Non-alcoholic fatty liver disease (NAFLD) is now more common than alcoholic liver disease owing to the rapid rise in the prevalence of obesity (Marchesini et al., 2008), and NAFLD is the most common cause of abnormal liver function tests (Clark et al., 2011).

Its prevalence worldwide is thought to be approximately 20% in the general population and up to 70% in patients with type 2 diabetes mellitus (Chalasani et al., 2012). The first recognisable stage of NAFLD is hepatic steatosis, when fat content exceeds 5% of liver volume. Simple steatosis is usually benign in terms of risk of progression to more advanced liver disease, but given its high prevalence it none the less represents an important cause of cirrhosis (Vernon et al., 2011). Notably, NAFLD is strongly associated with insulin resistance and hyperglycaemia and it is therefore closely linked to type 2 diabetes.

Non-alcoholic steatohepatitis (NASH), the next stage of NAFLD, develops when hepatic inflammation ensues, and its prevalence in the general population is estimated at 3-5% (Chalasani et al., 2012); people with NASH are at much higher risk of clinically significant and progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma (Musso et al., 2011; Vernon et al., 2011).

Who Gets NAFLD?

Obesity is a major risk factor for the development of NAFLD. The increase in obesity is therefore the main driver for the greater prevalence of NAFLD in the community. There is a strong link between NAFLD and type 2 diabetes, even beyond adiposity (Sung et al., 2012).

Male sex and a family history of type 2 diabetes are also associated with a greater risk of NAFLD and NASH at any given body mass index (Loomba et al., 2012), and preliminary evidence suggests greater liver fat content in certain ethnicities that are also known to be at increased risk of type 2 diabetes (Petersen et al., 2006).

Preliminary evidence suggests a genetic predisposition to hepatic accumulation of fat in some people through the PNP3A gene (Yki-Jarvinen, 2014). Such people may not necessarily display the usual metabolic associations with NAFLD, but genetic screening for PNP3A is not currently recommended (Chalasani et al., 2012).

Strictly speaking, NAFLD should only be diagnosed in people who consume no or only modest amounts of alcohol (daily intake <20 g (2.5 units) in women and <30 g (3.75 units) in men), although the clinical reality is that in many people both obesity and alcohol will contribute to their level of liver fat and risk of progressive liver disease (Hart el al., 2010).

Uncommon causes of fatty liver also should be considered, such as:

• Drugs including amiodarone, diltiazem, steroids, synthetic oestrogens, tamoxifen, and highly active antiretroviral therapy;
• Refeeding syndrome and total parenteral nutrition;
• Severe weight loss after jejunoileal or gastric bypass; and
• Lipodystrophy and other rare disorders.

It is important to stress that many patients with NAFLD will be overweight or obese, asymptomatic, and have normal liver function test results.

References

Marchesini, G., Moscatiello, S., Di Domizio, S. & Forlani, G. (2008) Obesity-associated Liver Disease. Journal of Clinical Endocrinology and Metabolism. 93(11 Suppl 1), pp.S74-S80.

Clark, J.M., Brancati, F.L. & Diehl, A.M.E. (2011) Nonalcoholic Fatty Liver Disease: The Most Common Cause of Abnormal Liver Enzymes in the US Population. Gastroenterology. 120(5 Suppl 1), pp.A65.

Chalasani, N., Younossi, Z., Lavine, J.E., Diehl, A.M.E., Brunt, E.M., Cusi, K. et al. (2012) The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guidelines by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 55, pp.2005-2023.

Vernon, G., Baranova, A. & Younossi, Z.M. (2011) Systematic Review: The Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis in Adults. Aliment Pharmacological Therapeutics. 34, pp.274-285.

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 Test for Liver Disease Severity. Annals of Medicine. 43, pp.617-649.

Sung, K.C., Jeong, W.S., Wild, S.H. & Byrne, C.D. (2012) Combined Influence of Insulin Resistance, Overweight/Obesity, and Fatty Liver as Risk Factors for Type 2 Diabetes. Diabetes Care. 35, pp.717-722.

Loomba, R., Abraham, M., Unalp, A., Wilson, L., Lavine, J., Doo, E. et al. (2012) Association between Diabetes, Family History of Diabetes, and Risk of Nonalcoholic Steatohepatitis and Fibrosis. Hepatology. 56, pp.943-951.

Petersen, K.F., Dufour, S., Feng, J., Befroy, D., Dziura, J., Dalla, M.C., et al. (2006) Increased Prevalence of Insulin Resistance and Nonalcoholic Fatty Liver Disease in Asian-Indian Men. Proc Natl Acad Sci USA. 103, pp.18273-18277.

Yki-Jarvinen, H. (2014) Non-alcoholic Fatty Liver Disease as a Cause and a Consequence of Metabolic Syndrome. Lancet Diabetes Endocrinology. Published online 07 Apr 2014.

Hart, C.L., Morrison, D.S., Batty, G.D., Mitchell, R.J. & Davey, S.G. (2010) Effect of Body Mass Index and Alcohol Consumption on Liver Disease: Analysis of Data from Two Prospective Cohort Studies. British Medical Journal. BMJ2010;340:c1240.