Endocrinol Metab.  2021 Oct;36(5):1016-1028. 10.3803/EnM.2021.1110.

Changes in Insulin Resistance Index and the Risk of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease without Diabetes: Kangbuk Samsung Health Study

• Koo DJ
• Lee MY
• Jung I
• Moon SJ
• Kwon H
• Park SE
• Rhee EJ
• Lee WY

• KMID: 2521950
• DOI: http://doi.org/10.3803/EnM.2021.1110

Abstract

Background
Fibrosis is the most important prognostic factor for nonalcoholic fatty liver disease (NAFLD). Insulin resistance plays a key role of fibrosis progression. We evaluated the association between changes in homeostasis model assessment of insulin resistance (HOMA-IR) values and changes in fibrosis status in NAFLD.
Methods
We analyzed the data of 15,728 participants with NAFLD (86% men, mean age 40.5 years) who had no diabetes at baseline and visited our centers for health check-ups both in 2012 and 2016. The participants were classified into four groups according to the degree of change in HOMA-IR values from baseline to the end of follow-up: G1 (<0), G2 (0–0.50), G3 (0.51–1.00), and G4 (>1.00). NAFLD was assessed by ultrasonography, and fibrosis status was evaluated by the NAFLD fibrosis score (NFS) and the aspartate aminotransferase to platelet ratio index (APRI).
Results
After the 4-year follow-up, the multivariable-adjusted odds ratio (OR) for progression of fibrosis probability increased with increasing HOMA-IR values (OR, 2.25; 95% confidence interval [CI], 1.87 to 2.71 for NFS; and OR, 2.55; 95% CI, 2.05 to 3.18 for APRI, G4). This tendency remained consistent throughout the subgroup analyses, except in those for female sex and a body mass index <25 kg/m². The OR for regression of fibrosis probability decreased with increasing HOMA-IR values (OR, 0.33; 95% CI, 0.25 to 0.43 for NFS, G4).
Conclusion
Changes in HOMA-IR values were associated with changes in fibrosis status in patients with NAFLD without diabetes, which underscores the role of insulin resistance in liver fibrosis.

Keyword

Insulin resistance; Fatty liver; Fibrosis; Body mass index; Cohort studies

Figure

• 

  Fig. 1 Flow chart for study participants. USG, ultrasonography; NAFLD, nonalcoholic fatty liver disease; HBs Ag, hepatitis B virus surface antigen; HCV Ab, hepatitis C virus antibody; Hx., history; DM, diabetes mellitus; HbA1c, hemoglobin A1c.

• 

  Fig. 2 Prevalence of progression and regression of fibrosis probability by group according to changes in homeostatic model assessment of insulin resistance (HOMA-IR) values. (A) Nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), (B) aspartate aminotransferase to platelet ratio index (APRI).

• 

  Fig. 3 Odds ratio for nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS)-based fibrosis progression and regression in participants belonging to G4 (group with highest increase in homeostatic model assessment of insulin resistance [HOMA-IR]) compared to G1 (group with decreased HOMA-IR). CI, confidence interval; BMI, body mass index. aAdjusted for sex, center (Seoul or Suwon), systolic blood pressure, regular exercise, current alcohol consumption, smoking status, waist circumference, hemoglobin A1c, high-sensitivity C-reactive protein, low-density lipoprotein cholesterol (LDL-C), triglycerides, new onset diabetes, and baseline HOMA-IR; bCurrent alcohol consumption was defined as daily alcohol consumption above the median value (12 g/day for men and 2 g/day for women); cDyslipidemia was defined as an LDL-C level >3.4 mmol/L, total cholesterol level >5.2 mmol/L, triglyceride >1.7 mmol/L, high-density lipoprotein cholesterol <0.9 mmol/L for men and <1.3 mmol/L for women, or the current use of anti-dyslipidemia medication.

Reference

1. 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; 67:328–57.

2. Sayiner M, Otgonsuren M, Cable R, Younossi I, Afendy M, Golabi P, et al. Variables associated with inpatient and outpatient resource utilization among medicare beneficiaries with nonalcoholic fatty liver disease with or without cirrhosis. J Clin Gastroenterol. 2017; 51:254–60.

3. 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; 44:865–73.

4. Younossi Z, Henry L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality. Gastroenterology. 2016; 150:1778–85.

5. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013; 5:1544–60.

6. Utzschneider KM, Kahn SE. Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2006; 91:4753–61.

7. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005; 48:634–42.

8. Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic fatty liver disease: mechanisms and clinical implications. Semin Liver Dis. 2015; 35:132–45.

9. Kitade H, Chen G, Ni Y, Ota T. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients. 2017; 9:387.

10. Sorrentino P, Terracciano L, D’Angelo S, Ferbo U, Bracigliano A, Vecchione R. Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension. Am J Gastroenterol. 2010; 105:336–44.

11. Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013; 59:550–6.

