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 TREATMENT OF CHOLEDOCHOLITHIASIS WITH CHOLUDEXAN 
BARBAKADZE G. – MD, PhD, Professor
KILADZE M.– MD, PhD, Professor
ABULADZE D. MD
Thoracoabdominal Clinic named acad. Z. Ckhakaia;
Tbilisi First City Hospital
Common bile duct stones (choledocholithiasis) pose a high risk for complications and nearly always warrant treatment. There are various options available: especially intervential (surgical) and therapeutical. It is not clear yet which one is best.
 
The prevalence of gallstones is age- and sex-related. Women are affected 4-5 times more often than men. The incidence of gallstone disease in Georgia is in the range of case 12-14% and of common bile duct stone disease is case 15 %.
 
In the past, when common bile duct stones were suspected, the approach was open surgery (open cholecystectomy) and surgical exploration of the common bile duct. This required a wide abdominal incision.
 
Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) is now the most frequently used procedure for detecting and managing common bile duct stones. Laparoscopic cholecystectomy also is increasingly being used for detection and removal of common bile duct stones. This is an approach through the abdomen, but it uses small incisions instead of one large incision. It is used in combination with ultrasound or a cholangiography.
 
Experts are currently debating the choice between laparoscopy and ERCP. Many surgeons believe that laparoscopy is becoming safe and effective and should be the first choice. Still, laparoscopy for common bile duct stones should be performed only by surgeons experienced in this technique.
 
Oral agents used to dissolve gallstones and lithotripsy (alone or in combination with other drugs) had gained some popularity from 90 years. Oral dissolution therapy uses bile acids in pill form to dissolve gallstones, and may be used in conjunction with lithotripsy. Ursodeoxycholic acid - Choludexan (“World Medicine”, England) and chenodeoxycholic acid are the standard oral bile acid dissolution drugs. Most Authors prefer ursodeoxycholic acid, which is considered to be among the safest of common drugs. Long-term treatment appears to notably reduce the risk of biliary pain and acute cholecystitis.
 
Patients most likely to benefit from oral dissolution therapy are those with small stones (less than 1.5 cm in diameter) that have a high cholesterol content.
 
Patients who probably will not benefit from this treatment include obese patients and those with gallstones that are calcified or composed of bile pigments, also those patients, whom compliance is often a problem.
 
Ursodeoxycholic acid (UDCA) - Choludexan is tertiary bile acid, whose concentration in the bile of healthy humans is about 1-5 %. While the dissolution of gallstones depends on the alteration in the composition of the bile acid pool due to exogenous ursodeoxycholic acid; the effects of this agent in cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis is due to its influence on immunological processes, as well as to its anti-inflammatory properties and its cytoprotective role in affecting the process of apoptosis.
 
Ursodeoxycholic acid is very well-tolerated by patients for periods of up to 12 years in documented studies. It is the least toxic of all the naturally occurring bile acids in humans. First pilot studies and case reports of the use of UDCA in pregnant woman have not revealed evidence of any harmful impact on either the mothers or the foetus.
 
Our study cohort included 38 consecutive patients with gallstones and choledocholithiasis who underwent ERCP with endoscopic sphincterotomy and 7 patients with choledocholithiasis without ERCP-intervention. All patients underwent liver ultrasound examination before and after treatment. ERCP was indicated in case when ultrasound investigation revealed either more than 5 mm common bile duct stones or lesser 1 cm but with acoustic shadow.
 
Also in all patients (38+7=45) liver parameters were performed. The patients’ age ranged between 23-75 years. Mean age was 48,5± 6,5 yr. Among them 10 (23%) were males, 35 (77%) – females. Mean body weight was 78± 8,5 kg. Mean BMI (Body Mass Index) was 27,5± 3,5.
 
The patients were arranged into 2 groups according to their treatment regimen: In I group (34 patients) ERCP was combined with Choludexan-therapy: 300mg/d once, while the II group (11 patients) received only Choludexan: 300 mg per os twice/d for a period of 1 month and than 300mg/d once for 3 months administrated at bedtime. The analytical schedule was started for each patient when aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl-transpeptidase (gamma-GT) levels were 120 IU/L or less and serum total bilirubin was 4 mg/dl or less, and no other serious functional disorder was observed. During the treatment course all patients received a standard            gastrointestinal         diet.
For determination of the cholesterol saturation index (SI) of hepatic bile, total cholesterol and total bilirubin were measured. The SI was calculated by the formula established by Thomas and Hofmann. The mean interval values for cholesterol SI in all subjects, before administration and during bedtime administration were 2.4±0.5, 1.6±0.3 respectively. The mean values significantly decreased during Choludexan administration at bedtime. The treatment with Choludexan improved the cholesterol SI and induced litholysis.
 
The levels of total bilirubin and transaminases tended to decrease during bedtime Choludexan administration. The differences in the mean interval values of AP or gamma-GT were not significant.
 
Changes in the differential amount of bile acid before Choludexan administration and during bedtime administration in patients with gallstone and choledocholithiasis were significant. Prior to Choludexan administration, the concentrations of UDCA in bile elevated in all subjects with a mean value of 0.01±0.03mol/l. The UDCA level increased rapidly after the bedtime administration.
 
These findings suggest that patients respond in terms of cholesterol saturation index to the bedtime administration of Choludexan. The oral administration of the ursodeoxycholic acid (Choludexan) reduces the cholesterol saturation index in fasting gallbladder bile and aids in the solubilization of cholesterol-derived gallstones. A significant increase in the rate of gallstone dissolution in patients who were administered Choludexan at bedtime with a low cholesterol diet. Compositionally, no difference in the levels of conjugated bile acids between cholesterol gallstone patients and normal controls was evident. These findings suggest that conjugated bile acid composition is not affected by treatment with        Choludexan.

The present paper describes a study in which the bedtime administration of Choludexan is alternated with combination of this medicine with ERCP. In all cases patients symptoms, laboratory and radiological findings disappeared after the treatment. Also follow up within 8 months was made in 5 patients: no recurrence was observed. Choludexan is generally preferred over Chenodeoxycholic acid for use in gallstone dissolution in contrast to the latter bile acid, because it does not cause diarrhea and hypertransaminasemia. Therefore bedtime of Choludexan administration enhances the rate of dissolution of gallstone.
 
These data insist on the minimum effective dose of UDCA which is available at present Choludexan “World Medicine”, compared with administration 3 times per day. The single, daily administration at bedtime appears to be a more effective, since better compliance would be expected for this medicine.
 
 

REFERENCES:
 
1. Afdhal NH.: Diseases of the Gallbladder and Bile Ducts. In: Goldman L, Ausiello D. (eds.).
 
2. Cecil Textbook of Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007.
 
3. Henegouwen van Berge: Efficacy of Ursodeoxycholic Acid. 2001
 
4. Claessen M; Vlegaar F; Tytgat K; Siersema P; van Buuren: High lifetime risk of cancer in primary sclerosing cholangitis. Journal of Hepatology, 2009, Vol 50 (1):150-157
 
5. Roda E; Azzaroli F; Nigro G: Greater biliary enrichment and improved liver tests with higher dosis of ursodeoxycholic acid in primary biliary cirrhosis.
 
6. Sato H, Macchiarulo A, Thomas C, Gioiello A, Une M, Hofmann AF, Saladin R, Schoonjans K, Pellicciari R, Auwerx J.: Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem. 2008 Mar 27;51(6):1831-41.
 
7. Williams EJ, Green J, Beckingham I, et al. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7):1004-1021.