Cholestatic Liver Diseases by klutzfu58

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									        XXXI Pan American Congress of Gastroenterology
Falk Workshop ‘Digestive Diseases: State-of-the-Art & Daily Practice‘
              Santiago de Chile, November 12, 2008




 Cholestatic Liver Diseases
                  Michael Trauner, M.D.
         Div. of Gastroenterology & Hepatology
            Department of Internal Medicine
           Medical University of Graz, Austria
    State-of-the-Art & Daily Practice

•   Clinically relevant molecular advances
•   Focus on cholangiopathies: PBC, (P)SC
•   Intrahepatic cholestasis of pregnancy
•   New(ly defined) diseases
•   Medical treatment: UDCA & beyond
        Principal Mechanisms & Clinical
            Spectrum of Cholestasis
     Bland Cholestasis                                   Inflammatory Cholestasis

                                                                                      Drugs
                      Hormones                                                        Alcohol
                                                                     Cytokines
                       Drugs                                       Inflammation       Viral
Hepatocytes            Genetic                                                        Sepsis




Small Ducts                              Bile Duct
                                          Injury            Ductopenia (VBDS)            PBC


                                                         Mechanical Obstruction PSC
                                                        • Extraluminal Compression Tu
Large Ducts
                                                        • Intraluminal Obstruction

   Whitehead et al., Gut 2001; 48: 409               Trauner et al., J Clin Gastro 2005; 39: S111
Bile Secretion
& Cholestasis


 Hepatocytes
                                                        Canalicular Bile
                                                             70%
                           BSEP

                         Hereditary
                         & Acquired                          Cholestasis
                          Defects                             Jaundice


                                                            Ductal Bile
        Cholangiocytes
                                                              30%



                                  Trauner et al., New Engl J Med 1998; 339: 1217
       Hereditary Transport Defects:
  A Continuous Spectrum of Liver Diseases
                                  Genetic Diagnosis


 Homozygous                            PFIC                   Neonates, Infants
                                         (Byler)
                                                                 Childhood
 “Milder“ Mutations                    BRIC
                              (Summerskill-Walshe-Tygstrup)


 Heterozygous                       LPAC                  Adults
     Suceptibility                ICP, DILD
                                                          Unexplained
                                              MDR3 1/3Cholestasis
                            Biliary Fibrosis, IAD (Phospholipids)
                                                BSEP (Bile Acids)
  Decompensation by              PBC, PSC       Modifyer Genes?
        2o Injury:                                               FIC1 (Byler)
     Hormone (ICP)                                        Ziol et al., Gastro 2008; 135: 131
Drug (DILD), Inflammation           Reviewed in: Trauner et al., Sem Liver Dis 2007; 27: 77
Intrahepatic Cholestasis of Pregnancy

 • Complex etiology
   – Genetic (ABC transporters, FXR)
   – Endocrine (estrogen, progesterone)
   – Environmental (viral, selenium)
 • Diagnostic criteria
   – Pruritus in (2nd and) 3rd trimenon
   – Serum bile acids > 10 µM (high fetal risk > 40)
   – Clinical/biochemical resolution after delivery
                         Reviews: Lammert et al., J Hepatol 2000; 33: 1012
                           Pusl & Beuers, Orphanet J Rare Dis 2007; 2: 26
                                          Hay, Hepatology 2008; 47: 1067
Effect of Ursodeoxycholic Acid in ICP



                       Glantz et al., Hepatology 2005; 42: 1399




                     Kondrackiene et al., Gastro 2005; 129: 894
Management of Cholestatic Pruritus

•   (UDCA: effective only in ICP)
•   Cholestyramine: 4 g qid (4hrs UDCA)
•   Rifampicin (150-600 mg/d) ~10% Hepatotoxicity
•   Central: naltrexone (25-50mg/d), sertraline
•   Extracorporeal liver support
•   Liver transplantation


                 Recent Reviews: Bergasa, Clinics in Liver Disease 2008; 12: 219
                                            Kremer et al., Drugs 2008; 68: 2163
  Pregnane X Receptor (PXR) and Constitutive
Androstane Receptor (CAR) Stimulate Adaptation
                          For renal excretion

