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1.
Hepatology ; 51(2): 501-10, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20101754

ABSTRACT

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.


Subject(s)
Hemochromatosis/genetics , Iron Overload/genetics , Female , Hemochromatosis/epidemiology , Hemochromatosis/etiology , Humans , Iron Overload/epidemiology , Iron Overload/etiology , Italy , Male , Middle Aged , Retrospective Studies , Risk Factors , Severity of Illness Index , Time Factors
2.
Haematologica ; 94(2): 276-9, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19144662

ABSTRACT

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.


Subject(s)
Antimicrobial Cationic Peptides/genetics , Hemochromatosis/genetics , Mutation , Receptors, Transferrin/genetics , Antimicrobial Cationic Peptides/urine , Female , Gene Expression Profiling , Hepcidins , Humans , Middle Aged
3.
World J Gastroenterol ; 14(30): 4745-52, 2008 Aug 14.
Article in English | MEDLINE | ID: mdl-18720534

ABSTRACT

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.


Subject(s)
Fatty Liver/diagnosis , Insulin Resistance , Iron Overload/etiology , Iron/metabolism , Liver/metabolism , Metabolic Syndrome/diagnosis , Adult , Aged , Fatty Liver/complications , Fatty Liver/metabolism , Fatty Liver/pathology , Fatty Liver/physiopathology , Female , Hemochromatosis/genetics , Hemochromatosis/metabolism , Hemochromatosis Protein , Histocompatibility Antigens Class I/genetics , Humans , Iron Overload/metabolism , Iron Overload/pathology , Iron Overload/physiopathology , Liver/pathology , Male , Membrane Proteins/genetics , Metabolic Syndrome/complications , Metabolic Syndrome/metabolism , Metabolic Syndrome/pathology , Metabolic Syndrome/physiopathology , Middle Aged , Predictive Value of Tests , ROC Curve , Risk Factors , Severity of Illness Index , Transferrin/metabolism
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