20/11/18

1

What’s new in autoimmune hepatitis ?

SANCT GALLEN Symposium 2018

David Semela, MD PhD

Klinik für Gastroenterologie & Hepatologie

Kantonsspital St. Gallen

20/11/18

2

DefinitionAIH is a non-resolving chronic liver disease that occurs in both

sexes but affects mainly affecting females. It is characterized by:

ü  Increased AST and ALT levels

ü  Hypergammaglobulinaemia

ü  Autoantibody seropositivity (ANA, SMA, LKM-1, LC1)

ü  Interface hepatitis on histology

ü  Response to immunosuppressive treatment

Epidemiology

&

Clinical Course

20/11/18

3

Estimated prevalence of hepatopathies in CHNAFLD,NASH 1:5Alcoholicliverdisease 1:75Chronichepa

20/11/18

5

1) Asymptomatic or with non-specific symptoms (40-60%, especially adults): •  Fatigue, Arthralgias •  Nausea/vomiting, anorexia, amenorrhoea, abdominal pain 2) Acute onset (25% of cases, especially children): •  Acute exacerbation of chronic AIH, or •  True acute AIH without histological findings of chronic liver disease •  Centrilobular zone 3 necrosis (central perivenulitis) usually predominant •  Autoantibodies or other classical features can be absent 3) Cirrhosis already present in 20-37% of patients at diagnosis (children 50%) •  Due to delay in diagnosis (often long asymptomatic course)

Clinical presentation & symptoms

EASL CPG AIH, J Hepatol 2015

Patients with severe disease (untreated):

•  40% die within 6 months of diagnosis

•  40% of survivors develop cirrhosis

•  54% of cirrhotics develop varices within 2

years of diagnosis of cirrhosis

•  20% of patients with varices will bleed

Natural history

20/11/18

6

Pathogenesis

MolecularPathogenesisofAIH

Manns MP et al. J Hepatol 2015

20/11/18

7

DiagnosisAutoimmunehepa@@sisaclinicaldiagnosis

Diagnosisisusuallybasedontypicaldiseasephenotype

-Plusexclusionofotherchronicliverdisease(yet,comorbidityispossible)

Diagnosis of AIH is based on history, laboratory and histological features:

ü Increased AST and ALT levels ü Hypergammaglobulinaemia ü Seropositivity for autoantibodies ü Histological evidence of interface hepatitis

Diagnosis

20/11/18

8

Man

ns M

P et

al.

J H

epat

ol 2

015

Autoantibodies

Two forms of AIH can be distinguished by the presence of different autoantibodies: •  Type 1 AIH: ANA, SMA and/or SLA antibodies

•  Type 2 AIH: LKM-1 or LC1 antibodies

Compared to AIH-1, AIH-2 presents •  at a younger age, with IgA deficiency •  less frequently with cirrhosis (38% vs 69%) •  more frequently with acute liver failure (25% vs 3%) •  More treatment failures, more often relapse after drug withdrawal Both forms affect mainly females (75% of cases) and are associated with other autoimmune disorders (20%).

Subclassifictation of AIH

20/11/18

9

HistologyHistologicaldemonstra@onofhepa

20/11/18

11

Manns MP et al. J Hepatol 2015 HE 160x

Rosetting of hepatocytes in area of interface hepatitis

Rose]e

Emperipolesis: Endocytosed lymphocyte in hepatocyte

Manns MP et al. J Hepatol 2015 HE 240x

20/11/18

12

•  No morphological features are pathognomonic of AIH •  Suggestive of AIH: Interface hepatitis, lymphoplasmacytic infiltrate,

rosetting of hepatocytes, periportal necrosis, emperipolesis

•  These features should be reported by the pathologist •  In addition: grading (hepatitis activity index (HAI)) and fibrosis staging

should be reported

A liver biopsy is essential for the diagnosis of AIH

•  Gender •  AP/AST, ALT ratio •  Serum globulins/IgG •  ANA, ASMA, LKM-1 •  AMA positivitty •  Viral serologies •  Drug history

•  Alcohol intake •  Liver histology •  Other autoimmune

diseases •  HLA DR3/DR4 •  Response to therapy

Johnson PJ et al., Hepatology 1993

Original autoimmune hepatitis score�by the International AIH Group (IAIHG 1993/1999)

20/11/18

13

IAIHG simplified diagnostic criteria for AIH (2008)

Hennesetal.,Hepatology,2008

Feature/parameter Discriminator Score

AnULN>1.1xULN+1+2

Liverhistology(evidenceofhepa@@sisrequired)

AtypicalCompa

20/11/18

15

*Treatmentprobablynolongerindicatedindecompensated,burned-outcirrhosis,unlesshighinflammatoryscoreonliverbiopsy

DiagnosisofAIH

Advancedfibrosis/cirrhosis*

Ac

20/11/18

17

Week Predniso(lo)ne(mg/day) Azathioprine(mg/day)Week1 60(=1mg/kgbodyweight) -Week2 50 -Week3 40 50Week4 30 50Week5 25 100(=1-2mg/kgbodyweight)Week6 20 100Weeks7+8 15 100Weeks9+10 12.5 100Fromweek10 10 100

Mod

ified

from

EAS

LCP

G,JHe

patol201

5

EASL treatment proposal for adult patients with AIH (e.g. 60 kg) �

Week Predniso(lo)ne(mg/day) Azathioprine(mg/day)Week1 60(=1mg/kgbodyweight) -Week2 50 -Week3 40 50Week4 30 50Week5 25 100(=1-2mg/kgbodyweight)Week6 20 100Weeks7+8 15 100Weeks9+10 12.5 100Fromweek10 10 100