              Sinusoidal membrane
                                                          3           Phase 3
                                                                      MRP3
                                                                      MRP4
                        Phase 1
 1                      CYP3A11
                        CYP2B10
                                    Conjugated &
                                    poly-hydroxylated                  6-Ethyl-CDCA
                                    Bile acids                         (Ethichendiol)
                                                                       Phase II / PBC

                    2                  Phase 2                  FXR
 Retained                              UGT1A1
 bile acids                            SULT2A1
                                                          PXR         CAR
                                                        Rifampicin   Phenobarbital
     Wagner et al., Hepatology 2005; 42: 420
     Marschall et al., Gastroenterology 2005 129: 476
   Chronic Cholangiopathies

                               PBC
Liver
                                Small duct PSC



                               PSC


           Common bile duct



           Duodenum
                              Courtesy G. Paumgartner
Primary Biliary Cirrhosis (PBC)
                                        Autoimmune
                                        destruction of
 Liver                                  small bile ducts




                     AMA                Genetic
                                          - Family risk
                               Tregs
            Common bile duct              - Polymorphisms
                                        Environmental
                                          - Infections
          Novosphingobium aromaticivorans
                                          - Xenobiotics
            Duodenum
                                       Molecular Mimicry
Major Clinical Callenges in PBC

• Identification of patients at risk for cirrhosis
• Optimize treatment (non-responders)
• Extrahepatic manifestations &
  complications
  – Pruritus, fatigue, cognitive dysfunction
  – Cardiovascular risk, osteoporosis
  – Associated immune disorders
PBC – A Variably Progressive Disease
           Number of Bile Ducts

• Subclinical PBC (AMA+)               Cholestasis
• Non-progressive PBC                  (AP, GGT)
  (asymptomatic)
                                           Jaundice
• Slowly progressive PBC
                                           (Bilirubin)
                                   • Liver histology
  (+ symptoms)
                                   • Sp100, gp210
• Rapidly progressive PBC          • Albumin, bili
  (premature ductopenic)           • NR to UDCA
                                                 Liver-
                                              Cirrhosis


              Duration (Years – Decades)
                                                          cm
Excellent Prognosis in PBC Patients with
   Biochemical Response to UDCA
     Responder                 Non-Responder




                     Pares et al., Gastroenterology 2006; 130: 715
Pathogenesis and Therapeutic Targets in PBC
Immune-mediated Bile Duct Injury


 Aggravation of Duct Lesion by
     Cytotoxic Bile (Salts)                     Treat early (stages)


 Cholestasis with Retention of                   Ursodeoxycholic
   Bile Salts in Hepatocytes                     Acid (UDCA)
                                                 13-15 mg/kg/d
     Necrosis, Apoptosis,
      Fibrosis, Cirrhosis


          Liver Failure       Paumgartner & Beuers, Hepatology 2002; 36: 525
                             Beuers, Nature Clin Pract Gastro Hep 2006; 3: 318
Excellent Prognosis in PBC Patients with
   Biochemical Response to UDCA



                                 Responder




                                 Suboptimal
                                            33(-61)%
                                 Responder


                      Corpechot et al., Hepatology 2008; 48: 871
 Pathogenesis and Therapeutic Targets in PBC
    Anti-Retroviral? Antibiotic?
                                   Tamoxifen?     Methotrexate
 Immunologic Bile Duct Injury Raloxifen?
                                                  CSA, MMF
     Anti-CD20 (Rituximab)?
                                                  Thalidomide, Sulindac
                                                  Azathioprine
Aggravation of Duct Lesion by Fibrates?
                              Statins?
                                                  Predniso(lo)ne
     Cytotoxic Bile Salts                         Budesonide

                                            Combination Therapy
Cholestasis with Retention of
  Bile Salts in Hepatocytes                     Ursodeoxycholic
                                                Acid (UDCA)

    Necrosis, Apoptosis,                        Colchicine, Silymarin
     Fibrosis, Cirrhosis                        D- Penicillamine

