Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrh

[Guest guest]

Increased risk of hepatocellular carcinoma among patients with

hepatitis C cirrhosis and diabetes mellitus

Hepatology June 2008

Bart J. Veldt 1, Wendong Chen 2, E. Heathcote 2, Heiner

Wedemeyer 3, Juerg Reichen 4, W. Hofmann 5, J. de Knegt

1, Stefan Zeuzem 5, P. Manns 3, Bettina E. Hansen 1 6, Solko

W. Schalm 1, Harry L. A. Janssen 1 *

1Erasmus MC University Medical Center, Department of Gastroenterology

and Hepatology, Rotterdam, the Netherlands

2Toronto Western Hospital, University Health Network, Toronto,

Ontario, Canada

3Department of Gastroenterology, Hepatology, and Endocrinology,

Medical School Hannover, Hannover, Germany

4Institute of Clinical Pharmacology, University of Berne, Berne,

Switzerland

5Saarland University Hospital, Department of Internal Medicine II,

Homburg/Saar, Germany

6Erasmus MC University Medical Center, Department of Epidemiology and

Biostatistics, Rotterdam, the Netherlands

from Jules: its possible that curing HCV and reducing fibrosis may

eliminate or reduce the risk for diabetes increasing the risk for

HCC, but I don't think this study examines that specific question.

Abstract

Recent studies suggest that diabetes mellitus increases the risk of

developing hepatocellular carcinoma (HCC). The aim of this study is

to quantify the risk of HCC among patients with both diabetes

mellitus and hepatitis C in a large cohort of patients with chronic

hepatitis C and advanced fibrosis. We included 541 patients of whom

85 (16%) had diabetes mellitus. The median age at inclusion was 50

years. The prevalence of diabetes mellitus was 10.5% for patients

with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for

Ishak score 6. Multiple logistic regression analysis showed an

increased risk of diabetes mellitus for patients with an elevated

body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval

[CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus

for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-

1.04; P = 0.095). During a median follow-up of 4.0 years

(interquartile range, 2.0-6.7), 11 patients (13%) with diabetes

mellitus versus 27 patients (5.9%) without diabetes mellitus

developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-

19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013).

Multivariate regression analysis of patients with Ishak 6

cirrhosis showed that diabetes mellitus was independently associated

with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P

= 0.009).

Conclusion: For patients with chronic hepatitis C and advanced

cirrhosis, diabetes mellitus increases the risk of developing HCC.

Recent epidemiological studies suggest that the presence of diabetes

mellitus increases the risk of hepatocellular carcinoma (HCC).[1][2]

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.[3]

Diabetes mellitus is more prevalent among patients with chronic

hepatitis C than in the general population.[4] Liver disease

contributes to insulin resistance because it leads to a progressive

impairment of insulin secretion and it induces hepatic insulin

resistance.[5] Studies in transgenic mouse models that harbored the

hepatitis C core gene have shown that hepatic insulin resistance may

be caused by elevated levels of tumor necrosis factor-alpha, which

disturbs the tyrosine phosphorylation of insulin receptor substrate-1.

[6]

Chronic hepatitis C virus (HCV) infection itself also increases the

risk of HCC. It leads to chronic inflammation of the liver, to liver

fibrosis, and it may eventually progress to cirrhosis. For patients

with hepatitis C cirrhosis the risk for development of HCC is 0.54 to

2.0% per year.[7][8]

Therefore, among patients with both chronic hepatitis C and diabetes

mellitus there are two potential ways in which HCC may develop: by

the metabolic pathway and by the carcinogenic effect of the HCV.

The aim of this study was to quantify the risk of HCC among patients

with both diabetes mellitus and chronic hepatitis C in a large cohort

of patients with chronic hepatitis C and advanced fibrosis.

Patients and Methods

We included in the study all consecutive patients with chronic

hepatitis C and biopsy-proven advanced fibrosis or cirrhosis (Ishak

score 4 to 6) treated between 1990 and 2003 in five large hepatology

units in Europe and Canada. Patients were not eligible if they were

infected with hepatitis B (hepatitis B surface antigen positive) or

human immunodeficiency virus.

Results

A total of 541 patients were eligible and were included in the study,

85 (16%) of them had a diagnosis of diabetes mellitus at the time of

inclusion.

The median age at inclusion was 50 years, the patients with diabetes

mellitus being older than those without diabetes (median 51 versus 49

years) (Table 1).

