Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of fat in hepatocytes with or without evidence of significant necro-inflammation or fibrosis.
NAFLD has a histologic spectrum that ranges from the relatively benign NAFLD to the aggressive form of nonalcoholic steatohepatitis with or without liver fibrosis to nonalcoholic steatohepatitis-cirrhosis leading to end-stage liver disease (1).
Today, NAFLD is a major cause of hepatocellular carcinoma (HCC) (2). HCC is one of the most common cancer in the world. Incidence varies across the world and generally follows geographical distribution of viral hepatitis B and C (3).
NAFLD is considered the hepatic manifestation of insulin resistance that characterizes type 2 diabetes mellitus (T2DM) (1).
The prevalence of diabetes mellitus in the world is steadily increasing due to the increase in the average age of the general population and changes in lifestyle (4). The global prevalence of diabetes mellitus has doubled in the last thirty years (5). In 2010, an estimated 285 million people had diabetes mellitus, 90% of whom T2DM (4). Globally, prevalence of diabetes mellitus is estimated to rise to 439 million by 2030, that represents 7.7% of the total adult population of the world aged 20–79 years (6).
In fact, diabetes mellitus can be considered a silent killer and a possible trigger of multiple diseases, both cardiovascular and liver related.
A recent prospective study of 0.5 million people showed that individuals with known diabetes and those not aware to have diabetes with higher blood glucose levels have significantly increased risk of major chronic liver diseases and HCC. Compared with those without diabetes, those with diabetes had adjusted hazard ratios (HRs) of 1.49 (95% CI, 1.30–1.70) for HCC, 1.81 (1.57–2.09) for cirrhosis, 1.76 (1.47–2.16) for NAFLD, and 2.24 (1.42–3.54) for alcoholic liver disease (ALD). Among those without previously diagnosed diabetes, random plasma glucose (RPG) was significantly associated with liver diseases, with adjusted HRs per 1 mmol/L higher RPG of 1.04 (1.03–1.06) for HCC, 1.07 (1.05–1.09) for cirrhosis, 1.07 (1.05–1.10) for NAFLD, and 1.10 (1.05–1.15) for ALD. According to the authors, one of the most important mechanisms that could explain the association between diabetes and liver disease is insulin resistance. In fact, insulin promotes tumor cell growth both directly and indirectly through the insulin-like growth factor (IGF). Authors concluded that early detection of diabetes could help identify patients at increased risk for chronic liver disease, reducing progression to cirrhosis and HCC (7).
A possible correlation between diabetes and liver disease has also been suggested by other studies.
In particular, a retrospective court study reported HCC incidence to be significantly more frequent in diabetic than in non-diabetic people. Moreover, risk of HCC increased in patients with diabetes and comorbidities, such as cirrhosis, hepatitis C and B. Increased risk of HCC in patients with diabetes and cirrhosis, hepatitis C, and/or B may be due to a synergistic effect between diabetes and these concomitant liver comorbidities (8).
Seven cohort studies and two case-control studies evaluated the associations between diabetes mellitus, body mass index and steatosis and the risk of HCC in patients with chronic hepatitis C. The risk of HCC associated with diabetes mellitus was significantly increased in 5 of the 7 studies (9).
Recently, some diabetes medications have been evaluated for the treatment of NAFLD with encouraging results.
It has been reported that both treatment with sulfonylureas and insulin could be responsible for an increased risk of NAFLD and HCC (12).
In a randomized study, Sitagliptin, dipeptidyl peptidase-4 inhibitor, was not shown to be useful in improving hepatic steatosis and fibrosis (13).
A recent multicenter, double-blind, randomized study has shown that liraglutide improves NASH. The liraglutide has been linked to a slowing of the progression of liver fibrosis and to an improvement of its biomarkers (16). Moreover, Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was reported to improve NASH. Exenatide has been associated with weight loss, reduced levels of glucose, insulin, lipid and transaminase, representing a possible resource in the treatment of NAFLD (17).
In conclusion, there is a clear association of diabetes with both advanced liver disease and HCC. Further studies are needed to provide more information about the role of anti-diabetes therapies as prevention of liver disease progression.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Alkhouri N, Poordad F, Lawitz E. Management of Nonalcoholic Fatty Liver Disease: Lessons Learned From Type 2 Diabetes. Hepatol Commun 2018;2:778-85. [Crossref] [PubMed]
- White DL, Thrift AP, Kanwal F, et al. Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012. Gastroenterology 2017;152:812-20.e5. [Crossref] [PubMed]
- Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86. [Crossref] [PubMed]
- Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782-7. [Crossref] [PubMed]
- Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 2011;378:31-40. [Crossref] [PubMed]
- Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4-14. [Crossref] [PubMed]
- Pang Y, Kartsonaki C, Turnbull I, et al. Diabetes, plasma glucose and incidence of fatty liver, cirrhosis and liver cancer: A prospective study of 0.5 million people. Hepatology 2018. [Epub ahead of print]. [Crossref] [PubMed]
- Lai SW, Chen PC, Liao KF, et al. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 2012;107:46-52. [Crossref] [PubMed]
- Dyal HK, Aguilar M, Bartos G, et al. Diabetes Mellitus Increases Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients: A Systematic Review. Dig Dis Sci 2016;61:636-45. [Crossref] [PubMed]
- Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-68. [Crossref] [PubMed]
- Rakoski MO, Singal AG, Rogers MA, et al. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2010;32:1211-21. [Crossref] [PubMed]
- Mazzotti A, Caletti MT, Marchignoli F, et al. Which treatment for type 2 diabetes associated with non-alcoholic fatty liver disease? Dig Liver Dis 2017;49:235-40. [Crossref] [PubMed]
- Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016;65:369-76. [Crossref] [PubMed]
- Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85. [Crossref] [PubMed]
- Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med 2016;165:305-15. [Crossref] [PubMed]
- Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90. [Crossref] [PubMed]
- Li S, Wang X, Zhang J, et al. Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease. Braz J Med Biol Res 2018;51. [Crossref] [PubMed]
Cite this article as: Terrana L, Mancuso A. Diabetes mellitus and liver disease. AME Med J 2018;3:93.