HFE gene is a major histocompatibility complex class I-like gene, which was identified as a candidate gene for hemochromatosis in 1996. The proposed role for HFE is its part in the regulation of the interaction of the transferrin receptor with transferrin. Hemochromatosis, the common autosomal recessive disease of iron overload, affects at least 1 in 300 Caucasians. The identification of the C282Y mutation in the HFE gene has led to population screening studies. Much of this work has also included the analysis of a second mutation, H63D, which appears to have a low penetrability. HFE protein was recently found to coprecipitate with the transferrin receptor and to affect the reaction between transferrin and the transferrin receptor. Functional data suggest that the mutation C282Y abolishes the association of the HFE protein with beta 2-microglobulin (beta 2M), making the complex unable to reach the cell surface. Clearly, if the mutation protein is unable to reach the cell surface, this regulatory feature is missing. The role of a second mutation in the HFE gene, H63D, is less clear. Current data suggest that this mutation protein can associate with beta 2-microglobulin and does reach the cell surface and that the defect lies in a failure to modify the affinity of the transferrin receptor for transferrin. This does not explain the low degree of penetrability associated with this mutation.
Gene Frequency ; HLA Antigens ; genetics ; Hemochromatosis ; genetics ; Hemochromatosis Protein ; Histocompatibility Antigens Class I ; genetics ; Humans ; Membrane Proteins ; Mutation

Hemochromatosis/genetics* ; Histocompatibility Antigens Class I/genetics* ; Humans ; Mutation ; Receptors, Transferrin/genetics*

Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.
Male ; Humans ; Female ; Hemochromatosis/therapy* ; Hemochromatosis Protein/genetics* ; Carcinoma, Hepatocellular/complications* ; Iron Overload/genetics* ; Ferritins ; Liver Cirrhosis/complications* ; Iron ; Fibrosis ; Liver Neoplasms/complications* ; Transferrins

Hemochromatosis ; etiology ; genetics ; Hepatolenticular Degeneration ; etiology ; genetics ; Humans ; Hyperbilirubinemia, Hereditary ; etiology

OBJECTIVETo describe the clinical features of a hereditary hemochromatosis pedigree and to explore preliminarily the genetic basis of this pedigree.

METHODSSurvey was carried out among the family members, including history taking, physical examination, laboratory examination (such as iron-biochemistry indexes, liver function, blood sugar), multiple-organs MRI scan, iron staining of liver biopsy tissues and making the pedigree chart. The blood samples of the pedigree were collected, the genomic DNA was extracted, the PCR amplification was made and finally the sequence analysis for several mutations of common hereditary hemochromatosis genes was done.

RESULTSIn this pedigree, 7 members were found with iron overload and clinically diagnosed as hereditary hemochromatosis. The features are transmitted from generation to generation without gender difference and the gene penetrance is about 46%. The common mutations of SLC40A1 and HFE were not found in the family members.

CONCLUSIONCutaneous pigmentation and iron overload in liver and spleen are the most typical characters in this hereditary hemochromatosis pedigree, which corresponds with autosomal dominant inheritance. However, the genetic basis of this pedigree is unknown yet.

Adult ; Aged ; Child ; Female ; Hemochromatosis ; diagnosis ; genetics ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree

Hereditary hemochromatosis (HFE), which affects 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals in Western population, results in multiple organ damage caused by iron deposition, and is treatable if detected early. C282Y mutation in HFE gene has been known to be responsible for the most hereditary hemochromatosis cases and 5-10% of white subjects are heterozygous for this mutation. However, the prevalence of hemochromatosis in the Asian population was reported to be very low and ethnic heterogeneity has been suspected. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutations in 502 unrelated Koreans. Results revealed that none of them had the mutant gene, suggesting a significant ethnic difference when compared with Caucasians. Our study excluded underlying possibility of hereditary hemochromatosis in Korean which could mimic the findings of alcoholic liver disease with iron overload or liver cirrhosis with chronic hepatitis C.
Alleles ; Caucasoid Race/genetics* ; DNA Primers ; Genetic Screening ; Genotype ; HLA Antigens/genetics ; Hemochromatosis/genetics* ; Hemochromatosis/ethnology* ; Histocompatibility Antigens Class I/genetics ; Human ; Korea/epidemiology ; Mongoloid Race/genetics* ; Point Mutation* ; Prevalence

