Biliary heavy metal concentrations in carcinoma of the gall bladder: case-control study

BMJ 1998; 317 doi: (Published 07 November 1998) Cite this as: BMJ 1998;317:1288
  1. V K Shukla, professor of surgerya (vkshukla{at},
  2. A Prakash, senior resident in surgerya,
  3. B D Tripathib, reader,
  4. D C S Reddy, reader in community medicinea,
  5. S Singh, research associate in surgerya
  1. aDepartments of Surgery and Community Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, India
  2. bDepartment of Botany, Faculty of Science, Banaras Hindu University
  1. Correspondence to: Professor Shukla
  • Accepted 8 June 1998

Carcinoma of the gall bladder is the third most common malignancy of the gastrointestinal tract in the eastern Uttar Pradesh and western Bihar regions of India.1 The two regions lie down stream of the river Ganges, which is the main source of drinking, bathing, and irrigation water in this part of India and receives untreated domestic sewage and industrial and agricultural effluent. High concentrations of cadmium have been reported in sewage, irrigation water, and vegetables grown in the area, and higher concentrations of heavy metals than recommended by the World Health Organisation have been reported in water from this region. Heavy metals as environmental pollutants have been implicated in human carcinogenesis.2 These metals, especially cadmium, are excreted and concentrated in the hepatobiliary system.3

We investigated whether gallbladder cancer was associated with exposure to heavy metals and hence high biliary concentrations.


Cadmium, chromium, and lead concentrations in patients with gall stones and gallbladder cancer

Patients, methods, and results

The study was carried out in 96 patients with gallbladder diseases admitted to the surgical unit of the University Hospital, Varanasi, from January 1995 to March 1996. All these patients were from the same geographical area. Thirty eight patients had histologically diagnosed carcinoma of the gall bladder (mean age 53.5 years; 11 men and 27 women; 25 had associated calculi) and 58 had gall stones (control group; mean age 48.3 years; 14 men and 44 women). Bile (10 ml) was taken by needle aspiration from the gall bladder of all patients at the time of surgery for estimation of cadmium, chromium, and lead concentrations. The sample was stored at −20°C until analysed by the method described in the 1982 manual for Perkin-Elmer's model 2380 atomic absorption spectrophotometer. Student's t test was carried out using MSTAT software.

The figure shows that mean biliary concentrations of cadmium, chromium, and lead were significantly higher in patients with carcinoma of the gall bladder than in those with gall stones (cadmium: 0.19 (SE 0.07) mg/l v 0.09 (0.04) mg/l, difference 0.10 (95% confidence interval 0.08 to 0.12), t=11.63, df=93.63, P<0.001; chromium: 1.26 (0.06) mg/l v0.55 (0.03) mg/l, difference 0.71 (0.58 to 0.84), t=9.84, df=57.45, P<0.001; lead: 58.38 (1.76) mg/l v 3.99 (0.43) mg/l, difference 54.4 (50.7 to 58.0), t=30.07, df=41.43, P<0.001)


Carcinoma of the gall bladder continues to be a disease of uncertain aetiology, late presentation, and ineffectual treatment.1-3Various risk factors have been proposed in its pathogenesis, but none has stood the test of time.

The incidence of carcinoma of the lung, paranasal sinus, and gastrointestinal tract with exposure to chromates has been reported by Leonard.2 Cadmium causes prostate cancer and increases the risk of lung cancer,4 and lead is carcinogenic in rats.5 These studies have proved heavy metals to be related to carcinogenesis, but, to our knowledge, biliary heavy metal concentrations have not been measured in patients with gallbladder cancer. Using histochemical techniques, however, we have found that the expression of metallothionein was 70% in patients with gallbladder cancer and 25% in those with gall stones. In our current study cadmium, chromium, and lead concentrations were significantly higher in carcinoma of the gall bladder than in gall stones. This can be explained by the presence of dangerously high concentrations of these metals in drinking water in this part of India. These metals are known chemical carcinogens, so the high biliary concentrations of these metals in carcinoma of the gall bladder may be a factor in this cancer.


Contributors: VKS was the principal investigator of the study project. He initiated and coordinated the formulation of the primary study hypothesis, discussed core ideas, designed the protocol, and participated in data collection, analysis, and writing the paper. AP initiated the research and participated in the study design, data collection, and analysis. BDT participated in the methodological aspect of the study and in interpreting the findings. DCSR participated in the design of the study protocol, in the interpretation of the findings, and in the statistical analysis. SS initiated and coordinated the formulation of the primary study, designed the protocol, and participated in data collection, analysis, and writing the paper. VKS is guarantor for the study.


  • Funding This study was supported by the department of surgery at this university.

  • Conflict of interest None.


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