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Acute Intermittent Porphyria

AIP

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.


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).

Acute Intermittent Porphyria
  • No significant difference was found between women with latent acute intermittent porphyria and manifest acute intermittent porphyria.[ncbi.nlm.nih.gov]
  • We report a case of acute intermittent porphyria associated with in vitro fertilization treatment.[ncbi.nlm.nih.gov]
  • Acute intermittent porphyria is a metabolic disorder rarely seen in prepubertal children. A delay in diagnosis of acute intermittent porphyria is common because of variable and nonspecific symptoms.[ncbi.nlm.nih.gov]
  • […] suffering from acute intermittent porphyria.[ncbi.nlm.nih.gov]
  • The association of abdominal pain, mental status changes, and autonomic dysfunction should arouse the suspicion of acute intermittent porphyria. Acute intermittent porphyria can be associated with posterior reversible encephalopathy syndrome.[ncbi.nlm.nih.gov]
Anemia
  • The analysis of hematological and biochemical parameters during the second crisis showed anemia, leukocytosis, hyponatremia, mild hypokalemia, uremia and elevated C-reactive protein.[ncbi.nlm.nih.gov]
  • A Chinese female patient with very typical AIP symptoms of severe abdominal pain, seizures, hypertension, and tachycardia, accompanied with hyponatremia, anemia, and hyperbilirubinemia.[ncbi.nlm.nih.gov]
  • However, lead poisoning causes a decrease in the number of blood cells (anemia), which is not seen in acute intermittent porphyria.[thinkgenetic.com]
  • Manifestations of porphyria include gastrointestinal, neurologic, and psychologic symptoms, cutaneous photosensitivity, pigmentation of the face (and later of the bones), and anemia with enlargement of the spleen.[medical-dictionary.thefreedictionary.com]
  • P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias[icd10data.com]
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]
  • Tachycardia and hypertension , and less frequently fever, sweating, restlessness, and tremor are also observed. In up to 40% of patients, hypertension may become sustained between acute attacks. Neuropathy is a common feature of AIP.[diagnose-me.com]
  • Other precipitating factors, including illicit drug use, smoking, stress, hypothermia, infection, fever and dehydration, should also be avoided.[symptoma.com]
  • Most common side effects are headache, fever, infusion site reactions, and vein inflammation. To report SUSPECTED SIDE EFFECTS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1800-FDA-1088 or www.fda.gov/medwatch .[panhematin.com]
Abdominal Pain
  • A 35-year-old woman with tubal factor infertility presented to our clinic with persistent low abdominal pain and hyponatremia after transvaginal oocyte retrieval.[ncbi.nlm.nih.gov]
  • This is a strong diagnostic clue for AIP when ambiguous abdominal pain patients presented with seizures and PRES on brain MRI.[ncbi.nlm.nih.gov]
  • While acute abdominal pain is the most common presenting symptom in children, seizures are commonly seen and may precede the diagnosis of AIP.[ncbi.nlm.nih.gov]
  • A 9-year-old girl underwent an appendectomy after developing abdominal pain.[ncbi.nlm.nih.gov]
  • An 18-year-old girl was admitted to our hospital with recurrent abdominal pain and 2 episodes of convulsions. She had undergone an appendectomy earlier at another hospital for abdominal pain.[ncbi.nlm.nih.gov]
Vomiting
  • Additional frequent symptoms are vomiting, hypertension, peripheral neuropathy, seizures, depression, delirium and coma.[ncbi.nlm.nih.gov]
  • AIP is characterised by intermittent attacks of abdominal pain, vomiting, and neurological complaints.[ncbi.nlm.nih.gov]
  • As an example, we report a 9year old developmentally normal pre-pubertal boy who presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy.[ncbi.nlm.nih.gov]
  • She subsequently developed bilateral visual disturbance, confusion, seizures, hypertension, tachycardia, nausea, vomiting, constipation, dark tea-colored urine, and recurrent abdominal pain.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
Constipation
  • Some additional factors must also be present such as drugs, hormones, dietary changes, infections diseases and surgery that trigger the appearance of symptoms, which include neurological disorders, abdominal pain, constipation, and muscle weakness.[ncbi.nlm.nih.gov]
  • Severe pain may be treated with narcotics along with laxatives and stool softeners to prevent further constipation.[symptoma.com]
  • We report here a 60-year-old non-alcoholic male who had typical manifestations of AIP, including abdominal pain, constipation, tachycardia, hypertension, mental disturbances, psychiatric manifestations, seizures, peripheral neuropathy, and excessive excretion[ncbi.nlm.nih.gov]
  • Patients with AIP typically give a history of constipation, fatigue, irritability, and insomnia that precede their acute attack.[ncbi.nlm.nih.gov]
  • As an example, we report a 9year old developmentally normal pre-pubertal boy who presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy.[ncbi.nlm.nih.gov]
Nausea
  • Acute attacks present with episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. A high index of suspicion is required for the initial diagnosis of AIP.[ncbi.nlm.nih.gov]
  • PRES is a clinicoradiological condition caused by the failure of the posterior circulation to autoregulate, resulting in cerebral oedema, headaches, nausea and seizures.[ncbi.nlm.nih.gov]
