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

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background & Aims</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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, <jats:italic>P</jats:italic> < .001), followed by cirrhosis (HR/CI: 2.06/1.39‐3.06, <jats:italic>P</jats:italic> < .001), male sex (HR/CI: 2.01/1.29‐3.13, <jats:italic>P</jats:italic> = .002) and age (HR/CI: 1.05/1.03‐1.17, <jats:italic>P</jats:italic> < .001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6‐GGT levels (<jats:italic>P</jats:italic> = .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 (<jats:italic>P</jats:italic> < .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, <jats:italic>P</jats:italic> < .001), followed by age (HR/CI: 1.07/1.04‐1.09, <jats:italic>P</jats:italic> < .001). Non‐cirrhotic elderly patients with high M6‐GGT levels had a similarly high HCC risk as cirrhotic patients did (<jats:italic>P</jats:italic> = .29).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>On‐treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non‐cirrhotic patients, treated with NAs.</jats:p></jats:sec>