A 63-year-old Caucasian woman presented with depressive syndrome and elevated liver enzymes but no extrahepatic manifestations. Liver biopsy showed cirrhosis with moderate activity and pericentral necrosis. She was treated with prednisone and azathioprine, achieving remission within 3 months. Azathioprine was stopped after 2 years due to normal liver enzymes and decreased IgG levels. Her case illustrates treatment and monitoring of autoimmune hepatitis.

1. Hépatite Auto-Immune
FHU
Jean-Charles Duclos-Vallée

2. Cas Clinique
• Femme de 63 ans
• Sans antécédents particuliers
• Caucasiene
• Syndrome dépressif
• Sans Manifestations extra hépatiques
• À l’admission:
– Poids= 52Kgs
– TP: 72% ,
– ALT: 10 X N; AST: 5 X N
– Bilirubin totale: 20 mmol/L
– IgG: 22 g/dL
– ANA: 1/640; ML: 1/320; anti SLA/LP- ; AMA-
– Biopsie hépatique: F4 avec activité modérée et nécrose péricentrale
– HLADRB1*04:01

3. © 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG
3
Fulminant
Acute
Severe
Chronic
EASL Clinical Practice Guidelines: Autoimmune Hepatitis, J Hepatol 2015
Clinical Presentation of Autoimmune
Hepatitis: A Large Spectrum

4. Age and sex-specific incidence rates of
autoimmune hepatitis in Denmark, 1994-2012
0
O
1
2
3
4
5
20 40 60 80
yrs
Incidencerate
Per100,000
Peryear
Women
Men
Danielsson Borssen A, et al. Scan J Gastroenterol 2017
Gronbaek et al. J Hepatol 2014
EASL Clinical Practice Guidelines: Autoimmune Hepatitis J Hepatol 2015
Diagnosis and Management of AIH in Adults and Children, 2019 Practice guidance
and guidelines from the AASLD Hepatology 2019
Incidence 50% increase in
Spain, Denmark, Sweden
and Netherlands

5. Baseline factors associated with
Cirrhosis at AIH at diagnosis
Ngu et al. Hepatology 2013

6. Diagnostic criteria
Score simplifié = 8
HAI « certaine »
EASL Clinical Practice Guidelines: Autoimmune Hepatitis, J Hepatol 2015

7. Antigen-Antibody Relation in
Autoimmune Hepatitis
(72% des cas, isolé 9-14%)
(85% des HAI2)
(30% des HAI2)
(Seuls dans 10%)
(50-80%)
12
Anti LKM Ab
Anti LC1 Ab
Anti SLA Ab: Sp: 99%
Anti Actin Ab
Type 2 AIH Type 1 AIHBallot E and Duclos-Vallée JC
Wies I et al.Lancet 2000
Palioura et al. Science 2009
Efe C et al. Liver Int. 2013
Anti Nuclear Ab

8. The different pattern of histological
lesions of AIH
Pratt DS et al. Gastroenterology 1997
Te HS et al. Gut 1997
Singh R et al. Am J Gastroenterol 2002
Zen Y et al. Hum Pathol 2007
Balitzer D et al. Mod Pathol 2017
In the portal tract:
Interface hepatitis
Rosetting of hepatocytes
Predominant Lymphocytic/
Plasma cell infiltration
In the centrilobular zone
(acute liver failure):
Central perivenulitis: 65%
Plama cell-enriched inflammatory infiltrate: 63%
Massive hepatic necrosis: 42%
Lymphoid follicles: 32%

9. Prediction of Short-and Long-Term Outcome in
Patients with Autoimmune Hepatitis
Kirstein et al. Hepatology 2015

10.  Introduction par 1mg/Kg prednisolone puis Azathioprine
(1mg/kg)
 Rémission complète (normalisation of ALT and Ig G: 12 g/dL)
était obtenue après 3 mois de la combinaison thérapeutique

 A 1 an du fait de la normalisation des transaminases,
prednisolone était arrêtée et azathioprine maintenue à50
mg/j
 A 2 ans après le diagnostic, azathioprine était arrêtée du fait
d’un maintien de la normalisation of ALAT et une
décroissance du taux d’IgG à 14.5 g/dL (N < 12.0 g/dL)
Cas Clinique

