Gonca TATAR, Gökhan GEDİKOĞLU, Yasemin H. BALABAN, Hale GÖKCAN, Halis ŞİMŞEK, Gülsen HASÇELİK, Engin YILMAZ

Iron Overload and Insulin Resistance in a Sample of Turkish Patients with Non-Alcoholic Steatohepatitis

Amaç: Bu çalışmada alkole bağlı olmayan steatohepatit (NASH) tanısı olan hastalarda H63D mutasyonunun demiryüklenmesi ve karaciğer hasarı üzerindeki etkisi; insülin direnci ve metabolik sendrom ile ilişkisi araştırıldı.Yöntem ve Gereçler: Hacettepe Üniversitesi, Gastroenteroloji polikliniğinde klinik ve laboratuar olarak NASH tanısıalan 32 hasta çalışmaya alındı. Hastalar metabolik sendrom açısından sorgulandı. Bel kalça oranı ve vücut kitleindeksleri hesaplandı. H63D gen mutasyonu, serum ve karaciğer dokusunda demir parametreleri ve boyanması;karaciğer histopatolojik özellikleri incelendi. İnsülin direnci ve metabolik sendrom ile ilişkili olarak açlık ve tokluk kanşekeri, lipid profili, 75-gr oral glukoz tolerans testi ve HOMA insulin direnci hesaplaması yapıldı.Sonuç: Ortalama vücut--kitle indeksi (VKİ) 28,1i33 kg/m2 olan 32 hasta çalışmaya alındı. Hipertansiyon (%25), obezite(%37), hiperkolesterolemi (%56), hipertrigliseridemi (%28) ve insülin direnci (%39) oldukça sıktı. İki hasta hariç tümhastaların ferritin ve transferrin saturasyonu normaldi. Hastaların %41'inde HIC 1600 ug/g'ın üzerinde saptandı.H63D mutasyonu 12 (%40) hastada heterezigot, (%3) hastada ise homozigot saptandı. NASH hastalarında H63Dalel frekansı %23,4 idi (%3,3 homozigot, %20 heterozigot). H63D mutasyonu olan hastalarda serum ve doku demirbelirteçleri normal idi. H63D mutasyonu ile histopatolojik bulgular arasında ilişki saptanmadı. 2. saat kan şekeriölçümü evre fibrozisi olan hastalarda evre olan hastalara göre, sınıf hastalarında sınıf s3 olan hastalara göreistatistiksel olarak yüksek saptandı.Sonuç: H63D mutasyonunun serum demir belirteçlerine veya histopatolojiye etkisi saptanmadı. Bununla birliktenon--alkolik steatohepatit hastalarında insülin direnci fibrosis ile iliskili bulundu.

Türk Toplumu Örnekleminde Alkole Bağlı Olmayan Steatohepatit Hastalığının Demir Yüklenmesi ve İnsülin Direnci ile İlişkisi

Aim: We investigated the role ofthe H63D mutation on the development of hepatic iron overload and hepatic injuryin non-alcoholic Steatohepatitis patients and its association with insulin resistance and metabolic alterations.Material and Methods: Thirty-two patients with NASH, who were diagnosed at Hacettepe UniversityGastroenterology Outpatient Clinic depending on clinic and laboratory findings, were included into study.Metabolic syndrome was sought. Waist hip ratio and body mass index were calculated. H63D gene mutation, ironlevel at serum and liver biopsy specimens and histopathologic exam on liver biopsy specimens were studied instudy group. Fasting and post-prandial blood sugar, lipid profile, 75-gr-glucose tolerance test and HOMA insulinresistance were measured to document the insulin resistance and metabolic syndrome.Results: Thirty-two patients with mean body mass index was 28.1 kg/m2i3,3 were included in study. Hypertension,obesity, hypercholesterolemia, hypertriglyceridemia, insulin resistance were found at 25 %, 37 %, 56 %, 28 and 39%, respectively. Serum ferritin and transferrin saturation values were within normal limits in all but except patients.Hepatic iron concentration was 1600ug in 12 (41%) of patients. H63D mutation was homozygote in (3%) andheterozygote 12 (40%) patients. Therefore the H63D allele frequencies were 3.3% for homozygous, 20% forheterozygous and as total 23.4%. The patients with H63D mutation had normal serum and tissue iron parameters.There was no statistically significant relationship between H63D mutation and histopathological findings. Two hourblood sugar levels were higher in Stage patients than in Stage patients (p=0.05), and also higher in Classpatients than in Class S3 patients (p=0.05).Conclusion: The H63D mutation did not affected either serum iron parameters or histopathology. However, theinsulin resistance was related with fibrosis in non-alcoholic steatohepatitis patients.

