Diabetes mellitus is one of the most prevalent metabolic diseases worldwide, causing an enormous burden on the economies of both developed and developing nations. Nonalcoholic fatty liver disease (NAFLD) is very closely associated with diabetes, and the two diseases are known to cause an increase in morbidity and mortality. Timely referral of a diabetic with NAFLD to a hepatologist can definitely delay disease progression and the related complications. Despite the magnitude, there are no guidelines that recommend a screening algorithm that must be followed for evaluating NAFLD in at-risk diabetics at the primary care level and their further referral to hepatologists. Nonalcoholic fatty liver disease management needs heightened awareness among primary care physicians/endocrinologists and hepatologists, and a collaborative care approach is paramount in these patients. Certain antidiabetic drugs are found to be beneficial in the treatment of NAFLD patients with diabetes, however, none of them are FDA approved.
Pepper W. Saccharine diabetes. Med Rec 1884;25:9–12.
Connor CL. Fatty infiltration of the liver and the development of cirrhosis in diabetes and chronic alcoholism. Am J Pathol 1938; 14(3):347–364. PMID: 19970395.
Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018;20(2):12. DOI: 10.1007/s11906-018-0812-z.
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(5):1212–1218. DOI: 10.2337/dc06-2247.
Williamson RM, Price JF, Glancy S, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes Care 2011;34(5):1139–1144. DOI: 10.2337/dc10-2229.
Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143(10):722–728. DOI: 10.7326/0003-4819-143-10-200511150-00009.
Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005;15(3):310–315. DOI: 10.1381/0960892053576820.
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. Diabetologia 2016;59(6):1121–1140. DOI: 10.1007/s00125-016-3902-y.
Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease? BMJ 2011;343:d3897. DOI: 10.1136/bmj.d3897.
Tanase DM, Gosav EM, Costea CF, et al. The intricate relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). J Diabetes Res 2020;2020:3920196. DOI: 10.1155/2020/3920196.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016;65(8): 1038–1048. DOI: 10.1016/j.metabol.2015.12.012.
Knop FK. EJE PRIZE 2018: A gut feeling about glucagon. Eur J Endocrinol 2018;178(6):R267–R280. DOI: 10.1530/EJE-18-0197.
Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes Metab 2016;42(3):142–156. DOI: 10.1016/j.diabet.2016.04.002.
Ballestri S, Zona S, Targher G, et al. 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 2016;31(5):936–944. DOI: 10.1111/jgh.13264.
Adams LA, Lymp JF, St. Sauver J, et al. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005;129(1):113–121. DOI: 10.1053/j.gastro.2005.04.014.
Bazick J, Donithan M, Neuschwander-Tetri BA, et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: Guidelines for referral in NAFLD. Diabetes Care 2015;38(7):1347–1355. DOI: 10.2337/dc14-1239.
Younossi ZM, Golabi P, de Avila L, 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.
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126(2):460–468. DOI: 10.1053/j.gastro.2003.10.065.
Aleksandrova K, Boeing H, Nöthlings U, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 2014;60(3):858–871. DOI: 10.1002/hep.27016.
Afolabi BI, Ibitoye BO, Ikem RT, et al. The relationship between glycaemic control and non-alcoholic fatty liver disease in Nigerian type 2 diabetic patients. J Natl Med Assoc 2018;110(3):256–264. DOI: 10.1016/j.jnma.2017.06.001.
Targher G, Bertolini L, Rodella S, 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):2119–2121. DOI: 10.2337/dc07-0349.
Targher G, Bertolini L, Rodella S, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51(3):444–450. DOI: 10.1007/s00125-007-0897-4.
Williams KH, Burns K, Constantino M, et al. An association of large-fibre peripheral nerve dysfunction with non-invasive measures of liver fibrosis secondary to non-alcoholic fatty liver disease in diabetes. J Diabetes Complications 2015;29(8):1240–1247. DOI: 10.1016/j.jdiacomp.2015.06.015.
Ziegler D, Strom A, Kupriyanova Y, et al. Association of lower cardiovagal tone and baroreflex sensitivity with higher liver fat content early in type 2 diabetes. J Clin Endocrinol Metab 2018;103(3):1130–1138. DOI: 10.1210/jc.2017-02294.
Younossi ZM, Koenig AB, Abdelatif D, et al. 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.
Non-alcoholic Fatty Liver Disease Study Group, Lonardo A, Bellentani S, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis 2015;47(12):997–1006. DOI: 10.1016/j.dld.2015.08.004.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55(6):2005–2023. DOI: 10.1002/hep.25762.
American Diabetes Association. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019;42(Suppl 1):S34–S45. DOI: 10.2337/dc19-S004.
Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137(1):1–10. DOI: 10.7326/0003-4819-137-1-200207020-00006.
Armstrong MJ, Marchesini G. Referral pathways for NAFLD fibrosis in primary care–No longer a ‘needle in a haystack’. J Hepatol 2019;71(2):246–248. DOI: 10.1016/j.jhep.2019.05.010.
Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology 2017;66(1): 84–95. DOI: 10.1002/hep.29113.
Nones RB, Ivantes CP, Pedroso MLA. Can FIB4 and NAFLD fibrosis scores help endocrinologists refer patients with non-alcoholic fat liver disease to a hepatologist? Arch Endocrinol Metab 2017;61(3): 276–281. DOI: 10.1590/2359-3997000000233.
Harman DJ, Ryder SD, James MW, et al. Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: A cross-sectional study using transient elastography. Aliment Pharmacol Ther 2018;47(4):504–515. DOI: 10.1111/apt.14463.
Vieira Barbosa J, Lai M. Nonalcoholic fatty liver disease screening in type 2 diabetes mellitus patients in the primary care setting. Hepatol Commun 2020;5(2):158–167. DOI: 10.1002/hep4.1618.
Davyduke T, Tandon P, Al-Karaghouli M, et al. Impact of implementing a “FIB-4 First” strategy on a pathway for patients with NAFLD referred from primary care. Hepatol Commun 2019;3(10):1322–1333. DOI: 10.1002/hep4.1411.
Boursier J, Guillaume M, Leroy V, et al. New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD. J Hepatol 2019;71(2):389–396. DOI: 10.1016/j.jhep.2019.04.020.
Patel PJ, Banh X, Horsfall LU, et al. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: Limited awareness of surrogate markers of fibrosis. Intern Med J 2018;48(2):144–151. DOI: 10.1111/imj.13667.
Sasso M, Beaugrand M, de Ledinghen V, et al. Controlled attenuation parameter (CAP): A novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: Preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol 2010;36(11):1825–1835. DOI: 10.1016/j.ultrasmedbio.2010.07.005.
Cusi K. A diabetologist's perspective of non-alcoholic steatohepatitis (NASH): Knowledge gaps and future directions. Liver Int 2020;40(Suppl 1):82–88. DOI: 10.1111/liv.14350.
Sasso M, Tengher-Barna I, Ziol M, et al. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): Validation in chronic hepatitis C. J Viral Hepat 2012;19(4):244–253. DOI: 10.1111/j.1365-2893.2011.01534.x.
de Lédinghen V, Vergniol J, Capdepont M, et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinations. J Hepatol 2014;60(5): 1026–1031. DOI: 10.1016/j.jhep.2013.12.018.
Lee JH, Kim D, Kim HJ, et al. Hepatic steatosis index: A simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis 2010;42(7):503–508. DOI: 10.1016/j.dld.2009.08.002.
Nair S, Diehl AM, Wiseman M, et al. Metformin in the treatment of non-alcoholic steatohepatitis: A pilot open label trial. Aliment Pharmacol Ther 2004;20(1):23–28. DOI: 10.1111/j.1365-2036.2004.02025.x.
Haukeland JW, Konopski Z, Eggesbø HB, et al. Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial. Scand J Gastroenterol 2009;44(7):853–860. DOI: 10.1080/00365520902845268.
Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: One-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology 2008;135(1):100–110. DOI: 10.1053/j.gastro.2008.03.078.
Musso G, Cassader M, Paschetta E, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis. JAMA Intern Med 2017;177(5):633–640. DOI: 10.1001/jamainternmed.2016.9607.
García Díaz E, Guagnozzi D, Gutiérrez V, et al. Effect of incretin therapies compared to pioglitazone and gliclazide in non-alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study. Endocrinol Nutr 2016;63(5): 194–201. DOI: 10.1016/j.endonu.2016.01.006.
Shao N, Kuang HY, Hao M, et al. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev 2014;30(6): 521–529. DOI: 10.1002/dmrr.2561.
Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016;65(2):369–376. DOI: 10.1016/j.jhep.2016.04.021.
Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial. World J Gastroenterol 2017;23(1):141–150. DOI: 10.3748/wjg.v23.i1.141.
Ohki T, Isogawa A, Toda N, et al. Effectiveness of Ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, as a second-line treatment for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus who do not respond to incretin-based therapies including glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors. Clin Drug Investig 2016;36(4):313–319. DOI: 10.1007/s40261-016-0383-1.
Takase T, Nakamura A, Miyoshi H, et al. Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: An association with glucose-lowering effects. Endocr J 2017;64(3):363–367. DOI: 10.1507/endocrj.EJ16-0295.