In this first-ever U.S. population-based study to examine risk factors for cholangiocarcinoma by anatomical site, several medical conditions were significantly related to both ECC and ICC. These conditions include biliary cirrhosis, cholelithiasis and choledocholithiasis, cholecystitis and cholecystectomy, alcoholic liver disease, liver cirrhosis, type II diabetes, thyrotoxicosis, chronic pancreatitis and possibly duodenal ulcer disease. In addition, HCV infection, obesity, chronic non-alcoholic liver disease, and smoking were significantly more common among ICC, but not ECC, patients. As HCV infection, obesity, and chronic non-alcoholic liver disease are increasing in the US,21-23
these conditions may be contributing to the divergent trends in ECC and ICC and may also explain similar trends in ICC and HCC.24
Among the biliary tract conditions examined, both cholangitis (most likely primary sclerosing cholangitis, PSC) and primary biliary cirrhosis (PBC) were significantly associated with ICC and ECC. PSC and PBC are autoimmune-mediated cholangiopathies25-27
associated with the chronic destruction of bile ducts, but the pathogenesis and pattern of bile duct involvement differ considerably. PSC involves the intra- and extrahepatic biliary tree, is associated with inflammatory bowel disease and is a known risk factor for cholangiocarcinoma.28
Although PSC-related cancers are reported to peak in the 4th
the association between PSC and cholangiocarcinoma was also observed the current study's elderly population. In contrast, PBC which occurs in the small intralobular bile ducts, has not previously been associated with cholangiocarcinoma.31
Chronic inflammation and cholestasis, as well as chronic liver damage, are associated with risk of malignant biliary transformation,32
suggesting that an association between PBC and ICC is biologically plausible. However, reasons for the association between PBC and ECC are less clear. The small numbers of PBC and absence of information on diagnostic confirmation suggest that the reported association should be confirmed in other studies. It should also be noted that although the ICD-9 code for biliary cirrhosis refers to primary biliary cirrhosis, it is possible that some secondary biliary cirrhosis diagnoses were included.
As anticipated, Crohn's disease and ulcerative colitis were more prevalent among the cases than the controls. Although ulcerative colitis was only significantly associated with ICC, the relationship with ECC was in the predicted direction and may not have attained significance due to small numbers.
Biliary tract stone disease (cholelithiasis, and choledocholithiasis), as well as possible surrogates for symptomatic lithiasis, cholecystitis and cholecystectomy, were significantly more prevalent in cases than controls. Hepatolithiasis, although uncommon in the West, is endemic in some parts of Asia and has consistently been associated with ICC because of inflammation and epithelial proliferation.33
In parallel, extrahepatic lithiasis may promote chronic inflammatory changes in the extrahepatic bile ducts and thereby increase ECC risk. Reasons why extrahepatic biliary lithiasis would increase the risk for ICC are less clear. However, this association was also reported by a recent ICC case-control study in Denmark.34
Extrahepatic lithiasis may be associated with cholestasis. It is also possible that the increased ICC risk may result from factors that favor the development of biliary lithiasis itself, such as altered bile composition or conditions associated with metabolic syndrome.
Cholecystectomy has been previously reported to be associated with decreased risk for ECC.35
In the ICC study in Denmark, however, cholecystectomy was associated with a non-significant increased risk.36
In the current study, cholecystectomy was more frequent in both ECC and ICC cases than in controls. It should be noted, however, that the majority (85% for ECC and 91% for ICC) of surgical procedures were performed in the year prior to tumor diagnosis, indicating that cholecystectomy may be due to the disease process itself. It is also possible that some patients underwent cholecystectomy for presumed cholecystitis when the symptoms were a result of the underlying cancer.
Chronic liver diseases such as alcoholic liver disease and cirrhosis were significantly associated with ICC, as they were in the previously reported ICC study in Denmark.37
Both alcoholic liver disease and cirrhosis are well established risk factors for HCC.38, 39
Conceivably, alcohol may be related to ICC in a similar way, particularly as there is evidence that both types of primary liver cancers arise from common progenitor cells that may give rise to tumors with hepatocellular or cholangiocellular phenotypes.40
Alcoholic liver disease was also significantly associated with ECC, consistent with a previous study that reported alcohol consumption was a risk factor for ECC among PSC patients (N. Chalasani, personal communication).41
Obesity and non-alcoholic liver disease were significantly associated with ICC but not ECC. In recent years, obesity and non-alcoholic fatty liver disease (NAFLD) have received increasing attention as NAFLD may act as a co-factor in HCV- and alcohol-related liver disease.42-47
In addition, non-alcoholic steatohepatitis (NASH) represents an independent risk factor for the development of liver fibrosis, cirrhosis, and ultimately HCC.48, 49
In the current study, the same constellation of conditions was associated with ICC. If the associations are confirmed, there are possible public health consequences as recent studies suggest that hepatic steatosis may be present in up to one third of the population,50, 51
and NASH may be present in 2-5%. The current study also found that diabetes was significantly associated with ECC and ICC. Although elevated insulin and glucose levels may directly stimulate fibrogenesis and release of connective tissue growth factors and favor inflammatory changes,52-54
the interplay of the components of the metabolic syndrome (obesity, hyperlipidemia, NAFLD, diabetes) is complex, and requires further study to investigate the independent contributions of each factor.
