Thursday, August 9, 2012

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma

Original article | Published 6 August 2012, doi:10.4414/smw.2012.13651
Cite this as: Swiss Med Wkly. 2012;142:w13651
Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma

Lorenz Kuskea, Armand Mensenb, Beat Müllhauptc, Francesco Negrod, David Semelae, Darius Moradpourf, Pierre Jean Maléd, Markus H. Heimg, Raffaele Malinvernih, Andreas Cernyi, Jean-François Dufoura,j, on behalf of the Swiss Hepatitis C Cohort Study
a Hepatology, Department of Clinical Research, University of Berne, Switzerland
b Clinic Barmelweid, Switzerland
c Department of Gastroenterology and Hepatology, University Hospital of Zürich, Switzerland
d Division of Gastroenterology and Hepatology, University Hospitals of Geneva, Switzerland
e Department of Gastroenterology and Hepatology, Hospital of St. Gallen, Switzerland
f Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
g Department of Gastroenterology, University Hospital of Basel, Switzerland
h Department of Internal Medicine, Hospital of Neuchâtel, Switzerland
I Hepatology, Hospital Moncucco Lugano, Switzerland
j University Clinic of Visceral Surgery and Medicine, Inselspital, University of Berne, Switzerland

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC.

METHODS: Analysis of the database of the Swiss Hepatitis C Cohort Study, a multicentre study that is being carried out in eight major Swiss hospitals since the year 2000. Patients with chronic hepatitis C and HCC were regrouped and compared to the patients without HCC.

RESULTS: Among the 3,390 patients of the cohort, 130 developed an HCC. Age was one of the determining factors. Cirrhosis and its complications ascites and porto-systemic encephalopathy were associated with HCC. Males presented a higher risk for HCC than females. Alcohol consumption was associated with HCC. Diabetes mellitus was an important risk factor, especially in patients with low fibrosis. Patients with Hepatitis C genotype 2 had significantly less HCC than patients with other genotypes. A low socioeconomic status (income, education, profession) was associated with HCC.

CONCLUSIONS: Beside the expected characteristics (age, gender, cirrhosis, alcohol), these data
stress the role of diabetes mellitus and reveal the importance of low socioeconomic status as a risk factor for HCC in Swiss patients infected with hepatitis C virus. This vulnerable population should be closely monitored.

Key words: hepatitis C virus; hepatocellular carcinoma; risk factors; socioeconomic

Discussion "Only"
Full Text Available @ SMW-Swiss Medical Weekly

There are a number of co-factors influencing the development of HCC in patients with chronic hepatitis C. In the SCCS we identified male gender, cirrhosis, alcohol intake, diabetes and lack of education as being significantly associated with HCC.

We found a different age distribution with non-HCC patients being much younger than HCC patients. There was an increased risk after the age of 42 and a further increase in risk after 60. This is consistent with data on 2166 chronic hepatitis C patients which reported a 15-fold higher risk for HCC in patients over 65 years of age compared to patients in their 20’s [6]. The age peak in our study was between 60 and 69 years. A US study showed an age peak in patients aged 70–74 years for the years 2000 to 2002 [3]. They reported a substantial shift towards younger age with the maximum age being 75–79 in 1991–1993 and 80–84 years in 1982–1984. Our age peak was in line with this trend towards younger age over time.

In almost every study, HCC is reported to be more frequent in male than in female patients. Our analysis identified male gender as an independent risk factor. It showed a male to female ratio of 2.7:1. This ratio is rather low ratio since other studies reported a male to female ratio up to 5:1 [3]. Several reasons may explain this male predominance. First, men likely expose themselves to more risk factors. They generally drink more alcohol. Second, there are biological factors [7]. A study with telomerase-deficient mice showed that male mice had a 2 to 8-fold higher risk for HCC than female mice [8]. This implies that male gender hormones may favour liver cancer development. Mice lacking androgen receptor present delayed development of HCC [9]. The unfavourable effect of androgens can be further underlined by a study from Taiwan that associated elevated serum testosterone levels with the development of HCC [10].

In our cohort, alcohol consumption was more frequent in patients with HCC (50%) than in patients without HCC (45%). Age and gender adjusted OR of 1.55 (95%CI 1.06–2.27) with a p-value of under 0.05 suggested that alcohol is a risk factor for HCC in HCV patients. This is in line with the published evidence. A European study reported that alcohol consumption of over 11 litres per year increased the risk of liver cancer by 26% in men and 14% in women [11]. Donato et al. reported that HCC risk increases linearly with alcohol consumption [12].

