AACE Endocrine Practice Journal: Published on May, 2022

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting 25% of the global population. 

NAFLD is associated with cardiometabolic disorders: (1) obesity, (2) insulin resistance, (3) type 2 diabetes mellitus, (4) high blood pressure, and (5) atherogenic dyslipidemia, all of which increase the risk of a heart attack or stroke, the most common cause of death.

Term NAFLD used for the broad spectrum of the disease, ranging from hepatic steatosis only to steatohepatitis (NASH) to cirrhosis, in the absence of ongoing or recent consumption of significant amounts of alcohol or the presence of other secondary causes of fatty liver disease.

Summary of Recommendations

Diagnosis of NAFLD in adults

Q1. Which adults with NAFLD should be considered at “high risk” of clinically significant fibrosis (stages F2-F4) and at risk of cirrhosis?

Clinicians should consider persons with obesity and/or features of metabolic syndrome, those with prediabetes or T2D, and those with hepatic steatosis on any imaging study and/or persistently elevated plasma aminotransferase levels (over 6 months) to be “high risk” and screen for NAFLD and advanced fibrosis.

Persons undergoing bariatric surgery should be evaluated for the presence and severity of NASH, and a liver biopsy should be considered at the time of bariatric surgery. Liver biopsy should be recommended if presurgical stratification suggests indeterminate or high risk of liver fibrosis.

Evidence Base

The diagnosis of NAFLD is based on the following: (1) presence of hepatic steatosis, in addition to (2) lack of significant alcohol consumption, and (3) exclusion of other liver diseases.

Initial evaluation in persons with suspected or incidental finding of hepatic steatosis on imaging should include investigations to exclude competing causes for hepatic steatosis and liver disease (eg, hepatitis B and C serology, antimitochondrial antibodies, antinuclear antibodies, anti–smooth muscle antibodies, serum ferritin, alpha 1 antitrypsin, and evaluation for MetS.)

Q2. What blood tests (eg, diagnostic panels and specific biomarkers) can be used to diagnose NAFLD with clinically significant fibrosis (stages F2-F4) in adults?

Clinicians should use liver fibrosis prediction calculations to assess the risk of NAFLD with liver fibrosis. The preferred noninvasive initial test is the FIB-4.

Clinicians should consider persons belonging to the “high-risk” groups who have an indeterminate or high FIB-4 score for further workup with an LSM (transient elastography) or ELF test, as available.

FIB-4 (Fibrosis-4 index): An index to estimate the risk of hepatic cirrhosis calculated from the computation of age, plasma aminotransferases (AST and ALT), and platelet count. This noninvasive estimate of liver scarring is used to assess the need for biopsy. The score is calculated using a person’s age, AST level, platelet count (PLT), and ALT level.

FIB-4 score = age (years) × AST (U/L)/[PLT (109/L) × ALT ½ (U/L).

Q3. What imaging studies can be used to diagnose NAFLD with clinically significant fibrosis (stages F2-F4) in adults?

To stage the risk of fibrosis in persons with NAFLD, clinicians should prefer the use of VCTE as best validated to identify advanced disease and predict liver-related outcomes. Alternative imaging approaches may be considered, including shear wave elastography (less well validated) and/or magnetic resonance elastography (most accurate but with a high cost and limited availability; best if ordered by liver specialist for selected cases).

Q4. Should all persons with diabetes mellitus be screened for clinically significant fibrosis (stages F2-F4) associated with NAFLD?

In persons with T2D, clinicians should consider screening for clinically significant fibrosis (stages F2-F4) using the FIB-4, even if they have normal liver enzyme levels.

In persons with T1D, clinicians may consider screening for NAFLD with clinically significant fibrosis (stages F2-F4) using the FIB-4, only if there are risk factors such as obesity, features of metabolic syndrome, elevated plasma aminotransferase levels (>30 U/L), or hepatic steatosis on imaging.

Clinicians should further risk stratify persons with T2D, or T1D with cardiometabolic risk factors and/or elevated plasma aminotransferase levels (>30 U/L) using the FIB-4, elastography, and/or ELF test.

Q5. When should an adult be referred to a gastroenterologist/hepatologist for management?

Persons with persistently elevated ALT or AST levels and/or with hepatic steatosis on imaging and indeterminate risk (FIB-4, 1.3-2.67; LSM, 8-12 kPa; or ELF test, 7.7-9.8) or high risk (FIB-4, >2.67; LSM, >12 kPa; or ELF test, >9.8) based on blood tests and/or imaging should be referred to a gastroenterologist or hepatologist for further assessment, which may include a liver biopsy.

Clinicians should refer persons with clinical evidence of advanced liver disease (ascites, hepatic encephalopathy, esophageal varices, or evidence of hepatic synthetic dysfunction) to a gastroenterologist/hepatologist for further care.

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