What’s the Significance of NAFLD in Diabetes?
Kim A. Carmichael, MD—Series Editor
Carmichael KA. What’s the significance of NAFLD in diabetes?
Q. What are the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) in persons with diabetes?
A. NAFLD is the most common liver disease in the United States, with a reported overall prevalence of 19% to 46%,1 affecting between 75 million and 100 million persons.2 In general, obesity, male sex, and a positive family history of diabetes are risk factors.3
NAFLD is much more prevalent in persons with type 2 diabetes (T2D) (approximately 70%, depending on the methodology of measuring liver fat content) than in persons with type 1 diabetes (T1D) (approximately 8.8%).1
Interestingly, NAFLD is much more common in persons with T2D not previously treated with insulin (75.6%) compared with those treated with insulin (61.7%).1 Liver fat content, confirmed by magnetic resonance imaging, is also greater in this population than compared with persons with insulin-treated T2D or those with T1D.
There is no association between hemoglobin A1c level and liver fat content, but insulin dose requirements are higher among persons who have NAFLD.1
In persons with diabetes and NAFLD, it is important to consider the possibility of alcoholic liver disease or liver disease from other causes.
Q. What are the predisposing factors for NAFLD?
A. In persons with T1D or T2D, mean body mass index (BMI) is associated with elevated liver fat content. In persons with T2D, the mean fasting glucose level, triglyceride level, and transaminase level are higher among those with NAFLD.1 Among persons treated with insulin, serum free fatty-acid levels tend to be higher, and those who are insulin-naive tend to have a longer duration of diabetes and a higher level of adiponectin. Persons who are obese are at greater risk of progressing to a more severe form, nonalcoholic steatohepatitis (NASH). In persons with T1D, older age, hypertension, and an elevated serum urate level are more likely to be associated with NAFLD.
Q. What abnormal laboratory test findings may be seen in persons with NAFLD and diabetes?
A. Although NAFLD typically may be associated with elevated transaminase levels, particularly alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT),3 it may also be an incidental finding on abdominal imaging.4
In a study of 103 adults with T2D and a normal transaminase level, NAFLD was discovered via magnetic resonance spectroscopy in 50% of participants; among participants in that subset with NAFLD, 56% had advanced to NASH.4 In this study, individuals with greater weight and higher hemoglobin A1c levels were more likely to have NAFLD. However, routine ultrasonography is not recommended, since it has low sensitivity in detecting serious disease.3
Q. What complications may arise in persons with NAFLD and diabetes?
A. Individuals with NAFLD are at higher risk of developing NASH, with a greater incidence of fibrosis, cirrhosis, hepatocellular carcinoma, and associated cardiovascular disease.2 Persons with NASH have more-severe insulin resistance and are more likely to have chronic lipotoxicity. Fibrosis occurs in approximately 1 in 6 middle-aged adults with T2D, and this is a risk factor for subsequent cirrhosis.5
Q. What are the current treatment options for NAFLD?
A. It has been postulated that insulin therapy suppresses lipolysis, resulting in lower free fatty-acid content and reduced subsequent fatty uptake into the liver.1 Improvement in insulin sensitivity by way of lifestyle interventions, weight loss of approximately 10%, and even bariatric surgery may improve NAFLD and NASH,2 but long-term studies are lacking. Lifestyle modification may effectively lower ALT and GGT levels, as well.3
Statin therapy, even high-potency regimens, is safe and effective in NAFLD and thus should not be avoided, as long as transaminase levels remain less than 3 times the upper normal limit.3,6
A recent meta-analysis of 8 randomized clinical trials of pioglitazone use in persons with NAFLD, even among those without diabetes, demonstrated an improvement of histologic features in the setting of advanced fibrosis.5
Despite these findings, insufficient evidence exists to recommend pioglitazone therapy in the absence of advanced fibrosis; moreover, there are no data regarding clinical outcomes.7 Treatment may result in improvement in the incidence of cardiovascular events, but pioglitazone also is associated with fluid retention, an increased risk of heart failure and, in women, measurable bone loss.2
Insufficient evidence exists for any direct reduction in NAFLD associated with the use of metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, or sodium-glucose cotransporter-2 inhibitors, although there may be secondary benefit based on improved glycemic control.2
Q. When should persons with NAFLD be referred for specialty evaluation and follow-up?
A. Due to the high prevalence of NAFLD among the general population, and especially among the subset of the population with diabetes, refer patients to a gastroenterologist only when a high risk of progressive liver disease is present.3 One useful tool may be the BARD score, in which an AST:ALT ratio of greater than 0.8 suggests a higher risk for advanced disease. Transaminase levels greater than 3 times normal, or elevated alkaline phosphatase levels, are markers of more severe involvement, necessitating referral.
Imaging may also identify individuals with more-advanced disease, fibrosis, or hepatocellular carcinoma, but ultrasonography has poor sensitivity in detecting steatosis compared with biopsy.3
Kim A. Carmichael, MD, is an associate professor of medicine in the Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, at Washington University School of Medicine in St. Louis, Missouri. He discloses that he is on the speakers bureau for Janssen, which may be relevant to the content of this article.
- Cusi K, Sanyal AJ, Zhang S, et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diab Obes Metab. 2017;19(11):1630-1634.
- Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia. 2016;59(6):1112-1120.
- Sattar N, Forrest E, Preiss D. Non-alcoholic fatty liver disease. BMJ. 2014;349:g4596. doi:10.1136/bmj.g4596
- Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015;100(6):2231-2238.
- Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017;177(5):633-640.
- Bril F, Portillo-Sanchez P, Lomonaco R, et al. Liver safety of statins in prediabetes or T2DM and nonalcoholic steatohepatitis: post hoc analysis of a randomized trial. J Clin Endocrinol Metab. 2017;102(8):2950-2961.
- Yee HF Jr. The role of pioglitazone in the management of nonalcoholic steatohepatitis: are we there yet? JAMA Intern Med. 2017;177(5):640-641.