Nucleation time, cholesterol saturation index, and biliary bile acid pattern. A comparison in responders and nonresponders to systemic litholysis with bile acids.

Scandinavian Journal of Gastroenterology

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Nucleation Time, Cholesterol Saturation Index, and Biliary Bile Acid Pattern:A Comparison in Responders and Nonresponders to Systemic Litholysis with Bile Acids P. Janowitz, J. G. Wechsler, A. Janowitz, K. Kuhn, W. Swobodnik & H. Ditschuneit To cite this article: P. Janowitz, J. G. Wechsler, A. Janowitz, K. Kuhn, W. Swobodnik & H. Ditschuneit (1991) Nucleation Time, Cholesterol Saturation Index, and Biliary Bile Acid Pattern:A Comparison in Responders and Nonresponders to Systemic Litholysis with Bile Acids, Scandinavian Journal of Gastroenterology, 26:4, 367-373, DOI: 10.3109/00365529108996496 To link to this article: http://dx.doi.org/10.3109/00365529108996496

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Nucleation Time, Cholesterol Saturation Index, and Biliary Bile Acid Pattern A Comparison in Responders and Nonresponders to Systemic Litholysis with Bile Acids

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P. JANOWITZ, J. G. WECHSLER, A. JANOWITZ, K. KUHN, W. SWOBODNIK & H. DITSCHUNEIT Dept. of Internal Medicine I1 and Dept. of Radiology, University Clinic Ulm, Ulm, Germany Janowitz P, Wechsler JG, Janowitz A, Kuhn K, Swobodnik W, Ditschuneit H. Nucleation time, cholesterol saturation index, and biliary bile acid pattern. A comparison in responders and nonresponders to systemic litholysis with bile acids. Scand J Gastroenterol 1991, 26, 367-373

In a 24-month trial of a combination therapy with ursodeoxycholic acid and chenodeoxycholic acid complete dissolution of radiolucent gallstones was achieved in 15 of 55 patients (27.3%). A decrease of stone volume of >35% was achieved in a further 28 patients (50.9%). In 12 patients (21.8%) inadequate compliance (3.6%), a nonfunctioning gallbladder (3.6%), absence of size decrease (10.9%), or acute cholecystitis (3.6%) required interruption of therapy. Determination of the cholesterol saturation index (CSI) did not facilitate patient selection, nor was there a statistically significant difference between responders and nonresponders to dissolution therapy. In the course of treatment the average CSI showed a statistically significant decrease from 1.54 t 0.12 to 0.82 ? 0.06 (p < 0.001). Patients in whom complete dissolution was achieved and those in whom no improvement was observed differed significantly in nucleation time (4.7 t 0.8 versus 15.0 ? 2.2 days; p < 0.001) and initial gallstone volume (274 2 78 versus 1045 i 180 mm’). The nucleation time increased statistically significantly during the therapy in the successfully treated group. The percentages of glycocholic acid (8.1 ? 1.13 versus 4.1 & 0.55%; p < 0.01), taurocholic acid (2.2 t 0.45 versus 0.8 ? 0.23%; p < 0.05), and glycodeoxycholic acid (4.9 ? 0.70 versus 1.4 t 0.37%; p < 0,001) were statistically significantly different after the treatment. There were no statistically significant differences between patients with complete and incomplete stone dissolution with regard to age, mean body weight, or laboratory variables. Key words: Bile acids; chenodeoxycholic acid; cholesterol saturation index; gallstones; gallstone therapy; nucleation time; systemic litholysis; ursodeoxycholic acid Paul Janowitz, M. D., Abteilung Innere Medizin II der Uniuersitaet Ulm, Uniuersitaet Ulm, Robert-Koch-Strasse 8, 7900 Ulm, Germany

Since 1972 chenodeoxycholic acid (CDCA) and since 1973 ursodeoxycholic acid (UDCA) have been used for the in vivo dissolution of cholesterol gallstones (1-3). The success of this therapy is dose-dependent, with CDCA administered in daily doses of 15 mg/kg body weight and UDCA in daily doses of 10mg/kg body weight. An increase in dosage above these levels led to no

observable change in the efficacy of therapy (4, 5). CDCA inhibits HMG-coenzyme-A reductase together with 7-alpha-hydroxylase. This results in decreased secretion of both cholesteeol and bile acids. CDCA is able to dissolve biliary cholesterol in micelles and in this manner compensates for decreased bile acid production, so that the total bile acid balance remains intact. Hepatotoxicity,


