Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones M. Zuin, M. L. Petroni, G. Grandinetti, A. Crosignani, E. Bertolini, P. M. Battezzati & M. Podda To cite this article: M. Zuin, M. L. Petroni, G. Grandinetti, A. Crosignani, E. Bertolini, P. M. Battezzati & M. Podda (1991) Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones, Scandinavian Journal of Gastroenterology, 26:3, 257-262, DOI: 10.3109/00365529109025039 To link to this article: http://dx.doi.org/10.3109/00365529109025039
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [University of California, San Diego]
Date: 17 March 2016, At: 08:00
Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
M. ZUIN, M. L. PETRONI, G. GRANDINETTI, A. CROSIGNANI, E. BERTOLINI, P. M. BATIZZZATI & M. PODDA Dept. of Internal Medicine, Institute of Biomedical Science, Ospedale S. Paolo, University of Milan, Milan, Italy
Zuin M, Petroni ML, Grandinetti G , Crosignani A, Bertolini E, Battezzati PM, Podda M. Comparison of effects of chenodeoxycholic and ursodeoxycholic acid and their combination on biliary lipids in obese patients with gallstones. Scand J Gastroenterol 1991, 26, 257-262 To study the effects of different bile acids on biliary lipids in obese patients with radiolucent gallstones, 12 subjects were given chenodeoxycholic acid (CDCA) at a dose of 15 mg/kg/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and an equimolar combination of the two (7.5 + 7.5 mg/kg/day) in accordance with a double-blind crossover design. Mean molar percentage of cholesterol and cholesterol saturation index corrected for urso-rich bile (CSI) decreased significantly with all three treatments, but the combination was more effective in decreasing the CSI than either of the two bile acids given alone 0,< 0.05). Bile became desaturated in 10 of 12 patients receiving the combination, in 4 of 12 receiving CDCA, and 3 of 12 receiving UDCA alone. Combination treatment was well tolerated since mild diarrhea and slight increase in transaminases were observed only in a few patients. We conclude that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for dissolution of gallstones in obese patients. Key words: Bile; bile acids; chenodeoxycholic acid; cholelithiasis; obesity; ursodeoxycholic acid Mauro Podda, M . D . , Dept. of Internal Medicine, Ospedale S. Paolo, Via Di Rudini 8, Milano, Italy
Obesity is considered a limitation to successful bile acid therapy in patients with radiolucent gallbladder stones, since obese gallstone subjects have been shown to be poorly responsive to chenodeoxycholic acid (CDCA) treatment (1).In the National Cooperative Gallstone Study, after treatment with CDCA in patients weighing more than their ideal body weight (IBW) gallstone dissolution was achieved one-third as often as in those weighing less than their IBW ( 2 ) .Resistance of obese patients to CDCA treatment has been attributed to the persistent secretion of bile supersaturated with cholesterol, even when doses higher than 15 mg/kg are given. Only scanty and
non-conclusive data are available on the effects of ursodeoxycholic acid (UDCA) on biliary lipids (3,4) and on the rate of gallstone dissolution in obese patients (5). It has been shown that CDCA and UDCA administered in combination are more effective in reducing biliary cholesterol saturation than either of the two bile acids given alone to normal-weight patients with radiolucent gallstones (6,7). There is also evidence that the combination induces faster stone dissolution than UDCA (8). To ascertain which form of treatment, if any, is more effective on bile cholesterol saturation, we compared the effects of CDCA, UDCA, and
258
M. Zuin et al.
an equimolar combination of the two, in a doubleblind crossover design, on biliary lipids and tolerability in obese patients with radiolucent gallstones.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
PATIENTS AND METHODS Patients and study design Twelve obese patients with radiolucent stones in functioning gallbladders were admitted to the study. Informed consent was obtained. Eight subjects had single stones, and four had multiple stones, with a maximum diameter not larger than 15 mm. Obesity was arbitrarily defined as a body mass index (BMI) equal to or higher than 30. The patients’ characteristics (sex, age, body weight, BMI) and sequences of treatments are reported in Table I. None of the patients had clinical or laboratory evidence of liver or thyroid dysfunction, malabsorption, or diabetes mellitus; none was taking clofibrate or barbiturates. Women of child-bearing age were using non-hormonal contraceptive methods. All patients continued their dietary habits throughout the study; their body weight did not change by more than 5 4 % during the investigation. Three types of treatment were compared: CDCA (15 mg/kg/day), UDCA (15 mg/kg/day),
and C D C A + UDCA (7.5mg/kg/day each), divided into two daily administrations given at mealtimes. The three types of treatment were administered in identical capsules containing 250mg of bile acids, and the total doses vaned from 14.3 to 17.0 mg/kg/day in accordance with the patients’ weights (Table I). Patients were given the three treatments, by a double-blind design, for three consecutive periods ranging from 48 to 60 days, more than long enough to obtain a steady state of bile lipid composition (9). The sequence of treatments in each patient (Table I) was assigned on the basis of a balanced Latin-square design, repeated twice. At each visit the occurrence of any side effects was recorded. A number of capsules slightly exceeding that required to complete each period of treatment was given to each patient, and compliance was checked by counting the remaining capsules. Fasting blood samples and duodenal bile aspirates were collected in basal conditions and at the end of each period of treatment. Standard liver function tests, serum total and high-density lipoprotein cholesterol, serum triglycerides, and serum total bile acids were measured. In bile phospholipids, cholesterol, total and individual bile acids, and bile acid pool size were determined, as described below.
Table I. Patients’ characteristics and sequence of treatments ~
Initials
Sex
~~~
Weight, kg
BMI
Sequence of treatments
~~~
LA.
