|Year : 2008 | Volume
| Issue : 1 | Page : 16-26
Risk factors for gallbladder cancer : A population based case-control study in Delhi
BB Tyagi1, N Manoharan1, V Raina2
1 Department of Delhi Cancer Registry, B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||30-May-2009|
B B Tyagi
Department of Delhi Cancer Registry, B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Background : Gallbladder (GB) cancer ranks among the first five common cancers in females in Delhi, India. The incidence rate of GB carcinoma is higher in North India compared to South India. Methods : A population based case-control study on 333 GB incident cases was carried out in Delhi to identify the risk factors. Cases were matched with two controls based on age (± 5 years), sex and marital status (in case of females) Results : Smoking and alcohol consumption increase the risk of GB cancer. The risk among those who smoke cigarette (OR=3.05, CI=1.33-6.98) was higher than that seen among bidi smokers (OR=2.25, CI=1.38-3.69). History of typhoid in the past and cholelithiasis increased the risk of GB cancer. Post menopausal women had a significant risk of GB cancer than the menstruating women. Consumption of urad dhal, moong dhal, milk, cottage cheese and butter also increased the risk of GB cancer. Conclusion : Smoking, alcohol consumption, typhoid in the past, cholelithiasis and certain dietary items are the some of the most important risk factors for gallbladder cancer.
|How to cite this article:|
Tyagi B B, Manoharan N, Raina V. Risk factors for gallbladder cancer : A population based case-control study in Delhi. Indian J Med Paediatr Oncol 2008;29:16-26
|How to cite this URL:|
Tyagi B B, Manoharan N, Raina V. Risk factors for gallbladder cancer : A population based case-control study in Delhi. Indian J Med Paediatr Oncol [serial online] 2008 [cited 2016 May 4];29:16-26. Available from: http://www.ijmpo.org/text.asp?2008/29/1/16/51442
| Introduction|| |
Cancer of Gallbladder (GB) is a rare neoplasm with varying demographic distribution in different parts of the world. Though this type of cancer is uncommon in US and and Europe, it is more common in Chile, Peru, Japan and Korea.  In India, cancer of GB shows varying geographic distribution, as the incidence is much higher in Delhi population as compared to South India.  Detailed analysis shows an increasing trend in the incidence rate of this cancer in the urban population of Delhi. The age adjusted incidence rate which was 1/100,000 in males and 3.3/100,000 in females in the year 1987 gradually increased to 3.9/100,000 in males and 9.0/100,000 in females in 1996. Comparison of the data from the various population based cancer registries in India indicates that it is common in Northern India. Epidemology studies demonstrate a close association between GB cancer and gall stone. ,,,,,, The incidence of GB cancer parallels the prevalence of gallstone disease; large and longstanding gallstones being associated with a higher risk of GB carcinoma.  The risk of GB carcinoma in patients with gallstones has been reported to have increased four to seven times. , The strength of this relationship varies considerable between various ethics groups. Even though ethnic and geographic variation in the incidence of gallstone is well known, the cause of gallstone formation is obscure. Now progress has been made in understanding the process of gallstone formation. Researchers believe that gallstones may be caused by a combination of factors, including inherited body chemistry, body weight, GB motility (movement), and perhaps diet. Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Besides gallstone, the other only strong risk factor observed for GB cancer was obesity ,, . Hereditary, diet and environmental factor are other risk factors, which need to be studied to elucidate the underlying chances of developing the disease. To provide further information in this issue a case-control study on GB carcinoma was conducted in Delhi.
| Methods|| |
This study was conducted between 1 st April 1997 and 31 st July 2001. Cancer cases were defined as the newly diagnosed and resident cases of Delhi for more than 1 year identified through the Delhi Population Based Cancer Registry. The diagnosis was confirmed through histological or cytological examination. For each case two controls were taken. One control was a healthy neighborhood whereas the second was the healthy relative of the patients. If the healthy relative was not available then another healthy neighborhood control was taken. Controls were matched to cases by ± 5 years of age, sex and marital status (in case of females only).
