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    • 1. Ursodeoxycholic acid [UDCA] Dr. B. K. Iyer
    • 2. The topics for discussion• Bile acids – background• Ursodil – background• Liver diseases- background• UDCA – details• Indications
    • 3. Bile acids– what?• Bile acids are steroid acids found predominantly in the bile of mammals.• Bile salts are bile acids compounded with a cation, usually sodium.• In the liver, bile acids are made by cytochrome P450-mediated oxidation of cholesterol. They are conjugated with taurine or the amino acid glycine, or with a sulfate or a glucuronide, & are then stored in the gall bladder which concentrates the salts by removing the water
    • 4. Bile acids– why?• An increase in bile flow is exhibited with an increased secretion of bile acids.• The main function of bile acid is to facilitate the formation of micelles, which promotes emulsifying of dietary fats.• Body produces about 800 mg cholesterol / day – Half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily. – About 90% of excreted bile acids are reabsorbed by active transport in the ileum and recycled
    • 5. Bile acids– who?• The 2 primary bile acids In humans: – Cholic acid and chenodeoxycholic acid.• The 2 secondary bile acids found in lower concentrations, [resulting from bacterial action in the intestine] which are absorbed and resecreted by the liver are – Deoxycholic acid and lithocholic acid.• Prior to secretion by the liver, bile acids are conjugated with either the amino acid glycine or taurine.
    • 6. Bile acids– where?• Primary bile acids are produced by the liver and stored in the gall bladder.• When secreted into the colon, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. – The bile acids get absorbed and resecreted by the liver and this is called enterohepatic secretion. Bile acid sequestrants are compounds that bind bile acids and remove them from enterohepatic circulation.• UDCA is also a secondary bile acid.
    • 7. UDCA – what?• UDCA means Ursodiol or Ursodeoxycholic acid is Ursodeoxycholic acid 1 is the 7[beta]-hydroxy epimer of chenodeoxycholic acid and is normally present in as a very small proportion (up to 5 mol %) of the total biliary bile acids.• Oral administration of pharmacological doses increases this fraction in a dose-related manner, and UDCA may become the major biliary bile acid (usually to 40 to 50 mol %).
    • 8. UDCA – where?• UDCA is metabolized by intestinal bacteriae to lithocholic acid which does not accumulate in the circulating bile acids because of efficient hepatic sulfation.• UDCA dosing causes – ↓ cholesterol absorption, – ↑ bile acid biosynthesis, and – ↓ biliary cholesterol secretion.
    • 9. UDCA – why?• UDCA is a choleretic agent, as all bile acids, but differs from other dihydroxy–bile acids in being non-cytotoxic – Because it has less affinity for membranes, and when present at micellar concentrations does not solubilize membranes. – Chronic administration of UDCA appears to increase canalicular transport.
    • 10. UDCA – how?• UDCA is being increasingly used for treatment of cholestatic liver diseases.• Experimental evidence suggests 3 major mechanisms of action for UDCA: 1. Protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, 2. Stimulation of hepatobiliary secretion, 3. Protection of hepatocytes against bile acid-induced apoptosis, 4. Also used to dissolve certain types of gallstones as well as to prevent gallstones from forming in obese patients who are losing weight rapidly.
    • 11. UDCA – side effects• Well tolerated, with diarrhoea [2%] occurring in only a very small proportion of patients.• Liver function tests do not show any clear trend towards abnormally increased values, and indeed many studies show a slight decrease in transaminase serum concentrations• Relatively free of effects on intestinal function or morphology compared to often troublesome intestinal secretagogic effects seen with chenodeoxycholic acid.
    • 12. UDCA – Dosage• For gallbladder cholesterol gallstones dissolution the current recommended dosage is 450 or 600 mg/day in divided doses with meals,• Published studies suggest that 8 to 10 mg / kg / day provides an accurate estimate of optimum dosage, with some evidence suggesting that a single night-time dosage may be suitable.• Cholecystography or ultrasonography, carried out at 6 months, provides a means of monitoring success or failure of therapy.
    • 13. UDCA – gall bladder stone• UDCA at pharmacological doses markedly decreases biliary cholesterol saturation.• Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with UDCA in studies of 6 months duration.• Patients showing partial gallstone dissolution are likely to continue improving possibly to complete gallstone dissolution with continued therapy.
    • 14. UDCA – gall bladder stone• Success rates with UDCA may be increased to about 80% if we include only those with non- calcified floating cholesterol stones of less than 10 to 15mm diameter.• Those with calcified stones or stones greater than 15mm diameter are unlikely to respond to UDCA therapy.