IS. T.G. S.F. E.C. U.P. C.B. R.S. M.P. S.A. L.B. V.T.
F M F F M F M M F F F
M
78.5 90.5 97.5 86.5 88.5 86.5 109.5 94.5 83.0 90.0 92.5 104.5
35.1 37.2 40.7 36.1 31.9 32.4 40.7 32.0 35.0 39.5 36.6
30.5
U U+C C U C U +C C U +C U
c U U
+C
C U
u+c u+c
U C
u+c
U C U C
u+c
u+c C u c u+c U u C u+c u+c U c
16.0 16.6 15.4 16.2 17.O 14.4 16.0 15.8 15.0 16.6 16.2 14.3
Abbreviations: M = male; F = female; BMI = body mass index; U = ursodeoxycholic acid (UDCA); and C = chenodeoxycholic acid (CDCA). * During U + C treatment the dosage indicated above corresponds to an equimolar combination of the two bile acids.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
Bile Acids for Obese Gallstone Patients
Biliary lipid analysis After a 12-h overnight fast, a sample of gallbladder bile was collected by duodenal intubation. The tube was positioned under fluoroscopic control, and cerulein (0.3 pg/kg body weight; Ceruletide, Farmitalia, Milano, Italy) was injected intramuscularly, to stimulate gallbladder contraction. Concentrated duodenal bile was diluted 1:10 with isopropanol and stored at -20°C. Concentrations of bile acids, phospholipids, and cholesterol in bile were determined by the enzymatic methods of Talalay (lo), Svanborg & Svennerholm (ll),and Roda et al. (12). All biliary lipid analyses were run in triplicate; mean values were calculated from single results and did not differ more than 3%. When variation was greater, the determination was repeated. Biliary lipid composition was expressed both as molar percentage of biliary bile acids, cholesterol, phospholipids and as cholesterol saturation index. This was calculated by using the polynomial equation of Thomas & Hofmann (13) on cholesterol solubility lines described by Hegardt & Dam (14) and Holzbach et al. (15) and was corrected by means of the factor proposed by Carey & KO (16) for UDCA-rich bile. The total bile acid pool was estimated by isotope dilution with the method of Duane et al. (17), with intravenous administration of 10 pCi of ~arboxyl-'~C-cholicacid sodium salt (specific activity, 59 mCi/mmol (The Radiochemical Centre, Amersham, England)) the evening before duodenal intubation. Measurement of total bile acid concentration (BA) and concentration of radioactivity (dpm) in the sample of concentrated duodenal bile enables the calculation of bile acid pool by means of the following equation: Total bile acid pool (mg)/radioactivity administered = BA/dpm. Biliary bile acid composition was analyzed by gas-liquid chromatography (18).
Other laboratory methods Serum alanine aminotransferase, serum aspartate aminotransferase, bilirubin, alkaline phos-
259
phatase, gamma-glutamyl transpeptidase, albumin, fasting plasma cholesterol, and triglycerides were determined by routine laboratory methods. Serum high-density lipoprotein cholesterol was determined after precipitation with heparin manganese (19). Total serum bile acids were determined by radioimmunoassay (Beckton & Dickinson, commercial kit).
Statistical analysis The results were analyzed by analysis of variance; when the general F test gave a significant result @ < 0.05), the statistical significance of the differences between treatments was further analyzed with Scheffe's test for binomial comparison of means (20). RESULTS
Patient compliance and interruption of treatment No patient dropped out of the study. In case 2, the second treatment, corresponding to UDCA, was interrupted after 18 days when the patient developed pneumonia, then restarted after 3 weeks, and continued for the whole period of 2 months. In three patients, cases 4,7, and 11, the dose of CDCA had to be reduced for 4-10 days during the initial period of treatment because of diarrhea. All 12 subjects returned the remaining capsules for counting at the end of each cycle. The number of remaining capsules was always correct for 8 patients, whereas in the other 4 it differed'by -5% to +4%. Biliary lipid composition Biliary bile acid composition was markedly affected by all treatments. CDCA became the predominant bile acid in bile when it was administered alone (range, 75-92%) or in combination (range, 41-60%), mainly at the expense of both cholic acid and deoxycholic acid (Table 11). UDCA ranged from 47% to 64% when given alone and from 22% to 38% when given in combination. Lithocholic acid in bile increased when CDCA was administered alone or in combination. Bile enrichment of litholytic bile acids (CDCA
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
260
M. Zuin et al.
and UDCA) was significantly higher after CDCA given alone or in combination than after UDCA alone (Table 11). Whereas only minor changes were observed in the molar percentages of bile acids and phospholipids, cholesterol content decreased significantly with all three treatments, UDCA and UDCA + CDCA being more effective than CDCA alone (p < 0.05) (Table 111). The cholesterol saturation index decreased markedly after all treatments; no difference was noted between CDCA and UDCA, whereas the combination was significantly 0)< 0.05) more effective than either of the two bile acids given alone (Table 111). No significant changes from basal values were observed in total bile acid pool size during any treatment.
CDCA, 3.6 5 1.8 pmol/l after UDCA, and 3.9 k 1.7 pmol/l after CDCA UDCA. Diarrhea and abdominal discomfort were experienced by four patients soon after starting treatment with CDCA, mild diarrhea by one patient after the combination, and constipation by one patient after UDCA.
