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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.

A sample of 126 patients with cholelithiasis was treated with chenodeoxycholic acid (CDCA) (375 or 750 mg g.d.) for 2 years. Hepatotoxicity was assessed by sequential light (LM) and electron microscopic (EM) analysis of liver biopsies obtained before and after 9 and 24 months of therapy. Patients were without symptoms of biliary colic for 3 months prior to biopsy, less than 70 years old, and had normal tests of liver function. All light microscopy was read blindly by two morphologists, and electron microscopy by one. Only four biopsies (3%) showed severe (3+) abnormalities preventing admission to the study. On evaluation, moderate (2+) LM changes were present in less than 12% of biopsies, while milder changes (1+) were seen more frequently. No severe, dose-related abnormalities were seen in LM over the 2 years of study. However, mild changes (hepatocyte ballooning and lipofuscin, binucleate cells, glycogen nuclei, ductular proliferation, enlarged and fibrotic triads, and sinusoidal congestion) became more prevalent with time (p less than or equal to 0.01) regardless of CDCA dose, according to 1 of the 2 morphologists. Because patients with "proven" cholelithiasis for greater than 2 years (33% of the study population) did not have a greater incidence of morphologic abnormalities than those with the diagnosis for less than 2 years, it is unlikely that these changes were due to the natural history of gallstone disease. Furthermore, electron microscopic findings demonstrated worsening intrahepatic cholestasis and a lesion in two patients which was identical to that produced in animals administered lithocholic acid, the 7-alpha-dehydroxylated metabolite of CDCA. the possibility that clinically significant hepatotoxicity could develop with CDCA therapy greater than 24 months thus cannot be excluded by this study.

The chemical structure of individual bile acids in 255 duodenal bile samples obtained from patients with radiolucent gallstones before and during treatment with chenodeoxycholic acid (375 or 750 mg/day) was determined by coupled gas chromatography/mass spectrometry. The two primary bile acids, cholic acid and chenodeoxycholic acid, and their metabolic products, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, were present in all bile samples and constituted greater than 97% of all bile acids. In pretreatment samples, the 12-oxo derivative of deoxycholic acid (3 alpha-hydroxy-12-oxo-cholanoic acid) was the next most abundant bile acid, being present in 62% of the samples; the average concentration was 1%, but three individuals had 6% to 8% of this bile acid. The 7-oxo derivative of chenodeoxycholic acid was also present in the majority of samples, but at a lower proportion (0.3%); five individuals had 2% to 3%. The 7-oxo derivative of cholic acid was present in a minority of samples (37%) in trace concentrations; isodeoxycholic acid and the 3-oxo derivatives of chenodeoxycholic acid and deoxycholic acid were also present in trace amounts. Four patients had 1% to 11% ursocholic acid in bile. During treatment with chenodeoxycholic acid, bile became enriched in it in direct relation to dosage; the concentration of its bacterial metabolites increased, and the proportion of cholic acid and its bacterial metabolites showed a reciprocal decrease. No unusual bile acids appeared, indicating that treatment with these doses of chenodeoxycholic acid does not result in the occurrence of additional uncommon bile acids in bile. It is suggested that the paucity of uncommon bile acids in bile, which contrasts strikingly with the great variety of uncommon bile acids known to be present in urine and feces, is the result of two factors: (1) the conversion of uncommon bile acids to common bile acids by reduction, hydroxylation, or epimerization during hepatic passage; and (2) efficient hepatic transport of common but not uncommon bile acids into bile.

Subjects in the National Cooperative Gallstone Study undergoing 12 mo of therapy with chenodeoxycholic acid for the dissolution of gallstones (low-dose, 375 mg/day, n =252; high-dose, 750 mg/day, n = 253) had a mean increase in serum cholesterol of 20 mg/dl as compared with a 5 mg/dl increase in the placebo group (n = 258). The effect of chenodeoxycholic acid on lipoproteins was determined in a random subset of the high-dose (n = 136) and placebo (n = 143) groups. For men, the mean baseline adjusted estimated low-density lipoprotein cholesterol level at 12 mo was significantly higher in the high-dose group than in the placebo group (159 vs. 148 mg/dl, p less than 0.01), whereas among women this difference was not demonstrated. Change in low-density lipoprotein cholesterol level was inversely related to baseline cholesterol to an equivalent degree in each group among men and women. Women in the high-dose group had significantly lower very-low-density lipoprotein cholesterol levels than did the corresponding placebo group (27 vs. 32 mg/dl, p less than 0.003). Very-low-density lipoprotein cholesterol levels did not differ significantly between the high-dose and placebo group in men. Treatment did not significantly affect the levels of high-density lipoprotein cholesterol or apoproteins A-I, A-II, or B. Chenodeoxycholic acid therapy produces an increase in total cholesterol and low-density lipoprotein cholesterol but does not alter high-density lipoprotein cholesterol levels.

Chenodeoxycholic acid, by reducing the concentration of biliary cholesterol relative to that of bile acid and phospholipid, dissolves cholesterol gallstones. This bile acid, however, has potential dose-related hepatotoxicity and causes dose-related diarrhea. Therefore, the feasibility of low-dose and intermittent therapy was assessed by studying the induction and persistence of chenodeoxycholic acid-induced biliary lipid changes. Biliary lipid composition with each of 3 doses of chenodeoxycholic acid was determined in bile samples obtained by cholecystokinin-stimulated duodenal drainage before, after one week and one month of treatment, and up to 9 weeks after discontinuation of treatment. The lowest dose that significantly reduced the relative concentration of biliary cholesterol was 250 mg/day. A significant reduction occurred one week after initiation of treatment and was maintained for 9 weeks following discontinuation of treatment. Thus, clinical trials on low-dose and intermittent chenodeoxycholic acid therapy for gallstone prophylaxis or dissolution are warranted.

