遗传性血色病基因突变与肝脏疾病相关性的研究进展
施文娟,甘肃省兰州电机有限责任公司医院肝病诊疗中心 甘肃省兰州市 730050
成军,北京地坛医院传染病研究所 北京市 100011
通讯作者:成军, 100011, 北京市东城区安外大街地坛公园13号, 北京地坛医院传染病研究所. cj@genetherapy.com.cn
电话: 010-64481639 传真: 010-64281540
收稿日期: 2005-01-10 接受日期: 2005-01-20
摘要遗传性血色病是一种是常见的先天性铁代谢异常性疾病.分子生物学研究表明，遗传性血色病主要与6号染色体上的一种基因，即HFE基因的突变有关.HFE基因的突变造成体内铁代谢路径的改变，造成肝脏等多器官的损害.近年来的研究表明，HFE基因的突变与病毒性肝炎、非酒精性脂肪性肝病(NAFLD)、肝纤维化/肝硬化、肝细胞癌(HCC)的发生发展密切相关，因而具有十分重要的意义.这提示体内铁代谢的异常，参与各种不同类型的肝脏疾病的发病过程，研究HFE基因的突变不仅有利于阐明遗传性血色病的发病机理，而且有助于其他类型肝脏疾病的防治研究.
, 百拇医药
施文娟, 成军. 遗传性血色病基因突变与肝脏疾病相关性的研究进展. 世界华人消化杂志 2005;13(9):1123-11261 Bacon BR, Powell LM, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis:at the
crossroads. Gastroenterology 1999;116:193-207
2 Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, Bacon BR, Sly WS. Immunohistochemistry
of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in
, 百拇医药
gastrointestinal tract. Proc Natl Acad Sci USA 1997;94:2534-2539
3 Cable EE, Connor JR, Isom HC. Accumulation of iron by primary rat hepatocytes in long-term culture:changes in
nuclear shape mediated by non-transferrin-bound forms of iron. Am J Pathol 1998;152:781-792
4 Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalconholic
, http://www.100md.com
steatosis syndromes. Semin Liver Dis 2001;21:17-26
5 Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN.
Nonalcoholic steatohepatitis:association of insulin resistance and mitochondrial abnormalities.
Gastroenterology 2001;120:1183-1192
6 Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease:predictors of nonalcoholicsteatohepatitis and
, 百拇医药
liver fibrosis in the severely obese. Gastroenterology 2001;121:91-100
7 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, LenziM, McCullough AJ, Natale S, Forlani G, Melchionda N.
Nonalcoholic fatty liver disease: a featureof the metabolic syndrome. Diabetes 2001;50:1844-1850
8 Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM,Fung C, Karim R, Lin R, Samarasinghe D, Liddle C,Weltman M, George J. NASH and insulinresistance:insulin hypersecretion and specific association with theinsulin
, 百拇医药
resistance syndrome. Hepatology 2002;35:373-379
9 Turlin B, Mendler MN, Moirand R, Guyader D, Guillygomarc'hA, Deugnier Y. Histologic features of the liver in insulin
resistance associated iron overload. Astudy of 139 patients. Am J Clin Pathol 2001;116:263-270
10 Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D,Fociani P, Taioli E, Valenti L, Fiorelli G. Hyperferritine
, http://www.100md.com
iron overload, and multiple metabolicalterations identify patients at risk for nonalcoholic steatohepatitis.
Am J Gastroenterol 2001;96:2448-2455
11 Washington K, Wright K, Shyr Y, Hunter EB, Olson S, Raiford DS.Hepatic stellate cell activation in nonalcoholic
steatohepatitis and fatty liver. HumPathol 2000;31:822-828
12 Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P,Musso A, De Paolis P, Capussotti L, Salizzoni M,Rizzetto M. Expanding natural historyof nonalcoholic steatohepatitis:from cryptogenic cirrhosis tohepatocellular
, http://www.100md.com
carcinoma. Gastroenterology 2002;123:134-140
13 Dimitrijevic J, Bojanic N, Skaro-Milic A, Mijuskovic P, Ilic S,Nozic D. Morphologic characteristics of HBV markers and
products of iron metabolism in livertissue in patients with hepatitis B virus. Vojnosanit Pregl 2002;49:477-483
14 Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, LecisE, Burra P, Floreani A, Cecchetto A, Naccarato R. Iron
, http://www.100md.com
storage, lipid peroxidation andglutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995;22:449-456
