Advertisement

Risk factors for non-alcoholic fatty liver disease-associated hepatic fibrosis in type 2 diabetes patients

  • Asieh Mansour
  • Mohammad Reza Mohajeri-Tehrani
  • Majid Samadi
  • Hadis Gerami
  • Mostafa Qorbani
  • Nick Bellissimo
  • Hossein Poustchi
  • Azita HekmatdoostEmail author
Original Article

Abstract

Aims

In patients with type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and liver fibrosis is frequent and presumably associated with increased cardiovascular disease risk and mortality. The objective was to investigate risk factors associated with hepatic fibrosis in patients with type 2 diabetes and NAFLD to provide a basis for the prevention and treatment.

Methods

Liver stiffness measurements (LSM) expressed in kilopascals (kPa) and controlled attenuation parameter (CAP) expressed in dB/m were diagnosed by transient elastography. Hepatic steatosis and significant fibrosis were defined as having a CAP score ≥ 260 dB/m and an LSM score ≥ 8 kPa, respectively. Associations between fibrosis categories with anthropometric and metabolic variables were determined; then, variables with statistical significance in the univariate analysis were included in multivariate model.

Results

A total of 108 participant with type 2 diabetes and NAFLD (mean age: 44.69 ± 5.57 years; mean duration of diabetes 4.68 ± 4.24 years) were recruited. In these patients, body mass index, obesity, fat mass, waist circumferences, resting energy expenditure, CAP score, fasting insulin, C-peptide, HbA1C, hs-CRP as well as liver enzymes and systolic blood pressure and diastolic blood pressure were positively associated with fibrosis (all p < 0.05). Using multivariate logistic regression, serum aspartate aminotransferase (OR 1.12; 95% CI 1.06–1.19), waist circumferences (odds ratio [OR] 1.15; 95% CI 1.05–1.25) and C-peptide (OR 3.81; 95% CI 1.5–9.7) remained as independently associated with liver fibrosis.

Conclusion

For participants with type 2 diabetes with coexisting NAFLD, stratification by independent risk factors for fibrosis could have important prognostic value.

