Acute Intermittent Porphyria

Clinical Characteristics: Acute intermittent porphyria (AIP), an autosomal dominant disorder, occurs in heterozygotes for an HMBS pathogenic variant that causes reduced activity of the enzyme porphobilinogen deaminase. AIP is considered "overt" in a heterozygote who was previously or is currently symptomatic; AIP is considered "latent" in a heterozygote who has never had symptoms, and typically has been identified during molecular genetic testing of at-risk family members. Note that GeneReviews does not use the term "carrier" for an individual who is heterozygous for an autosomal dominant pathogenic variant; GeneReviews reserves the term "carrier" for an individual who is heterozygous for an autosomal recessive disorder and thus is not expected to ever develop manifestations of the disorder. Overt AIP is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 3%-8% (mainly women) have recurrent attacks (defined as >3 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. Latent AIP. While all individuals heterozygous for an HMBS pathogenic variant that predisposes to AIP are at risk of developing overt AIP, most have latent AIP and never have symptoms.
Diagnosis/testing: The diagnosis of overt AIP in a symptomatic proband is based on detection of increased concentration of porphobilinogen (PBG) in urine on biochemical testing. Molecular genetic testing is not a first-line diagnostic test for probands; detection of a heterozygous HMBS pathogenic variant is mainly used in difficult diagnostic situations – for example, when the proband is not available for testing.
Management: Treatment of manifestations : Acute neurovisceral attacks. Stop medications that can exacerbate AIP; provide adequate caloric intake by intravenous infusion if required (hypotonic dextrose water solutions should be avoided). Treat any intercurrent infections or disease using drugs known to be safe in acute porphyria. Treat pain with opiate analgesia (often in large amounts); support from a pain team may be required. Treat agitation, vomiting, hypertension, and tachycardia using non-porphyrinogenic drugs (those that will not act as triggers for acute porphyria; also known as "safe" drugs). Monitor fluid balance and correct electrolyte disturbances, especially hyponatremia; treat severe hyponatremia with saline infusions, not fluid restriction. Monitor neurologic status carefully and provide respiratory support as needed. Prompt administration of human hemin (panhematin or heme arginate) is the specific treatment of choice to curtail acute neurovisceral attacks and avoid paresis. Patients treated regularly with heme arginate require monitoring of iron status to detect iron overload. Mild attacks. Manage by symptomatic treatment, increased calorie intake, and fluid replacement. Recurrent acute attacks. Manage together with a porphyria specialist; treatment options include ovulation suppression with gonadorelin analogs, regular hematin infusions, or (as a last resort) liver transplantation. Evaluation of relatives at risk : If the HMBS pathogenic variant is known in a family, at-risk relatives can benefit from molecular genetic testing to clarify their genetic status, so that those at increased risk of developing acute attacks of AIP can be identified early and counseled about preventive measures to reduce the risk of acute attacks. Prevention of primary manifestations : All individuals with latent AIP, the parents of affected individuals, and patients with overt AIP who are in remission should be advised about measures that diminish the risk of acute attacks: Avoid precipitating factors (unsafe prescribed and illicit drugs, excessive alcohol consumption, smoking, and severe calorie restriction). Adopt safe practices (maintenance of a regular, balanced diet; prompt treatment of infections; and reduction of stress). Surveillance: Individuals who have experienced acute attacks require monitoring of renal function; in some countries annual hepatic imaging to detect HCC is also offered to all individuals with an HMBS pathogenic variant after age 50 years (whether or not they have experienced acute attacks). Therapies Under Investigation: Givosiran (ALN-AS1), an interference RNA that represses ALAS1, has completed Phase I and III clinical trials that showed reduction of 5-aminolevulinic acid and PBG excretion to near normal levels and a reduction in the rate of porphyria attacks when compared to a placebo.
Genetic Counseling: AIP is inherited in an autosomal dominant manner. Sibs and offspring of individuals with an HMBS pathogenic variant are at 50% risk of inheriting the HMBS pathogenic variant; however, because penetrance is low, the likelihood of an individual with an inherited HMBS pathogenic variant having an acute attack is small. Once an HMBS variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, because clinical penetrance is low, the finding of an HMBS pathogenic variant on prenatal testing cannot be used to predict whether an individual will become symptomatic – or if they do become symptomatic, the age of onset, severity, or type of symptoms.
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