+
DISCUSSION
The experimental design of the study enabled us to compare the effects on biliary lipid composition in the same patients of the three treatments, regardless of their sequence of administration. The blinded nature and the objective end points of the study, based on laboratory comparison of active treatments, minimized any possible biases even though placebo was not administered. Our data indicate that in obese gallstone patients the combination of CDCA and UDCA Plasma lipids and tolerability There were no significant changes in plasma induces the conditions considered most favorable triglycerides or total and high-density lipoprotein for gallstone dissolution. In fact, both the comcholesterol after any of the treatments. Serum bination and UDCA were more effective in transaminases increased, up to 2.5 times the nor- decreasing biliary cholesterol content than CDCA mal upper limit, in four patients after CDCA alone, but when the ability to solubilize choltreatment and in one subject after the combi- esterol into micelles was expressed as the satunation; they returned to normal after the end of ration index, the combination was the most the treatment; other liver function indices re- effective treatment, as previously shown in normained normal. mal-weight patients by others and by us (6,7). Serum bile acid levels did not significantly More than 80% of patients had unsaturated bile change during treatment. Their mean values were when receiving the combination, as compared 2.6 2 1.6 pmol/l initially, 3.8 2 1.5 pmol/l after with about one-fourth of patients receiving
Table 11. Phospholipids, total and individual bile acids in bile, and total bile acid pool size (mean and after treatments
CDCA (%) UDCA (%) Cholic acid (%) Deoxycholic acid (%) Lithocholic acid (%) Bile acids (molar %) Phospholipids (molar %) CDCA + UDCA (%) Total bile acid pool size (g)
* p < 0.05 versus values at entry.
t p < 0.05 versus CDCA. $p
< 0.05 versus UDCA.
At entry
CDCA
UDCA
30.7 f 8.2 0.6 2 0.4 36.6 rf: 7.3 28.0 2 8.8 3.9 2 1.4 66.0 t 6.7 22.5 rf: 5.9 31.4 2 8.1 2.55 2 0.86
84.0 f 5.4* 1.4 f 1.1 4.6 f 2.9*$ 3.2 f 2.6' 6.8 & 1.9*$ 66.9 7.2 24.7 f 5.9 85.4 2 4.8*$ 2.96 f 0.84
19.9 4.9*t 55.4 f 6.1*t 12.1 f 3.5* 8.3 2 2.6" 4.2 1.4 68.1 f 7.3 26.0 t 6.9 15.3 2 5.5* 2.51 2 0.96
*
* *
* SD) before
CDCA + UDCA 49.0 rf: 5.6*t$ 32.1 4.7*t$ 8.3 f 3.0* 5.4 f 1.3* 5.9 f 1.3* 69.2 6.6 25.3 2 5.8 81 .O f 3.4*$ 3.07 1.06
* * *
Bile Acids for Obese Gallstone Patients
261
Table 111. Molar percentages of biliary cholesterol and saturation indexes (corrected for percentage UDCA in bile) before and after treatments Saturation indexes
Cholesterol molar % CDCA At entry
L.A. IS.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
T.G. S.F.
E.C. U.P. C.B. R.S.
M.P. S.A. L.B. V.T. Mean S.D.
11.6 11.1 7.8 16.2 10.2 11.9 12.3 10.8 17.3 10.2 10.4 14.2 12.0 2.7
+
CDCA At
+
CDCA
UDCA
UDCA
entry
CDCA
UDCA
UDCA
8.0 10.9 6.7 9.5 6.2 10.7 8.0 10.0 9.6 5.2 6.8
6.6 4.0 4.1 6.1 5.1 7.2 6.1 7.6 7.6 7.8 3.9 5.5
5.8 4.0 3.2 5.8 4.3 6.9 6.2 6.4 6.6 7.7 4.0 5.1
1.77 1.50 1.47 1.96 1.40 1.74 1.50 1.96 2.11 1.58 1.34 1.72
1.15 1.32 0.96 1.37 0.84 1.30 0.97 1.28 1.22 1.25 0.87 1.03
1.03 0.95 0.74 1.07 0.80 1.47 1.01 1.24 1.27 1.47 1.25 1.06
0.88 0.74 0.55 0.95 0.61 1.08 0.91 0.92 0.93 1.11 0.96 0.90
8.4* 1.9
6.0at 1.5
5S*t 1.4
1.67 0.25
1.13* 0.19
1.11* 0.23
0.17
9.0
0.88*$
* p < 0.05 versus values at entry.
t p < 0.05 versus CDCA. $p
< 0.05 versus CDCA and UDCA given alone.
CDCA or UDCA alone. Furthermore, with CDCA plus UDCA treatment, the two bile acids were present in high concentrations in a desaturated bile, so that both mechanisms of cholesterol solubilization-that is, micellation by CDCA and liquid crystals by UDCA-could act. The effect of CDCA on biliary lipids was similar to that previously reported for obese patients treated with the same dose of 15 mg/kg: CDCA can decrease cholesterol secretion in bile, but not enough to achieve desaturation of bile (1). Only after increasing the dose of CDCA to around 20 mg/kg day, which causes an unacceptable incidence of side effects, did some patients have bile desaturated with cholesterol (21). Only a few data are available on the effect of UDCA on biliary lipids in obese gallstone patients (3,4). In our study 15 mg/kg UDCA induced a 50% reduction of cholesterol content in bile, to an extent similar to that observed in normalweight gallstone patients (22), and it was more effective than the same dose of CDCA. These data are in agreement with those of Roda et al. (3), showing in four patients a more marked decrease in cholesterol secretion after 7.5 mg/kg
UDCA than 12.5 mg/kg CDCA. Nevertheless, in our study, when the lesser ability to solubilize micelles of UDCA-rich bile was taken into account in the calculation of the saturation index, the proportion of patients treated with UDCA who had bile supersaturated with cholesterol was similar to that of patients treated with CDCA. Marked decreases in molar percentage of biliary cholesterol and desaturation of bile could be achieved in the vast majority of our obese patients only by combined administration of CDCA and UDCA, and the effect on biliary cholesterol saturation was only slightly less than that reported in normal-weight patients treated with the same dose (6). Our data do not enable us to explain the reasons why UDCA and CDCA given in combination are more effective also in obese patients, although it might be due to the different and, in many aspects, complementary physicochemical and metabolic properties of the two bile acids (23). The combination of about 7.5 mg/kg of CDCA and 7.5 mg/kg of UDCA was well tolerated; the incidence of side effects was lower than that expected on the basis of previous experience with
