Johnson L. Thistle

Dissolution of Cholesterol Gallstones by Chenodeoxycholic Acid

Abstract Seven women with gallstones were given 0.75 to 4.5 g per day of chenodeoxycholic acid, a primary bile acid, to promote micellar solubilization of cholesterol in bile. In Case 1 three stones that had remained unchanged in size during six years of observations disappeared after six months of treatment. A single stone in Case 2 and multiple calculi in Cases 3 and 4 progressively grew smaller during 14 to 22 months of chenodeoxycholic acid administration. Gallstone size did not change in the other three. Chenodeoxycholic acid and total bile acid pool sizes (measured in two patients), which were reduced before therapy, were markedly expanded by chenodeoxycholic acid, and the ratio of bile acids and lecithin to cholesterol in bile increased in all patients. Liver function and morphology remained normal; moderate dose-related diarrhea occurred. Chenodeoxycholic acid may offer medical treatment for cholesterol cholelithiasis in man.

Chenodiol (Chenodeoxycholic Acid) for Dissolution of Gallstones: The National Cooperative Gallstone Study: A Controlled Trial of Efficacy and Safety

A double-masked study was conducted to determine the efficacy and safety of randomly allocated chenodiol (chenodeoxycholic acid, 750 mg/d or 350 mg/d) or placebo administered for 2 years to 916 patients for dissolution of radiolucent gallstones. There was confirmed complete dissolution in 13.5% of patients (750 mg/d), 5.2% (375 mg/d), and 0.8% (placebo), p less than 0.0001. Partial (over 50%) or complete dissolution (by validated roentgenographic metrology) occurred in 40.8% (750 mg/d), 23.6% (375 mg/d), and 11.0% (placebo), p less than 0.0001. Dissolution occurred more frequently in women, thin patients, or patients with small or floating gallstones or serum cholesterol greater than or equal to 227 mg/dL. Clinically significant hepatotoxicity occurred in 3% of patients (750 mg/d), 0.4% (375 mg/d), and 0.4% (placebo), p less than 0.007, and always was reversible biochemically. Elevations of 10% or more of serum cholesterol, mostly low-density lipoproteins, occurred in 85.2% of patients (750 mg/d), 82.8% (375 mg/d), and 67.0% (placebo), p less than 0.001. Chenodiol, 750 mg/d for up to 2 years, is appropriate therapy for dissolution of gallstones in selected patients who are informed of the risks and benefits.

Efficacy and Specificity of Chenodeoxycholic Acid Therapy for Dissolving Gallstones

Abstract In a controlled trial, 53 patients with asymptomatic radiolucent gallstones in functioning gallbladders were treated with chenodeoxycholic acid, cholic acid or placebo. At six months, 11 o...

Selenium Deficiency and Fatal Cardiomyopathy in a Patient on Home Parenteral Nutrition

An adult patient with chronic idiopathic intestinal pseudo-obstruction maintained on home parenteral nutrition for 6 consecutive years died from cardiomyopathy and ventricular fibrillation. Postmortem examination of the heart revealed widespread myocytolysis and replacement fibrosis similar to that seen in the selenium deficient cardiomyopathy in China (Keshan disease) and animal models. Selenium deficiency in this patient was documented with extremely low concentrations of selenium and decreased activity of the selenoprotein, glutathione peroxidase, in blood, heart, liver, and skeletal muscle. Reports of selenium deficient diets causing myocardial damage in humans and animals and the findings in our patient strongly suggest that his fatal cardiomyopathy was caused by selenium deficiency.

The Natural History of Cholelithiasis: The National Cooperative Gallstone Study

The National Cooperative Gallstone Study, a double-masked, placebo-controlled, therapeutic trial of chenodiol (chenodeoxycholic acid), provided an opportunity to study the natural history of cholelithiasis in patients who choose nonsurgical management. The major component of the study comprised 916 patients, 305 of whom were randomly assigned to receive a placebo for 24 months. Among these 305 patients, the probability of having biliary tract pain during the 24 months of prospective evaluation was significantly increased if the patient had had a history of biliary tract pain in the 12 months before entry into the study (69% versus 31%). Thirty-eight percent of patients had stone growth (greater than 0.5 cm3), and 18% had a spontaneous decrease in stone volume. Despite the high incidence of biliary tract pain, nonelective cholecystectomy was required in only 4% of patients during the 24 months.