Studies examining the association of hemochromatosis (HFE) gene polymorphisms and susceptibility to alcoholic liver disease (ALD) yielded inconsistent results. Thus, we performed a metaanalysis to investigate whether the variations in HFE gene increase the risk of ALD. The studies published up to Feb. 2014 were identified by searching PubMed/MEDLINE, ISI Web of Science, EMBASE and China National Knowledge Infrastructure databases, which was complemented by screening the references of the retrieved studies. For all genotypes and alleles, the odds ratios (ORs) with 95% confidence intervals (CIs) according to the heterogeneity were pooled using fixed-effect model. Sixteen studies with 1933 cases and 9874 controls were included for this meta-analysis. C282Y/C282Y, C282Y/wild type, H63D/wild type and C282Y/H63D were found not to be associated with susceptibility to ALD, but increased risk of H63D/H63D (OR: 1.52, 95% CI: 1.05-2.22, P=0.029) was observed for ALD when compared to total control. Comparison of ALD patients with alcoholics without liver damage revealed a significant association of D allele, as well as a marginal association of H63D/wild type with ALD, while H63D/H63D was not significantly associated with ALD although increased value of OR was obtained. The presence of Y allele and other genotypes yielded insignificant findings when ALD patients were compared with alcoholics without liver damage. No evident publication bias or significant heterogeneity among studies was detected in this meta-analysis. In conclusion, our metaanalysis showed a marginal higher prevalence of H63D variant in ALD but did not support an increased risk of C282Y mutation.
Alleles ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Hemochromatosis Protein ; genetics ; Humans ; Liver Diseases, Alcoholic ; genetics ; pathology ; Mutation ; Polymorphism, Single Nucleotide

OBJECTIVETo investigate the frequency of HFE gene variants in patients with hepatocellular carcinoma following chronic hepatitis B and to analyze their relationships.

METHODS56 patients with hepatocellular carcinoma following chronic hepatitis B (HCC group) and 60 healthy blood donors (control group) were studied for the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr = C282Y) of the HFE gene. The codon 63 and 282 dimorphisms were defined by PCR amplification of genomic DNA samples and restriction enzyme digestion using RsaI for C282Y and BclI for H63D. The association between hepatocellular carcinoma following chronic hepatitis B and HFE mutations were analyzed by Chi-square test.

RESULTSThe genotype frequency of C2/C2 in the HCC group was markedly higher than that in the normal control group (10.7% vs 0) and there was a significant correlation between them. At the same time, the allele frequency of C2 in the HCC group was markedly higher than that in the normal control group (16.1% vs 1.7%) and there was a significant correlation between them also.

CONCLUSIONThe mutation of C282Y may be related with susceptibility to HCC after chronic hepatitis B. This outcome suggests that host HFE mutation may be an important factor related to the pathogenesis of HCC.

Adult ; Aged ; Carcinoma, Hepatocellular ; complications ; genetics ; Female ; Hemochromatosis Protein ; Hepatitis B, Chronic ; complications ; genetics ; Histocompatibility Antigens Class I ; genetics ; Humans ; Liver Neoplasms ; complications ; genetics ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Mutation

OBJECTIVETo detect the incidence of the HFE gene C282Y and H63D mutations in patients with myelodysplastic syndromes (MDS) and aplastic anemia (AA), and analyze the relationship of these mutations with iron metabolism, and organs impairment from iron overload.

