Published June 24, 2022
Published June 23, 2022
Primary care clinicians are all too aware of the growing problem of nonalcoholic fatty liver disease (NAFLD) in our midst. According to the American Liver Foundation, approximately one-quarter of Americans has NAFLD. Among these individuals, 12-14% develop nonalcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, portal hypertension, decompensated liver disease, and hepatocellular carcinoma. NASH currently follows hepatitis C as the second most common reason for liver transplantation in the US.
In May 2022, the American Association of Clinical Endocrinology (AACE), co-sponsored by the American Association for the Study of Liver Diseases (AASLD), released the first guidelines on the diagnosis and management of NAFLD aimed at primary care clinicians and endocrinologists.1 Primary care clinicians, in particular, are ideally placed to identify individuals with NAFLD, mitigate comorbid conditions, and prevent complications.
This article highlights the first-ever AACE guidelines on NAFLD and how primary care clinicians can diagnose, manage, and treat this condition.
Early Identification of NAFLD
Screen all patients at high risk for NAFLD, including those with obesity, prediabetes, T2DM, and/or ≥2 other features of metabolic syndrome. Other individuals who should be screened include those with hepatic steatosis found on imaging and/or those with persistently elevated (>6 months) liver enzyme levels for which no other cause has been found.
Despite the high prevalence of NAFLD, fewer than 5% of individuals with the condition are aware that they have it.2,3 Even clinicians, including PCPs, endocrinologists, gastroenterologists, and hepatologist, underestimate the prevalence of NAFLD in high-risk groups.4
The development and degree of hepatic fibrosis is a major predictor of liver-related and all-cause mortality in NAFLD. Assessment of liver fibrosis is more important than diagnosing steatosis. Because abdominal ultrasound is suboptimally sensitive for mild-to-moderate steatosis, operator-dependent, and—especially—because it does not provide information about the severity of fibrosis (except in cases of cirrhosis), abdominal ultrasound is not required to diagnose NAFLD in high-risk individuals. Instead, clinicians should use liver fibrosis prediction calculations to assess the risk for NAFLD with liver fibrosis.
Recommendation: Use the screening test for NAFLD in adults is the fibrosis-4 (FIB-4) index.
This tool is inexpensive, easy to use, and takes advantage of readily obtainable lab results. In a primary care setting, FIB-4 scores are strongly associated with severe liver disease outcomes among individuals both with and without known chronic liver disease. The FIB-4 score is calculated using the patient's age, AST and ALT levels, and platelet (PLT) count. FIB-4 score = age (years) x AST (U/L)/[PLT (109/L) x ALT ½ (U/L).
AST and ALT play an important role in the FIB-4 index; however, in adults, plasma liver aminotransferase levels should not be used alone to screen for NAFDL as they are often normal, even in individuals with clinically significant fibrosis. On the other hand, serum ALT is recommended to screen for NAFLD in high-risk children and adolescents (those with obesity, T2DM, or polycystic ovary syndrome) as liver fibrosis prediction calculations are unreliable in this population.
FIB-4 Index Stratification for Liver Fibrosis
Low risk (FIB-4 <1.3) individuals can be managed in a primary care setting with a focus on obesity management and CVD prevention.
Intermediate risk (FIB-4 4.13-2.67) individuals should undergo either a liver stiffness measurement (LSM) by transient elastography or an enhanced liver fibrosis (ELF) blood test. If the patient is found to be at high risk or is still indeterminant after two non-invasive tests, referral should be placed to a hepatologist for further evaluation and treatment.
High risk (FIB-4 >2.67) individuals should be referred to a liver specialist with a multidisciplinary team to mitigate the risk of CVD and progression to cirrhosis.
There are multiple proprietary biomarkers for liver fibrosis, including the ELF, FibroTest, NIS4, and protopeptide of type III collagen. However, although the high specificity and negative predictive value of these tests can be used to rule out NAFLD, the tests have lower sensitivity and positive predictive value for establishing the presence of advanced fibrosis. Therefore, the 2022 AACE NAFLD guidelines do not recommend using these biomarkers in isolation when screening for and stratifying liver fibrosis. These biomarkers are also not recommended in children and adolescents as they are inaccurate or require further validation in this age group.
Treatment in the Primary Care Setting
Dietary modifications and physical activity that improves body composition and cardiometabolic health should be offered to all individuals with NAFLD.
Recommendation: Clinicians should recommend weight reduction for individuals who are obese or overweight, with a weight loss goal of at least 5% and preferably ≥10% as more weight loss is often associated with greater cardiometabolic benefit and reductions in steatohepatitis or liver fibrosis (≥10% weight loss).
Anti-obesity medications, structured weight loss programs, and bariatric surgery should be recommended if indicated, and tailored when possible, to the individual’s lifestyle and preferences. A GLP-1 receptor agonist (semaglutide [best evidence] or liraglutide) should be given preference when anti-obesity medication is used.
In addition to obesity management, patients with NAFLD should receive standard-of-care treatment of T2DM, prediabetes, metabolic syndrome, hypertension, dyslipidemia, and CVD. At present, no medications have an FDA indication to treat NAFLD. However, pioglitazone, semaglutide, and liraglutide demonstrated efficacy in treating NASH and preventing progression in adults.
Recommendation: Use pioglitazone or a GLP-1 RA for adult patients with T2DM and biopsy-proven NASH and suggest considering one of these medications for adults with a high probability of having NASH based on elevated liver enzymes and noninvasive tests. The guidelines state that a GLP-1 RA (best evidence for liraglutide) may be considered to treat pediatric obesity and/or T2DM, and such treatment may benefit pediatric NAFLD, although clinical trials in this area are lacking.
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1. Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocrine Practice. 2022;28(5):528-562.
2. Cleveland ER, Ning H, Vos MB, et al. Low Awareness of Nonalcoholic Fatty Liver Disease in a Population-Based Cohort Sample: the CARDIA Study. J Gen Intern Med. 2019;34(12):2772-2778.
3. Alqahtani SA, Paik JM, Biswas R, Arshad T, Henry L, Younossi ZM. Poor Awareness of Liver Disease Among Adults With NAFLD in the United States. Hepatol Commun. 2021;5(11):1833-1847.
4. Kanwal F, Shubrook JH, Younossi Z, et al. Preparing for the NASH Epidemic: A Call to Action. Diabetes Care. 2021;44(9):2162-2172.