Study Highlights Limitations of Clinical Pathways for MASLD-Related Hepatocellular Carcinoma

Over 25% of patients with metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) without cirrhosis have a low fibrosis-4 index (FIB-4), yet new findings suggest current clinical care pathways may not identify these patients for additional evaluations.¹

These findings resulted from new research into MASLD, which represents a spectrum of conditions ranging from steatosis to metabolic dysfunction-associated steatohepatitis. The latter is known to be the fastest-rising HCC cause in the world, with guidelines recommending the use of FIB-4 as the first step to stratifying risk among those with MASLD.²

This new research was led, in part, by Darren Jun Hao Tan of the Yong Loo Lin School of Medicine at the National University of Singapore. Tan et al. noted that the American Gastroenterology Association (AGA), the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL) had urged those with a FIB-4 of 1.3 or higher to undergo a secondary risk assessment.

“However, it is unknown what proportion of people with MASLD-related HCC have a low FIB-4 (FIB-4 < 1.3, or < 2.0 if aged > 65 years) and may not be identified for further specialist evaluation by the AGA pathway or AASLD guidance, especially given the relatively high proportion of MASLD-related HCC without cirrhosis,” Tan and colleagues wrote. “Therefore, we performed a multicentre cohort study from seven international sites to determine the proportion of people with MASLD-related HCC who have a low FIB-4.”¹

Trial Design

A retrospective, longitudinal cohort analysis was utilized by Tan’s team of investigators, with the team assessing those aged 18 years and older with diagnoses of MASLD-related HCC between January 2008 - August 2023. This was done across 7 tertiary healthcare centers in Singapore, India, Australia, Japan, South Korea, and the United States.

Clinical, imaging, and laboratory data were gathered by the investigators using comprehensive reviews of medical records, with standardized case reporting forms implemented. The research team’s criteria for inclusion in their study aimed at adult participants with MASLD-related HCC.

They defined MASLD by the noted existence of hepatic steatosis, excluding significant alcohol use (defined as ≥14 drinks per week for males or ≥7 drinks per week for females). They also excluded other notable hepatic steatosis causes, 1 of which was viral hepatitis.

Study subjects previously given the label of cryptogenic cirrhosis who also were shown to have met the team’s criteria for obesity, which was defined as a BMI ≥27.5 kg/m² for Asian individuals and a BMI ≥30.0 kg/m² for Caucasians. Those with type 2 diabetes were also considered to meet the criteria if they had MASLD, following multi-stakeholder workgroup recommendations.

Criteria for exclusion from the team’s research included chronic hepatitis C, chronic hepatitis B, autoimmune hepatitis, Wilson’s disease, primary sclerosing cholangitis, alcohol-associated liver disease, and other noted chronic liver conditions.

Notable Findings on Low FIB-4 Scores

The investigators’ main goal had been to identify the proportion of study subjects with a low FIB-4 score—which would have been a FIB-4 <1.3 or <2 for those over the age of 65—among those without cirrhosis. Among their 615 participants, the mean age was noted as 71 (±11) years, with the average BMI being 27 (±7) kg/m².

Of the 615 subjects, the research team concluded that 38% had been found not to have any known cirrhosis, and there was a median FIB-4 score of 3.90 (IQR 2.42–6.42). Among 13% of subjects, the team observed a low FIB-4 score.

In fact, the investigators found that 26% of those without cirrhosis were shown to have a low FIB-4. Individuals showing a low FIB-4 also had lower median serum alpha-fetoprotein levels (P = .005) and a notably larger median total tumor diameter (P < .001) compared to other participants.

The research team also reported that while cirrhosis was linked to lower odds of having a low FIB-4 score, other elements such as type 2 diabetes, male sex, and obesity showed no significant link.

References

1. ^{Tan, D., Tamaki, N., Kim, B., Wijarnpreecha, K., Aboona, M., Faulkner, C., Kench, C., Salimi, S., Sabih, A.-H., Lim, W., Danpanichkul, P., Tay, B., Teh, Y., Mok, J., Nah, B., Ng, C., Muthiah, M., Kulkarni, A., Lee, S., Liu, K., Loomba, R., Huang, D. and (2024), Prevalence of Low FIB-4 in MASLD-Related Hepatocellular Carcinoma: A Multicentre Study. Aliment Pharmacol Ther. https://doi.org/10.1111/apt.18346.}
2. ^{J. H. Koh, C. H. Ng, B. Nah, D. J. H. Tan, R. Loomba, and D. Q. Huang, “NASH Is the Leading Cause of Hepatocellular Carcinoma in Liver Transplant Candidates,” Clinical Gastroenterology and Hepatology 22, no. 1 (2024): 197–199.e3.}