    • 15. UDCA – pharmacokinetics• Reach maximum concentrations at about 60 minutes after ingestion, with another peak recorded at 3 hours.
    • 16. NASH• Nonalcoholic steatohepatitis (NASH) is a reasonably well-defined clinicopathological entity; – More common in women than in men or children – most closely associated with obesity, diabetes mellitus and related abnormalities, such as hyperlipidaemia and hyperglycaemia. – Spans a wide spectrum of presentation • uncomplicated, clinically non-progressive fatty liver → slowly progressive fatty liver with inflammation & fibrosis → steatohepatitis with submassive hepatic necrosis.
    • 17. NASH• Non-progressive fatty liver appears to be common and is of little clinical importance but slowly progressive. – Patients may present with cirrhosis and even HCC arising from steatohepatitic cirrhosis.• Avoidance of fast weight loss & careful control of diabetes are important parts of management.• Therapy of established steatohepatitic cirrhosis does not differ substantially from that of other types of cirrhosis.
    • 18. NASH• Most commonly, patients diagnosed with NASH present with abnormal enzyme levels identified during the course of routine screening.• At times, it is recognized following some drug induced hepato-toxicity that may or may not have anything to do with the observed condition• Some patients with NASH present with fatigue and vague right upper quadrant pain. – No laboratory studies are characteristic of NASH except the histological liver biopsy examination by experienced pathologist
    • 19. Hepatobiliary complications – Role of UDCA in various diseases Cholestatic Liver diseases Protection of Protection Stimulation of cholangiocytes of hepatobiliary against cytotoxicity hepatocytes secretion Primary Primary Hepatitis Non Intrahepatic Dissolve Sclerosing Biliary C alcoholic cholestasis of certain Cholangitis Cirrhosis Steatosis pregnancy types of gallstones• In primary biliary cirrhosis, UDCA improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival.• In primary sclerosing cholangitis, UDCA improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated.• Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis.
    • 20. Colombo et al, Sem Liv Dis 1998
    • 21. Bile acid treatment of gallstone disease - Historical Aspects -1873 M Schiff Suggestion to treat gallstone L‘Imparziale disease with bile acids 1873;13:971876 WC Dabney Treatment of gallstone disease Am J Med Sci with bile acids 1876;71:4101937 AG Rewbridge The disappearance of gallstone Surgery shadows following the prolonged 1937;1:395 administration of bile salts1972 RG Danzinger Dissolution of cholesterol N Engl J Med et al. gallstones by chenodeoxycholic 1972;286:1 acid1975 I Makino et al Dissolution of cholesterol Jpn J gallstones by ursodeoxycholic Gastroenterol acid 1974;72:690
    • 22. Ursodeoxycholic acid in gallstone disease - Therapeutic Use  Which patient ?  Which stone ?  Which problems ?
    • 23. Stages of Gallstone DiseaseAsymptomatic 18.5 % in women, 9.5 % in men * * Attili et al., Am J Epidemiol 1995;141:158
    • 24. Stages of Gallstone DiseaseAsymptomatic 18.5 % in women, 9.5 % in men * ~20 %Symptomatic Abdominal pain in the epigastrium or RUQ lasting for > 15 min ** * Attili et al., Am J Epidemiol 1995;141:158
    • 25. Stages of Gallstone Disease Asymptomatic 18.5 % in women, 9.5 % in men * ~20 % Symptomatic Abdominal pain in the epigastrium or RUQ lasting for 1-2 % per year > 15 min ** Complicated Acute cholecystitis, choledocho-lithiasis, pancreatitis, gallbladder cancer, gallstone ileus* Attili et al., Am J Epidemiol 1995;141:158** GREPCO, Dig Dis Sci 1987;32:349
    • 26. Management of Gallstone Disease Asymptomatic No treatment (except stones > 3 cm, porcelain gallbladder) Symptomatic Laparoscopic (or open) cholecystectomy or Nonsurgical treatment Complicated Acute intervention
    • 27. Ursodeoxycholic Acid in Gallstone Disease - - Therapeutic Use -  Which patient ?  Which stone ?  Which problems ?
