Fibrosis-4 Index as a Robust Long-Term Predictor of Cancers in Metabolic Dysfunction-Associated Steatotic Liver Disease

Ayumi Kanamoto; Teruki Miyake; Shinya Furukawa; Osamu Yoshida; Keiichiro Horiuchi; Yoshimasa Murakami; Masumi Miyazaki; Hironobu Nakaguchi; Ryo Yano; Yuki Okazaki; Sho Ishikawa; Yuki Numata; Atsushi Yukimoto; Yoshiko Nakamura; Mitsuhito Koizumi; Takao Watanabe; Yasunori Yamamoto; Yoshio Tokumoto; Masashi Hirooka; Masanori Abe; Yoichi Hiasa

doi:10.1111/hepr.70159

Fibrosis-4 Index as a Robust Long-Term Predictor of Cancers in Metabolic Dysfunction-Associated Steatotic Liver Disease

Hepatol Res. 2026 Mar 17. doi: 10.1111/hepr.70159. Online ahead of print.

Authors

Ayumi Kanamoto¹, Teruki Miyake², Shinya Furukawa³, Osamu Yoshida⁴, Keiichiro Horiuchi⁴, Yoshimasa Murakami⁴, Masumi Miyazaki⁴, Hironobu Nakaguchi², Ryo Yano⁴, Yuki Okazaki⁴, Sho Ishikawa⁴, Yuki Numata⁴, Atsushi Yukimoto⁴, Yoshiko Nakamura⁴, Mitsuhito Koizumi⁴, Takao Watanabe⁴, Yasunori Yamamoto⁴, Yoshio Tokumoto⁴, Masashi Hirooka⁴, Masanori Abe¹, Yoichi Hiasa⁴

Affiliations

¹ Department of Community and General Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
² Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
³ Health Services Center, Ehime University, Matsuyama, Ehime, Japan.
⁴ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

PMID: 41842768
DOI: 10.1111/hepr.70159

Abstract

Aim: We investigated whether the baseline fibrosis-4 (FIB-4) index stratifies long-term cancer risk in patients with biopsy-proven MASLD and compared its discrimination for HCC and extrahepatic malignancies against other noninvasive fibrosis markers.

Methods: In this single-center retrospective cohort study, 417 adults with biopsy-proven MASLD (2001-2024) were followed for incident malignancy (median follow-up, 4.75 years). Patients were categorized using standard FIB-4 thresholds (< 1.3, 1.3-2.67, ≥ 2.67). Cause-specific Cox models and Fine-Gray competing-risk models were used to estimate adjusted hazard ratios (HRs) for HCC and extrahepatic cancer. Discriminative performance was evaluated using Harrell's C-index and time-dependent area under the curve (AUC) values at 3, 5, and 10 years.

Results: During followup, 24 patients (5.8%) developed HCC, whereas 40 (9.6%) developed extrahepatic cancer. The ≥ 2.67 category was associated with markedly increased risks of HCC (adjusted HR 35.31) and extrahepatic cancer (adjusted HR 13.10) compared with < 1.3. Associations remained robust in competing-risk and age-adjusted sensitivity analyses. FIB-4 showed the highest and most consistent discriminative performance among the evaluated indices (C-indices of 0.83 for HCC and 0.78 for extrahepatic cancer). Time-dependent AUCs improved over time and exceeded 0.80 for HCC after 5 years.

Conclusion: The FIB-4 index provides consistent long-term risk stratification for HCC and shows an association with extrahepatic cancer among commonly used noninvasive fibrosis markers. Its strong time-dependent discrimination for HCC and moderate discrimination for extrahepatic cancer support its potential role as a simple, widely accessible tool for long-term risk stratification in MASLD.

Keywords: extrahepatic cancer; fibrosis; fibrosis markers; hepatocellular carcinoma; liver; liver‐related event; metabolic dysfunction–associated steatotic liver disease.