At therapeutic doses, Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid, in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Chenodiol has no effect on radiopaque (calcified) gallstones or on radiolucent bile pigment stones.

Chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted in bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of Chenodiol resides mainly in the enterohepatic circulation; serum and urinary bile acid levels are not significantly affected during Chenodiol therapy.

At steady-state, an amount of Chenodiol near the daily dose escapes to the colon and is converted by bacterial action to lithocholic acid. About 80% of the lithocholate is excreted in the feces; the remainder is absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. During Chenodiol therapy there is only a minor increase in biliary lithocholate, while fecal bile acids are increased three- to four-fold.

Chenodiol is unequivocally hepatotoxic in many animal species, including sub-human primates at doses close to the human dose. Although the theoretical cause is the metabolite, lithocholic acid, an established hepatotoxin, and man has an efficient mechanism for sulfating and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity is partly due to Chenodiol per se. The hepatotoxicity of lithocholic acid is characterized biochemically and morphologically as cholestatic.

Man has the capacity to form sulfate conjugates of lithocholic acid. Variation in this capacity among individuals has not been well established and a recent published report suggests that patients who develop Chenodiol-induced serum aminotransferase elevations are poor sulfators of lithocholic acid (see ADVERSE REACTIONS and WARNINGS).

General Clinical Results: Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Gallstone Study (NCGS) involving 305 patients in each treatment group, placebo and Chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2% and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28% to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n = 86) achieved complete confirmed dissolutions.

Observed stone dissolution rates achieved with Chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patients with small (less than 15 mm in diameter) radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled trails using 13 to 16 mg/kg/day doses of Chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones. (See Floatable versus Nonfloatable Stones below). Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of Chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of Chenodiol, doses that are too low are associated with increased cholecystectomy rates (see ADVERSE REACTIONS).

Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with Chenodiol has proven successful in dissolving some newly formed stones, the indications for, and safety of, retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in all clinical trials and are dose-related (refer to ADVERSE REACTIONS and WARNINGSsections for full information).

Floatable versus Nonfloatable Stones: A major finding in clinical trials was a difference between floatable and nonfloatable stones, with respect to both natural history and response to Chenodiol. Over the two-year course of the National Cooperative Gallstone Study (NCGS), placebo-treated patients with floatable stones (n = 47) had significantly higher rates of biliary pain and cholecystectomy than patients with nonfloatable stones (n = 258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750 mg/day) compared to placebo was associated with a significant reduction in both biliary pain and the cholecystectomy rates in the group with floatable stones (27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm) floatable stones (n = 10) had complete confirmed dissolution.

In the NCGS in patients with nonfloatable stones, Chenodiol produced no reduction in biliary pain and showed a tendency to increase the cholecystectomy rate (8% versus 4%). This finding was more pronounced with doses of Chenodiol below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history of biliary pain had the highest rates of cholecystectomy and aminotransferase elevations during Chenodiol treatment. Except for the NCGS subgroup with pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea have occurred with equal frequency in patients with floatable or nonfloatable stones. In the uncontrolled clinical trial mentioned above, 27% of the patients with nonfloatable stones (n = 59) had complete confirmed dissolutions, including 35% with small (less than 15 mm) (n= 40) and only 11% with large, nonfloatable stones (n= 19).

Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form (horizontal X-ray beam) to float in the dye-laden bile during oral cholecystography using iopanoic acid. Other investigators report similar findings. Floatable stones are not detected by ultrasonography in the absence of dye. Chemical analysis has shown floatable stones to be essentially pure cholesterol.

Other Radiographic and Laboratory Features: Radiolucent stones may have rims or centers of opacity representing calcification. Pigment stones and partially calcified radiolucent stones do not respond to Chenodiol. Subtle calcification can sometimes be detected in flat film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable stones, cholesterol stones are more apt than pigment stones to be smooth surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As stone size number and volume increase, the probability of dissolution within 24 months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and bacterial invasion of the biliary system predispose to pigment gallstone formation. Pigment stones of primary biliary cirrhosis should be suspected in patients with elevated alkaline phosphates, especially if positive anti-mitochondrial antibodies are present. The presence of microscopic cholesterol crystals in aspirated gallbladder bile, and demonstration of cholesterol super saturation by bile lipid analysis increase the likelihood that the stones are cholesterol stones.

PATIENT SELECTION

Evaluation of Surgical Risk: Surgery offers the advantage of immediate and permanent stone removal but carries a fairly high risk in some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.

    Mortality per Operation (Smoothed rates with denominators adjusted to one death) 

Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

Relatively young patients requiring treatment might be better treated by surgery than with Chenodiol, because treatment with Chenodiol, even if successful, is associated with a high rate of recurrence. The long-term consequences of repeated courses of Chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not known. 

Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27% in five years. Presumably the rate is higher for patients already having symptoms.