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Risk factors for gallbladder cancer (GBC) except gallstones are not well known. The objective was to study the risk factors for GBC. In a case–control study, 200 patients with GBC, 200 healthy controls and 200 gallstones patients as diseased controls were included prospectively. The risk factors studied were related to socioeconomic profile, life style, reproduction, diet and bile acids. On comparing GBC patients (mean age 51.7 years; 130 females) with healthy controls, risk factors were chemical exposure [odd ratios (OR): 7.0 (2.7–18.2); p < 0.001)], family history of gallstones [OR: 5.3 (1.5–18.9); p < 0.01)], tobacco [OR: 4.1 (1.8–9.7); p < 0.001)], fried foods [OR: 3.1 (1.7–5.6); p < 0.001], joint family [OR: 3.2 (1.7–6.2); p < 0.001], long interval between meals [OR: 1.4 (1.2–1.6); p < 0.001] and residence in Gangetic belt [OR: 3.3 (1.8–6.2); p < 0.001]. On comparing GBC cases with gallstone controls, risk factors were female gender [OR: 2.4 (1.3–4.3); p = 0.004], residence in Gangetic belt [OR: 2.3 (1.2–4.4); p = 0.012], fried foods [OR: 2.5 (1.4–4.4); p < 0.001], diabetes [OR: 2.7 (1.2–6.4); p = 0.02)], tobacco [OR 3.8 (1.7–8.1); p < 0.001)] and joint family [OR: 2.1 (1.2–3.4); p = 0.004]. The ratio of secondary to primary bile acids was significantly higher in GBC cases than gallstone controls (20.8 vs. 0.44). Fried foods, tobacco, chemical exposure, family history of gallstones, residence in Gangetic belt and secondary bile acids were significant risk factors for GBC.
Gallbladder cancer (GBC) is one of the commonest gastrointestinal malignancies, especially among females. The incidence of GBC is high in many parts of the world including Chile, Peru, Bolivia, Korea, Japan, Czech Republic, Slovakia, Spain and India.1 The incidence of GBC among women in northern India is one of the highest in the world, and the incidence of GBC is steadily increasing from 10.1/100,000 population in women in 1993 to 19.6/100,000 population in 2006.2, 3 The prognosis of GBC is poor with <10% of patients suitable for curative resection and an overall 5-year survival of <5%.4 The etiopathogenesis of GBC is not well understood. The study of the risk factors for GBC is important not only for understanding the etiopathogenesis but also for preventive strategies. The putative risk factors for GBC include female sex, gallstones, chronic Salmonella typhi carrier status, dietary factors and environmental exposure to specific chemicals.5–13 However, the current knowledge about the risk factors for GBC is limited, and there is inconsistency about the role of risk factors in various studies from different centers. For example, the role of dietary factors and female sex hormones in the pathogenesis of GBC is ambiguous.14–16 Furthermore, one of the major issues in many previous studies was the confounding effect of gallstones while determining the risk associated with other factors. Although the causality is not established, it is well known that gallstones are strongly associated with GBC. It is quite possible that given their similar profile, patients with GBC and those with gallstones share many of the risk factors. Thus, it is important that a study to assess the risk factors for GBC should take into account the confounding effect of gallstones.
The present study was conducted in northern India, a high-incidence area for GBC, with the objective to find out various risk factors related to sociodemographic profile, diet, lifestyle, biliary bile acids, biliary infection, occupational factors, etc., that might be associated with GBC while adjusting for the confounding effect of gallstones.
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GBC is a highly malignant tumor and often diagnosed at an advanced stage. To decrease mortality from GBC, we need to implement preventive and surveillance strategies. Identifying significant risk factors is an important step in that direction. In the present case–control study, we investigated many risk factors for GBC including those related to environmental influences, such as diet, alcohol, smoking, geographical area, and host factors such as bile acids, family history and gallstones in a comprehensive manner. We included two groups of controls—one healthy and the other with gallstones. Because patients with GBC often have associated gallstones,1, 8, 20 patients with GBC and those with gallstone might share certain risk factors. Hence, a control group of gallstones patients was included to take care of the confounding effect of gallstones and study risk factors other than gallstones.
The risk factors that turned out to be significant in the present study were fried foods, tobacco use, exposure to wood and coal dust, long interval between the meals, family history of gallstone disease, joint family, and residence in Gangetic belt. The significant risk factors that turned out to be common between different analyses, i.e., comparing GBC with healthy controls, and GBC with GS controls for all patients and for females, were preference to fried food, joint family and residence in Gangetic belt.
Among the dietary factors, fried food was found to be a risk factor for GBC. A study from Japan had shown that increased risk of the cancer was associated with increased consumption of oily food.21 A longer interval between the meals was found to be a risk factor. Long interval between meals increases the contact time of bile with the gallbladder mucosa. Frequent consumption of green leafy vegetables was found to be a risk factor in the present study when GBC patients were compared to gallstone controls. This is contradictory to the results of earlier studies.22, 23 The probable reason could be less frequent consumption of green leafy vegetables by patient with gallstone as there is a belief that these might increase the risk of stone formation. Thus, the association is likely to be spurious.