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
262
M. Zuin et al.
low doses of CDCA (2), and it was similar to that observed during administration of UDCA alone (22). The slight increase of serum cholesterol level during CDCA shown in the National Cooperative Gallstone Study (2) was not seen in our study either when this bile acid was administered alone or when administered in combination. The different patient populations composed of obese subjects and, especially, the short duration of treatment and the limited number of cases might preclude such a finding. In conclusion, our data suggest that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for obese patients too, for both gallstone dissolution and adjuvant therapy of extracorporeal shock wave lithotripsy. REFERENCES 1. Iser JH, Maton PN, Murphy GM, Dowling RH. Resistance to chenodeoxycholicacid (CDCA) treatment in obese patients with gallstones. Br Med J 1978, 1 , 1509-1512 2. National Cooperative Gallstone Study Group. Chenodiol (chenodeoxycholic acid) for dissolution of gallstones. Ann Intern Med 1981, 95, 257-282 3. Roda E, Mazzella G, Roda A, et al. Effect of chenodeoxycholic and ursodeoxycholic acid administration on biliary lipid secretion in normalweight and gallstone patients. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids and lipids. MTP, Lancaster, U.K., 1981, 189-193 4. Maton PN, Murphy GM, Dowling RH. Lack of response to chenodeoxycholic acid in obese and non-obese patients. Gut 1980, 21, 1082-1086 5. Tint GS, Salen G, Colalillo A, et al. Ursodeoxycholic acid: a safe and effective agent for dissolving cholesterol gallstones. Ann Intern Med 1982, 351-356 6. Stiehl A, Raedsch R, Czygan P, et al. Effects of biliary bile acid composition on biliary cholesterol saturation in gallstone patients treated with chenodeoxycholic acid and/or ursodeoxycholic acid. Gastroenterology 1980, 79, 1192-1198 7. Podda M, Zuin M, Dioguardi ML, Festorazzi S , Dioguardi N. A combination of ursodeoxycholic acid and chenodeoxydholic acid is more effective than either alone in reducing biliary choiesterol saturation. Hepatology 1982, 2, 334-339 8. Podda M, Zuin M, Battezzati PM, Ghezzi C, De Fazio C, Dioguardi ML. Efficacy and safety of a
Received 8 June 1990 Accepted 11 September 1990
combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: a comparison with ursodeoxycholic acid alone. Gastroenterology 1989, 96, 222-229 9. Iser JH, Murphy GM, Dowling RH. Speed of change in biliary lipids and bile acids with chenodeoxycholic acid-Is intermittent therapy feasible? Gut 1977. 18, 7-15 10. Talalay P. Enzymatic analysis of steroid hormones. Anal Biochem 1960, 119-143 11. Svanborg A, Svennerholm M. Plasma total lipid cholesterol, tryglicerides, phospholipids and free fatty acids in healthy Scandinavianpopulation. Acta Med Scand 1961, 169, 4 H 9 12. Roda A, Festi D, Sama C, et al. Enzymatic determination of cholesterol in bile. Clin Chim Acta 1975, 64, 337-341 13. Thomas PJ, Hofmann AF. A simple calculation of the lithogenic index of bile: expressing biliary lipid composition on rectangular coordinates. Gastroenterology 1973, 65, 698-700 14. Hegardt FG, Dam H. The solubility of cholesterol in aqueous solutions of bile salts and lecithin. Z Ernaehrungswiss 1971, 10, 223-233 15. Holzbach RT, Marsh M, Olszewski M, et al. Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 1973, 52, 1467-1479 16. Carey MC, KO G. The importance of total lipid concentration in determining cholesterol solubility in bile and the development of critical tables for calculating ‘percent cholesterol saturation’ with a correction factor for ursodeoxycholate-richbile. In: Paumgartner G, Stiehl A, Gerok W, eds. Biological effects of bile acids. MTP, Lancaster, U.K., 1979, 299-308 17. Duane WC, Adler RD, Bennion LJ, et al. Determination of bile acid pool size in man: a simplified method with advantages of increased precision, shortened analysis time and decreased isotope exposure. J Lipid Res 1975, 16, 155-158 18. Klassen CD. Gas-liquid chromatographic determination of bile acids in bile. Clin Chim Acta 1971, 35,225-229 19. Burstein M, Samaille J. Sur un dosage rapide du cholesterol lit5 aux a- et aux /3-lipoproteines du serum. Clin Chim Acta 1960, 5, 609 20. Snedecor GW, Cochran WC. Statistical methods. 7th ed. Iowa State University Press, Ames, Iowa, 1980 21. Mok HYI, Bell GD, Dowling RH. Effect of different doses of chenodeoxycholic acid on bile-lipid composition. Lancet 1974, 2, 253-257 22. Bachrach WH, Hofmann AF. Ursodeoxycholicacid in the treatment of cholesterol cholelithiasis. Dis Dig Sci 1982, 27, 737-761 23. Tint GS, Salen G, Shefer S . Effect of ursodeoxycholicacid on cholesterol and bile acid metabolism. Gastroenterology 1986, 91, 1007-1018 -
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones M. Zuin, M. L. Petroni, G. Grandinetti, A. Crosignani, E. Bertolini, P. M. Battezzati & M. Podda To cite this article: M. Zuin, M. L. Petroni, G. Grandinetti, A. Crosignani, E. Bertolini, P. M. Battezzati & M. Podda (1991) Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones, Scandinavian Journal of Gastroenterology, 26:3, 257-262, DOI: 10.3109/00365529109025039 To link to this article: http://dx.doi.org/10.3109/00365529109025039
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [University of California, San Diego]
Date: 17 March 2016, At: 08:00
Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