11. Therapy
EASL Clinical Practice Guidelines: Autoimmune Hepatitis J Hepatol 2015

12. The importance of the initial response
Tan P et al. Liver Int 2005
Werner M et al. Scand J Gastroentrol 2010

13. Treatment Response in Patients
with Autoimmune Hepatitis
No Cirrhosis:
Initial dose of prednisolone of 1 mg/kg of
body weight
Tapered to within the next 3 months
to a maintenance dose to 5 to 10 mg/day
+
From the beginning, combination with
Azathioprine
at a dose of 1 to 1.5 mg/kg of body weight
Schramm C et al. Hepatology 2010

14.  The rapidity of response is the most important
Index of outcome and the liver aminotransferase
levels should improve within 2 weeks
 Elderly patients (≥ 60yrs old) respond more
quickly to treatment than young adults
 Biochemical remission that is achieved within
6 months is associated with a significantly lower
frequency of porgression to cirrhosis or need for LT

15. Predinsolone dosage and chance of remission in
patients with autoimmune hepatitis
Pape et al Clinical Gastroenterology and Hepatology 2019

16. Budesonide and AIH

17. Azathioprine with Budesonide induces Remission
Manns et al. Gastroenterology 2010

18. Manns MP, Jaeckel E, and Taubert R

19. Manns MP, Jaeckel E, and Taubert R

21. Diagnosis and Management of AIH in Adults and Children, 2019 Practice guidance
and guidelines from the AASLD Hepatology 2019

22. A real-world study focused
on the long-term efficacy of MMF
as first-line treatment of autoimmune hepatitis
Zachou et al. APT 2016
75% of patients in whom MMF treatment
was withdrawn remained in complete remission
For a median of 2 years

23. Zachou et al. APT 2016
Yu ZJ et al. Eur J Gastroenterol Hepatol 2019
MMF as a first line of therapy

24. AASLD Hepatology 2019

25. AASLD Hepatology 2019

26. Biological Criteria of Remission
in patients with AIH
Elevated levels of aminotranferases +
IgG/gamma-globulins, or both
indicate
histological activity
But when ?
Luth S et al. J Clin Gastroenterol 2008
Montano-Loza AJ et al. Am J Gastreonterol 2007

27. SECOND LINE TREATMENTS
7-9%
AASLD Hepatology 2019

28. A non response
Non-response:
• A lack of reduction of transaminases by more
than 25 % of transaminases after 2 weeks
EASL Clinical Practice Guidelines: Autoimmune Hepatitis, J Hepatol 2015

29. Nicoll et al APT 2019

30. Nicoll et al APT 2019

31. Meta analysis of MMF
Santiago P et al. APT 2019
Response rate

32. Tacrolimus as second line of therapy
Efe C et al. Clin Gastroenterol Hepatol 2017
Efe C et al. Dig Dis sSci 2018
Than NN et al. Scan J Gastroenterol 2016
 3 single center studies:
Normalization of aminotransferases in 91-92%
Normailisatio of either serum ALT or IGG level in 79%
 Multicenter study:
Normalization of serum aminotransferases in 73% (94%
with AZA-intolerance and 57% with incomplete reponse
of treatment failure
 Two metaanalyses:
Normalization of serum aminotransferases: 75-94%
Hanouneh M et al. Scan J Gastroenterol 2019
Tannous MM et al APT 2011

33. Diagnosis and Management of AIH in Adults and Children, 2019 Practice guidance
and guidelines from the AASLD Hepatology 2019

36. Expert clinical management of AIH in the real world
Second line of therapy
Liberal R APT 2017

37. Salvage therapies (1)
Anti-TNF-a
N=11 (7 cirrhosis)
 6 patients normalized aminotransferase and
IgG levels
 7 patients develepd infectious complications
 1 patient stopped treatment due to allergic
reaction
Weiler-Normann C et al. J Hepatol 2013

38. • 6 Adults ( 3 with AZA intolerance and 3 non
responders to Steroids/aza and MMF)
• Serum and IgG levels improved signficantly in
all patients
• Biochemical remission: 67%
• A prospective randomized clinical trial is
ongoing that evaluates Ianalumab (VAY736)
Burak et al. Can J Gastroenterol 2013
Salvage therapies (2)
Anti CD20

