Cancer risk in patients with cholelithiasis
and after cholecystectomy: a nationwide cohort
study
Yen-Kung Chen • Jiann-Horng Yeh •
Cheng-Li Lin • Chiao-Ling Peng • Fung-Chang Sung •
Ing-Ming Hwang • Chia-Hung Kao
Introduction
The presence of stones in the gallbladder is referred to as cholelithiasis [from the Greek words chol (bile), lith
(stone), and iasis (process)]. In the United States, it affects 10–15 % of the population [1]. In Asia, gallstone disease is found in 5–10 % of the population [2]. Gallstones in the
gallbladder may lead to an inflammatory condition characterized by the retention of bile in the gallbladder and
often a secondary infection of the intestine. Consequently, a possible relationship between cholelithiasis and cancer risk has been examined for cancer of the gallbladder, liver, biliary tract, and pancreas [3, 4].
When the gallbladder is removed (cholecystectomy), biliary fluids are secreted into the duodenum continuously and may increase the duodenogastric bile reflux [5], which in turn has been proposed to increase the risk of colorectal and gastric cancer [6, 7]. Although numerous epidemiological investigations and meta-analyses have addressed
the relation between cholecystectomy and the risk of colorectal and gastric cancer, the possible association has not been conclusively confirmed [8–10].
Subsequent types of cancer may be caused by cholelithiasis [11]. Cancer may occur because of chronic inflammation [12]. However, the pathogenetic mechanism of the interaction among cholelithiasis, cholecystectomy, and cancer remains unclear. Because of the increasing incidence of cholelithiasis, the health consequences of these patients
are crucial [2, 13]. In Taiwan, pigmented stones are more prevalent, whereas the majority of gallstones found in
Western populations are cholesterol stones [14]. Epidemiologic data on the association among cholelithiasis, cholecystectomy, and cancer provide useful information for
primary prevention and etiology research. We conducted a nationwide study to evaluate the cancer risk in Chinese patients with cholelithiasis and cholecystectomy.
Methods Study design
We conducted a nationwide cohort study using the Taiwan National Health Institute Research Database (NHIRD) from 2000 to 2010. Taiwan began its single-payer national health insurance (NHI) program in 1995, consolidating 13 insurance programs into a universal system of health care for all residents. This insurance program provides health care to[99 % of more than 23 million people of Taiwan, and is contracted with 97 % of hospitals and clinics. The insurance programs were connected, and patient information was scrambled to generate data suitable for research.
We used the linked identification files, including the sociodemographic information, registry of inpatient orders, and
outpatient care of each patient. Details regarding the database have been published in previous studies [15, 16]. The International Classification of Disease, Ninth Revision (ICD-9), was used to define diagnostic disease codes. Previous studies have shown the accuracy and high validity of diagnosis in the NHIRD [17, 18]. With approval from the NHI and China Medical University, this study was
exempted by the Institutional Review Board (IRB) (CMUREC-101-012).
Study sample
A total of 15545 patients newly diagnosed with cholelithiasis (ICD-9 code 714) between 2000 and 2010 were
identified in our study. Patients with a history of cancer (ICD-9 codes 140–208) before the index date, or with incomplete age or sex information, were excluded. All patients without a history of cholelithiasis were randomly
sampled from 1 million people enrolled in the NHI system. To increase the statistical power, we used a method 4-fold in number (62,180) for each study case, matching our requirements to select the study sample. Any diagnosis of cancer, except metastatic (ICD-9 codes 140–195,
200–208), was observed until the date at which the patients were diagnosed with.
Identification of cancer cases
Newly diagnosed patients with cancer were confirmed by the Registry for Catastrophic Illness Patient Database (RCIPD); the index date was the date of cancer registration. The categories of cancer classification were considered, including head and neck cancer (ICD-9 codes
140–149), esophageal cancer (ICD-9 code 150), stomach cancer (ICD-9 code 151), duodenum cancer (ICD-9 code 152), colorectal cancer (ICD-9 codes 153 and 154), liver cancer (ICD-9 code 155), gallbladder and extrahepatic bile ducts (ICD-9 code 156), pancreatic cancer (ICD-9 code 157), laryngeal cancer (ICD-9 code 161), lung cancer (ICD-9 code 162), melanoma (ICD-9 code 172), skin cancer (ICD-9 code 173), breast cancer (ICD-9 codes 174 and 175), uterine and corpus cancer (ICD-9 codes 179 and 182), cervical cancer (ICD-9 codes 180, 181, and 183), prostate cancer (ICD-9 code 185), bladder cancer (ICD-9 code 188), kidney cancer (ICD-9 code 189), brain cancer (ICD-9 code 191), thyroid cancer (ICD-9 code 193), hematologic malignancy (ICD-9 codes 200–208), and others. Definition of comorbidity and intervention
Potential confounding factors were listed based on established risk factors, and an analysis was performed to
establish whether these variables were substantially associated with cancer. Patients with at least one service claim
from 2000 to 2010 for either outpatient or inpatient health care before the index date were considered for probable comorbidities, such as diabetes mellitus (ICD-9 code 250), hyperlipidemia (ICD-9 code 272), hepatitis B (V02.61, 070.20, 070.22, 070.30, and 070.32), hepatitis C (V02.62, 070.41, 070.44, 070.51, and 070.54), menopause (V49.81,
627.2, 627.8, and 627.9), and cirrhosis (571). Intervention with cholecystectomy in cholelithiasis patients was calculated in our study. We calculated all study patients with
these comorbidities into 4 segments as follows: 0, 1, 2, 3, and C4.
