Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda

Abstract

Inherited and acquired factors have been implicated in the pathogenesis of porphyria cutanea tarda (PCT), a disorder characterized by a photosensitive dermatosis and hepatic siderosis. This study, comprising 108 patients with PCT, was intended to define the role of hemochromatosis gene (HFE) mutations in the expression of PCT and to determine the contribution of acquired factors including alcohol, hepatitis C virus (HCV), and estrogen. The 2 known HFEmutations, cysteine 282 tyrosine (Cys282Tyr) and histidine 63 asparagine (His63Asp), were detected by polymerase chain reaction, and anti-HCV immunoglobulin G was detected serologically. Liver biopsies were graded for iron content, inflammation, and fibrosis. Estimates of alcohol and estrogen use were based on a questionnaire. Of the PCT patients tested, 19% were homozygous for the Cys282Tyr mutation; controls were equal to 0.5%. The compound heterozygous genotype was detected in 7% of the PCT patients; controls were less than 1%. The transferrin saturation, serum ferritin, and liver iron burden of all PCT patients were higher than those of nonporphyric controls. The highest values were found in PCT patients homozygous for the Cys282Tyr mutation. Of the patients studied, 59% were HCV positive (compared with 1.8% of the population), and 46% consumed more than 70 g of alcohol daily. Of the female patients, 63% were ingesting estrogens. Hepatic damage was most marked in patients with the Cys282Tyr/Cys282Tyr genotype who had HCV and drank heavily. Homozygosity for the Cys282Tyrmutation and HCV are the greatest risk factors for expression of PCT, and in most patients, more than 1 risk factor was identified. It was common for patients with HCV to consume alcohol. Patients with PCT should be screened for HFE mutations and for HCV.

Developmental and Inherited Liver Disease

“…809 The interaction of the HFE mutation and susceptibility to sporadic PCT has been discussed in several studies. [810][811][812][813] Mild to moderate iron overload is found in 60-70% of patients with PCT; 10% have increases in the range of hereditary haemochromatosis. 814 In almost all studies, a high prevalence of HFE gene mutations has been detected, with differences between patients of northern European ancestry and those of Mediterranean origin.…”

“…815 In a U.S. study, 19% of the PCT patients tested were homozygous for the C282Y mutation, and 7% were compound heterozygous (0.5% and 1.0%, respectively, in the general population). 810 Viral infections may trigger PCT. Initial reports documented a high incidence (40%, 57% and 70.7% in three series) of hepatitis B serological markers in PCT [816][817][818] and anecdotal cases of HIV infection.…”

Extrahepatic manifestations of chronic hepatitis C

“…Moreover, the prevalence of HFE gene mutations in North American patients with PCT is also high (73%). 17 Lichen planus is a chronic inflammatory mucocutaneous disease process that usually presents as small, purplish, flat-topped papules. The flexor wrists and forearms, extensor hands and ankles, lumbar region, shins, and genital area are the usual distribution of LP.…”

Uroporphyria caused by ethanol in Hfe (−/−) mice as a model for porphyria cutanea tarda

“…The disease can be sporadic or familial, but 71% to 81% of U.S. cases are sporadic. 4,5 Most patients with familial PCT are heterozygous for a mutation in the uroporphyrinogen decarboxylase (UROD) gene, leading to a 50% loss of UROD activity. [1][2][3] In patients with both sporadic and familial PCT, UROD becomes highly inactivated in the liver, resulting in increased accumulation of uroporphyrinogen, which is oxidized to URO.…”

“…Both sporadic and familial PCT are multifactorial diseases 5 and are most commonly precipitated in susceptible individuals by consumption of alcoholic beverages. [2][3][4][5] Other precipitants include estrogenic steroids and infection with hepatitis C virus. 1,3,5 The mechanism of action of the precipitants is not known.…”