Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? Rahim MN et al., Liver Transplantation 2019 Jun; 25(6):946-959. Journal Club 08.08.2019 – Stephanie Gärtner

Definitions Acute liver failure (ALF - AASLD) absence of preexisting liver disease, acute onset ≤ 26 weeks, INR ≥ 1,5, hepatic encephalopathy (HE) Onset HE: hyperacute (7d), acute (8-28d), subacute (>28d) Acute severe autoimmunhepatitis (AS-AIH)? Czaja et al./Yeoman et al.: acute presentation ≤ 26 weeks, INR ≥ 1,5, histological no cirrhosis Rahim MN et al.: Acute AIH: icteric, no evidence of coagulopathy or HE AS-AIH: icteric, INR ≥ 1,5, no HE AS-AIH with ALF: icteric, INR ≥ 1,5, HE Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Clinical presentation of AIH Diverse! Acute hepatitis: de novo, spontaneous exacerbation, super imposed infection, DILI on preexistent liver disease Chronic hepatitis Cirrhosis Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Autoimmun DILI AIH with superimposed DILI DILI-induced AIH Immune-mediated DILI: autoantibodies not always present, corticosteroids!? Biopsy! AIH DILI Emperipolesis eosinophil infiltration Rosette formation centrilobular necrosis Autoantibodies common in nitrofurantoin/minocycline-induced hepatitis hepatocellular injury secondary to immune checkpoint inhibitors (e.g. nivolumab - Opdivo) usually don`t show pos. auto-ab, but respond to steroids + other features of autoimmunity, similar in infliximab, adalimumab anti-tuberculosis medication can induce hypersensitivity reactions, leading to b cell-mediated autoantibody production and cyctotoxic T cell responses that resemble spontaneous idiopathic AIH – maybe steroids, if drug withdrawal is not enough, re-exposure with anti-TB med. may be possible Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

AS-AIH as a cause of ALF AIH is an important cause of ALF and ALF-UO Percentages of patients with AIH who develop ALF vary (59-69% or less?) Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Diagnostic criteria of AS-AIH and ALF Liberal R et al. Diagnostic criteria of autoimmune hepatitis, Autoimmun Rev. 2014 Apr-May;13(4-5):435-40 Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Clinical, laboratory, and radiological features of AS-AIH Acute vs. chronic AIH More common in acute AIH: jaundice, anorexia, higher bilirubin and INR, “typical” histological features No difference in fibrosis stage – preexisting liver disease in acute cases? Acute AIH Antibodies, IgG not necessarily pos./increased – sign for severe AIH? Imaging limited in AS-AIH Antibody production later during clinical course, assay sensitivity ANA undetected/weakly pos. 29-39% in severe/fulminant AIH Yeoman et al. 88% pos. for ANA, ASMA and /or LKM – with IAIHG AB strength only 66% IgG 25-39% normal in AS-AIH/fulminant AIH, and lower levels in AS-AIH compared with acute exacerbation of chronic AIH Unenhanced computed tomography (CT): heterogenous hypoattenuated regions within the liver in 65% of patients with AIH-associated ALF when compared with patients with viral-associated ALF, Liver volume on CT is significantly reduced in nonacetaminophen cases of acute liver injury (ALI)/ALF when compared with acetaminophen-induced ALI/ALF Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Histological features of AS-AIH Diagnosis and excluding differential diagnoses Timing! Acute onset AIH Centrilobular necrosis AS-AIH Necrosis around central vein, centrilobular/multiacinar necrosis Plasmacell enrichment, lymphoid aggregates, central venulitis Chronic (active) AIH Interface hepatitis, portal inflammation (plasma cells), rossettes fibrosis Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Criteria for corticosteroids use and stratification of patients based on corticosteroid response 80% remission under corticosteroids Increased likelihood of treatment failure in AS-AIH i.v. vs. oral < 0,5 mg/kg/day vs. ≥ 0.5 mg/kg/day in AIH Mortality higher in steroids non-responder – severity of coagulopathy is best correlator Steroids do not improve overall/spontaneous survival in autoimmune LF Increased mortality in patients on steroids and MELD >40 Little benefit once HE has developed Septic complications The normalization of INR (median, 20 days) and bilirubin (median, 72 days) were quicker than the normalization of aspartate aminotransferase (median, 80 days) in the corticosteroid-responder group. Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Role of Other Immunisuppressants None in AS-AIH! Azathioprine: poor drug metabolism, worsening cholestasis just small observational studies available and not specific AS-AIH: calcineurin inhibitors, MMF Tacrolimus, low-dose in 9 patients + 7,5 mg predinisolone MMF: Of 36 patients on MMF included in the analysis, 14 patients (39%) experienced remission. A total of 22 patients (61%) did not respond sufficiently to MMF. The response rate to MMF was dependent on the cause of treatment cessation of azathioprine. Of eight patients with prior nonresponse to azathioprine, six (75%) did not respond to MMF and only two (25%) reached biochemical remission. Of 28 patients with azathioprine intolerance in 16 (57%) patients, the response to MMF was insufficient and in 12 patients (43%) remission was reached GCP EASL Budesonid + Azathioprin Tacrolimus , Cyclosporin Sirolimus Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Timing of Liver Transplantation (LT) Best option in AS-AIH High-grade HE in AS-AIH = LT immediately MELD ≤ 28, low-grade HE, absence of massive hepatic necrosis on histology, improvement of bilirubine/INR in first 4 days – higher response rates to steroids No improvement of MELD-Na or UK Model for End-Stage Liver disease within 7 days of steroids – high risk of progressing to ALF Recurrence of AIH in 17-42% after LT (histology of explant) Increased acute or late rejection compared to non-AIH liver diseases Elevated liver enzymes and immunoglobulins before LT and lymphoplasmacytic infiltration with moderate-to-severe inflammatory activity in explants may be associated with a greater likelihood of AIH recurrence after LT. – Complete steroid withdrawal should depend on these factors. Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Algorithm for corticosteroids use and timing of LT in acute presentation of AIH Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Management of ALF Secondary to Seropositive and Seronegative AIH In AS-AIH and ALF early contact with transplant center Biopsy and CT volumetrics other diagnoses excluded – start steroids Nonresponse or HE - transfer to transplant center Vigilant monitoring! Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Prognosis and Mortality Pretransplant era survival rate in fulminant AIH < 20% Placebo controlled trial (> 40 yrs ago): 5-year survival rate of 32% in untreated vs. 82% in corticosteroid-treated patients Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Conclusion Consider AIH as a cause for seronegative ALF DILI: withdrawal of the causing drug Corticosteroids as long as no HE – dose, route, length?! Other immunosuppressants? Early evaluation of the therapy Assessment for LT at the same time Optimal timing for LT? Classification of acute presentation of AIH Prednisone 0.5-1 mg/kg/day Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? 08.08.2019

Discussion Thank you for your attention