15 Cozzolongo R, Cuppone R, Manghisi OG. The treatment of chronichepatitis C not responding to interferon.
Curr Pharm Des 2002;8:967-975
16 Boucher E, Bourienne A, Adams P, Turlin B, Brissot P, Deugnier Y.Liver iron concentration and distribution in chronic
, http://www.100md.com
hepatitis C before and afterinterferon treatment. Gut 1997;41:115-120
17 Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygenlevels modulate iron-regulatory protein activities
in vivo. Science 2004;306:2087-2090
18 Olynyk JK, Reddy KR, Di-Bisceglie AM, Jeffers LJ, Parker TI, RadickJL, Schiff ER, Bacon BR. Hepatic iron concentration
as a predictor of response tointerferon alfa therapy in chronic hepatitis C. Gastroenterology 2001;108:1104-1109
, 百拇医药
19 Griffiths A, Olynyk JK. Iron and the response to treatment ofhepatitis C. Am J Gastroenterol 2002;97:788-790
20 Kochman F, Ducrocq F, Parquet PJ. Cyclic oro-alimentary disorders. RevPrat 1997;47:1913-1916
21 Cauza E, Peck-Radosavljevic M, Ulrich-Pur H, Datz C, Gschwantler M,Schoniger-Hekele M, Hackl F, Polli C,Rasoul-Rockenschaub S, Muller C, WrbaF, Gangl A, Ferenci P. Mutations of the HFE gene in patients withhepatocellular
, http://www.100md.com
carcinoma. Am J Gastroenterol 2003;98:442-447
22 池肇春. 遗传性血色病性肝硬化近展. 临床肝胆病杂志 2000;16:81-83
23 Blanc JF, De Ledinghen V, Bernard PH, de Verneuil H, Winnock M, Le Bail B, Carles J, Saric J, Balabaud C,Bioulac-Sage P. Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular
carcinoma developed in non-cirrhotic liver. J Hepatol 2000;32:805-811
, 百拇医药
24 Lauret E, Rodriguez M, Gonzalez S, Linares A, Lopez-Vazquez A, Martinez-Borra J, Rodrigo L, Lopez-Larrea C. HFE
gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma.
Am J Gastroenterol 2002;97:1016-1021
25 Willis G, Wimperis JZ, Lonsdale R, Fellows IW, Watson MA, Skipper LM, Jennings BA. Incidence of liver disease in
people with HFE mutations. Gut 2000;46:401-404
26 Racchi O, Mangerini R, Rapezzi D, Gaetani GF, Nobile MT, Picciotto A, Ferraris AM. Mutations of the HFE gene and
the risk of hepatocellular carcinoma. Blood Cells Mol Dis 1999;25:350-353
编辑 张海宁, 百拇医药( 施文娟,成 军)
成军,北京地坛医院传染病研究所 北京市 100011
通讯作者:成军, 100011, 北京市东城区安外大街地坛公园13号, 北京地坛医院传染病研究所. cj@genetherapy.com.cn
电话: 010-64481639 传真: 010-64281540
收稿日期: 2005-01-10 接受日期: 2005-01-20
摘要遗传性血色病是一种是常见的先天性铁代谢异常性疾病.分子生物学研究表明，遗传性血色病主要与6号染色体上的一种基因，即HFE基因的突变有关.HFE基因的突变造成体内铁代谢路径的改变，造成肝脏等多器官的损害.近年来的研究表明，HFE基因的突变与病毒性肝炎、非酒精性脂肪性肝病(NAFLD)、肝纤维化/肝硬化、肝细胞癌(HCC)的发生发展密切相关，因而具有十分重要的意义.这提示体内铁代谢的异常，参与各种不同类型的肝脏疾病的发病过程，研究HFE基因的突变不仅有利于阐明遗传性血色病的发病机理，而且有助于其他类型肝脏疾病的防治研究.
, 百拇医药
施文娟, 成军. 遗传性血色病基因突变与肝脏疾病相关性的研究进展. 世界华人消化杂志 2005;13(9):1123-11261 Bacon BR, Powell LM, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis:at the
crossroads. Gastroenterology 1999;116:193-207
2 Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, Bacon BR, Sly WS. Immunohistochemistry
of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in
, 百拇医药
gastrointestinal tract. Proc Natl Acad Sci USA 1997;94:2534-2539
3 Cable EE, Connor JR, Isom HC. Accumulation of iron by primary rat hepatocytes in long-term culture:changes in
nuclear shape mediated by non-transferrin-bound forms of iron. Am J Pathol 1998;152:781-792
4 Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalconholic
, http://www.100md.com
steatosis syndromes. Semin Liver Dis 2001;21:17-26
5 Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN.
Nonalcoholic steatohepatitis:association of insulin resistance and mitochondrial abnormalities.
Gastroenterology 2001;120:1183-1192
6 Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease:predictors of nonalcoholicsteatohepatitis and
, 百拇医药
liver fibrosis in the severely obese. Gastroenterology 2001;121:91-100
7 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, LenziM, McCullough AJ, Natale S, Forlani G, Melchionda N.