Patients with diabetes mellitus had more severe fibrosis, lower mean

albumin levels, and lower mean platelet counts. The prevalence of

diabetes mellitus was 10.5% among patients with an Ishak fibrosis

score of 4, 12.5% for Ishak fibrosis score 5, and 19.1% for Ishak

fibrosis score 6. Of the 85 patients with a diagnosis of diabetes

mellitus, 20 used subcutaneous insulin, 34 used oral antidiabetic

medication, and 31 had dietary measures only. The mean fasting

glucose was 8.3 mmol/L (standard deviation 3.1) for patients on

treatment (oral or insulin) and 7.2 mmol/L (standard deviation 2.4)

for patients on dietary measures. The prevalence of diabetes mellitus

was similar among the European and the Canadian patients enrolled in

the study (15.9% versus 15.5%, P = 0.91). A total of 72% of the

patients had a complete follow-up until January 1, 2005, 6 months

prior to the data acquisition.

Effects of BMI and Previous Alcohol Use.

A total of 144 patients without diabetes mellitus (39%) and 32

patients with diabetes mellitus (44%) were overweight, 58 (16%)

versus 11 (15%) were obese, and 22 (6%) versus 10 (14%) had morbid

obesity. Patients with diabetes mellitus tended to have higher median

BMIs than patients without diabetes mellitus (28 kg/m2 versus 26

kg/m2; P = 0.25; Table 1). Multiple logistic regression analysis

showed a strong trend toward a higher risk of diabetes mellitus among

patients with an elevated BMI (OR, 1.05; 95% CI, 0.99-1.11; P =

0.060), and a trend toward a lower risk of diabetes mellitus for

patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-

1.04; P = 0.095) and higher platelet count (OR, 0.95; 95% CI, 0.88-

1.02; P = 0.181). The effects of age, gender, fibrosis stage, and

bilirubin levels were not significant.

A total of 20 patients had a history of previous alcohol abuse and

one of them developed HCC. A total of three patients both had a

history of alcohol abuse and had diabetes mellitus, but none of these

three patients developed HCC. Past alcohol abuse was not associated

with development of HCC in univariate regression analysis (HR,

0.77; CI, 0.11-5.58; P = 0.79).

Diabetes Mellitus and Development of HCC.

HCC developed more frequently among patients with diabetes mellitus.

During a median follow-up of 4.0 years (interquartile range [iQR],

2.0-6.7), 11 patients (13%) with diabetes developed HCC, versus 27

patients (5.9%) without diabetes mellitus. A total of 24 cases (65%)

had a histological diagnosis.

The median time interval between the last imaging without tumor

(ultrasound, computed tomography, or magnetic resonance imaging) and

the confirmation of the diagnosis of HCC was similar for patients

with and without diabetes mellitus (0.9 years [iQR, 0.1-2.1] versus

0.9 years [iQR, 0.5-1.7]), respectively (P = 0.68). The 5-year

occurrence of HCC was 11.4% (95% CI, 3.0-19.8%) for chronic hepatitis

C patients with diabetes mellitus and 5.0% (95% CI, 2.2-7.8%) for

patients without diabetes mellitus (P = 0.013). Univariate

regression analysis showed that there were no statistically

significant differences in the risk of developing HCC between

patients using insulin or oral antidiabetic medication and patients

on dietary measures (HR, 1.11; CI, 0.32-3.79; P = 0.87). Among

patients with diabetes mellitus, there was a trend toward a higher

risk of HCC as fasting glucose levels increased (HR, 1.22; CI, 0.98-

1.52; P = 0.082).

Multivariate regression analysis of the overall study population

showed that male gender (HR, 2.97; 95% CI, 1.20-7.39; P = 0.019) and

older age (HR, 1.07; 95% CI, 1.03-1.11; P = 0.001) were significantly

associated with an elevated risk of developing HCC. In addition,

there was a strong trend toward a higher incidence of HCC among

patients with diabetes mellitus (HR, 2.07; 95% CI, 0.95-4.47; P =

0.066). The associations with BMI, platelet count, bilirubin, and

albumin levels were not statistically significant.

All 11 diabetic patients who developed HCC had Ishak fibrosis score 6

(Fig. 1). We performed a subgroup analysis on patients with Ishak

fibrosis score 6 (n = 303), in which diabetes mellitus was

significantly associated with the development of HCC (HR, 3.28; 95%

CI, 1.35-7.97; P = 0.0087). Other factors predictive of HCC among

patients with Ishak fibrosis score 6 were male sex (HR, 2.91; 95% CI,

1.03-8.26; P = 0.044) and older age (HR, 1.07; 95% CI, 1.02-1.12; P =

0.007; Table 2).

Effect of HCV Treatment

All patients were treated for chronic hepatitis C with (peg)

interferon with or without ribavirin. A total of 20 patients with

diabetes mellitus (24%) and 139 patients without diabetes mellitus

(30%) reached sustained virological response after one or more

treatment courses. Logistic regression analysis showed no

statistically significant effect of the presence of diabetes mellitus

on the chance of responding to HCV treatment, in this population with

advanced liver disease (OR, 0.70; 95% CI, 0.41-1.20; P = 0.20).

