During the June 2019 ADA conference, one of the topics highlighted was Non-Alcoholic Fatty Liver Disease (NAFLD), a frequently overlooked complication in patients with diabetes. Patients are often asymptomatic and unless specific laboratory testing or imaging is done, the condition may remain undetected for many years. NAFLD encompasses a spectrum of potentially progressive disease from simple steatosis to more severe forms such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. The focus on NAFLD is growing in importance as we recognize the morbidity and mortality associated with the cardiovascular and hepatic sequelae of the disease. In a 2005 study by Adam et al., 25% of deaths that occurred in their cohort of 420 patients with NAFLD were due to ischemic heart disease¹. With the growing obesity epidemic worldwide, the prevalence of NAFLD has also increased and is currently estimated to be around 24%². A strong association is seen between NAFLD and type 2 diabetes mellitus (T2DM) with a reported 55.5% prevalence in this group globally, while the prevalence of NASH was 37.3%³. Recent real world data also found diabetes to be an independent risk factor for disease progression to cirrhosis or hepatocellular carcinoma⁴.

NAFLD is strongly linked with hepatic and adipose tissue insulin resistance as well as systemic insulin resistance. Whether insulin resistance causes hepatic steatosis or whether the accumulation of hepatic fat occurs as the principal event that leads to hepatic and then later peripheral insulin resistance is not well-understood⁵.  There is also a complex interplay between genetic and environmental factors in influencing the progression of NAFLD. Patatin-like phospholipase domain-containing 3 (PNPLA3) gene, transmembrane 6 superfamily member 2 (TM6SF2) gene, and the glucokinase regulator (GCKR) gene are the three common genetic variants linked to the progression of NAFLD⁶.

Diagnosis of NAFLD is based on the presence of hepatic steatosis confirmed by imaging or histology and exclusion of other causes of hepatic steatosis such as alcohol consumption, hepatitis C, Wilson disease, and severe malnutrition; coexisting causes of chronic liver disease must also be excluded⁷.  The gold standard for diagnosing NAFLD is liver biopsy; however, as it is invasive, the procedure should be used selectively and only in patients in whom the benefit will likely outweigh associated risks. Ultrasound of the liver is the most accessible noninvasive imaging method and can detect both hepatic steatosis and cirrhosis. (However, in hepatic steatosis, ultrasonography is only able to detect when hepatocytes contain more than 20% of fat droplets⁸.) Elastographic imaging, such as ultrasound elastography or magnetic resonance elastography, can be used to assess liver stiffness and aid in risk stratification for advanced fibrosis. Clinical prediction scores, such as those obtained with the Fibrosis 4 calculator (FIB-4), NAFLD fibrosis score (NFS), and aspartate aminotransferase to platelet ratio index (APRI), can be used to monitor patients at risk of fibrosis. Use of both elastography imaging and clinical prediction scores can help guide patient selection for liver biopsy.

Treatment for NAFLD encompasses not only hepatic-directed therapy, but also the coexisting metabolic syndrome. Weight loss is strongly recommended to decrease hepatic fat accumulation and delay the development of inflammation and fibrosis. Weight reduction in the range of 5% to 7% can decrease steatosis, however, at least 8% to 10% weight reduction is needed to reverse steatohepatitis⁹.  Pharmacologic treatment is indicated for NASH and fibrosis that have been confirmed by biopsy. Current options are limited to pioglitazone (a thiazolidinedione) and vitamin E. Pioglitazone can be used in patients with or without type 2 diabetes who also have NASH. Due to the lack of studies in patients with diabetes⁷, vitamin E is recommended for use only in patients without diabetes. Phase III studies that include patients with diabetes have been completed for several newer drugs to evaluate improvement in fibrosis and NASH. However, as we await more data, lifestyle modification and weight loss remain the cornerstone of therapy for NAFLD and NASH.

References:

1. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology. 2005;129:113-121.
2. Younossi ZM, Tacke F, Arrese M, et al. Global perspectives on non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis. Hepatology. 2019;69(6):2672-2682.
3. Younoussi ZM, Golabi P, de Avilla 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; DOI: 10.1016/j.jhep.2019.06.021
4. Alexander M, Loomis AK, van der Lei J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17(1):95.
5. Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease, 
   J Clin Endocrinol Metab. 2006;91(12):4753-4761.
6. Danford CJ, Yao ZM, Jiang ZG. Non-alcoholic fatty liver disease: a narrative review of genetics. 
   J Biomed Res. 2018;32(5):389–400.
7. Chalasani N, Younossi Z, Lavine JE, 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(1):328–357. 
8. Li Q, Dhyani M, Grajo JR, et al. Current status of imaging in nonalcoholic fatty liver disease. World J Hepatol. 2018;10(8):530–542.
9. Kim KS, Lee BW, Kim YJ, et al. Nonalcoholic fatty liver disease and diabetes: Part II: treatment. Diabetes Metab J. 2019;43(2):127–143.

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