M. ZUIN, M. L. PETRONI, G. GRANDINETTI, A. CROSIGNANI, E. BERTOLINI, P. M. BATIZZZATI & M. PODDA Dept. of Internal Medicine, Institute of Biomedical Science, Ospedale S. Paolo, University of Milan, Milan, Italy
Zuin M, Petroni ML, Grandinetti G , Crosignani A, Bertolini E, Battezzati PM, Podda M. Comparison of effects of chenodeoxycholic and ursodeoxycholic acid and their combination on biliary lipids in obese patients with gallstones. Scand J Gastroenterol 1991, 26, 257-262 To study the effects of different bile acids on biliary lipids in obese patients with radiolucent gallstones, 12 subjects were given chenodeoxycholic acid (CDCA) at a dose of 15 mg/kg/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and an equimolar combination of the two (7.5 + 7.5 mg/kg/day) in accordance with a double-blind crossover design. Mean molar percentage of cholesterol and cholesterol saturation index corrected for urso-rich bile (CSI) decreased significantly with all three treatments, but the combination was more effective in decreasing the CSI than either of the two bile acids given alone 0,< 0.05). Bile became desaturated in 10 of 12 patients receiving the combination, in 4 of 12 receiving CDCA, and 3 of 12 receiving UDCA alone. Combination treatment was well tolerated since mild diarrhea and slight increase in transaminases were observed only in a few patients. We conclude that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for dissolution of gallstones in obese patients. Key words: Bile; bile acids; chenodeoxycholic acid; cholelithiasis; obesity; ursodeoxycholic acid Mauro Podda, M . D . , Dept. of Internal Medicine, Ospedale S. Paolo, Via Di Rudini 8, Milano, Italy
Obesity is considered a limitation to successful bile acid therapy in patients with radiolucent gallbladder stones, since obese gallstone subjects have been shown to be poorly responsive to chenodeoxycholic acid (CDCA) treatment (1).In the National Cooperative Gallstone Study, after treatment with CDCA in patients weighing more than their ideal body weight (IBW) gallstone dissolution was achieved one-third as often as in those weighing less than their IBW ( 2 ) .Resistance of obese patients to CDCA treatment has been attributed to the persistent secretion of bile supersaturated with cholesterol, even when doses higher than 15 mg/kg are given. Only scanty and
non-conclusive data are available on the effects of ursodeoxycholic acid (UDCA) on biliary lipids (3,4) and on the rate of gallstone dissolution in obese patients (5). It has been shown that CDCA and UDCA administered in combination are more effective in reducing biliary cholesterol saturation than either of the two bile acids given alone to normal-weight patients with radiolucent gallstones (6,7). There is also evidence that the combination induces faster stone dissolution than UDCA (8). To ascertain which form of treatment, if any, is more effective on bile cholesterol saturation, we compared the effects of CDCA, UDCA, and
258
M. Zuin et al.
an equimolar combination of the two, in a doubleblind crossover design, on biliary lipids and tolerability in obese patients with radiolucent gallstones.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
PATIENTS AND METHODS Patients and study design Twelve obese patients with radiolucent stones in functioning gallbladders were admitted to the study. Informed consent was obtained. Eight subjects had single stones, and four had multiple stones, with a maximum diameter not larger than 15 mm. Obesity was arbitrarily defined as a body mass index (BMI) equal to or higher than 30. The patients’ characteristics (sex, age, body weight, BMI) and sequences of treatments are reported in Table I. None of the patients had clinical or laboratory evidence of liver or thyroid dysfunction, malabsorption, or diabetes mellitus; none was taking clofibrate or barbiturates. Women of child-bearing age were using non-hormonal contraceptive methods. All patients continued their dietary habits throughout the study; their body weight did not change by more than 5 4 % during the investigation. Three types of treatment were compared: CDCA (15 mg/kg/day), UDCA (15 mg/kg/day),
and C D C A + UDCA (7.5mg/kg/day each), divided into two daily administrations given at mealtimes. The three types of treatment were administered in identical capsules containing 250mg of bile acids, and the total doses vaned from 14.3 to 17.0 mg/kg/day in accordance with the patients’ weights (Table I). Patients were given the three treatments, by a double-blind design, for three consecutive periods ranging from 48 to 60 days, more than long enough to obtain a steady state of bile lipid composition (9). The sequence of treatments in each patient (Table I) was assigned on the basis of a balanced Latin-square design, repeated twice. At each visit the occurrence of any side effects was recorded. A number of capsules slightly exceeding that required to complete each period of treatment was given to each patient, and compliance was checked by counting the remaining capsules. Fasting blood samples and duodenal bile aspirates were collected in basal conditions and at the end of each period of treatment. Standard liver function tests, serum total and high-density lipoprotein cholesterol, serum triglycerides, and serum total bile acids were measured. In bile phospholipids, cholesterol, total and individual bile acids, and bile acid pool size were determined, as described below.
Table I. Patients’ characteristics and sequence of treatments ~
Initials
Sex
~~~
Weight, kg
BMI
Sequence of treatments
~~~
LA.
