Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies

Autoři: Helen Jarvis aff001;  Dawn Craig aff001;  Robert Barker aff001;  Gemma Spiers aff001;  Daniel Stow aff001;  Quentin M. Anstee aff002;  Barbara Hanratty aff001
Působiště autorů: Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom aff001;  Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom aff002;  NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom aff003
Vyšlo v časopise: Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med 17(4): e1003100. doi:10.1371/journal.pmed.1003100
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003100



Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. Many individuals have risk factors associated with NAFLD, but the majority do not develop advanced liver disease: cirrhosis, hepatic decompensation, or hepatocellular carcinoma. Identifying people at high risk of experiencing these complications is important in order to prevent disease progression. This review synthesises the evidence on metabolic risk factors and their potential to predict liver disease outcomes in the general population at risk of NAFLD or with diagnosed NAFLD.

Methods and findings

We conducted a systematic review and meta-analysis of population-based cohort studies. Databases (including MEDLINE, EMBASE, the Cochrane Library, and were searched up to 9 January 2020. Studies were included that reported severe liver disease outcomes (defined as liver cirrhosis, complications of cirrhosis, or liver-related death) or advanced fibrosis/non-alcoholic steatohepatitis (NASH) in adult individuals with metabolic risk factors, compared with individuals with no metabolic risk factors. Cohorts selected on the basis of a clinically indicated liver biopsy were excluded to better reflect general population risk. Risk of bias was assessed using the QUIPS tool. The results of similar studies were pooled, and overall estimates of hazard ratio (HR) were obtained using random-effects meta-analyses. Of 7,300 unique citations, 22 studies met the inclusion criteria and were of sufficient quality, with 18 studies contributing data suitable for pooling in 2 random-effects meta-analyses. Type 2 diabetes mellitus (T2DM) was associated with an increased risk of incident severe liver disease events (adjusted HR 2.25, 95% CI 1.83–2.76, p < 0.001, I2 99%). T2DM data were from 12 studies, with 22.8 million individuals followed up for a median of 10 years (IQR 6.4 to 16.9) experiencing 72,792 liver events. Fourteen studies were included in the meta-analysis of obesity (BMI > 30 kg/m2) as a prognostic factor, providing data on 19.3 million individuals followed up for a median of 13.8 years (IQR 9.0 to 19.8) experiencing 49,541 liver events. Obesity was associated with a modest increase in risk of incident severe liver disease outcomes (adjusted HR 1.20, 95% CI 1.12–1.28, p < 0.001, I2 87%). There was also evidence to suggest that lipid abnormalities (low high-density lipoprotein and high triglycerides) and hypertension were both independently associated with incident severe liver disease. Significant study heterogeneity observed in the meta-analyses and possible under-publishing of smaller negative studies are acknowledged to be limitations, as well as the potential effect of competing risks on outcome.


In this review, we observed that T2DM is associated with a greater than 2-fold increase in the risk of developing severe liver disease. As the incidence of diabetes and obesity continue to rise, using these findings to improve case finding for people at high risk of liver disease will allow for effective management to help address the increasing morbidity and mortality from liver disease.

Trial registration

PROSPERO CRD42018115459.

Klíčová slova:

Body mass index – Cirrhosis – Fatty liver – Liver diseases – Medical risk factors – Metaanalysis – Obesity – Type 2 diabetes


1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431 26707365

2. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402. doi: 10.1016/j.jhep.2015.11.004 27062661

3. Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–54. doi: 10.1002/hep.27368 25125077

4. Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265–73. doi: 10.1016/j.jhep.2017.07.027 28803953

5. 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. doi: 10.1053/j.gastro.2013.06.057 23860502

6. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59(9):1265–9. doi: 10.1136/gut.2010.216077 20801772

7. Morling JR, Fallowfield JA, Guha IN, Nee LD, Glancy S, Williamson RM, et al. Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study. J Hepatol. 2014;60(2):384–91. doi: 10.1016/j.jhep.2013.10.017 24512822

8. American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes–2020. Diabetes Care. 2020;43(Suppl 1):S37–S47. doi: 10.2337/dc20-S004 31862747

9. El-Gohary M, Moore M, Roderick P, Watkins E, Dash J, Reinson T, et al. Local care and treatment of liver disease (LOCATE)—a cluster-randomized feasibility study to discover, assess and manage early liver disease in primary care. PLoS ONE. 2018;13(12):e0208798. doi: 10.1371/journal.pone.0208798 30576330

