AIM:To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D,and S65C) in patients with chronic liver disorders (CLD) and controls. METHODS:To identify patients with iron ov...AIM:To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D,and S65C) in patients with chronic liver disorders (CLD) and controls. METHODS:To identify patients with iron overload (transferrin saturation > 45% in females and > 50% in males and serum ferritin > 1000 ng/mL) we evaluated 236 patients with CLD,including 59 with non-alcoholic steatohepatitis (NASH),22 with alcoholic liver disease (ALD),19 of cirrhosis due to viruses (HBV,HCV),and 136 with cryptogenic cirrhosis. Mutations of the HFE gene were analyzed by PCR-RE. hundred controls were screened for iron status and the mutations. RESULTS:Seventeen patients with CLD showed evidence of iron overload. Fifteen cases of iron overload had cryptogenic cirrhosis and two had ALD. None of the controls showed iron overload. We did not find any individual with 282Y or 65C either in the cases or in the controls. The prevalence of H63D heterozygosity was 12% in normal individuals,14.8% in 236 patients (16.9% in NASH,13.6% in ALD,26.3% in viral and 12.5% in cryptogenic cirrhosis) and the overall prevalence was 13.98%. Only two of the 17 patients with primary iron overload were heterozygous for H63D. One patient with NASH and one normal individual who were homozygous for H63D showed no iron overload.CONCLUSION:Primary iron overload in Indians is nonHFE type,which is different from that in Europeans and further molecular studies are required to determine the defect in various iron regulatory genes.展开更多
MM： To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS： One hundred and fifty-three heavy drinkers （defined as alcohol co...MM： To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS： One hundred and fifty-three heavy drinkers （defined as alcohol consumption 〉 80 g/d for at least 5 years） were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics （LDA）] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics （NLDA）], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS： Gender ratio was similar in both study groups. LDA patients were older than NLDA patients （52 ± 10 years vs 48 ± 11 years, P = 0.03）. One third and one fifth of the study population had serum transferrin saturation （TS） greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS （51 ± 27 vs 36 ± 13, P 〈 0.001） and ferritin levels （559 ± 607 ng/mL vs 159 ± 122 ng/mL, P 〈 0.001）, and lower total iron binding capacity （TIBC） （241 ± 88 μg/dL vs 279 ± 40 μg/dL, P = 0.001）. The odds ratio for having liver disease with TS greater than 45% was 2.20 （95% confidence interval （CI）： 1.37-3.54）. There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients （0.25 vs 0.16, P = 0.03）. LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients （49.5% vs 31.6%, P = 0.02）. The odds ratio for LDA in patients with H63D mutation was 1.57 （95% CI： 1.02-2.40）. CONCLUSION： The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease, in parallel with an increased frequency of H63D HFE mutation.展开更多
To study the clinical correlates of the H63D mu-tation we have analysed the phenotype of H63D homozygotes identified through mutation analysis in a referral laboratory. A total of 366 blood samples referred for lIFE a...To study the clinical correlates of the H63D mu-tation we have analysed the phenotype of H63D homozygotes identified through mutation analysis in a referral laboratory. A total of 366 blood samples referred for lIFE analysis were screened for C282Y and H63D mutations. Four H63D homozygotes were identified. All had raised serum ferritin but normal transferrin saturation. They were negative for hepatitis B and C and only one patient consumed excess alcohol. In all 4 cases ultrasonography revealed fatty liver. In two patients a liver biopsy was done and showed mild siderosis with an unusual distribution and macrovesicular steatosis. These data confirm the association between fatty liver, hyperferritinaemia and increased hepatic iron, but do not clarify whether siderosis was related to steatosis rather than homozygosity for the H63D mutation. Patients with fatty liver may complicate the interpretation of data in population studies of the expression of H63D homozygosity.展开更多
To determine whether the H63D and C282Y mutations in HFE (hemochromatosis) gene are associated with the risk of gestational diabetes mellitus (GDM), we conducted the study of 65 incident cases. The class of gestationa...To determine whether the H63D and C282Y mutations in HFE (hemochromatosis) gene are associated with the risk of gestational diabetes mellitus (GDM), we conducted the study of 65 incident cases. The class of gestational diabetes (A1, A2, B) in pregnant women was defined based on the results of glycemic profile and 75-g oral glucose tolerance test. Two single nucleotide polymorphisms (H63D and C282Y) in HFE gene were genotyped by PCR and RFLP (Restriction Fragment Length Polymorphism). The frequencies of mutations in patients cohort were: 0.14 for H63D and 0.02 for C282Y, which are similar to the data reported for Belarusian population (0.16 and 0.04 respectively). The detailed analysis of case subjects indicated association of H63D mutation with the severity of gestational diabetes mellitus. In the frequencies of H63D mutation and genotypes between the case subjects with A1 and B gestational diabetes were detected significant differences. Our data indicated that the presence of H63D mutation in pregnant women with GDM aggravates the disease—odds ratio 7.4 (95% CI 1.8 - 30.5). Women with gestational diabetes have severe increased risk for illness progressing to class B if they are H63D mutation carriers.展开更多
Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.E...Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.展开更多
基金a grant from the Department of Biotechnology, India
文摘AIM:To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D,and S65C) in patients with chronic liver disorders (CLD) and controls. METHODS:To identify patients with iron overload (transferrin saturation > 45% in females and > 50% in males and serum ferritin > 1000 ng/mL) we evaluated 236 patients with CLD,including 59 with non-alcoholic steatohepatitis (NASH),22 with alcoholic liver disease (ALD),19 of cirrhosis due to viruses (HBV,HCV),and 136 with cryptogenic cirrhosis. Mutations of the HFE gene were analyzed by PCR-RE. hundred controls were screened for iron status and the mutations. RESULTS:Seventeen patients with CLD showed evidence of iron overload. Fifteen cases of iron overload had cryptogenic cirrhosis and two had ALD. None of the controls showed iron overload. We did not find any individual with 282Y or 65C either in the cases or in the controls. The prevalence of H63D heterozygosity was 12% in normal individuals,14.8% in 236 patients (16.9% in NASH,13.6% in ALD,26.3% in viral and 12.5% in cryptogenic cirrhosis) and the overall prevalence was 13.98%. Only two of the 17 patients with primary iron overload were heterozygous for H63D. One patient with NASH and one normal individual who were homozygous for H63D showed no iron overload.CONCLUSION:Primary iron overload in Indians is nonHFE type,which is different from that in Europeans and further molecular studies are required to determine the defect in various iron regulatory genes.
文摘MM： To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS： One hundred and fifty-three heavy drinkers （defined as alcohol consumption 〉 80 g/d for at least 5 years） were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics （LDA）] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics （NLDA）], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS： Gender ratio was similar in both study groups. LDA patients were older than NLDA patients （52 ± 10 years vs 48 ± 11 years, P = 0.03）. One third and one fifth of the study population had serum transferrin saturation （TS） greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS （51 ± 27 vs 36 ± 13, P 〈 0.001） and ferritin levels （559 ± 607 ng/mL vs 159 ± 122 ng/mL, P 〈 0.001）, and lower total iron binding capacity （TIBC） （241 ± 88 μg/dL vs 279 ± 40 μg/dL, P = 0.001）. The odds ratio for having liver disease with TS greater than 45% was 2.20 （95% confidence interval （CI）： 1.37-3.54）. There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients （0.25 vs 0.16, P = 0.03）. LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients （49.5% vs 31.6%, P = 0.02）. The odds ratio for LDA in patients with H63D mutation was 1.57 （95% CI： 1.02-2.40）. CONCLUSION： The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease, in parallel with an increased frequency of H63D HFE mutation.
基金Supported by the European Commission Fifth Framework Programme Grant No. QLK6-CT-1999-02237. GS was supported by a Clinical Fellowship from the European Commission (Leonardo da Vinci Grant I/99/2/09209/PL/II. 1.2.a/FPI)
文摘To study the clinical correlates of the H63D mu-tation we have analysed the phenotype of H63D homozygotes identified through mutation analysis in a referral laboratory. A total of 366 blood samples referred for lIFE analysis were screened for C282Y and H63D mutations. Four H63D homozygotes were identified. All had raised serum ferritin but normal transferrin saturation. They were negative for hepatitis B and C and only one patient consumed excess alcohol. In all 4 cases ultrasonography revealed fatty liver. In two patients a liver biopsy was done and showed mild siderosis with an unusual distribution and macrovesicular steatosis. These data confirm the association between fatty liver, hyperferritinaemia and increased hepatic iron, but do not clarify whether siderosis was related to steatosis rather than homozygosity for the H63D mutation. Patients with fatty liver may complicate the interpretation of data in population studies of the expression of H63D homozygosity.
文摘To determine whether the H63D and C282Y mutations in HFE (hemochromatosis) gene are associated with the risk of gestational diabetes mellitus (GDM), we conducted the study of 65 incident cases. The class of gestational diabetes (A1, A2, B) in pregnant women was defined based on the results of glycemic profile and 75-g oral glucose tolerance test. Two single nucleotide polymorphisms (H63D and C282Y) in HFE gene were genotyped by PCR and RFLP (Restriction Fragment Length Polymorphism). The frequencies of mutations in patients cohort were: 0.14 for H63D and 0.02 for C282Y, which are similar to the data reported for Belarusian population (0.16 and 0.04 respectively). The detailed analysis of case subjects indicated association of H63D mutation with the severity of gestational diabetes mellitus. In the frequencies of H63D mutation and genotypes between the case subjects with A1 and B gestational diabetes were detected significant differences. Our data indicated that the presence of H63D mutation in pregnant women with GDM aggravates the disease—odds ratio 7.4 (95% CI 1.8 - 30.5). Women with gestational diabetes have severe increased risk for illness progressing to class B if they are H63D mutation carriers.
文摘Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.