Mod

ified

from

EAS

LCP

G,JHe

patol201

5

EASL treatment proposal for adult patients with AIH (e.g. 60 kg) �

•  Reduction of predniso(lo)ne to 7.5 mg/day if aminotransferases reach normal levels

•  After 3-4 months to 5 mg/day

•  Tapering out at 3-4 months intervals depending on patient’s risk factors and response

•  Longterm maintenance treatment with azathioprine monotherapy

20/11/18

18

Maintenance therapy options for AIH

•  Azathioprine (1-2 mg/kg) ± Prednis(ol)on ≤ 7.5 mg/day •  Azathioprine (1-2 mg/kg) ± Budesonide 2 x 3 mg/day

In case of Azathioprine intolerance: •  Replace Azathioprine with Mercaptopurine (i.e. 50 mg/day) •  Prednis(ol)on ≤ 7.5 mg/day monotherapy •  Budesonide 2 x 3 mg/day monotherapy

•  ±± Trouble shooting in AIH with inadequate treatment response

•  Check compliance and treatment adherence (i.e. switch to budesonide 3x3 mg if patient stopped due PDN side effects)

•  Consider alternative diagnosis (overlap with PBC or PSC, see differential diagnosis)

•  Restart induction therapy for 4 weeks (i.e. 60 mg prednisone p.o. monotherapy), taper according response

•  If insufficient repsonse: Refer to specialist centre for alternative immunosuppression

20/11/18

19

Secondlinetherapiesforautoimmunehepa@@s

Modified from Manns MP et al. J Hepatol 2015

Medica

20/11/18

21

Pischke S et al. PlosOne 2014

969ptstestedforan@-HEVIgG:•  208AIH•  537Controls•  114Rheumatoidarthri@s•  109HBV/HCVpa@ents

•  7.7%AIHptsHEVposi

20/11/18

23

AIH treatment withdrawalNo specific recommendations for treatment withdrawal available

“General consensus”: Termination of therapy should be considered only after at least 2 years of treatment if:

•  liver function tests have been repeatedly normal and

•  immunoglobulin levels have been repeatedly normal and •  no inflammatory activity is detectable on repeat biopsy

However, relapse rates are high (>90%)

Remission (normal ALT / normal IgG)

Reduce immuno-suppression stepwise

Relapse

Stable remission on monotherapy for >24 (36) months

Taper out immunosuppression (consider prior liver biopsy)

Stable remission without treatment

Monitor life-long (3-monthly for 1 year, than 6-monthly)

Long-term (life-long?) maintenance treatment

Tapering immunosuppression in AIH

Mod

ified

from

EAS

LCP

G,JHe

patol201

5

Taper steroids, adapt Azathioprine-dose (check 6-TG levels) as required to retain remission

Remission

Re-induce remission with predniso(lo)ne

(induction dose)

20/11/18

24

Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal

•  28 pts with well-defined AIH

•  Median Tx duration: 48.5 months (range 35-179)

•  Sustained remission: 45 months (range 24-111)

•  All pts in remission on monotherapy for at least 2 years before Tx withdrawal

•  15 patients (54%) remained in long-term remission after a median of 28 months follow-up (range 17-57)

•  Higher ALT and IgG levels - although within the normal range in all pts - were associated with the time to relapse

•  All patients who remained in remission had ALT levels less than half the ULN and IgG levels

20/11/18

25

Usefulness of biochemical remission and transient elastography in monitoring disease course in AIH

Hartl J et al. J Hepatol 2017

General measures

20/11/18

26

General measures in AIH patients•  Regular intake of milk and dairy products should be recommended in

all patients on corticosteroid treatment

•  As adjunctive measure for bone disease a regular weight baring exercise programme should be instituted

•  Adjuvant therapies (vitamin D, calcium and, where appropriate, bone active agents such as bisphosphonates) should be implemented

•  Annual dermatological controls for non-melanoma skin cancer

•  Vaccination against HAV, HBV, pneumococcus and influenza

•  If cirrhosis: upper endoscopy for variceal screening at diagnosis and hepatic ultrasound every 6 months for HCC surveillance

General measures in AIH patients

•  The risk of hepatocellular carcinoma (HCC) in AIH is associated with the presence of cirrhosis

•  Three separate studies have shown that the prevalence of HCC amongst AIH patients with underlying cirrhosis ranges between 2-6%:

Yeoman et al, Hepatology 2008

Wong et al, Dig Dis Sci 2011

Borssen et al, Scan J Gastro, 2015

20/11/18

27

Liver Transplantation

•  The long-term prognosis for patients with AIH who respond to immunosuppressive treatment is excellent

•  Most patients are able to live a normal life on low-dose medication

Liver transplantation for AIH•  OLT for AIH is successful with a 5- and 10-year patient survival

approaching 75%

•  Recurrence of AIH post-transplant: Monitor auto-antibodies and IgG levels regularly

•  Post-OLT recurrence of AIH is approx. 30% with an average time to recurrence of 4.6 years

•  In order to avoid recurrence of AIH after OLT, steroid treatment should be maintained in the long term and at doses higher than those generally used after LT for other conditions

•  Treatment of AIH recurrence: Use azathioprine, mycophenolate mofetil and/or prednisolone (5-7.5 mg) as part of the immunosuppressive regimen

20/11/18

28

Summary

Summary & Conclusions

•  AIHisachronicinflammatorydiseasewithafemalepredominanceoccurringinallagesandracesthatmaystartwithanepisodeofacutehepa