ORIGINAL ARTICLE

Risk factors for choledocholithiasis in a south Indianpopulation: A case–control study

Alexander Palapatti Chandran & Ramya Ramakrishnan Sivarajan &

Melpakkam Srinivas & Vijaya Srinivasan &

Jayanthi Venkataraman

Received: 8 December 2012 /Accepted: 18 July 2013 /Published online: 26 September 2013# Indian Society of Gastroenterology 2013

AbstractAim To identify risk factors for common bile duct (CBD) stonesin a south Indian population.Methods Demographic characteristics and diet details wereobtained from patients with isolated CBD stones (Gp I) andthose with combined CBD and gallstones (Gp II) and age- andsex-matched controls. The risk factors were compared be-tween the two groups.Results The demographic characteristics were similar betweenthe two groups and matched controls. The significant riskfactors for Gp I were infrequent consumption of green vegeta-ble (odds ratio (OR), 2.3; p<0.05), intake of tea/coffee (OR 3.3;p<0.01) and less consumption of sugar (p<0.01). For Gp II, therisk factors were frequent intake (>3 times per week) of spices(OR, 2.8; p<0.05), fried foods (OR, 2.7; p<0.05), tamarind(OR, 2.8; p<0.01), and quantum of oil (p<0.01) per month.Green vegetables (OR, 8.5; p<0.00001) and sugar (9.5+4.2 vs.13.8+11.2 g; p<0.00001) were protective. Between the twogroups, the risk factors for Gp II were less frequent greenvegetable intake (OR: 6.4; p<0.00001), more frequent spicyfood (0-3 times per week) (OR, 7.0; p<0.05), and highermonthly oil intake (251+105 vs. 292+89 mL; p<0.05).Conclusion CBD stones in both groups were associated withreduced intake of sugar and green vegetables. Our findingsneed to be validated in larger studies.

Keywords Epidemiology . Gallstones . Sugar . Vegetables

Introduction

Gallbladder (GB) stones in south India are predominantlypigment or mixed stones [1, 2], and their risk factors havebeen studied [3]. Primary stones in the common bile duct(CBD) are rare. Combination of stones in the GB and theCBD are not uncommon. The common risk factors describedinclude obesity, larger consumption of long-chain saturatedfatty acids, chronic hemolysis, estrogen exposure, weight lossfollowing bariatric surgery, and prior cholecystectomy. Prima-ry bile duct stones tend to be higher in bilirubin content, andlower in cholesterol content, than secondary stones. Kumaret al. [4] studied the composition of CBD stones in northernIndian patients and found them to be predominantly choles-terol stones. Even in patients with isolated CBD stones (withstoneless GB in situ), three-quarters were cholesterol stones.

In theWestern world, most stones in the CBD arise from thepassage of GB stones into the CBD. Stones in the commonduct occur in 10 % to 15 % of people who have GB stones [5]and occur more frequently in the elderly. The prevalence ofCBD stones seems to increase with age, ie. 30 % to 50 % ofpatients more than 60 years old with gallstones (GS) haveCBD stones. Coexistent GB and common duct stones corre-lates with increasing age, Asian descent, chronic inflammatoryconditions (primary sclerosing cholangitis, acquired immuno-deficiency syndrome, parasites), and possibly hypothyroidism.

The patient characteristics and risk factors for patients withCBD stones in the Indian subcontinent have not been previ-ously studied. The aim of this study was to identify demo-graphic and lifestyle-related risk factors for isolated CBD andcombined CBD and GB stones in a south Indian population.

