Saturday 24 URSODEOXYCHOLIC ACID TREATMENT OF GALLSTONES*
Dose-response Study and Possible Mechanism of Action P. N. MATON G. M. MURPHY R. H. DOWLING
Gastroenterology Unit, Guy’s Hospital and Medical School, London SE1 9RT
To determine the optimum dose for the medical treatment of gallstones with ursodeoxycholic acid (U.D.C.A.), 11 non-obese patients with radiolucent gallstones were given 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-1 day-1 for 6 weeks each. Apart from 3 patients who required surgery for gallstone
Summary
complications, treatment was well tolerated, and both dyspeptic symptoms and frequency of biliary colic were reduced. Neither diarrhœa nor hypertransaminasæmia occurred during therapy. Of 3 patients completing 6 months’ treatment with an average of 8 mg U.D.C.A. kg-1 day-1, 1 showed complete and 2 partial dissolution of gallstones. There were significant correlations between the biliary cholesterol-saturation index and (i) daily dose of U.D.C.A. in mg kg-1, (ii) percentage U.D.C.A., and (iii) percentage U.D.C.A. + chenodeoxycholic acid (C.D.C.A.) in biliary bile acids. Mean &ggr;-glutamyl transpeptidase fell significantly during treatment, whereas other liver-function tests and hepatic histology remained normal. Mean serum-cholesterol levels did not change, and although there was a 13-35% fall in fasting serum-triglycerides, this difference was not statistically significant. U.D.C.A., like C.D.C.A., seems to act by inhibiting hepatic cholesterogenesis. In 5 patients treated with 5 mg U.D.C.A. kg-1 day-1 for 1-6 months, mean hepatic hydroxymethylglutaryl-coenzyme-A-reductase activity was 28% lower than in untreated gallstone patients. These preliminary results suggest that U.D.C.A. is as effective as C.D.C.A. in ½—2/3 the dose and that 10 mg U.D.C.A. kg-1 day-1 should be effective in most gallstone patients.
an
effective
treat-
for
dissolving cholesterol gallstones, *’* acts by lowering biliary cholesterol secretion,9.10 probably by reducing the activity of the enzyme controlling hepatic ment
*Presented in part
ber,
1977
at
the Medical Research Society meeting, DecemG. M., Dowling, R. H. Clin. Sci.
(Maton, P. N., Murphy, mol. Med. 1978, 54, 32 abstr.).
31 December 1977
cholesterol synthesis-hydroxymethyl-glutaryl-coenzyme-A reductase (H.M.G.CoAR.).11.12 However, with this treatment stones may take up to 2 years to dissolve. C.D.C.A. causes dose-related diarrhoea’3 and hypertransaminasaemia,14.1S and although liver histology is not affected,IS-17 the hepatotoxic metabolite of C.D.C.A., lithocholic acid, accumulates in bile during chenotherapy.18 For all these reasons, ever since c.D.c.A. was introduced a search has been made for alternative gallstone-dissolving agents. The most promising is ursodeoxycholic acid (U.D.C.A.), which is structurally related to C.D.C.A. Studies from Japan suggest that u.D.c.A. produces unsaturated bile in smaller doses than C.D.C.A.19 It dissolves gallstones faster and lowers fasting serum-triglyceride levels more effectively without producing either diarrhoea or hypertransaminasaemia.19 To date, however, information about u.D.c.A. is limited, and until now there has been no formal U.D.C.A. dose-response study. We therefore examined the effects of 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-1 day 1 on bile-lipid and bile-acid composition in 11 gallstone patients. We monitored liver-function tests and fasting serum-lipids, noted the frequency of symptoms and side-effects of treatment, and in 3 patients recorded either partial or complete gallstone dissolution. We also measured the effect of 1-6 months of U.D.C.A. treatment on H.M.G.COAR. activity in operative liver-biopsy material from 5
patients undergoing cholecystectomy. Patients and Methods Patients 6 We studied 10 women and 1 man (mean age 44 +S.E.m. 4.6 ideal years, range 29-79), all of whom were non-obese (< 120% body-weight), since obese patients are known to respond poorly to C.D.C.A.20 All had radiolucent gallstones in a "functioning" gallbladder-i.e., one which opacifies well during oral cholecystography and contracts after a fatty meal. All patients (including those who had operative liver biopsies) gave their
informed consent.
Study Design
Introduction
CHENODEOXYCHOLic acid (C.D.C.A.),
&
Dose-response study.-Patients were given V.D.C.A. in 125 mg capsules in doses of approximately 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-’ day-’, each dose being given for 6 weeks. Samples of bile-rich fluid aspirated from the duodenum after an overnight fast and after 100 units of intravenous cholecystokinin (Boots ’Pancreozymin’) were collected before and after the 6-week treatment period on each dose. They were stored at -20°C until analysed for bile-lipid and bile-acid composition. 8052/3 ©-The
Lancet Ltd, 1977
1298
(MEANS
TABLE I-FASTING SERUM-LIPIDS AND LIVER-FUNCTION TESTS MG. AND 15 MG U.D.C.A.
