Hépatite auto-immune. aigue sévère
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1 9 eme journée des Centres de Reference et de Compétence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immune (MIVB-H) llaborat ions des équipes impliquées dans l' ex plora char ge des ef et s indésirables des immuno t hérap INSCRIPTIONS es d organe, heurs, nts toxicités i-cancéreuses. Hépatite auto-immune ORGANISATEURS : Aurélien Marabelle, Olivier Lambotte, Stéphane Champiat aigue sévère formation.gustaveroussy.fr/ shop/symp Envoyez vos abstracts pour présentation orale ou poster à helene.de-gramont@gustaveroussy.fr ÉCOLE DES SCIENCES DU CANCER Eleonora De Martin Centre Hépato-biliaire, Hôpital Paul Brousse Villejuif - France
2 Miss M, 26 year old January 2018 : admitted to the hospital for acute severe hepatitis Since 1 month: jaundice, fatigue Biology at admission AST IU/L 1401 Tot bili μmol/l 175 GB G/L 3.08 ALT IU/L 866 PT % 33 PNN 1.7 GGT IU/L 74 INR 2.36 Hb g/l 10.5 ALP IU/L 200 FV % 34 Plts G/L 155
3 Medical history Lifestyle: - Not married and no child - Works in the finance - Alcohol consumption : occasional - Tobacco 10 cigarettes/day Past medical history: - Gougerot-Sjörgren Sdr + Purpura plaquenil Hyperthyroidism (Basedow) remission Recent travel to NY, no drugs, no medications
4 Etiological work-up Virology Ac HAV, Ag HBs, Ab HBs, Ab HBc, Ab HCV, HIV, HTLV 1-2, PCR CMV, EBV, HSV, HHV6, HHV8, HEV NEGATIVES Immunology Anti-tissue Ab: ANA > 1:1280 spickeled AMA, ASMA, anti-lkm1, anti-lc1 NEGATIVES IgG 63 (N<12.5), IgA (N<2.54), IgM 2.07 (N<2.01) Infection ECBU -, Hemoc - Toxic Plasma and urine : -
5 At CT scan
6 IAIHG simplified diagnostic criteria probable AIH; 7 points : definite AIH =6 Hennes, Hepatology 2008
7 At histology Pour courtoisie du Dr M Sebagh «Subacute hepatitis (A3F2 according to METAVIR) with sub-massive necrosis»
8 At histology Pour courtoisie du Dr M Sebagh «Subacute hepatitis (A3F2 according to METAVIR) with sub-massive necrosis. The presence of plasma cells is compatible with AIH»
9 Is acute severe autoimmune hepatitis the right diagnosis?
10 Acute Severe AIH : diagnosis
11 Different spectrum of AIH Acute Chronic Severe Fulminant
12 Acute onset of AIH Multicenter retrospective Italian study, 204 patients with acute hepatitis Characteristic AIH Histological acute onset (83 pts) AIH Histological acute on chronic onset (45 pts) GGT, g/l 19 (16-60) 24 (9-36) Albumin, g/l 40 (23-58) 36 (18-62) 0.02 INR 1.1 (1-1.76) 1.26 (1-3) 0.02 IgG x ULN 1.12 (0.5-2) 1.4 ( ) Cirrhosis 0 9 (20) <.0001 p Muratori, Dig Liv Dis 2018
13 IAIHG simplified diagnostic criteria probable AIH; 7 points : definite AIH Hennes, Hepatology 2008
14 IAIHG simplified diagnostic criteria in Fulminant Hepatic Failure 70 patients with non-acetaminophen FHF. Simplified IAIHG criteria appears less sensitive the 1999 criteria, in ascribing an overall (probable or definite) diagnosis of AIH (24% versus 40%). Yeaoman, Hepatology 2009
15 IAIHG simplified diagnostic criteria in acute onset of AIH Fujiwara, Liver International 2011
16 AS-AIH: diagnostic challenge - Auto-antibodies : absents or weakly positives in 30%-40% of patients - IgG level : normal in 25%-40% of patients - Histology: typical and compatible? Exhaustive? EASL Guidelines, Journal of Hepatol 2015 Czaja, Dig Dis Sci 2013
17 Anti-nuclear antibodies (ANA) Immunofluorescence pattern on rodent liver section Liberal, J of Autoimm 2013
18 AIH Histology Typical - Interface hepatitis - Lymphocytic/lymphoplasm acytic infiltrates in portal tracts and extending into the lobule - Emperipolesis - Hepatic rosette Compatible - Chronic hepatitis with lymphocytic infiltration without all the features considered typical EASL Guidelines, Journal of Hepatol 2015
19 Histology in acute onset of AIH Fujiwara, Liver International 2011
20 Centrilobular necrosis Infiltration of Plasma Cells into Liver Tissue Abe, Clinical Gstroenterol and Hepatol 2007
21 Characteristic histological features in AIH-ALF 72 patients from the ALF Study. The diagnosis of probable AIH-ALF was based on 4 features: 1. Massive hepatic necrosis 2. Lymphoid follicles 3. Plasma-cell infiltration 4. Central perivenulitis Histological features of AIH-ALF predominate in the centrilobular zone Stravitz, Hepatology 2011
22 Imaging in ALF 47 patients with ALF none with cirrhosis: 65% Ascites 28% Splenomegaly 23% Nodular surface Imaging findings are variable and can resemble to cirrhosis need for liver biopsy Romero, Dig Dis Sci 2014