39. • 64% of patients normalized aminotransferases
• 11%: side effects
• Of 38 patients treated for intolerance side
effects of AZA, 29 (76%) were able to continue
treatment and 24 achieved biochemical
remission
Legue C et al. Clin Gastroenterol Hepatol 2018
Van den Brand F et al. APT 2018
Salvage therapies (3)
Thioguanine

40. Immunological and clinical effects of low-dose
interleukin-2 across 11 autoimmune autoimmune
diseases in a single, open clinical trial
Lim et al Hepatology 2018

41. Low-dose Interleukine-2 for refratory
Autoimmune Hepatitis
Lim et al Hepatology 2018

42. Lim et al Hepatology 2018
Low-dose Interleukine-2 for refratory
Autoimmune Hepatitis

44. 0’Brien C et al. Hepatology Communications 2018

45.  Introduction par 1mg/Kg prednisolone puis Azathioprine
(1mg/kg)
 Rémission complète (normalisation of ALT and Ig G: 12 g/dL)
était obtenue après 3 mois de la combinaison thérapeutique

 A 1 an du fait de la normalisation des transaminases,
prednisolone était arrêtée et azathioprine maintenue à50
mg/j
 A 2 ans après le diagnostic, azathioprine était arrêtée du
fait d’un maintien de la normalisation of ALAT et une
décroissance du taux d’IgG à 14.5 g/dL (N < 12.0 g/dL)
Cas Clinique (3)

46.  Ictère
 Ascite and Encephalopathie= 0
 Bilirubine totale: 60 mmol/L, conj: 35 mmol/L
 ALAT: 10 X ULN
 TP: 58%, F V: 68%
 IgG: 25 g/dL
 Echo: parenchyme hétérogène
 Tests viraux (HBV, VHC, VHE) négatifs
Cas Clinique

47. Follow-up
EASL Clinical Practice Guidelines: Autoimmune Hepatitis J Hepatol 2015

48. Relapse is almost universal after withdrawal of
immunosuppressive medication in patients with AIH in
remission
Van Gerven et al. J Hepatol 2012
Relapse: ALT > 3 ULN
Loss of remission: rising ALT necessitating the reinstitution of the treatment
Retrospective study
n=131
Therapy was tapered after at
least 2 yrs of clinical and
biochemical
remission
7 academic
+ 14 regional centres 92% of the patients who underwent liver
biopsy
prior to drug withdrawal relapsed or had
loss of remission despite a
normal liver biopsy

49. Relapse is almost universal after withdrawal of
immunosuppressive medication in patients with AIH in
remission
Van Gerven et al. J Hepatol 2012
Relapse: ALT > 3 ULN
Loss of remission: rising ALT necessitating
the reinstitution of the treatment

50. Principal predisposing factors
for relapse
• Duration and completeness of inactive disease
prior to treatment withdrawal
• Pyschohological stress
• Concurrent autoimmune disease
• Treatment with multiple agents
• Increased serum ALT and IgG levels at drug withdrawal
• Portal plasma cells in the liver tissue pre-withdrawal
• Delayed biochemical remission 6-TGN
• Predinosolone monotherapy
Hartl J et al J Hepatol 2015
Guirguis J et al. Gastroenterol Rep 2018
Dhaliwal HK et al. Hepatology 2012
Stellon AJ et al; Lancet 1985

51. Diagnosis and Management of AIH in Adults and Children, 2019 Practice guidance
and guidelines from the AASLD Hepatology 2019

52. Late relapse !
> 20 yrs !

53. A big Problem!
Lack of a strict definition of relapse
• Elevation ALT > 2ULN => 50%: histological
disease activity
• Normal ALT level: 19% had active histolgical
features

54. Treatment of relapse
EASL Clinical Practice Guidelines: Autoimmune Hepatitis J Hepatol 2015

55. Identifying opportunities to improve management of AIH:
Evaluation of drug adherence and psychosocial factors
Sockalingam et al. J Hepatol 2012
Janik MK et al. Liver int 2019

56. Identifying opportunities to improve management of AIH:
Evaluation of drug adherence and psychosocial factors
Weziler-Norman C et al. J Hepatol 2012
Sockalingam et al. J Hepatol 2012
Janik MK et al. Liver int 2019
 Depression :
Moderate: 19%
Severe: 10%
 Anxiety predisposes
to non adherence

58. Merci !
FHU