ABSTRACT
BACKGROUND: Patients with PSC and IBD have a high incidence of colonic carcinomas (CRC), and the annual incidence of CRC increases with duration of disease. UDCA treatment has been suggested to reduce colonic dysplasias and carcinomas. AIMS: The annual incidence of colorectal carcinomas after long-term UDCA treatment was studied. METHODS: Patients included in a prospective study on the outcome after ursodeoxycholic acid (UDCA) treatment were evaluated. RESULTS: A total of 120 of 171 PSC patients included had IBD (108 UC and 12 CD). All patients were treated with UDCA for a median time of 6.7 years. Seven patients with PSC and IBD developed a CRC yielding a prevalence of 5.8%. In years 0-3 (n = 120) after the start of UDCA, the annual incidence rate of CRC was 0.62/100 patient years; in years 3-6 (n = 93) it increased to 1.28 and decreased thereafter in years 6-9 (n = 67) to 1.17, then in years 9-12 (n = 42) to 0 and after >12 years (n = 24) it remained 0. In PSC with IBD, Kaplan-Meier estimate of CRC formation increased with time in the first years of treatment and reached a plateau after 9 years; after treatment for ≥ 9 years, no further CRC were observed. CONCLUSION: After the start of UDCA, the annual incidence of CRC increased up to 6 years and subsequently decreased. In PSC with IBD treated with UDCA, most colonic carcinomas develop in the first years after the start of treatment.
Subject(s)
Cholangitis, Sclerosing/drug therapy , Colorectal Neoplasms/chemically induced , Ursodeoxycholic Acid/adverse effects , Adolescent , Adult , Aged , Child , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/adverse effects , Cholagogues and Choleretics/therapeutic use , Cholangiopancreatography, Endoscopic Retrograde , Cholangitis, Sclerosing/diagnosis , Colonoscopy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/epidemiology , Disease Progression , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Germany/epidemiology , Humans , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Risk Factors , Time Factors , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/therapeutic use , Young AdultABSTRACT
UNLABELLED: Bile salts may initiate or aggravate cholestasis in man. Infusion of Taurochenodeoxycholate (TCDCA) represents a model of bile salt-induced cholestasis in rat. The events leading to cholestasis are incompletely understood. The canalicular conjugate export pump Mrp2 is the major driving force for the bile salt-independent bile flow. Redistribution of Mrp2 has been suggested to cause reduction in bile flow in others models of acute cholestasis (i.e. endotoxin, phalloidin, GSH-depletion). We have studied the effects of TCDCA on the distribution of Mrp2 and P-glycoproteins with respect to changes in the actin cytoskeleton and actin associated proteins radixin and ZO-1. Bile duct cannulated rats were infused with TCDCA (0.1 and 0.4 micromol/min/100g body weight) and bile flow was measured. After 30 min livers were removed and distribution of Mrp2, P-glycoproteins, actin, actin-associated radixin and ZO1 were studied by immunofluorescence analysis. TCDCA at subcholestatic amounts (0.1 micromol/min/100 g body weight) led to distortion and dilation of the canaliculi which was apparent in actin, ZO-1, and Mrp2 fluorescence. Administration of higher amounts of TCDCA (0.4 micromol/min/100g body weight) led to a reduction of bile flow to 31 % of control bile flow. Radixin, which localized strictly to the plasmamembrane in controls, was detected in intracellular structures partially colocalizing with actin aggregates especially at the sinusoidal membranes as visualized by double-immunofluorescence staining. Mrp2 appeared in pericanalicular membrane structures in cholestatic animals whereas P-glycoproteins remained unchanged under these conditions. CONCLUSIONS: Bile salt-induced cholestasis is associated with changes of the actin cytoskeleton and actin binding protein radixin and a retrieval of the canalicular export pump Mrp2.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Actin Cytoskeleton/chemistry , Bile Acids and Salts/chemistry , Cholestasis/chemically induced , Cytoskeletal Proteins/chemistry , Membrane Proteins/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Actin Cytoskeleton/metabolism , Animals , Bile Ducts/pathology , Humans , Male , Microscopy, Fluorescence/methods , Models, Biological , Rats , Rats, Wistar , Time FactorsABSTRACT
In primary sclerosing cholangitis (PSC), biliary enrichment of ursodeoxycholic acid (UDCA) may represent the decisive factor for its presumable beneficial effect. Up to now it is not clear how colitis and colectomy with ileo-anal pouch affect the biliary enrichment of UDCA and the biliary bile acid composition. We determined the biliary bile acid composition in 63 patients with PSC including 7 patients with ileo-anal pouch, 31 patients with colitis, and 25 patients without colitis. No differences existed between patients with and those without colitis. In patients with colectomy and pouch at a UDCA dose of 17.7 +/- 1.6 mg/kg (n = 7), biliary UDCA represented 46.4 +/- 6.7% (mean +/- SD) of total bile acids. An increase in the dose in six pouch patients from 12.5 +/- 0.9 to 22.3 +/- 1.6 mg/kg led to a slight increase in biliary enrichment of UDCA, from 39.8 +/- 8.1 to 49.4 +/- 10.7%. In five of seven patients with ileo-anal pouch, biliary UDCA enrichment was within the normal range, and in two of seven it was permanently or intermittently abnormally low. During UDCA treatment, in pouch patients the biliary content of deoxycholic acid and lithocholic acid was reduced, whereas all other bile acids were unchanged. In a minority of patients with ileo-anal pouch, biliary enrichment of UDCA may be markedly reduced, whereas patients with colitis have a biliary UDCA enrichment not different from that of patient without colitis.
Subject(s)
Cholangitis, Sclerosing/drug therapy , Colitis/diagnosis , Colonic Pouches , Ursodeoxycholic Acid/pharmacokinetics , Ursodeoxycholic Acid/therapeutic use , Adult , Bile Acids and Salts/metabolism , Case-Control Studies , Cholangitis, Sclerosing/diagnosis , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Probability , Reference Values , Risk Assessment , Treatment OutcomeABSTRACT
BACKGROUND: Ursodeoxycholic acid (UDCA) and its taurine conjugate (TUDCA) exert a protective effect in cholestatic liver diseases. A greater hepatoprotective effect of TUDCA has been suggested. Absorption appears to be a limiting factor and up to now has not been studied in man. METHODS: We studied absorption and biliary bile acid secretion and composition after administration of UDCA and TUDCA in patients who had complete extrahepatic biliary obstruction caused by pancreatic carcinoma but had no intestinal or liver disease. After 5 days of intact enterohepatic circulation eight patients with a percutaneous biliary-duodenal drainage received, during two study periods, 1000 mg (1916.9 micromol; mean 29.6 micromol kg(-1)) TUDCA and 750 mg (1910.4 micromol; mean 29.5 micromol kg(-1)) UDCA in random order. Each patient served as his own control. RESULTS: After UDCA and TUDCA administration the biliary UDCA content increased to 55.2% and 54.6% of total bile acids, respectively (not significant). Biliary secretion of cholic and chenodeoxycholic acids remained unchanged whereas that of lithocholic acid increased slightly. A total of 64.6% of the orally administered TUDCA and 55.1% of the UDCA was absorbed (not significant). After TUDCA administration, biliary UDCA was preferentially (95.4%) taurine-conjugated whereas after UDCA administration biliary UDCA was mainly (79.8%) glycine-conjugated. CONCLUSIONS: After oral administration of TUDCA and UDCA, no significant differences in their absorption and in biliary bile acid secretion exist. Whether biliary enrichment with taurine conjugates of UDCA instead of glycine conjugates offers advantages in the treatment of cholestatic liver disease is unclear at present.
