Family history of gallstones and the risk of biliary tract cancer and gallstones: A population-based study in Shanghai, China

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20852, USA.
International Journal of Cancer (Impact Factor: 5.09). 08/2007; 121(4):832-8. DOI: 10.1002/ijc.22756
Source: PubMed


Cancers of the biliary tract arise from the gallbladder, extrahepatic bile ducts and ampulla of Vater. Although relatively uncommon, the incidence of biliary tract cancer rose more than 100% in Shanghai, China between 1972 and 1994. Gallstones are the predominant risk factor for biliary tract cancers, with over 60% of the cancer cases having gallstones. A familial tendency to gallstones has been reported and may elevate the risk of gallbladder cancer further. As part of a large population-based case-control study of biliary tract cancers in Shanghai, China, we examined the association between a family history of gallstones and biliary tract cancers as well as biliary stones. A total of 627 biliary tract cancers (368 gallbladder, 191 bile duct, 68 ampulla of Vater), 1,037 biliary stone cases (774 gallbladder, 263 bile duct) and 959 healthy subjects randomly selected from the population were included in this study. Information on family history of gallstones among first-degree relatives (i.e., parents, siblings, offspring) was obtained through a self-reported history during in-person interviews. A family history of gallstones was associated with increased risks of biliary stones [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 2.1-3.8], gallbladder cancer (OR = 2.1, 95% CI = 1.4-3.3) and bile duct cancer (OR = 1.5, 95% CI = 0.9-2.5), after adjustment for age, gender, marital status, education, smoking, alcohol drinking and body mass index. For gallbladder cancer, subjects with gallstones but without a family history of gallstones had a 21-fold risk (95% CI 14.8-30.1), while those with both gallstones and a positive family history had a 57-fold risk (95% CI 32.0-110.5). Significant risks for gallbladder cancer persisted after additional adjustment for gallstones, and when the analysis was restricted to subjects with first-degree relatives whose gallstones were treated with cholecystectomy. The significant associations with a family history of gallstones were seen for all first-degree relatives, including parents, siblings and offspring, but not spouses. This large population-based study not only supports the role of gallstones in biliary carcinogenesis but also suggests that the underlying genetic or lifestyle determinants of stones within families contribute to the risk of biliary tract cancer.

