Most common hepatic porphyria.
Accounts for 80% of all symptomatic cases of porphyria.
A family of rare genetic disorders caused by defects in heme biosynthesis enzymes.
Mutations in the gene that causes acute intermittent porphyria is relatively common approximately, one in 1600 white persons, but the disease penetrance among maturation carries is approximately 1% of the general population and up to 50% of families with a history of disorder.
it is caused by a partial deficiency of the third enzyme of heme synthesis, PBG deaminase.
Autosomal dominant inheritance, with variable expression.
It has a low penetrance of less than 10% of persons with a pathogenic mutation have symptoms.
Acute intermittent porphyria results from mutations in HMBS, the gene including hydroxymethylbilane synthase, which plays an integral role in heme synthesis.
Carriers and clinically affected patients have about a 50% deficiency of porphobilinogen deaminase activity.
Only clinically affected patients excrete large amounts of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) into the urine.
AIP results in acute attacks in which the heme pool in the liver is used up, leading to a buildup of delta aminolevulinic acid and porphobilinogen.
A rare disease with an estimated prevalence of 5.4 cases per million.
The classic presentation occurs in young women, with symptoms of fatigue, difficulty concentrating, abdominal pain, nausea and vomiting.
Patients may have hypertension, tachycardia and subtle neurologic signs with with otherwise normal physical examination.
The disease has an incomplete penetrance of approximately 10-20% in genetically infected persons.
Most common hepatic porphyria.
The presence of elevated aminolevulinic acid accumulating in the liver, the central and peripheral nervous systems, and the kidneys may account for these coexisting conditions.
Patients may have peripheral neuropathy and autonomic neuropathy, with the latter resulting in cardiac arrhythmias, dysautonomia, and gastrointestinal manifestations.
There is a significant increase risk of diagnosis of schizophrenia and bipolar disorder.
Because of the association of AIP and hepatocellular carcinoma, annual screening for alpha-fetoprotein is recommended starting at 50 years of age.
About 90% of heterozygotes remain asymptomatic all of their lives.
Patients present with neurological manifestations but never have skin photosensitivity.
Acute porphyria can cause elevated catecholamines.
Common laboratory findings include hyponatremia and mild liver enzyme elevations.
Imaging studies may show an ileus.
Latent before puberty.
Females have more frequent symptoms than males.
Typical patient with AIP is a woman between ages of 18-45 years.
Attacks typically warrant urgent medical attention and sometimes prolong hospitalization and rehabilitation.
By inducing hepatic ALA synthetase, which is the rate limiting step in the heme biosynthesis pathway, hormones, drugs and nutritional factors may aggravate the disease.
Acute episodes can be precipitated by the ingestion of alcohol, infections, low calorie intake, elevated levels of reproductive hormones, and medications, particularly anti-seizure drugs.
Common laboratory abnormalities include: hyponatremia, hypomagnesemia, mild elevations of aminotransferase levels, and mild leukocytosis.
Hyponatremia occurs in 25- 60% of the acute attacks and is attributed to elevated levels of antidiuretic hormone.
Patient with AIP may have urine that appears red or brown and darkens with exposure to oxygen, light, or heat because urinary porphyrins undergo auto conversion of porphobilinogen and into porphobilin.
Elevated porphobilinogen levels relative to the urinary creatine level is consistent with the diagnosis. and a normal value during an acute flair rules out AIP.
Elevations of Deltaaminolevulinic acid and porphyrins are not specific to porphyria: acute hepatic porphyria is diagnosed by substantial elevations in urinary PBG levels.
Attacks of acute intermittent porphyria can be precipitated by progestational surges associated with menses, caloric deprivation, or medications.
Treatment of flares start with intravenous administration of dextrose.
Dextrose inhibits transcription of the gene encoding transhepatic 5-aminolevulinate synthase 1 (ALAS1).
Opioids are sometimes used to manage pain but is not effective long-term and is associated with dependence.
Hematin given intravenously bypasses the defective HMBS gene.
Hematin may take up to three days to be effective.
Givosiran is an RNA interference therapy targeting targeting ALAS1, it is approved for the prevention of porphyria flares.
Patient should avoid triggers, including alcohol beverages, calorie restriction, and predisposing medication‘s including hormonal contraception.
Pre-menopausal women may benefit from suppressing their hormones.
Hemin can be given periodically to prevent attacks or control symptoms, but long-term therapy causes thrombotic complication and may produce iron overload, and renal insufficiency.
Common symptoms with AIP is abdominal pain at 74%, nausea and vomiting 73%, constipation 60%, and anxiety and depression 55%.
About 55% of patients have intermittent and acute symptoms.
Approximately 18% report nearly constant symptoms, including chronic abdominal pain.
Patients who receive gIvosiran have a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations for those who receive placebo.