Gallstones, cholecystectomy, and the risk for developing pancreatic cancer

Abstract

We examined the relation between gallstones, cholecystectomy, and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 104 856 women and 48 928 men without cancer at baseline, we documented 349 cases of pancreatic cancer during up to 16 years of follow-up. Participants were classified according to a history of gallstones or cholecystectomy. The age-adjusted relative risk of pancreatic cancer following cholecystectomy or diagnosis of gallstones was 1.31 (95% CI, 0.93 -1.83). However, adjustment for other pancreatic cancer risk factors attenuated the association (RR=1.11, 95% CI, 0.78 -1.56); this risk did not increase with increasing time following cholecystectomy or gallstones. Gallstones or cholecystectomy do not appear to be significant risk factors for pancreatic cancer. Pancreatic cancer is the fifth leading cause of cancer-related mortality in the US (Greenlee et al, 2001). New environmental risk factors have consistently been linked to the risk of pancreatic cancer. Animal models suggest an important role for cytokines in experimental pancreatic carcinogenesis (Watanapa and Williamson, 1993). Cholecystokinin (CCK) has been shown to stimulate both gallbladder contraction and pancreatic enzyme secretion (Marx et al, 1987;Smith et al, 1990) and to have a trophic effect on pancreatic acinar cells (Rivard et al, 1991). The presumed increased release of CCK following cholecystectomy (Hyvarinen and Partanen, 1987) might contribute to an increased risk for pancreatic cancer risk following gallbladder removal. In addition, cholecystectomy may suppress the normal inhibitory effect of CCK on the Sphincter of Oddi (Luman et al, 1997). The presence of gallstones, on the other hand, appears to be associated with chronic pancreatitis (Hardt et al, 2001), but whether chronic pancreatitis predisposes to pancreas cancer remains controversial (Lowenfels et al, 1993;Ekbom et al, 1994). Some of the earlier studies reported relative risks of pancreatic cancer of 1.2 -2.0 among individuals who had undergone a cholecystectomy previously (Haines et al, 1982;Shibata et al, 1994;Ekbom et al, 1996;Chow et al, 1999;Gullo, 1999;Silverman et al, 1999;Coughlin et al, 2000); however, the strength of the association remains uncertain because of the retrospective design of most analyses and the reliance on nextof-kin respondents. Prospective studies can overcome these limitations. We examined the relation between cholecystectomy or gallstones and pancreatic cancer risk in two large cohorts, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). MATERIALS AND METHODS Study cohortsThe Nurses' Health Study (NHS) enrolled 121 700 female, registered nurses aged 30 -55 years in 1976, and information on their health status, medical history, and known and suspected risk factors for cancer and coronary heart disease was gathered through mailed questionnaires. The Health Professionals Follow-up Study (HPFS) began in 1986, when 51 529 American male dentists, o...

Risk Factors for Pancreatic Cancer: Case-Control Study

“…In this study, we found no significant relationship between gallstones or prior cholecystectomy and pancreatic cancer after controlling for potential confounding variables as shown in Table 3. Our finding is consistent with previous studies (61,62). It is possible that the observed positive association between cholecystectomy and pancreatic cancer in previous studies is confounded by other risk factors such as cigarette smoking, diabetes, chronic pancreatitis, heavy alcohol consumption, or family history of pancreatic cancer.…”

Reply: Gallstones, cholecystectomy, and the risk for developing pancreatic cancer

“…Thus, our findings are consistent with those of the Nurses' Health Study and the Health Professional Follow-up Studies (Schernhammer et al, 2002), and indicate that cholelithiasis is not materially associated with pancreatic cancer risk after major identified confounding factors have been considered. A modestly increased risk was observed 10 years after a diagnosis of cholelithiasis, but no greater excess risk can be found 10 or more years after.…”

“…The issue of a possible association between gallstones or cholecystectomy and cancer of the pancreas is, however, still open to discussion, because several investigations reported an excess pancreatic risk in patients with gallstones. Apart from the papers quoted in Schernhammer et al (2002), some excess risks were found in cohort studies from the United States (Bansal and Sonnenberg, 1996), Denmark (Johansen et al, 1996), and Sweden (Ye et al, 2001), and case -control studies from the United Kingdom (Cuzick and Babiker, 1989), Greece (Kalapothaki et al, 1993), and Israel (Schattner et al, 1997). The strength of the association, however, was variable across studies, and different potential confounding factors were not always taken into account.…”

“…In a combined analysis of the Nurses' Health Study and the Health Professional Follow-up Study, on a total of 206 women and 143 men with cancer of the pancreas, Schernhammer et al (2002) did not find an increased risk of pancreatic cancer in relation to history of gallstones or cholecystectomy after adjusting for potential confounding factors. The issue of a possible association between gallstones or cholecystectomy and cancer of the pancreas is, however, still open to discussion, because several investigations reported an excess pancreatic risk in patients with gallstones.…”

Cancer after cholecystectomy: record-linkage cohort study

“…The results of these three as well as the previous cohort studies have not removed uncertainty about any causal association between cholecystectomy and colon cancer. Other cancers, too, have been studied after cholecystectomy, but the evidence on causality associations with cancers of the pancreas, liver, and stomach is also inconsistent (Ekbom et al, 1996;Johansen et al, 1996;Chow et al, 1999;Schernhammer et al, 2002).…”