"Recent epidemiological studies suggest that the presence of diabetes mellitus increases the risk of . . . HCC," write Bart J. Veldt, MD, from the Erasmus MC University Medical Center in Rotterdam, the Netherlands, and colleagues. "An explanation for this association may be that diabetes often occurs as part of the metabolic syndrome, which increases the risk of nonalcoholic steatohepatitis (NASH), and that HCC can be a late complication of NASH. Diabetes mellitus is more prevalent among patients with chronic hepatitis C than in the general population."

In a large cohort of patients with chronic hepatitis C and advanced fibrosis, the investigators aimed to quantify the risk for HCC in patients with both diabetes mellitus and hepatitis C. Of 541 patients studied, 85 (16%) had diabetes mellitus, with median age at study inclusion of 50 years.

For patients with an Ishak fibrosis score of 4, the prevalence of diabetes mellitus was 10.5%; this value increased to 12.5% for an Ishak score of 5 and 19.1% for an Ishak score of 6. The risk for diabetes mellitus was increased for patients with elevated body mass index (BMI; odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00 - 1.11; P = .06), and the risk for diabetes mellitus was decreased for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63 - 1.04; P = .095) based on multiple logistic regression analysis.

Median follow-up was 4.0 years (interquartile range, 2.0 - 6.7 years). During follow-up, HCC developed in 11 (13%) patients with diabetes mellitus vs 27 (5.9%) patients without diabetes mellitus. The 5-year occurrence of HCC was 11.4% (95% CI, 3.0% - 19.8%) and 5.0% (95% CI, 2.2% - 7.8%), respectively (P = .013). Diabetes mellitus was independently associated with the development of HCC, according to multivariate Cox regression analysis of patients with Ishak 6 cirrhosis (hazard ratio, 3.28; 95% CI, 1.35 - 7.97; P = .009).

Limitations of this study include lack of data about tobacco use and exclusion of patients with active alcohol abuse.

"For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC," the study authors write. "Higher fasting glucose levels are associated with higher compensatory insulin levels in patients with diabetes mellitus and because previous in vitro studies have shown that hyperinsulinemia enhances the proliferation of human hepatocellular cancer cells, we hypothesize that the presence of hyperinsulinemia might further explain the increased risk of HCC among patients with diabetes mellitus."

The Netherlands Organisation for Health Research and Development supported this study in part. The study authors have disclosed no relevant financial relationships.

Hepatology. 2008;47:1856-1862.

Clinical Context

The presence of diabetes mellitus increases the risk for HCC. This risk may be from the metabolic effects of diabetes, which increase the risk for NASH because HCC can be a late complication of NASH. Chronic hepatitis C virus infection also increases the risk for HCC, and for patients with hepatitis C cirrhosis, the risk for the development of HCC is 0.54% to 2.0% per year.

This is a study of consecutive patients with chronic hepatitis C and biopsy-proven advanced cirrhosis from 5 hepatology units in Europe and Canada to determine if the risk for HCC is increased in patients with diabetes vs those without diabetes.

Study Highlights

• Included were patients with an Ishak score of 4 to 6 with chronic hepatitis C cirrhosis.
• Excluded were those with concurrent hepatitis B or HIV virus or recent alcohol abuse.
• Patients were diagnosed with diabetes mellitus according to elevated fasting glucose levels (> 6.1 mmol/L), a positive glucose tolerance test, or use of antidiabetic medications.
• Patients received laboratory testing, had BMI documented, and details of hepatitis C treatment were available.
• HCC was diagnosed at follow-up based on histologic or radiologic testing.
• A new diagnosis was made if confirmed on histologic examination, a new focal lesion was more than 2 cm with arterial hypervascularization, or a new focal lesion was more than 2 cm with arterial hypervascularization in the presence of an alpha-fetoprotein level of more than 400 ng/mL.
• The risk for the development of HCC according to the presence of diabetes in patients with hepatitis C cirrhosis was determined at 4 years of follow-up.
• 541 patients were eligible, of whom 16% had a diagnosis of diabetes.
• Median age at inclusion was 50 years, and those with diabetes were older (median age, 51 vs 49 years).
• Those with diabetes had more fibrosis, lower mean albumin levels, and lower mean platelet counts.
• The prevalence of diabetes was 10.5% for those with an Ishak score of 4, 12.5% for an Ishak score of 5, and 19.1% for an Ishak score of 6.
• The prevalence of diabetes was similar for the European and Canadian centers (15.9% vs 15.5%).
• 144 (39%) patients without diabetes mellitus and 32 (44%) with diabetes mellitus were overweight, 16% vs 15% were obese, and 6% vs 14% had morbid obesity.
• Patients with diabetes had higher median BMI.
• There was a strong trend toward a higher risk for diabetes in patients with elevated BMI (OR, 1.05; P = .060) and a lower risk for diabetes among patients with higher serum albumin levels (OR, 0.81; P = .095) and higher platelet count (OR, 0.95; P = .181).
• The effects of age, sex, fibrosis, stage, and bilirubin levels were not significant.
• HCC developed more frequently among patients with diabetes vs those without diabetes.
• During a median of 4.0 years of follow-up, HCC developed in 13% of those with diabetes vs 5.9% of those without diabetes.
• Of these, 65% had a histologic diagnosis.
• The median time between the last imaging without tumor and a diagnosis of new HCC was similar for those with and without diabetes at 0.9 years.
• The 5-year occurrence of HCC was 11.4% in those with diabetes and 5.0% in those without diabetes (P = .066).
• Overall, diabetes was independently associated with HCC risk with an HR of 3.28 (P = .009).
• The risk for HCC was not affected by treatment modality for diabetes (insulin, oral medication, or diet).
• The risk for HCC was higher for higher levels of fasting glucose (HR, 1.22).
• Other risk factors for HCC among patients with hepatitis C cirrhosis were male sex (HR, 2.97) and older age (HR, 1.07).
• BMI, platelet count, and bilirubin and albumin levels were not associated with the risk for HCC.
• All patients in whom HCC developed had an Ishak score of 6.
• Other predictors of HCC among those with an Ishak score of 6 were male sex (HR, 2.91) and older age (HR, 1.07).
• In patients in whom HCC developed, 24% of those with diabetes and 30% of those without diabetes had sustained virologic response to pegylated interferon after 1 or more treatment courses.

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