Autoimmunity and the Liver: translation to the clinic

Instituto de Investigación Biomédica de Malaga, IBIMA Malaga Biomedical Research Institute 26 Jjanuary 2016 Giorgina Mieli-Vergani Paediatric Liver, GI & Nutrition Centre King’s College Hospital, London, UK Autoimmunity and the Liver: Translation to the clinic type 1: adults and children Autoimmune Hepatitis Autoimmune Hepatitis type 2: mainly children  adults: often chronic, mild/moderate severity  children/young adults: often acute, aggressive Autoimmune Hepatitis Autoimmune Hepatitis Presentation type 1 (ANA/SMA positive): 2/3 type 2 (LKM1 positive): 1/3 Juvenile Autoimmune Hepatitis Juvenile Autoimmune Hepatitis Juvenile Autoimmune Hepatitis Juvenile Autoimmune Hepatitis females: 75% Similarities between Type 1 and Type 2 AIH Type 1 and Type 2 AIH associated AI disorders: 20% family history of AI disease: 40% high IgG: 80%  at a younger age Differences between Type 1 and Type 2 AIH Type 1 and Type 2 AIH LKM1 positive AIH presents: Juvenile Autoimmune Hepatitis Juvenile Autoimmune Hepatitis  with partial IgA deficiency  less frequently with cirrhosis  more frequently with acute hepatic failure ~ 50% of children/adolescents with AIH-1 serology have an overlap syndrome with sclerosing cholangitis Juvenile Autoimmune Hepatitis Juvenile Autoimmune Hepatitis Autoimmune Autoimmune Sclerosing Sclerosing Cholangitis Cholangitis Autoimmune Autoimmune sclerosing sclerosing cholangitis cholangitis  autoantibodies (ANA/SMA)  high IgG Diagnostic Criteria  interface hepatitis  abnormal cholangiogram Gregorio et al, Hepatology 2001;33:544-553 GGT and AP often normal at presentation particularly high IgG levels frequently associated with IBD (sometimes asymptomatic) Autoimmune Autoimmune sclerosing sclerosing cholangitis cholangitis affects equally males and females frequent positivity for ANCA Adulthood AIH Adulthood AIH 2 mg/Kg/day (maximum 60 mg/day) Juvenile AIH Juvenile AIH Prednisolone gradually decreased over 4 4- -8 weeks 8 weeks to 2.5 to 2.5- -5 mg/day 5 mg/day depending on age + UDCA if ASC ASC (15 mg/Kg/day) Juvenile AIH Juvenile AIH Azathioprine  add if high steroid dose required to maintain normal or nearly normal AST or in the presence of serious steroid side effects  myelosuppressive myelosuppressive: start at low dose (0.5 mg/Kg/day) and increase gradually to 2 mg/Kg/day  hepatotoxic hepatotoxic: never first line Rx in ill, jaundiced patients weekly LFTs, INR, FBC ‘ ‘Fine tuning Fine tuning’ ’to avoid severe side effects: aim to 80% AST decrease 80% AST decrease within 6 weeks Juvenile AIH Juvenile AIH Rx schedule at King’s 80% ultimately require azathioprine Juvenile AIH Juvenile AIH sustained remission on azathioprine azathioprine monotherapy monotherapy (Johnson et al, New Engl J Med 1995;333:958) successful in ANA/SMA+ AIH less successful in LKM1+ AIH In children: In adults: : AIH AIH - -Maintenance of remission Maintenance of remission King’s criteria for stopping treatment* *  at least one further year of normal normal LFTs LFTs & IgG IgG, negative negative or low titre low titre autoantibodies autoantibodies (checked 3 monthly) * never just before or during puberty * never just before or during puberty Juvenile AIH Juvenile AIH  no inflammation no inflammation on liver biopsy liver biopsy performed at the end of the year  gradual gradual discontinuation of azathioprine, then prednisolone  daily daily treatment for at least three years three years 13-year (8-29) follow up – Transplant-free survival AIH AIH vs ASC ASC Scalori et al, Hepatology 2007;46 Suppl 1:555A Survival Plot (PL estimates) 0 5 10 15 20 0.00 0.25 0.50 0.75 1.00 Survivor Times AIH SC P<0.009, Log Rank ASC ASC AIH AIH survivors years AIH AIH- -1 1AIH AIH- -2 2ASC ASC Gregorio et al, Hepatology 2001;33:544-553 Scalori et al, Hepatology 2007;46 Suppl 1:555A Outcome (King’s prospective study) recurrence post LT 0% 0% 0% 0% 71% 71% LT rate 27% 27% 14% 14% 6% 6% AIH AIH vs ASC ASC progression of liver disease and recurrence post transplant are associated to active inflammatory bowel disease active inflammatory bowel disease Autoimmune Autoimmune sclerosing sclerosing cholangitis cholangitis King’s prospective study Aw et al, J Hepatol 2009;51:156 Difficult Difficult- -to to- -treat patients: resistant or unresponsive treat patients: resistant or unresponsive Calcineurin Calcineurin inhibitors inhibitors anecdotal experience Rituximab Rituximab anti anti- -TNF TNFα α Thank you Children’s Liver Disease Foundation Adulthood AIH Adulthood AIH Adulthood AIH Adulthood AIH Adulthood AIH Adulthood AIH