  • She subsequently developed bilateral visual disturbance, confusion, seizures, hypertension, tachycardia, nausea, vomiting, constipation, dark tea-colored urine, and recurrent abdominal pain.[ncbi.nlm.nih.gov]
  • Nausea , vomiting , constipation , and diarrhea can also occur.[en.wikipedia.org]
  • If you’ve been searching for the cause of your unexplained severe abdominal pain and other symptoms—such as muscle weakness, nausea or vomiting, constipation, rapid heart rate, or emotional changes—there’s something you should know: these may be signs[isitaip.com]
Severe Abdominal Pain
  • Acute attacks present with episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. A high index of suspicion is required for the initial diagnosis of AIP.[ncbi.nlm.nih.gov]
  • The disease is clinically manifested with severe abdominal pain, confusion, and seizures which may be life threatening.[ncbi.nlm.nih.gov]
  • A Chinese female patient with very typical AIP symptoms of severe abdominal pain, seizures, hypertension, and tachycardia, accompanied with hyponatremia, anemia, and hyperbilirubinemia.[ncbi.nlm.nih.gov]
  • Severe abdominal pain: the most common AIP symptom The most common symptom of AIP is severe abdominal pain that usually cannot be relieved with pain medicine such as Advil (ibuprofen) or Tylenol (acetaminophen).[panhematin.com]
  • If you’ve been searching for the cause of your unexplained severe abdominal pain and other symptoms—such as muscle weakness, nausea or vomiting, constipation, rapid heart rate, or emotional changes—there’s something you should know: these may be signs[isitaip.com]
Hypertension
  • Acute transient hypertension during the attack of porphyria caused the rupture of an intracranial arterial aneurysm.[ncbi.nlm.nih.gov]
  • Previous reports have focused on hypertension as the principal etiological factor.[ncbi.nlm.nih.gov]
  • We report a 36-year-old woman presenting with hypertensive encephalopathy followed by bulbar palsy and quadriplegia.[ncbi.nlm.nih.gov]
  • Additional frequent symptoms are vomiting, hypertension, peripheral neuropathy, seizures, depression, delirium and coma.[ncbi.nlm.nih.gov]
  • While in first case severe pain in abdomen with intermittent exacerbation was the only presentation, the second patient presented as accelerated hypertension and acute abdominal crises in whom the clinical course was characterized by development of deep[ncbi.nlm.nih.gov]
Tachycardia
  • We report here a 60-year-old non-alcoholic male who had typical manifestations of AIP, including abdominal pain, constipation, tachycardia, hypertension, mental disturbances, psychiatric manifestations, seizures, peripheral neuropathy, and excessive excretion[ncbi.nlm.nih.gov]
  • A Chinese female patient with very typical AIP symptoms of severe abdominal pain, seizures, hypertension, and tachycardia, accompanied with hyponatremia, anemia, and hyperbilirubinemia.[ncbi.nlm.nih.gov]
  • She subsequently developed bilateral visual disturbance, confusion, seizures, hypertension, tachycardia, nausea, vomiting, constipation, dark tea-colored urine, and recurrent abdominal pain.[ncbi.nlm.nih.gov]
  • On evaluation, she had hyponatremia, episodic abnormal behavior, generalized muscle pain, hypertension, and sinus tachycardia. In view of the above clinical picture, a clinical diagnosis of acute intermittent porphyria was made.[ncbi.nlm.nih.gov]
  • The most common presenting features include pain in the abdomen, extremities, back, and chest; tachycardia; hypertension; nausea and vomiting; constipation; and peripheral motor neuropathy.[bestpractice.bmj.com]
Orthostatic Hypotension
Muscle Weakness
  • Some additional factors must also be present such as drugs, hormones, dietary changes, infections diseases and surgery that trigger the appearance of symptoms, which include neurological disorders, abdominal pain, constipation, and muscle weakness.[ncbi.nlm.nih.gov]
  • Following withdrawal of diclofenac and metoclopramide and treatment with IV 20% dextrose, a marked improvement occurred with resolution of muscle weakness and hyponatremia.[endocrine-abstracts.org]
  • Severe attacks of acute porphyria can cause lasting nerve damage and muscle weakness that can take months to resolve. Treatment of cutaneous porphyria depends on the specific type and the severity of the symptoms.[webmd.com]
  • If you’ve been searching for the cause of your unexplained severe abdominal pain and other symptoms—such as muscle weakness, nausea or vomiting, constipation, rapid heart rate, or emotional changes—there’s something you should know: these may be signs[isitaip.com]
  • Proximal muscle weakness typically beginning in the arms is characteristic; there can be muscle pain, tingling, numbness, weakness or paralysis; [5] muscle weakness seen in AIP can progress to include the muscles of breathing causing respiratory failure[en.wikipedia.org]
Back Pain
  • Back pain (10/32) was the most frequent AIP pain symptom and sweet craving (10/15) was the most frequent PMS symptom.[ncbi.nlm.nih.gov]
  • Symptoms may include vomiting, abdominal or back pain, weakness in arms or legs, and mental symptoms. Laboratory tests are done on urine samples taken during the attack.[merckmanuals.com]
  • 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]
  • Patient B was a woman, 36 years of age, who was initially under the care of an orthopedic surgeon for severe back pain and was referred to a consultant physician for investigation of multiple symptoms, including urinary retention, dysuria, back pain,[clinchem.aaccjnls.org]