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    • "Moreover, an increased number, volume, weight, cholesterol type and long-standing carriage of gallstones are also associated with a high risk for GBC. Subjects with gallstones but no family history of gallstones have a 21-fold risk, while those with both gallstones and a positive family history have a 57-fold risk (Hsing et al., 2007). In 1924, Leitch studied gallbladder carcinogenesis by introducing human gallstones, glass pebbles and pitch pellets into the gallbladder of guinea pigs. "
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    ABSTRACT: Gallbladder cancer (GBC) is a deadly biliary neo-plasia with marked ethnic and geographical distribution. The prognosis of GBC is often dismal due to late diagnosis and lack of effective therapeutic options. The main risk factor for GBC is gallstone carriage over long periods of time, which leads to persistent damage and chronic inflammation. This condition promotes genetic/epigenetic alterations and the progressive impairment of the epithelial architecture, mainly through a metaplasia–dysplasia–carcinoma sequence. New molecular alterations have been identified that may help improve the clinical management of patients through the application of more specific therapies. The application of new DNA sequencing technologies is making it possible to catalogue the spectrum of genetic alterations that charac-terise GBC and is aiding in the understanding of the biology behind gallbladder carcinogenesis. Here, a stepwise model of morphogenetic progression from inflammatory to neoplastic tissues is proposed based on currently available evidence. Epidemiology Gallbladder cancer (GBC) is an infrequent neoplasm with marked ethnic and geographical variations. High incidence rates occur in South American natives, particularly from Andean regions. Other high-risk areas are India, Pakistan and Eastern Europe. The high incidences observed in American natives suggest a considerable genetic component in the development of this disease, along with an important environmental influence, including diet and lifestyle (Stinton and Shaffer, 2012). GBC affects women 2–6 times more frequently than men, and its incidence increases progressively with age in both sexes. Although GBC is uncommon in most Western regions, for some countries, such as Chile and Bolivia, this disease is a public health problem. GBC is often diagnosed late when the disease is at advanced stages mainly due to its anatomical location and vague symptoms overlapped with gallstone disease. The overall mean survival rate for patients with advanced GBC is 6 months, with a 5-year survival rate of 5% (Stinton and Shaffer, 2012). Treatment of advanced GBC involves chemotherapeutic agents such as gem-citabine and 5-fluorouracil; however, these drugs extend the life of patients only a few weeks. Therefore, there is an urgent need to identify potential new therapeutic targets for GBC treatment. The most important risk factor for GBC is gallstones, present in over 95% of patients with chronic cholecystitis and 85–95% of patients with GBC (Roa et al., 1996, 2014b). In most regions with a high incidence of GBC, a high incidence of gallstone disease is also observed. However, around 10–25% of patients with GBC have no cholelithiasis and, importantly, only 1–3% of patients with gallstones will develop GBC. Other important risk factors are obesity, female gender, biliary infections and an anomalous pancreatobiliary ductal junction (Goldin and Roa, 2009). Gallstones >3 cm in size carry a 10-fold increased risk for GBC compared to smaller stones. Moreover, an increased eLS
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    • "Intermediate incidences (3.7 to 9.1 per 100,000) occur elsewhere in South Americans of Indian descent, and in Israel (5/100,000) and Japan (7/100,000).184 The frequency is increasing in Shanghai, China and now accounts for the most frequent gastrointestinal malignancy and is a substantial cause of mortality.188 Although the majority of the world has decreasing mortality trends in gallbladder cancer, Iceland, Costa Rica, and Korea have an increase in mortality for men.189 "
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    ABSTRACT: Diseases of the gallbladder are common and costly. The best epidemiological screening method to accurately determine point prevalence of gallstone disease is ultrasonography. Many risk factors for cholesterol gallstone formation are not modifiable such as ethnic background, increasing age, female gender and family history or genetics. Conversely, the modifiable risks for cholesterol gallstones are obesity, rapid weight loss and a sedentary lifestyle. The rising epidemic of obesity and the metabolic syndrome predicts an escalation of cholesterol gallstone frequency. Risk factors for biliary sludge 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. Gallstone disease in childhood, once considered rare, has become increasingly recognized with similar risk factors as those in adults, particularly obesity. Gallbladder cancer is uncommon in developed countries. In the U.S., it accounts for only ~ 5,000 cases per year. Elsewhere, high incidence rates occur in North and South American Indians. 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.
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    • "Ethnic, family predisposition and geographic variation suggests that besides gall stones other factors also contributes to the occurrence of GC e.g. genetic predisposition, shared metabolic and life style factors including obesity, dietary habits, infection and parity [12-16]. "
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    ABSTRACT: Gallbladder carcinoma (GC) is a relatively rare malignancy worldwide but is the second commonest gastrointestinal cancer in Pakistani women. Gallstones have a positive association with GC but other factors also influence in causation. This is a retrospective case control study over a period of 19 years. The cases (Group A) were patients with histopathological proven carcinoma gallbladder (N = 60) and controls were patients with cholelithiasis but no carcinoma gallbladder on histopathology (N = 120). Multivariate regression analysis was done to calculate the odds ratio, 95% confidence interval and P-Value. A positive relationship was found between size of stone > 1 cm, solitary stone, age > 55 years and multi-parity in women. There were 60 patients in Group A and 120 patients in Group B. mean age of diagnosis in Group A patients was 57 ± 2.4 years while mean age of diagnosis in Group B patients was 48 ± 1.35 years. Sixty seven percent of cancer group patients were female as compared to 78% females in non-cancer group. In Group A, 69% of female patients were multiparous (parity of more than 5) while 43% of group B patients were multiparous. For body mass index (BMI), both groups were not very different in our study population i.e. around 78% patients in each group has BMI of more than 23 Kg/m2. In Group A, 37% (n = 22) have solitary stones as compared to 15% (n = 18) in group B. similarly Group A patients has larger stone size as compared to Group B i.e.59% (n = 36) patients in Group A have stones of more than 1 cm when compared to 35% (n = 41) patients in Group B. After using multivariate regression analysis, age more than 55 years (OR - 7.27, p value- < 0.001), solitary stone (OR - 3.33, p value - 0.002) and stone of more than 1 cm (OR - 2.73, p value - 0.004) were found to be independent risk factors for development of gallbladder cancer. Most of the patients (78%) with GC were female, and the statistically significant risk factors were older age, solitary stones and stones size more than one centimeter. A case can be made for prophylactic cholecystectomy in such a high risk group. However a population based study is required to calculate the true incidence of GC in Karachi and a prospective multi center study is needed to produce strong evidence for screening and prophylactic cholecystectomy. As this was a retrospective review of medical records, as per institution policy, its gives waiver from any registration (ethical/trial).
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