Chenodeoxycholic acid (CDC), through its metabolite, lithocholic acid (LC), is hepatotoxic in certain species. The cause of elevations of serum transaminase in 25% of humans ingesting CDC, however, is unknown, but also may be due to LC. Because efficient hepatic sulfation of LC may protect against hepatic injury, the aim of this study was to determine if sulfation of LC might modify CDC-induced elevations of transaminase. Pretreatment sulfation fraction (SF) was estimated in 63 randomly selected patients with gallstones in a double-blind randomized trial of CDC, 750 mg/d, 375 mg/d, or placebo; in 27 of these, SF was repeated at 1 or 2 yr. In four other patients, the SF was measured at 2 yr only. Serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were determined monthly for 3 mo and then every 3 or 4 mo; an elevation of transaminase was defined as > 150% of the normal upper limit in asymptomatic patients. 10 muCi of (3)H-glyco-LC (sp act 84 mCi/mol) was ingested 10-12 h before fasting duodenal biliary drainage. Bile acids in bile were separated by thin-layer chromatography. The SF was estimated as a percentage of total radioactivity (scintillation counting) in sulfated glyco-LC. The standard deviation for replicate SF determinations (n = 311) was 2.1% The pretreatment SF (mean 60.7+/-1.7 SEM) correlated inversely with age (r = 0.336, P < 0.005) and directly with the obesity index (r = 0.495, P > 0.001), but was independent of sex. The SF, remeasured at 1 or 2 yr, did not change significantly with time or CDC. Among CDC-treated patients, elevations of transaminase occurred in 75% of patients with a SF < 45% vs. 11% with a SF > 45% (P < 0.001). In conclusion, a SF < 45% occurred in patients with gallstones who had a high probability of developing elevated serum transaminase when treated with CDC. Thus, sulfation of lithocholate may modify CDC-induced elevations of serum transaminase.

The National Cooperative Gallstone Study (NCGS) was a cooperative, randomized, controlled trial of a drug, chenodiol, for the medical dissolution of gallstones. The design and procedures of the NCGS were complex, having developed as a result of extensive involvement of many experts in the field of gallstone disease and biliary lipids. During the design and implementation of the protocol, many important issues required consideration and resolution. The aim of this article is to review these issues and the deliberations surrounding their resolution and provide personal conclusions and recommendations that may be helpful to other investigators involved in cooperative, controlled trials.

Electron microscopy was performed to assess potential hepatotoxicity before and after 9 and 24 months of chenodeoxycholic acid (CDCA) therapy (375 or 750 mg, daily) in 103 patients with cholelithiasis. Prior to treatment, 64% of the biopsies demonstrated ultrastructural evidence of intrahepatic cholestasis, manifested by abnormal bile canaliculi, thickened pericanalicular ectoplasm, and retention of biliary material within liver cells or pericellular spaces. After 9 months of CDCA therapy, several changes (including increased free cytoplasmic "biliary pigment," decreased canalicular microvilli, and increased pericanalicular ectoplasm) consistent with intrahepatic cholestasis became more prevalent (63% prior to therapy, 89% at 9 months, p less than 0.01) regardless of CDCA dose. After 24 months of therapy, canalicular microvilli and pericanalicular ectoplasm continued to be abnormal (p less than 0.01). This study indicates that ultrastructural evidence of intrahepatic cholestasis is a common subclinical abnormality in patients with cholelithiasis which increases during CDCA therapy, changes which could represent either the natural history of cholelithiasis or CDCA toxicity. A drug effect is suggested by the lack of correlation of these abnormalities with the duration of cholelithiasis prior to CDCA treatment and their "increasing" prevalence after only 9 months of therapy. In addition, canalicular membrane lesions developed in two patients which were similar to lithocholate toxicity in animals. It is not known whether these abnormalities would result in clinically significant hepatoxicity if therapy is continued for longer than 24 months.

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 National Cooperative Gallstone Study was a double-masked trial conducted to determine the efficacy and safety of chenodeoxycholic acid (chenodiol) for dissolution of cholesterol gallstones. Patients with radiolucent gallstones were randomly allocated to either a high dose (750 mg/d, n = 305) or low dose (375 mg/d, n = 306) of chenodiol or placebo (n = 305) administered for 2 yr. Specimens of gallbladder bile were obtained for biliary lipid analysis on 50% of all white obtained for biliary lipid analysis on 50% of all white patients at base line and after 3-mo therapy, on 45% at 12 mo, and on 36% at 24 mo. Among these specimens, 20% were inadequate for analysis. For analysis of data, available values during therapy were averaged up to time of dissolution, study exit, or study termination. In the high-dose group, percent chenodiol (molar percent of all bile acids) increased markedly and remained high during the 2 yr of follow-up. Also, molar percent cholesterol decreased significantly and remained low during the 2 yr of follow-up. In the low-dose group, percent chenodiol increased and remained significantly increased. Percent cholesterol saturation decreased at 3 mo, but at 24 mo it was not different from that in the placebo group, suggesting a physiological adaptation to the low dose by 2 yr. 79% of patients on high dose had greater than 70% chenodiol. Among these, half showed unsaturated bile (less than 100% cholesterol saturation) while the remainder were supersaturated; in the former group with unsaturated bile, 23% had complete dissolution and 51% had partial (greater than 50% reduction in stone size) or complete dissolution. In contrast, those with over 70% chenodiol and supersaturated bile had only 5% complete dissolution. Thus, development of unsaturated bile was a major factor associated with gallstone dissolution. The data also indicate that values for percent cholesterol saturation were a better predictor of gallstone dissolution than molar percent chenodiol, although a high percent chenodiol usually was required to obtain unsaturation.