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Ursodeoxycholic acid [UDCA]



          Dr. B. K. Iyer
The topics for discussion
•   Bile acids – background
•   Ursodil – background
•   Liver diseases- background
•   UDCA – details
•   Indications
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
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
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.
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.
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 %).
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.
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.
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.
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.
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.
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.
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.
UDCA – pharmacokinetics
• Reach maximum concentrations at about 60
  minutes after ingestion, with another peak
  recorded at 3 hours.
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.
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.
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
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.
Colombo et al, Sem Liv Dis 1998
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
Ursodeoxycholic acid in gallstone disease -
           Therapeutic Use


              Which patient ?

              Which stone ?

              Which problems ?
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   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
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
Management of Gallstone Disease

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

  Symptomatic
                 Laparoscopic (or open)
                 cholecystectomy
                 or
                 Nonsurgical treatment
  Complicated
                 Acute intervention
Ursodeoxycholic Acid in Gallstone
  Disease - - Therapeutic Use -


         Which patient ?

         Which stone ?

         Which problems ?
Gallstones




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




                 Rettenmaier
Pathogenesis of Cholesterol Gallstone Disease



          Super-                   Rapid
         saturation              nucleation
           of bile




                      Gallbladder
                      hypomotility
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
Effects of UDCA on Cholesterol Gallstone Disease



           Super-                   Rapid
          saturation              nucleation
            of bile




                       Gallbladder
                       hypomotility
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
Effects of UDCA on Cholesterol Gallstone Disease



           Super-                   Rapid
          saturation              nucleation
            of bile




                       Gallbladder
                       hypomotility
Effect of UDCA on Gallbladder Muscle
             Contractility


                                 After 4 weeks of
                                      UDCA


                                  After 4 weeks of
                                      Placebo




                           Guarino et al., Gut
                           2007;56:815
Effects of UDCA on Cholesterol Gallstone Disease



           Super-                   Rapid
          saturation              nucleation
            of bile




                       Gallbladder
                       hypomotility
Ursodeoxycholic Acid in Gallstone
           Disease
          - Therapeutic Use -


         Which patient ?

         Which stone ?

         Which problems ?
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
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
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
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
Ursodeoxycholic Acid in Gallstone
           Disease
           - Prophylactic Use -


Protection against:

          Biliary colic ?

          Stone formation ?
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
Ursodeoxycholic Acid Does not Reduce Short-term
    Risk of Biliary Colic in Gallstone Disease




             Venneman et al., Hepatology 2006;43:1276
Ursodeoxycholic Acid in Gallstone
           Disease
           - Prophylactic Use -


Protection against:

          Biliary colic ?

          Stone formation ?
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
                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
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
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
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
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
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
Liver disease, before & after UDCA
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
PSC
  Cirrhosis



Expanded Portal Tracts
       (Blue)
IBD and PSC
• 2-10% of IBD patients will develop PSC

• ~ 70% of PSC patients have evidence of IBD
Pathogenesis of PSC
•   Multifactorial/ Complex
•   Cellular immunity
•   Autoimmunity?
•   Bacterial Antigens
•   Aberrant Lymphocyte Homing
•   Cytokines
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
UDCA
UDCA
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)
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
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
UDCA – Mechanism’s of Action
Trials of UDCA in PSC
• Limited good quality trials
• Small numbers
• Short follow up
Summary of trials of UDCA in PSC




                     Cullen S APT 2005

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UDCA

  • 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;13:97 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 ?
  • 28. Gallstones Anatom. 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 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
  • 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 Cirrhosis Expanded 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
  • 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
  • 65. Trials of UDCA in PSC • Limited good quality trials • Small numbers • Short follow up
  • 66. Summary of trials of UDCA in PSC Cullen S APT 2005

Editor's Notes

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