    • 28. GallstonesAnatom. Museum Friedrich August Walter, Belitz & Braun,Berlin 1796
    • 29. Cholesterol Gallstone Rettenmaier
    • 30. Pathogenesis of Cholesterol Gallstone Disease Super- Rapid saturation nucleation of bile Gallbladder hypomotility
    • 31. Effect of Bile Acid Therapy on Bile Lithogenicity Before After 8 weeks of p UDCA UDCACholesterol (mmol/L) 11.1 ± 2.1 5.8 ± 2.4 0.001Phospholipids (mmol/L) 24.6 ± 9.2 29.4 ± 7.9 NSBile salts (mmol/L) 119.1 ± 37.7 118.5 ± 36.2 NSCholesterol Saturation Index 1.42 ± 0.42 0.62 ± 0.19 0.001 Sharma et al., Gastroenterology 1998; 115: 124
    • 32. Effects of UDCA on Cholesterol Gallstone Disease Super- Rapid saturation nucleation of bile Gallbladder hypomotility
    • 33. Effect of UDCA on Bile Lithogenicity Before After 8 weeks of p UDCA UDCANucleation time (days) 8.5 ± 1.5 19.0 ± 1.7 0.001 Sharma et al., Gastroenterology 1998; 115: 124
    • 34. Effects of UDCA on Cholesterol Gallstone Disease Super- Rapid saturation nucleation of bile Gallbladder hypomotility
    • 35. Effect of UDCA on Gallbladder Muscle Contractility After 4 weeks of UDCA After 4 weeks of Placebo Guarino et al., Gut 2007;56:815
    • 36. Effects of UDCA on Cholesterol Gallstone Disease Super- Rapid saturation nucleation of bile Gallbladder hypomotility
    • 37. Ursodeoxycholic Acid in Gallstone Disease - Therapeutic Use -  Which patient ?  Which stone ?  Which problems ?
    • 38. Kinetics of in vitro Gallstone Dissolution by UDCA 24 4000 20 16 3000 Diameter Diameter 12 Weight [mm] 2000 [mg] 8 1000 4 Weight % 0 0 0 4 8 12 16 20 Treatment time [month] Senior et al., Gastroenterology 1990;99:249
    • 39. Gallstone Recurrence after Bile Acid Dissolution Therapy 100 80 % 60RECURRENCE RATE 40 20 0 0 2 4 6 8 10 12 TIME FROM DISSOLUTION (yr) 98 83 78 69 62 53 46 36 28 22 12 2 Subjects at risk Villanova et al., Gastroenterology 1989;97:727
    • 40. Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy Stage of disease: symptomatic Stone: < 5mm (optimal), 6-10 mm (acceptable) radiolucent (CT: iso-/hypodense tobile) Gallbladder: patency of cystic duct andemptying after test meal(ultrasound) Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107
    • 41. Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy Stage of disease: symptomatic Stone: < 5mm (optimal), 6-10 mm (acceptable) radiolucent (CT: iso-/hypodense tobile) Gallbladder: patency of cystic duct andemptying after test meal(ultrasound) Patients with gallstone disease Optimal qualified for UDCA treatment 3% Acceptable 12% Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107
    • 42. Ursodeoxycholic Acid in Gallstone Disease - Prophylactic Use -Protection against:  Biliary colic ?  Stone formation ?
    • 43. Ursodeoxycholic Acid Reduces Long-term Risk of Biliary Colic in Gallstone Disease 100 A : P<0.001 A: symptomatic, no therapy : P<0.05 80 B: symptomatic, UDCA Cumulative BProbability ofBiliary Colic 60 (%) 40 C C: asymptomatic, no 20 therapy D 0 D: asymptomatic, UDCA 0 6 12 18 Time (years) Patients at risk A 112 61 19 7 4 1 0 0 0 B 74 57 40 3 28 13 7 3 1 C 234 227 178 1545 141 74 18 3 1 D 107 105 71 58 48 17 7 2 1 Tomida et al., Hepatology
    • 44. Ursodeoxycholic Acid Does not Reduce Short-term Risk of Biliary Colic in Gallstone Disease Venneman et al., Hepatology 2006;43:1276
    • 45. Ursodeoxycholic Acid in Gallstone Disease - Prophylactic Use -Protection against:  Biliary colic ?  Stone formation ?
    • 46. Strong Risk Factors for Gallstone Formation  Rapid weight loss  Total parenteral nutrition  Somatostatin / octreotide treatment
    • 47. Ursodeoxycholic Acid Protects against GallstoneFormation during Diet-Induced Rapid Weight Loss 35 40 134 Men 30 17 Women 68 25 20 % of Patients 15 11 5 10 4 122 65 63 4 5 2 130 0 136 70 0 Placebo 300 600 1200 UDCA Dose (mg/day) Shiffman et al., Ann Intern Med 1995;122:902
    • 48. Ursodeoxycholic Acid Protects against Gallstone Formation after Bariatric Surgery - Meta-analysis - Gallstone formation after bariatric surgery (n=521) UDCA 8.8 % Placebo 27.7 % Relative risk (RRUDCA) 0.43 (0.22-0.83) Uy et al., Obes Surgery 2008;18:1532
    • 49. Gewichtsreductie en cholecystolithiasis - NVVH Richtlijn 2007 - Elke vorm van gewichtsreductie van meer dan 1.5kg / w bij patienten zwaarder dan 100 kg en / of <7-10 g vet/d leidt tot een sterk verhoogde kans opgalsteenvorming 600 mg / d UDCA is een adequate beschermingMijnhout et al. NTvG 2004;148:174Miller et al. Ann Surg 2003;238:697 Niveau 2aWeinzier et al. Am J Med 1995;98:115
    • 50. Prophylactic Use of Ursodeoxycholic Acid to Prevent Gallstone Formation  Rapid weight loss  Gene defects causing gallstone formation Rosmorduc et al., Gastroenterology 2001;120:1459  MDR 3 / ABCB4 deficiency EASL Clinical Practice Guidelines, J Hepatol 2009;51:237  Cholesterol 7α-hydroxylase deficiency Pullinger et al., J Clin Invest 2002;110:109
    • 51. Mechanisms of action of UDCA in cholestatic liver diseases• Replacement/displacement of toxic endogenous bile acids• Cytoprotective and antiapoptotic effects• Immunomodulatory effect• Increase in bile secretion: – stimulation of exocytosis and insertion of canalicular membrane transporters – stimulation of defective gene expression downregulated in cholestasis – bicarbonate-rich hypercholeresis
    • 52. UDCA for liver diseaseEffect on Characteristics Evidence obtained fromLiver biochemistry consistently improved RCT *Quantitative liver function improvement not pilot studies consistently maintainedBiliary drainage often normalized pilot studiesLiver histology ⇓ bile duct proliferation, RCT * inflammation, fibrosisFat absorption no effect RCT *Nutritional status improvement in severely pilot studies malnourished patientsEssential fatty acid (EFA) improvement in EFA RCT *Status deficiencyNeed for transplantation not determined -mortality
    • 53. Liver disease, before & after UDCA
    • 54. Primary Sclerosing Cholangitis• Chronic progressive cholestatic liver disease• Median survival between 12 and 18yrs• Biliary Stricturing• Cholangitis• Cholangiocarcinoma prevalence 6-20% incidence 1-5% / year Martin et al Ann Surg 1990, Ponsioen et al Gut 2002, Boberg et al Scand J Gastro 2002
    • 55. PSC CirrhosisExpanded Portal Tracts (Blue)
    • 56. IBD and PSC• 2-10% of IBD patients will develop PSC• ~ 70% of PSC patients have evidence of IBD
    • 57. Pathogenesis of PSC• Multifactorial/ Complex• Cellular immunity• Autoimmunity?• Bacterial Antigens• Aberrant Lymphocyte Homing• Cytokines
    • 58. Diagnosis of PSC• Most diagnoses are made after the discovery of abnormal LFT’s at IBD FU• Cholestatic LFT’s (normal or fluctuating)• Atypical p-ANCA -in 33-88%• Abnormal MRCP or ERCP• Liver Biopsy
    • 59. Small Duct PSC• Subgroup of PSC• Normal ERCP/MRCP• Typical histological changes• Benign course- only 12 % progress to classical PSC• No reports of CholangioCa• Similar rates of IBD (? CD>UC)
    • 60. UDCA in PSC• Widely used in cholestatic liver disease• Hydophilic• Mechanisms of action unclear• Hydrophobic bile acids are toxic• Probably not a detergent effect• May cause damage by Fas-mediated apoptosis
    • 61. UDCA – Mechanism’s of Action• Displaces hydrophobic bile acids• Choleretic effect• Small amounts normally present• 80% absorbed through small bowel• Reduced bioavailability in cholestasis BSEP NTCP TAU Canniliculus UDCA UDCA GLY OATP Hepatocyte Portal Blood
    • 62. UDCA – Mechanism’s of Action
    • 63. Trials of UDCA in PSC• Limited good quality trials• Small numbers• Short follow up
    • 64. Summary of trials of UDCA in PSC Cullen S APT 2005