Statistical analysis
The distributions of categorical characteristics were compared and examined using the Chi square test between the
cholelithiasis group and the controls. The follow-up person-years were calculated for assessing incidence density rates until the cancer was either identified or censored. Poisson regression models were used to evaluate the study cohort to comparison cohort rate ratios and 95 % confidence intervals (CI). To estimate the effect of age on the
absolute and relative risk of cancer, we divided patients in categories based on age (0–35, 36–50, 51–64, and
C65 years) at the index date of cholelithiasis. Cox proportional-hazards analyses were used to investigate the
association between cholelithiasis and the risk of developing cancer over time, and were also adjusted for cofactors significantly related to cholelithiasis. Patients with cholelithiasis significantly affect developing cancers had also concerned after receiving the cholecystectomy. Further analysis was performed to assess whether the association of cancer type varied according to the length of the follow-up period after cholelithiasis was diagnosed. We divided the time lag into the following 2 periods after receiving cholecystectomy: B5 years and [5 years. All statistic analyses were performed using the SAS package (Version 9.1 for Windows; SAS institute, Inc., Cary, NC, USA). A two-tailed p value lower than 0.05 was considered significant.
Results
Demographic characteristics are shown in Table 1. More
female patients were present in our study, and almost threefifths of the patients were aged over 50 years (mean age
55.0 years). The prevalence of comorbidities was greater in the cholelithiasis group.
The incidence densities (relative risk) and adjusted
hazard ratio (AHR, absolute risk) between the cholelithiasis and control groups are shown in Table 2. The overall
incidence rate of all types of cancer was 63 % higher in the cholelithiasis group than in the control group (11.8 vs 7.26 per 1000 person-years), with an AHR of 1.52 (95 % CI 1.41–1.64) in the following 11 years. For females, the
incidence density rates are 9.81 and 5.94 per 1000 personyears between the 2 groups. Men have a significantly
higher risk (51 %) of developing all types of cancer compared to women (95 % CI 1.42–1.62). The results were
stratified by age; the incidence density rates of all types of cancer increase with age, and are the highest in the oldest patients of both groups (14.5 and 22.6 per 1000 personyears). After adjusting for cofactors, the risk of developing
all types of cancer increased with age (patients B35 years of age were the reference group) with an AHR of 12.6 (95 % CI 9.75–16.3). Cholelithiasis patients had a higher risk of developing all types of cancer with the prevalent types of comorbidities (IRR = 2.25, 95 % CI 1.68–3.02; AHR = 1.84, 95 % CI 1.49–2.28).
The specific analyses on different cancer types between the cholelithiasis group and the control group are shown in Table 3. Compared to the control group, the AHRs of
developing cancer, especially in the gallbladder and extra hepatic bile ducts, pancreas, liver, stomach, and colorectum
were 19.0, 3.12, 1.90, 1.71, and 1.36-fold for the cholelithiasis group, respectively. Specifically, the subtypes of
gallbladder and extrahepatic bile duct cancer had a 59.3-fold and 10.7-59.3-fold risk, respectively, which was statistically significantly higher for patients with cholelithiasis (95 % CI 7.70–457.5 and 4.41–26.1, respectively).
The AHR after receiving a cholecystectomy in the cholelithiasis group is shown in Table 4. A total of 5850 (37.6 %) cholelithiasis patients received a cholecystectomy. Compared to the non-cholecystectomy group, the
statistically significant risk of developing cancer, especially stomach and colorectal, was identified. Stratified by cancer
site, a 2.98-fold risk (95 % CI 1.08–8.21) was shown for proximal colon cancer, and a 2.46-fold risk (95 % CI
1.13–5.39) was shown for rectal cancer; these were statistically significantly higher for cholelithiasis patients who
had cholecystectomies.