When response to treatment was entered as a time-dependent covariate

in the regression model, it had no statistically significant

effect on development of HCC (HR, 0.54; CI, 0.16-1.88; P = 0.33).

Moreover, after adjusting for response to treatment, the effect of

diabetes mellitus on HCC development remained essentially unchanged:

HR, 1.77; CI, 0.77-4.09; P = 0.182 for the overall study population;

and HR, 3.35; CI, 1.28-8.74; P = 0.014 for patients with Ishak

fibrosis score 6.

Discussion

This large cohort study gives, for the first time, a quantification

of the risk of developing HCC over time for patients with chronic

hepatitis C, advanced fibrosis, and diabetes mellitus. The 5-year

risk of developing HCC is 11.4% for patients with both diabetes

mellitus and chronic hepatitis C with advanced fibrosis. Patients

without diabetes mellitus included in our study had a lower risk of

HCC with occurrence of HCC in 5.0% after 5 years, which is consistent

with the 2.7%-10% that has been described in the literature for

patients with cirrhosis due to hepatitis C.[7][8]

A Japanese study of 279 chronic hepatitis C patients without

cirrhosis showed that the 5-year incidence of HCC was 9.5% for

diabetics and 2.0% for nondiabetics.[2] Although in a Western

population development of HCC is very infrequent among patients

without cirrhosis, the rate of diabetics versus nondiabetics

developing HCC is similar.

All patients in our cohort have been treated with an interferon-based

regimen. A previous study in the same cohort of patients showed that

two of three sustained virological responders who developed HCC

during follow-up had diabetes mellitus and this study failed to show

a statistically significant effect of treatment response on the risk

of developing HCC.[9]

In the present study, advanced liver disease itself turned out to be

one of the factors determining the risk of diabetes mellitus. This

concurs with previous reports, showing that advanced liver disease

can lead to insulin resistance, independent of the cause of cirrhosis.

[13]

In subgroup analysis of patients with Ishak fibrosis score 6,

diabetes mellitus was an independent predictor of HCC. Although there

probably is a range for true severity of cirrhosis within fibrosis

stage 6, diabetes mellitus was still an independent predictor of HCC

if we corrected for other markers of advanced liver disease such as

platelet count, bilirubin, and albumin levels. This suggests that the

presence of diabetes mellitus is more than just a marker for more

severe liver disease with a greater propensity to progress to HCC.

[14] Moreover, a large population-based case-control study in the

United States has shown that diabetes mellitus was independently

associated with a three-fold increase of the risk of HCC even for

subjects without concomitant disease such as chronic hepatitis C.[15]

The effect of diabetes mellitus on HCC development may be partly

explained by behavioral factors such as alcohol use, tobacco smoking,

and a high-fat diet.[16] It is well established that high BMI is a

risk factor for diabetes mellitus and steatohepatitis. In addition,

tobacco smokers have a 1.5-fold increased risk of developing diabetes

mellitus[17][18] and although moderate alcohol consumption may have a

protective effect on the development of diabetes mellitus, it clearly

is an additional risk factor for steatohepatitis.[19]

Alcoholic steatohepatitis or NASH superimposed on chronic

inflammation due to hepatitis C may lead to an elevated risk of

carcinogenesis. A cohort study in an Asian population of patients

with hepatitis C suggested that steatosis is an independent risk

factor for development of HCC.[20] A recent Australian case-control

study found similar amounts of steatosis in patients with chronic

hepatitis C who subsequently developed HCC and matched controls.

However, the size of this study was limited.[21] Among chronic

hepatitis C patients, genotype 3 is most commonly associated with

liver steatosis.[22] In our cohort, we found no effect of hepatitis C

genotype 3 on the risk of HCC (Table 1). Furthermore, the prevalence

of obesity was high, both among patients with and without diabetes

mellitus, suggesting that obesity is frequent among all chronic

hepatitis C patients with advanced fibrosis.

Unfortunately, we did not have data about tobacco use in our study

population. Our cohort includes patients treated for HCV and because

recent alcohol abuse was a contraindication for treatment, no

patients with active alcohol abuse were included. We found no

increased risk of HCC among patients with a past history of alcohol

abuse.

Interestingly, among patients with diabetes mellitus, there was a

trend toward a higher risk of HCC as fasting glucose levels

increased. Higher fasting glucose levels are associated with higher

compensatory insulin levels in patients with diabetes mellitus[23]

and because previous in vitro studies have shown that

hyperinsulinemia enhances the proliferation of human hepatocellular

cancer cells,[24][25] we hypothesize that the presence of

hyperinsulinemia might further explain the increased risk of HCC

among patients with diabetes mellitus.

In conclusion, for patients with chronic hepatitis C and cirrhosis,

diabetes mellitus increases the risk of developing HCC.