Autoimmune Liver Disease and Primary Sclerosing Cholangitis

Transcription

1 OTC - King Faisal Specialist Hospital and Research Center Riyadh Autoimmune Liver Disease and Primary Sclerosing Cholangitis M. Burdelski

2 Paper case I: D.G.* (male) 16 months : diabetes mell. I + 1 Pt 20 months : diarrhea 36 months : hepatopathy, jaundice AP / ALAT : < Pt IgG : 1.5x normal + 1,5 SMA > 1: Pt Viral markers : neg + 3 Pt HLA B 8 pos + 1 Pt Histology : lobular hepatitis ; response to steroids : + 6 Pt

3 Incidence and Prevalence Autoimmune Hepatitis : Incidence : 1-2 / / year Prevalence : /

4 Definition of AIH Viruses, bacteria, chemicals and drugs triggering a selfperpetuating inflammatory disease process in genetically susceptible individuals

5 Classification of AIH AIH type Marker Genetic predisposition Type 1 ANA, SMA and /or anti-actin + HLA A1, B8, DRB1, DR4 Type 2 Anti LKM, Anti CYP2D6 + HLA B 14, DR3, C4A-Q0 Type 3 SLA, LC1, LP, ASGPR + Like type 1, HCV Drug-induced LKM-2, LM? Post-LTX ANA, SMA?

6 Diagnostic and Prognostic Markers Autoantibodies Antigens Principal features ANA Diverse nuclear proteins Associated with HLA-DBR1*03 Anti SLA trnp Anti-Actin Polymerized F-Actin Associated with early onset and poorer prognosis Anti-α.actinin Component of actin Associated with anti-ss DNA Associated with severe clinical and histological disease Anti-LC1 Formimimotransferase cyclodeaminase Associated with early age of onset, concurrent immune disease rapid progression to cirrhosis Anti-LKM1 CYP2D6 Diagnostic marker of type 2AIH Anti-LKM3 UGT Present in 8% of patients with type 2AIH, 6% with chronic HDV SMA Actin and nonactin Components Vimentin, skeltin Conventional diagnostic marker of type 1 AIH Czaja AJ, Manns M Gastroenterology 2010, 139:58-72

7 Advances in the understanding of pathogenic mechanisms Advance Nature Principal Features Characterization of target antigens Cytochrome 2D6, trnp Formimimotransfersase cyclodeaminase, UGT Cytochrome 1 A2 Target antigens for anti-lkm 1, SLA, LC1, LKM3, APECED Classification of molecular mimicry HCV, CMV, HSV Cross-reacting antibodies, concurrent autoimmune diseases Identification of genetic risk factors inside the MHC Identification of genetic risk factors outside the MHC Recognition of deficiencies in cellular regulators DRB1/0301, DRB1*0401 :caucasians, DRB1* 0404, DRB1*0405: Mexico, Japan, China; DRB1*1301 : South America CTLA gene polymorphism, TNFA*2 gene polymorphism TNFRSF6 gene polymorphisme Tyrosine phosphatase CD45 mutation, Vitamin D receptor polymorphism Regulatory CD4 + CD25 + T-cells, NKT cells Influence susceptibility, phenotype and severity in different ethnic groups Not disease specific, affect clinical phenotype, ethnic variability Deficient number and function impair CD8 + T cells CzajaAJ, Manns M, Gastroenterology 2010, 139:58-72

8 Autoimmune Mechansism (Mod.from:Mieli-Vergani, 1996) APC Autoantigens HLA II Hepa tocyte complement TNF,IL-1 T suppr TH 0 HLA I M IL-4 IL-12 IFN-γ TH 2 TH 1 T cytotoxic IL-5 IL-6 EBV? IL-4 IL-10 B TNF IL-2 YYYY

