Overlap Syndromes

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					Overlap Syndromes

 Internistisches Facharztzentrum
  Frankfurt am Main, Germany

 XIII Falk Liver Week
      October 6 – 11, 2006
       Freiburg, Germany
  Definition of Overlap Syndromes (OLS)

There is no unequivocal definition of an OLS

The OLS can be defined as: coexistence of two
autoimmune liver diseases in one patient
    a) simultaneously
    b) successively
                           Autoimmune Liver Diseases
● Classic form of AIH
   Peculiar features of classic AIH (acute, insidious, fluctuating, relapsing etc.)
● Variant forms of AIH
   AIH + AMA                            AIH + bile duct injury
   AIH + cholestasis                    AIH without ANA, SMA, LKM
   AIH + ulcerative colitis             AIH resistant to immunosuppressants
● Classic form of PBC
   Peculiar features of classic PBC (missing histol. features, piecemeal necros. etc)
● Variant forms of PBC
   PBC – AMA negative                   PBC without biochemical cholestasis
● Classic and variant forms of PSC (diff.antibody spectr., small duct PSC)
● PBC/PSC-OLS                                     R.Poupon, Clin Liver Dis, 2003: 865-878
3 diseases (AIH, PBC, PSC):
 18 peculiar/variant forms

    What does overlap syndrome mean?
Atypical Manifestations of Autoimmune Hepatitis
 Overlap Syndromes (two diseases in one liver)
             -AIH/PBC = AIC
             -AIH/HepC,B ?

 Outlier Syndromes (cannot be classified)
             -AIC (AMA negative PBC ?)
             -Cryptogenic chronic hepatitis
 Changing diagnosis (switch over time)
             -PBC           AIH
             -AIH           PSC
 Prevalence of Serological and Morphological Features Common to Chronic
                               Liver Diseases

     Hepatitic Liver Disease                                  Cholestatic Liver Disease
                     Hepatitis C               Auto-                AIC
                                      10%     immune
PBC:primary biliary cirrhosis          chronic                PSC
PSC: primary sclerosing cholangitis   Hepatitis
AIC: autoimmune cholangitis

                                                                 Mod.: Czaja AJ. Ann Intern Med 1996;125:588-598
 Tools for diagnosing an Overlap
● Etiology ?
● Immunogenetics ?
● Biochemical/serological characteristics ?
● Liver histology ?
● Response to treatment ?
   Pathogenes, Toxins,          Pathogenes, Toxins,
        HLA-Type                     HLA-Type

                  Etiology of OLS´s

PBC               PSC         PBC               PSC

         AIH                           AIH

              Genetics of Autoimmune Liver Disease

Disease                HLA-association                     Characteristics

AIH type 1             DR3                                 early onset, severe disease
                       DR4                                 older-onset, extrahep.manifesta-
                                                           tions, good response to therapy,
                                                           protective in children?

                       DR2                                 alleles in Japan
                       DR4                                 see above
AIH type 2             -                                   -
PBC                    DR8                                 stage III,IV 24 %, stage I,II 5%,
                                                           marginally significant
AIC                    DR3, DR4                            has to be confirmed
PSC                    B8-DR3, DR2, DR6                    strong with B8-DR3, neg.with DR4

PSC/IBD                                                    little genetic overlap between genes
Donaldson PT: in Immunology and Liver, Manns MP,Paumgartner G ,Leuschner U (edit.), Kluwer:2000, pp115-132
    Immunogenetical Characterization of the
         Overlap Syndrome AIH/PBC
■ A genetic susceptibility influences the dis-
    ease course
■ When AIH characteristics HLA B8-, DR3 or DR4
    present, OLS develops a more hepatitic picture
■ Spillover of the autoimmune bile duct inflammation
    to the lobules
■ Therapy consequences ?

Ref.: Lohse AW et al. Hepatology 1999;29:1078-1084
                   Overlap Syndrome - AIH/PBC

 • Histology: criteria of PBC+AIH
 • Serology: AMA-M2 (PDC-E2)

Definition: (● AIH: ALT 4-times, IgG 2-times, SMA, histology)
                 (● PBC: AP 2-times, or GGT 5-times, AMA, histology)

• IgG rather low, IgM higher concentrations
• ANA, SMA lower titers than in AIH

 • HLA: DR3, DR4

Chazouillères O et al. Hepatology 1998;28:296-301. Johi S et al. Hepatology 2002;35:409-413
Primary Biliary Cirrhosis/Autoimmune Hepatitis Overlap

            Variant I (AIH/PBC)                                      Variant II (AIC)

     Histology: PBC+AIH                                     Histology: PBC (not AIH)
     Serology: AMA-M2                                       Serology: AMA negative
     HLA: DR3, DR4;(DR8 neg.)                               HLA: DR3, DR4; (DR8 neg.)
     (= OLS)                                                (= OLS or AMA-neg.PBC ?)

