Malcolm P. Tyor

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.

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.

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.

THE EFFECT OF INDUCED HYPERAMMONEMIA ON RENAL AMMONIA METABOLISM

Although the excretion of ammonia into urine has been extensively studied, there is little information in animals or man concerning the quantitative and regulatory aspects of the ammonia released into the renal veins. Previous observations in this laboratory and in others have demonstrated that the kidney consistently releases ammonia into the systemic circulation of normal subjects and patients with liver disease whose arterial ammonia concentrations are normal (1-5). Patients with liver disease and moderate to marked hyperammonemia, however, usually release minimal quantities of ammonia into their renal veins and occasionally exhibit renal uptake of ammonia from the circulation (2). In order to further define the possible role of the blood ammonia concentration on renal ammonia release, acute hyperammonemia has been induced in normal subjects and the subsequent changes in renal vein ammonia release and urine ammonia excretion determined.

Amino Acid Uptake and Fatty Acid Esterification by Intestinal Mucosa from Patients with Whipple's Disease and Nontropical Sprue

Summary 1)The uptake of C 14 -L-arginine, C 14 -Llysine, C 14 -DL-ornithine, and C 14 -L-phenylalanine by duodenal mucosa from 3 patients with Whipples disease, 2 patients with nontropical sprue, and 10 control patients with normal intestinal mucosal morphology has been determined. In most experiments the ability of similar mucosal tissue to incorporate C 14 -labeled palmitic acid into triglyceride was obtained concomitantly. 2)The uptake of C 14 -L-arginine, C 14 -lysine, and C 14 -DL-ornithine by duodenal mucosa from patients with Whipples disease and nontropical sprue was consistently lower than corresponding values obtained in control patients and healthy volunteers.1o The mucosal uptake of C 14 -L-phenylalanine was more variable, and a definite reduction in the uptake of this amino acid was apparent only in two patients with untreated Whipples disease, and one patient with severe nontropical sprue. With the exception of one determination in a patient with Whipples disease, the rate of incorporaton of C 14 -labeled palmitic acid into triglyceride was uniformly lower in Whipples disease and nontropical sprue than values obtained from similar measurements in control patients and healthy volunteers. 3)The similarity in amino acid uptake and lipid esterification values by duodenal mucosa from patients with Whipples disease and nontropical sprue has been discussed in light of the recognized lack of morphological alteration in the mucosal epithelial cell of patients with Whipples disease as contrasted with the consistent epithelial cell changes seen in nontropical sprue.

Additional Chenodiol Therapy After Partial Dissolution of Gallstones with Two Years of Treatment

During the National Cooperative Gallstone Study, therapy with chenodiol, 750 or 375 mg/d, for 2 years resulted in confirmed, complete gallstone dissolution in 14% and 5% of patients, respectively, and partial dissolution (greater than 50%) in 27% and 18%. The present study was done to determine the frequency with which complete dissolution occurs in patients having partial dissolution of gallstones who receive additional therapy. Eighty-six of one hundred thirty-eight eligible patients continued to receive 750 mg/d (61 patients) or 375 mg/d (25 patients) of chenodiol for 1 year. Patients whose oral cholecystogram at the end of the year showed further (greater than 50%) dissolution continued to receive chenodiol, (28 patients at 750 mg/d and 11 patients at 375 mg/d) for a second year (total duration of therapy, 4 years). A final oral cholecystogram was taken at the end of the fourth year. Complete dissolution occurred in 23% and 16% of patients receiving chenodiol, 750 or 375 mg/d, respectively, for an additional 1 or 2 years.

Measurements of the Disappearance of Radioactive Tagged Albumin from Serum and the Excretion of I181 in the Urine of Patients with Cirrhosis

Summary 1.A tracer dose of iodinated serum albumin was injected into 9 patients with cirrhosis of the liver and 22 patients with various other diseases. 2.The rate of disappearance of the tagged albumin from the vascular compartment was similar in the two groups. 3.A significant decrease in the excretion of inorganic iodide was found during the first 24 hours in the patients with cirrhosis.

THE EFFECT OF ACUTE ALKALOSIS ON RENAL METABOLISM OF AMMONIA IN CIRRHOTICS

The kidney consistently releases ammonia into the renal venous circulation of normal subjects and patients with compensated liver disease (1-4). Under conditions of normal acid-base balance, the quantity released usually approximates the amount of ammonia excreted into urine (3, 4). From determinations of arteriovenous ammonia differences across various organs, it has become apparent that the release of ammonia into the renal vein represents a major source of the normal ammonia concentration in blood (5). Of possible clinical importance in this regard is the observation that under certain conditions patients with liver disease may increase their renal contribution of ammonia to the systemic circulation. The increase of blood ammonia concentration seen after the intravenous administration of acetazolamide and chlorothiazide can be adequately explained by concomitant increases in release of ammonia into renal vein (3, 6). It has been suggested that the alterations in renal ammonia release seen during carbonic anhydrase inhibition may result from a shift in the normal partition of ammonia between urine and renal venous blood because of a disproportionate increase in pH of urine as compared with that of peritubular fluid (3). The present study deals with acute metabolic and respiratory alkalosis and was designed to obtain additional information on the role of the kidney in the regulation of the ammonia concentration in blood and to evaluate the effects of acute systemic alkalosis on total bidirectional renal release of ammonia.