Keywords

Hepatic fibrosis Type 2 diabetes NAFLD Risk factors Liver enzymes 

Notes

Acknowledgements

This study was financially supported by a grant from National Institute for Medical Research Development to AH and AM with Grant No 957225, and the National Nutrition and Food Technology, Research Institute Shahid Beheshti University of Medical Science, Tehran, Iran. We also thank Maryam Sharafkhah for contribution in analysis of data.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were in accordance with the ethical standards of the institutional research committee (Ethics Committee of the National Institute for Medical Research Development and National Nutrition and Food Technology Research Institute) and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Bril F, Cusi K (2017) Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 40(3):419–430Google Scholar
  2. 2.
    Miele L, Gasbarrini G, Giorgio V, Gasbarrini A, Grieco A (2016) Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome. Intern Emerg Med 11(1):3–10Google Scholar
  3. 3.
    Mantovani A, Byrne CD, Bonora E, Targher G (2018) Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 41(2):372–382Google Scholar
  4. 4.
    Ballestri S, Zona S, Targher G et al (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 31(5):936–944Google Scholar
  5. 5.
    Musso G, Gambino R, Cassader M, Pagano G (2011) Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 43(8):617–649Google Scholar
  6. 6.
    Yeung M-W, Wong GL-H, Choi KC et al (2018) Advanced liver fibrosis but not steatosis is independently associated with albuminuria in Chinese patients with type 2 diabetes. J Hepatol 68(1):147–156Google Scholar
  7. 7.
    Chang Y, Jung H-S, Yun KE, Cho J, Cho YK, Ryu S (2013) Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol 108(12):1861Google Scholar
  8. 8.
    Han E, Lee Y-h (2017) Non-alcoholic fatty liver disease: the emerging burden in cardiometabolic and renal diseases. Diabetes Metab J 41(6):430–437Google Scholar
  9. 9.
    Ratziu V, Giral P, Charlotte F et al (2000) Liver fibrosis in overweight patients. Gastroenterology 118(6):1117–1123Google Scholar
  10. 10.
    Petta S, Eslam M, Valenti L et al (2017) Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: an age-dependent risk profiling study. Liver Int 37(9):1389–1396Google Scholar
  11. 11.
    Mena Á, Pedreira JD, Castro Á, López S, Vázquez P, Poveda E (2014) Metabolic syndrome association with fibrosis development in chronic hepatitis B virus inactive carriers. J Gastroenterol Hepatol 29(1):173–178Google Scholar
  12. 12.
    Cai S, Ou Z, Liu D et al (2018) Risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patient with component of metabolic syndrome. United Eur Gastroenterol J 6(4):558–566Google Scholar
  13. 13.
    Hui JM, Sud A, Farrell GC et al (2003) Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression. Gastroenterology 125(6):1695–1704Google Scholar
  14. 14.
    Zhao H, Song X, Li Z, Wang X (2018) Risk factors associated with nonalcohol fatty liver disease and fibrosis among patients with type 2 diabetes mellitus. Medicine 97(37):e12356Google Scholar
  15. 15.
    Williamson R, Price J, Hayes P et al (2011) Prevalence and markers of advanced liver disease in type 2 diabetes. QJM Int J Med 105(5):425–432Google Scholar
  16. 16.
    Domanski JP, Harrison SA (2013) The AST to ALT ratio: a pattern worth considering. Curr Hepat Rep 12(1):47–52Google Scholar
  17. 17.
    Mofrad P, Contos MJ, Haque M et al (2003) Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37(6):1286–1292Google Scholar
  18. 18.
    Saadeh S, Younossi ZM, Remer EM et al (2002) The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123(3):745–750Google Scholar
  19. 19.
    Mohr R, Boesecke C, Dold L et al (2018) Return-to-health effect of modern combined antiretroviral therapy potentially predisposes HIV patients to hepatic steatosis. Medicine 97(17):e0462Google Scholar
  20. 20.
    Azizi F, Hadaegh F, Khalili D et al (2010) Appropriate definition of metabolic syndrome among Iranian adults: report of the Iranian National Committee of Obesity. Arch Iran Med 13(5):426Google Scholar
  21. 21.
    Muzzi A, Leandro G, Rubbia-Brandt L et al (2005) Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol 42(1):41–46Google Scholar
  22. 22.
    Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata M (2011) Insulin resistance and chronic liver disease. World J Hepatol 3(5):99Google Scholar
  23. 23.
    Paradis V, Perlemuter G, Bonvoust F et al (2001) High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34(4):738–744Google Scholar
  24. 24.
    Leighton E, Sainsbury CA, Jones GC (2017) A practical review of C-peptide testing in diabetes. Diabetes Ther 8(3):475–487Google Scholar
  25. 25.
    Atsawarungruangkit A, Chenbhanich J, Dickstein G (2018) C-peptide as a key risk factor for non-alcoholic fatty liver disease in the United States population. World J Gastroenterol 24(32):3663Google Scholar
  26. 26.
    van Genderen FT, Gorus FK, Pipeleers DG, van Schravendijk CF (2013) Sensitive and specific time-resolved fluorescence immunoassay of rat C-peptide for measuring hormone secretory and storage capacity of β-cells in vivo and in vitro. Endocrinology 154(5):1934–1939Google Scholar