We calculated the AHR according to the length of the follow-up period after cholecystectomy was performed, as shown in Table 5. For colorectal cancer, a 2.03-fold risk of developing cancer was found for the less than and equal to 5-year follow-up periods (95 % CI 1.50–2.74). However,
for stomach cancer, higher risks were observed for developing cancer in both the less than 5 year and over 5 year
follow-up periods (95 % CI 2.59–5.68 and 2.39–7.59, respectively).
Discussion
We used a comprehensive national database to investigate the incidence of cancer in a group of 15545 cholelithiasis patients. A 1-to-4 comparison was conducted for 62180 controls, who were randomly frequency-matched for age, sex, and index year, with adjustments made for baseline comorbidities that may cause a predisposition to cancer, including diabetes mellitus, hyperlipidemia, hepatitis B, hepatitis C, cirrhosis, and menopause. These risk factors were published in a recent article regarding the Taiwanese population [14]. Risk factors for cholelithiasis include pregnancy, drugs like ceftiaxone, octreotide and thiazide diuretics, and total parenteral nutrition or fasting. Diseases like cirrhosis, chronic hemolysis and ileal Crohn’s disease are risk factors for black pigment stones. Other than ethnicity and female gender, additional risk factors for gallbladder cancer include cholelithiasis, advancing age,
chronic inflammatory conditions affecting the gallbladder, congenital biliary abnormalities, and diagnostic confusion
over gallbladder polyps. Several risk factors for gallstones are also implicated in the pathogenesis of gallbladder
cancer [19]. Cholelithiasis patients were more likely to be diagnosed with stomach, colorectal, liver, gallbladder, extrahepatic bile duct, and pancreatic cancer, with an AHR
of 1.71, 1.36, 1.9, 59.3, 10.7, and 3.12, respectively. Knowing the cancer risk is valuable for the prevention and care of cholelithiasis patients. In addition, this study showed that men and older patients in the cholelithiasis cohort had a higher risk of developing cancer compared
with female and younger patients, respectively. Post-cholecystectomy patients were more likely to be diagnosed
with stomach and colorectal cancer, with an AHR of 1.81 and 1.56, respectively. The AHR was high for the
subsequent development of stomach and colorectal cancer in post-cholecystectomy patients within 5 years.
These results confirm that the risk of liver, gallbladder, extrahepatic bile duct, and pancreatic cancer is appreciably elevated in patients with a history of cholelithiasis [3, 4]. Cholelithiasis patients have an increased risk of stomach and colorectal cancer, which is consistent with the results of the Lowenfels study [20]. However, certain other studies reported results that were inconsistent with our results, which revealed that cholelithiasis patients have an increased risk of small intestine, prostate, and kidney cancer [11, 21]. Overall, cholelithiasis is a major risk factor
for gallbladder and extrahepatic bile duct cancer. There were four major kinds of gallstones in Taiwan:
cholesterol/mixed stones, high-residue black formed pigment stones, low-residue brown formed pigment stones,
and muddy pigment stones. The surgical incidence of all types of stones increased steadily during the past four decades. During the past 15 years, the relative frequencies for mixed, formed pigment, and muddy pigment stones had been roughly 40, 40, and 20 %, respectively, with a further increase in the mixed stones and a decrease in the muddy pigment stones in recent years. Improvement of nutritional status and living standards might contribute to such changes. Cholesterol content in the common duct and gallbladder biles was higher in the mixed stone group than in
other groups [22, 23]. Gallbladder pigment stones, which are more predominant in the Asian population, are composed primarily of bilirubinate salts and oxidized tetrapyrrolic
derivatives formed by the polymerization of
unconjugated bilirubin [24, 25]. This type of gallstone is linked to hemolysis, bacterial infection, or liver disease, rather than to hormonal factors [26].
Chronic liver disease is a well-recognized risk factor for cholelithiasis [27]. Fatty liver, diabetes mellitus, hepatitis B, hepatitis C, elevated ALT levels, and cirrhosis have been found to be related to cholelithiasis in certain studies [2, 14, 26]. Taiwan has a higher prevalence of viral hepatitis than other regions [14]. Our study also confirms that
hepatitis B, hepatitis C, and cirrhosis contribute a significant risk for cholelithiasis. Identifying the major risk factors for cholelithiasis is an important step in preventing the formation of gallstones and reducing cholelithiasis-related illnesses.
