FIB-4 Could ID Liver Risk in Primary Care

Jim Kling

December 13, 2021

Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.

FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.

"This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we've ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues," said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Schreiner is general internist at the Medical University of South Carolina, Charleston.

He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.

To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.

65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).

The population had more liver risk than expected. "[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies," said Schreiner.

Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.

"Troublingly," said Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. "This is a tremendous opportunity to improve diagnosis in this setting."

After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).

Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.

During the question-and-answer session after the talk, Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team's hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. "For us in the primary care setting, it's just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues," said Schreiner.

Comoderator Kathleen Corey, MD, asked Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. "We've seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?" asked Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.

Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don't use it or even know about it. "FIB-4 is very popular in the hepatology literature, but in primary care, we don't talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I'm worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well," said Schreiner.

Schreiner has no relevant financial disclosures. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.

This article originally appeared on, part of the Medscape Professional Network.


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