for on-treatment values compared with controls. *=p
Dose-response Study and Possible Mechanism of Action P. N. MATON G. M. MURPHY R. H. DOWLING
Gastroenterology Unit, Guy’s Hospital and Medical School, London SE1 9RT
To determine the optimum dose for the medical treatment of gallstones with ursodeoxycholic acid (U.D.C.A.), 11 non-obese patients with radiolucent gallstones were given 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-1 day-1 for 6 weeks each. Apart from 3 patients who required surgery for gallstone
Summary
complications, treatment was well tolerated, and both dyspeptic symptoms and frequency of biliary colic were reduced. Neither diarrhœa nor hypertransaminasæmia occurred during therapy. Of 3 patients completing 6 months’ treatment with an average of 8 mg U.D.C.A. kg-1 day-1, 1 showed complete and 2 partial dissolution of gallstones. There were significant correlations between the biliary cholesterol-saturation index and (i) daily dose of U.D.C.A. in mg kg-1, (ii) percentage U.D.C.A., and (iii) percentage U.D.C.A. + chenodeoxycholic acid (C.D.C.A.) in biliary bile acids. Mean &ggr;-glutamyl transpeptidase fell significantly during treatment, whereas other liver-function tests and hepatic histology remained normal. Mean serum-cholesterol levels did not change, and although there was a 13-35% fall in fasting serum-triglycerides, this difference was not statistically significant. U.D.C.A., like C.D.C.A., seems to act by inhibiting hepatic cholesterogenesis. In 5 patients treated with 5 mg U.D.C.A. kg-1 day-1 for 1-6 months, mean hepatic hydroxymethylglutaryl-coenzyme-A-reductase activity was 28% lower than in untreated gallstone patients. These preliminary results suggest that U.D.C.A. is as effective as C.D.C.A. in ½—2/3 the dose and that 10 mg U.D.C.A. kg-1 day-1 should be effective in most gallstone patients.
an
effective
treat-
for
dissolving cholesterol gallstones, *’* acts by lowering biliary cholesterol secretion,9.10 probably by reducing the activity of the enzyme controlling hepatic ment
*Presented in part
ber,
1977
at
the Medical Research Society meeting, DecemG. M., Dowling, R. H. Clin. Sci.
(Maton, P. N., Murphy, mol. Med. 1978, 54, 32 abstr.).
31 December 1977
cholesterol synthesis-hydroxymethyl-glutaryl-coenzyme-A reductase (H.M.G.CoAR.).11.12 However, with this treatment stones may take up to 2 years to dissolve. C.D.C.A. causes dose-related diarrhoea’3 and hypertransaminasaemia,14.1S and although liver histology is not affected,IS-17 the hepatotoxic metabolite of C.D.C.A., lithocholic acid, accumulates in bile during chenotherapy.18 For all these reasons, ever since c.D.c.A. was introduced a search has been made for alternative gallstone-dissolving agents. The most promising is ursodeoxycholic acid (U.D.C.A.), which is structurally related to C.D.C.A. Studies from Japan suggest that u.D.c.A. produces unsaturated bile in smaller doses than C.D.C.A.19 It dissolves gallstones faster and lowers fasting serum-triglyceride levels more effectively without producing either diarrhoea or hypertransaminasaemia.19 To date, however, information about u.D.c.A. is limited, and until now there has been no formal U.D.C.A. dose-response study. We therefore examined the effects of 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-1 day 1 on bile-lipid and bile-acid composition in 11 gallstone patients. We monitored liver-function tests and fasting serum-lipids, noted the frequency of symptoms and side-effects of treatment, and in 3 patients recorded either partial or complete gallstone dissolution. We also measured the effect of 1-6 months of U.D.C.A. treatment on H.M.G.COAR. activity in operative liver-biopsy material from 5
patients undergoing cholecystectomy. Patients and Methods Patients 6 We studied 10 women and 1 man (mean age 44 +S.E.m. 4.6 ideal years, range 29-79), all of whom were non-obese (< 120% body-weight), since obese patients are known to respond poorly to C.D.C.A.20 All had radiolucent gallstones in a "functioning" gallbladder-i.e., one which opacifies well during oral cholecystography and contracts after a fatty meal. All patients (including those who had operative liver biopsies) gave their
informed consent.
Study Design
Introduction
CHENODEOXYCHOLic acid (C.D.C.A.),
&
Dose-response study.-Patients were given V.D.C.A. in 125 mg capsules in doses of approximately 5 mg, 10 mg, and 15 mg U.D.C.A. kg body-weight-’ day-’, each dose being given for 6 weeks. Samples of bile-rich fluid aspirated from the duodenum after an overnight fast and after 100 units of intravenous cholecystokinin (Boots ’Pancreozymin’) were collected before and after the 6-week treatment period on each dose. They were stored at -20°C until analysed for bile-lipid and bile-acid composition. 8052/3 ©-The
Lancet Ltd, 1977
1298
(MEANS
TABLE I-FASTING SERUM-LIPIDS AND LIVER-FUNCTION TESTS MG. AND 15 MG U.D.C.A.
for on-treatment values compared with controls. *=p