METHODSThe incidence of the C282Y and H63D mutations in 271 MDS, 402 AA patients and 1615 normal subjects was measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combining with DNA sequencing. Iron metabolism parameters and iron overload indices were retrospectively compared between HFE gene mutation and unmutation groups in MDS and AA patients with no transfusion history.

RESULTSNo C282Y and C282Y/H63D compound mutation was detected in all the three groups. The incidence of H63D heterozygous and homozygous genotype did not significantly differ between AA cases and controls (9.7% vs 10.2%, 0.25% vs 0.24% respectively, both P > 0.05). The frequency of H63D heterozygous genotype in MDS patients was significantly lower than that in controls (4.1% vs 10.2%, P = 0.002). H63D homozygous was not found in MDS patients. In both MDS and AA patients with no RBC transfusion history, serum ferritin (SF), transferrin saturation value (TS), serum iron concentration (SI) were close to or higher than normal; and unsaturated iron-binding capacity (UIBC) value was significantly lower. There was no significant difference in SF, SI, TS values between HFE-mutation and -unmutation MDS patients. For AA patients, only the level of SI was significantly higher in HFE-mutant group than in -unmutation group [42.6 (24.6-60.4) micromol/L vs 32.0 (8.4-63.3) micromol/L, P = 0.011]. There was no significant difference in the values of liver enzyme, fasting blood sugar (FBS), abnormal electrocardiogram (ECG), peripheral blood indices between HFE-mutation and -unmutation MDS and AA groups (all P > 0.05).

CONCLUSIONThe distribution of C282Y and H63D mutations has ethnic and genetic disparity, the frequency in Chinese population is lower than that in Caucasian. It seems that MDS and AA patients are susceptible to iron overload, in the diseases itself and the mutations of HFE gene are not the major factor for iron overload in the patients.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic ; complications ; genetics ; Case-Control Studies ; Child ; Child, Preschool ; China ; Female ; Genotype ; Hemochromatosis Protein ; Histocompatibility Antigens Class I ; genetics ; Humans ; Iron ; blood ; Iron Overload ; etiology ; genetics ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Mutation ; Myelodysplastic Syndromes ; complications ; genetics ; Young Adult

OBJECTIVETo investigate the hepatic expression of immunological markers relevant to a cytotoxic response in relation to viral genotype.

METHODSThe frozen liver biopsies were obtained from 28 HF genotyped patients and made the sections stained. The morphometry was used to analyze the major histocompatibility complex class I (MHC-I), CD8, beta(2)-microglobulin (beta(2) -mG), HFE and CD68 in the stained sections. Biopsy data of response to therapy with interferon were available in 18 cases.

RESULTSCD8+ was usually clustered together and localized in portal tracts and sinusoids, and seen to interact with MHC I positive lining cells. MHC-I and beta(2) -mG were expressed mainly in endothelial and Kupffer cells. HFE was expressed in most round and dendritic CD68+ cells. Patients with virus genotype 3a had higher hepatic MHC-I and HFE expression, and a better sustained response to interferon (IFN) therapy than patients without.

CONCLUSIONThe MHC-I expression in the liver of patient with chronic hepatitis C virus infection seems to relate to viral-genotype. The hepatic MHC-I and HFE expression are higher in patients with virus genotype 3a than that in patients with non-3a genotype.

Adult ; Antigens, CD ; metabolism ; Antigens, Differentiation, Myelomonocytic ; metabolism ; Antiviral Agents ; therapeutic use ; Blotting, Western ; CD8 Antigens ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Genotype ; Hemochromatosis Protein ; Hepacivirus ; drug effects ; genetics ; Hepatitis C, Chronic ; genetics ; metabolism ; virology ; Histocompatibility Antigens Class I ; genetics ; metabolism ; Humans ; Interferons ; therapeutic use ; Liver ; immunology ; metabolism ; virology ; Male ; Membrane Proteins ; genetics ; metabolism ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction