Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disease ranging from simple liver fat accumulation to severe hepatic necro-inflammation (nonalcoholic steatohepatitis or NASH), and eventually cirrhosis . Nonalcoholic fatty liver disease has become the most common cause of chronic liver disease and its prevalence will continue to increase as a consequence of the obesity epidemic. According to a study by Szczepaniak et al.  using the current gold-standard magnetic resonance imaging and spectroscopy (MRS) technique, about one third of the adult US population and as many as two thirds International Textbook of Diabetes Mellitus, Fourth Edition. Edited by Ralph A. DeFronzo, Ele Ferrannini, Paul Zimmet, and K. George M. M. Alberti. © 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd. of obese adults have NAFLD. More importantly, a significant number of patients are believed to have NASH. The real proportion remains uncertain depending on the population studied, clinical setting, and diagnostic screening approach. In patients screened for NAFLD in tertiary medical care settings, the prevalence of liver biopsy-proven NASH among patients with steatosis ranges from 30% to 44% [3,4].
Previously thought to be a harmless condition associated with the metabolic syndrome, NAFLD and NASH are now recognized as important risk factors for cardiovascular disease [5,6], type 2 diabetes mellitus (T2DM) , cirrhosis , and hepatocellular carcinoma . This emphasizes the importance of early diagnosis. However, the diagnosis of NASH can be challenging as it depends on performing a liver biopsy, which many primary care physicians and patients are unwilling to undergo.
Once NASH is diagnosed in a patient with T2DM, the main issue is how this diagnosis will affect the patient’s overall management. At present, there is no drug specifically approved for the treatment of NAFLD or NASH.While some pharmacologic agents appear to be promising [10,11], lifestyle intervention (mainly diet plus exercise) remains the standard of care to avoid disease progression [12,13].
Several drugs have been assessed in clinical trials for the treatment of NASH [10,11,14–19]. However, most of the studies have been small, of short duration, or had relied on surrogate markers (liver enzymes or ultrasound) for the diagnosis of NAFLD and for outcome measures. Only vitamin E (in patients without T2DM) and pioglitazone (in both patients with or without T2DM) have proven to be safe and effective in randomized, placebo-controlled trials [10,11]. Ongoing studies are assessing novel drugs for NAFLD/NASH but clinical use may be a few years away at the present time. Therefore, this chapter focuses primarily on the available evidence of nonpharmacologic and pharmacologic approaches for NAFLD and NASH.
Role of lifestyle intervention in NAFLD
It has been shown that hypocaloric diets, with or without physical activity, reduce the risk of cardiovascular disease (CVD) and T2DM [20,21]. However, their effect in patients with NAFLD has been less well studied. Most studies have had serious shortcomings ranging from small sample size to short duration [22–28], or simply lacking a control group [29–31]. Even in strongly controlled studies, significant variability in the dietary or exercise protocols make comparisons between studies and generalized conclusions difficult [32,33]. Another problem is that in the majority of trials, the diagnosis of NAFLD and treatment effect were not assessed by means of liver histology (liver biopsy), but rather with the use of surrogate markers [34–38]. Beyond these limitations, there appears to be consensus that patients with NAFLD benefit from diet and physical activity , although it is still unclear which lifestyle intervention strategy is the most beneficial. Studies have been inconsistent when assessing different types of diet (low fat, low carbohydrates, and so on) [22–24,39,40], and exercise training protocols (i.e., aerobic vs. resistance training) , either with or without weight reduction. In the following sections we will discuss efforts in trying to establish the best approach for patients with NAFLD/NASH.