RIUNIONE MONOTEMATICA AISF 2013 Personalizzazione della Cura in Epatologia 17-19 ottobre 2013, PISA Prototypes of autoimmune hepatitis and sclerosing cholangitis in childhood La sottoscritta dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label Giorgina Mieli-Vergani King s College London School of Medicine
Case 1 3 year-old girl presenting with jaundice bilirubin 150µmol/l AST/ALT 1500/2000 IU/l albumin 33 g/l INR 2.5 family history of IDDM and AI thyroiditis? acute hepatitis: observe fluctuating LFTs specialised centre
Case 1 US mildly enlarged spleen anti-lkm1 1/5120, mildly elevated IgG steroids rapid improvement of AST/ALT & INR liver biopsy: severe interface hepatitis multilobular collapse moderately increased fibrosis 20 yrs later: normal LFTs, AI thyroiditis on Rx no signs of portal hypertension Rx: prednisolone 2.5mg/day azathioprine 37.5mg/day
Case 2 16 yrs old female, Hispanic, student, from Southern California high IgG transaminases 21X UNV bilirubin 14X UNV ANA, SMA, AMA negative no treatment diagnosis: cryptogenic hepatitis Duchini et al, Am J Gastroenterol 2000;95:3238
Case 2 25 years of age: end-stage liver disease liver transplant death Duchini et al, Am J Gastroenterol 2000;95:3238
Case 3 15 year-old girl with amenorrhoea, acne, tiredness, decreased school performance bilirubin 65 µmol/l AST/ALT 150/190 IU/l GGT/AP 102/280 IU/l albumin 31 g/l IgG 21 g/l INR 1.2 family history of colitis and rheumatoid arthritis
Case 3 OE: splenomegaly, spider nevi US: splenomegaly ANA 1/320; SMA 1/160 liver biopsy: interface hepatitis increased fibrosis? cirrhotic transformation MRCP: normal colonoscopy: normal
Case 3 Rx: pred pred + azathioprine normal LFTs & IgG levels, negative autoantibodies for 4 years liver biopsy planned for possible treatment withdrawal
Case 4 14 year-old boy with tiredness, mild abdominal pain (no diarrhoea), poor school performance bilirubin 55 µmol/l AST/ALT 102/130 IU/l GGT/AP 90/210 IU/l albumin 38 g/l IgG 29 g/l INR 1.1 family history of colitis
US: splenomegaly Case 4 OE: splenomegaly, spider nevi ANA 1/320; SMA 1/160 liver biopsy: interface hepatitis increased fibrosis mild bile duct damage copper binding protein +ve MRCP: intrahepatic cholangiopathy colonoscopy: indeterminate colitis (?UC)
Case 4 Rx: pred/azathioprine/udca/mesalazine normal LFTs, but persistently high IgG and positive autoantibodies difficult to control IBD UC diagnosed two years after presentation escalation of IBD treatment (MMF, CI): poor histological control
Case 4 progression of bile duct disease jaundice end-stage liver disease liver transplant 8 years after diagnosis persistent UC AISC recurrence 2 years after transplant listed for re-transplant 4 years after recurrence
Autoimmune hepatitis - AIH Diagnostic Criteria high IgG autoantibodies (ANA/SMA/LKM1) interface hepatitis Gregorio et al, Hepatology 2001;33:544-553 normal cholangiogram
Autoimmune hepatitis anti-nuclear antibody type 1 (ANA/SMA positive): 2/3 of patients anti-smooth muscle antibody type 2 (LKM1/LC1 positive): 1/3 of patients anti-liver kidney microsomal type1 anti-liver liver cytosol type1
Autoimmune sclerosing cholangitis - AISC Diagnostic Criteria high IgG autoantibodies (ANA/SMA/LKM1) interface hepatitis Gregorio et al, Hepatology 2001;33:544-553 abnormal cholangiogram
AIH versus AISC Clinical features and mode of presentation AISC AIH-1 AIH-2 ANA/SMA+ LKM1+ median age at diagnosis (yrs) 12 11 7 female (%) 55 75 75 mode of presentation (%) acute hepatitis (often fluctuating course) 37 insidious onset 37 complications of CLD 26 47 38 12 40 25 10 inflammatory bowel disease (%) 44 20 12 Gregorio et al, Hepatology 2001;33:544-553
AIH versus AISC Laboratory parameters at presentation AIH AISC bilirubin 35 (4-306) 20 (4-179) albumin 35 (25-47) 39 (27-54) AST 333 (24-4830) 102 (18-1215) INR 1.2 (0.96-2.5) 1.1 (0.9-1.6) GGT 76 (29-383) 129 (13-948) AP 356 (131-878) 303 (104-1710) AP/AST ratio 1.14 (0.05-14.75) 3.96 (0.20-14.20) Gregorio et al, Hepatology 2001;33:544-553
AIH versus AISC HLA association 222 Caucasoid patients AIH 1 # 109 AIH 2 # 49 ASC # 64 controls DRB1*03 72% 36% 19% 26% DRB1*07 13% 54% 10% 14% DRB1*1301 17% 14% 42% 17%
AIH versus AISC standard treatment: prednisolone + UDCA if AISC azathioprine
AIH vs AISC Rx response (King s prospective study: 54 pts 1984-2013) AIH-1 AIH-2 AISC remission rate 97% 87% 89% median time to remission 6 mts 9 mts 2 mts relapse rate 42% 46% 45% cessation of treatment 19% 0% 5% Gregorio et al, Hepatology 2001;33:544-553 Scalori et al, Hepatology 2007;46 Suppl 1:555A
AIH vs AISC Outcome (King s prospective study: 54 pts 1984-2013) AIH-1 AIH-2 AISC LT rate 6%* 14%* 27%** recurrence post LT 0% 0% 71% * 8-14 yrs after ** 1-12 yrs after Gregorio et al, Hepatology 2001;33:544-553 Scalori et al, Hepatology 2007;46 Suppl 1:555A
Evolution from AIH to AISC Index case: AIH + UC Two further cases of AIH have evolved to ASC 13 and 14 years after diagnosis: both with IBD At diagnosis 8 years later
AIH vs AISC Transplant-free survival AIH SC Survivor survivors 1.00 0.75 Survival Plot (PL estimates) AIH ASC P<0.009, Log Rank 0.50 0.25 0.00 0 5 10 15 20 years Times Scalori et al, Hepatology 2007;46 Suppl 1:555A
Autoimmune sclerosing cholangitis King s prospective study progression of liver disease and recurrence post transplant are associated to active inflammatory bowel disease