On‐treatment gamma‐glutamyl transferase predicts the development of hepatocellular carcinoma in chronic hepatitis B patients

Abstract Background & Aims Gamma‐glutamyl transferase (GGT) has been predictive of chronic hepatitis C‐related hepatocellular carcinoma (HCC) development. Its role in the risk of HCC in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs) is elusive. Methods A total of 2172 CHB patients from East Asia were randomized into development and validation groups in a 1:2 ratio. Serum GGT levels before and 6 months (M6) after initiating NAs and the potential risk factors were measured. The primary endpoint was HCC development 12 months after NA initiation. Results The annual incidence of HCC was 1.4/100 person‐years in a follow‐up period of 11 370.7 person‐years. The strongest factor associated with HCC development was high M6‐GGT levels (>25 U/L; hazard ratio [HR]/95% confidence interval [CI]: 3.31/2.02‐5.42, P < .001), followed by cirrhosis (HR/CI: 2.06/1.39‐3.06, P < .001), male sex (HR/CI: 2.01/1.29‐3.13, P = .002) and age (HR/CI: 1.05/1.03‐1.17, P < .001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6‐GGT levels ( P = .09). In contrast, among non‐cirrhotic patients, the incidence of HCC was significantly higher for those with M6‐GGT level >25 U/L than for their counterparts ( P < .001). Cox regression analysis revealed that the strongest factor associated with HCC development in non‐cirrhotic patients was high M6‐GGT levels (HR/CI: 5.05/2.52‐10.16, P < .001), followed by age (HR/CI: 1.07/1.04‐1.09, P < .001). Non‐cirrhotic elderly patients with high M6‐GGT levels had a similarly high HCC risk as cirrhotic patients did ( P = .29). Conclusions On‐treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non‐cirrhotic patients, treated with NAs.