IS. T.G. S.F. E.C. U.P. C.B. R.S. M.P. S.A. L.B. V.T.
F M F F M F M M F F F
M
78.5 90.5 97.5 86.5 88.5 86.5 109.5 94.5 83.0 90.0 92.5 104.5
35.1 37.2 40.7 36.1 31.9 32.4 40.7 32.0 35.0 39.5 36.6
30.5
U U+C C U C U +C C U +C U
c U U
+C
C U
u+c u+c
U C
u+c
U C U C
u+c
u+c C u c u+c U u C u+c u+c U c
16.0 16.6 15.4 16.2 17.O 14.4 16.0 15.8 15.0 16.6 16.2 14.3
Abbreviations: M = male; F = female; BMI = body mass index; U = ursodeoxycholic acid (UDCA); and C = chenodeoxycholic acid (CDCA). * During U + C treatment the dosage indicated above corresponds to an equimolar combination of the two bile acids.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
Bile Acids for Obese Gallstone Patients
Biliary lipid analysis After a 12-h overnight fast, a sample of gallbladder bile was collected by duodenal intubation. The tube was positioned under fluoroscopic control, and cerulein (0.3 pg/kg body weight; Ceruletide, Farmitalia, Milano, Italy) was injected intramuscularly, to stimulate gallbladder contraction. Concentrated duodenal bile was diluted 1:10 with isopropanol and stored at -20°C. Concentrations of bile acids, phospholipids, and cholesterol in bile were determined by the enzymatic methods of Talalay (lo), Svanborg & Svennerholm (ll),and Roda et al. (12). All biliary lipid analyses were run in triplicate; mean values were calculated from single results and did not differ more than 3%. When variation was greater, the determination was repeated. Biliary lipid composition was expressed both as molar percentage of biliary bile acids, cholesterol, phospholipids and as cholesterol saturation index. This was calculated by using the polynomial equation of Thomas & Hofmann (13) on cholesterol solubility lines described by Hegardt & Dam (14) and Holzbach et al. (15) and was corrected by means of the factor proposed by Carey & KO (16) for UDCA-rich bile. The total bile acid pool was estimated by isotope dilution with the method of Duane et al. (17), with intravenous administration of 10 pCi of ~arboxyl-'~C-cholicacid sodium salt (specific activity, 59 mCi/mmol (The Radiochemical Centre, Amersham, England)) the evening before duodenal intubation. Measurement of total bile acid concentration (BA) and concentration of radioactivity (dpm) in the sample of concentrated duodenal bile enables the calculation of bile acid pool by means of the following equation: Total bile acid pool (mg)/radioactivity administered = BA/dpm. Biliary bile acid composition was analyzed by gas-liquid chromatography (18).
Other laboratory methods Serum alanine aminotransferase, serum aspartate aminotransferase, bilirubin, alkaline phos-
259
phatase, gamma-glutamyl transpeptidase, albumin, fasting plasma cholesterol, and triglycerides were determined by routine laboratory methods. Serum high-density lipoprotein cholesterol was determined after precipitation with heparin manganese (19). Total serum bile acids were determined by radioimmunoassay (Beckton & Dickinson, commercial kit).
Statistical analysis The results were analyzed by analysis of variance; when the general F test gave a significant result @ < 0.05), the statistical significance of the differences between treatments was further analyzed with Scheffe's test for binomial comparison of means (20). RESULTS
Patient compliance and interruption of treatment No patient dropped out of the study. In case 2, the second treatment, corresponding to UDCA, was interrupted after 18 days when the patient developed pneumonia, then restarted after 3 weeks, and continued for the whole period of 2 months. In three patients, cases 4,7, and 11, the dose of CDCA had to be reduced for 4-10 days during the initial period of treatment because of diarrhea. All 12 subjects returned the remaining capsules for counting at the end of each cycle. The number of remaining capsules was always correct for 8 patients, whereas in the other 4 it differed'by -5% to +4%. Biliary lipid composition Biliary bile acid composition was markedly affected by all treatments. CDCA became the predominant bile acid in bile when it was administered alone (range, 75-92%) or in combination (range, 41-60%), mainly at the expense of both cholic acid and deoxycholic acid (Table 11). UDCA ranged from 47% to 64% when given alone and from 22% to 38% when given in combination. Lithocholic acid in bile increased when CDCA was administered alone or in combination. Bile enrichment of litholytic bile acids (CDCA
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
260
M. Zuin et al.
and UDCA) was significantly higher after CDCA given alone or in combination than after UDCA alone (Table 11). Whereas only minor changes were observed in the molar percentages of bile acids and phospholipids, cholesterol content decreased significantly with all three treatments, UDCA and UDCA + CDCA being more effective than CDCA alone (p < 0.05) (Table 111). The cholesterol saturation index decreased markedly after all treatments; no difference was noted between CDCA and UDCA, whereas the combination was significantly 0)< 0.05) more effective than either of the two bile acids given alone (Table 111). No significant changes from basal values were observed in total bile acid pool size during any treatment.
CDCA, 3.6 5 1.8 pmol/l after UDCA, and 3.9 k 1.7 pmol/l after CDCA UDCA. Diarrhea and abdominal discomfort were experienced by four patients soon after starting treatment with CDCA, mild diarrhea by one patient after the combination, and constipation by one patient after UDCA.
