1 Brazilian Journal of Medical and Biological Research 2003 Vol: 36(6):. DOI: 10.1590/S0100-879X2003000600009

Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

The hypothesis of the role of iron overload associated with HFE gene mutations in the pathogenesis of nonalcoholic steatohepatitis (NASH) has been raised in recent years. In the present study, biochemical and histopathological evidence of iron overload and HFE mutations was investigated in NASH patients. Thirty-two NASH patients, 19 females (59%), average 49.2 years, 72% Caucasians, 12% Mulattoes and 12% Asians, were submitted to serum aminotransferase and iron profile determinations. Liver biopsies were analyzed for necroinflammatory activity, architectural damage and iron deposition. In 31 of the patients, C282Y and H63D mutations were tested by PCR-RFLP. Alanine aminotransferase levels were increased in 30 patients, 2.42 ± 1.12 times the upper normal limit on average. Serum iron concentration, transferrin saturation and ferritin averages were 99.4 ± 31.3 g/dl, 33.1 ± 12.7% and 219.8 ± 163.8 µg/dl, respectively, corresponding to normal values in 93.5, 68.7 and 78.1% of the patients. Hepatic siderosis was observed in three patients and was not associated with architectural damage (P = 0.53) or with necroinflammatory activity (P = 0.27). The allelic frequencies (N = 31) found were 1.6 and 14.1% for C282Y and H63D, respectively, which were compatible with those described for the local population. In conclusion, no evidence of an association of hepatic iron overload and HFE mutations with NASH was found. Brazilian NASH patients comprise a heterogeneous group with many associated conditions such as hyperinsulinism, environmental hepatotoxin exposure and drugs, but not hepatic iron overload, and their disease susceptibility could be related to genetic and environmental features other than HFE mutations.

  1. Ludwig J, Viggiano TR, McGill DB & Ott BJ. Nonalcoholic steatohepatitis. Mayo Clinic Experiences with a hitherto unnamed disease. Mayo Clinic Proceedings 55, 434-438 (1980) .
  2. James OF & Day CP. Nonalcoholic steatohepatitis (NASH): a disease of emerging identity and importance. Journal of Hepatology 29, 495-501 (1998) .
  3. Itoh S, Yougel T & Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. American Journal of Gastroenterology 82, 650-654 (1987) .
  4. Diehl AM, Goodman Z & Ishak KG. Alcohol-like disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology 95, 1056-1062 (1988) .
  5. Powell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW & Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 11, 74-80 (1990) .
  6. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Human Pathology 20, 594-598 (1989) .
  7. Bacon BR, Farakvash MJ, Janney CG & Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107, 1103-1109 (1994) .
  8. Lonardo A, Bellini M, Tondelli E, Frazzoni M, Grisendi A, Pulvirenti M & Della-Casa G. Nonoalcoholic steatohepatitis and the "bright liver syndrome": should a recently expanded clinical entity be further expanded? (Letter). American Journal of Gastroenterology 90, 2072-2074 (1995) .
  9. Propst A, Propst T, Judmaier G & Vogel W. Prognosis in nonalcoholic steatohepatitis. Gastroenterology1607 108, (1995) .
  10. James O & Day C. Nonalcoholic steatohepatitis: another disease of affluence. Lancet 353, 1634-1636 (1999) .
  11. Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 13, 399-408 (1996) .
  12. Adams PC. Population screening for hemochromatosis. Hepatology 29, 1324-1327 (1999) .
  13. Gochee PA, Powell LW, Cullen DJ, Sart DD, Rossi E & Olynyk JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 122, 646-651 (2002) .
  14. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC & Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114, 311-318 (1998) .
  15. Bonkovsky HL, Jawaid Q, Tortorelli K, Leclair P, Cobb J, Lambrecht RW & Banner BF. Nonalcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in nonalcoholic steatohepatitis. Journal of Hepatology 31, 421-429 (1999) .
  16. Bonkovsky HL, Zivny J, Tortorelli K, Liu Q & Lambrecht RW. Nonalcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload? (Letter). Journal of Hepatology 33, 1025-1026 (2000) .
  17. Datz C, Lalloz MRA, Vogel W et al. Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis. Journal of Hepatology 27, 773-779 (1997) .
  18. Mendler M, Turlin B, Moirand R, Jouanolle A, Sapey T, Guyader D, Le Gall J, Brissot P, David V & Deugnier Y. Insulin resistance-associated hepatic iron overload. Gastroenterology 117, 1155-1163 (1999) .
  19. Agostinho MF, Arruda VR, Basseres DS, Bordin S, Soares MCP, Menezes RC, Costa FF & Saad STO. Mutation analysis of the HFE gene in Brazilian populations. Blood Cells, Molecules, and Diseases 25, 324-327 (1999) .
  20. Guillygomarc'h A, Mendler MH, Moirand R, Jouanolle AM, David V & Deugnier Y. HFE mutations in insulin resistance-associated hepatic iron overload (Letter). Journal of Hepatology 33, 515-516 (2000) .
  21. Moirand R, Mendler MH, Guillygomarc'h A, Brissot P & Deugnier Y. Nonalcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload? (Letter). Journal of Hepatology 33, 1024-1026 (2000) .
  22. Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O'Neill RO & McCullough AJ. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 30, 847-850 (1999) .
  23. Alves-Silva J,da Silva-Santos M,Guimarães PE, Ferreira AC, Bandelt HJ, Pena SD & Prado VF. TheancestryofBrazilianmtDNAlineages.American Journal of Human Genetics 67, 444-461 (2000) .
  24. Lumeng L & Crabb DW. Genetic aspects and risk factors in alcoholism and alcoholic liver disease. Gastroenterology 107, 572-578 (1994) .
  25. Franco LJ. Diabetes in Japanese-Brazilians - influence of the acculturation process. Diabetes Research and Clinical Practice, 34 (Suppl): S51-S57 , (1996) .
  26. Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, Inuzuka S, Sata M & Tanikawa K. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. Journal of Hepatology 27, 103-107 (1997) .
  27. Cotrim HP, Andrade ZA, Parana R, Portugal ML, Lyra LG & Freitas LAR. Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers. Liver 19, 299-304 (1999) .
  28. Neuschwander-Tetri BA & Bacon BB. Nonalcoholic steatohepatitis. Medical Clinics of North America 80, 1147-1166 (1996) .
  29. Vazquez CM, Molina MT & Ilundain A. Distal small bowel resection increases mucosal permeability in the large intestine. Digestion 40, 168-172 (1988) .
  30. Schimpl G, Feierl G, Linni K, Uitz K, Ozbey H & Hollwarth ME. Bacterial translocation in short-bowel syndrome in rats. European Journal of Pediatric Surgery 9, 224-227 (1999) .
  31. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH & Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of nonalcoholic steatohepatitis. Gut 48, 206-211 (2001) .