  27. 27.
    Chai S-Y, Pan X-Y, Song K-X et al (2014) Differential patterns of insulin secretion and sensitivity in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease versus patients with type 2 diabetes mellitus alone. Lipids Health Dis 13(1):7Google Scholar
  28. 28.
    Lomonaco R, Bril F, Portillo-Sanchez P et al (2016) Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 39:632–638Google Scholar
  29. 29.
    Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H (2008) Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135(1):122–130Google Scholar
  30. 30.
    Bril F, Lomonaco R, Orsak B et al (2014) Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology 59(6):2178–2187Google Scholar
  31. 31.
    Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G (2002) Mechanisms of hyperinsulinaemia in Child’s disease grade B liver cirrhosis investigated in free living conditions. Gut 51(6):870–875Google Scholar
  32. 32.
    Patel PJ, Hossain F, Horsfall LU et al (2018) Controlled attenuation parameter in NAFLD identifies risk of suboptimal glycaemic and metabolic control. J Diabetes Complicat 32(8):799–804Google Scholar
  33. 33.
    Ryysy L, Häkkinen A-M, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49(5):749–758Google Scholar
  34. 34.
    Lonardo A, Lugari S, Ballestri S, Nascimbeni F, Baldelli E, Maurantonio M (2019) A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol 56(4):385–396Google Scholar
  35. 35.
    Spreghini N, Cianfarani S, Spreghini MR et al (2019) Oral glucose effectiveness and metabolic risk in obese children and adolescents. Acta Diabetol.  https://doi.org/10.1007/s00592-019-01303-y Google Scholar
  36. 36.
    Manco M, Bedogni G, Marcellini M et al (2008) Waist circumference correlates with liver fibrosis in children with non alcoholic steatohepatitis. Gut 57:1283–1287Google Scholar
  37. 37.
    Nobili V, Alisi A, Vania A, Tiribelli C, Pietrobattista A, Bedogni G (2009) The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med 7(1):21Google Scholar
  38. 38.
    van der Poorten D, Milner KL, Hui J et al (2008) Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48(2):449–457Google Scholar
  39. 39.
    El-Koofy NM, Anwar GM, El-Raziky MS et al (2012) The association of metabolic syndrome, insulin resistance and non-alcoholic fatty liver disease in overweight/obese children. Saudi J Gastroenterol 18(1):44Google Scholar
  40. 40.
    Newsome PN, Cramb R, Davison SM et al (2018) Guidelines on the management of abnormal liver blood tests. Gut 67(1):6–19Google Scholar
  41. 41.
    Cho NH, Jang HC, Choi SH et al (2007) Abnormal liver function test predicts type 2 diabetes: a community-based prospective study. Diabetes Care 30(10):2566–2568Google Scholar
  42. 42.
    Wannamethee SG, Shaper AG, Lennon L, Whincup PH (2005) Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care 28(12):2913–2918Google Scholar
  43. 43.
    Williams AL, Hoofnagle JH (1988) Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis relationship to cirrhosis. Gastroenterology 95(3):734–739Google Scholar
  44. 44.
    Park GJH, Lin BP, Ngu MC, Jones DB, Katelaris PH (2000) Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? J Gastroenterol Hepatol 15(4):386–390Google Scholar
  45. 45.
    Teshale E, Lu M, Rupp L et al (2014) APRI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CH e CS). J Viral Hepatitis 21(12):917–920Google Scholar
  46. 46.
    Giannini E, Risso D, Botta F et al (2003) Validity and clinical utility of the aspartate aminotransferase–alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 163(2):218–224Google Scholar
  47. 47.
    Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC (2008) Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 47(4):1363–1370Google Scholar
  48. 48.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W (2013) Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 108(6):881Google Scholar
  49. 49.
    Li L, You W, Ren W (2017) The ZJU index is a powerful index for identifying NAFLD in the general Chinese population. Acta Diabetol 54(10):905–911Google Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  • Asieh Mansour
    • 1
  • Mohammad Reza Mohajeri-Tehrani
    • 2
  • Majid Samadi
    • 3
  • Hadis Gerami
    • 4
  • Mostafa Qorbani
    • 5
    • 6
  • Nick Bellissimo
    • 7
  • Hossein Poustchi
    • 8
  • Azita Hekmatdoost
    • 1
    Email author
  1. 1.Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research InstituteShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
  3. 3.Radiology Department, Shariati HospitalTehran University of Medical SciencesTehranIran
  4. 4.Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
  5. 5.Non-communicable Diseases Research CenterAlborz University of Medical SciencesKarajIran
  6. 6.Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Endocrinology and Metabolism Research InstituteTehran University of Medical SciencesTehranIran
  7. 7.School of Nutrition, Faculty of Community ServicesRyerson UniversityTorontoCanada
  8. 8.Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research InstituteTehran University of Medical SciencesTehranIran

Personalised recommendations