1. Autore: Dott.ssa Claudia Coppo Tutor: Prof.ssa Patrizia Zentilin
Autoimmune Hepatitis
Autore: Dott.ssa Claudia Coppo
Tutor: Prof.ssa Patrizia Zentilin

2. Autoimmune Hepatitis
Immune-mediated chronic hepatitis of unknown etiology that, if untreated, can evolve to cirrhosis and end stage liver disease.
Incidence: from 0.5 to 1.9 x 105/year
Prevalence: from 4 to 43 x 105
Serum autoantibodies
Interface Hepatitis
Hypergammaglobulinemia without cirrhosis

3. Autoimmune Hepatitis
Under serological profile Autoimmune Hepatitis can be divided in two types
Type 1 Autoimmune Hepatitis
ANA: anti nuclear antibodies
SMA: smooth muscle antibodies
Anti-SLA: soluble liver antigen
Type 2 Autoimmune Hepatitis
LKM1: liver kidney microsome type 1
LC1: liver cytosol type 1

4. Anormal liver blood tests
Autoimmune Hepatitis
Chronic/Insidious onset
Asymptomatic onset
Acute onset
Fever
Jaundice
Sickness
Anormal liver blood tests
Arthritis
Abdominal
pain
Fatigue
Amenorrhea
Ascites

5. Autoimmune Hepatitis

6. Autoimmune Hepatitis IAHG 1999
Gender
Female +2
ALP/AST (ratio)
>3 -2
<1.5
1.5-3
-globulin (unl)
> 2.0 +3
1.5-2
ANA/SMA/LKM1
>1:80
1:80
1:40 +1
<1:40
AMA
Positive -4
Viral markers -3
Negative
Drugs
Yes No
Alcohol
<25g/day
>60g/day
HLA
DR3/DR4 +1
Immune disease
Thyroiditis/colitis +2
Other markers
Anti-SLA/LP, actin; LC1, pANCA
Histology
Interface hepatitis +3
Plasmacells
Rosettes
None of the above -5
Biliary changes -3
Other features
Treatment response
Complete
Relapse
≥10 pts: probable AIH
>15 pts: definite AIH
Pre-treatment
≥12 pts: probable AIH
>17 pts: definite AIH
Post-treatment
Alvarez F et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;

7. Autoimmune Hepatitis IAHG 2008
ANA/SMA/LKM1
>1:40 +1
>1:80 +2
IgG or-globulin
>UNL
>1.156 x UNL
Liver histology
Compatible with AIH
Tipical AIH
Absence of viral hepatitis
Yes No
≥6 pts: probable AIH
≥7 pts: definite AIH
Validation set:
cut off ≥ 6 pts sensitivity 97%, specificity 97%
cut off ≥ 7 pts sensitivity 85%, specificity 98%
Hennes EM et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;

8. Guidelines AASLD 2010- Diagnosis
Autoimmune Hepatitis
Guidelines AASLD Diagnosis
Clinical, biochemical and sierological abnormalities. Histological features.
Absence of other causes of liver disease.
Score system
Anti-SLA and atypical p-ANCA
APECED syndrome (multiendocrine disordes, AIRE gene)
Colangiography (PSC) in adults with no response after 3 months of steroid therapy
Manns MP et al; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010 Jun;

9. Autoabs in AIH - diagnosis
Autoabs anticipate autoimmune disorders for many years (even lifelong).
This means: much more autoabs than diseases
Diagnostic relevance of autoabs is age-dependent (immune senescence)
Threshold of ANA IIF positivity: 1:80 adults, 1:20-1:10 children.
AILD: a few well-defined disorders which can overlap each other.
“overlap syndrome”: coexistenxe of features of two distinct AILD.
Overlap can occurr also sequentially during time.

10. Autoabs in AIH - diagnosis
- diagnostic, not pathogenic
reflect the abnormal immune regulation underlying the disease
probably result from a molecular mimicry between environmental agents and self antigens, in individuals genetically predisposed to autoimmunity

11. ANA – SMA IN AIH
- frequently (~ 50% patients) associated (ANA and SMA), sometimes longitudinally; when associated, their diagnostic relevance for AIH is higher
disease profile substantially unaffected by type (ANA or SMA), number (either or both) and titer of ANA - SMA
titer can decline under therapy, but goal of therapy is disease remission, not ANA-SMA disappearence!