Epidemiologic studies have identified cholecystectomy as a possible risk factor for cancer in Western countries. Two meta-analyses have addressed the relationship
between a history of cholecystectomy and colorectal cancer. One suggested a moderately increased risk in 33 case– control studies (RR = 1.34, 95 % CI 1.14–1.57) for cancer in the proximal colon (RR = 1.88) [8]. In most studies, the risk was greater when the first 5–15 years following the surgery were excluded. Another meta-analysis of 35 studies found an overall modest positive association
(RR = 1.11, 95 % CI 1.02–1.21), which was slightly stronger among women (OR = 1.14, 95 % CI 1.01–1.28) and for right-sided colon cancer (OR = 1.86, 95 % CI
1.31–2.65) [9]. A positive risk association of cholecystectomy with cancer of the proximal colon, which diminishes
in the distant colon and the rectum, has been reported in
some [20, 28–30], but not all studies [31, 32]. Our study shows a statistically significant increased risk of colorectal
cancer following cholecystectomy; consistent with other studies, the risk appears to be slightly greater for cancer types of the proximal colon and rectum [29].
Several epidemiological studies have evaluated the risk of developing gastric cancer after cholecystectomy for
benign gallbladder disease with inconsistent results [7, 11,
31, 33]. When the risk of gastric cancer was related to the time following a cholecystectomy, a significantly increased risk (RR 2.67) was found during the first post-operation year. After the first post-operative year, the relative risk was towards a decrease in the cancer risk with increasing observation time [7]. Fall et al. [33] found an 11 % overall excess risk for gastric cancer compared with the background population of a large population-based cohort of
cholecystectomy patients observed for 27 years after surgery. However, the overall small excess risk decreased
over time, and was inconsistent for sex and age at cholecystectomy. Goldacre et al. [31] also found a short-term
significant elevation of the rates of cancer of the colon, pancreas, liver, and stomach post-cholecystectomy, but no long-term elevation was observed in the rates. A metaanalysis demonstrated that cholecystectomy was not associated with the risk of gastric cancer (SRRs—1.03; 95 %
CI 0.93–1.13; n = 5 studies) [10]. Certain studies revealed that cholecystectomy increased the risk of intestinal cancer [11, 28]. However, no data about intestinal cancer was shown in the results.
These findings indicate a strong relationship between
cholelithiasis or the risk factors associated with cholelithiasis and gallbladder, extrahepatic bile duct, pancreatic,
liver, stomach, and colorectal cancer. A functional relationship between chronic inflammation and cancer has
been supported by clinical and epidemiological evidence [34, 35]. However, the relationship among cholelithiasis, inflammation, and cancer is complex and remains unclear. Removal of gallstones also reduces the risk of this disease for most related types of cancer. Several studies have reported gastric cancer linked to increased duodenogastric bile reflux and reactive gastritis following cholecystectomy [33]. In addition, an increase in the enterohepatic circulation of the bile pool and its greater exposure to degradation by bacteria into secondary bile acids has been shown to be higher in patients with colorectal cancer [9].
The strengths of our study included its use of population-based data that are highly representative of the general population. However, certain limitations to our findings should be considered. First, the NHIRD does not contain detailed information regarding smoking habits, alcohol consumption, socioeconomic status, and family history for patients with systemic diseases, all of which may be risk factors for cholelithiasis or cancer. Second, the evidence derived from a retrospective cohort study is generally lower in statistical quality than that from randomized trials, because of potential bias related to adjustments for confounding
variables. Despite our meticulous study design and control measures for confounding factors, bias resulting
from unknown confounders may have affected our
results. Third, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology findings, and serum laboratory data were unavailable regarding our study patient cases. However, the data regarding cholelithiasis, cholecystectomy, and cancer diagnoses were highly reliable.
This study provides valuable information. This is the first large-scale nationwide cohort study of cholelithiasis, post-cholecystectomies, and cancer conducted in an Asian population. Patients with cholelithiasis, particularly older patients, are at a higher risk of developing gallbladder, extrahepatic bile duct, pancreatic, liver, stomach, and colorectal cancer compared to the general population. Regarding patients post-cholecystectomy, a statistically significant increased risk of stomach and colorectal cancer was found. In addition, post-cholecystectomy patients have an increased relative risk of developing colorectal and stomach cancer within 5 years and persisting more than 5 years, respectively.
Clinicians managing cholelithiasis patients, especially older patients, must be aware of the possible increased risk of gastrointestinal cancer. Patients post-cholecystectomy have an increased risk of colorectal and stomach cancer within 5 and persisting over 5 years, respectively. Therefore,
strategies to facilitate the prevention of gastrointestinal cancer are recommended for these patients.
