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.
21. Bile acid treatment of gallstone disease
- Historical Aspects -
1873 M Schiff Suggestion to treat gallstone L‘Imparziale
disease with bile acids 1873;13:97
1876 WC Dabney Treatment of gallstone disease Am J Med Sci
with bile acids 1876;71:410
1937 AG Rewbridge The disappearance of gallstone Surgery
shadows following the prolonged 1937;1:395
administration of bile salts
1972 RG Danzinger Dissolution of cholesterol N Engl J Med
et al. gallstones by chenodeoxycholic 1972;286:1
acid
1975 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 Disease
Asymptomatic 18.5 % in women, 9.5 % in
men *
* Attili et al., Am J Epidemiol
1995;141:158
24. Stages of Gallstone Disease
Asymptomatic 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 ?
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 UDCA
Cholesterol (mmol/L) 11.1 ± 2.1 5.8 ± 2.4 0.001
Phospholipids (mmol/L) 24.6 ± 9.2 29.4 ± 7.9 NS
Bile salts (mmol/L) 119.1 ± 37.7 118.5 ± 36.2 NS
Cholesterol 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 UDCA
Nucleation 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
% 60
RECURRENCE
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 to
bile)
Gallbladder: patency of cystic duct and
emptying 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 to
bile)
Gallbladder: patency of cystic duct and
emptying 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 B
Probability of
Biliary 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 Gallstone
Formation 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 1.5
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 Niveau 2a
Weinzier 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 disease
Effect on Characteristics Evidence
obtained from
Liver biochemistry consistently improved RCT *
Quantitative liver function improvement not pilot studies
consistently maintained
Biliary drainage often normalized pilot studies
Liver histology ⇓ bile duct proliferation, RCT *
inflammation, fibrosis
Fat absorption no effect RCT *
Nutritional status improvement in severely pilot studies
malnourished patients
Essential fatty acid (EFA) improvement in EFA RCT *
Status deficiency
Need for transplantation not determined -
mortality
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
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.
60.
61. 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)
62. 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
63. 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
![Ursodeoxycholic acid [UDCA]
Dr. B. K. Iyer](https://image.slidesharecdn.com/udca-120308011131-phpapp02/85/UDCA-1-320.jpg)