Methods

Consecutive patients attending a Gastroenterology Unit of a900-bedded Government tertiary referral hospital in Chennai

A. P. Chandran : R. R. SivarajanDepartment of Medicine, Stanley Medical College, Old Jail Road,Royapuram, Chennai 600 001, India

M. Srinivas :V. Srinivasan (*) : J. VenkataramanDepartment of Gastroenterology and Hepatology, Global Hospitalsand Health City, 439, Cheran Nagar, Perumbakkam,Chennai 600 100, Indiae-mail: Vijaya_srinivasan48@yahoo.com

Indian J Gastroenterol (November–December 2013) 32(6):381–385DOI 10.1007/s12664-013-0354-x

Table 1 Risk factors for common bile duct stones: case versus control

Characteristic CBD stones(68)

Controls(68)

p-valuea Odds ratiob

(95 % CI)

BMI (mean±SD); kg/m2 23.3±2.9 22.6±3.3 NS

Comorbid illness present, n (%) 11 (16.2) 13 (19.2) NS

Smokers (ever), n (%) 27 (39.7) 25 (36.7) NS

Alcohol (ever), n (%) 31 (45.6) 26 (38.2) NS

<3 cups tea/coffee per day, n (%) 57 (83.9) 43 (63.2) <0.01 3.30 (1.3 to 7.4)

Grams of sugar/day (mean±SD) 10±3.4 13.5±10.4 <0.01

Meat ≥3 times/week, n (%) 14 (20.6) 7 (10.3) NS

Rice all days in a week, n (%) 67 (98.5) 65 (95.6) NS

Wheat average days per week (mean±SD) 1.7±1.0 2.2±1.7 <0.05

Green vegetables average days per week (mean±SD) 3.5±1.5 4.3±1.8 <0.01

Green vegetables <3 times a week (mean±SD) 21 (30.9) 11 (16.2) <0.05 2.3 (1 to 5.7)

Fruits <3 times a week (mean±SD) 51 (75.0) 47 (69.1) NS

Tamarind: average per week (mean±SD) 5.0±1.8 4.8±2.0 NS

Spices/curry: average per week (mean±SD) 3.0±1.3 2.7±1.2 NS

Fried foods: average per week (mean±SD) 2.2±1.0 2.2±1.0 NS

Average amount of oil per month (mL) (mean±SD) 251±105 244±79 NS

Demographic variables between cases and controls (mean age, sex, occupation, education, and average annual per capita income)

CBD common bile ducta Chi-square (for percentage comparison) or ANOVA (for means comparison) as applicableb Done when chi-square p-value significant

Table 2 Risk factors for patients with both common bile duct and gallstones versus control

Characteristic GS with CBD stones (n=55) Control (n=55) p-valuea Odds ratio (95 % CI)

BMI in kg/m2 (mean±SD) 23.1±3.4 22.7±2.7 NS

Comorbid illness present, n (%) 12 (21.8) 8 (14.5) NS

Smokers (ever), n (%) 26 (47.3) 21 (36.2) NS

Alcohol (ever), n (%) 27 (49.4) 21 (36.2) NS

>3 cups of tea/coffee per day, n (%) 13 (23.6) 18 (32.7) NS

Grams of sugar/day (mean±SD); 9.5±4.2 13.8±11.2 <0.01

Nonvegetarian <3 times/week, n (%) 29 (52.7) 44 (80.0) <0.01 3.2 (1.3 to 7.8)

Rice: all days a week 53 (96.4) 53 (96.4) similar

Wheat: all days a week, n (%) 11 (20.0) 10 (18.2) NS

Green vegetables: average days/week (mean±SD) 2.6±1.1 4.1±1.8 <10−5

Green vegetables <3 times a week 45 (81.8) 19 (34.5) <10−5 8.5 (3.3 to 22.9)

Fruits <3 times/week 54 (98.2) 48 (87.3) <0.05 7.9 (NS)

Tamarind: average days/week (mean±SD); 5.2±1.7 4.0±1.4 <10−5

Tamarind <3 times/week 34 (61.8) 20 (36.3) < 0.01 2.8 (1.2 to 6.6)

Spices/curry <3 times/week 34 (61.8) 45 (81.8) <0.05 1.6 (1.1 to 2.2)

