AACE Endocrine Practice Journal: Published on May, 2022

Nonalcoholic fatty liver disease (NAFLD) is part of a multisystemic disease and is closely associated with obesity, insulin resistance (IR), type 2 diabetes mellitus (T2D), hypertension, and atherogenic dyslipidemia.

The definition of NAFLD is based on the presence of hepatic steatosis in >5% of hepatocytes in the absence of significant ongoing or recent alcohol consumption and other known causes of liver disease.

Nonalcoholic steatohepatitis (NASH), more likely to progress to advanced stages of fibrosis, is characterized by the presence of active hepatocyte injury (ballooning) and inflammation in addition to steatosis.

Summary of Recommendations

Management of NAFLD in adults

Q1 How should cardiometabolic risk and other extrahepatic complications be managed in the setting of NAFLD?

Clinicians must manage persons with NAFLD for obesity, metabolic syndrome, prediabetes, diabetes mellitus, dyslipidemia, hypertension, and CVD based on the current standards of care.

Q2 What lifestyle modifications (dietary intervention and exercise) should be recommended in adults with NAFLD?

Clinicians should recommend lifestyle changes in persons with excess adiposity and NAFLD with a goal of at least 5%, preferably ≥10%, weight loss, as more weight loss is often associated with greater liver histologic and cardiometabolic benefit, depending on individualized risk assessments. Clinicians must recommend participation in a structured weight loss program, when possible, tailored to the individual’s lifestyle and personal preferences.

Clinicians must recommend dietary modification in persons with NAFLD, including a reduction of macronutrient content to induce an energy deficit (with restriction of saturated fat, starch, and added sugar) and adoption of healthier eating patterns, such as the Mediterranean diet.

In persons with NAFLD, clinicians must recommend physical activity that improves body composition and cardiometabolic health. Participation in a structured exercise program should be recommended, when possible, tailored to the individual’s lifestyle and personal preferences.

Q3 What medications have proven to be effective for the treatment of liver disease and cardiometabolic conditions associated with NAFLD or NASH?

Pioglitazone and GLP-1 RAs are recommended for persons with T2D and biopsy-proven NASH.

Clinicians must consider treating diabetes with pioglitazone and/or GLP-1 RAs when there is an elevated probability of having NASH based on elevated plasma aminotransferase levels and noninvasive tests.

To offer cardiometabolic benefit in persons with T2D and NAFLD, clinicians must consider treatment with GLP-1 RAs, pioglitazone, or SGLT2 inhibitors; however, there is no evidence of benefit for treatment of steatohepatitis with SGLT2 inhibitors.

Due to the lack of evidence of efficacy, metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin are not recommended for the treatment of steatohepatitis (no benefit on hepatocyte necrosis or inflammation) but may be continued as needed for the treatment of hyperglycemia in persons with T2D and NAFLD or NASH.

Vitamin E can be considered for the treatment of NASH in persons without T2D, but there is not enough evidence at this time to recommend for persons with T2D or advanced fibrosis.

Q4 What obesity pharmacotherapies have proven benefit for the treatment of liver disease and cardiometabolic conditions associated with NAFLD or NASH in adults?

Clinicians should recommend the use of obesity pharmacotherapy as adjunctive therapy to lifestyle modification for individuals with obesity and NAFLD or NASH with a goal of at least 5%, preferably ≥10 %, weight loss, as more weight loss is often associated with greater liver histologic and cardiometabolic benefit, when this is not effectively achieved by lifestyle modification alone.

For chronic weight management in individuals with a BMI of ≥27 kg/m² and NAFLD or NASH, clinicians should give preference to semaglutide 2.4 mg/week (best evidence) or liraglutide 3 mg/day.

Clinicians must consider obesity pharmacotherapy (with preference to semaglutide 2.4 mg/week [best evidence] or liraglutide 3 mg/day) as adjunctive therapy to lifestyle modification for individuals with obesity and NAFLD or NASH to promote cardiometabolic health and treat or prevent T2D, CVD, and other end-stage manifestations of obesity.

Q5 What is the effect of bariatric surgery on liver disease and cardiometabolic conditions associated with NAFLD or NASH in adults?

Clinicians should consider bariatric surgery as an option to treat NAFLD and improve cardiometabolic health in persons with NAFLD and a BMI of ≥35 kg/m² (≥32.5 kg/m² in Asian populations), particularly if T2D is present. It should also be considered an option in those with a BMI of ≥30 to 34.9 kg/m² (≥27.5 to 32.4 kg/m² in Asian populations)

For persons with NASH and compensated cirrhosis, clinicians should exercise caution in recommending bariatric surgery, which should be highly individualized if prescribed and performed at experienced centers.

In persons with decompensated cirrhosis, bariatric surgery should not be recommended due to limited evidence and potential for harm.

Endoscopic bariatric and metabolic therapies and orally ingested devices should not be recommended in persons with NAFLD due to insufficient evidence.