  • Other neurologic signs and symptoms of AIP include seizures , peripheral neuropathy , abnormal sensations , chest pain, leg pain, back pain or headache, and coma . Nausea , vomiting , constipation , and diarrhea can also occur.[en.wikipedia.org]
Myalgia
  • Her abdominal pain and myalgia subsided on the third day of dialysis. Her lower limb muscle power improved and she became ambulant by the fourth day. Urinary retention improved within 4 days. Hematin was imported by then from the United States.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
Photosensitivity
  • 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]
  • The presence of fluorescent red cells (fluorocytes) in AIP is probably under-recognized since AIP is a hepatic porphyria and not associated with photosensitivity.[ncbi.nlm.nih.gov]
  • Clinical manifestations include photosensitivity, abdominal pain and neuropsychiatric symptoms.[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. Healing is slow and is associated with scarring and hair growth, especially on the face.[scientificamerican.com]
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]
  • […] crinium Veränderungen der Haarfarbe Canities vorzeitiges Ergrauen (vorzeitiges Ergrauen) Heterochromie der Haare ( Heterochromie der Haare) Poliosis circumscripta Hypertrichose Angeborene Hypertrichose persistierende Lanugobehaarung (siehe Lanugohaar ) Hypertrichosis[bionity.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 . Hemolytic anemia usually develops.[house.wikia.com]
Hirsutism
  • Most of the time the facial hairs are fine, so the hirsutism is barely noticeable. Sometimes, however, the hair growth can give the appearance of a werewolf, leading to speculations that the myths may have had a medical basis.[scientificamerican.com]
Hysteria
  • […] porphyria In porphyria …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]
  • Snapshot A 32-year-old woman presents to the psychiatric emergency room for uncooperative behavior and hysteria. She complains of abdominal pain. While being evaluated, she had a generalized tonic-tonic seizure.[medbullets.com]
  • 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.[symptoma.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]
Delusion
  • Psychiatric signs and symptoms of AIP may manifest as anxiety , paranoia , irritability, delusions , hallucinations , confusion , and depression . [4] Signs that suggest increased activity of the sympathetic nervous system may be evident including tachycardia[en.wikipedia.org]
Visual Hallucination
  • Psychological symptoms are variable: irritability, emotionality, depression, considerable anxiety and, more rarely, auditory and visual hallucinations, disorientation, mental confusion.[orpha.net]
Abnormal Behavior
  • On evaluation, she had hyponatremia, episodic abnormal behavior, generalized muscle pain, hypertension, and sinus tachycardia. In view of the above clinical picture, a clinical diagnosis of acute intermittent porphyria was made.[ncbi.nlm.nih.gov]
Urinary Retention
  • Urinary retention improved within 4 days. Hematin was imported by then from the United States. Later, 2 doses of hematin (4 mg/kg-160 mg in 20% albumin) were given via a central vein. She was maintained on physiotherapy.[ncbi.nlm.nih.gov]
  • 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 retention, incontinence , dysuria , and frequency may be observed. Tachycardia and hypertension , and less frequently fever, sweating, restlessness, and tremor are also observed.[diagnose-me.com]
  • Other symptoms in Acute intermittent porphyria Pain in arms and legs as well as in the back Muscle weakness caused by damage in the nerves that supplies the muscles Urinary retention Confusion, seizures and hallucinations Palpitation Diagnosis This disease[ehealthwall.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]
Red Urine
  • A 7-year-old boy demonstrating hepatosplenomegaly, mild anaemia, mild mental retardation, yellow-brown teeth and dark red urine had excessively elevated levels of urinary delta-aminolevulinic acid, porphobilinogen and uroporphyrin.[ncbi.nlm.nih.gov]
  • Her urine was not red at that time (on further questioning, she remembered she had had an episode of “red urine” recently). Two days later, after the PBG result came back positive, treatment was initiated for porphyria.[mdedge.com]
  • With the block in heme synthesis at the PBG deaminase reaction the resulting in increases in ALA and PBG synthesis leads to marked increases in urinary excretion of both compounds resulting in deep red urine, a hallmark of AIP.[themedicalbiochemistrypage.org]
  • URINARY SYSTEM SYMPTOMS Dark-colored urine Red urine Other common AIP symptoms Symptoms can also occur in many different areas of your body during an AIP attack. These AIP symptoms are also common in other conditions.[panhematin.com]
  • Even a purple hue or red urine may be seen. Diagnosis Edit Porphyrin studies Edit Porphyria is diagnosed through biochemical analysis of blood , urine , and stool .[house.wikia.com]
Dark Urine
  • A 47-year-old man presented with abdominal pain, neck stiffness, severe transient hypertension and unusually dark urine. Cerebrospinal fluid investigations and angiography confirmed the diagnosis of a subarachnoid haemorrhage.[ncbi.nlm.nih.gov]
  • Seven years later, acute intermittent porphyria was diagnosed as she developed an acute episode of abdominal pain, dark urine, and hyponatremia.[ncbi.nlm.nih.gov]
  • 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
  • Urinary retention, incontinence , dysuria , and frequency may be observed. Tachycardia and hypertension , and less frequently fever, sweating, restlessness, and tremor are also observed.[diagnose-me.com]