                                                      Recent Review:
         Liver Failure                                Silveira & Lindor
                                                LTx   Clin Liver Dis 2008; 12: 425
   Clinical and Molecular Effects of
UDCA/Budesonide Combination Therapy
  Clinical Effect (de novo)                    Molecular Synergism (AE2)




                             Caveat:
                            Portal HT
                            Cirrhosis                                          GR


 Rautiainen et al., Hepatology 2005; 41: 747    Arenas et al., J Clin Invest 2008; 118: 695
Bile Secretion
& Cholestasis


 Hepatocytes

                                    BSEP




                                                   Poupon et al., J Hepatol 2008 online

                                                                   Primary Biliary
         Cholangiocytes                                               Cirrhosis
                                                                 Ae2 Knockout Mouse
                                                                 Salas et al., Gastro 2008
    Lazaridis et al., Gastro 2004
                                           Trauner et al., New Engl J Med 1998
   Primary Sclerosing Cholangitis (PSC)

                                                      Small Duct PSC
            Liver


Gut-primed T cells
                                                                       Obliterative fibrosis
                                                                       of bile ducts
           LPS


 Colitis (~75%)      • Right-sided
                     • Oligo-symptom.
                     • Backwash ileitis
                     • Rectal sparing Common            bile duct
                     • CRC (5x>UC)
                     Loftus et al., Gut 2005
                                               MRC                      ERC
                                           Duodenum Berstad et al., Clin Gastroerol Hepatol 2006
Prognosis: Small vs. Large Duct


                                                      Small-duct PSC
                                                           (5%)


                                                                   Very rare




          Malignancy                                  Large-duct PSC
        • CCC (15%)                                       (95%)
        • Colorectal
        • Pancreas, HCC
Bergquist et al., J Hepatol 2002; 36: 321   Angulo et al., Hepatology 2002; 35: 1494
Major Clinical Callenges in PSC

• Disease heterogeneity (mixed bag?)
• Lack of effective medical treatment
• Malignancy (screening, treatment)
               MRCP                        FISH
                                           LTx

                                                  Extrahepatic




                          Malhi & Gores, J Hepatol 2006; 45: 856
                            Gores et al., J Hepatol 2007; 47: 454
              Immunological
               Mechanisms                      Cytokines
                                                                  Transport
                                                                   Defects
Atypical pANCA
CD4-pos. Infiltrates                                              Toxic Bile


                              Ineffective in PSC:
                              • Immunosuppressants
                              • Anti-inflammatory
                              • Anti-fibrotics
                              • Antibiotics
                                                           Fibrogenesis


        IBD

        Intestinal                                              Ischemia
      Translocation    PAMPs (LPS…)

                                              PSC as Immune-mediated
                       Gut-primed T cells     Inflammatory “Disease“
    Treatment of PSC with UDCA
                             Placebo - Controlled Trials
Prevention of Beuers Stiehl Lindor Mitchell Olsson
CRC (& CCC?) (n=14)  (n=20) (n=105) (n=26)  (n=110)


Dose (mg/kg/d)      13 -15    10 -12 13 -15              20          17-23

Serum liver tests     +          +           +            +             -

Histology            (+)        (+)           -           +

Cholangiography                                           +             -

Survival                                      -                         -

                                 Reviewed in: Pusl & Beuers, WJG 2006; 12: 3487
                                  Paumgartner & Pusl, Clin Liver Dis 2008; 12: 53
     High-dose UDCA in PSC

• Pilot study promising (30 mg/kg/d, 2 y)
  – Biochemistry, Mayo risk score improved
• Recent RCT (28-30 mg/kg/d, 3 y) negative
  – 76 vs. 74 pts
  – Biochemistry improved
  – Varices, histological progression RR x 2.2
  – Death, transplant RR x 3.3
       Only established Rx
        (80% survival / 10y)
                                    Cullen et al., J Hepatol 2008; 48: 792
                               Lindor et al., AASLD 2008 (LB Abstract #2)
 UDCA Combined with Endoscopic Treatment of
Strictures Improves Survival of Patients with PSC

        100                            UDCA + Endoscopic Treatment
Probability
    of 80                                        Survival predicted by
 Survival                                                 Mayo Model
          60
                                            • Dilatation
         40                                 • Short term stenting
                   Patients at risk         • Antibiotic coverage
         20        n=61    55     41   33   • Brushing 14
                                            24 20 & biopsy