The cases and control were interviewed in Hindi by trained social investigator using standard questionnaire. The interviewers were intensively trained by the senior staff of the registry for one month in abstracting information, medical terminology etc. The training level was compared using Kappa Statistic and it was 0.8.
A pilot study was conducted and anomalies found in the questionnaire were removed and the questionnaire was revised.
The variables included in the questionnaire were demographic characteristics, medical history, marital history, history of past/present illness, family history of cancer, life style factors, reproductive history and diet presumed to be risk factor for gall bladder cancer. Numerous food and beverage items that were commonly consumed among Delhi population (either daily or weekly or monthly or rarely) were included in the questionnaire and were evaluated using dietary recall method. The food items that were evaluated as potential risk factors for gall bladder cancer are beef, meat, chicken, green vegetables, bread, rice, wheat, milk, coffee, tea, bear, others liquors, carrot, citric fruit, other fruits and other types of food items like dhal, sweets various types of oil etc.
All the cases were interviewed as soon as they were diagnosed, either in the hospital itself or in their home. The same interviewer interviewed both the cases and controls.
Standard measurements were used to elicit information about the quantity of dietary items consumed. The measurements used were Katori/bowl (contains 200 gm of food items) teaspoon, tablespoon, cup and glass.
Frequencies were obtained for all variables, and cross tabulations for each potential risk factor versus case control status were made. The unadjusted conditional odds ratio (OR) was used as the measure of association between variables of interest and GB cancer.  Multivariate logistic regression analysis was also performed.  Statistical significance was assessed using 95% confidence intervals (CI) along with p-values. The data were analyzed using SPSS software.
| Results|| |
This study population consisted a total of 999 persons with 333 GB cancer cases and 666 controls. Their distribution by matching and other variables that were included in the study are shown in [Table 1]. As expected the majority of case patients were women and most were middle aged or older. ,,, Majority of cases and controls were Hindus, illiterate and the total monthly family income was more than five thousand rupees.
| History of Past/Present Illness|| |
To examine history of past/present illness the following variables were evaluated: typhoid, hepatitis, amoebiasis, other liver diseases, TB, peptic ulcer, diabetes, GB diseases, Pancreatic diseases, Heart diseases, hypertension and family history of other diseases. The odds ratio of history of typhoid in the past [Table 2] was predictive of GB cancer (OR = 8.92, CI=5.0-15.9) p<.001. Though there was an increased risk of GB cancer in persons with family history of GB cancer, it was not significant p<.06. There was an elevated risk for GB cancer for the patients with cholithaiasis (OR =446.56, CI =107.88- 2629.15) , p<.001.
Lifestyle Habits (chewing, smoking, drinking)
The data in [Table 3] indicate the risk associated with the life style factors like smoking, drinking and chewing.
For smoking odds ratio were calculated using non smokers as reference group. The ever smokers had increased risk of GB cancer (OR=2.38, CI=1.54-3.66) p<.001. The OR of past smokers was higher than the current smokers. Among the type of smoking-both cigarette (OR=3.05, CI=1.33-6.98) and bidi smokers had (OR=2.25, CI=1.38-3.69) significantly increased risk of GB cancer. Also an increased risk of GB cancer was observed among the current cigarette and bidi smokers than the past smokers.
Alcohol consumption habit was significantly associated with the risk of GB cancer (OR =2.40, CI =1.32 - 4.36). Past drinker had higher risk of GB cancer (OR= 31.32, CI= 4.03-4.36), p<.001. No consistent pattern was evident which type of alcohol increased the risk. All types had elevated odds ratio except beer, with wine showing the highest odds ratio (4.25).
The OR was calculated using non-chewers as reference category. Non significant elevated risk was seen for the habit of chewing (OR = 1.51, CI =0.85 - 2.67), p=.164.