No association was seen with alcohol and smoking in the present study although tobacco came out to be a significant risk factor for GBC when compared with healthy controls and gallstones. Earlier studies were contradictory with regard to the effect of alcohol, smoking or tobacco on GBC.24–27
Tea and coffee were found to be protective factors in the present study. Tyagi et al.28 showed tea to be a protective factor, but their results showed coffee to be a risk factor for GBC. However, a study from Japan reported a low risk of GBC among coffee-drinkers.21
A family history of gallstone disease was found to be a significant risk factor and might suggest a genetic predisposition to develop gallbladder diseases including gallstones and GBC. Hsing et al.29 also showed the association of family history of gallstone disease with increased risk of biliary stones, GBC and bile duct cancer.
The risk of GBC was found to be 3.2 times higher in subjects living in joint families when compared with those living in nuclear families in the present study. In India, joint family system is quite prevalent especially in rural areas. Joint family is a proxy for other factors such as poor sanitation and increased chances of food and water borne infections.
Exposure to coal or wood dust was found to be an independent risk factor in the present study. High cadmium, chromium and lead contents have been suggested to be risk factor for GBC along the Gangetic belt.18 Occupational risk factors leading to high-biliary metal content have also been reported to be associated with GBC.1, 30, 31
The majority (82%) of the patients belonged to the Gangetic belt (i.e., Bihar, Uttar Pradesh and Uttarakhand) in the present study. A few earlier studies had also shown that the incidence of GBC was relatively high in these states of India.18, 32 These studies suggest that water borne infections, soil contents or predominantly rural cooking practices such as wood and coal burning might be some of the important contributing factors for such a geographical proclivity to GBC within the same country.
We investigated reproductive variables as risk factors, because GBC is more common among females. In the present study, 65% of the patients were females. An earlier study by Dutta et al.8 showed that the percentage of females was 76.5%. Other studies also support that GBC is more commonly seen in females.33, 34 Among the reproductive factors, the number of live births and a younger age at marriage were found to be important risk factors on comparison of patients with GBC and healthy controls (females) in the present study. Similar results were obtained by Shukla et al.35 They showed that a younger age at menarche (<13 years), higher number of child births (>4), higher number of pregnancies (>4) and a higher age at last childbirth (>25 years) were factors responsible for a relatively increased risk of GBC. Singh et al.36 reported a high risk of GBC in women with early menarche, late marriage, late pregnancy and prolonged reproductive phase. Andreotti et al.37 also showed that high parity led to an increased risk of GBC in Chinese patients with biliary tract cancers. Age at menarche has been controversial in this regard. Some authors have shown a late age, and others have shown an early age at menarche to be a risk factor.37, 38 These observations from various studies suggest a possible role of female hormonal factors in the pathogenesis of GBC. Another possibility is that there is stasis of bile during pregnancy, which may be toxic to the gallbladder mucosa.
Bile acids have been implicated in the pathogenesis of GBC. Only a few studies are available in which the individual bile acids were measured in GBC patients. Furthermore, the sample size was small in these studies.39, 40 Park et al.40 showed that the GBC patients had both significantly lower total bile acid concentration and deoxycholic acid (DCA) concentration. But they included only six GBC patients. The decrease in biliary bile acids was associated with bile acid accumulation in the liver. Earlier studies have shown that DCA acid is cytotoxic, and the carcinogenic potential is due to high upregulation of COX-2 and CDX-2 and downregulation of DNA repair enzymes.41 One of the important findings of the present study was a very high relative concentration of secondary bile acids in GBC patients. The ratio of secondary to primary bile acids was completely reversed in patients with GBC. An earlier study had also shown that the concentrations of secondary bile acids were much higher in patients with GBC when compared with gallstone patients.42 Bacterial degradation of primary bile acids in the gallbladder itself could be responsible for gallbladder carcinogenesis although GBC patients with negative bile culture also had significantly high secondary bile acids.
It is still not clear whether this increase in the secondary bile acids is a cause or effect and whether the increase in the percentage of secondary bile acids is due to increased conversion of primary bile acids to secondary bile acids or due to decreased rate of synthesis of primary bile acids. It might be useful to study hepatic or gallbladder bile without biliary obstruction. But this is difficult due to the practical reasons that include (i) most GBC patients present with obstruction and (ii) GB is generally replaced by a mass and there is hardly any bile in the GB.
There are a few potential limitations of the present study. In particular, the case–control design may render some results difficult to interpret due to a possibility of recall bias and reverse causation. For example, recall bias might explain the very high OR for exposure to coal and dust and reverse causation the inverse association with coffee.
We conclude that the important risk factors identified for GBC were fried foods, tobacco use, a long interval between the meals, chemical exposure, family history of gallstone disease, residence in Gangetic belt and relatively high concentration of secondary bile acids. Increased number of live birth and a younger age at marriage and at first child birth were found to be additional risk factors for GBC in females.