  • Patient B was a woman, 36 years of age, who was initially under the care of an orthopedic surgeon for severe back pain and was referred to a consultant physician for investigation of multiple symptoms, including urinary retention, dysuria, back pain,[clinchem.aaccjnls.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]
Urinary Incontinence
  • Meanwhile, she developed flaccid quardriparesis with urinary incontinence and bulbar palsy. Her brain MRI was normal. Her nerve conduction study was suggestive of motor radiculoneuropathy. Specific treatment for severe porphyric crisis was planned.[ncbi.nlm.nih.gov]
  • Urinary signs and symptoms such as painful urination , urinary retention , urinary incontinence , or dark urine have also been known to occur.[en.wikipedia.org]
Seizure
  • However, AIP should also be considered when seizures and PRES are associated with unexplained abdominal pain. Both the patients were presented with seizures and PRES on brain magnetic resonance imaging (MRI).[ncbi.nlm.nih.gov]
  • The authors recommend testing for porphyria in cases of Rasmussen encephalitis and other intractable seizures.[ncbi.nlm.nih.gov]
  • While acute abdominal pain is the most common presenting symptom in children, seizures are commonly seen and may precede the diagnosis of AIP.[ncbi.nlm.nih.gov]
  • Our interest lies in the differentiation of co-morbidity of two different disorders or presence of epileptic seizures as the clinical picture of latent AIP.[ncbi.nlm.nih.gov]
  • PRES is a clinicoradiological condition caused by the failure of the posterior circulation to autoregulate, resulting in cerebral oedema, headaches, nausea and seizures.[ncbi.nlm.nih.gov]
Confusion
  • Acute attacks present with episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. A high index of suspicion is required for the initial diagnosis of AIP.[ncbi.nlm.nih.gov]
  • The highly variable symptomatic presentation of AIP causes confusion with other diseases and results in a high misdiagnosis rate (68% in China) and delayed effective treatments.[ncbi.nlm.nih.gov]
  • The disease is clinically manifested with severe abdominal pain, confusion, and seizures which may be life threatening.[ncbi.nlm.nih.gov]
  • AIP can be confused with other causes of acute abdominal disorders such as appendicitis with peritonitis or nephrolithiasis.[ncbi.nlm.nih.gov]
  • This disease shows nonspecific signs and symptoms that can be confused with other diseases, thereby making the diagnosis difficult.[ncbi.nlm.nih.gov]
Peripheral Neuropathy
  • Both had a very poor quality of life as a result of years of frequent acute porphyria symptoms, chronic peripheral neuropathy and renal failure requiring dialysis. After transplantation, clinical and biochemical signs of porphyria disappeared.[ncbi.nlm.nih.gov]
  • The clinical presentations of abdominal pain, peripheral neuropathy and changes in mental status are the classic triad of an acute attack.[ncbi.nlm.nih.gov]
  • Additional frequent symptoms are vomiting, hypertension, peripheral neuropathy, seizures, depression, delirium and coma.[ncbi.nlm.nih.gov]
  • We report here a 60-year-old non-alcoholic male who had typical manifestations of AIP, including abdominal pain, constipation, tachycardia, hypertension, mental disturbances, psychiatric manifestations, seizures, peripheral neuropathy, and excessive excretion[ncbi.nlm.nih.gov]
  • Usually, peripheral neuropathy is considered the most common neurological manifestation of AIP. However, AIP should also be considered when seizures and PRES are associated with unexplained abdominal pain.[ncbi.nlm.nih.gov]
Convulsions
  • We report a series of six cases who presented with convulsion and/or polyneuropathy early in the course of disease to highlight this fact.[ncbi.nlm.nih.gov]
  • A 15-year old girl was admitted in the medicine department of Sylhet MAG Osmani Medical College with the complaints of recurrent abdominal pain, convulsions and weakness of lower limbs.[ncbi.nlm.nih.gov]
  • The authors presented the case of a 38-years-old patient admitted for persistent abdominal pain that previously presented two generalized convulsive seizures. The diagnosis of AIP was established by the raised concentration of urinary porphyrins.[ncbi.nlm.nih.gov]
  • Nine patients experienced neurological symptoms involving the central nervous system (consciousness disturbance, n 8; convulsion/seizure, n 4; behavior change, n 1), while 7 patients experienced peripheral neuropathies (motor paresis, n 7; impairment[ncbi.nlm.nih.gov]
  • An 18-year-old girl was admitted to our hospital with recurrent abdominal pain and 2 episodes of convulsions. She had undergone an appendectomy earlier at another hospital for abdominal pain.[ncbi.nlm.nih.gov]
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]
  • Tachycardia and hypertension , and less frequently fever, sweating, restlessness, and tremor are also observed. In up to 40% of patients, hypertension may become sustained between acute attacks. Neuropathy is a common feature of AIP.[diagnose-me.com]
  • […] delusions , hallucinations , confusion , and depression . [4] 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]
  • […] symptoms such as pain abdomen (85-95%), vomiting (50%), constipation (50%), peripheral neuropathy (42-68%), seizures (10-16%), delirium, coma and depression. [4] Autonomic disturbances may manifest as urinary retention, paralytic ileus, restlessness, tremor[joacp.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]

