Dr Trivedi discusses key presentations of research on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) from the 2021 meeting of the American Association for the Study of Liver Diseases.

Hirsh Trivedi, MD, is the transplant hepatology fellow at Beth Israel Deaconess Medical Center in Boston, Massachusetts.

TRANSCRIPT:

Hirsh Trivedi:  Thank you to the Gastroenterology Learning Network for inviting me to briefly summarize the key features of NAFLD and NASH research presented at the recent AASLD Liver Meeting. My name is Hirsh Trivedi. I'm the transplant hepatology fellow at Beth Israel Deaconess Medical Center in Boston, Massachusetts.

As you know, the growing epidemic of NAFLD has led to increasing amounts of related research being conducted and presented at the liver meeting each year. The scope of this summary is by no means exhaustive.

To start off, Dr. Quentin Anstee described optimal methods of risk stratification of NAFLD by differentiating those patients at low risk of fibrosis progression from those with high risk. Data from Taylor et al shows increased risk of liver and all-cause-related mortality at fibrosis stage 2 levels and beyond, making this a useful cutoff for risk stratification.

When evaluating noninvasive markers of fibrosis. Dr. Anstee describes how a high negative predictive value to rule out advanced disease is ideal in low prevalence areas like the primary care setting. Whereas the high positive predictive value is needed in specialty hepatology clinics, where NAFLD and NASH have a higher prevalence.

FIB-4 score has been shown recently to not only be a good diagnostic tool but is also good for prognostication, as well as for monitoring liver disease progression. Angulo et al have previously shown the prognostic ability of noninvasive tests like NAFLD score, as well as the FIB-4 score, in predicting outcomes like transplantation and death.

Recently, Hagstrom et al showed the utility of FIB-4 in monitoring disease progression longitudinally over time. In fact, they have found a one-unit increase in FIB-4 had a hazard ratio of 1.8 for developing severe liver disease. It is known that type 2 diabetics have higher risk of NAFLD and its complications.

An abstract presented by our group from Beth Israel Deaconess shows that patients with complications of type 2 diabetes have higher FIB-4 scores compared to those with type 2 diabetes without complications, suggesting possible increased fibrosis risk in those with nephropathy, neuropathy, or retinopathy.

FIB-4 score can be potentially used to evaluate these high-risk populations, especially in resource-limited settings, where other methods of fibrosis assessment may not be available. The indeterminant zones of FIB-4 and other biomarkers that have two separate cut-offs do pose a challenge, as they consequentially increase the risk of misclassification.

However, this can be circumvented by using sequential tests like ELF score or transient elastography to reduce the indeterminant zone. This strategy is supported by increasing amounts of research being presented at the liver meeting.

In a recent talk by Dr. Kathleen Corey, she shows that 25% of mortality in NAFLD patients is from cardiovascular disease.

In the systematic review and a meta-analysis published in "The Lancet" this year, of 36 longitudinal studies with around six million participants, they found that NAFLD was independently associated with cardiovascular events, with the pooled hazard ratio of 1.4. The risk increases with each fibrosis stage.

Using data from the PROMIS trial, Dr. Corey's group found that baseline steatosis is significantly associated with higher ASCVD risk scores and major adverse cardiovascular events, even after controlling for important covariates, with a hazard ratio of 1.7.

Another important topic is HCC in non-cirrhotic NASH. A recent epidemiologic study from gastroenterology 2018 shows the HCC risk for non-cirrhotic patients with NASH is .08 per 1000 patient-years, compared to 10.6 per 1000 patient-years in those with cirrhosis.

Although the individual risk of HCC in non-cirrhotic NASH is small. This risk is applied to a large population of patients worldwide, given the growing prevalence of NASH, and is therefore relevant. The utility of surveillance in these patients is still not proven, as the incidence of disease in the target population remains below the screening threshold cutoff of 1.5%.

Lastly, there are many potential therapies for NASH on the horizon. Many such trials are now using noninvasive measures of steatosis and fibrosis as clinical endpoints. One agent presented by Dr. Noureddin is resmeritom. This is a THR beta-agonist in phase III development.

In the phase III MAESTRO-NASH trial, Dr. Noureddin's group showed that 100 milligrams of resmeritom led to a significant reduction in the MAST score, which is a combination of both MRI plus AST, at week 16 and 52.

In addition to this agent, there are many future agents being evaluated, currently in phase II and phase III trials, including but not limited to, obeticholic acid, semaglutide, and Lanifibranor. Discussions of these individual agents is beyond the scope of this review. Thank you for your attention.