Hepatitis Central

About 20 million Americans have gallstones, which add more than $1 billion annually to US health-care costs. One million new cases are diagnosed each year -- the majority involving women, and many of these overweight -- and more than half a million cholecystectomies are done annually. Although these procedures are safe and effective, producing an immediate and permanent cure, some 1% of patients have retained common duct stones and 20% have postcholecystectomy syndrome. Silent gallstones are very common; only 20% to 30% of patients are symptomatic, with biliary colic the most common symptom. Expectant management is indicated for most patients with silent gallstones. Two oral bile acids are used for dissolving cholesterol gallstones -- chenodeoxycholic acid (chenodiol) and ursodeoxycholic acid (ursodiol, available in the United States as Actigall/Summit Pharmaceuticals). These agents expand the bile acid pool and also lower biliary secretion of cholesterol by inhibiting hepatic cholesterol synthesis. Complete gallstone dissolution takes months to years. Only about 20% of patients are candidates for bile acid therapy.

Two new techniques -- cholesterol-solvent instillation and shock-wave lithotripsy -- are proving effective for gallstone dissolution. When small amounts of the solvent methyl tert-butyl ether are pumped into the gallbladder, stones are readily dissolved and can be removed. Usually 12 hours are required for complete stone dissolution, although small residual fragments are left in 70% of patients. Side effects include pain from catheterization and occasionally anesthetization from the ether. Again, only about 20% of patients are suitable candidates. Extracorporeal shock-wave lithotripsy, the treatment of choice for kidney stones, has also proved to be effective for noncalcified gallstones. The major side effect is colic (from passage of fragments). As with the other treatments, not all patients are suitable candidates. Perhaps 50% of patients who undergo stone dissolution will have a recurrence of gallstones; only cholecystectomy reliably prevents recurrence.

Is there any way to prevent gallstone formation? The typical gallstone patient has been described as fat, forty, fertile, fecund, and female with a family history of gallstones. Of these risk factors, only weight can be modified, at least theoretically. Obesity is a well-studied risk factor for gallstone formation. Compared with normal- weight individuals, obese people synthesize more cholesterol, secrete more cholesterol into the bile, and may be less efficient at gallbladder emptying. However, it should be noted that a substantial number of gallstone patients are not overweight. In the Harvard Nurses Study, only 53% of symptomatic gallstones were attributable to high body mass index, and in one Danish study, 9.1% of normal-weight women aged 30 - 60 had gallstones.

Recently [1993] Heaton et al. reported the results of their study of one particular factor associated with gallstones: slow intestinal transit time (in a word, constipation). In their population survey, 1058 woman aged 25-69 underwent cholecystosonography. Gallstones were identified in 48 women, 15 of whom were normal weight. The normal-weight women along with age-matched controls with healthy gallbladders underwent measurement of whole-gut transit time. Measurement was done directly when possible, or calculated from records of three defecations. The mean transit time was significantly longer in the women with gallstones than in controls (82 hours versus 63 hours). Stool output was also lower in the women with gallstones (74 g versus 141 g per 24 hours). Matched patients and controls did not differ significantly in any other gallstone-associated factor (body mass index, waist-hip ratio, plasma triglycerides, plasma HDL-cholesterol, number of pregnancies, family history of gallstones, alcohol intake, or hormone therapy). By contrast, a separate study of overweight women with gallstones showed no tendency for slow intestinal transit, although the women did have other risk factors.

The investigators suggested that slow intestinal transit could enhance the formation and absorption of deoxycholate from the colon. Deoxycholate, a secondary bile salt, promotes the hepatic secretion of cholesterol and favors the nucleation of cholesterol crystals. Subjects with slow intestinal transit have been shown to have high biliary deoxycholate concentrations. In a study of healthy volunteers who were administered enough antidiarrheal medication to prolong the whole-gut transit time from 48 hours to 103 hours, the bile composition was altered, becoming more like that of subjects with gallstones; deoxycholate concentration increased and the bile became more saturated with cholesterol. When constipated subjects were given effective doses of laxatives, bile deoxycholate and cholesterol concentrations decreased.

Comparative studies have shown that women have slower intestinal transit and more constipation than men, and this may explain why they have a higher incidence of gallstones. According to the investigators, "Pregnancy and the administration of female sex hormones render the composition of bile more lithogenic, and these effects are usually explained by direct action of hormones on hepatic metabolism. Our findings suggest another way in which female sex hormones and pregnancy could lead to lithogenic bile -- namely, by inducing slower colonic transit and increased deoxycholate absorption." To get back to the question, can gallstones be prevented? -- perhaps dietary change could reduce the risk. Dietary fiber is known to decrease intestinal transit time. To quote Lancet editorialist Howard Spiro, "(G)allstones thus join colon cancer, and maybe even breast cancer, as punishment for enjoying a refined low-fiber diet." (Heaton KW et al. Lancet 1993; 341: 8 - 10. Spiro HM. Lancet 1993; 341: 26.)

table Of Contents