There was an increase in risk of GB cancer as there was an increase in the age at menarche but the association was not statistically significant [Table 4]. Also the menopausal women had a significant risk of GB cancer than the menstruating women (OR = 3.17, CI =1.56-6.47), p<.001.
As the numbers of abortions increased, there was an increased risk of GB cancer but the relationship was not statistically significant. Similarly there was an increased risk of GB cancers with higher no of pregnancies.
Various dietary items that were commonly consumed were evaluated. A significant reduction in odds ratio was seen with the consumption of channa (OR=0.5, CI=0.33 - 0.75), brinjal (OR=0.49, CI=0,30 - 0.80) and bhindi (OR=0.52, CI=0.33 - 0.82). On the other hand a statistically significant increase in odds ratio was observed with consumption of urad dhal (OR=2.07, CI=1.52 - 2.82), moong dhal (OR=1.54, CI=1.12-2.11), milk (OR=1.45, CI=1.06-1.99), cottage cheese (OR=1.85 CI=1.09-3.13), butter (OR=4.06, CI=1.98-8.32), curd (OR=1.53, CI=1.05-2.24), mustard leaves (OR=3.92, CI=1.72- 8.93), tamarind (OR=1.82, CI=1.07,3.08), papaya (OR=1.43, CI=1.01-2.03), pineapple (OR=1.70, CI=1.00-2.90) and pomegranate (OR=2.72, CI=1.35-5.46). [Table 5] presents the list of dietary items that showed significant increase in odds ratio on consumption. Though rice, wheat, masoor dhal, beans, capsicum, green peas, mushroom, sulgum, red chilly, sweets, orange, fish, beef, mutton, chicken, groundnut oil, mustard oil, palm oil, sunflower oil and coffee increase the risk of GB cancer the difference was not statistically significant.
There was an inverse relationship between the weight of person in kilograms and risk of GB cancer [Table 6]. As the weight increase (>60 kgs), the risk of GB cancer decreases and it was statistically significant. There was no relationship between the Quit let's index and GB cancer.
Regression analysis [Table 7] showed typhoid in the past topped the list of risk factors for development of GB cancer followed by butter and mustard leaves. Patients who had typhoid in the past had 9 times increased risk of GB cancer (OR=9.12, CI=4.6-18.08). Smoking, alcohol, consumption of pomegranate, urad dhal and radish were other risk factors for development of GB cancer. Channa and bhindi have protective factor.
| Discussion|| |
Typhoid in the past was found to be one of the important risk factors for the development of GB cancer in the current study. Some other studies also confirmed the relationship between physician diagnosed typhoid and GB carcinoma , Chronic S. typhi infection can be carried in the GB. Chile has an extremely high incidence of typhoid and a high prevalent of typhoid carriage and is known to have a very high risk of GB cancer.  Several other studies also suggested an association between GB cancer and typhoid carrier state ,,,,, . However, the association found in the current study can be only suggestive and was not confirmed by the serological examination. So this hypothesis must be reevaluated in subsequent studies.
The other medical variable that have been postulated to be associated with GB cancer was history of cholelithiasis ,, which was also confirmed in the current study and a high proportion of patients had long-term symptoms of cholelithiasis before discovery of tumour. , However, it is worth mentioning that two cohort studies did not find any association between GB and gallstones. ,
As carcinoma of GB, gallstone and typhoid carrier state are all more common in women, it was not surprising to find female preponderance among the cases and controls.  Women with higher parity were at an increased risk for developing GB cancer. This finding is consistent with some previous studies on the association of parity and GB cancer. ,,, A combination of factors such as malnutrition, decreased antioxidants in the diet may be operating on them.