Effect of Oral Chenodeoxycholic Acid on Bile Acid Kinetics and Biliary Lipid Composition in Women with Cholelithiasis

Bile acid kinetics and biliary lipid composition were characterized in six women with gallstones before and after 6 mo of oral therapy with chenodeoxycholic acid, an agent that induces dissolution of cholesterol gallstones in man. Over a dosage range of 1-4 g/day, absorption varied from 0.8 to 2.3 g/day. The chenodeoxycholic acid pool expanded two-to sixfold, and bile became composed predominantly (> 90%) of chenodeoxycholic acid conjugated chiefly with glycine. Cholic acid and deoxycholic acid pools decreased markedly, so that the total bile acid pool expanded much less, about twofold on the average. Cholic acid synthesis decreased in five of the six patients, consistent with negative feedback inhibition of cholic acid synthesis by chenodeoxycholic acid. In four patients whose bile was above or close to saturation with cholesterol, the bile became unsaturated; in two patients, whose bile was unsaturated, it remained so. In five patients with radiolucent gallstones, chenodeoxycholic acid therapy was continued after completion of kinetic and composition measurements; the stones decreased in size or dissolved entirely during the subsequent 6 to 18 mo. Similar measurements of bile acid kinetics and biliary lipid composition were made before and after a 6-mo period without medication in a control group of six healthy women; no changes occurred.

Lithogenic Bile among Young Indian Women

Abstract Chippewa Indian women have a high prevalence of symptomatic gallstones. Lithogenic bile is characterized by a low ratio of bile acids plus lecithin to cholesterol. The ratios of bile acid plus lecithin to cholesterol in duodenal bile among 12 young Indian women without gallstones were significantly lower, 9.4 ± 0.82 (mean ± S.E.), than among white controls, 16.4 ± 1.0 (p less than 0.001), and Indian men, 14.8 ± 2.2 (p less than 0.02), and not different from those previously reported among white women with gallstones: 11.3 ± 1.3. Administration of chenodeoxycholic acid resulted in a bile acid composition of 96 per cent chenodeoxycholic acid and significantly increased the ratio of bile acid plus lecithin to cholesterol to 14.2 ± 1.9, without adverse reactions. These observations suggest that lithogenic bile precedes gallstone formation in Chippewa women and that administration of chenodeoxycholic acid decreases this lithogenic potential.

Pretreatment biliary lipid composition in white patients with radiolucent gallstones in the National Cooperative Gallstone Study

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Design and methodological considerations in the National Cooperative Gallstone Study: a multicenter clinical trial.

From The Biostatistics Center, Department of Statistics, George Washington University, Bethesda, Maryland; Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California; and School of Medicine, University of California at Los Angeles; Duke University; National Institute of Arthritis, Metabolism and Digestive Diseases; Veterans Administration Hospital and University of California at San Diego; George Washington University; the Mayo Clinic; and Veterans Administration Hospital, Richmond, Virginia

Low-Dose Chenodiol to Prevent Gallstone Recurrence After Dissolution Therapy

Chenodiol is a safe and effective agent for the medical dissolution of gallstones in selected patients; however, after dissolution and cessation of treatment, gallstones recur. This study was done to determine the recurrence rate after successful medical treatment and cessation of chenodiol therapy; compare the efficacy and safety of low-dose chenodiol, as compared to placebo, for prophylaxis against recurrence; and identify factors predictive of recurrence. In a randomized, double-blind fashion, 53 patients with gallstone dissolution received either chenodiol, 375 mg/d, or placebo, for at least 2 years. Standardized oral cholecystograms were done at 6 months, 1 year, and then yearly thereafter. Routine laboratory testing was done every 6 months. The cumulative rate of recurrence (life-table) was 27% in patients followed for up to 3.5 years. Chenodiol, 375 mg/d, was ineffective in preventing the recurrence of gallstones. No demographic, clinical, roentgenographic, or biochemical characteristics were predictive of recurrence.