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diarrhea, and changes in serum lipids and lipoproteins have been reported as side effects of CDCA therapy (4, 6 , 7). UDCA reduces cholesterol resorption in the intestine, dissolves biliary cholesterol in the form of liquid crystals, and prolongs the nucleation time in gallbladder bile of patients with cholesterol gallstones ( 5 , 8-10). The calcification of cholesterol stones in some 10% of patients during UDCA therapy has been described as a secondary effect (11,12). The incidence of colic in the course of UDCA therapy is less than that during CDCA monotherapy, perhaps because of a reduced contractility of the gallbladder (13). Recently conducted studies have shown that, in comparison with either CDCA or UDCA monotherapy, the combined administration of both these substances leads to more rapid stone dissolution at a lower overall dose and to a higher passage rate (6, 7 , 14). The incidence of side effects is also lower. In selected patients oral cholelitholysis leads to stone dissolution in 13.565% of cases in the course of 24 months of therapy (4, 6, 7 , 15, 16). The objective of the present study was to determine whether the determination of the cholesterol saturation index (CSI) and nucleation time (NT) as additional selection criteria would yield appreciable benefits in the patient selection process. PATIENTS AND METHODS A total of 55 patients (11 men and 44 women) were included in our clinically controlled prospective study. The average age of this group was 44.0 5.3 years, and mean body weight was 107.5% of the ideal body weight as determined by the Metropolitan Life Insurance Company. The oral cholelitholysis was begun with an initial dose of 500 mg UDCA and 500 mg CDCA. These drugs were administered in split doses at midday and at bedtime together with a glass of milk (bedtime milk). All patients received dietetic counseling and were advised to consume diets rich in fiber and to limit dietary cholesterol to 300 mg/day . Patient selection was carried out on the basis of the criteria listed in Table I . Patients with a

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Table I. Patient selection criteria for the oral cholelitholYsis therapy Cooperative patients with minor symptoms Radiolucent gallstones with a diameter of 1.0 Normal gallbladder emptying (positive gallbladder function in ultrasound) Total stone volume not exceeding two-thirds of total gallbladder volume No contraindications to therapy with UDCA or CDCA (pregnancy, underlying malignant or inflammatory conditions, obstruction of the cystic duct, gallbladder abnormalities, gastric and/or duodenal ulcers)

CSI value below 1.O (cholesterol hyposaturation) were not admitted to the study. Before starting the oral dissolution therapy, patients were subjected to a sonographic examination, roentgenography of the upper right quadrant of the abdomen, ultrasound evaluation of gallbladder emptying, and the endoscopic removal of bile. The gallbladder was stimulated with 2.5-7.5 pg ceruletid (TakusB) intravenously, and prepapillary bile aspiration was carried out under visual control via a cannula introduced through the biopsy channel. Only the darkest bile samples were subsequently analyzed. In each case, bile was obtained between 0800 h and 0900 h, after 12h of fasting. None of the subjects received medication that influenced biliary lipids. The bile samples were ultracentrifuged for 2 h at 100,000 g (37"C), and the resulting isotropic (cholesteroland liquid crystal-free) phase was incubated at 37°C under sterile conditions. The sediment was also examined for solid cholesterol monohydrate crystals. The N T was determined with the method of Holan et al. (17), defined as the time of earliest appearance (expressed in days) of cholesterol monohydrate crystals in aliquots of the incubated isotropic bile phase. Bile acid analysis was carried out using highpressure liquid chromatography with dexamethasone as the internal standard (18). The cholesterol concentration was measured enzymatically (CHOD-PAP-Method, enzymatic color test, Boehringer Mannheim, Germany), as was the phospholipid concentration (enzymatic color test, Boehringer Mannheim). The total lipid con-


NT, CSI, and Bile Acid Pattern

centration (TLC) as a measure of bile dilution derives from the individual bile acid, phospholipid, and cholesterol concentrations and was expressed in g/dl (cholesterol, 386 g/mol; bile acids, 495 g/mol; lecithin, 735 g/mol). The CSI was determined by the method of Admirand & Small (19), using a microcomputer program described by Kuroki et al. (20). A second endoscopic removal of the bile was conducted 12 months after initiation of therapy. UDCA and CDCA doses were increased in patients showing an inadequate CSI decrease (CSI greater than 1.0). Administration of both drugs in unchanged doses was continued for 3 months after complete stone dissolution. standard All data are presented as mean mean error (SEM). The statistical significances were calculated by using the Student t test for dependent or independent random samples (p < 0.05).

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RESULTS Complete dissolution of gallbladder stones was achieved in an average of 13.6 months (range, 324 months) in 27.3% of the patients (n = 15). Incomplete dissolution (approximately 35% reduction in stone volume) was achieved in a further 28 study subjects (50.9%). Treatment of these patients was discontinued after 24 months of therapy. Therapy interruption within 24 months of initiation was necessary in 12 patients (21.8%) because of noncompliance (3.6%), failure to respond to therapy (no stone reduction, 10.9%), nonfunctioning gallbladder (3.6%), and acute cholecystitis (3.6%). Two patients (3.6%) experienced transient diarrhea, which resolved spontaneously without dose reduction or discontinuation of treatment. Significant side effects resulting from the oral cholelitholysis therapy were not observed in the course of the study period. Calcification of a solitary stone was observed in two patients (3.6%) showing no tendency toward reduction of stone volume. These calcifications were verifiable only on the computed tomographic scan of the gallbladder. The CSI of the total group was reduced sig-

Fig. 1. Cholesterol saturation index (CSI) before and after dissolution therapy in patients with and without complete dissolution of radiolucent gallstones.

