Advertisement

Current Hepatology Reports

, Volume 14, Issue 2, pp 69–76 | Cite as

Long-Term Outcomes of Nonalcoholic Fatty Liver Disease

  • Min-Sun Kwak
  • Donghee Kim
Fatty Liver Disease (SA Harrison and J George, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent disease with 20–30 % of the population affected in many developed and developing countries. Studies assessing the prognosis of NAFLD have shown that simple steatosis has a benign long-term outcome without excess mortality compared to the general population but that patients with NASH or with fibrosis have increased long-term mortality with standardized mortality ratio of 1.34–2.6 and hazard ratio of 1.004–1.05. The excess mortality of NAFLD patients is mainly due to cardiovascular disease. Liver-related mortality is also elevated in patients with NAFLD, especially in those patients with NASH or advanced fibrosis. A simple noninvasive fibrosis marker such as the NAFLD fibrosis score might be useful for predicting overall mortality and cause-specific mortality in these patients. A proportion of NAFLD develop concomitant or subsequent NASH at a rate of 10–20 %, and about 10 % of NASH cases progress to cirrhosis. NAFLD can progress to HCC, especially in patients with cirrhosis or advanced liver fibrosis. In addition to these liver-related complications, metabolic complications can also occur. The incidence of newly developed diabetes is elevated in NAFLD patients, and nonfatal and fatal cardiovascular diseases occur more frequently in patients with NAFLD. Therefore, cardiovascular assessment and liver-related surveillance might be considered in patients with NAFLD. In summary, we should pay more attention to patients with NAFLD, especially those with advanced forms of the disease because these individuals have increased morbidity and mortality.

Keywords

Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Survival Cirrhosis Hepatocellular carcinoma Diabetes 