In the current study, HCV infection was associated with ICC, as previously reported11
, but not ECC. Recent studies from Korea, Japan and Italy have also reported an association between HCV and cholangiocarcinoma.55-57
In support of these findings, HCV RNA has been isolated from cholangiocarcinoma tissue58
and HCV has been shown to cause bile duct epithelial cell injury.59
Similar to HCV related-HCC, the increased risk of ICC in patients with HCV may result from HCV-associated chronic liver damage.
The current study found a significant association between hyperthyroidism and ICC and ECC, in line with a previous study that reported a higher prevalence of thyroid diseases in cholangiocarcinoma patients.60
Restriction of analyses to patients with autoimmune thyroiditis (Grave's disease) found an increased risk for cholangiocarcinoma, however the association did not attain statistical significance. The association of hypermetabolic state in hyperthyroidism and oxidative tissue injury been summarized in a recent review.61
Elevated thyroxine (T4) and triiodothyronine (T3) levels were reported to alter hepatic lipid peroxidation, promote protein oxidation, and radical oxygen species induced-DNA damage, which may explain the increased risk of cholangiocarcinoma in thyrotoxicosis patients.
Duodenal ulcer disease, which may be a surrogate for Helicobacter pylori (H. pylori) infection and chronic pancreatitis, was significantly more common among ECC and ICC cases than controls. H. pylori, a major cause of duodenal ulcer disease, is classified as a group 1 carcinogen by the International Agency for Research on Cancer.62
Several studies have also proposed an association between H. pylori and cholangiocarcinoma63-65
though the association remains controversial. Therefore, these findings should be interpreted cautiously, as ECC patients, in particular, frequently undergo endoscopy for diagnosis and palliative stent implantation, favoring the possibility of diagnostic bias.
In the current study, chronic pancreatitis was significantly associated with both ECC and ICC. Several mechanisms, including chronic inflammatory changes, could explain the association. In addition, chronic pancreatitis is often associated with obstructive cholestasis favoring malignant transformation through compression of the intrapancreatic portion of the common bile duct.66
However, confounding by alcoholism, a major risk factor for chronic pancreatitis, cannot be excluded.67
As previously reported,68
cigarette smoking was significantly associated with ICC. Consistent with previous reports, there was no association with smoking and ECC.69
The current study was large and multiethnic but had several potential limitations. As the study only included patients of age 68 and older, the findings may not be generalizable to younger patients. In the SEER registries, however, the median age at diagnosis of both tumors is between 70 and 74 years, thus the study population is representative of the high-risk groups for these tumors. Completeness and accuracy of the Medicare data are not well reported. To minimize the possibility of missing diagnoses, however, analyses were restricted to patients with at least 3 years of continuous enrollment in Medicare. Furthermore, patients who were enrolled in Medicare HMO plans were excluded, as the HMOs have differing claims submission requirements.70
The possibility of diagnostic bias cannot be excluded as persons with serious medical conditions are more likely to undergo testing and thus have more diagnoses than other persons. In the case of a biliary tumor such as ECC or ICC, individuals are likely to undergo endoscopy and to be tested for hepatitis virus infections.
Although the current study of almost 1100 cholangiocarcinoma patients was quite large, the small numbers of some pre-existing medical conditions merit caution in drawing strong conclusions. In addition, the exclusion of diagnoses that were made at least 1 year prior to cancer diagnosis likely affected the power to detect significant associations. Finally, as Medicare data are collected for billing, rather than research, purposes, the prevalences of smoking and obesity were almost certainly underrepresented. The current manuscript includes these variables, nevertheless, as a possible means of stimulating hypotheses in these areas.
Important strengths of this study are related to the source of the data, as well as the case and control definitions. SEER has a 98% case ascertainment rate and data quality that has been well-demonstrated. The use of Medicare Parts A and B data rather than personal interview to determine pre-existing medical conditions likely avoided recall bias, while the matching of cases and controls on the search for risk factors minimized the possibility of differing testing and diagnostic trends.
In summary, ICC and ECC share some common risk factors, which include choledochal cysts, cholangitis, ulcerative colitis, biliary tract stone disease, cirrhosis, alcoholic liver disease as surrogate for alcohol consumption, type II diabetes, thyrotoxicosis, and pancreatitis, and possibly duodenal ulcer disease. As chronic non-alcoholic liver disease, obesity and HCV infection were associated with ICC and are increasing in incidence, they may explain the divergent trends in ICC and ECC rates.