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1. Santos L, Molina EG, Jeffers L. Prevalence of nonalcoholic steatohepatitis among ethnic groups. Gastroenterology 2001;120 Suppl 1:630.
2. Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995;40:2002-2009.
3. Baldridge A, Perez-Atayde A, GraemeCook F, et al. Idiopathic steatohepatitis in childhood: A multicenter retrospective study. J Pediatr 1995;127:700-704.
4. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of fortytwo patients for up to 21 years. Hepatology 1990;11:74-80.
5. Kumar KS, Malet PF. Nonalcoholic Steatohepatitis. Mayo Clin Proc 2000;75:733-739.
6. Bacon BR, Farahvash MJ, Janney CG, et al. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103-1109.
7. Sreppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312.
8. Marchesini G, Brizi M, Morselli-Labate AM, et al.. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450-455.
9. Ikai E, Ishizaki M, Suzuki Y, et al. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens 1995;9:101-105.
10. Neri S, Pulvirenti D, Santo S, et al. The HFE gene heterozygosis H63D: a cofactor for liver damage in patients with steatohepatitis? Epidemiological and clinical considerations. Intern Med J 2008;38(4):254-258.
11. Bugianesi E, Manzini P, D'Antico S, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance tofibrosis in nonalcoholic fatty liver. Hepatology 2004;39:179-187.
12. Younossi ZM, Gramlich T, Bacon BR, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 1999;30:847-850.
13. úimûek H, Sümer H, YÖlmaz E, et al. Frequency of HFE Mutations among Turkish Blood Donors According To Transferrin Saturation. Genotype screening for hereditary hemochromatosis among voluntary blood donors in Turkey. J Clin Gastroenterol 2004;38:671-675.
14. Simsek H, Balaban YH, Yilmaz E, et al. Mutations of the HFE gene among Turkish hereditary hemochromatosis patients. Ann Hematol 2005;84:646-649.
15. Simsek H, Balaban YH, Sümer H, et al. HFE mutations analysis of Turkish patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2006 ;51:1723-1724.
16. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications--Part 1: Diagnosis and classification of diabetes mellitus. Geneva: World Health Organiza tion; 1999:20-21.
17. Haffner MS, Miettinen H, Stern MP. The homeostasis model in the san Antonio Heart Study. Diabetes Care 1997;20:1087- 1092.
18. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.Hepatology. 2003 Apr;37(4):917-23.
19. Brunt EM, Janney CG, Di Bisceglie AM, et al. Non-alcoholic steatohepatitis: a proposal for grading and staging the histologic lesions. Am J Gastroenterol 1999;94:2467- 74.
20. Roderick R.M., MacSween R.N.M., Antony P.P., Scheuer P.J., editors. Pathology of the liver. 2 nd ed..Edinburgh: Churcill Livingstone; 1987.p.185.
21. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology1986; 6:24.
22. Bacon BR, Britton RS. Hemochromatosis. Sleisenger and Fordtran's Gastrointestinal and Liver Disease (Ed. M.H. Sleisenger, B.F. Scharschmidt ve M Feldman)8th Edition W.B. Saunders Company Press, USA, 2006;1589-1599.
23. Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002;35:367-372.
24. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373-379.
25. Kral JG, Schaffner F, Pierson RN Jr, et al Body fat topography as an independent predictor of fatty liver. Metabolism 1993;42:548-551.
26. Angulo P, Keech JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-1362.
27. Barut G, Balci H, Bozdayi M, ve ark. Screening for iron overload in the Turkish population. Dig Dis 2003; 21:279-285.
28. Yönal Ö, HatÖrnaz O, Akyüz F, ve ark. HFE gene mutation, chronic liver disease, and iron overload In Turkey. Dig Dis Sci 2007;52:3298-3302.
29. George DK, Goldwurm S, Macdonald GA, et al. Increased hepatic iron stores on non alcoholic steatohepatitis are associated with the hemochromatosis mutation and increased liver damage. Gastroenterology 1998;114:311-318.
30. Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Nonalcoholic steatohepatitis and iron: increased prevalanceof mutations of the HFE gene in nonalcoholic steatohepatitis. J Hepatol 1999;31:421-429.
31. Duseja A, Das R, Nanda M, et al. Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations. World J Gastroenterol 2005;21;11:393-395.
32. Chitturi S, Weltman M, Farrell GC, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002;36:142-149.
33. Zamin I Jr, Mattos AA, Mattos AZ, et al. Prevalence of the hemochromatosis gene mutation in patients with nonalcoholic steatohepatitis and correlation with degree of liver fibrosis.Arq Gastroenterol 2006;43:224-228.
34. Lee SH, Jeong SH, Lee D, et al. An epidemiologic study on the incidence and significance of HFE mutations in a Korean cohort with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2010;44:154-161.
35. Herneaz R, Yeung E, Clark JM, et al. Hemochromatosis gene and nonalcoholic fatty liver disease: a systematic rewiew and meta-analysis. J.Hepatol 2011;55: 1079- 1085.
36. Sanyal AJ, MBBS. Nonalcoholic steatohepatitis. Clinical perspectives in Gastroenterology 2000;129-139.
37. Moirand R, Mendler MH, Guillygomarc'h A.,et al. Non-alcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload? J Hepatol 2000;33:1024-1026.
38. Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation and liver fibrosis in patients with nonalcoholic fatty liver disesase. Gastroenterology. 2010;138:905-912