Optimum dose of ursodeoxycholic acid in primary biliary cirrhosis.
BACKGROUND
Ursodeoxycholic acid (UDCA) improves liver function tests and prolongs survival in primary biliary cirrhosis (PBC). The dose of 10- 15 mg/kg/day used in the large trials has largely been based on that used for gallstone dissolution. The only dose-response study of UDCA in PBC suggested that a dose of 8 mg/kg/day was the most efficacious. However, disease stage of the patients was not known, higher doses of UDCA were not tried and there was no 'washout period' between the different doses. The aim of this study was to determine the optimum dose of UDCA in early-stage PBC (stage 1 and 2).


METHODS
Twenty-four biopsy-proven early-stage PBC patients (one male, 23 female) received five doses of UDCA (0, 300, 600, 900, 1200 mg/day) each for 8 weeks with 4-week washout periods between doses. Symptoms (pruritus, fatigue, diarrhoea) were assessed on a four-point scale (none, mild, moderate, severe). Liver function tests (LFTs) were performed using conventional methods, and serum bile acids were measured using gas liquid chromatography.


RESULTS
The dose of 900 mg/day produced the greatest enrichment of UDCA in serum bile acids; although there was no difference in the enrichment of UDCA between the different doses. There was a trend towards normalization of the abnormal LFTs in a dose-dependent manner (for y-glutamyl transferase (yGT), alkaline phosphatase (ALP), alanine transaminase (ALT) and IgM). Multi-factorial analysis showed that UDCA treatment, irrespective of dose, was significantly better than placebo for all the variables. The 900 and 1200 mg doses were better than both 300 and 600 mg using yGT and total bilirubin as variables, better than 300 mg using ALP and IgM as variables, and better than 600 mg using albumin as a variable. No variables showed a significant difference between 900 and 1200 mg.


CONCLUSIONS
The optimum dose of UDCA is 900 mg/day (equivalent to 13.5 mg/kg/day).
Verma
A
A
Division of Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK.
Jazrawi
R P
RP
Ahmed
H A
HA
Davis
T
T
Bland
J M
JM
Benson
M
M
Orchard
R T
RT
Theodossi
A
A
Maxwell
J D
JD
Northfield
T C
TC
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D002756:Cholagogues and Choleretics / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000188:drug therapy*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D007075:Immunoglobulin M; D014580:Ursodeoxycholic Acid; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase