Ursodeoxycholzuur bij Galsteenlijden

1. Ursodeoxycholzuur bij Galsteenlijden Delft, 26.1.2010 U. Beuers Afdeling Maag-, Darm- en Leverziekten Academisch Medisch Centrum Universiteit van Amsterdam

2. Bile Acid Treatment of Gallstone Disease - Historical Aspects - 1873 M Schiff Suggestion to treat gallstone disease with bile acids 1876 WC Dabney Treatment of gallstone disease with bile acids 1937 AG Rewbridge “The disappearance of gallstone shadows following the prolonged administration of bile salts“ 1972 RG Danzinger et al. Dissolution of cholesterol gallstones by chenodeoxycholic acid 1975 I Makino et al. Dissolution of cholesterol gallstones by ursodeoxycholic acid L‘Imparziale 1873;13:97 Am J Med Sci 1876;71:410 Surgery 1937;1:395 N Engl J Med 1972;286:1 Jpn J Gastroenterol 1974;72:690

3. Ursodeoxycholic Acid in Gallstone Disease - Therapeutic Use - • Which patient ? • Which stone ? • Which problems ?

4. Stages of Gallstone Disease Asymptomatic 18.5 % in women, 9.5 % in men * * Attili et al., Am J Epidemiol 1995;141:158

5. Stages of Gallstone Disease Asymptomatic Symptomatic 18.5 % in women, 9.5 % in men * ~20 % Abdominal pain in the epigastrium or RUQ lasting for > 15 min ** * Attili et al., Am J Epidemiol 1995;141:158 ** GREPCO, Dig Dis Sci 1987;32:349

6. Stages of Gallstone Disease Asymptomatic Symptomatic Complicated 18.5 % in women, 9.5 % in men * ~20 % Abdominal pain in the epigastrium or RUQ lasting for > 15 min ** 1-2 % per year 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

7. Management of Gallstone Disease Asymptomatic Symptomatic Complicated No treatment (except stones > 3 cm, porcelain gallbladder)

8. Management of Gallstone Disease Asymptomatic Symptomatic Complicated No treatment (except stones > 3 cm, porcelain gallbladder) Laparoscopic (or open) cholecystectomy or Nonsurgical treatment

9. Management of Gallstone Disease Asymptomatic Symptomatic Complicated No treatment (except stones > 3 cm, porcelain gallbladder) Laparoscopic(or open) cholecystectomy or Nonsurgical treatment Acute intervention

10. Ursodeoxycholic Acid in Gallstone Disease - Therapeutic Use - • Which patient ? • Which stone ? • Which problems ?

11. Gallstones Anatom. Museum Friedrich August Walter, Berlin Belitz & Braun, 1796

12. Cholesterol Gallstone Rettenmaier

13. Pathogenesis of Cholesterol Gallstone Disease Super- saturation of bile Rapid nucleation Gallbladder hypomotility

14. Effect of Bile Acid Therapy on Bile Lithogenicity Before UDCA After 8 weeks of UDCA p 11.1 ± 2.1 5.8 ± 2.4 Cholesterol (mmol/L) 0.001 Phospholipids (mmol/L) 24.6 ± 9.2 29.4 ± 7.9 NS 119.1 ± 37.7 118.5 ± 36.2 NS Bile salts (mmol/L) Cholesterol Saturation Index 1.42 ± 0.42 0.62 ± 0.19 0.001 Sharma et al., Gastroenterology 1998; 115: 124

15. Effects of UDCA on Cholesterol Gallstone Disease Super- saturation of bile Rapid nucleation Gallbladder hypomotility

16. Effect of UDCA on Bile Lithogenicity Before UDCA After 8 weeks of UDCA p Nucleation time (days) 8.5 ± 1.5 19.0 ± 1.7 0.001 Sharma et al., Gastroenterology 1998; 115: 124

17. Effects of UDCA on Cholesterol Gallstone Disease Super- saturation of bile Rapid nucleation Gallbladder hypomotility

18. Effect of UDCA on Gallbladder Muscle Contractility After 4 weeks of UDCA After 4 weeks of Placebo Guarino et al., Gut 2007;56:815