12. Gomez de la Cuesta S, Aller de la Fuente R, Tafur Sanchez C, Izaola O, Garcia Sanchez C, Mora N, et al. Analytical, anthropometric and dietary factors associated with the development of fibrosis in patients with nonalcoholic fatty liver disease. Rev Esp Enferm Dig. 2018; 110:292–8.

13. Fujii H, Imajo K, Yoneda M, Nakahara T, Hyogo H, Takahashi H, et al. HOMA-IR: an independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2019; 34:1390–5.

14. Aller R, Siguenza R, Pina M, Laserna C, Antolin B, Burgueno B, et al. Insulin resistance is related with liver fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease proven biopsy and Mediterranean diet pattern as a protective factor. Endocrine. 2020; 68:557–63.

15. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013; 10:330–44.

16. Cox KL, Burke V, Morton AR, Beilin LJ, Puddey IB. Independent and additive effects of energy restriction and exercise on glucose and insulin concentrations in sedentary overweight men. Am J Clin Nutr. 2004; 80:308–16.

17. Yoon YS, Oh SW, Baik HW, Park HS, Kim WY. Alcohol consumption and the metabolic syndrome in Korean adults: the 1998 Korean National Health and Nutrition Examination Survey. Am J Clin Nutr. 2004; 80:217–24.

18. Chun MY. Validity and reliability of Korean version of international physical activity questionnaire short form in the elderly. Korean J Fam Med. 2012; 33:144–51.

19. Antuna-Puente B, Disse E, Rabasa-Lhoret R, Laville M, Capeau J, Bastard JP. How can we measure insulin sensitivity/resistance? Diabetes Metab. 2011; 37:179–88.

20. Hamer OW, Aguirre DA, Casola G, Lavine JE, Woenckhaus M, Sirlin CB. Fatty liver: imaging patterns and pitfalls. Radiographics. 2006; 26:1637–53.

21. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007; 45:846–54.

22. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38:518–26.

23. Li B, Zhang C, Zhan YT. Nonalcoholic fatty liver disease cirrhosis: a review of its epidemiology, risk factors, clinical presentation, diagnosis, management, and prognosis. Can J Gastroenterol Hepatol. 2018; 2018:2784537.

24. Salomone F, Micek A, Godos J. Simple scores of fibrosis and mortality in patients with NAFLD: a systematic review with meta-analysis. J Clin Med. 2018; 7:219.

25. 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; 64:1388–402.

26. 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; 64:73–84.

27. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017; 66:1138–53.

28. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017; 66:1486–501.

29. Polyzos SA, Slavakis A, Koumerkeridis G, Katsinelos P, Kountouras J. Noninvasive liver fibrosis tests in patients with nonalcoholic fatty liver disease: an external validation cohort. Horm Metab Res. 2019; 51:134–40.

30. Koo DJ, Lee MY, Jung I, Moon SJ, Kwon H, Park SE, et al. Baseline homeostasis model assessment of insulin resistance associated with fibrosis progression in patients with nonalcoholic fatty liver disease without diabetes: a cohort study. PLoS One. 2021; 16:e0255535.

31. 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; 59:1265–9.

32. Rhee EJ, Lee WY, Cho YK, Kim BI, Sung KC. Hyperinsulinemia and the development of nonalcoholic Fatty liver disease in nondiabetic adults. Am J Med. 2011; 124:69–76.

33. Motamed N, Miresmail SJ, Rabiee B, Keyvani H, Farahani B, Maadi M, et al. Optimal cutoff points for HOMA-IR and QUICKI in the diagnosis of metabolic syndrome and non-alcoholic fatty liver disease: a population based study. J Diabetes Complications. 2016; 30:269–74.

34. Salgado AL, Carvalho Ld, Oliveira AC, Santos VN, Vieira JG, Parise ER. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. Arq Gastroenterol. 2010; 47:165–9.

35. Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. 2017; 16:203.

36. Gruben N, Shiri-Sverdlov R, Koonen DP, Hofker MH. Nonalcoholic fatty liver disease: a main driver of insulin resistance or a dangerous liaison? Biochim Biophys Acta. 2014; 1842:2329–43.

37. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol. 2007; 47:142–56.

38. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004; 351:1106–18.

39. Stein LL, Dong MH, Loomba R. Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: current status. Adv Ther. 2009; 26:893–907.

40. Taguchi K, Yamanaka-Okumura H, Mizuno A, Nakamura T, Shimada M, Doi T, et al. Insulin resistance as early sign of hepatic dysfunction in liver cirrhosis. J Med Invest. 2014; 61:180–9.

41. Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, et al. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol. 2005; 42:41–6.

42. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010; 51:121–9.

43. Kim Y, Chang Y, Cho YK, Ahn J, Shin H, Ryu S. Obesity and weight gain are associated with progression of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019; 17:543–50.

44. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014; 20:475–85.