9 Molecular mimicry ( Manns, 1991) Epitopes CYP2D E 1 E 2/3 E 4 E 5 CYP 2D6 -His-Arg-Met-Thr-Trp-Asp-Pro-Ala-Gln-Pro-Pro-Arg-Asp HSV (IE 175) Pro-Ala-Gln-Pro-Pro-Arg

10 Clinical features acute hepatitis : jaundice, anorexia, abdominal discomfort (50%) fulminant hepatic failure ( 11%) non-specific symptoms (39%)

11 Diagnostic criteria Auto-antibodies hyper-γ-globulinemia genetic markers lack of viral markers response to immunosuppressive therapy predisposition of female gender Histology

12 Scoring systems for Diagnosis of AIH Johnson 1993*1 Definite >15 points Probable points I AIH Group 1999*2 Definite >15 points Probable Points Simplified Score 2008*3 Definite > 7 points Probable > 6 points Gender Male : 0 Female :+2 Female :+2 AP/ALT >3: -2 <3 : +2 IgG >2xn : +3 1,5-2: +2 IgG >2xn : +3 1,5-2xn :+2 IgG >n :+1 >1.1xn : +2 ANA >1:20 : +3 1:10-20 :+2 ANA >1: 80: +3 1:80:+2 ANA or SMA LKM or SLA >1:40:+1 >1:40:+2 SMA >1.20 : +3 1:20 : +2 AMA + : -4 Viral markers Anti HBc+ : -3 Other markers : -3 Viral markers + : -3 - : +3 Viral markers : Neg. +2 Exposition to drugs Response to therapy Pos : -2 Response to therapy Complete : +2 Relapse +3 Other AI-D Histology : Pos : +1 Histology : Pos. : + 2 Interface h.:+3 None : -5 Histology Typical : +2 Compatible : +1 *1 : JohnsonPJ, Hepatology 1993; *2 : Intrn. AIH Group : J of Hepatol 1999 ; *3 Hennes EM, Hepatology 2008

13 Utility of Simplified Criteria for the Diagnosis of AIH in Children Simplified Scoring System Variable Cut-off Points Cut-off Points ANA or SMA > 1 : 40 1 > 1 : 80 2 LKM > 1 : 40 2 SLA positive 2 IgG > Upper normal limit 1 > 1.1 times Upper normal Limit 2 Liver Histology Absence of Viral hepatitis Compatible with AIH 1 Typical of AIH 2 yes 2 Probable AIH : 6 points Definite AIH : > 7 points Hiejima E et al, J Pediatr Gastroenterol Nutr 2011, 52,

14 Comparison of clinical diagnoses and scoring diagnoses using each system Def. AIH Prob.AIH Nondiagn. Clin Diagnosis 1999 Sc. Simpl. Sc Sc Simpl Sc 1999 Sc Simpl.Sc AIH (n=20) Chron.hep. (n=18) PSC (n=5) Chr. HBV hep (n=2) Chr.EBV hep (n=2) NASH (n= 2) GSD I (n=1) W.D (n=1) Crypt. Hep. (n=5) Hiejima E et al. J Pediatr Gastroenterol Nutr 2011: 52:

15 Performance Parameter Performance Parameter 1999 Score : n, (%) Simplified Score n, (%) Sensitivity 20/20 (100) 11/20 (55) Specificity 29/36 ( 81) 31/36 (86) Pos. predictive value 20/27 ( 74) 11/16 (69) Neg. predictive value 29/29 (100) 31/40 (78)

16 Associated disorders Adults (Manns, 1997) Children (Shepherd,1999) Autoimmune-thyroiditis Autoimmune thyroiditis CREST-syndrome Graves` disease Diabetes mellitus I Diabetes mellitus I Ulcerative colitis Inflammatory bowel dis. Synovitis Coeliac syndrome JRA Sjoegren s syndrome Lichen planus Haemolytic anemia Vitiligo Glomerulonephritis Nail dystrophy ITP Alopecia

