Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors.

UNLABELLED: The clinical presentation of hereditary hemochromatosis has changed markedly in recent years. The aim of this study was to analyze a large series of consecutive Italian patients with hemochromatosis diagnosed between 1976 and 2007 to determine whether the genetic background and the presence of acquired risk factors influenced the severity of iron overload and the natural history of the disease. A cohort of 452 Italian patients with iron overload-338 HFE-related (C282Y homozygotes or compound C82Y/H63D heterozygotes) and 114 non-HFE-related-were followed prospectively for a median of 112 months. Alcohol intake, smoking habits, and iron removed to depletion were similar in patients with and without HFE-related iron overload. Hepatitis B virus (4% and 9%; P = 0.04) and hepatitis C virus (6% and 19%; P = 0.002) infections were more frequent in patients with non-HFE-related iron overload. Seventy-three percent of patients with HFE and 61% of patients with non-HFE-related disease had no acquired risk factor. Cirrhosis was significantly more frequent in non-HFE patients independent of the presence of acquired risk factors (P = 0.02). Sex, alcohol intake, prevalence of smoking, hepatitis C virus infection, glucose, lipids, iron-related parameters, and prevalence of C282Y/H63D differed significantly over the years. At enrollment, cirrhosis was present in 145 cases and was significantly more frequent in the first decade (80%, 47%, and 13%; P = 0.001). Survival did not differ across the decades in cirrhotic patients; hepatocellular carcinoma occurred similarly in HFE and non-HFE patients. CONCLUSION: Patients with HFE and non-HFE-related iron overload have comparable iron overload and similar clinical history. Patients who were diagnosed during the last 10 years and were not identified as cirrhotic at enrollment have less severe disease and lower prevalence of acquired risk factors, independent of genetic background.

Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2.

Transferrin receptor-2 (TFR2) regulates hepatic hepcidin secretion and when mutated causes type-3 hemochromatosis. No functional study is available in humans. We studied a 47 year-old woman with hemochromatosis. TFR2 DNA and its hepatic transcript were directly sequenced. Hepatic expression of hepcidin and other iron-related genes were measured by qRT-PCR. Urinary hepcidin was measured at baseline and after an oral iron challenge (ferrous sulfate, 65 mg) by SELDI-TOF-MS. A novel homozygous TFR2 mutation was identified in the splicing donor site of intron 4 (c.614+4 A>G) causing exon 4 skipping. Hepcidin and hemojuvelin expression were markedly reduced. Urinary hepcidin was lower than normal and further decreased after iron challenge. This is the first description of iron-related gene expression profiles in a TFR2 mutated patient. The decreased hepatic and urinary expression of hepcidin and lack of acute response to iron challenge confirms the primary role of TFR2 in iron homeostasis.

Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome.

AIM: To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. METHODS: We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome (MS) was defined according to ATPIII criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak's score and iron accumulation by Deugnier's score; steatosis was diagnosed when present in >or=5% of hepatocytes. RESULTS: According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P<0.0001). Patients with >or=2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with <2 MS components and absence of steatosis. CONCLUSION: In our patients, the presence of >or2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation>or=60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload.