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Associate Professor of Medicine
McGill University Health Centre
Division of Gastroenterology and Hepatology and Division of Infectious Diseases
Research Institute of McGill University Health Centre
Montreal, Quebec, Canada
Giada Sebastiani, MD, has disclosed that she has received funds for research support from Merck and Theratec; consulting fees from Allergan, Intercept, Gilead Sciences, Merck, Novartis, Novo Nordisk, and Pfizer; and fees for non-CME/CE services from AbbVie, Gilead Sciences, Merck, Novartis, Novo Nordisk, and Pfizer.
There are no treatments that are approved by the FDA for nonalcoholic steatohepatitis (NASH). But there are still ways to manage it. My current management of NASH relies on a 3-tiered approach: lifestyle interventions, specific pharmacotherapy, and metabolic risk management.
According to the 3 main international guidelines on management of nonalcoholic fatty liver disease (NAFLD) (AASLD 2018, EASL 2016, and APASL 2020), lifestyle modification is the cornerstone of treatment. Even a 3% loss in body weight can improve steatosis, and a 7% to 10% loss improves NASH and liver fibrosis.
The main problem in delivering effective lifestyle change in the real world is that few patients are able to sustain weight loss. As such, it is essential to involve the patient by explaining what NAFLD is and how it is reversible with lifestyle change. Individualization of the target is also key: It is important to set goals that, for the individual patient, are SMART: specific, measurable, achievable, relevant, and timely. I try to discuss appropriate interventions, such as regular meal patterns, reduced snacking, portion control, and avoiding fast food. I also encourage regular weighing of oneself, using calorie and activity tracking, reading nutrition information labels, and developing skills in meal planning and food preparation. Finally, I recommend group activities, such as local exercise or weight management programs, community gyms, and walking groups.
Evidence for Diet and Exercise
Dietary changes should aim to achieve a 500-1000 kcal energy deficit to induce a weight loss of 500-1000 g weekly. NAFLD-promoting components, such as processed food and food and beverages high in added fructose, should be avoided.
Some evidence suggests that the Mediterranean diet may be beneficial in NAFLD. This diet is rich in monounsaturated omega-3 and omega-6 fatty acids, polyphenols, dietary fibers, prebiotics, and plant proteins. Conversely, the Mediterranean diet is low in saturated and trans fats, animal proteins, and simple sugars.
Other diets with recent evidence of benefit in NAFLD include the green-Mediterranean diet, which is more enriched in polyphenols; a low-carbohydrate diet; and an intermittent calorie restriction diet.
Exercise may reduce or prevent hepatic steatosis, although its effect on other histologic features of NASH is unknown. Both aerobic exercise and resistance training reduce liver fat, so the choice of which exercise to recommend should be tailored to patient preferences to optimize adherence. Finally, bariatric surgery is an option in eligible patients as it improves histologic lesions of NASH, including fibrosis. The decision for bariatric surgery should be carefully individualized in patients with liver cirrhosis.
Currently recommended pharmacotherapies for NASH include the antioxidant vitamin E and the antidiabetic drug pioglitazone. In the landmark 2010 PIVENS trial, both vitamin E and pioglitazone improved histologic features of NASH but not liver fibrosis. Subsequent studies found that vitamin E improved both NAFLD activity score and liver fibrosis and also improved transplant-free survival and hepatic decompensation in NASH. A few studies also showed that pioglitazone may improve liver fibrosis.
The use of vitamin E and pioglitazone should be reserved for patients with biopsy proven NASH and liver fibrosis. Before deciding on their use, safety issues should be discussed with the patient, carefully considering the risk-to-benefit ratio:
Overall, I consider vitamin E in patients with NASH and liver fibrosis, without type 2 diabetes, particularly if obese, younger than 50 years of age, with baseline aspartate aminotransferase >50 U/L and liability to lose 5-10 kg (approximately 10-20 lb). I consider pioglitazone in patients with biopsy proven NASH and fibrosis when affected by type 2 diabetes.
Diabetes Drugs in NASH
Since type 2 diabetes is the most important risk factor for advanced fibrosis in NASH—and since weight loss can improve the histologic features of NASH and fibrosis—there may be potential for some diabetes drugs to have an effect on NAFLD. After all, the American Diabetes Association guidelines recommend GLP-1 receptor agonists (RAs) or SGLT2 inhibitors in adults with type 2 diabetes who need to minimize weight gain or promote weight loss.
Semaglutide, a GLP-1 RA, has been recently shown to induce weight loss of 14.9% in patients with obesity/overweight and no diabetes. Moreover, in a phase II trial in patients with overweight and biopsy-proven NASH, semaglutide was associated with NASH resolution without worsening of fibrosis. And the E-LIFT study of the SGLT2 inhibitor empagliflozin in patients with diabetes and NAFLD showed improvement in liver fat. None of these GLP-1 RAs or SGLT2 inhibitors is currently recommended specifically for treating NASH, but studies are ongoing.
Cardiometabolic Risk Management
Patients with NAFLD are also at high risk for cardiovascular mortality. Cardiovascular risk stratification and management of cardiometabolic risk should be an integral part of the therapeutic approach to NAFLD. Hyperglycemia should be treated, preferentially with GLP-1 RAs and/or SGLT2 inhibitors in patients for whom weight loss could be beneficial. Smoking cessation should be pursued and hypertension appropriately controlled. Statins should be considered in all patients with NAFLD and dyslipidemia. Of interest, preliminary data suggest that statins may lower the risk of portal hypertension in patients with liver cirrhosis.
How do you manage NAFLD and NASH with currently available approaches? Answer the polling question and join the conversation by posting in the discussion section.