The porphyrias are a group of inherited and acquired metabolic disorders, each resulting from the deficient or increased activity of a specific enzyme in the heme biosynthetic pathway. These enzyme alterations are inherited as autosomal-dominant or -recessive and X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic. These disorders are classified as either hepatic or erythropoietic, depending on the primary site of overproduction and accumulation of the porphyrin precursor(s) or porphyrin(s) (Table 162-1). Clinically, they are classified as acute and cutaneous, although some have overlapping features. Manifestations of the acute hepatic porphyrias are primarily neurologic, including severe abdominal pain, neuropathy, and secondary mental symptoms, whereas the erythropoietic porphyrias characteristically cause cutaneous phototoxicity.
PATHOGENESIS AND EPIDEMIOLOGY
The neurologic involvement in the hepatic porphyrias, which typically presents after puberty, results from the hepatic overproduction of a neurotoxic metabolite(s). Certain steroid hormones, porphyrinogenic drugs, and dieting influence the production of porphyrin precursors and porphyrins, thereby precipitating acute attacks. In the cutaneous porphyrias, sensitivity to sunlight may occur in infancy or childhood because of the excitation of excess porphyrins in the skin by long-wave ultraviolet light, which can lead to cell damage, scarring, and deformation.
These disorders are rare. The acute hepatic porphyrias have a prevalence of 3 to 5 per 100,000 and occur more frequently in Scandinavia, South Africa, and the United Kingdom. Recent estimates of the prevalence suggest that 1 in approxiamately 1700 Caucasians have pathogenic mutations for the most common acute hepatic porphyria, acute intermittent porphyria (AIP). However, the penetrance may be as low as 1%, indicating the importance of environmental and genetic precipitating/preventative factors. PCT is the most common porphyria, and its estimated prevalence is approximately 5 to 10 per 100,000 in Caucasians. Erythropoietic protoporphyria is the most common erythropoietic porphyria and is the most common porphyria in children. Aminolevulinic acid (ALA) dehydrogenase-deficient porphyria (ADP), congenital erythropoietic porphyria, and X-linked protoporphyria all are extremely rare with 10, more than 200, and approximately 50 patients, respectively, reported in the literature.
TABLE 162-1CLINICAL, METABOLIC, AND GENETIC CHARACTERISTICS OF THE HUMAN PORPHYRIAS ||Download (.pdf) TABLE 162-1CLINICAL, METABOLIC, AND GENETIC CHARACTERISTICS OF THE HUMAN PORPHYRIAS
|Type/Porphyria ||Deficient Enzyme ||Inheritance ||Photosensitivity ||Neurovisceral Symptoms ||Increased Erythrocyte Porphyrins ||Porphyrin Excretion |
|Urine ||Stool |
|Hepatic Porphyrias |
|ALA dehydratase deficiency (ADP) ||ALA dehydratase ||AR ||— ||+ ||PROTO ||ALA, COPRO III ||— |
|Acute intermittent porphyria (AIP) ||HMB-synthase ||AD ||— ||+ ||— ||ALA, PBG ||— |
|Porphyria cutanea tarda (PCT) ||URO-decarboxylase ||AD ||+++ ||— ||— ||URO I, 7-carboxylate porphyrin ||ISOCOPRO |
|Hepatoerythropoietic porphyria ||URO-decarboxylase ||AR ||+++ ||+/– || || || |
|Hereditary coproporphyria (HCP) ||COPRO-oxidase ||AD ||+ ||+ ||— ||ALA, PBG, COPRO III ||COPRO III |
|Variegate porphyria (VP) ||PROTO-oxidase ||AD ||+ ||+ ||— ||ALA, PBG, COPRO III ||PROTO IX, 5-carboxylate porphyrin |
|Erythropoietic Porphyrias |
|Congenital erythropoietic porphyria (CEP) ||URO-synthase ||AR ||+++ ||— ||URO I ||URO I ||COPRO ...|