10. Harman DJ, Ryder SD, James MW, Jelpke M, Ottey DS, Wilkes EA, et al. Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography. BMJ Open. 2015;5(4):e007516. doi: 10.1136/bmjopen-2014-007516 25941185

11. Tanajewski L, Harris R, Harman DJ, Aithal GP, Card TR, Gkountouras G, et al. Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study. BMJ Open. 2017;7(6):e015659. doi: 10.1136/bmjopen-2016-015659 28679676

12. National Institute for Health and Care Excellence. Non-alcoholic fatty liver disease (NAFLD): assessment and management. NICE guidance NG49. London: National Institute for Health and Care Excellence; 2016 [cited 2020 Apr 9]. Available from:

13. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. doi: 10.1002/hep.29367 28714183

14. Williams R, Aspinall R, Bellis M, Camps-Walsh G, Cramp M, Dhawan A, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet. 2014;384(9958):1953–97. doi: 10.1016/S0140-6736(14)61838-9 25433429

15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–97. doi: 10.1001/jama.285.19.2486 11368702

16. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi: 10.1136/bmj.b2535 19622551

17. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210. doi: 10.1186/s13643-016-0384-4 27919275

18. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to systematic review and meta-analysis of prognostic factor studies. BMJ. 2019;364:k4597. doi: 10.1136/bmj.k4597 30700442

19. Nordic Cochrane Centre. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre; 2014.

20. Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17(1):95. doi: 10.1186/s12916-019-1321-x 31104631

21. Andreasson A, Carlsson AC, Önnerhag K, Hagström H. Waist/hip ratio better predicts development of severe liver disease within 20 years than body mass index: a population-based cohort study. Clin Gastroenterol Hepatol. 2017;15(8):1294–301.e2. doi: 10.1016/j.cgh.2017.02.040 28342948

22. Björkström K, Franzen S, Eliasson B, Miftaraj M, Gudbjörnsdottir S, Trolle-Lagerros Y, et al. Risk factors for severe liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2019;17(13):2769–75. doi: 10.1016/j.cgh.2019.04.038 31009793

23. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–8. doi: 10.1053/j.gastro.2003.10.065 14762783

24. Goh GB-B, Pan A, Chow W-C, Yuan J-M, Koh W-P. Association between diabetes mellitus and cirrhosis mortality: the Singapore Chinese Health Study. Liver Int. 2017;37(2):251–8. doi: 10.1111/liv.13241 27566448

25. Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore). 2018;97(13):e0214.

26. Hagström H, Stål P, Hultcrantz R, Hemmingsson T, Andreasson A. Overweight in late adolescence predicts development of severe liver disease later in life: a 39years follow-up study. J Hepatol. 2016;65(2):363–8. doi: 10.1016/j.jhep.2016.03.019 27321729

27. Hagström H, Tynelius P, Rasmussen F. High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men. Gut. 2018;67(8):1536–42. doi: 10.1136/gutjnl-2016-313622 28320770

28. Hagström H, Höijer J, Andreasson A, Bottai M, Johansson K, Ludvigsson JF, et al. Body mass index in early pregnancy and future risk of severe liver disease: a population-based cohort study. Aliment Pharmacol Ther. 2019;49(6):789–96. doi: 10.1111/apt.15162 30714185

29. Ioannou GN, Weiss NS, Kowdley KV, Dominitz JA. Is obesity a risk factor for cirrhosis-related death or hospitalization? A population-based cohort study. Gastroenterology. 2003;125(4):1053–9. doi: 10.1016/s0016-5085(03)01200-9 14517789

30. Ioannou GN, Weiss NS, Boyko EJ, Kowdley KV, Kahn SE, Carithers RL, et al. Is central obesity associated with cirrhosis-related death or hospitalization? A population-based, cohort study. Clin Gastroenterol Hepatol. 2005;3(1):67–74. doi: 10.1016/s1542-3565(04)00442-2 15645407

31. Kanwal F, Kramer J, Li L, Dai J, Natarajan Y, Yu X, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in non-alcoholic fatty liver disease. Hepatology. 2019;71(3):808–19. doi: 10.1002/hep.31014 31675427