The present study also has shown a relationship between the smoking habit and GB cancer. It is consistent with several other studies. ,, Several dietary items such as green chili, bhindi, onion, brinjal etc. and fruits like mango, banana etc. have shown a protective effect, which was consistent with other studies.  But some other dietary items have been shown to increase the risk. In our study tea was found to be a protective factor. This observation was consistent with some other studies. Researchers have proposed that tea might protect against cancer because of its antioxidant content.  A study contacted on Poland reported an inverse association with the amount of tea drunk throughout life.  In our study coffee was found to be a risk factor for GB cancer. Coffee has been suggested to be carcinogenic due to presence of mutagens. A study reported that regular coffee was consumed by 74.5% of the subjects and trend was seen towards slightly higher prevalence of GB stones in coffee drinkers  . But a study in Japan, reported a low risk of GB cancer with frequent intake of coffee.  A statistically non significant increased odds was observed for sweet consumption in our study. Sugar has been stated to be one of the risk factors for biliary tract cancer. In a study it was found that for GB cancer the association with the intake of sugar was significant and there was a two-fold increase in risk in the upper tertile of intake  . However another case-control study found a positive association between low intake of sugar as soft drinks with GB cancer. 
The Indian diet is a complex one and is subject to various biases. So it is better to examine the ingredients in these factors in depth before drawing any conclusion.
Obesity is known to be very strong risk factor for cholelithiasis.  Our study shows an inverse relationship between the weight and GB cancer even though a statistically significant association was found between cholilithiasis and GB cancer. So, this study shows that there is no relationship between cholilithiasis and weight, which is consistent with a study reported by Khuroo et al.  Another reason for inverse relation may be due to cachexia in GB cancer cases. Under such circumstances the weight may be an effect rather than the cause of GB cancer.
In this study there was an inverse relationship between Quitlet's index and GB cancer. This is consistent with Framingham Study,  which showed a consistent and strong association with total calorie intake, but not with Quitlet's index.
The main limitation of this study is the recall bias. There are problems of reliability of information concerning the distant past which the subject may forget to recall.
In conclusion, this study reconfirms the association between typhoid in the past, cholelithiasis and gallbladder cancer. The data are also suggestive of an association with smoking and certain dietary patterns.
| Acknowledgement|| |
This study was funded by National Cancer Registry Programme (NCRP), Indian Council of Medical Research, New Delhi. Our special thanks are to Dr. A. Nandakumar, Officer incharge, NCRP, ICMR, Bangalore for his technical support.
| References|| |
|1.||Curado MP, Edwards B, Shin HR. Cancer Incidence in Five Continents, Vol. IX. International Agency for Research Cancer, Lyon, France, 2007, Scientific Publications, No.160. |
|2.||National Cancer Registry Programme, Consolidated reports of the population based cancer registries 1990-96, Indian Council of Medical Research, New Delhi, India, August 2001. |
|3.||Diel AK. Epidemiology of gall bladder cancer: a synthesis of recent data. J.Nat.Cancer. Inst. 1980;65:1209-1213. |
