 100,000) [4].

    Sex distribution
    Age distribution

    Pathophysiology

    AIP is caused by an autosomal dominant mutation in the HMBS gene which results in a defective PBGD enzyme [1]. PBGD in a vital enzyme in the heme biosynthetic pathway in the liver that catalyzes the conversion of porphobilinogen to hydroxymethylbilane [6]. The dysfunctional PBGD enzyme observed in AIP, leads to accumulation of porphobilinogen and amino-levulinic acid (ALA, porphyrin precursors). Neurologic damage appears to be the predominant problem with AIP which leads to central and peripheral neuropathies and psychiatric manifestations [5]. The connection between elevated porphobilinogen and ALA and acute attacks is unclear, due to the fact that most patients with the HMBS gene mutation have elevated porphyrin but are asymptomatic.

    The genetic mutations observed in AIP result in marked deficiencies in the biosynthesis of the metalloporphyrin heme in the liver [6]. Free heme, detected at intracellular and extracellular levels, is degraded by heme oxygenase (HO) into carbon monoxide (CO) and bilirubin. The reasons for neurological involvement in AIP are not well understood, however, an interaction between CO and nitric oxide (NO) in enteric neurons of the internal anal sphincter may explain gastrointestinal dysfunction in some patients [7]. Other hypotheses include the direct neurotoxicity of ALA by interactions with the Gamma-Aminobutyric acid (GABA) receptor, altered tryptophan metabolism, or heme-dependent neural respiratory enzymatic deficiency in nerve cells [8]. Evidence suggests that axonal degeneration rather than demyelination of peripheral and autonomic nerve fibers is responsible. Usually the neurological effects of AIP are reversible although incomplete recovery has been reported in some cases.

    Prevention

    Patients should avoid medications that incite porphyria (lists are available) including barbiturates, some antiepileptics, erythromycin and chloramphenicol. Alcohol consumption should be limited and low-caloric diets and fasting should be avoided. Other precipitating factors, including illicit drug use, smoking, stress, hypothermia, infection, fever and dehydration, should also be avoided. Adopting a healthy lifestyle that includes a balanced diet, prompt medical treatment and stress reduction is recommended. Iron status should be monitored in patients receiving regular heme arginate to detect iron overload. Genetic counseling may be beneficial to patients and their families to help identify susceptible individuals and their risk of developing or transmitting the disease.

    Summary

    Acute intermittent porphyria (AIP) is an autosomal dominant condition with low penetrance that causes defects in the heme biosynthetic pathway [1]. Affected individuals have genetic mutations leading to a deficiency in porphobilinogen deaminase (PBGD, previously called uroporphobilinogen I synthetase) synthesis or activity which causes the excessive production of porphyrin and its precursors [1]. The clinical features of AIP, which are due to effects on the central, peripheral and visceral nervous system, may develop from puberty onward but most often arise from age 20 to age 30. Patients with AIP display a spectrum of signs and symptoms that may include abdominal pain, neuropathies, constipation and mental disturbances that are often amplified by other factors, such as drugs [2]. Symptoms usually occur intermittently and can be life threatening due to neurologic complications, such as seizures and paralysis.

    Management of AIP is often challenging due to the diverse manifestations of this disease and potentially fatal attacks. It is important to provide timely intervention in an attempt to resolve and prevent attacks and vigilant long-term monitoring for complications in essential. Along with treating AIP directly, addressing other conditions that may have triggered attacks, such as infection or drug use, is important.

    Patient Information

    Acute intermittent porphyria (AIP) is a dominant inherited disorder (only need diseased gene from one parent) that is the most common acute porphyria (disease associated with porphyrin build up). AIP occurs in people from every ethnic group and is more common in women than men. AIP attacks typically occur after puberty and cause a sudden onset of neurologic symptoms along with abdominal pain. Patients with AIP have a deficiency in the enzyme porphobilinogen deaminase, due to a genetic mutation, that leads to the accumulation of heme precursors (porphobilinogen and amino-levulinic acid) in the liver. Symptoms, including developmental abnormalities, may appear in childhood.

    The most common symptom is abdominal pain. Gastrointestinal symptoms may also arise including nausea, vomiting, constipation and diarrhea. Some patients may experience difficulty urinating, which may result in an excessively full bladder. Neural dysfunction may lead to muscle weakness that usually starts in the shoulders and arms.

    Diagnosis is achieved through testing patients urine during an attack, which will have elevated levels of porphobilinogen and amino-levulinic acid in AIP. Rapid treatment usually results in a full recovery, however, if treatment is delayed recovery may take longer and permanent nerve damage may occur. Primary therapies will aim at decreasing porphyrin levels, but physicians may also administer medications to address other symptoms, such as opioids for pain.

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    References

    1. Ackner B, Cooper JE, Gray CH, et al. Acuteporphyria: a neuropsychiatric and biochemical study. J Psychosom Res. 1962; 6:1-24.
    2. Desnick RJ. The porphyrias. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw Hill Companies Inc; 2001: 2261–7.
    3. Goldberg A. Acute intermittent porphyria: a study of 50 cases. Q J Med. 1959; 28(110):183-209.
    4. Tishler PV, Woodward B, O'Connor J, et al. High prevalence of intermittent acuteporphyria in a psychiatric patient population. Am J Psychiatry. 1985;142(12):1430-6.
    5. Kuo HC, Huang CC, Chu CC, et al. Neurological complications of acute intermittent porphyria. Eur Neurol. 2011; 66(5):247-52.
    6. Elder GH, Hift RJ, Meissner PN. The acute porphyrias. Lancet. 1997; 31;349(9065):1613-7.
    7. Battish R, Cao GY, Lynn RB, et al. Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric oxide synthase. Am J Physiol Gastrointest Liver Physiol. 2000; 278(1):G148-55.
    8. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis. 1998;18(1):43-52.
    9. Anyaegbu E, Goodman M, Ahn SY, et al. Acute Intermittent Porphyria: A Diagnostic Challenge. J Child Neurol. 2011.
    10. Menegueti MG, Gil Cezar AT, Casarini KA, et al. Acute intermittent porphyria associated with respiratory failure: a multidisciplinary approach. Crit Care Res Pract. 2011; 283690.

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    Media References

    1. Porphobilinogen, Public Domain

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