Ursodeoxycholzuur

bij

Galsteenlijden

Delft, 26.1.2010

U. BeuersAfdeling Maag-, Darm- en Leverziekten

Academisch Medisch CentrumUniversiteit van Amsterdam

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

Surgery 1937;1:395

N Engl J Med 1972;286:1

Jpn J Gastroenterol 1974;72:690

Am J Med Sci 1876;71:410

Which patient ?

Which stone ?

Which problems ?

Ursodeoxycholic Acid in Gallstone Disease- Therapeutic Use -

Stages of Gallstone Disease

Asymptomatic 18.5 % in women, 9.5 % in men *

* Attili et al., Am J Epidemiol 1995;141:158

Stages of Gallstone Disease

Asymptomatic

Symptomatic Abdominal pain in the epigastrium or RUQ lasting for > 15 min **

~20 %

18.5 % in women, 9.5 % in men *

* Attili et al., Am J Epidemiol 1995;141:158** GREPCO, Dig Dis Sci 1987;32:349

Stages of Gallstone Disease

Asymptomatic

Symptomatic

Complicated

Abdominal pain in the epigastrium or RUQ lasting for > 15 min **

1-2 % per year

Acute cholecystitis, choledocho-lithiasis, pancreatitis, gallbladder cancer, gallstone ileus

18.5 % in women, 9.5 % in men *

* Attili et al., Am J Epidemiol 1995;141:158** GREPCO, Dig Dis Sci 1987;32:349

~20 %

Management of Gallstone Disease

Asymptomatic

Symptomatic

Complicated

No treatment(except stones > 3 cm, porcelain gallbladder)

Management of Gallstone Disease

Asymptomatic

Symptomatic

Complicated

Laparoscopic (or open) cholecystectomyorNonsurgical treatment

No treatment(except stones > 3 cm, porcelain gallbladder)

Management of Gallstone Disease

Asymptomatic

Symptomatic

Complicated

Laparoscopic (or open) cholecystectomyor

Nonsurgical treatment

Acute intervention

No treatment(except stones > 3 cm, porcelain gallbladder)

Which patient ?

Which stone ?

Which problems ?

Ursodeoxycholic Acid in Gallstone Disease- Therapeutic Use -

Gallstones

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

Cholesterol Gallstone

Rettenmaier

Pathogenesis of Cholesterol Gallstone Disease

Gallbladder hypomotility

Super-saturation

of bile

Rapid nucleation

Effect of Bile Acid Therapy on Bile Lithogenicity

Sharma et al., Gastroenterology 1998; 115: 124

Phospholipids (mmol/L)

Bile salts (mmol/L)

Cholesterol Saturation Index

Cholesterol (mmol/L)

24.6 ± 9.2

119.1 ± 37.7

1.42 ± 0.42

11.1 ± 2.1

BeforeUDCA

29.4 ± 7.9

118.5 ± 36.2

0.62 ± 0.19

5.8 ± 2.4

After 8 weeks ofUDCA

NS

NS

0.001

0.001

p

Effects of UDCA on Cholesterol Gallstone Disease

Gallbladder hypomotility

Super-saturation

of bile

Rapid nucleation

Effect of UDCA on Bile Lithogenicity

Sharma et al., Gastroenterology 1998; 115: 124

Nucleation time (days) 8.5 ± 1.5

BeforeUDCA

19.0 ± 1.7

After 8 weeks ofUDCA

0.001

p

Effects of UDCA on Cholesterol Gallstone Disease

Gallbladder hypomotility

Super-saturation

of bile

Rapid nucleation

Effect of UDCA on Gallbladder Muscle Contractility

Guarino et al., Gut 2007;56:815

After 4 weeks ofPlacebo

After 4 weeks ofUDCA

Effects of UDCA on Cholesterol Gallstone Disease

Gallbladder hypomotility

Super-saturation

of bile

Rapid nucleation

Which patient ?

Which stone ?

Which problems ?

Ursodeoxycholic Acid in Gallstone Disease- Therapeutic Use -

Kinetics of in vitro Gallstone Dissolution by UDCA

Senior et al., Gastroenterology 1990;99:249

Treatment time [month]

Diameter[mm]

Weight[mg]

24

20

16

12

8

4

0

4000

3000

2000

1000

0

201612840

Weight %

Diameter

Gallstone Recurrence after Bile Acid Dissolution Therapy

Villanova et al., Gastroenterology 1989;97:727

Subjects at risk98 83 78 69 62 53 46 36 28 22 12 2

100

80

60

40

20

010 12640 2 8

TIME FROM DISSOLUTION (yr)

%RECURRENCE

RATE

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)

Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy

Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107

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)

Optimal

Acceptable 12%

3%

Patients with gallstone diseasequalified for UDCA treatment

Paumgartner. In: Sleizenger & Fordtran‘ Gastrointestinal and Liver Diseases, 2002:1107

Selection Criteria for Ursodeoxycholic Acid Dissolution Therapy

Biliary colic ?

Stone formation ?

Protection against:

Ursodeoxycholic Acid in Gallstone Disease- Prophylactic Use -

Ursodeoxycholic Acid Reduces Long-term Risk of Biliary Colic in Gallstone Disease

Tomida et al., Hepatology 1999;30: 9

A: symptomatic, no therapy

B: symptomatic, UDCA

C: asymptomatic, no therapy

D: asymptomatic, UDCA

Patients at riskABCD

0111

0332

07187

1137417

42814148

73515458

194017871

6157227105

11274234107

100 A : P<0.001

B

D

C

: P<0.05

180 6 12

80

0

60

40

20

Time (years)

CumulativeProbability ofBiliary Colic

(%)

Ursodeoxycholic Acid Does not Reduce Short-term Risk of Biliary Colic in Gallstone Disease

Venneman et al., Hepatology 2006;43:1276

Biliary colic ?

Stone formation ?

Protection against:

Ursodeoxycholic Acid in Gallstone Disease- Prophylactic Use -

Strong Risk Factors for Gallstone Formation

Rapid weight loss

Total parenteral nutrition

Somatostatin / octreotide treatment

Ursodeoxycholic Acid Protects against Gallstone Formation during Diet-Induced Rapid Weight Loss

Shiffman et al., Ann Intern Med 1995;122:902

MenWomen

Placebo 300 600 1200

% ofPatients

25

30

20

15

10

5

0

35

UDCA Dose (mg/day)

17

68

4

63

2

136

4

130

40

134

5

65

11

122

0

70

Ursodeoxycholic Acid Protects against Gallstone Formation after Bariatric Surgery

- Meta-analysis -

Uy et al., Obes Surgery 2008;18:1532

Gallstone formation after bariatric surgery (n=521)

UDCA 8.8 %Placebo 27.7 %

Relative risk (RRUDCA) 0.43 (0.22-0.83)

Gewichtsreductie en cholecystolithiasis

- NVVH Richtlijn 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;148:174Miller et al. Ann Surg 2003;238:697Weinzier et al. Am J Med 1995;98:115

Niveau 2a

Prophylactic Use of Ursodeoxycholic Acid to Prevent Gallstone Formation

Rapid weight loss

Gene defects causing gallstone formation

MDR 3 / ABCB4 deficiency

Cholesterol 7-hydroxylase deficiency

Pullinger et al., J Clin Invest 2002;110:109

Rosmorduc et al., Gastroenterology 2001;120:1459EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

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