First Fatty Liver Guidelines for Endocrinology, Primary Care

Miriam E. Tucker

May 13, 2022

New clinical practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) are the first to be targeted specifically to primary care and endocrinology clinical settings.

They include 34 evidence-based clinical practice recommendations for screening, diagnosis, management, and referral, presented in a table and an algorithm flow chart as well as detailed text.

The new guidelines are by the American Association of Clinical Endocrinology (AACE) and co-sponsored by the American Association for the Study of Liver Diseases. They were presented May 12 at the AACE Annual Meeting 2022 and simultaneously published in Endocrine Practice.

These are "the first of this type for this field of medicine. The vast majority of patients with NAFLD are being seen in the primary care and endocrinology settings. Only when they get to the more advanced disease are they being referred to the liver specialists. So, we need to be the ones who are diagnosing and managing these patients because there just aren't enough liver specialists to do that," Scott Isaacs, MD, co-chair of the writing panel for the guidelines, told Medscape Medical News.

80 Million Americans Have NAFLD, but Very Few Are Aware

The spectrum of NAFLD ranges from nonprogressive steatosis to the progressive conditions nonalcoholic steatohepatitis (NASH), fibrotic NASH, and end-stage NASH cirrhosis. And NASH, in turn, is a major cause of liver cancer. NAFLD is also strongly associated with insulin resistance, type 2 diabetes, atherogenesis, and myocardial dysfunction.

The global prevalence of NAFLD is about 25% and NASH, about 12% to 14%. However, a recent study found that among patients in endocrine and primary care clinics, more than 70% of patients with type 2 diabetes and more than 90% with type 2 diabetes who had a body mass index (BMI) above 35 kg/m2 also had NAFLD, and more than 20% of those patients had significant liver fibrosis.

Problematically, very few people are aware they have either. "It's so common. At least 80 million Americans have this but only about 6% know they have it. We talk about it a lot, but it's not talked about enough," said Isaacs, an endocrinologist who practices in Atlanta, Georgia.

In fact, most cases of NAFLD are diagnosed incidentally when people undergo an ultrasound or a CT scan for another reason. And, in about 70% of cases the liver enzymes are normal, and those patients rarely undergo liver workups, Isaacs noted.    

In an accompanying editorial, Suthat Liangpunsakul, MD, writes: "In my perspective, as a hepatologist, this AACE guideline is very practical and easy to incorporate into routine practice in primary care and endocrinology settings...Early identification and risk stratification of patients with NAFLD, especially the degree of hepatic fibrosis, are required to reduce downstream healthcare costs and triage unwarranted specialty care referrals."

And "an effective screening strategy may also identify those in primary care and endocrinology settings who may benefit from an appropriate referral to hepatologists before the development of portal hypertension complications, decompensated liver disease, and hepatocellular carcinoma," added Liangpunsakul, professor of medicine in the Division of Gastroenterology and Hepatology at Indiana University School of Medicine, Indianapolis.

Screening Advised Using New FIB-4 Test

The guideline calls for screening all patients at high risk for NAFLD, including those with prediabetes, type 2 diabetes, obesity, and/or two or more cardiometabolic risk factors, or those with hepatic steatosis found on imaging, and/or persistently elevated plasma aminotransferase levels (ie, for more than 6 months).

The recommended screening test is the fibrosis-4 (FIB-4) index, calculated using the patient's age, AST level, platelet (PLT) count, and ALT level: FIB-4 score = age (years) x AST (U/L)/[PLT (109/L) x ALT ½ (U/L)].

Recently approved by the US Food and Drug Administration (FDA), the FIB-4 has been demonstrated to help identify liver disease in primary care settings.

"We really want to encourage clinicians to do the screening. The first step is the FIB-4 test. It's a mathematical calculation using blood tests that we do anyway," Isaacs told Medscape Medical News.

The FIB-4 stratifies patients as being low, intermediate, or high risk for liver fibrosis. Those at low risk can be managed in primary care or endocrinology settings with a focus on obesity management and cardiovascular disease prevention. "Those at low risk on FIB-4 still have a high cardiovascular disease risk. They still need to be managed," Isaacs observed.

For those at intermediate risk, a second noninvasive test — either a liver stiffness measurement by elastography or an enhanced liver fibrosis (ELF) test — is advised. If the patient is found to be at high risk or is still indeterminant after two non-invasive tests, referral to a liver specialist for further testing, including possible biopsy, is advised.

Those found to be at high risk with the FIB-4 should also be referred to hepatology. In both the intermediate- and high-risk groups, management should be multidisciplinary, including a hepatologist, endocrinologist, and other professionals to prevent both cardiovascular disease and progression to cirrhosis, the guidelines say.

"The diagnosis isn't about diagnosing liver fat. It's about diagnosing fibrosis, or the risk for clinically significant fibrosis. That's really where the challenge lies," Isaacs commented.

NAFLD Treatment in Endocrinology and Primary Care: CVD Prevention

During the presentation at the AACE meeting, guideline panel co-chair Kenneth Cusi, MD, chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, summarized current and future treatments for NAFLD.

Lifestyle intervention, cardiovascular risk reduction, and weight loss for those who are overweight or obese are recommended for all patients with NAFLD, including structured weight loss programs, anti-obesity medications, and bariatric surgery if indicated.

There are currently no FDA-approved medications specifically for NASH, but pioglitazone, approved for type 2 diabetes, and glucagon-like peptide-1 (GLP-1) agonists, approved for type 2 diabetes and weight loss, have been shown to be effective in treating the condition and preventing progression. Other treatments are in development, Cusi said.  

The guideline also includes a section on diagnosis and management of NAFLD in children and adolescents. Here, the FIB-4 is not recommended because it isn't accurate due to the age part of the equation, so liver enzyme tests are used in pediatric patients considered at high risk due to clinical factors. Management is similar to adults, except not all medications used in adults are approved for use in children.

In the editorial, Liangpunsakul cautions that "the level of uptake and usage of the guideline may be an obstacle."

To remedy that, he advises that "the next effort should gear toward distributing this guideline to the targeted providers and developing the 'feedback platforms' on its execution in the real-world...The successful implementation of this AACE guideline by the primary care providers and endocrinologists, hopefully, will deescalate the future burden of NAFLD-related morbidity and mortality."

Isaacs and Liangpunsakul have reported no relevant financial relationships. Cusi has reported receiving research support towards the University of Florida as principal investigator from the National Institute of Health, Echosens, Inventiva, Nordic Bioscience, Novo Nordisk, Poxel, Labcorp, and Zydus, and is a consultant for Altimmune, Akero, Arrowhead, AstraZeneca, 89Bio, BMS, Coherus, Intercept, Lilly, Madrigal, Merck, Novo Nordisk, Quest, Sagimet, Sonic Incytes, Terns, and Thera Technologies.

AACE 2022 Annual Meeting. Presented May 12, 2022.

Endocr Pract. Published online May 15, 2022. Full text, Editorial

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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