Fried foods: average days/week (mean±SD) 2.5±1.1 1.9±1.0 <0.005

Fried foods <3 times/week, n (%) 30 (54.6) 42 (76.4) <0.05 2.7 (1.1 to 6.6)

Average amount of oil per month (mL) (mean±SD) 292±89 250±72 <0.01

GS gallstones, CBD common bile ducta Chi-square (for percentage comparison) or ANOVA (for means comparison) as applicable

382 Indian J Gastroenterol (November–December 2013) 32(6):381–385

between 2008 and 2010 with confirmed CBD stones at endo-scopic retrograde cholangiopancreatography (ERCP) or atsurgery were included in the study. Most patients reportingat this center belonged to low middle or poor socioeconomicstatus. Patients with iatrogenic biliary stricture, intrahepaticlithiasis, parasitic infestation (roundworm), and past history ofCBD stones or biliary surgery were excluded.

Data on demographic profile (age, gender, occupation, percapita income, and religion), lifestyle variables (smoking andalcohol), body mass index (BMI), and diet recall were col-lected by a questionnaire survey from all patients and controls.Diet recall included number of days in a week that cereals(rice, wheat, others), green vegetables, fruits, nonvegetarianitems (eggs, fish, meat, and chicken), spicy, and fried foodwere consumed. Subjects were considered nonvegetarian ifthey took any nonvegetarian item during the dietary recall forthat particular week. The amount of oil used per individual permonth was also calculated as total quantum purchased dividedby number of family members above the age of 5 years.Tamarind (Tamarindus indica) is an important constituent ofa south Indian cuisine. The number of days in a week that thisitem was used for preparation of various dishes was noted.Number of cups of tea/coffee taken per day was noted (eachcup equivalent to 200 mL); if the case/control took less than orequal to three cups of coffee/tea per day was considered as aninfrequent consumer as related to those who took greater than

three cups of tea/coffee. Sugar intake was measured as gramsper day (1 teaspoon=5 g). Controls were patients with dys-pepsia who had a normal upper endoscopy and ultrasound andbelonged to the same socioeconomic strata. One age- and sex-matched control was assigned to each patient.

The data were collected by APC and RS, after training andstandardization of the responses were verified by JV. TheEthics Committee of the institution approved the study.

Statistical analysis

Two groups of patients were studied, isolated CBD stones(Gp I) and combined CBD+GB stones (Gp II). They werecompared with respective healthy age–sex matched controls.Comparative analysis for risk factors was also done betweenGp I and Gp II. The minimum frequency of weekly consump-tion of each food item achieving statistical significance, if any,between the groups and controls was also determined (eg. greenvegetables 0–3 times vs. >3 times per week). Chi-square testwas done to compare the prevalence of risk factors. Odds ratio(OR) with 95 % confidence interval (CI) was calculated usingone-way analysis. Logistic regression was done for significantrisk factors noted by one-way analysis and age (binary classi-fied) for case–control data. Logistic regression was not reportedwhen the model was not a good fit. Averages of the food itemsconsumedwere compared using analysis of variance (ANOVA).

Results

There were 68 patients in Gp I and 55 patients in Gp II. Thedemographic characteristics between case and controls in thetwo groups as well as between group 1 and group II weresimilar (Tables 1, 2, and 3).

Comparison of Gp I and controls

The life style, BMI, and dietary risk factors for cases andcontrols are shown in Table 1. On univariate analysis, numberof times green vegetables taken per week (p<0.05; OR, 2.3 %to 95 % CI, 1.0 to 5.7), wheat per week (1.7±1.0 vs. 2.2±1.7)(p<0.05), sugar per day (10±3.4 vs. 13.5±10.4 g andp<0.01), and number of cups of tea/coffee taken per day(p<0.01; OR, 3.3 % to 95 % CI, 1.3 to 7.4) were infrequentin patients. Of these, infrequent intake of green vegetables (logodds, 2.9) and tea/coffee (log odds, 2.6) were significant(p<0.05) by logistic regression analysis