|4.||Diel AK. Gallstone size and risk of gall bladder cancer, J Amer. Med Ass, 1983;250:2323-2326. |
|5.||Black WC, Key CR, Carvant JB et al. Carcinoma of the gall bladder is a population of South-Western American Indians. Cancer 1977;39:1267-1279. |
|6.||Lowewfels AB, Lindstrom CG, Conway MJ et al. Gallstone and risk of gall bladder cancer. J Nat Cancer Inst 1985;7:577-80. |
|7.||Hart J, Modan B, and Shanti, M. Cholelithiosis in the etiology of gall bladder neoplasm. Lancet 1971;I:1151-1153. |
|8.||Kato K, Akai S, Toninga KS et al. A Case-Control study of biliary tract cancer in Nigata prefecture, Japan. Jap J Cancer Res 1989;80:932-938. |
|9.||Zantonski WA, La Veccia C, Przewoznial et al. Risk factor for gall bladder cancer in a Polish case-control study, Int J Cancer 1992;51:707-11. |
|10.||Kapoor VK, Mcmichael AG. Gallbladder Cancer: An 'Indian' disease. Nat Med J India 2003;16 (4):209-13. |
|11.||Maram ES, Ludwig J, Kurland LT et al. Carcinoma of the gallbladder and extrahepatic biliary ducts in Rochester, Minnesota, 1935-71. Am J Epidemiol 1979;109:152-75. |
|12.||Nervi F, Duarte I, Gomez G et al. Frequency of the gallbladder carcinoma in Chile. Int J Cancer 1988;41:657. |
|13.||Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis 1979;32:563-576. |
|14.||Zatonski WA, Lowenfels AB, Boyle P et al. Epidemiologic aspects of gallbladder cancer: A casecontrol study of the SEARCH Program of the International Agency for Research on Cancer. J Nat Cancer Inst 1997;89:1132-1138. |
|15.||Rothman KJ. Sander Greenland. Modern Epidemiology. Pub. Lippincott, Philadelphia. 1998,2ndEdition p183-300. |
|16.||Hosmer DW, Lemeshow S. Applied Logistic Regression. Pub.John Wiley& Sons, 1989. |
|17.||Strom BL, Soloway RD, Rios-Dalenz JL et al. Risk factors for gall bladder cancer. An international collaborative case-control study. Cancer 1995;76:1747- 1756. |
|18.||World Health Organisation, Cancer Incidence in five continents, Vol. VIII Lyon, International Agency for Research on cancer. 1997. |
|19.||Strom BL, Nelson WL, Henson DE et al. Carcinoma of gall bladder. In: Cohen S, Soloway RD, editors. Gallstones. New York: Chmchill Living stone. 1985;275- 278. |
|20.||Strom BL, Hibberd PL, Soper KA et al. International variations in epidemiology of cancer of the extra hepatic biliary tract. Cancer Res 1985;45:5165-5168. |
|21.||Caygill CP, Hill MJ, Braddicc M et al. Cancer mortality in chronic typhoid and para typhoid carves. Lancet 1997;343; 83-84. |
|22.||Mellemgaard A, Gaarsle K. Risk of hepatobilions cancer in carriers of Salmonella typhi. J Nat Cancer Inst 1988;80:288. |
|23.||Welton JC, Marr JS, Friedman SM. Association between hepatobiliary cancer and typhoid carrier state. Lancet 1979;1:791- 43. |
|24.||Robbins S, Chuang VP, Hersh T. The development of hepatobiliary cancer in a carrier of salmonella typhoid. Am J Gastroenterol 1988;83:675-678. |
|25.||Shukla VK, Singh H, Pandey M et al. Carcinoma of the gall bladder - is it a sequel of typhoid. Dig Dis Sci 2000;45(5): 900-903. |
|26.||Nath G, Singh H, Shukla VK. Chronic typhoid carriage and carcinoma of the gallbladder. Eur J Cancer Prev 1997; 6:557-559. |
|27.||Perpetoo MM, Valdivieso M, Heilbrun LK et al. Natural - history study of gall bladder cancer. Cancer 1978;42:330-335. |
|28.||Comfort MW, Gray HK, Wilson JM. The silent gallstones: A 10 to 20 years follow up. Ann Surg 1966;128:931-936 |
|29.||Wenckert A, Robertson B. The natural course of gallstone disease Gastroenterol 1966;50:376-381. |
|30.||Ledingham JCG. The carrier problem in enteric fever. In: Legingham J.C.G., Arkwright J.A., eds. The carrier problem in infections disease. London: Edward Arnold, 1912:115-35. |