12. IIF: largely dependent on observer’s experience
Autoabs detection
IMMUNO-MORPHOLOGICAL METHODS:
- indirect immunofluorescence (IIF)
on HEp-2 cells ANA
on rodent tissue sections SMA, AMA, LKM
IIF: screening test
IIF: largely dependent on observer’s experience
IMMUNO-CHEMICAL METHODS:
enzyme-linked immunosorbent assay (ELISA)
immunoblot (IB) - dot blot (DB) multi-line blot

13. ANA in AIH Prevalence: 60-80%
IIF patterns: - homogeneous (ANA-H) or diffuse %
- speckled (ANA-S) or granular %
ELISA, IB reactivities, target:
- anti-native DNA (nDNA)
- anti-histone
- anti-chromatin
- “rheumatological” anti-ENA
- heterogeneous NRP
30-60%,
ANA-H related
20-50%,
ANA-S related
Low-level positivity: PBC, PSC, HCV (ANA-S), NASH, drugs

14. ANA-H !!

15. ANA-S !!

16. SMA in AIH Prevalence: 60-80% IIF patterns (kidney sections):
- SMA-V % staining of Vessels
- SMA-G 3-5% staining of Vessels + Glomeruli
- SMA-T % staining of Vessels  Glomeruli + peri-Tubule
Bottazzo et al
Antigenic targets:
microfilaments (MF) actin
intermediate filaments - vimentin
- desmin
- cytokeratin
SMA-T, SMA-G, SMA-V
SMA-V
Low-level positivity: infiammatory disease, neoplasm, hepatic and reumatological diseases

17. SMA-T

18. SMA in AIH SMA with anti-actin specificity = specific marker of AIH
SMA-T, SMA-G - always related to anti-actin antibodies
- high titer
- anti-MF (microfilaments) by IIF on HEp2
SMA-V - only rarely related to anti-actin antibodies
- common unspecific finding
- usually low titer
Anti-actin abs:
not only diagnostic, but also prognostic markers of AIH
- earlier age of onset
- poorer response to therapy
- more frequent death for liver failure or OLT
- HLA B8 DR3

19. Anti-MF on fibroblasts

20. Others abs in AIH LC1 (liver cytosol type 1)
with LKM-1, disease activity, early onset of disease, concomitant autoimmune disease
Target: formiminotransferase ciclodeaminase, liver metabolic enzime
Anti-SLA: soluble liver antigen
high specificity (99% of AIH), associated with HLA DRB1*03
Target: ribonucleoprotein complex (RNP)

21. Guidelines AASLD 2010- Therapy
Autoimmune Hepatitis
Guidelines AASLD Therapy
AST/ALT 10x
AST/ALT 5x + gglob 2x
Bridging necrosis or multiacinar necrosis
Manns MP et al; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis.
Hepatology 2010 Jun;

22. AIH - therapy
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015 Oct;

23. AIH - therapy
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015 Oct;

24. Adverse prognostic factors for AIH
YES NO
Cirrhosis at diagnosis: Feld, Roberts 1996
Werner, Ngu, 2013
Kirkstein Yoshisawa, 2012
Groenbak, Li, 2016
Development of cirrhosis Verma, 2004* Roberts 1996
Presence of symptoms Kogan Feld 2005
High level of transaminases Al-Chalabi, 2008
Muratori P, 2016
Recurrent relapses Montano-Loza, 2007*
Yoshisawa, 2012

25. Adverse prognostic factors for AIH

26. Autoimmune Hepatitis

27. Autoimmune Hepatitis
Kaplan–Meier curves indicating differences in death from hepatic failure or need for liver transplantation between patients who relapsed (relapse) and patients who sustained remission (remission) after withdrawal of the first treatment Montano-Loza, 2007

28. Autoimmune Hepatitis
Kaplan–Meier curves indicating differences in the development of cirrhosis between patients who relapsed (relapse) and patients who sustained remission (remission) after withdrawal of the first treatment.
Montano-Loza,2007

29. Autoimmune Hepatitis
A sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2 years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse.
Hartl, 2015
Only a minority of patients with AIH had sustained remission of AIH without immunosuppressive therapy. Extended duration of remission was associated with signicantly lower relapse rates after cessation of immunosuppressive therapy.
Treatment withdrawal should not be made before 4 years of references continued therapy. Patients with remaining disease activity should be kept on immunosuppression, if necessary life-long.
Kanzler, 2013

30. Autoimmune Hepatitis
Normalization of serum parameters is not a reliable marker for complete histologic remission; however, normalized serum parameters identified patients at low risk of fibrosis progression. Thus, the common clinical practice of disease monitoring by serum markers seems to be suitable for regular follow-up.
Luth, 2008
Repeated relapse and retreatment are associated with progression to cirrhosis, death from liver failure, or need for OLT.
Initial corticosteroid treatment should not be withdrawn unless the laboratory indices are normal.
Montano-Loza, 2007

31. Autoimmune Hepatitis
Weiler-Norman, 2013

32. Autoimmune Hepatitis in pediatric population
Acute presentation (50-60%), also fulminant
AIH2 LKM+ in 38% of cases
Alteration biliary tree
Therapy:
Treatment withdrawal more successful after at least 3 years of therapy
rather than immediately before or during puberty.
Elevated IgG is a risk factor for relapse after withdrawal of immunosuppression in adults, but not in children.
- Celiac disease guideline suggests screening all patients with AIH for celiac disease. Any formal recommendation to screen patients with AIH for autoimmune thyroid disease. Screening of all children with AIH for celiac disease and thyroid disease should be routine.
Mark Deneau, 2014

33. Conclusions AIH diagnosis remains a challenge for phisycians.
Multifactorial diagnosis (see AASLD 2010).
Importance of “time to diagnosis”!!
Further research are needed to more fully quantify the therapeutic approach.