Comparison of Gp II and controls

The life style and BMI between cases and controls weresimilar (Table 2). On univariate analysis, the significant riskfactors among patients were increased intake of oil (292±89

Table 3 Demographic characteristics of common bile duct stones casesand common bile duct with gallstones cases

Characteristic CBD stones(n=68)

GS with CBDstones (n=55)

p-valuea

Age in years(mean±SD)

47.3±14.4 52.6±14.4 NS

N (%) N (%)

M/F ratio 37:31 (1:0.83) 32:23 (1:0.72) NS

Occupation

Housewives 23 (33.8) 16 (29.1) NSLaborers 14 (20.6) 13 (23.6)

White collar 10 (14.7) 5 (9.1)

Blue collar 4 (5.9) 9 (16.4)

Petty business 6 (8.8) 2 (3.6)

Farmer 4 (5.9) 3 (5.4)

Others 7 (10.3) 7 (12.7)

Literacy

Illiterate 18 (26.5) 15 (27.3) NSPrimary schooling 13 (19.1) 13 (23.6)

Secondary schooling 22 (32.4) 21 (38.2)

College and above 15 (22.1) 6 (10.9)

Per capita annual income(Rupees) (mean±SD)

5603±4143 4655±2975 NS

CBD common bile duct, GS gallstones, NS not significanta Chi-square (for percentage comparison) orANOVA (formeans comparison)

Indian J Gastroenterol (November–December 2013) 32(6):381–385 383

vs. 250±72mL), more frequent intake of spices (p<0.05; OR,2.8 % to 95 % CI, 1.1 to 7.3), fried foods (p<0.05; OR, 2.7 %to 95 % CI, 1.1 to 4.2), nonvegetarian items (p<0.01; OR, 3.2(95 % CI, 1.3 to 7.8), and tamarind per week (p<0.01; OR,2.8 % to 95 % CI, 1.2 to 6.6). Green vegetables (p<0.00001;OR, 8.5; 95% CI, 3.3 to 22.9) and fruits (p<0.05; OR 7.9) perweek were taken less often and lesser quantity of sugar takenper day (p<0.00001; 9.5±4.2 vs. 13.8±11.2 g) by patients.On logistic regression, none of the factors noted on univariateanalysis emerged significant.

Comparison of Gp I and Gp II

The life style variables and BMI in the two groups were similar(Table 4). Gp II patients consumed more oil (251±105 vs.292±89 mL; p<0.05) and spicy food (p<0.01; OR, 2.5 % to95 % CI, 1.1 to 5.5) but took green vegetables less frequently(p<0.00001; odds ratio, 6.4 % to 95 % CI, 2.6 to 16.3)compared to Gp I.

Discussion

The present study has for the first time compared the basicdemographic characteristics, social customs (smoking andalcohol), BMI, and dietary factors in three groups of patients,ie. CBD stones, combinedGSwith CBD stone, and those withGS. While the sociodemographic characteristics in all thethree groups were similar, there were differences in age andBMI. Patients with CBD stones were significantly younger

and also with a lower BMI than patients with GS. In the USA,CBD patients present 10 years older than cholelithiasis pa-tients. The high BMI among GS patients is similar to ourearlier report in 2005 [3]. The smoking pattern and alcoholintake in CBD stone patients were intermediate between gall-stone and combination site stone patients indicating that GSprobably has an additional risk to CBD stone.

The role of dietary factor in the pathogenesis of CBDstones is not known, though there are reports of higher con-sumption of long-chain saturated fatty acids in these patients.Most studies extrapolate the dietary risk factors of GS tocholedocholithiasis as the two are often closely linked to eachother. We could not find any literature on dietary risk factorsfor primary choledocholithiasis. An interesting observationwas that unlike patients with GS with or withoutcholedocholithiasis, spices, fried foods, and oil were not a riskfactor for primary choledocholithiasis. Also, tamarind whichwas a significant risk factor for gallstones, the risk was leastfor choledocholithiasis. The findings were similar to our earlierstudy where tamarind was a risk factor for GS. Green vegeta-bles uniformly were a protective factor for all three groups ofpatients, and it was intermediate for choledocholithiasis.Though sugar consumption was less compared to controls inall the three groups, it was taken in excess in CBD stonepatients when compared to patients with GS with or withoutCBD stones.

