Genes and nonalcoholic fatty liver disease

  • Nimantha Mark Wilfred de Alwis
  • Christopher Paul Day
Article

Abstract

Whereas most individuals with nonalcoholic fatty liver disease (NAFLD) will have steatosis, only a minority will ever develop progressive disease. Family studies and interethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor-α, transforming growth factor-β, and angiotensinogen may be associated with steatohepatitis and/or fibrosis. With the advent of high-throughput gene analyses and the reduced cost of whole genomewide scans, it seems likely that genes contributing to inherited susceptibility to this common disease will be identified in the near future.

References and Recommended Reading

  1. 1.
    Neuschwander-Tetri B, Caldwell S: Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003, 37:1202–1219.PubMedCrossRefGoogle Scholar
  2. 2.
    Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990, 12:1106–1110.PubMedCrossRefGoogle Scholar
  3. 3.
    Dixon J, Bhathal P, O’Brian P: Non-alcoholic fatty liver disease: predictors of non-alcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001, 121:91–100.PubMedCrossRefGoogle Scholar
  4. 4.
    De Alwis N, Day CP: Non alcoholic fatty liver disease: the mist gradually clears. J Hepatol 2008, In press.Google Scholar
  5. 5.
    Day CP: Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002, 16:663–678.PubMedCrossRefGoogle Scholar
  6. 6.
    Day CP: From fat to inflammation. Gastroenterology 2006, 130:207–210.PubMedCrossRefGoogle Scholar
  7. 7.
    Hui J, Hodge A, Farrell G, et al.: Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004, 40:46–54.PubMedCrossRefGoogle Scholar
  8. 8.
    Musso G, Gambino R, De Michieli F, et al.: Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003, 37:909–916.PubMedCrossRefGoogle Scholar
  9. 9.
    Wigg A, Roberts-Thomson IC, Dymock RB, et al.: The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001, 48:206–211.PubMedCrossRefGoogle Scholar
  10. 10.
    Singh H, Pollock R, Uhanova J, et al.: Symptoms of obstructive sleep apnoea in patients with nonalcoholic fatty liver disease. Dig Dis Sci 2005, 50:2338–2343.PubMedCrossRefGoogle Scholar
  11. 11.
    Struben VMD, Hespenheide EE, Caldwell SH: Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindres. Am J Med 2000, 108:9–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Willner I, Waters B, Patil S, et al.: Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001, 96:2957–2961.PubMedCrossRefGoogle Scholar
  13. 13.
    Browning JD, Kumar KS, Saboorian MH, Thiele DL: Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 2004, 99:292–298.PubMedCrossRefGoogle Scholar
  14. 14.
    Caldwell SH, Harris DM, Patrie JT, Hespenheide EE: Is NASH underdiagnosed among African Americans? Am J Gastroenterol 2002, 97:1496–1500.PubMedCrossRefGoogle Scholar
  15. 15.
    Daly A, Day C: Candidate gene case-control association studies: advantages and potential pitfalls. Br J Clin Pharmacol 2001, 52:489–499.PubMedCrossRefGoogle Scholar
  16. 16.
    Baranova A, Liotta L, Petricoin E, Younnossi Z: The role of genomics and proteomics: technologies in studying nonalcoholic fatty liver disease. Clin Liver Dis 2007, 11:209–220.PubMedCrossRefGoogle Scholar
  17. 17.
    Younossi ZM, Gorreta F, Ong JP, et al.: Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis. Liver Int 2005, 25:760–771.PubMedCrossRefGoogle Scholar
  18. 18.
    Sreekumar R, Rosado B, Rasmussen D, Charlton M: Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology 2003, 38:244–251.PubMedCrossRefGoogle Scholar
  19. 19.
    Rubio A, Guruceaga E, Vazquez-Chantada M, et al.: Identification of a gene-pathway associated with non-alcoholic steatohepatitis. J Hepatol 2007, 46:708–718.PubMedCrossRefGoogle Scholar
  20. 20.
    Issaq H, Conrads T, Prieto D, et al.: SELDI-TOF MS for diagnostic proteomics. Anal Chem 2003, 75:148A–155A.PubMedCrossRefGoogle Scholar
  21. 21.
    Younossi ZM, Baranova A, Ziegler K, et al.: A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology 2005, 42:665–674.PubMedCrossRefGoogle Scholar
  22. 22.
    Calvert V, Collantes R, Elariny H, et al.: A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis. Hepatology 2007, 46:166–172.PubMedCrossRefGoogle Scholar
  23. 23.
    Ludwig J, Viggiano TR, McGill DB, Ott BJ: Nonalcoholic steatohepatitis. Mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980, 55:434–438.PubMedGoogle Scholar
  24. 24.
    Clark JM, Bracanti FL, Diehl AM: Nonalcoholic fatty liver disease. Gastroenterology 2002, 122:1647–1657.CrossRefGoogle Scholar
  25. 25.
    Ostberg JE, Thomas EL, Hamilton G, et al.: Excess visceral and hepatic adipose tissue in Turner syndrome determined by magnetic resonance imaging: estrogen deficiency associated with hepatic adipose content. J Clin Endocrinol Metab 2005, 90:2631–2635.PubMedCrossRefGoogle Scholar
  26. 26.
