Semiquantitative and qualitative assessment of hepatic iron in patients with chronic viral hepatitis: relation with grading, staging and haemochromatosis mutations.

BACKGROUND: Hepatic iron overload is a common but still poorly characterized finding in patients with chronic viral hepatitis. AIM: To evaluate lobular and cellular distribution of iron in patients with chronic viral hepatitis, the relation between hepatic iron distribution, grading and staging, and the frequency of haemochromatosis gene mutations. PATIENTS: Thirty-four patients with chronic viral hepatitis and iron overload; 34 matched chronic viral hepatitis controls without iron overload; 139 healthy controls. METHODS: Hepatic iron was assessed by hepatic iron concentration and Deugnier's score, histological grading and staging by Ishak's score, and frequency of haemochromatosis gene mutations by polymerase chain reaction-restriction assays. RESULTS AND CONCLUSIONS: Iron deposits were found in hepatocytes (94% of the patients), sinusoidal tracts (88%) and portal cells (59%). In 41%, iron deposits were homogeneously distributed in the hepatic specimen. Hepatocytic iron showed a decreasing gradient from Rappaport's zone 1 to 3. Heavy alcohol intake influenced the distribution rather than the amount of hepatic iron by increasing sinusoidal iron. Haemochromatosis gene mutations were more frequent in chronic viral hepatitis patients with iron overload than in those without iron overload and in healthy controls suggesting they contribute to pathogenesis of hepatic iron accumulation. The correlation between hepatic fibrosis and portal iron supports the fibrogenetic role of iron in chronic viral hepatitis.

Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations.

Mild to moderate hepatic iron overload is frequent in patients with chronic viral hepatitis (CH). We evaluated the role of hemochromatosis (HFE) gene mutations and other acquired factors in the development of iron overload in these patients. We studied 110 patients with chronic B or C viral hepatitis (31 women, 79 men), including 20 with cirrhosis, and 139 controls. Hepatic iron was evaluated by semiquantitative analysis in all the patients, and hepatic iron concentration (HIC) was determined in 97 of them (26 women, 71 men). C282Y and H63D mutations were sought in all the subjects by a polymerase chain reaction-restriction assay. The frequency of HFE genotypes and alleles did not differ in patients and controls. No relation was detected between hepatic iron stores and HFE gene mutations in women. In men, all C282Y heterozygotes had iron overload, and the H63D mutation was significantly more frequent in patients with more marked hepatic siderosis than in those with mild or no siderosis (P = .0039) and in controls (P = .0008). Heavy alcohol intake and hepatic cirrhosis were also associated with increased hepatic iron stores in the men. In the 71 men in whom HIC was measured, multiple regression analysis showed that this variable was related independently only to alcohol intake and HFE gene mutations. We suggest that in patients with CH, iron accumulates in the liver as the result of an interplay between genetic and acquired factors, and that increased liver iron stores may influence progression toward liver fibrosis.

High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda.

Sporadic porphyria cutanea tarda (PCT) is caused by a reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Mild to moderate iron overload is common in PCT, as iron is one of the factors which trigger the clinical manifestations of the disease through the inactivation of URO-D. A role for genetic hemochromatosis in the development of iron overload in sporadic PCT has been hypothesized in the past. The aim of this work was to investigate whether mutations of HFE, which is a candidate gene for hemochromatosis, play the role of genetic susceptibility factors for PCT in Italian patients, who have a high prevalence of acquired triggering factors, such as hepatitis C virus (HCV) chronic infection and alcohol. We determined HFE genotypes of 68 male patients with PCT. Our data do not confirm an association of PCT with the Cys282Tyr HFE mutation, strongly associated with hemochromatosis in Northern European countries. A second mutation of HFE, His63Asp, however, had a significantly increased frequency as it was present in half of the patients. Surprisingly, the presence of the His63Asp mutation was not related to the iron status of patients, suggesting that a subtle abnormality of iron metabolism induced by this mutation could escape detection by the standard parameters of iron status. In PCT patients with liver disease, the presence of the mutation could contribute to the inactivation of URO-D, either directly or through a synergistic action with other factors that cause liver damage.