Abbreviations

CI

Confidence interval

HCV

Hepatitis C virus

HCC

Hepatocellular carcinoma

HR

Hazard ratio

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

NFS

Nonalcoholic fatty liver disease fibrosis score

OR

Odds ratio

US

Ultrasonography

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Min-Sun Kwak and Donghee Kim declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Sanyal AJ. NASH: a global health problem. Hepatol Res. 2011;41(7):670–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Salamone F, Bugianesi E. Nonalcoholic fatty liver disease: the hepatic trigger of the metabolic syndrome. J Hepatol. 2010;53(6):1146–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single topic conference. Hepatology. 2003;37(5):1202–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol. 2014;20(36):12956–80.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30(8):2119–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med. 2005;37(5):347–56.PubMedCrossRefGoogle Scholar
  9. 9.•
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129(1):113–21. First study to describe the natural history of NAFLD in a large cohort of community-based patients.PubMedCrossRefGoogle Scholar
  10. 10.
    Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, et al. Fatty liver index and mortality: the Cremona study in the 15th year of follow-up. Hepatology. 2011;54(1):145–52.PubMedCrossRefGoogle Scholar
  11. 11.•
    Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44(4):865–73. Large long-term follow-up study evaluating biopsy-proven referred NAFLD patients.PubMedCrossRefGoogle Scholar
  12. 12.
    Jepsen P, Vilstrup H, Mellemkjaer L, Thulstrup AM, Olsen JH, Baron JA, et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepato-Gastroenterology. 2003;50(54):2101–4.PubMedGoogle Scholar
  13. 13.
    Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608–12.PubMedCrossRefGoogle Scholar
  14. 14.•
    Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595–602. Longest follow-up study of patients with biopsy proven NAFLD.PubMedCrossRefGoogle Scholar
  15. 15.
    Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53(5):750–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.•
    Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57(4):1357–65. Largest study evaluating long-term outcome of ultrasonography-diagnoses NAFLD and evaluated the usefulness of noninvasive markers predicting prognosis in population based study.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Dunn W, Xu R, Wingard DL, Rogers C, Angulo P, Younossi ZM, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263–71.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Angulo P, Bugianesi E, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Barrera F, et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145(4):782–9. e4.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Rinella ME. Will the increased prevalence of nonalcoholic steatohepatitis (NASH) in the age of better hepatitis C virus therapy make NASH the deadlier disease? Hepatology. 2011;54(4):1118–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Mohanty SR, Troy TN, Huo D, O’Brien BL, Jensen DM, Hart J. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J Hepatol. 2009;50(4):797–804.PubMedCrossRefGoogle Scholar
  22. 22.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–5.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883–94.PubMedCrossRefGoogle Scholar
  24. 24.•
    Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234–8. Large long-term follow-up study evaluating biopsy-proven NAFLD patients.PubMedCrossRefGoogle Scholar
  25. 25.
    Choi SY, Kim D, Kim HJ, Kang JH, Chung SJ, Park MJ, et al. The relation between non-alcoholic fatty liver disease and the risk of coronary heart disease in Koreans. Am J Gastroenterol. 2009;104(8):1953–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim D, Choi SY, Park EH, Lee W, Kang JH, Kim W, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012;56(2):605–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363(14):1341–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Yun KE, Shin CY, Yoon YS, Park HS. Elevated alanine aminotransferase levels predict mortality from cardiovascular disease and diabetes in Koreans. Atherosclerosis. 2009;205(2):533–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617–49.PubMedCrossRefGoogle Scholar
  30. 30.
    Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol. 2004;40(4):578–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54(4):1208–16.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38(2):420–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43(4):682–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51(5):1820–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Yoshioka Y, Hashimoto E, Yatsuji S, Kaneda H, Taniai M, Tokushige K, et al. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol. 2004;39(12):1215–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10(11):656–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Nishikawa H, Osaki Y. Non-B, non-C hepatocellular carcinoma (review). Int J Oncol. 2013;43(5):1333–42.PubMedGoogle Scholar
  39. 39.
    Yang JD, Kim B, Sanderson SO, St Sauver JL, Yawn BP, Pedersen RA, et al. Hepatocellular carcinoma in Olmsted county, Minnesota, 1976-2008. Mayo Clin Proc. 2012;87(1):9–16.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol. 2012;107(2):253–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K, et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 2009;44 Suppl 19:89–95.PubMedCrossRefGoogle Scholar
  42. 42.
    White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342–59. e2.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Alexander J, Torbenson M, Wu TT, Yeh MM. Non-alcoholic fatty liver disease contributes to hepatocarcinogenesis in non-cirrhotic liver: a clinical and pathological study. J Gastroenterol Hepatol. 2013;28(5):848–54.PubMedCrossRefGoogle Scholar
  44. 44.
    Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol. 2014;20(36):12945–55.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med. 2008;132(11):1761–6.PubMedGoogle Scholar
  46. 46.
    Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49(3):851–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol. 2009;24(2):248–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Tokushige K, Hashimoto E, Kodama K. Hepatocarcinogenesis in non-alcoholic fatty liver disease in Japan. J Gastroenterol Hepatol. 2013;28 Suppl 4:88–92.PubMedCrossRefGoogle Scholar
  50. 50.
    El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130(7):1639–48.PubMedCrossRefGoogle Scholar
  52. 52.
    Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004;10(2 Suppl 1):S69–73.PubMedCrossRefGoogle Scholar
  53. 53.
    Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46 Suppl 1:63–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer. 2009;115(24):5651–61.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Tokushige K, Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, et al. Prospective study of hepatocellular carcinoma in nonalcoholic steatohepatitis in comparison with hepatocellular carcinoma caused by chronic hepatitis C. J Gastroenterol. 2010;45(9):960–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59(3):1174–97.PubMedCrossRefGoogle Scholar
  57. 57.
    Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care. 2007;30(11):2940–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Kim CH, Park JY, Lee KU, Kim JH, Kim HK. Fatty liver is an independent risk factor for the development of type 2 diabetes in Korean adults. Diabetic Med. 2008;25(4):476–81.PubMedCrossRefGoogle Scholar
  59. 59.
    Goessling W, Massaro JM, Vasan RS, D’Agostino Sr RB, Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology. 2008;135(6):1935–44. 44 e1.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Hamaguchi M, Kojima T, Takeda N, Nagata C, Takeda J, Sarui H, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13(10):1579–84.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Oni ET, Agatston AS, Blaha MJ, Fialkow J, Cury R, Sposito A, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis. 2013;230(2):258–67.PubMedCrossRefGoogle Scholar
  62. 62.
    Choi SY, Kim D, Kang JH, Park MJ, Kim YS, Lim SH, et al. Nonalcoholic fatty liver disease as a risk factor of cardiovascular disease: relation of non-alcoholic fatty liver disease to carotid atherosclerosis. Korean J Hepatol. 2008;14(1):77–88.PubMedCrossRefGoogle Scholar
  63. 63.
    Bedogni G, Miglioli L, Masutti F, Castiglione A, Croce LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology. 2007;46(5):1387–91.PubMedCrossRefGoogle Scholar
  64. 64.
    Omagari K, Morikawa S, Nagaoka S, Sadakane Y, Sato M, Hamasaki M, et al. Predictive factors for the development or regression of fatty liver in Japanese adults. J Clin Biochem Nutr. 2009;45(1):56–67.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol. 2012;56(5):1145–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34(4):729–49.PubMedCrossRefGoogle Scholar
  67. 67.
    Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123(3):745–50.PubMedCrossRefGoogle Scholar
  68. 68.
    Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42(1):132–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):371–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59(7):969–74.PubMedCrossRefGoogle Scholar
  71. 71.
    Yu J, Shen J, Sun TT, Zhang X, Wong N. Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol. 2013;23(6 Pt B):483–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam CenterSeoul National University HospitalGangnam-GuSouth Korea
  2. 2.Division of Gastroenterology and HepatologyStanford University School of MedicineStanfordUSA

Personalised recommendations