This was a retrospective study consisting of consecutive CHB patients at the Fifth Affiliated Hospital of Zhengzhou University in Zhengzhou, China during the period of December 2013 to February 2021. The inclusion criteria were as follows: (1) Hepatitis B surface antigen (HBsAg) positivity for more than 6 mo; (2) Valid clinical characteristics and laboratory outcomes; (3) No hepatotrophic virus coinfection; (4) Presence of cirrhosis; (5) No alcoholic hepatic diseases or HCC; and (6) No type 1 DM. The final number of patients included in this study was 412. Patients were divided into a T2DM group (n = 196) and a non-T2DM group (n = 216). This study was conducted under compliance with the Declaration of Helsinki and was approved by the Human Ethics Committee of the Fifth Affiliated Hospital of Zhengzhou University (KY2021031).

Patient data were obtained from the electronic medical record database of the hospital. The prothrombin time and international normalized ratio were measured with an ACL TOP coagulation analyzer (Instrumentation Laboratory, Beckman Coulter, Sydney, NSW, Australia). Platelet count was monitored with an LH 750 Automated Hematology Analyzer (Instrumentation Laboratory, Beckman Coulter). Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, albumin, total bilirubin, and creatinine levels were measured using an AU5800 Clinical Chemistry Analyzer (Instrumentation Laboratory, Beckman Coulter). The serum HBV-DNA level was quantified by polymerase chain reaction using a Roche LightCycler (Roche Diagnostics, Basel, Switzerland). HBsAg and hepatitis B e-antigen were determined using an AutoLumo A2000Plus Chemiluminescence Detector (Autobio, Zhengzhou, China).

Continuous variables are expressed as medians (the first to third quartiles), and the Mann-Whitney U test was used to assess continuous variables. The χ² test or Fisher’s test was used to analyze categorical variables. The incidence of HCC was analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used to screen and identify factors associated with mortality and hepatocarcinogenesis. Multivariate logistic regression analysis was also performed to identify potential factors associated with T2DM. The model for end-stage liver disease score was calculated according to the standard formula[13]. The following cutoffs of analyzed factors were based on previous reports: Age of 65 years[14], HBsAg of 2.0 log IU/mL[15], and HBV-DNA of 20000 IU/mL[16]. P < 0.05 was considered statistically significant. All statistical analyses were performed with the SPSS software package (version 22.0; IBM Corp., Armonk, NY, United States).

A total of 412 CHB patients with cirrhosis were enrolled in this study, including 196 patients with pre-existing T2DM at baseline and 216 patients without. Their characteristics are summarized in Table 1. Compared to patients in the non-T2DM group, patients in the T2DM group had significantly lower prothrombin time [11.8 (10.8-14.1) vs 10.4 (9.6-11.3), respectively, P < 0.001] and international normalized ratio [1.05 (0.96-1.24) vs 0.94 (0.87-1.01), respectively, P < 0.001]. Since nucleos(t)ide analogues (NUCs) may affect HCC development, we compared the use of NUCs between the two groups. We found that the proportion of different HBV therapies between the two groups did not differ significantly (Supplementary Table 1). Therefore, the HBV therapy may not affect the risk of HCC in this study. The other baseline characteristics did not show significant differences between the two groups.

In the T2DM group, 22.4% (44/196) of patients had been diagnosed with T2DM for less than 2.0 years, 21.4% (42/196) for 2.1-5.0 years, 26.5% (52/196) for 5.1-10.0 years, and 29.6% (58/196) for more than 10.0 years. Among all the T2DM patients, 57.1% (112/196) were treated with metformin with or without sulfonylurea treatment, 25.5% (50/196) were treated with insulin with or without sulfonylurea treatment, and 17.3% (34/196) controlled T2DM with diet alone.

The factors related to hepatocarcinogenesis were assessed (Table 2). The analyzed factors included age, sex, smoking status, alcohol abuse status, dyslipidemia, T2DM, ascites, esophagogastric varices, alpha-fetoprotein (AFP), HBsAg, hepatitis B e-antigen, HBV-DNA, and antiviral treatment. The univariate analysis showed that sex (P < 0.001), smoking status (P = 0.013), T2DM (P = 0.002), and ascites (P = 0.016) were significantly related to hepatocarcinogenesis. Then, the multivariate analysis was conducted to analyze the factors associated with hepatocarcinogenesis. The results showed that sex [hazard ratio (HR) = 3.47, 95% confidence interval (CI): 1.36-8.89, P = 0.010], alcohol abuse status (HR = 1.38, 95%CI: 0.80-1.68, P = 0.008), T2DM (HR = 6.73, 95%CI: 2.77-16.36, P < 0.001), AFP (HR = 3.89, 95%CI: 1.06-14.27, P = 0.041), and HBsAg (HR = 4.10, 95%CI: 1.52-11.12, P = 0.005) were significantly related with hepatocarcinogenesis.

