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Director, NAFLD Research Center
Professor of Medicine
Director of Hepatology
University of California at San Diego
La Jolla, California
Rohit Loomba, MD, MHSc: consultant: 89bio, Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead, AstraZeneca, Bristol-Myers Squibb, CohBar, Galmed, Gilead Sciences, Glympse Bio, HighTide, Inipharm, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, Theratechnologies, Terns, Viking Therapeutics; researcher: Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Galectin Therapeutics, Galmed, Gilead Sciences, Hanmi, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, Terns Pharmaceuticals; cofounder: LipoNexus.
When dealing with patients with nonalcoholic fatty liver disease (NAFLD), one of the most important things is trying to identify who has the progressive form of fatty liver disease and is likely to advance to cirrhosis and perhaps die from liver disease. Liver disease is the third leading cause of mortality in patients with NAFLD but only in a subset who progress to advanced liver disease. The good news is that most will not.
Stratifying Risk in Persons With NAFLD
How do we stratify risk in these patients? Many of these patients are first seen in primary care clinics or endocrine clinics. That is because many of them have type 2 diabetes (T2D) and obesity, but both of these conditions are associated with increased risk of liver fibrosis. As such, the American Gastroenterological Association (AGA) has developed an algorithm for risk stratification of patients with NAFLD. In addition, the American Association of Clinical Endocrinology and the American Association for the Study of Liver Diseases have cosponsored a guideline for assessment and care for patients with NAFLD.
For example, in a patient with T2D or metabolic syndrome, the AGA suggests that we first look at routinely available labs, including tests of liver function, such serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and platelet count, along with a patient's age. These parameters can be inputted into a cirrhosis clinical prediction equation, the FIB-4.
Those who have metabolic syndrome or T2D and FIB-4 <1.3 have low risk for having advanced fibrosis. From the primary care standpoint, they do not need to be seen by a hepatologist immediately but can be managed with lifestyle interventions. These interventions might include weight management, exercise, and dietary changes to see if we might improve the liver disease without other modalities. We also recommend that people decrease consumption of alcohol. Among those with an FIB-4 ≥1.3, we might consider some additional liver testing. Those who have a FIB-4 ≥2.67 are considered high risk. These persons should be evaluated by a hepatologist either directly or undergo additional testing with transient elastography or magnetic resonance elastography. These noninvasive evaluations can estimate liver stiffness as a surrogate for fibrosis or scarring in the liver and can be very useful to determine whether a referral should be made to a hepatologist.
Management Recommendations for Persons With NAFLD
We always recommend that patients with NAFLD who are overweight or obese try to lose weight. Weight loss of 5% to 10% can help to reduce risk of progression, but to see actual improvements in fibrosis, 10% weight loss is usually necessary. Comorbid conditions must be adequately managed as well. For instance, those with high cholesterol—very common in patients with NAFLD—should be receiving a statin, and I would emphasize that mildly elevated ALT or AST should not be a contraindication to statin use. In those with diabetes, we like to see good glucose control with hemoglobin A1C <7% as our target. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are good medicines for these patients because they are not only effective for glycemic control but both also reduce cardiovascular risk; GLP-1 receptor agonists are also effective in weight loss.
What About Patients With Nonalcoholic Steatohepatitis?
Currently, there are no drugs that are approved by the FDA for the treatment of nonalcoholic steatohepatitis (NASH)–related fibrosis, but studies are underway, both with drugs approved for other indications and investigational agents. Once patients with NASH develop cirrhosis, they have a high risk for developing hepatocellular carcinoma (HCC)—the risk is approximately 1.5% to 2.0% per year. There is also a subset of patients who have NASH without cirrhosis who develop HCC, but we don’t yet know how to identify those individuals. Current recommendations for those who have cirrhosis due to NASH are to undergo ultrasound imaging of their liver every 6 months along with measurement of α-fetoprotein. Unfortunately, there is evidence that the ultrasound failure rate can be high in NASH cirrhosis, but this can be improved by using MRI.
Who Else Is at Risk for Advanced Fibrosis?
A recent publication showed that those with a first-degree relative with NASH cirrhosis have a 14% to 15% risk of also developing advanced fibrosis. For these persons, we would recommend screening with FIB-4 or elastography with FibroScan or magnetic resonance elastography.
It Takes a Village
By following these recommendations and implementing these basic screening tests, other specialties including primary care can begin to be more involved in the identification and care of these patients. For primary care providers who would like to implement these tests more consistently in their practice, I’d recommend screening using the FIB-4 in patients with T2D because they would be the highest risk. Additional patients who would benefit from the screening would be those with obesity, those with metabolic syndrome, and those who are 40 years of age or older.
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