    Ameen C, Oscarsson J: Sex difference in hepatic microsomal triglyceride transfer protein expression is determined by the growth hormone secretory pattern in the rat. Endocrinology 2003, 144:3914–3921.PubMedCrossRefGoogle Scholar
  27. 27.
    Lonardo A, Carani C, Carulli N, Loria P: ’Endocrine NAFLD’ a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J Hepatol 2006, 44:1196–1207.PubMedCrossRefGoogle Scholar
  28. 28.
    Day CP, James OF: Hepatic steatosis: innocent bystander or guilty party? Hepatology 1998, 27:1463–1466.PubMedCrossRefGoogle Scholar
  29. 29.
    Yamaguchi K, Yang L, McCall S, et al.: Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45:1366–1374.PubMedCrossRefGoogle Scholar
  30. 30.
    Namikawa C, Shu-Ping Z, Vyselaar J, et al.: Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in nonalcoholic steatohepatitis. J Hepatol 2004, 40:781–786.PubMedCrossRefGoogle Scholar
  31. 31.
    Bernard S, Touzet S, Personne I, et al.: Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia 2000, 43:995–999.PubMedCrossRefGoogle Scholar
  32. 32.
    Dong H, Wang J, Li C, et al.: The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 2007, 46:915–920.PubMedCrossRefGoogle Scholar
  33. 33.
    De Alwis N, Daly A, Aithal G, et al.: Genetic evidence that lipid trafficking plays a key role in fibrosis in nonalocholic fatty liver disease. Hepatology 2007, 46:753A.Google Scholar
  34. 34.
    Targher G, Bertolini L, Padovani R, et al.: Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007, 30:1212–1218.PubMedCrossRefGoogle Scholar
  35. 35.
    Fan C, Pan J, Usuda N, et al.: Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem 1998, 273:15639–15645.PubMedCrossRefGoogle Scholar
  36. 36.
    Merriman R, Aouizerat B, Molloy M, et al.: A genetic mutation in the peroxisome proliferator-activated receptor alpha gene in patients with non-alcoholic steatohepatitis. Hepatology 2001, 34:441A.CrossRefGoogle Scholar
  37. 37.
    Xu A, Wang Y, Keshaw H, et al.: The fat-derived hormone adiponectin alleviates alcoholic and non-alcoholic fatty liver disease in mice. J Clin Invest 2003, 112:91–100.PubMedGoogle Scholar
  38. 38.
    Yamauchi T, Kamon J, Minokoshi Y, et al.: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002, 8:1288–1295.PubMedCrossRefGoogle Scholar
  39. 39.
    George D, Goldwurm S, Macdonald G, et al.: Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998, 114:311–318.PubMedCrossRefGoogle Scholar
  40. 40.
    Nelson J, Bhattacharya R, Lindor K, et al.: HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology 2007, 46:723–729.PubMedCrossRefGoogle Scholar
  41. 41.
    Bugianesi E, Manzini P, D’Antico S, et al.: Relative contribution of iron burden, HFE mutations and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004, 39:179–187.PubMedCrossRefGoogle Scholar
  42. 42.
    Saksena S, Daly A, Leathart J, Day C: Mangaense dependent superoxide dismutase (SOD2) targeting sequence polymorphism is associated with advanced fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2003, 38(Suppl 2):47.Google Scholar
  43. 43.
    Nobili V, Daly A, Al-Serri A, et al.: The mitochondrial superoxide dismutase 2 (SOD2) targeting sequence polymorphism is associated with fibrotic NAFLD: consistent evidence from case-control and intra-familial allelic association studies. Hepatology 2007, 46:760A.Google Scholar
  44. 44.
    Baldini M, Lohman I, Halonen M, et al.: A polymorphism* in the 5′; flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999, 20:976–983.PubMedGoogle Scholar
  45. 45.
    Day C, Leathart J, McTernan P, et al.: Genetic evidence for a role of gut flora in the pathogenesis of NASH in humans. Hepatology 2006, 44(Suppl 1):261A.Google Scholar
  46. 46.
    Valenti L, Fracanzani A, Dongiovanni P, et al.: Tumour necrosis factor promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 2002, 122:272–280.CrossRefGoogle Scholar
  47. 47.
    Tokushige K, Takakura M, Tsuchiya-Matsushita N, et al.: Influence of TNF gene polymorphism in Japanese patients with NASH and simple steatosis. J Hepatol 2007, 46:1104–1110.PubMedCrossRefGoogle Scholar
  48. 48.
    Bataller R, North K, Brenner D: Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003, 37:493–503.PubMedCrossRefGoogle Scholar
  49. 49.
    Dixon J, Bhathal P, Jonsson J, et al.: Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J Hepatol 2003, 39:967–970.PubMedCrossRefGoogle Scholar
  50. 50.
    Sutton A, Nahon P, Pessayre D, et al.: Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol induced cirrhosis. Cancer Res 2006, 66:2844–2852.PubMedCrossRefGoogle Scholar
  51. 51.
    Saffroy R, Pham P, Chiappini F, et al.: The MTHFR 677C>T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis. Carcinogenesis 2004, 25:1443–1448.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  • Nimantha Mark Wilfred de Alwis
  • Christopher Paul Day
    • 1
  1. 1.The Medical School, Framlington PlaceSchool of Clinical Medicial SciencesNewcastle upon TyneUK

Personalised recommendations