More than 1 billion people worldwide have nonalcoholic NAFLD. Most of these individuals have liver disease that will not progress to cirrhosis; however, a subset will progress, and these are the patients with NASH. Liver biopsy is currently used for the identification of NASH, but it would not be practical to have 1 billion people undergo this procedure, so we need noninvasive risk stratification tools. 

Patients who have NASH and fibrosis stage 2 or higher have progressive forms of NAFLD, and some of this disease may be reversible. Thus, the idea is to develop and use noninvasive tests as part of a high-yield approach to risk stratification, to identify those patients with NAFLD who will progress to develop cirrhosis and liver-related morbidity and mortality. Toward that end, we have made great progress. The Fibrosis-4 (FIB-4) Index for Liver Fibrosis is a simple clinical calculator that uses the patient’s age and aspartate transaminase, alanine transaminase, and platelet counts. It could easily be incorporated into an electronic medical records system. The likelihood of advanced disease is very low at the lower cutoff (ie, FIB-4 <1.3), and we can rule out significant disease in most of these patients. Values at and above the upper cutoff (ie, FIB-4 ≥2.67) are suggestive of advanced disease; however, the positive predictive value is not great, and we still fail to categorize approximately 50% of patients with this test, including those with scores that fall into the indeterminant zone (ie, between the 2 cutoffs). When the FIB-4 is between 1.3 and 2.67, you can do a second test to shrink that indeterminant zone and to gain more certainty.

The Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) project aims to standardize and validate noninvasive tests for the diagnosis and staging of NASH. The results of the NIMBLE Stage 1-NASH Clinical Research Network study were presented at the virtual AASLD meeting in a late-breaking abstract (abstract LO1). Important takeaways include that the NIS4 had superior diagnostic accuracy relative to alanine transaminase for the diagnosis of NASH and that the Enhanced Liver Fibrosis (ELF) test was very good for the detection of fibrosis. ELF was superior to FIB-4, and, for increasing stages of fibrosis, ELF showed increasing diagnostic accuracy. Additionally, the FibroMeter VCTE, which combines serum-based testing with FibroScan-based liver stiffness testing, had a high diagnostic accuracy that was relative to FIB-4. To summarize, the results of the NIMBLE study provide cross-sectional data that are very helpful for determining the characteristics of various tests for either the diagnosis of NASH and fibrosis stage 2 or higher or the detection of any state of fibrosis. 

To contextualize these findings from the NIMBLE project with some other data, we have previously shown that combining magnetic resonance elastography (MRE) with FIB-4 is associated with very high diagnostic accuracy. As clinicians, when we discuss test results with patients, I think that we really want positive test results to be true positives. That is why we developed the MRE combined with FIB-4 (MEFIB) index. With MRE 3.3 kPa or greater and FIB-4 1.6 or greater, the clinical prediction rule for patients with fibrosis stage 2 or higher had a positive predictive value of 97.1% in the University of California at San Diego–NAFLD cohort, and that is a relatively high level of certainty.

I believe that risk stratification is important today—right now—even though US Food and Drug Administration–approved treatments for NASH are not yet available. You want to know if a patient sitting in your clinic has silent cirrhosis. Hepatocellular carcinoma, which typically happens in the setting of cirrhosis, is a leading cause of cancer-related mortality worldwide, and that mortality is increasing in the United States. Many groups of patients are at an increased risk for advanced liver disease, including certain ethnicities (eg, Hispanics and Native Americans) and patients with type 2 diabetes. The risk of advanced fibrosis in a 50-year-old patient with diabetes, for instance, is approximately 10%, which is high, so we could be doing these patients a disservice by not seeing if they have cirrhosis. Additionally, if you diagnose somebody with NASH, even today, you can offer them vitamin E. You would likely also be more aggressive in getting their body weight controlled, and the patient might be more motivated to improve their liver disease.