17 Prof. Schäfer, UKE AIH : HE Staining

18 Prof. Schäfer, UKE AIH : CD8 Staining

19 Prof. Schäfer, UKE Recurrence after LTX : 7 months p.o.

20 Differential diagnosis of AIH and PSC Immunodeficiency : IgA + IgG 2, Hyper- IgMsyndrome Overlap-syndrome Autoimmune cholangitis cryptogenic hepatitis

21 Paper case I: D.G.* (male) 16 months : diabetes mell. I + 1 Pt 20 months : diarrhea 36 months : hepatopathy, jaundice AP / ALAT : < Pt IgG : 1.5x normal + 1,5 SMA > 1: Pt Viral markers : neg + 3 Pt HLA B 8 pos + 1 Pt Histology : lobular hepatitis ; response to steroids : + 6 Pt 18,5 Pt Definite Dg

22 PSC Definition : chronic inflammatory disorder of both intra- and extrahepatic bile ducts leading to fibrosis and cirrhosis. Diagnosis : visualization of biliary tree Ultrasound, ERCP, PTC, MRCP Histology

23 Clinical features Neonatal onset: slow progression to cirrhosis, Post-neonatal onset : delayed diagnosis by insidious nature : 50% portal hypertension, pruritus, intermittent jaundice.

24 Associated disorders Association with other disorders : 67 % IBD : 33 % Histiocytosis X : 19 % Immunodeficiency : 12 % others : 3 % idiopathic : 22 %

25 Other Differential Diagnosis Autoimmune-sklerosing cholangitis, secondary SC Wilson s disease

26 Paper case II R.M. (female) : * /2 years : intermittent acholic stools hepatopathy,hepatosplenomegaly Ap / ALAT : 4 IgG : 1-1,5x normal ANA, SMA : 1 : 40 viral markers : neg HLA neg Histology : sclerosing cholangitis, secondary biliary cirrhosis

27 Primary Sclerosing Cholangitis

28 Differential Diagnosis Overlap s. (n=12) Small duct sc (n=16) PSC (n=47) Median age at d. 13,5y 10,5y 11y Male gender (%) Mean ggt (IU/L) Mean ALT ( IU/L) Pos. AI Marker (%) Fibrosis stage 3-4 (%) UC (%) C s d (%) LTX (%) Kerkar N, Miloh T, Curr Gastroenterol Rep, 2010, 12:

29 Modified from : Mieli-Vergani, JPGN, 2009 Diagnostic/Therapeutic Approach Wilson s disease Hepatopathy Ceruloplasmin Copper excretion i.u Ultrasound MRCP Histology Copper det. Pred + Aza No response Frequent relaps Pred + MMF Pred + CNI normal abnormal Diagnosis confirmed Remission Normal transaminases Normal IgG Low antibody titer Treatment failure LTX Endoscopy Pred + Aza + UDCA No response Frequent relaps Pred + CNI +UDCA

30 Therapy Monitoring AZA : a) White cell blood count b) Pancreatitis 8 c) 6TGN :Target value : pmol/8x10 rbc Pred.: blood sugar, art. hypertension, bone metabolism, Cushing syndrome UDCA : Diarrhea, serum bile acid concentrations

31 Prognosis and Therapy AIH : Response : Pred + Aza : 80-95% Relapse : about 40% Liver transplantation : fulminant presentation treatment failure (8,5%) Duration of therapy : minimum 4 years AISC : UDCA : 15 mg/kg/day, Pred : as much as needed Aza : 2 mg/kg/day Duration of therapy : longer than in AIH PSC : UDCA < 20 mg/kg/day, oral vancomycin Risk of Cholangio-Carcinoma > 10 y after diagnosis Risk of Colon- Carcinoma : Surveillance colonoscopy LTX : 19-21% of children with PSC

32 Prognosis AIH Type 1 : good, if diagnosed early AIH Type 2 : at risk of FHF PSC : questionable : Risk of cholangiocarcinoma, recurrence after LTX, coloncarcinoma