 IgG rather low, IgM higher conc.                       IgG rather low, IgM higher conc.
           ANA, ASMA < AIH                                  ANA, ASMA > than in PBC

Ref. Variant II: Taylor S et al: Am J Surg Pathol 1994;18:91-99. Invernizzi P et al. Hepatology 1997; 25:1090-
1095. Stone J et al. J Hepatol 2002;36:705-711
Definition of Autoimmune Cholangitis (AIC)
AIC is a variant of PBC
● No histological differences
● PDC-E2 expression on bile duct cells
● Carboanhydrase II-AB (not always) present
● Course of the disease identical with that of PBC
● Positive response to UDCA therapy

Kim WR et al. Hepatology 1997;26:22-26
Definition of Autoimmune Cholangitis (AIC)
AIC is a distinct liver disease

 ●  AST and IgM lower than in AMA-positive PBC
 ●  Carboanhydrase II-AB present
 ●  ANA, SMA > 1:160
 ●  AB against glycogen-phosphorylase
 ●  AB against nuclear envelop
 ●  PBC-spec. AB against 2-oxoglut.-dehydroge-
    nase complex (and PDC-E2) absent,
  ● Lymphocytes of the liver express Vβ.1 TCR
  ● HLA risk factors different from PBC (DR3,4;
    but DR8 absent)
Heathcote J in Cholestatic Liver Diseases, Leuschner U, Broomé U, Stiehl A (edit) Kluwer
2004, pp125-131 Taylor SL et al. Am J Surg Pathol 1994;18:91-99 Michieletti P et al. Gut
                Overlap Syndrome – AIH/PSC
■ ERC, MRC picture like in PSC
■ Histology: mostly PSC (sometimes AIH)
■ Association with IBD less frequent (30 – 60%)
       than in PSC
■ High concentrations of IgG (AP, GGT)
■ AP in children in 50% normal

Gregorio GV et al. Hepatology 2001;33:544-553 Kaya M et al. J Hepatol 2000;33:537-542 Boberg KM
et al. Hepatology 1996;23:1369-1376 van Buuren et al. J Hepatol 2000;33:543-548 Czaja AJ Ann Intern
Med 1996;125:588
     AIH/PSC Overlap Syndrome

                                                 ERC in a patient
                                                 with AIH/PSC OLS

Age 39 yrs., male      AP 866 U/l, GGT 238 U/l
ANA 1:160, IgG increased, AMA neg.
Ulcerative colitis since 6 yrs
Histology: PSC+AIH
           Hepatitis C/B – Autoimmune Hepatitis Overlap Syndrome
                                            Does it exist ?
  In patients with chronic HCV infection
                       ANA:       9 – 38%       p-ANCA: 10%
                       ASMA:      5 – 91%       AAA:        8%     HMG1,2 AB: 11%
                       LKM1,3: 0 -10% (different epitopes from AIH)
                       Moderate/severe interface hepatitis, lob.infiltrates, granulom.
 In patients with Autoimmune hepatitis
                                   HCV-AB      : 44 – 77% (EIA)
                                               : 12 – 35% (RIBA)
                                    HCV RNA : 19%
                                    Histol.characteristics of HCV-hepatitis

 But: No   female preponderance, weak assoc. with DR3, DR4

Ref.: Schiano T.D. et al.: Am J Gastroenterol 2001;96:2984-2991      Durazzo M. et al.: Dig Dis Sci
2003;48:423 – 430 Czaja AJ in: Cholestatic Liver Disease, Leuschner U, Broomé U, Stiehl A (edit),
Kluwer2004,pp 132-146 Clifford B.D. et al. Hepatology 1995;21:613-619
   Treatment of the AIH/PBC-Overlap Syndrome
                  130 consecutive pts with PBC

   Definition of OLS: AP > 2N or GGT > 5N, SMA,
                      AMA positive, ALT > 5N, IgG> 2N or ASMA
                      Bile duct lesions, piecemeal necrosis

           OLS:    n = 12 (9.2%)
           UDCA n = 5: incomplete response
           Cortic. n = 6: incomplete response

UDCA + corticoids was superior to UDCA- or cortic.- monotherapy

               Chazouillères O et al.Hepatology 1998
   Treatment Outcome in Patients with AIH/PSC Overlap
       Syndrome – Treatment with Glucocorticoids

225 patients with AIH investigated
 Overlap       AIH/PBC          : 5%
                AIH/PSC         : 6%
                AIH/AIC          : 5%
 Poor treatment outcome
                AIH/PSC         : 78%
                the others      : 17%
 Death or LTX
                AIH/PSC         : 33%
                vs. AIH          : 8% (p=0.05)

Czaja AJ Hepatology 1998:28:360-65
              Treatment of Overlap-Syndromes

AIC (AMA neg.PBC) UDCA 13 – 15 mg/kg/d
AIH/PBC:                 UDCA, glucocorticoids (when ALT ≥ 5-10-fold)

AIH/PSC:                 UDCA 15-25 mg/kg/d, (+ glucocorticoids ?)

AIH/HepC :               AIH > HepC (ANA > 1 : 320): glucocorticoids
                          HepC > AIH (ANA < 1 : 320): IFN + Riba

 Poupon R, Clin Liver Dis 2003;7: 868-878 Chazouillères O et al. Hepatology 1998;28:296-301
 Czaja AJ in: Leuschner U, Broomé U, Stiehl A, Kluwer 2004, 132-146 Saracco G et al. J Hepatol
 1990;11:339-343 Clifford BD et al. Hepatology 1998;21:613-619
                Changing Diagnosis and Overlap
               Syndrome in Chronic Autoimmune
                        Liver Diseases

                  AI -                             ?                     PBC


                     PSC                                             Overlap - S.

Colombato LA et al. Gastroenterology 1994;107:1839-1843 Abdo AA et al. Hepatology 2002;36:1393-1399
Mieli-Vergani G et al. Hepatology 2000; 32:309A Wilschanski M et al. Hepatology 1995;22:1414-1420
          Three diseases

    18 peculiar/variant forms
    and changing diagnosis !

What does „true“ overlap syndrome mean ?
  Summary and Conclusions
          Overlap Syndromes
               Old concepts
        Difficult to define and to diagnose

But require new therapy concepts
Increase the insight into autoimmune liver disease

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