Acute Hepatic Porphyrias: Review and Recent Progress

Abstract

The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%-3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long-term complications. Their first-degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down-regulate ALA synthase-1 and/or wild-type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.

Figure 1

Summary of the heme synthetic pathway, highlighting the enzymatic defects associated with the porphyrias. The heme synthetic pathway involves eight enzymes, four of which are active in the mitochondria and four of which are active in the cytoplasm. The pathway is initiated and completed in the mitochondria. Intermediate steps in the cytoplasm begin with the activity of ALA dehydratase, also known as PBG synthase. Open arrows indicate progression through the pathway. Deficiency (indicated by blocked red arrows) in any of the eight enzymes involved in the pathway may contribute to the development of acute or chronic hepatic porphyrias or erythropoietic porphyrias, as shown in red. Abbreviations: Ac, acetate; CoA, coenzyme A; Copro’gen, coproporphyrinogen; Pr, propionate; proto’gen, protoporphyrinogen; Uro’gen, uroporphyrinogen; and Vi, vinyl. (From 43, used with permission of the authors and publisher.)

Figure 2

Key role of heme in the regulation of hepatic ALAS‐1 and heme metabolism. The figure shows the central role of the regulatory heme pool in regulating the activity of hepatic ALAS‐1 at the level of mRNA stability and uptake of the pre‐enzyme into mitochondria. Heme also down‐regulates transcription of ALAS‐1 and increases the rate of breakdown of the mature enzyme in mitochondria.3 Abbreviation: CoA, coenzyme A.

Figure 3

The mechanism of siRNA therapy. Synthetic double‐stranded RNA containing an ALAS‐specific sequence is derivatized with N‐acetylgalactosamine to target the asialoorosomucoid (galactose) receptor, which is expressed nearly exclusively on hepatocytes. Within the hepatocytes, the RNA is processed into approximately 20 base pair (bp) fragments by a cellular enzyme (dicer) and then separated into single strands. The strand that is complementary to ALAS‐1 (the guide strand) binds to cellular ALAS‐1 mRNA and enters the RNA‐induced silencing complex, where the new double‐stranded RNA is cleaved by a group of factors that include argonaute, a ribonuclease. The result is a reduction in the level of ALAS‐1 protein and decreased production of ALA. Abbreviations: RISC, RNA‐induced silencing complex. (From 5, used by permission of the authors and publisher.)