In Asian patients, primary stones are not uncommon andare formed in the intrahepatic or extrahepatic bile ducts; thecommon cause being chronic bile duct inflammation second-ary to sclerosing cholangitis and parasitic infestation and

Table 4 Comparison of risk factors between common bile duct and common bile duct with gallstones

Characteristic CBD stones(n=68) N %

CBD with GS stones(n=55) N %

p-valuea Odds ratio(95 % CI)

BMI (mean±SD) 23.3±2.9 23.3±2.9 NS

Smoking (ever), n (%) 27 (39.7) 26 (47.3) NS

Alcohol (ever), n (%) 31 (45.6) 27 (49.4) NS

>3 cups of tea/coffee per day, n (%) 11 (16.1) 13 (23.6) NS

Average grams of sugar/day (mean±SD) 10±3.4 9.5±4.2 NS

Nonvegetarian <3 times/week, n (%) 54 (79.4) 41 (74.5) NS

Green vegetables average times per week (mean±SD) 3.5±1.5 2.6±1.1 <0.0001

Green vegetables <3 times per week, n (%) 28 (41.2) 45 (81.8) <0.0001 6.4 (2.6 to 16.3)

Fruits average days per week (mean±SD) 2.1±1.3 1.9±1.0 NS

Fruits <3 times per week, n (%) 51 (75.0) 41 (74.5) NS

Tamarind <3 times a week, n (%) 54 (79.4) 43 (78.2) NS

Spices/curry <3 times per week, n (%) 27 (39.7) 34 (61.8) <0.02 2.5 (1.1 to 5.5)

Fried foods <3 times per week, n (%) 58 (85.3) 43 (78.2) NS

Average amount of oil per month (mL) (mean±SD) 251±105 292±89 <0.05

CBD common bile duct, GS gallstones, NS not significanta Chi square (for percentage comparison) or ANOVA (for means comparison) as applicable

384 Indian J Gastroenterol (November–December 2013) 32(6):381–385

probably, hypothyroidism [6]. These stones usually are brownpigment stones. The pathogenesis of primary bile duct stonesdiffers from that of secondary bile duct stones. Previous studieshave implicated bacterial colonization and biliary stasis asimportant factors in the formation of primary duct stones [7].Bacteria have been found in mixed pigment stones, and bileinfection appears to precede stone formation [8]. In our seriesof 194 patients, bacterial infection was present in 20 % andnone of the patients had worm infestation of the biliarysystem. Infection therefore was not a major contributingfactor for CBD stones. Roundworm infestation of the bil-iary tract is common in north Indian state of Jammu andKashmir [9, 10]. In a recent series from Kashmir [11], calcu-lus in CBD constituted 49.26 % of all cases of CBD obstruc-tion, followed by oriental cholangiohepatitis in 30 %, andbenign biliary stricture in 9.63 %; miscellaneous causes were11.11 %. What percentage of choledocholithiasis patients hadascariasis is not known.

Genetic factors in presence of environmental factors mayhave a role in primary choledocholithiasis. A high prevalenceof choledocholithiasis has been reported amongHispanics andthose with MDR3 defects [12]. Latter may predispose to bilesludge, cholelithiasis, cholestasis of pregnancy, and subse-quent choledocholithiasis.

Summarizing, the demographic characteristics and diet pat-tern of patients with choledocholithiasis were distinct fromthose patients with gallstones with or without choledocholi-thiasis. Unlike in the West, factors other than long-chainunsaturated fatty acids such as low green vegetables and excesssugar in diet predispose an individual to choledocholithiasis.

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