+
DISCUSSION
The experimental design of the study enabled us to compare the effects on biliary lipid composition in the same patients of the three treatments, regardless of their sequence of administration. The blinded nature and the objective end points of the study, based on laboratory comparison of active treatments, minimized any possible biases even though placebo was not administered. Our data indicate that in obese gallstone patients the combination of CDCA and UDCA Plasma lipids and tolerability There were no significant changes in plasma induces the conditions considered most favorable triglycerides or total and high-density lipoprotein for gallstone dissolution. In fact, both the comcholesterol after any of the treatments. Serum bination and UDCA were more effective in transaminases increased, up to 2.5 times the nor- decreasing biliary cholesterol content than CDCA mal upper limit, in four patients after CDCA alone, but when the ability to solubilize choltreatment and in one subject after the combi- esterol into micelles was expressed as the satunation; they returned to normal after the end of ration index, the combination was the most the treatment; other liver function indices re- effective treatment, as previously shown in normained normal. mal-weight patients by others and by us (6,7). Serum bile acid levels did not significantly More than 80% of patients had unsaturated bile change during treatment. Their mean values were when receiving the combination, as compared 2.6 2 1.6 pmol/l initially, 3.8 2 1.5 pmol/l after with about one-fourth of patients receiving
Table 11. Phospholipids, total and individual bile acids in bile, and total bile acid pool size (mean and after treatments
CDCA (%) UDCA (%) Cholic acid (%) Deoxycholic acid (%) Lithocholic acid (%) Bile acids (molar %) Phospholipids (molar %) CDCA + UDCA (%) Total bile acid pool size (g)
* p < 0.05 versus values at entry.
t p < 0.05 versus CDCA. $p
< 0.05 versus UDCA.
At entry
CDCA
UDCA
30.7 f 8.2 0.6 2 0.4 36.6 rf: 7.3 28.0 2 8.8 3.9 2 1.4 66.0 t 6.7 22.5 rf: 5.9 31.4 2 8.1 2.55 2 0.86
84.0 f 5.4* 1.4 f 1.1 4.6 f 2.9*$ 3.2 f 2.6' 6.8 & 1.9*$ 66.9 7.2 24.7 f 5.9 85.4 2 4.8*$ 2.96 f 0.84
19.9 4.9*t 55.4 f 6.1*t 12.1 f 3.5* 8.3 2 2.6" 4.2 1.4 68.1 f 7.3 26.0 t 6.9 15.3 2 5.5* 2.51 2 0.96
*
* *
* SD) before
CDCA + UDCA 49.0 rf: 5.6*t$ 32.1 4.7*t$ 8.3 f 3.0* 5.4 f 1.3* 5.9 f 1.3* 69.2 6.6 25.3 2 5.8 81 .O f 3.4*$ 3.07 1.06
* * *
Bile Acids for Obese Gallstone Patients
261
Table 111. Molar percentages of biliary cholesterol and saturation indexes (corrected for percentage UDCA in bile) before and after treatments Saturation indexes
Cholesterol molar % CDCA At entry
L.A. IS.
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
T.G. S.F.
E.C. U.P. C.B. R.S.
M.P. S.A. L.B. V.T. Mean S.D.
11.6 11.1 7.8 16.2 10.2 11.9 12.3 10.8 17.3 10.2 10.4 14.2 12.0 2.7
+
CDCA At
+
CDCA
UDCA
UDCA
entry
CDCA
UDCA
UDCA
8.0 10.9 6.7 9.5 6.2 10.7 8.0 10.0 9.6 5.2 6.8
6.6 4.0 4.1 6.1 5.1 7.2 6.1 7.6 7.6 7.8 3.9 5.5
5.8 4.0 3.2 5.8 4.3 6.9 6.2 6.4 6.6 7.7 4.0 5.1
1.77 1.50 1.47 1.96 1.40 1.74 1.50 1.96 2.11 1.58 1.34 1.72
1.15 1.32 0.96 1.37 0.84 1.30 0.97 1.28 1.22 1.25 0.87 1.03
1.03 0.95 0.74 1.07 0.80 1.47 1.01 1.24 1.27 1.47 1.25 1.06
0.88 0.74 0.55 0.95 0.61 1.08 0.91 0.92 0.93 1.11 0.96 0.90
8.4* 1.9
6.0at 1.5
5S*t 1.4
1.67 0.25
1.13* 0.19
1.11* 0.23
0.17
9.0
0.88*$
* p < 0.05 versus values at entry.
t p < 0.05 versus CDCA. $p
< 0.05 versus CDCA and UDCA given alone.
CDCA or UDCA alone. Furthermore, with CDCA plus UDCA treatment, the two bile acids were present in high concentrations in a desaturated bile, so that both mechanisms of cholesterol solubilization-that is, micellation by CDCA and liquid crystals by UDCA-could act. The effect of CDCA on biliary lipids was similar to that previously reported for obese patients treated with the same dose of 15 mg/kg: CDCA can decrease cholesterol secretion in bile, but not enough to achieve desaturation of bile (1). Only after increasing the dose of CDCA to around 20 mg/kg day, which causes an unacceptable incidence of side effects, did some patients have bile desaturated with cholesterol (21). Only a few data are available on the effect of UDCA on biliary lipids in obese gallstone patients (3,4). In our study 15 mg/kg UDCA induced a 50% reduction of cholesterol content in bile, to an extent similar to that observed in normalweight gallstone patients (22), and it was more effective than the same dose of CDCA. These data are in agreement with those of Roda et al. (3), showing in four patients a more marked decrease in cholesterol secretion after 7.5 mg/kg
UDCA than 12.5 mg/kg CDCA. Nevertheless, in our study, when the lesser ability to solubilize micelles of UDCA-rich bile was taken into account in the calculation of the saturation index, the proportion of patients treated with UDCA who had bile supersaturated with cholesterol was similar to that of patients treated with CDCA. Marked decreases in molar percentage of biliary cholesterol and desaturation of bile could be achieved in the vast majority of our obese patients only by combined administration of CDCA and UDCA, and the effect on biliary cholesterol saturation was only slightly less than that reported in normal-weight patients treated with the same dose (6). Our data do not enable us to explain the reasons why UDCA and CDCA given in combination are more effective also in obese patients, although it might be due to the different and, in many aspects, complementary physicochemical and metabolic properties of the two bile acids (23). The combination of about 7.5 mg/kg of CDCA and 7.5 mg/kg of UDCA was well tolerated; the incidence of side effects was lower than that expected on the basis of previous experience with