          0
               0         20        40       60        80            100
                                     Months
                                                     Stiehl et. al., J Hepatol 1997
           norUDCA Reverses Sclerosing
           Cholangitis in Mdr2 -/- (KO) Mice
H&E                                                       pv
    bd                                                                      pv                          pv
                                                                                   bd
         pv                                bd                                                                   bd
                                                               bd




      WT
    WT (+/+)                                      KO (-/-)                 KO+UDCA                           KO+norUDCA
               (U/L)                                                       (U/L)
         ALT     800,0
                                                      †               AP                                †
               800                                                         500500

                 700,0                                                         450


                 600,0
               600                         *                               400400
                                 *                                             350
                 500,0
                                                                           300300             *
                 400,0
               400
                                                                               250
                                                                                                                 ‡
0         1      300,0
                         2                 3      Months       ‡           200200
                                                                               150
                 200,0
               200
                 100,0
                                     Rx                                    100100
                                                                                50

                   0,0                                                          0
                             1             2          3        4                         1    2          3       4

                                                      A                                  T               A
                         W
                             T
                                          KO       DC         CA                     W       KO       DC         CA   Conjugation
                                                                                                                          p<0.05
                                                 +U         UD      UDCA                            +U norUDCA UD
                                                          or                                                 or           * vs. WT
                                               KO      +n                                         KO      +n              † vs. KO
                                                    K O                                                K O                ‡ vs. KO
                                                                    Fickert et al., Gastroenterology 2006; 130: 465-81
        Sclerosing Cholangitis
                                                Gossard et al. Am J Gastro 2005



• Primary
  – Immune-mediated (gut?)
• Secondary
  – Bacterial, recurrent pyogenic cholangitis
  – IgG4-associated cholangitis      Bile Duct Cast in Rapidly
                                    Progressive SC after Sepsis
  – Posttraumatic, sepsis, burns
  – Ischemic cholangitis
  – AIDS cholangiopathy
  – Portal biliopathy

                             Abdalian & Heathcote, Hepatology 2006; 44: 1063
  IgG4-associated Cholangitis

• Synonyms
  – Autoimmune pancreatitis-associated SC
  – Sclerosing pancreato-cholangitis
• Clinical presentation: 75% acute jaundice
• Diagnostic test
  – IgG4 > 140mg/dL, (plasma cells), imaging
  – DDx: 9% of PSC have elevated IgG4
• Therapy
  – Steroids, (azathioprine, MMF)
                            Björnsson et al., Hepatology 2007; 45: 1547
                         Ghazale et al., Gastroenterology 2008; 134: 706
IgG4-associated Cholangitis




            90%




                  Björnsson et al., Hepatology 2007; 45: 1547
  IgG4-associated Cholangitis

• Clinical presentation: 75% acute jaundice
• Diagnostic tests
  – IgG4 > 140 mg/dL, ( + plasma cells on [L]Bx )
  – Imaging (MRCP, ERCP)
• Therapy
  – Steroids, (azathioprine, MMF)



                            Björnsson et al., Hepatology 2007; 45: 1547
                             Umemura et al., Hepatology 2007; 46: 463
                         Ghazale et al., Gastroenterology 2008; 134: 706
IgG4-associated Cholangitis
    Before          After Steroids (3m)




              Ghazale et al., Gastroenterology 2008; 134: 706
           Overlap-Syndromes


    AIH                           10%                      PBC

                            10%         rare
Abdalian et al.,
Hepatology 2008; 47: 949



                           10%

IgG4-assoc.
 Cholangitis                     PSC
                                    Mendes et al., Am J Gastro 2006; 101: 2070
     Summary & Conclusions

• Better understanding of pathogenesis of
  cholestasis & cholangiopathies
• “New“ cholangiopathies: IgG4, Sepsis
• UDCA basis of therapy
• New bile acid derivatives (norUDCA,
  6-ECDCA) on horizon
• Nuclear receptors as therapeutic targets
      University Hospital Graz




Thank you for your attention!

								
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