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

2. 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?

3. 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?

4. 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?

5. 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?

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

7. 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 % 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?

8. 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?

9. 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?

10. 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?

11. 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?

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

13. 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?

14. 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?

15. 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 mg/kg/day
Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation?

16. Discussion Thank you for your attention