Clinical Pearls & Morning Reports
Classic symptoms and signs of acute intermittent porphyria include severe, episodic abdominal pain and constipation, transient psychiatric manifestations, hyponatremia, and discolored urine. Read the NEJM Clinical Problem-Solving Article here.
Q: What causes acute intermittent porphyria?
A: Porphyrias are a group of metabolic disorders that result from defects in enzymes within the heme biosynthetic pathway. The most common are porphyria cutanea tarda, acute intermittent porphyria, and erythropoietic protoporphyria, in that order. Acute intermittent porphyria results from mutations in HMBS, the gene encoding hydroxymethylbilane synthase, which plays an integral role in heme synthesis. The disease manifests as acute attacks in which the heme pool in the liver is used up, leading to a buildup of δ-aminolevulinic acid and porphobilinogen (PBG).
Q: What type of cancer screening is recommended in patients with any form of acute porphyria?
A: Owing to the reported association between acute intermittent porphyria and hepatocellular carcinoma, experts recommend annual screening with hepatic ultrasonography as well as screening for alpha-fetoprotein starting at 50 years of age in patients with any form of acute porphyria.
A: Acute intermittent porphyria is a rare disease. The disease has incomplete penetrance (approximately 10 to 20% in genetically affected persons). The typical patient is a woman between the ages of 18 and 45 years. In a case series of 108 persons with acute intermittent porphyria, common symptoms included abdominal pain (74%), nausea and vomiting (73%), constipation (60%), and anxiety and depression (55%). Although symptoms were intermittent and acute in 55% of the patients, approximately 18% reported nearly constant symptoms, including chronic abdominal pain. Common but nonspecific laboratory findings associated with the onset of an acute intermittent porphyria attack include hyponatremia, hypomagnesemia, mild elevations of aminotransferase levels, and mild leukocytosis. In a cohort study from Sweden, researchers reported a significantly increased risk of diagnoses of schizophrenia and bipolar disorder among persons with acute intermittent porphyria. Given the challenges of diagnosing acute intermittent porphyria, patients may receive a misdiagnosis with primary psychiatric conditions.
A: Treatment of flares starts with intravenous administration of dextrose, which inhibits transcription of the gene encoding transhepatic 5′-aminolevulinate synthase 1 (ALAS1). A high-carbohydrate diet has also been suggested in case reports, and parenteral opioids are sometimes used in managing pain. However, up to 50% of patients may not report substantive improvement with opioids, and frequent or long-term use of opioids can have adverse effects, including the development of dependence. Hematin, administered intravenously, is also recommended; this treatment effectively bypasses the defective HMBS gene. Uncontrolled studies have suggested benefit, which may take up to 3 days; one small, placebo-controlled trial did not show clear evidence of benefit regarding symptoms of intermittent porphyria, but the trial was underpowered. Givosiran, an RNA interference therapy targeting ALAS1 messenger RNA, was recently approved for the prevention of porphyria flares on the basis of benefit reported in a phase 3 randomized trial in which givosiran significantly reduced the mean annual attack rate from 12.5 to 3.2 as compared with placebo. Patients should be counseled to avoid triggers, including alcoholic beverages, calorie restriction, and predisposing medications (including hormonal contraception). Premenopausal women may benefit from hormonal suppression. The prognosis is good if the disease is identified and measures are taken to minimize the risk of flares and to effectively treat those that occur.