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Overlap Syndromes
U.Leuschner
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/AIH-OLS
● PSC/AIH-OLS
● 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
-AIH/PSC
-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
PBC
Hepatitic Liver Disease Cholestatic Liver Disease
8%
Chronic
Hepatitis C Auto- AIC
10%
10% immune
hepatitis
13%
6%
Cryptogenic
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
Syndrome
● 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
AIH/PBC-, AIH/PSC- OLS AIH/PBC-, AIH/PSC - OLS
Genetics of Autoimmune Liver Disease
Disease HLA-association Characteristics
AIH type 1 DR3 early onset, severe disease
f>m
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
Syndromes
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
1994;35:260-265
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)
■ SMA, ANA, p-ANCA
■ 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)
Hypergammaglobulinemia
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
Cholangitis
AIH
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
Rediscovered
Difficult to define and to diagnose
But require new therapy concepts
Increase the insight into autoimmune liver disease