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.

Slowing
  • Recovery from severe paralysis is generally slow. Full DNA analysis of the HMBS gene is performed by full gene sequencing of all exons (coding regions), 20-30 base pairs into the introns (including splice sites), and the promoter region.[sema4genomics.com]
  • Healing is slow and is associated with scarring and hair growth, especially on the face. Most of the time the facial hairs are fine, so the hirsutism is barely noticeable.[scientificamerican.com]
  • Damage to nerves of the digestive system not only cause nerve pain in the abdominal area, but also cause slow movement of the bowels, especially the large intestine .[house.wikia.com]
Generalized Slowing
  • Recovery from severe paralysis is generally slow. Full DNA analysis of the HMBS gene is performed by full gene sequencing of all exons (coding regions), 20-30 base pairs into the introns (including splice sites), and the promoter region.[sema4genomics.com]
Hyponatremia
  • Neurovisceral symptoms resolved, and severe hyponatremia was corrected with IV saline solution without complications.[ncbi.nlm.nih.gov]
  • On evaluation, she had hyponatremia, episodic abnormal behavior, generalized muscle pain, hypertension, and sinus tachycardia. In view of the above clinical picture, a clinical diagnosis of acute intermittent porphyria was made.[ncbi.nlm.nih.gov]
  • SIADH was found to be the cause of hyponatremia.[endocrine-abstracts.org]
  • Supportive treatment includes opiate analgesia, monitoring for and treating complications such as hypertension and hyponatremia.[ncbi.nlm.nih.gov]
  • A 35-year-old woman with tubal factor infertility presented to our clinic with persistent low abdominal pain and hyponatremia after transvaginal oocyte retrieval.[ncbi.nlm.nih.gov]

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.

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.

References

Article

  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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Last updated: 2018-06-21 20:07