Pathogenesis, clinical manifestations, and diagnosis of acute intermittent porphyria
- Gagan K Sood, MD
Gagan K Sood, MD
- Associate Professor, Department of Surgery and Medicine
- Baylor College of Medicine
- Karl E Anderson, MD, FACP
Karl E Anderson, MD, FACP
- The University of Texas Medical Branch
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
Acute intermittent porphyria (AIP; also called Swedish porphyria, pyrroloporphyria, intermittent acute porphyria) is an acute neurovisceral porphyria resulting from a partial deficiency of the heme biosynthetic enzyme porphobilinogen deaminase (PBGD). It is an autosomal dominant disorder with low penetrance; development of symptoms is affected by a variety of exacerbating factors.
Despite its well characterized molecular genetics, the diagnosis of AIP is challenging. Symptoms are often vague and nonspecific; the other possible causes of neurologic findings and abdominal pain are numerous; and acute porphyria is often not considered because it is rare. Clues from the family history may be absent, because penetrance of AIP is low and symptoms may not manifest in the majority of family members with a disease-causing mutation. Even if acute porphyria is considered, many clinicians are unfamiliar with typical findings of the disease, appropriate testing, and interpretation of test results. As a consequence, diagnosis and life-saving treatment are often delayed.
The pathogenesis, clinical manifestations, and diagnosis of AIP will be reviewed here. Management of AIP and a general overview of the porphyrias are presented separately. (See "Management and prognosis of acute intermittent porphyria" and "Porphyrias: An overview".)
Porphyrias are caused by alterations in the enzymes of heme biosynthesis. Heme is essential in the function of hemoglobin and many other hemoproteins, including hepatic enzymes such as cytochrome P450 enzymes. The liver is the major source of overproduction of heme pathway intermediates in patients with hepatic porphyrias such as AIP; and the central, peripheral, autonomic, and enteric nervous systems are affected when levels of these intermediates are elevated in the circulation, suggesting neurotoxic effects of one or more intermediates. Some neurological manifestations may result from heme depletion in neuronal cells, although this remains unproven. (See 'Neurological dysfunction' below.)
Gene mutation — AIP is caused by heterozygosity for a mutation in the gene encoding porphobilinogen deaminase (PBGD), also called hydroxymethylbilane synthase (HMBS) and previously referred to as uroporphyrinogen I synthase. Inheritance is autosomal dominant with low penetrance. More than 300 PBGD gene mutations have been recognized in AIP, all of which lead to severe loss of PBGD enzymatic activity from the mutant allele. Virtually all remaining PBGD activity is due to expression from the unaffected allele.
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- Gene mutation
- Enzymatic defect
- Neurological dysfunction
- EXACERBATING FACTORS
- Ethanol and smoking
- Sex hormones
- Nutrition, glucose metabolism, and stress
- CLINICAL MANIFESTATIONS
- Acute attacks
- - Abdominal pain
- - Peripheral neuropathy
- - Autonomic, enteric, and central nervous system involvement
- - Bladder dysfunction/red urine
- - Laboratory and imaging findings
- Chronic manifestations
- DIAGNOSTIC EVALUATION
- Overview of the evaluation
- Symptomatic patients
- - Test urinary PBG and initiate treatment if positive
- - Obtain plasma and stool samples during the acute attack
- Asymptomatic patients
- Confirmatory testing
- - PBGD activity (erythrocytes)
- - DNA testing
- Diagnostic criteria
- DIFFERENTIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS