Autoimmune Hepatitis. DEIRDRE KELLY ESPGHAN GOES TO AFRICA CAPETOWN October 2013

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1 Autoimmune Hepatitis DEIRDRE KELLY ESPGHAN GOES TO AFRICA CAPETOWN October 2013

2 Autoimmune Hepatitis DEFINITION Progressive necroinflammatory disease Mononuclear infiltrate in the portal tract Increase in IgG Nonspecific autoantibodies Responds to immunosuppression

3 Autoimmune Hepatitis PATHOGENESIS Environmental trigger Immunogenetic disposition HLA DR3 & DR7 Loss of tolerance to hepatic antigens Failure of Treg cells T cell mediated attack

4 Auto immune Hepatitis Type 1 Autoimmune Hepatitis SMA/ANA positive attacks smooth muscle Type 2 Autoimmune Hepatitis LKM Antibody positive liver cytosol positive attacks cytochrome P450 Autoimmune Sclerosing Cholangitis panca pos

5 Autoimmune Hepatitis TYPE 1 AUTOMMUNE HEPATITIS Clinical Features acute or chronic hepatitis multi-organ involvement gut/kidney/lung/heart/cns Diagnosis ANA Double stranded DNA SMA

6 Autoimmune Hepatitis LKM positive Hepatitis & Hepatitis C LKM 1 : no antibodies to Hep C true autoimmune disease LKM 2 : antibodies to Hep C antibodies to drugs cryoglobulinaemia

7 Autoimmune Hepatitis Type 2 Autoimmune Hepatitis Clinical Features acute / fulminant hepatitis not associated with other organ involvement Diagnosis LKM antibody positive low complement high gammaglobulin

8 AUTOIMMUNE LIVER DISEASE Autoimmune hepatitis : Autoimmune hepatitis revised scoring system (1999) International Autoimmune Hepatitis Group Biochemical-ALP,AST Histology interface hepatitis, Immunoglobulins- IgG lymphoplasmacytic infiltrate Autoantibodies ANA, SMA, Response to treatment LKM1 HLA, Hepatitis C, other autoimmune disease Subtype: AIH type 1 ANA, SMA AIH type 2 LKM1 Liver cytosol type 1

9

10 SMA LKM-1 ANA

11 Autoimmune Hepatitis TYPE 1 TYPE 2 AGE SEX (F%) DURATION MULTIORGAN Kings College series

12 Autoimmune Hepatitis TYPE 1 TYPE 2 Bilirubin umol/l AST IU/l Albumin g/l INR IgG Kings College series

13 Autoimmune Hepatitis Response to immunosuppression No difference between Type 1 & 2 Relapse : higher in Type 2 Death Type 1: 6% Type 2: 21%

14 Autoimmune Hepatitis Management of Immunosuppression Prednisolone 2mg/kg (max 60mg/day) When AST/ALT normal Add: Azathioprine (0.5-2mg/kg) Reduce steroid to 7.5/5 alternate day

15 AUTOIMMUNE LIVER DISEASE Autoimmune Sclerosing Cholangitis Radiology (intra/extra hepatic biliary irregularity or strictures) Histological (evidence of biliary disease) Elevated Ig G Autoantibodies (ANA, SMA, panca ) Overlap syndrome Autoimmune hepatitis revised scoring system Evidence of biliary disease Clinical and biochemical Radiological Histology

16 Autoimmune Hepatitis Autoimmune sclerosing cholangitis Clinical Features Chronic hepatitis Jaundice/cholestasis Cirrhosis & portal hypertension Inflammatory bowel disease Diagnosis Histology Biliary imaging ANA/SMA panca

17 Autoimmune Hepatitis AUTOMMUNE SCLEROSING CHOLANGITIS alkaline phosphatase (> 3 normal) G-GT ( x 3 normal). Bilirubin: normal or intermittently elevated AST/ALT (3-5 x normal) PT and albumin levels normal Elevated PT: fat-soluble vitamin deficiency K

18 Autoimmune sclerosing cholangitis Cholangiography Percutaneous, transhepatic, endoscopic Magnetic resonance imaging

19 Autoimmune sclerosing cholangitis Histology Sclerosis of bile ducts and hepatitis

20 Autoimmune Hepatitis & Sclerosing Cholangitis ASC AIH n = 27 n = 28 ANA SMA LKM 1 8 ANCA 74% 36% Kings College series

21 AISC Treatment of Sclerosing Cholangitis Ursodeoxycholic Acid 20 mg/kg Prednisolone (if associated with Type 1) Azathioprine Supportive: - Fat soluble vitamins - Nutrition Early consideration for transplantation

22 Autoimmune Hepatitis Difficulties with immunosuppression? When to stop AST/ALT normal for 12 or 24 months normal liver biopsy? secondary to drugs eg lamotrigine Problems High rate of relapse More difficult to obtain remission Van Gerven NM; Weiler-Normann C in J Hepatol, 2013;

23 Autoimmune Hepatitis Difficulties with immunosuppression Resistance/Intolerance to pred/aza Cyclosporine/ Tacrolimus/mycophenolate Cyclophosphamide/sirolimus Rituximab or infliximab

24 Autoimmune Liver Disease Type I and II Indications for Transplant (20%) End stage disease /Acute liver Failure Resistant to Immunosuppression Severe side effects Poor quality of Life

25 Autoimmune Hepatitis INDICATIONS FOR TRANSPLANT Endstage Liver Disease Ascites Intractable bleeding Varices Malnutrition Fatigue

26 Autoimmune Liver Disease Indications for Transplant Resistant to Immunosuppression Second line medication: Cyclosporin Tacrolimus Mycophenolate mofetil

27 Autoimmune Liver Disease Indications for Transplant Intolerable side effects: Diabetes Bone disease Growth failure Poor Quality of life

28 Autoimmune Liver Disease Indications for Transplant Fulminant Liver Failure Type II (LKM positive) Coagulopathy Encephalopathy? Trial of steroids no response to steroids may increase encephalopathy

29 AUTOIMMUNE LIVER DISEASE INDICATIONS FOR TRANSPLANT AIH1 (n=8) AIH2 (n=5) ASC (n=4) OS (n=1) Progressive liver disease despite treatment Acute liver failure Compensated liver disease 1* 0 1** 0 *Hepatopulmonary syndrome **Poor quality of life, failure to thrive, drug complication

30 AUTOIMMUNE LIVER DISEASE PATIENT CHARACTERISTICS AIH1 AIH2 ASC OS Total patients (n=101) OLT patients (n=18) 8 (12%) 5 (27%) 4 (50%) 1 (12%) Male:Female Non OLT 1:1.6 1:1.6 1:0.4 1:0.4 OLT 1:3* 1:4* 1:1* 0:1 Median age (years) onset of disease (range) Non OLT 12.5 ( ) OLT 12.7* ( ) 7.3 ( ) 11.4* (1.7-16) 16.1 ( ) 8.4* (4-14.8) 5.4 ( ) 9.7 Median interval between diagnosis to OLT (months) (range) 34.3 (0.2-77) 1.0 (0.2-60) 44.3 (7.7-85) 92.3 * No significant difference

31 AUTOIMMUNE LIVER DISEASE TREATMENT RESPONSE AND ROUTE TO TRANSPLANT Not treated n=3 n=101 Treated (Prednisolone+Azathioprine+/-ursodeoxycholic acid) n=98 Relapse No response n=31 (31%) n=12 Response n=67 (69%) 2 nd line treatment (Mycophenolate, tacrolimus, cyclosporin) n=18 No response n=12/18 (66%) Response n=6/18 (33%) n=28 (42%) No response to increase steroids n=15/28 (54%) n=6 Response To increase steroids n=13/28 (46%)

32 AUTOIMMUNE LIVER DISEASE TREATMENT RESPONSE AND ROUTE TO TRANSPLANT Not treated n=3 n=101 Treated (Prednisolone+Azathioprine+/-ursodeoxycholic acid) n=98 Relapse No response n=31 (31%) n=12 Response n=67 (69%) 2 nd line treatment (Mycophenolate, tacrolimus, cyclosporin) n=18 No response n=12/18 (66%) Response n=6/18 (33%) n=28 (42%) No response to increase steroids n=15/28 (54%) n=6 Response to increase steroids n=13/28 (46%) AIH1=1 AIH1=4 AIH1=2 AIH1=1 AIH2=1 AIH2=2 AIH2=1 AIH2=1 ASC=2 ASC=2 OS=1 LIVER TRANSPLANT n=18

33 AUTOIMMUNE LIVER DISEASE POST LT OUTCOME : GRAFT REJECTION Kaplan Meier curve: Comparing acute graft rejection free time of children transplanted for AILD versus non AILD (isolated OLT ) 1.0 Cumulative graft rejection free survival Non AILD n -=273 AILD n=18 Log rank, p = 0.3 Graft rejection AIH1 (n=8) Acute 5 (62%) AIH2 (n=5) 4 (80%) Chronic 0 1 (20%) ASC (n=4) 2 (50% ) 1 (25% ) OS (n=1) Months post OLT

34 Transplantation for Autoimmune Liver Disease Immunosuppressive Protocols: Standard protocols: Cyclosporin A / Azathioprine / Steroids Tacrolimus / Steroids IL-2 antibodies / Tacrolimus / MMF? Role of steroid withdrawal? Role of steroid free protocols

35 Transplantation for Autoimmune Liver Disease Post Transplant Problems Reduced wound healing Increased risk of infection reduce pre-operative steroids

36 Autoimmune Hepatitis Post Transplant Problems? Lymphoproliferative disease? Recurrence? other organ involvement kidney/heart/lungs ulcerative colitis Colon cancer/cholangiocarcinoma

37 Transplantation for Autoimmune Liver Disease Incidence of Lymphoproliferative disease (5-10%) common in EBV negative recipients receiving adult EBV positive grafts? Less common in Autoimmune Liver disease More likely to be EBV positive Incidence reduced by: EBV PCR monitoring reduction in immunosuppression Good prognosis

38 Comparison of Chronic Hepatitis free survival post OLT in patients with or without AILD ( ) 1.0 Cumulative Chronic hepatitis (+ raised Ig G + autoantibodies ) free survival AILD N=18 Non AILD N=192 AILD Non AILD Log Rank, p<0.02 Months post OLT Kaplan Meier curve

39 Recurrence of Autoimmune Disease Post Liver Transplantation Recurrent Autoimmune hepatitis (25%) Clinical symptoms Characteristic histology Circulating autoantibodies Elevated immunoglobulins Response to steroids / azathioprine Poor prognosis Graft failure and retransplantation

40 Recurrence of Autoimmune Disease Post Liver Transplantation Duclos-Vallee et al (2003) 10 year follow up of 17 women Immunosuppression: Cya/steroids 7/17 (41%) recurrence 4 histological recurrence 1-5 years without abnormal biochemistry Response: Steroids/Tacrolimus/MMF Retransplantation in 2

41 Recurrence of Autoimmune Disease Post Liver Transplantation Sclerosing Cholangitis Recurrence 6-14% Diagnosis: Radiology and histology Differentiate: ischaemia biliary obstruction cholangitis Modified by immunosuppression No significant effect in short term

42 Transplantation for Sclerosing Cholangitis 52 children with PSC 14 had overlap syndrome 40 had inflammatory bowel disease 11 underwent transplantation: 6 years post diagnosis 3 developed recurrence 1 developed ulcerative colitis No difference in survival between AIH and PSC

43 De Novo Autoimmune Hepatitis Graft dysfunction Elevated immunoglobulins Positive autoantibodies Response to steroids/aza?mechanism HLA DR3/4 Confirmed in adults and children

44 Autoimmune Disease Autoimmune hepatitis & Sclerosing Cholangitis Immunological basis Medical treatment succesful Transplantation 20% Recurrence post transplant

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