Nonalcoholic fatty liver disease: a featureof the metabolic syndrome. Diabetes 2001;50:1844-1850
8 Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM,Fung C, Karim R, Lin R, Samarasinghe D, Liddle C,Weltman M, George J. NASH and insulinresistance:insulin hypersecretion and specific association with theinsulin
, 百拇医药
resistance syndrome. Hepatology 2002;35:373-379
9 Turlin B, Mendler MN, Moirand R, Guyader D, Guillygomarc'hA, Deugnier Y. Histologic features of the liver in insulin
resistance associated iron overload. Astudy of 139 patients. Am J Clin Pathol 2001;116:263-270
10 Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D,Fociani P, Taioli E, Valenti L, Fiorelli G. Hyperferritine
, http://www.100md.com
iron overload, and multiple metabolicalterations identify patients at risk for nonalcoholic steatohepatitis.
Am J Gastroenterol 2001;96:2448-2455
11 Washington K, Wright K, Shyr Y, Hunter EB, Olson S, Raiford DS.Hepatic stellate cell activation in nonalcoholic
steatohepatitis and fatty liver. HumPathol 2000;31:822-828
12 Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P,Musso A, De Paolis P, Capussotti L, Salizzoni M,Rizzetto M. Expanding natural historyof nonalcoholic steatohepatitis:from cryptogenic cirrhosis tohepatocellular
, http://www.100md.com
carcinoma. Gastroenterology 2002;123:134-140
13 Dimitrijevic J, Bojanic N, Skaro-Milic A, Mijuskovic P, Ilic S,Nozic D. Morphologic characteristics of HBV markers and
products of iron metabolism in livertissue in patients with hepatitis B virus. Vojnosanit Pregl 2002;49:477-483
14 Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, LecisE, Burra P, Floreani A, Cecchetto A, Naccarato R. Iron
, http://www.100md.com
storage, lipid peroxidation andglutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995;22:449-456
15 Cozzolongo R, Cuppone R, Manghisi OG. The treatment of chronichepatitis C not responding to interferon.
Curr Pharm Des 2002;8:967-975
16 Boucher E, Bourienne A, Adams P, Turlin B, Brissot P, Deugnier Y.Liver iron concentration and distribution in chronic
, http://www.100md.com
hepatitis C before and afterinterferon treatment. Gut 1997;41:115-120
17 Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygenlevels modulate iron-regulatory protein activities
in vivo. Science 2004;306:2087-2090
18 Olynyk JK, Reddy KR, Di-Bisceglie AM, Jeffers LJ, Parker TI, RadickJL, Schiff ER, Bacon BR. Hepatic iron concentration
as a predictor of response tointerferon alfa therapy in chronic hepatitis C. Gastroenterology 2001;108:1104-1109
, 百拇医药
19 Griffiths A, Olynyk JK. Iron and the response to treatment ofhepatitis C. Am J Gastroenterol 2002;97:788-790
20 Kochman F, Ducrocq F, Parquet PJ. Cyclic oro-alimentary disorders. RevPrat 1997;47:1913-1916
21 Cauza E, Peck-Radosavljevic M, Ulrich-Pur H, Datz C, Gschwantler M,Schoniger-Hekele M, Hackl F, Polli C,Rasoul-Rockenschaub S, Muller C, WrbaF, Gangl A, Ferenci P. Mutations of the HFE gene in patients withhepatocellular
, http://www.100md.com
carcinoma. Am J Gastroenterol 2003;98:442-447
22 池肇春. 遗传性血色病性肝硬化近展. 临床肝胆病杂志 2000;16:81-83
23 Blanc JF, De Ledinghen V, Bernard PH, de Verneuil H, Winnock M, Le Bail B, Carles J, Saric J, Balabaud C,Bioulac-Sage P. Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular
carcinoma developed in non-cirrhotic liver. J Hepatol 2000;32:805-811
, 百拇医药
24 Lauret E, Rodriguez M, Gonzalez S, Linares A, Lopez-Vazquez A, Martinez-Borra J, Rodrigo L, Lopez-Larrea C. HFE
gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma.
Am J Gastroenterol 2002;97:1016-1021
25 Willis G, Wimperis JZ, Lonsdale R, Fellows IW, Watson MA, Skipper LM, Jennings BA. Incidence of liver disease in
people with HFE mutations. Gut 2000;46:401-404
26 Racchi O, Mangerini R, Rapezzi D, Gaetani GF, Nobile MT, Picciotto A, Ferraris AM. Mutations of the HFE gene and
the risk of hepatocellular carcinoma. Blood Cells Mol Dis 1999;25:350-353
编辑 张海宁, 百拇医药( 施文娟,成 军)
参见：首页 > 医疗版 > 疾病专题 > 消化内科 > 血色病