The Kaplan-Meier survival curves showed that the hepatocarcinogenesis probability of the T2DM group and non-T2DM group was significantly different (Figure 1). The median time to hepatocarcinogenesis for the T2DM group and non-T2DM group was 30 mo and 34 mo, respectively. We then analyzed the relationship between T2DM and hepatocarcinogenesis among all subgroups (Figure 2). T2DM and hepatocarcinogenesis were significantly correlated in the following subgroups: Males (HR = 2.04, 95%CI: 1.08-3.84, P = 0.028), non-smokers (HR = 10.73, 95%CI: 3.12-36.98, P < 0.001), patients without alcohol abuse (HR = 2.49, 95%CI: 1.27-4.87, P = 0.008), patients with HBsAg > 2.0 log IU/mL (HR = 5.47, 95%CI: 2.36-12.65, P < 0.001), and patients not treated with antiviral medication (HR = 3.29, 95%CI: 1.44-7.54, P = 0.005).

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Figure 1 Rates of hepatocellular carcinoma development in patients with or without type 2 diabetes mellitus. The type 2 diabetes mellitus (DM) group had a significantly higher rate of hepatocellular carcinoma development than the non-DM group (P < 0.05). CI: Confidence interval; HR: Hazard ratio; DM: Diabetes mellitus.

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Figure 2 Correlation between type 2 diabetes mellitus and hepatocellular carcinoma development across different subgroups. The results showed that type 2 diabetes mellitus and hepatocarcinogenesis were significantly correlated in the male subgroup, the non-smoker subgroup, the no alcohol abuse subgroup, the hepatitis B surface antigen > 2.0 log IU/mL subgroup, and the no antiviral treatment subgroup (P < 0.05). AFP: Alpha-fetoprotein; CI: Confidence interval; HBV: Hepatitis B virus; HBeAg: Hepatitis B e-antigen.

Since T2DM was shown to be associated with hepatocarcinogenesis in CHB patients, we analyzed the relationship between T2DM characteristics and hepatocarcinogenesis in CHB patients with T2DM. We found that patient age over 65 years old (P < 0.001), male sex (P = 0.049), AFP > 20 ng/mL (P = 0.002), HBsAg > 2.0 log IU/mL (P = 0.001), or receipt of antiviral treatment (P = 0.007) were significantly correlated with hepatocarcinogenesis in the T2DM group (Table 3). Among T2DM characteristics, T2DM duration of more than 5 years (HR = 6.74, 95%CI: 2.36-19.29, P < 0.001), insulin ± sulfonylurea therapy (HR = 1.45, 95%CI: 0.26-7.96, P = 0.041), and diet control only (HR = 10.70, 95%CI: 2.91-39.31, P < 0.001) were significantly correlated with hepatocarcinogenesis in the T2DM group.

Type 2 diabetes mellitus (T2DM) has been shown to be correlated with hepatocellular carcinoma (HCC) development. However, the T2DM characteristics that affect HCC are unknown.

T2DM affects more than 440 million individuals globally. T2DM is a leading cause of death due to renal and heart complications as well as an increased risk of multiple cancers. Understanding the correlation between T2DM and HCC will benefit these patients.

This study aimed to investigate the relationship between T2DM clinical characteristics and HCC development in pre-existing T2DM patients with chronic hepatitis B (CHB).

Among 412 CHB patients enrolled in this study, there were 196 patients with T2DM. The patients were divided into the T2DM group and the non-T2DM group (n = 216). Clinical characteristics and outcomes of the two groups were compared.

T2DM was found to be significantly related to hepatocarcinogenesis in this study. In the multivariate analysis, T2DM, male sex, alcohol abuse status, alpha-fetoprotein (AFP) > 20 ng/mL, and hepatitis B surface antigen (HBsAg) > 2.0 log IU/mL were identifeid to be risk factors for HCC development. T2DM duration and therapy significantly increased the risk of hepatocarcinogenesis.

T2DM was found to be related to a poor CHB prognosis. Male sex, alcohol abuse status, AFP > 20 ng/mL and HBsAg > 2.0 log IU/mL were also significantly related with poor outcomes. T2DM characteristics, including T2DM duration more than 5 years and treatment of diet control or insulin ± sulfonylurea significantly increased the risk of hepatocarcinogenesis.

These findings confirmed the importance of diabetic management in CHB patients. The exact mechanism of how T2DM affects HCC development still warrants further study.