|31.||Plesko I, Preston - Martin S, Day NE et al. Parity and cancer risk in Slovakia. Int J Cancer 1985;36:529-33. |
|32.||DATTA U, Garg PK, Kumar Ramesh et al. Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gall bladder. The Am J Gastroenterology 2000;95(3):784-787. |
|33.||Pandey M, Shukla VK. Lifestyle, parity, menstrual and reproductive factors and risk of gallbladder cancer, Eur J Can Prev 2003; 2(4):269-272. |
|34.||Scott TE, Caroll M, Cogliano FD et al. A Casecontrol assessment of risk factors for gallbladder carcinoma. Dig Dis Sci 1999;44:1619-1625. |
|35.||Pandey M, Shukla VK. Diet and gallbladder cancer: a case-control study Eur J Cancer Prev 2002;11(4):365- 368. |
|36.||Rai A, Mohapatra SC, Shukla HS. A review of association of dietary factors in gallbladder cancer. Indian J Cancer 2004;41(4);147-151. |
|37.||Kratzer W, Kachele V, Mason RA et al. Gallstone prevalence in relation to smoking, alcohol, coffee consumption and nutrition. The Ulm gallstone study. Scand J Gastroenterol 1987;32:953-958. |
|38.||Moerman CJ, Bueno DE, Mesquita HB et al. Dietary sugar intake in the aetiology of biliary tract cancer. Int J Epidemiol 1993;22:207-214. |
|39.||Serra I, Yamamoto M, Calvo A et al. Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in Chilean population. Int J Cancer 2002;102:406-411. |
|40.||Strom BL, West SL. The epidemiology of gallstone disease. In: Cohen S, Soloway RD, editors. Gallstones, New York:Churchill Livingstone, 1985;1- 26. |
|41.||Khuroo MS, Mahajan R, Zargar SA et al. Prevalence of biliary tract disease in India: a sonographic study in adult population in Kahshmir. Gut 1989;30(2):201- 205. |
|42.||Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham study. J Chron Dis., 1966;19:273-292. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
|This article has been cited by|
||Smokeless tobacco-associated cancers: A systematic review and meta-analysis of Indian studies
| ||Dhirendra N. Sinha,Rizwan Suliankatchi Abdulkader,Prakash C. Gupta |
| ||International Journal of Cancer. 2016; 138(6): 1368 |
|[Pubmed] | [DOI]|
||Epidemiological Study of Gallbladder Cancer Patients from North Indian Gangetic Planes—a High-Volume Centre’s Experience
| ||Sameer Gupta,Channabasappa Kori,Vijay Kumar,Sanjeev Misra,Naseem Akhtar |
| ||Journal of Gastrointestinal Cancer. 2016; 47(1): 27 |
|[Pubmed] | [DOI]|
||Effects of PTEN gene alteration in patients with gallbladder cancer
| ||Asgar Ali,Pramod Kumar Mishra,Sadhana Sharma,Asit Arora,Sundeep Singh Saluja |
| ||Cancer Genetics. 2015; 208(12): 587 |
|[Pubmed] | [DOI]|
||Epidemiological Factors in Gall Bladder Cancer in Eastern India-A Single Centre Study
| ||Imran Khan,Nilanjan Panda,Manju Banerjee,Ruchira Das |
| ||Indian Journal of Surgical Oncology. 2013; 4(1): 67 |
|[Pubmed] | [DOI]|
||Risk factors for gallbladder cancer: A case-control study
| ||Kajal Jain,V. Sreenivas,T. Velpandian,Umesh Kapil,Pramod Kumar Garg |
| ||International Journal of Cancer. 2013; 132(7): 1660 |
|[Pubmed] | [DOI]|
||Study on Salmonella Typhi occurrence in gallbladder of patients suffering from chronic cholelithiasis—a predisposing factor for carcinoma of gallbladder
| ||Yogesh D. Walawalkar,Rajni Gaind,Vijayashree Nayak |
| ||Diagnostic Microbiology and Infectious Disease. 2013; 77(1): 69 |
|[Pubmed] | [DOI]|
||Genetics of biliary lithiasis from an ethnic perspective
| ||Marcin Krawczyk,Juan Francisco Miquel,Caroline S. Stokes,Silvia Zuniga,Jochen Hampe,Balraj Mittal,Frank Lammert |
| ||Clinics and Research in Hepatology and Gastroenterology. 2013; 37(2): 119 |
|[Pubmed] | [DOI]|