Downloaded by [University of California, San Diego] at 08:00 17 March 2016
262
M. Zuin et al.
low doses of CDCA (2), and it was similar to that observed during administration of UDCA alone (22). The slight increase of serum cholesterol level during CDCA shown in the National Cooperative Gallstone Study (2) was not seen in our study either when this bile acid was administered alone or when administered in combination. The different patient populations composed of obese subjects and, especially, the short duration of treatment and the limited number of cases might preclude such a finding. In conclusion, our data suggest that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for obese patients too, for both gallstone dissolution and adjuvant therapy of extracorporeal shock wave lithotripsy. REFERENCES 1. Iser JH, Maton PN, Murphy GM, Dowling RH. Resistance to chenodeoxycholicacid (CDCA) treatment in obese patients with gallstones. Br Med J 1978, 1 , 1509-1512 2. National Cooperative Gallstone Study Group. Chenodiol (chenodeoxycholic acid) for dissolution of gallstones. Ann Intern Med 1981, 95, 257-282 3. Roda E, Mazzella G, Roda A, et al. Effect of chenodeoxycholic and ursodeoxycholic acid administration on biliary lipid secretion in normalweight and gallstone patients. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids and lipids. MTP, Lancaster, U.K., 1981, 189-193 4. Maton PN, Murphy GM, Dowling RH. Lack of response to chenodeoxycholic acid in obese and non-obese patients. Gut 1980, 21, 1082-1086 5. Tint GS, Salen G, Colalillo A, et al. Ursodeoxycholic acid: a safe and effective agent for dissolving cholesterol gallstones. Ann Intern Med 1982, 351-356 6. Stiehl A, Raedsch R, Czygan P, et al. Effects of biliary bile acid composition on biliary cholesterol saturation in gallstone patients treated with chenodeoxycholic acid and/or ursodeoxycholic acid. Gastroenterology 1980, 79, 1192-1198 7. Podda M, Zuin M, Dioguardi ML, Festorazzi S , Dioguardi N. A combination of ursodeoxycholic acid and chenodeoxydholic acid is more effective than either alone in reducing biliary choiesterol saturation. Hepatology 1982, 2, 334-339 8. Podda M, Zuin M, Battezzati PM, Ghezzi C, De Fazio C, Dioguardi ML. Efficacy and safety of a
Received 8 June 1990 Accepted 11 September 1990
combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: a comparison with ursodeoxycholic acid alone. Gastroenterology 1989, 96, 222-229 9. Iser JH, Murphy GM, Dowling RH. Speed of change in biliary lipids and bile acids with chenodeoxycholic acid-Is intermittent therapy feasible? Gut 1977. 18, 7-15 10. Talalay P. Enzymatic analysis of steroid hormones. Anal Biochem 1960, 119-143 11. Svanborg A, Svennerholm M. Plasma total lipid cholesterol, tryglicerides, phospholipids and free fatty acids in healthy Scandinavianpopulation. Acta Med Scand 1961, 169, 4 H 9 12. Roda A, Festi D, Sama C, et al. Enzymatic determination of cholesterol in bile. Clin Chim Acta 1975, 64, 337-341 13. Thomas PJ, Hofmann AF. A simple calculation of the lithogenic index of bile: expressing biliary lipid composition on rectangular coordinates. Gastroenterology 1973, 65, 698-700 14. Hegardt FG, Dam H. The solubility of cholesterol in aqueous solutions of bile salts and lecithin. Z Ernaehrungswiss 1971, 10, 223-233 15. Holzbach RT, Marsh M, Olszewski M, et al. Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 1973, 52, 1467-1479 16. Carey MC, KO G. The importance of total lipid concentration in determining cholesterol solubility in bile and the development of critical tables for calculating ‘percent cholesterol saturation’ with a correction factor for ursodeoxycholate-richbile. In: Paumgartner G, Stiehl A, Gerok W, eds. Biological effects of bile acids. MTP, Lancaster, U.K., 1979, 299-308 17. Duane WC, Adler RD, Bennion LJ, et al. Determination of bile acid pool size in man: a simplified method with advantages of increased precision, shortened analysis time and decreased isotope exposure. J Lipid Res 1975, 16, 155-158 18. Klassen CD. Gas-liquid chromatographic determination of bile acids in bile. Clin Chim Acta 1971, 35,225-229 19. Burstein M, Samaille J. Sur un dosage rapide du cholesterol lit5 aux a- et aux /3-lipoproteines du serum. Clin Chim Acta 1960, 5, 609 20. Snedecor GW, Cochran WC. Statistical methods. 7th ed. Iowa State University Press, Ames, Iowa, 1980 21. Mok HYI, Bell GD, Dowling RH. Effect of different doses of chenodeoxycholic acid on bile-lipid composition. Lancet 1974, 2, 253-257 22. Bachrach WH, Hofmann AF. Ursodeoxycholicacid in the treatment of cholesterol cholelithiasis. Dis Dig Sci 1982, 27, 737-761 23. Tint GS, Salen G, Shefer S . Effect of ursodeoxycholicacid on cholesterol and bile acid metabolism. Gastroenterology 1986, 91, 1007-1018 -
