Research Article
Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma

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Background & Aims

Well established risk factors for intrahepatic cholangiocarcinoma such as biliary tract inflammation and liver flukes are not present in most Western countries patients. Although cirrhosis and other causes of chronic liver disease have been implicated, their contribution as risk factors for cholangiocarcinoma is unclear and our aims were to analyze these emerging potential risk factors by systematic examination of case–control series from geographically diverse regions.

Methods

We performed a literature review and meta-analysis of case–control studies on intrahepatic cholangiocarcinoma and cirrhosis and related risk factors. Tests of heterogeneity, publication bias and sensitivity analyses were performed and an overall odds ratio and 95% confidence intervals calculated.

Results

Eleven studies from both high and low prevalence regions were identified. All studies except those evaluating cirrhosis, diabetes, and obesity exhibited significant heterogeneity. Cirrhosis was associated with a combined OR of 22.92 (95% CI = 18.24–28.79). Meta-analysis estimated the overall odds ratio (with 95% confidence intervals) for defined risk factors such as hepatitis B: 5.10 (2.91–8.95), hepatitis C: 4.84 (2.41–9.71), obesity: 1.56 (1.26–1.94), diabetes mellitus type II: 1.89 (1.74–2.07), smoking: 1.31 (0.95–1.82), and alcohol use: 2.81 (1.52–5.21). Sensitivity analysis did not alter the odds ratio for any risk factors except smoking and there was no evidence of publication bias.

Conclusions

Cirrhosis, chronic hepatitis B and C, alcohol use, diabetes, and obesity are major risk factors for intrahepatic cholangiocarcinoma. These data suggest a common pathogenesis of primary intrahepatic epithelial cancers.

Introduction

Cholangiocarcinomas are aggressive malignancies arising from the biliary tract and are challenging to diagnose, prevent or treat [1]. The two major clinical phenotypes of cholangiocarcinoma are intrahepatic and ductal/peri-hilar cancers. These phenotypes differ in their anatomical locations, presentation, natural history, and management. Intrahepatic cholangiocarcinomas (IH-CCA) are similar to hepatocellular cancer (HCC) in their presentation as mass lesions within the liver. Both HCC and IH-CCA are primary epithelial malignancies of the liver and are often classified together as primary liver cancers in epidemiological reports. The incidence of HCC is increasing in the United States and other countries [2], [3]. In contrast to HCC, the true incidence and risk factors for IH-CCA are less well recognized possibly because of the much lower prevalence of these cancers relative to HCC. Recent reports suggest that the incidence of IH-CCA is also increasing [4], [5], [6], [7], [8], [9]. Data from the Surveillance, Epidemiology, and End Results program, for example, indicated an increase in the age-adjusted annual incidence of IH-CCA in the United States from 0.13 to 0.58 per 100,000 over a twenty-five-year period with similar trends observed from many other countries worldwide [7], [8]. However, more recent analyses indicate that these changes may have reflected differences in coding and diagnosis [10], [11], [12]. Hilar cholangiocarcinomas, for example, are inconsistently classified and their designation as intra-hepatic cholangiocarcinoma has made accurate determinations of true incidence rates for intrahepatic cancers impossible.

Most patients with IH-CCA do not have any apparent risk factors. Both infectious and non-infectious etiologies have been implicated as risk factors for IH-CCA [13]. Indeed, parasitic liver-flukes, primary sclerosing cholangitis, biliary cysts, hepatolithiasis, and toxins are well recognized risk factors [1], [14], [15], [16]. Some of the variations in the incidence of IH-CCA worldwide can be accounted for by differences in the geographic prevalence of causative liver fluke infectious. Other than in regions where liver flukes are endemic such as South East Asia, the majority of patients with IH-CCA do not have any of these risk factors. Salmonella and Helicobacter infections have been implicated in gallbladder cancer but their contribution to IH-CCA is unknown. Recent studies have identified several other conditions that can contribute to an increased risk of IH-CCA such as chronic viral hepatitis B and C, obesity, diabetes, alcohol, and smoking [9], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. The evaluation of these risk factors has led to conflicting results in some cases. It is unclear to what extent these differences reflect geographic differences, the study design or the population studied. Thus, our objectives were to evaluate these emerging risk factors for IH-CCA by systematically examining the results of reported case–control series from geographically diverse regions. The results of these meta-analyses identify that IH-CCA has many risk factors in common with HCC, and quantitate the overall odds ratios for selected risk factors. These studies support the presence of common mechanisms for the pathogenesis of primary epithelial neoplasia within the liver and lead to exciting hypotheses regarding the etiology and pathogenesis of these cancers. By defining populations at risk for IH-CCA, these observations can form the basis for future efforts at screening or surveillance for these cancers with the goal of decreasing the incidence and mortality from these cancers.

Section snippets

Literature search

Studies were identified by searching both the National Library of Medicine’s MEDLINE database using PubMed and by using Google Scholar search. Studies were not limited by language or to any geographic region. The most recent search was performed on August 12, 2011. The search strategy was based on combinations of the key words, “risk”, “smoking”, “diabetes”, “obesity”, “hepatitis” with “cholangiocarcinoma” or “biliary tract cancers”, and restricted to studies performed after 1990 to avoid any

Study characteristics

A search of PubMed and Google Scholar identified a total of 334 citations, of which 323 were excluded as they did not fulfill the selection criteria, were published prior to 1990, or were duplicates (Fig. 1). Eleven studies qualified for inclusion. The characteristics of the populations studied in these reports are summarized in Table 1. Studies were performed in both regions of high prevalence of hepatobiliary cancers such as Japan (1 study), Korea (1 study), and China (3 studies), as well as

Discussion

While the predisposition of biliary tract inflammation to carcinogenesis is recognized in the biliary tract, many patients with IH-CCA do not have readily recognizable biliary tract inflammation or infection. Traditional infectious risk factors for IH-CCA include the liver flukes Clonorchis sinensis and Opisthorchis viverrini, both of which are now recognized as group 1 carcinogens and causes of cholangiocarcinoma by the International Agency for Research in Cancer of the World Health

Financial support

Supported in part by NIH grant DK 069370 (TP).

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

The underlying research reported in this study was funded by the NIH Institutes of Health.

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