19. Effects of UDCA on Cholesterol Gallstone Disease Super- saturation of bile Rapid nucleation Gallbladder hypomotility

20. Ursodeoxycholic Acid in Gallstone Disease - Therapeutic Use - • Which patient ? • Which stone ? • Which problems ?

21. 24 4000 20 16 3000 12 2000 8 1000 4 0 0 0 4 8 12 16 20 Kinetics of in vitro Gallstone Dissolution by UDCA Diameter Diameter [mm] Weight [mg] Weight % Treatment time [month] Senior et al., Gastroenterology 1990;99:249

22. 98 83 78 69 62 53 46 36 28 22 2 12 Subjects at risk Gallstone Recurrence after Bile Acid Dissolution Therapy 100 80 60 % RECURRENCE RATE 40 20 0 0 2 4 6 8 10 12 TIME FROM DISSOLUTION (yr) Villanova et al., Gastroenterology 1989;97:727

23. Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy • Stage of disease:symptomatic • Stone:< 5mm (optimal), 6-10 mm (acceptable) radiolucent (CT: iso-/hypodense to bile) • Gallbladder: patency of cystic duct and emptying after test meal (ultrasound) Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107

24. Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy • Stage of disease:symptomatic • Stone:< 5mm (optimal), 6-10 mm (acceptable) radiolucent (CT: iso-/hypodense to bile) • Gallbladder: patency of cystic duct and emptying after test meal (ultrasound) Patients with gallstone disease qualified for UDCA treatment Optimal 3% Acceptable 12% Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107

25. Ursodeoxycholic Acid in Gallstone Disease - Prophylactic Use - Protection against: • Biliary colic ? • Stone formation ?

26. Ursodeoxycholic Acid Reduces Long-term Risk of Biliary Colic in Gallstone Disease Patients at risk A 112 61 19 7 4 1 0 0 0 74 57 40 35 28 13 7 3 1 B 234 227 178 154 141 74 18 3 1 C D 107 105 71 58 48 17 7 2 1 100 A : P<0.001 A: symptomatic, no therapy B: symptomatic,UDCA C: asymptomatic, no therapy D: asymptomatic, UDCA : P<0.05 80 Cumulative Probability of Biliary Colic (%) B 60 40 C 20 D 0 0 6 12 18 Time (years) Tomida et al., Hepatology 1999;30: 9

27. Ursodeoxycholic Acid Does not Reduce Short-term Risk of Biliary Colic in Gallstone Disease Venneman et al., Hepatology 2006;43:1276

28. Ursodeoxycholic Acid in Gallstone Disease - Prophylactic Use - Protection against: • Biliary colic ? • Stone formation ?

29. Strong Risk Factors for Gallstone Formation • Rapid weight loss • Total parenteral nutrition • Somatostatin / octreotide treatment

30. Men Women 17 68 40 11 5 0 4 2 4 134 130 136 122 70 63 65 Ursodeoxycholic Acid Protects against Gallstone Formation during Diet-Induced Rapid Weight Loss 35 30 25 20 % of Patients 15 10 5 0 Placebo 300 600 1200 UDCA Dose (mg/day) Shiffman et al., Ann Intern Med 1995;122:902

31. 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

32. Gewichtsreductie en cholecystolithiasis - NVVHRichtlijn 2007 - • Elke vorm van gewichtsreductie van meer dan 1.5 kg / w bij patienten zwaarder dan 100 kg en / of < 7-10 g vet/d leidt tot een sterk verhoogde kans op galsteenvorming • 600 mg / d UDCA is een adequate bescherming Mijnhout et al. NTvG 2004;148:174 Miller et al. Ann Surg 2003;238:697 Weinzier et al. Am J Med 1995;98:115 Niveau 2a

33. Prophylactic Use of Ursodeoxycholic Acid to Prevent Gallstone Formation • Rapid weight loss • Gene defects causing gallstone formation • MDR 3 / ABCB4 deficiency • Cholesterol 7a-hydroxylase deficiency Rosmorduc et al., Gastroenterology 2001;120:1459 EASL Clinical Practice Guidelines, J Hepatol 2009;51:237 Pullinger et al., J Clin Invest 2002;110:109

34. Ursodeoxycholzuur bij Galsteenlijden - Samenvatting - Ursodeoxycholzuur (>10 mg/kg/d ‘s avonds) • kan worden overwogen bij sterk geselecteerde symptomatische patienten en personen met verhoogd risico tot galsteenvorming • is beperkt door lange duur van behandeling en galsteen recurrence • is niet invasief en geassocieerd met zeer lage morbiditeit en geen mortaliteit