Abstract
Abstract
Heme is an essential molecule involved in various biochemical processes in many species. It is used in the formation of cytochromes P-450, mitochondrial cytochromes, hemoproteins, catalase, peroxidase, myoglobin, and hemoglobin. Formation of the heme molecule involves a multistep process using eight enzymes. Biosynthesis of heme occurs in the mitochondria and in the cytoplasm. Most tissues in the human body synthesize heme, but the main sites of formation are in the bone marrow (erythroblasts) and in the liver (hepatocytes). Porphyrias are a unique group of disorders mainly due to inborn errors of metabolism of the heme synthetic pathway. The deficient activity of the enzymes can lead to a build-up of heme precursors, resulting in wide heterogeneity of clinical symptoms. To date, there are nine described porphyrias: aminolevulinic acid dehydratase deficient porphyria (ALADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLPP). The classification of porphyrias is based on 1) the main sites of heme precursor synthesis (hepatic, erythropoietic), 2) acute or chronic porphyria, and 3) cutaneous involvement. In this review, we focus on AIP, PCT, and EPP, the three most common forms of porphyria in the United States. A case vignette for each of the three is provided and followed by a discussion regarding the clinical features, pathogenesis, diagnosis/management, and prognosis of each. Management of AIP currently revolves around avoidance of drugs and chemicals and severe caloric deprivation, which may trigger acute attacks, and use of intravenous heme for acute attacks. Exciting new therapies, particularly siRNA to down regulate hepatic 5-aminolevulinic acid synthase, are under active development. Management of EPP currently involves protection from sunlight, but implants of afamelanotide have shown good efficacy and are already approved by the European Medicines Agency.