32. Liu B, Balkwill A, Reeves G, Beral V, Million Women Study Collaborators. Body mass index and risk of liver cirrhosis in middle aged UK women: a prospective study. BMJ. 2010;340:c912. doi: 10.1136/bmj.c912 20223875

33. Nderitu P, Bosco C, Garmo H, Holmberg L, Malmström H, Hammar N, et al. The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort. Int J Cancer. 2017;141(6):1148–60. doi: 10.1002/ijc.30818 28577304

34. Otgonsuren M, Stepanova M, Gerber L, Younossi ZM. Anthropometric and clinical factors associated with mortality in subjects with nonalcoholic fatty liver disease. Dig Dis Sci. 2013;58(4):1132–40. doi: 10.1007/s10620-012-2446-3 23143735

35. Pang Y, Kartsonaki C, Turnbull I, Guo Y, Clarke R, Chen Y, et al. Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people. Hepatology. 2018;68(4):1308–18. doi: 10.1002/hep.30083 29734463

36. Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ. 2010;182(11):E526–31. doi: 10.1503/cmaj.092144 20566726

37. Schult A, Eriksson H, Wallerstedt S, Kaczynski J. Overweight and hypertriglyceridemia are risk factors for liver cirrhosis in middle-aged Swedish men. Scand J Gastroenterol. 2011;46(6):738–44. doi: 10.3109/00365521.2011.560679 21561285

38. Schult A, Mehlig K, Björkelund C, Wallerstedt S, Kaczynski J. Waist-to-hip ratio but not body mass index predicts liver cirrhosis in women. Scand J Gastroenterol. 2018;53(2):212–7. doi: 10.1080/00365521.2017.1420219 29276897

39. Simeone JC, Bae JP, Hoogwerf BJ, Li Q, Haupt A, Ali AK, et al. Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes. Clin Epidemiol. 2017;9:679–88. doi: 10.2147/CLEP.S144368 29276410

40. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59(10):1410–5. doi: 10.1136/gut.2010.213553 20660697

41. Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metab Clin Exp. 2013;62(3):352–60. doi: 10.1016/j.metabol.2012.08.005 22999011

42. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97.e10. doi: 10.1053/j.gastro.2015.04.043 25935633

43. Stepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58(10):3017–23. doi: 10.1007/s10620-013-2743-5 23775317

44. Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004;2(3):262–5. doi: 10.1016/s1542-3565(04)00014-x 15017611

45. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver versus nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643–54.e9. doi: 10.1016/j.cgh.2014.04.014 24768810

46. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55. doi: 10.1016/j.jhep.2014.11.034 25477264

47. Pelusi S, Petta S, Rosso C, Borroni V, Fracanzani AL, Dongiovanni P, et al. Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS ONE. 2016;11(9):e0163069. doi: 10.1371/journal.pone.0163069 27649410

48. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20. doi: 10.1038/nrgastro.2017.109 28930295

49. Younossi ZM, Golabi P, de Avila L, Minhui Paik J, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801. doi: 10.1016/j.jhep.2019.06.021 31279902

50. Williams R, Alexander G, Armstrong I, Baker A, Bhala N, Camps-Walsh G, et al. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet. 2018;391(10125):1097–107. doi: 10.1016/S0140-6736(17)32866-0 29198562

51. Hallsworth K, Avery L, Trenell MI. Targeting lifestyle behavior change in adults with NAFLD during a 20-min consultation: summary of the dietary and exercise literature. Curr Gastroenterol Rep. 2016;18(3):11. doi: 10.1007/s11894-016-0485-1 26908279

52. Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med. 2019;179(9):1262–71. doi: 10.1001/jamainternmed.2019.2248 31260026

53. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184–96. doi: 10.1016/S0140-6736(19)33041-7 31813633

54. Francque S, Vonghia L. Pharmacological treatment for non-alcoholic fatty liver disease. Adv Ther. 2019;36(5):1052–74. doi: 10.1007/s12325-019-00898-6 30888594

55. Srivastava A, Gailer R, Tanwar S, Trembling P, Parkes J, Rodger A, et al. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019;71(2):371–8. doi: 10.1016/j.jhep.2019.03.033 30965069

Interní lékařství

Článek vyšel v časopise

PLOS Medicine

2020 Číslo 4

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…

Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se

VIRTUÁLNÍ ČEKÁRNA ČR Jste praktický lékař nebo pediatr? Zapojte se! Jste praktik nebo pediatr? Zapojte se!