Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: a meta-analysis and systematic review

Figures & data

Figure 1 Flow diagram showing the search strategy along with the selection and screening processes for the eligible studies.

Abbreviations: DM, diabetes mellitus; HCC, hepatocellular carcinoma; HBV, hepatitis C virus.

Table 1 Baseline characteristics of the seven studies included

Study	Period, location	Study design	Group	n	Participants	DM ascertainment	HCC diagnosis
Lai et al^Citation14	1999–2002, Taiwan	Cohort	DM NDM		A total of 54,916 subjects aged ≥30 years from a community-based program; HBV-positive patients(n=6,545)	FBG >126 mg/dL, self-reported	AFP >400 mg/nL, positive imaging finding (enhanced CT, angiography), and histopathological confirmation
Chen et al^Citation15	1991–1992, Taiwan	Cohort	DM NDM	62 3,862	23,567 residents from a multiple township-based cancer-screening program; seropositive for HBsAg only (n=3,924)	Self-reported	1) National cancer registry; 2) histopathological confirmation; 3) two imaging findings (ultrasonography, angiography, or CT), one imaging diagnosis and AFP >400 ng/mL
Wang et al^Citation16	1997–2004, Taiwan	Cohort	DM NDM	47 649	5,929 residents >35 years old with hepatitis from a population-based screening program; seropositive for HBV only (n=696)	FBG ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or using hypoglycemic drugs	National cancer registry
Ko et al^Citation17	2004–2005, Taiwan	Case– control	DM NDM		Hospitalized inpatients first diagnosed with HCC (n=359) and non-HCC controls (n=1,536) randomly selected from a health-checkup program	FBG ≥126 mg/dL, current use of oral hyperglycemic agent or insulin injection at the time of recruitment	1) Histopathological verification; 2) AFP >400 ng/mL and at least one imaging study (ultrasonography, enhanced CT, or angiography)
Li et al^Citation19	2004–2008, Chinese mainland	Case– control	DM NDM	421 5,854	Patients aged ≥30 years hospitalized for HCC (n=1,105) or CHB (n=5,170) without HBV treatment	FBG ≥7 mmol/L, self-reported	1) Histopathological confirmation; 2) two imaging findings (ultrasonography, enhanced CT, or MRI); 3) AFP >400 ng/mL and one positive image finding
Fu et al^Citation20	1997–2009, Taiwan	Cohort	DM NDM	2,099 2,080	Chronic HBV patients with(n=2,099) or without DM (n=2,080) randomly selected from the national health-research database (1:1 ratio)	NA	National insurance-program registry (for catastrophic illness patient database)
Hsiang et al^Citation21	2000–2012, New Zealand	Cohort	DM NDM	50 173	223 HBV patients with transient elastography or radiological features of established cirrhosis with (n=50) or without DM (n=173)	FBG ≥7.0 mmol/L, random glucose level ≥11.1 mmol/L, or positive OGTT and/or HbA1c ≥6.5%, and active DM follow-up*	Combination of elevated AFP and positive imaging finding

Note:

* Under primary care with diabetes disease-management program or under hospital diabetes-service follow-up.

Abbreviations: CT, computed tomography; HbA_1c, glycosylated hemoglobin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HBsAg, HBV surface antigen; DM, diabetes mellitus; NDM, non-DM; MRI, magnetic resonance imaging; FBG, fasting blood glucose; OGTT, oral glucose-tolerance test; NA, not applicable.

Table 2 DM and incidence of HCC risk

Study	Group	n	HCC cases	HCC, %	OR/HR/RR		95% CI
Lai et al^Citation14	DM	NA	NA	NA	HR	1.04	0.37–2.93
	NDM	NA	NA	NA
Chen et al^Citation15	DM	62	8	12.9	RR	2.41	1.17–4.95
	NDM	3,862	179	4.6
Wang et al^Citation16	DM	47	NA	NA	HR	1.3	0.3–5.6
	NDM	649	NA	NA
Ko et al^Citation17	DM	NA	NA	NA	OR	4.32	1.92–9.70
	NDM	NA	NA	NA
Li et al^Citation19	DM	421	93	NA	OR	0.9	0.7–1.2
	NDM	5,854	1,012	NA
Fu et al^Citation20	DM	2,099	69	3.29	HR	1.798	1.194–2.707
	NDM	2,080	42	2.02
Hsiang et al^Citation21	DM	50	13	26	HR	2.36	1.14–4.85
	NDM	173	23	13.29

Abbreviations: DM, diabetes mellitus; HCC, hepatocellular carcinoma; NDM, non-DM; NA, not applicable.

Table 3 Factors adjusted in the multivariate regression analysis

Study	Adjusted confounders
Lai et al^Citation14	Age, gender, HCV status, smoking and cumulative consumption of alcohol
Chen et al^Citation15	Age, sex, cigarette smoking, habitual alcohol consumption, and education levels
Wang et al^Citation16	Age, sex, smoking habit, alcohol consumption, BMI, and diabetes status before the study
Ko et al^Citation17	Age, sex, and other viral hepatitis infection
Li et al^Citation19	Age, sex, city of residence, family history of liver cancer, HBeAg status and cirrhosis
Fu et al^Citation20	Age, sex, hyperlipidemia, HBV treatment, statin therapy, cirrhosis, comorbidity index, and obesity
Hsiang et al^Citation21	Age, sex, antiviral therapy, sustained viral suppression, and MELD score

Abbreviations: HCV, hepatitis C Virus; BMI, body-mass index, MELD, model for end-stage liver disease.

Figure 2 Forest plot of meta-analysis results comparing the incidence of HCC between patients with DM and those without DM.

Abbreviations: HCC, hepatocellular carcinoma; DM, diabetes mellitus.

Figure 3 Funnel plot of studies assessing the relationship between DM and risk of HCC.

Abbreviations: DM, diabetes mellitus; HCC, hepatocellular carcinoma.

Figure 4 Forest plot of results comparing overall mortality between DM and non-DM subjects.

Abbreviations: DM, diabetes mellitus; NDM, non-DM; M–H, Mantel–Haenszel.

Table 4 Quality evaluation of evidence

	Studies, n	Design	Patients, n	Effect	95% CI	Quality	Level
Incidence	4	Observational	11,643	1.88	1.28–2.47	ÅÅOO	Low
Overall mortality	2	Observational	4,402	1.93	1.64–2.27	ÅÅOO	Low
Age	2	Observational	4,402	2.81	−2.91 to 8.92	ÅÅOO	Low
Sex	2	Observational	4,402	0.99	0.91–1.08	ÅÅOO	Low
HBV treatment	2	Observational	4,402	1.07	0.73–1.55	ÅÅOO	Low
Follow-up, years	2	Observational	4,402	−0.35	−102 to 0.32	ÅÅOO	Low
% Diabetes mellitus	2	Observational	8,180	2.18	0.82–5.83	ÅÅOO	Low

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