Case-based discussion of the acute hepatic porphyrias: Updates on pathogenesis, diagnosis and management.

ABSTRACT

The acute hepatic porphyrias (AHPs) include three autosomal dominant disorders, acute intermittent porphyria, variegate porphyria  and hereditary coproporphyria, and the ultra-rare autosomal recessive 5-aminolevulinic acid dehydratase-deficient porphyria. All four are characterized by episodic acute neurovisceral attacks that can be life-threatening if left untreated. The attacks are precipitated by factors that induce hepatic 5-aminolevulinic acid synthase 1 (ALAS1), resulting in accumulation of the porphyrin precursors, 5-aminolevulinic acid and porphobilinogen, which are believed to cause neurotoxicity. Diagnosis of these rare disorders is often delayed because the symptoms are non-specific with many common aetiologies. However, once clinical suspicion of an AHP is raised, diagnosis can be made by specialized biochemical testing, particularly during attacks. Moderate or severe attacks are treated with intravenous hemin infusions, together with supportive care to relieve pain and other symptoms. Prophylactic treatments are recommended in patients with confirmed recurrent attacks (≥4 attacks in a maximum period of 12 months), the most effective being givosiran, an RNAi therapeutic targeting hepatocyte ALAS1 mRNA. AHP patients with clinically and/or biochemically active disease are at elevated risk for developing long-term complications, including chronic kidney disease, chronic hypertension and hepatocellular carcinoma, thus, surveillance is recommended. Here, using a case-based format, we provide an update on the pathogenesis, diagnosis and treatment of the AHPs based on literature review and clinical experiences.