Hepatic fibrosis is a key risk factor for HCC. We found the risk for HCC to increase up to an OR of 5.15 with increasing stadium of fibrosis. This is corroborated by the finding that cirrhosis was associated with an OR of 4.82. Results from other studies have already proven cirrhosis to be the main risk factor for HCC in hepatitis C patients [2]. Among the hepatitis C patients with cirrhosis the annual incidence of HCC is 1.4% in the USA, 2–4% in Italy and 4–8% in Japan [2]. Cirrhosis does not only influence the incidence of primary liver cancer but seems to also influence its severity. A study with North American patients reported that patients with liver cirrhosis develop more aggressive and less differentiated HCC than patients without cirrhosis [13]. In contrast, neither histological activity of chronic hepatitis C, nor steatosis were associated with the development of HCC in the SCCS.

Our results showed that patients with Child-Pugh class B had higher risk for HCC than those with Child-Pugh class A. This is not surprising and fits with data about the histological degree of fibrosis and the increased risk for HCC in patients with ascites and in patients with porto-systemic encephalopathy. However, it is less obvious why patients with Child Pugh class C do not have a higher HCC risk than patients with Child Pugh class B. One explanation might be that patients with Child Pugh class C have a short survival and when they reach this stage without HCC they die from liver failure and/or complications of portal hypertension.

A recent meta-analysis of 59 studies came to the conclusion that HBV/HCV co-infection does not increase the risk of HCC compared to HBV or HCV mono-infection [14]. Our analysis showed a significant difference between borderline anti-HBc test results to negative as well as positive test results. Both the univariate and multivariate analysis suggested that a borderline anti-HBc test result is an independent risk factor and based on the result of the hierarchical tree the importance is limited to patients under 42 years of age. These patients with borderline anti-HBc serology may be in a particularly oncogenic stage of occult hepatitis B infection.

In our results, 21% of the HCC patients and only 6% of the non-HCC patients were diabetics (OR 2.08, 95% CI: 1.30–3–34, p = 0.002). We identified diabetes mellitus as a strong risk factor for HCC in hepatitis C patients. This is a well-known association in North America [1517] as well as in Europe [1820]. Our results also suggested that diabetes the determining factor in middle aged patients (42–60) with low fibrosis stage. This concurs with recent findings of HCC in diabetic patients without significant fibrosis. [21]

One unique aspect of this work was to investigate the socioeconomic characteristics of Swiss hepatitis C patients who develop HCC. Our study took into account 3 socioeconomic factors: professional occupation, education level and annual income. We found no significant difference between employed and unemployed patients. Compared to patients with no education, patients with higher education had a lower risk (OR 0.5) for HCC. The largest differences of HCC risk was seen when comparing the patients’ annual income. The HCC risk increased as the income decreased. This is in line with the results of a study performed in Korea that compared patients with low income (<4000 USD/month) to patients with high income (>4000 USD/month). They found an odds ratio of 17 (95% CI 4.27–68.25), linking low income to higher HCC incidents [4]. We found no difference between the three factors in the multivariate analysis, which is mainly because the three groups are very similar. Patients with higher education generally have better jobs and earn more than patients with no education. Our conclusion is that patients with low socioeconomic status have a higher risk for HCC. A possible explanation may be that patients with little education and low income present additional co-factors [22]. Another possibility is that these patients do not seek medical attention and thereby are less likely to be treated. So far, in Switzerland, the socioeconomic status has no influence on treatment decisions [23]. Based on these results, however, patients with low income and education should be more closely monitored.

Genotype 1 is the most frequent genotype in the SCCS and patients with HCC slightly more frequently harbour this genotype. A meta-analysis came to the conclusion that patients with genotype 1b have an almost 2-fold (OR1.78, 95%CI 1.36–2.32) risk of developing HCC than those with other genotypes [24]. Our risk analysis showed that patients with genotype 2 had significantly less HCC risk than patients with genotype 1.

This work has limitations. It is descriptive by nature and does not provide mechanistic insights. It relies exclusively on the data of the SCCS database. The charts of the patients have not been reviewed and some important factors such as smoking are missing. Moreover, the effect of the antiviral therapy on the risk of developing HCC could not be evaluated. Nevertheless, this project has strengths. It is based on a very large database and provides unique information on Swiss patients infected with HCV who developed HCC. This information should help improving the management of these patients.

Full Text Available @ SMW-Swiss Medical Weekly

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