23 Miss M : Biological evolution ALT, IU/l Bilirubine, μmol/l ,36 2,77 3,03 3,19 PT INR
24 Would you treat this patients with corticosteroids and how would you evaluate treatment response?
25 Acute Severe AIH : treatment
26 Management of AS-AIH EASL Guidelines, Journal of Hepatol 2015
27 Steroid Use in Acute Liver Failure Overall and spontaneous survival among different aetiologies of ALF Mean INR 3.33 Karkhanis, Hepatology 2014
28 Uselessness of corticosteroids in severe and fulminant form of AIH Patient Characteristics 12/16 (75%) treated patients 10/12 (83%) liver transplantation Median INR 6.85 Ichai, Liver Transpl 2007
29 The role of corticosteroids in modifying outcome of AS-AIH 23/32 (75%) treated patients 10/23 (43%) liver transplantation Yeoman, J Hepatol 2015
30 Improvement of bilirubin at week 2: early prognostic factor of treatment response Biochemical response after 2 weeks of corticosteroids * p<0.001 Histological features of patients with early mortality: multilobular necrosis Czaja, Gastroenterology 1988
31 Predictors of corticosteroid response Characterisitcs of responders and non responders to medical therapy Verma, Hepatology 2009
32 Prognostic factors in AS-AIH patients treated with corticosteroids 15/17 (88%) treated patients Prognostic factors : 9/15 (60%) liver transplantation - Massive Hepatic Necrosis type 5 - INR at presentation : cut off MELD at presentation : cut off 28.5 INR ALT Moenne-Loccoz, J Hepatol 2016
33 Early predictors of treatment failure in icteric AIH.. At diagnosis - Median bilirubin (451 lmol/l vs 262 lmol/l, P ) - INR (1.62 vs 1.33, P ), - MELD score (26 vs 20, P ) - MELD-Na score (27 vs 22, P ) - UKELD score (59 vs 57, P ) Analysis of area under the AUROC values at day 7 - Delta bilirubin (AUROC 0.68) - Delta creatinine (0.69) - Delta MELD (0.79), - D MELD-Na (0.83) - D UKELD (0.83) Heterogeneous population including pediatric patients, severe and not severe AIH Yeoman, Hepatology 2011
34 SURFASA: multicenter study on AS-AIH Multicenter French retrospective study 128 Patients 115 (90%) Treated 13 (10%) Non-treated 30 (26%) 85 (74%) 12 (92%) 1 (8%) LT yes LT no LT yes LT no 3 (10%) 10 (12%) 1 (100%) Dead Dead Dead De Martin et al, AASLD 2017
35 Response probability Overall survival at 90 days Liver Transplantation free Survival Overall patients survival % Time (Days) Patients at Risk De Martin et al, AASLD 2017
36 Which are the predictive factors for corticosteroid response defined by the LT-free survival? 128 Patients 115 (90%) Treated 13 (10%) Non-treated 30 (26%) 85 (74%) 12 (92%) 1 (8%) LT yes LT no LT yes LT no 3 (10%) 10 (12%) 1 (100%) Dead Dead Dead De Martin et al, AASLD 2017
37 Predictive factors of corticosteroid response p OR CI 95% Day PT Δ%7-bilirubin* * (D7-D0)/D0-bilirubin Model retained at multivariate analysis X coeff (PT 0) + coeff (Δ%7-bilirubin) De Martin et al, AASLD 2017
38 12-Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan Jan-18 Miss M : Biological evolution D0 D7 D0 D ,36 2,77 3,03 3,19 3,23 2,97 2,62 ALT, IU/l Bilirubine, μmol/l PT INR Corticosteroid response continuation of therapy
39 Conclusion The diagnosis of AS-AIH is challenging as the main features of AIH may be absent. The liver biopsy is mandatory for the diagnosis and the assessment of a chronic disease. However the interpretation remains difficult. Corticosteroids are the therapy of choice. PT at day 0 and the improvement of bilirubin at day 7 since therapy introduction are associated with corticosteroid response The SURFASA score combining these variables predict whether corticosteroids should be continued or stopped and the patient rapidly evaluated for liver transplantation.
40 Acknowledgment Lille Brest Rennes Caen Rouen CHB Cochin Pitié Salp St Antoine Paris Beaujon Jean- Verdier Mondor Reims Strasbourg Besançon Poitiers Limoges Bordeaux Lyon Croix-Rousse Lyon Ed Herriot Grenoble Montpellier Toulouse Marseille la Timone
Optimal management of auto-immune
collaborations des équipes impliquées dans l' explorati en charge des ef ets indésirables des immunothérapies INSCRIPTIONS BLIC : cialistes d organe, Chercheur s, ovigilants ns l es toxicités es anti-cancéreuses.
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