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nificantly from 1.54 & 0.12 to 0.82 0.06 (p < 0.001). The reduction in the CSI of the successfully treated patients from 1.38 k 0.12 to 0.80 k 0.09 (p < 0.01) was comparable to that of the remaining patients (a reduction from 1.55 k 0.18 to 0.74 0.09; p < 0.001) (Fig. 1). This decrease in the CSI was correlated with a decrease in biliary cholesterol from 8.84 t 0.77 to 4.78 k 0.43 mol% (p < 0.001) in the total group (Table 11). The increase in total bile acids from 74.01 1.33 to 77.32 2 1.26 mol% and in biliary phospholipids from 17.10 & 0.97 to 17.87 k 1.02 mol% were not statistically significant (Table 11).

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Table 11. Biliary lipids (mol%) and cholesterol saturation index (CSI) before and after dissolution therapy (i ? SEM). There were no statistically significant differences between patients with complete and incomplete stone dissolution in relation to these variables

Cholesterol Phospholipids Bile acids CSI

Before

After

P

8.84 2 0.77 17.10 2 0.97 74.01 5 1.33 1.54 2 0.18

4.78 f 0.43 17.87 2 1.02 77.32 2 1.26 0.82 f 0.09

0.001 n.s. n.s. 0.001

P . Janowitz et al.

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The NT in the successfully treated group (4.7 0.8 days; n = 9) was significantly shorter than in the unsuccessfully treated group (15.0 2.2 days; n = 16; p < 0.001) (Fig. 2). The biliary TLC was 5.61 ? 0.76 g/dl and thus well concentrated and reliable for determination of the NT (21-23). The NT increased in both groups after treatment (20.5 2.33 days in the successfully treated group, p < 0.001; 17.1 2 2.5 days in the other group, NS) (Fig. 2). As expected, the total concentration of CDCA and UDCA conjugates increased statistically significantly during the dissolution therapy in both groups, whereas decreases in the concentration of cholate and deoxycholate were statistically significant. The percentages of glycocholic acid (GCA) (8.1 k 1.13 versus 4.1 ? O X % , p < 0.01), taurocholic acid (TCA) (2.2 k 0.45 versus 0.8 0.23%, p < 0.05), and glycodeoxycholic acid (GDCA) (4.9 0.70 versus 1.4 k 0.37%, p < 0.001) were statistically significantly higher in

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nonresponders after the treatment (Fig. 3a and 3b). The elevated levels of transaminases and serum cholesterol described in the literature were not observed in the present study. The alanine aminotransferase (ALAT) level decreased tendentially after 3 months of treatment (24.6 4.8 U/l to 17.3 ? 4.2 U/I; NS). There were no statistically significant differences between patients with complete and incomplete stone dissolution in relation to age, mean body weight, or laboratory variables. Initial stone volume was significantly smaller in the successfully treated group than in the unsuccessfully treated group (274 -C 78 mm3 versus 1045 180 mm3;p < 0.001). At termination of therapy after 24 months the mean stone volume in the unsuccessfully treated group had been reduced to 675 61 mm3. This represents a decrease in volume of 35.4% and a decrease in median diameter of 13.5%.

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DISCUSSION

Fig. 2. The nucleation time (NT) was statistically significantly shorter (p < 0.001) in the successfully treated group before treatment. After the treatment the NT increased in both groups. In responders to dissolution therapy the increase in the NT was significant (p < 0.001).

Combination therapy with UDCA and CDCA led to a complete dissolution of radiolucent gallstones in a surprisingly small percentage (27.3%) of patients. The therapeutic dose of UDCA was 8.5-10.8 mg/kg body weight, and that of CDCA was 7.1-10.7 mg/kg body weight. Nine of 15 successfully treated patients had an initial stone diameter between 3 and 7 mm. The remaining six had stone diameters between 10 and 15 mm. No instance of complete dissolution was observed in patients with stone diameters above 15 mm in the course of the 24 months of therapy. These results support the widely accepted belief that oral cholelitholysis should be limited to patients with stone diameters of less than 15mm (1,2,4,6). The stone volume of the successfully treated group (274mm3 or a diameter of about 8 m m ) was significantly smaller than that of patients in whom only incomplete dissolution could be achieved (1045mm3 or a diameter of 12mm). The median volume reduction of 370 mm3 (or a diameter of 9 mm) in the unsuccessfully treated group suggests that, at the above-mentioned

