40-15: Acute Intermittent Porphyria

Though there are several different types of porphyrias, the one with the most serious consequences and the one that usually presents in adulthood is acute intermittent porphyria (AIP), which is inherited as an autosomal dominant condition, though it remains clinically silent in most patients who carry a mutation in HMBS. Clinical illness usually develops in women. Symptoms begin in the teens or 20s, but onset can begin after menopause in rare cases. The disorder is caused by partial deficiency of hydroxymethylbilane synthase activity, leading to increased excretion of aminolevulinic acid and porphobilinogen in the urine. The diagnosis may be elusive if not specifically considered. The characteristic abdominal pain may be due to abnormalities in autonomic innervation in the gut. In contrast to other forms of porphyria, cutaneous photosensitivity is absent in AIP. Attacks are precipitated by numerous factors, including drugs and intercurrent infections. Harmful and relatively safe drugs for use in treatment are listed in Table 40–1. Hyponatremia may be seen, due in part to inappropriate release of antidiuretic hormone, although gastrointestinal loss of sodium in some patients may be a contributing factor.

A. Symptoms and Signs

Patients show intermittent abdominal pain of varying severity, and in some instances, it may so simulate acute abdomen as to lead to exploratory laparotomy. Because the origin of the abdominal pain is neurologic, there is an absence of fever and leukocytosis. Complete recovery between attacks is usual. Any part of the nervous system may be involved, with evidence for autonomic and peripheral neuropathy. Peripheral neuropathy may be symmetric or asymmetric and mild or profound; in the latter instance, it can even lead to quadriplegia with respiratory paralysis. Other central nervous system manifestations include seizures, altered consciousness, psychosis, and abnormalities of the basal ganglia. Hyponatremia may further cause or exacerbate central nervous system manifestations.

B. Laboratory Findings

Often there is profound hyponatremia. The diagnosis can be confirmed by demonstrating an increased amount of porphobilinogen in the urine during an acute attack. Freshly voided urine is of normal color but may turn dark upon standing in light and air.

Most families have different mutations in HMBS causing AIP. Mutations can be detected in 90% of patients and used for presymptomatic and prenatal diagnosis.

Avoidance of factors known to precipitate attacks of AIP—especially drugs—can reduce morbidity. Sulfonamides and barbiturates are the most common culprits; others are listed in Table 40–1 and on the Internet (www.drugs-porphyria.org). Starvation diets and prolonged fasting also cause attacks and so must be avoided. Hormonal changes during pregnancy can precipitate crises.

Treatment with a high-carbohydrate diet diminishes the number of attacks in some patients and is a reasonable empiric gesture considering its benignity. Acute attacks may be life-threatening and require prompt diagnosis, withdrawal of the inciting agent (if possible), and treatment with analgesics and intravenous glucose in saline and hematin. A minimum of 300 g of carbohydrate per day should be provided orally or intravenously. Electrolyte balance requires close attention. Hematin therapy should be undertaken with full recognition of adverse consequences, especially phlebitis and coagulopathy. The intravenous dosage is up to 4 mg/kg once or twice daily. Liver transplantation may provide an option for patients with disease poorly controlled by medical therapy.

• For management of severe abdominal pain, seizures, or psychosis.

• For preventive management when a patient with porphyria contemplates pregnancy.

• For genetic counseling and molecular diagnosis.

The patient should be hospitalized for an acute attack when accompanied by mental status changes, seizure, or hyponatremia.