Management of Nonalcoholic Fatty Liver Disease (NAFLD)

1. Introduction

When we consider the management of Nonalcoholic Fatty Liver Disease (NAFLD), two aspects should be considered. One is that it can be a part of the metabolic syndrome [1]. About 80% of patients with metabolic syndrome have NAFLD [2]. Although the prevalence of NAFLD is 20–40% in the general population, about 70% of type 2 diabetes mellitus [3] and 85% of patients with morbid obesity (BMI ≥ 40) have NAFLD [4]. In the general population, 80% of patients with NAFLD are overweight and 20% of NAFLD patients have normal weight as per ultrasonography [5]. Another aspect is that it covers a spectrum of hepatic involvement as it progresses slowly from one stage to another. Initially, it starts as simple steatosis or benign fatty liver disease or nonalcoholic fatty liver (NAFL), where there is only macrovesicular hepatic steatosis (>5% of hepatocytes are affected) without any inflammation, hepatocellular injury or fibrosis [6]. The second phase is nonalcoholic steatohepatitis (NASH) where there is not only hepatic steatosis but also ballooning degeneration of hepatocytes and mixed inflammatory cells (lymphocytes, plasma cells, monocytes, neutrophils and eosinophils) infiltrates mainly involving the hepatic acini [7]. The third phase is hepatic fibrosis which generally starts from zone 3 and progresses to bridging fibrosis, cirrhosis of liver and hepatocellular cancer. Prognosis depends on the degree of liver fibrosis [8].

2. Purpose

The main purpose of management of NAFLD is to halt the process as soon as it is diagnosed. The three main modalities of therapy include lifestyle modification, pharmacotherapy and bariatric surgery. Lifestyle modification is applicable to all stages of NAFLD, whereas pharmacotherapy and bariatric surgery should not be considered for patients with simple steatosis. Pharmacotherapy should be considered only for patients with biopsy-proven NASH and hepatic fibrosis as per the guideline of American Association for the Study of Liver Diseases (AASLD).

3. Lifestyle modification

As NAFLD is related to insulin resistance, gradual weight loss is extremely important in overweight and obese individuals [9]. Rapid weight loss can cause portal inflammation and fibrosis [10]. About 7–10% of weight loss over one year by lifestyle changes has been associated with histological improvement in simple steatosis and NASH [11]. Another study showed vigorous and moderate exercises were equally effective in reducing hepatic triglyceride content largely through weight loss [12]. Diet and moderate aerobic exercise are the first line measures to reduce weight and improve insulin resistance [13]. Dietary counseling should be highly encouraged. Consumption of high fructose containing food is the main cause of epidemic of obesity [14]. Patient should avoid high fructose containing foods like sweet, soda, desserts, breakfast cereals, granola bars and cakes. One study showed that in patients with NAFLD, fructokinase and fatty acid synthase activity are increased [15]. NAFLD may occur when there is a combination of genetic predisposition, sedentary life style and consumption of high-calorie foods [16]. One meta-analysis suggested that Omega-3 fatty acid supplementation in diet was beneficial in patients with NAFLD/NASH [17]. Patients should be encouraged to eat food rich in Omega-3 fatty acid (fish, canola, olive, perilla and chia). Food with high glycemic effects and saturated fat should be avoided [18].

In summary, lifestyle modification is the first line intervention in the management of NAFLD. This includes [1] weight loss of about 7–10% of body weight by a combination of diet and exercise [2], low-calorie diet [3], diet with high fructose and saturated fat should be avoided [4], diet with Omega-3 fatty acid supplement should be encouraged.

4. Pharmacotherapy

There are various pharmacological agents available for the management of NAFLD. Many of them have been found to be ineffective and some of them have high risk-benefit ratio [19]. There are various clinical trials ongoing. Here, we discuss the common agents available and the agents recommended by the American Association for the Study of Liver Diseases (ASSLD).

5. Elafibranor

Elafibranor is an agonist of PPAR-α and δ receptor. It has anti-inflammatory activity and can improve insulin sensitivity and lipid metabolism. It was evaluated in a phase II international study for the treatment of NASH [46]. In the post hoc analysis, elafibranor (120 mg/day for 1 year) group showed resolution of NASH without progression of fibrosis more than placebo (19% vs. 12%).

As the improvement was marginal, further studies are needed before using this agent in the treatment of NAFLD.

6. Future therapy

As hepatic inflammation, fibrosis, cirrhosis and subsequent malignancy are the main concerns of NAFLD, plenty of research and studies on anti-inflammatory and anti-fibrotic agents are on-going.

7. Summary

The management of NAFLD patients should be individualized (Table 1).

• Lifestyle change is the first line therapy: healthy food habit, increased physical activity, exercise and weight loss of 7–10%.

• Pharmacotherapy is to be considered when lifestyle changes fail to achieve the goal: vitamin E in nondiabetic biopsy-proven NASH, pioglitazone in both diabetic and nondiabetic biopsy-proven NASH, incretin mimetics in diabetes mellitus and NAFLD, statins in hyperlipidemia and NAFLD, orlistat in NAFLD and obesity when life-style changes fail to reduce weight loss.

• Bariatric surgery should be considered in obese individuals and noncirrhotic NAFLD.