Association of alkaline phosphatase, γ-glutamyl transferase, total bilirubin, and bile acid levels with HCC risk: a systematic review and meta-analysis

BACKGROUND: Cholestasis-related parameters are indicators of liver inflammation and damage, which contribute to hepatocellular carcinoma (HCC) development. OBJECTIVES: This systematic review and meta-analysis explored the association between key cholestasis-related parameters and the risk of new-onset HCC. METHODS: PubMed, EMBASE, and the Cochrane Library were searched from inception to July 15, 2024, for eligible studies investigating the association between alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), bile acids (BA), and total bilirubin (TB) and incident HCC. The Newcastle-Ottawa Scale was used to evaluate the risk of bias. Random-effects model was used to pooled the estimates, and sensitivity analysis was conducted using fixed-effects models. RESULTS: From 4053 entries, 155 studies were included (3,808,988 individuals). After confounder adjustment, elevated ALP (hazard ratios [HR] = 2.49, 95% confidence interval [CI] 1.66-3.75), GGT (HR = 2.57, 95% CI 2.15-3.08), and TB (HR = 1.89, 95% CI 1.36-2.61) were associated with increased risks of new-onset HCC, consistent with sensitivity analysis using fixed effects models. The multivariable analyses of ALP, GGT, and TB as continuous variables showed no associations with the risk of HCC. In multivariable analyses using the most commonly employed cutoffs, GGT > 50 U/L (HR = 2.51, 95% CI 1.55-4.06) and TB > 1.2 mg/dL (HR = 2.94, 95% CI 1.67-5.20) were independently associated with incident HCC. CONCLUSIONS: This meta-analysis suggests that elevated ALP, GGT, and TB might be associated with new-onset HCC, emphasizing the importance of monitoring these cholestasis-related parameters in clinical practice. BA could not be analyzed due to the small number of studies and the differences in reporting.