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To evaluate the a priori hypotheses that an increased level of glyco and tauro lithocholic acid, perhaps because of a decreased capacity for hepatic sulfation, contributed to the biochemical epidemiology of gallbladder cancer, a case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four cases with newly diagnosed histologically confirmed gallbladder cancer were compared with 264 controls with cholelithiasis or choledocholithiasis in the absence of cancer and with 126 controls with normal biliary tracts. All study subjects were undergoing abdominal surgery. Interview data were collected for all study subjects, as well as blood, bile, and gallstone specimens when feasible. Sera were analyzed for carcinoembryonic antigen, cholesterol concentration, and total bile acids. Bile specimens were analyzed for carcinoembryonic antigen; and for concentration of bile salts; cholesterol; phospholipids; and the glycine and taurine conjugates of cholic, ursodeoxycholic, chenodeoxycholic, deoxycholic, and lithocholates; sulfoglycolithocholate; and sulfotaurolithocholate. Gallstone specimens were analyzed for the percentage of cholesterol content, the percentage of calcium bilirubinate content, and the percentage of calcium carbonate content. Serum bile acids were increased in cases versus the two control groups (median 11.7 nmol/mL vs. 9.3 nmol/mL for stone controls and 8.2 nmol/L for nonstone controls, P < or = .02 for each pairwise comparison). Biliary bile acids were markedly decreased in the cases (median 3.98 micromol/mL vs. 33.09 micromol/mL, and 154.0 micromol/L, respectively, P < or = .0001 for each comparison), even after excluding those with a serum bilirubin higher than 2.0 mg/dL. Bile cholesterol was lower for the cases as well (median 1.70 micromol/mL vs. 4.90 micromol/mL, and 16.81 micromol/ mL, respectively, P < or = .02), as was the concentration of bile phospholipids (median 2.97 micromol/mL vs. 6.26 micromol/mL, and 52.69 micromol/mL, P = .1 and .0004, respectively). Contrary to our a priori hypothesis, there was no difference between the cases and either control group in their bile concentrations of lithocholate, the proportion of bile acids which were sulfated, or the concentration of nonsulfated lithocholate. However, the cases had a higher concentration of ursodeoxycholate (UDC) (P < .004 for both control groups), especially glycoursodeoxycholate (P < .001 for both control groups). A previously published suggestion that gallstone size differed between cases and controls was not confirmed. In conclusion, cases with gallbladder cancer differed from controls with stones and from controls with normal biliary tracts in their serum and bile biochemistries. These findings may be a reflection of the disease process, or may provide useful clues to its pathogenesis.

The poor prognosis of gallbladder cancer and the presence of high-risk populations make the identification of a screening test for this disease very desirable. As part of an ongoing case-control study of gallbladder cancer being conducted in Mexico City, Mexico, and in La Paz, Bolivia, blood specimens were sought from all patients with cancer of the gallbladder and on controls of similar age and sex undergoing upper abdominal surgery. Each sample was analyzed for carcino-embryonic antigen (CEA) and CA 19-9. Using the specimens from Bolivia, a serum CEA cutoff of 4.0 ng/ml yielded a sensitivity of 50.0% and a specificity of 92.7%, while a serum CA 19-9 cutoff of 20.0 units/ml yielded a sensitivity of 79.4% and a specificity of 79.2%. Using ROC curve analysis, the latter was a much better test than the former (p less than 0.05). Using the tests in series or in parallel did not substantively improve the results. The specimens from Mexico were used for validation purposes, and yielded very similar results. In conclusion, serum CA 19-9 and CEA are fairly good tests for discriminating patients with gallbladder cancer from patients with gallstones and no cancer, the former being a better test than the latter. These tests may be useful in identifying disease recurrences. In addition, if a sufficiently high-risk population could be identified, this could potentially become a useful screening test for this serious disease, allowing early intervention. However, additional data are needed prior to recommending this clinically.

In order to investigate the very high incidence of gallbladder cancer in Bolivia, a series of patients with gallbladder cancer and/or cholelithiasis from a hospital in La Paz was compared to a series of patients with cholelithiasis from Philadelphia. Each group demonstrated a similar female predilection. Bolivian patients with gallbladder cancer were older than patients with cholelithiasis who, in turn, were older than the general population (p less than 0.001). Racial differences demonstrated previously were confirmed. Bolivian gallstones were uniformly cholesterol in type, in contrast to the US series, in which 27% of patients had black pigment stones. Bile specimens obtained from Bolivian patients with cholelithiasis had a lower concentration of bile salts, phospholipids, and cholesterol than bile specimens from US cholelithiasis patients (p less than 0.01, less than 0.001, and less than 0.001, respectively). These biochemical differences may help to explain the differing incidence of cholelithiasis and gallbladder cancer in the US and Bolivia.

Data on patients with cancer of the gall bladder and cancer of the extra-hepatic bile ducts were obtained from the tumour registry in La Paz, Bolivia. Incidence rates were calculated using the Bolivian census data and compared to US incidence data from the Third National Cancer Survey. The age and population standardized incidence rates for cancer of the gall bladder in Bolivia were 5.3/100,000 males/year and 10.3/100,000 females/year. Comparable US rates were 1.0/100,000 males/year and 2.1/100,000 females/year. The age and population standardized incidence rates for cancer of the extra-hepatic bile ducts in Bolivia were 1.1/100,000 males/year and 4.1/100,000 females/year. Comparable US rates were 1.6/100,000 males/year and 1.0/100,000 females/year respectively. Both diseases occurred at younger ages in Bolivia than in the US and both showed marked racial variation. Differences in disease incidence between Bolivia and the US could not be fully explained by differences in age, sex, or racial distributions. Studies designed to investigate the causes of this remarkable variation in disease incidence could provide important clues to disease aetiology.