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NT,CSI, and Bile Acid Pattern

Fig. 3. Before treatment there were no differences in biliary bile acid pattern in responders and nonresponders. After the treatment the percentages of glycocholic acid (GC) (8.1 ? 1.13 versus 4.1 2 0.55%, p < 0.01), taurocholic acid (TC) (2.2 -t 0.45 versus 0.8 ? 0.23%, p < 0.05), and glycodeoxycholic acid (GDC) (4.9 -+ 0.70 versus 1.4 ? 0.37%, p < 0,001) were statistically significantly higher in nonresponders to the dissolution therapy.

doses of UDCA and CDCA, the dissolution of all stones of a diameter under 9 m m could be achieved within 2 years. That this is not the case

is probably explained by the probability that many calcifications escape detection through conventional radiologic methods and that an overly large

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proportion of mixed pigment gallstones was dis- deoxycholic acid has been seen in patients with early recurrence of gallstones. Despite the solved. The determination of the CSI as an additional significant differences in GCA, TCA, and GDCA selection criterion (CSI > 1.0) did not yield concentrations in responders and nonresponders, appreciable benefits in the selection process. their role in the dissolution process is not clear. At the initiation of therapy, all 55 study subjects Although the average CSI was lowered significantly from 1.54 k 0.12 to 0.82 0.06, there complained of upper abdominal pain or colic. was no difference between responders and non- This number was reduced to 12 of 55 after 6 responders either before or during the therapy months, 8 of 53 after 12 months, and 5 of 43 after 18 months. In other words, 88.3% of all patients period (Fig. 1). The NT of patients with complete stone dis- became symptom-free during the course of the solution (4.7 k 0.8 days) was significantly shorter combination therapy. The transient diarrhea than that of patients responding with only incom- observed in two patients resolved spontaneously plete dissolution (15.0 f 2.2 days) (Fig. 2). Deter- without dose reduction within 3 months. We did mination of NT, even in duodenal bile, as an not observe an increase in transaminases or serum additional selection criterion may lead to more cholesterol. Other laboratory values did not show effective patient selection (23). Patients with any statistically significant or tendential changes. shorter NT have cholesterol-containing, easily It is therefore possible to regard the combination dissolvable stones, whereas those with a longer therapy with UDCA and CDCA as essentially nucleation time probably have bilirubin stones or free of side effects. The success of cholelitholysis therapy is heavily mixed stones with a high bilirubin content, which do not respond to oral cholelitholysis therapy. dependent on adequate patient selection Recent studies agree that cholesterol mono- methods. A difference between responders and hydrate crystal formation (nucleation time) is nonresponders in our study could be observed in much more rapid in bile from patients with chol- the variables of initial gallstone size, nucleation esterol gallstones than in normal gallbladder bile time, and concentration of GDCA, TCA, and or in bile from patients with pigment stones. In GCA after dissolution therapy. patients with gallstones, cholesterol crystal occurrence better helped to identify cholesterol gallACKNOWLEDGEMENT stones (sensitivity, 87%; specificity, 97%) than did an abnormal cholesterol saturation index of A preliminary report of this study was presented bile (17, 22, 24, 25). A final determination of at the Ulm Spring Meeting of Gallstone Disease, the NT above which patient selection should be Ulm, Germany, 10 and 11 March 1989. conducted must be made through studies with a large number of patients. In our patient group


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the exclusion of patients with an NT of over 8

days would have increased the efficacy of the oral dissolution therapy by approximately 70%. The percentages of GCA (8.1 k 1.13 versus 4.1 f 0.55%, p < 0.01), TCA (2.2 2 0.45 versus 0.8 k 0.23%, p < 0.05), and GDCA (4.9 k 0.70 versus 1.4 2 0.37%, p < 0.001) were statistically significantly different in responders and nonresponders after the treatment. Although there is evidence that the level of deoxycholic acid in the bile influences biliary cholesterol saturation, its role in gallstone disease has not yet been proved (26, 27). An enhanced formation and input of

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NT, CSI, and Bile Acid Pattern

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Received 6 August 1990 Accepted 12 October 1990

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Speed of change in biliary lipids and bile acids with chenodeoxycholic acid--is intermittent therapy feasible?

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Bile acids and biliary carcinoma in pancreaticobiliary maljunction.

Desaturation of bile and cholesterol gallstone dissolution with chenodeoxycholic acid.

Lovastatin added to ursodeoxycholic acid further reduces biliary cholesterol saturation.

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A Comparison of Responders and Nonresponders Is Lacking.

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Treatment with bile acids.

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Effect of ursodeoxycholic acid administration on biliary lipid composition and bile acid kinetics in cholesterol gallstone patients.

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