Acute intermittent porphyria

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.


In patients with acute hepatic porphyria induction of hepatic ALA synthase1 results in the accumulation of neurotoxic heme intermediates, including ALA and potphobilinigen.

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.

The accumulation of ALA  and possibly porphobilinogencauses injury to the nervous system and other organs, resulting in life-threatening acute attacks and chronic disease manifestations.

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.

The disease is associated with long-term coexisting illnesses including chronic kidney disease, hypertension, chronic neuropathy, and liver disease with liver fibrosis, cirrhosis, and hepatocellular carcinoma.

Most common hepatic porphyria.

Persons with AIP have abdominal pain that is typically out of proportion to clinical findings, often resulting in delay in the diagnosis.

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.

Patients may have iron overload from repeated hemin treatment.

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 that occur in acute hepatic porphyria are more commonly seen in females and characterized by abdominal pain, muscle weakness, autonomic neuropathy today on changes in mental status.

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.

Management options include removing triggering factors and treatment with intravenous opioids, glucose, and hemin.

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.

Those patients have only a few attacks in their lifetime, but up to 8% have recurrent attacks.
Recurrent attacks may be as many as four or more attacks per year.
Treatment options: hormone suppression, prophylactic hemin, and in rare cases liver transplantation.

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.

GIvosiran Is a subcutaneously administered are in a interference therapeutic targeting the paddock ALAS1 messenger RNA, preventing the accumulation of ALA and porphobilinogen.
Givosiran is and RNA interference agent designed to block the synthesis of the ALAS1 enzyme.
Monthly subcutaneous givosiran prevents accumulation of toxic molecules such as  aminolevulinic acid and porphobilinogen and results in lower attack rates and lower numbers of hemin doses than placebo.

Leave a Reply

Your email address will not be published. Required fields are marked *