autoimmune hepatitis DM Gastroenterology

1. DIAGNOSIS AND
MANAGEMENT OF
AUTOIMMUNE HEPATITIS

2. EPIDEMIOLOGY
Age onset:
• All ages and all populations, regardless of race and ethnicity.
Trivedi P et al. Gut 2021
• Commonly 2 peaks : 2nd Decade, 50-60 years
• Sex:
Female predominance
adults (71%-95%)
children (60%-76%)

3. Lv T, Li M, Zeng N, et al. Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European,
and American population. J Gastroenterol Hepatol 2019
Annual incidence /lac Annual prevalence /lac
Worldwide 1.37 17.44
Asian 1.31 12.99
Europe 1.37 19.44
America 1.0 22.80

4. Choudhuri, G., Somani, S.K., Baba, C.S. et al. Autoimmune hepatitis in India: profile of an uncommon
disease. BMC Gastroenterol 5, 27 (2005)
INDIAN DATA
Study Prevalence Mean Age(Years) Gender
Choudhuri G et al 1.50% (38/2401) 36.2 89.4% Females
Gupta R et al 3.43%(39/1358) 31 M:F 1:3
Gupta R, Agarwal SR, Jain M, Malhotra V, Sarin SK. Autoimmune hepatitis in the Indian subcontinent: 7
years experience. J Gastroenterol Hepatol. 2001

5. PATHOGENESIS

7. Antibodies
Target Disease association
ANA Multiple nuclear antigens
AIH, SLE, PBC, PSC, drug hepatitis, alcoholic liver disease and
viral hepatitis.
AMA 2-oxo-acid-dehydrogenase complex PBC
pANCA h-Lamp-2, proteinase 3 AIH, PSC, PBC
ASMA Actin, troponin, tropomyosin
AIH I, infectious and rheumatic disorders
VGT pattern: earlier disease
LKM 1 CYP 2D6 AIH II, HCV
LKM 2 CYP 2C9 Tienilic acid-induced hepatitis
LKM 3 UGT1A AIH, hepatitis D
LM CYP 2A6 Hepatitis C, Dihydralazine induced hepatitis
LC1 FTCD AIH II or HCV
SLA/LP tRNP(Ser)Sec AIH I and II, PSC
LM CYP 1A2 Dihydralzine-induced hepatitis, APECED
ASGP-R Asialoglycoprotein receptor Autoimmune liver disease, HCV
ANA, anti-nuclear antibodies; AMA, anti-mitochondrial antibodies; ANCA, antineutrophilic cytoplasmatic antibodies; SMA, smooth muscle antibodies; LKM, liver kidney microsomal
antibodies; LM, liver microsomal antibodies; LC1, liver cytosolic antibodies type 1; SLA/LP, soluble liver antigen/liver pancreas antibodies; ASGPR-R, asialoglycoprotein receptor
antibodies; UGT1A, UDP glucuronosyltransferase family 1 A; FTCD, formimino-transferase cyclodeaminase; AIH, autoimmune hepatitis; PSC, primary sclerosing cholangitis; PBC, primary
biliary cirrhosis; HCV, hepatitis C virus; APECED,

8. Features Type 1 AIH Type 2 AIH
Frequency US adults, 96%
US children, 9%‐12%
UK children, 38%
Age at presentation Peripubertal and adults Usually under 14 years
Mode of presentation
Chronic symptoms common Acute onset (~40%)
Ascites or GI bleeding rare Acute liver failure possible
Asymptomatic in 25%‐34% Relapse frequent
Acute in 25%‐75%
Acute severe in 2%‐6%
Laboratoryfeatures Hypergammaglobulinemia IgA levels may be reduced
Autoantibodies
ANA 80% Anti‐LKM1
SMA 63%, anti‐actin Anti‐LC1, Anti‐LKM3
SLA 7-22% ; high specificity
Concurrentimmune diseases
Autoimmune thyroiditis Autoimmune thyroiditis
Rheumatic diseases Diabetes mellitus
IBD Vitiligo
Autoimmune overlap with PSC Common in children Rare
Atypical pANCA‐positive Atypical pANCA‐negative
Overlap with PBC Seen in adults (not children) Not reported
Cirrhosis at presentation
Adults, 28%‐33% (especially elderly)
Children, ≤33%
Rare
Remission after drug withdrawal Possible Rare, usually need long‐term immunosuppression

9. • Auto Antibody Negative AIH
• ANA AMA Anti LKM1 : Absent (19-34%)
• Similar :
• lab findings,
• histologic features,
• HLA phenotypes ,
• response to glucocorticoids.
• Atypical pANCA and anti SLA(15-20%) Anti LC 1
• Scoring system helpful.

10. OVERLAP SYNDROMES
AIH-PBC OVERLAP
SYNDROME
AIH COMPONENTS:
Interface hepatitis plus 1 of 2 features:
ALT ≥ 5 x ULN
IgG ≥ 2 x ULN or SMA present
PBC components (2 of 3 features):
Alk phos ≥ 2 x ULN or GGTP ≥ 5 x ULN
AMA present
Florid duct lesions
PARIS CRITERIA
SENITITIVITY 92%
SPECICIFICITY 97%

11. AIH-PSC OVERLAP Typical AIH features
AMA absent
Focal bile duct strictures and dilations
by cholangiography
Bile duct loss or damage, portal
edema, and fibrous obliterative
cholangitis possible on histologic
examination

12. • Asymptomatic (25%-34%)
• 12% spontaneous laboratory improvement
• Symptoms within 2 to 120 months (mean 32months).
Mack CL, Hepatology. 2020
CLINICAL PRESENTATIONS
• Acute onset hepatitis:
• Most frequent pattern worldwide
• AST ALT >5-10 X ULN
• Jaundice, INR prolonged
Muratori L, BMJ. 2023
Feb

13. • Acute liver failure “fulminant”:
• Difficult to diagnosis AIH in ALF
• ANA and IgG may be negative.
• Cirrhosis:
• 30% of AIH patients have cirrhosis at presentation

14. AIH Diagnosis
• DIAGNOSIS OF EXCLUSION
• NO DIAGNOSTIC TEST
• INTERNATIONAL SCORES : HELP DIAGNOSIS

15. REVISED International Autoimmune Hepatitis Group diagnostic (IAIHG) scoring system (1999)
Viral markers of active infection Positive −3
Negative +3
Hepatotoxic drug history Yes −4
No +1
Average alcohol <25 g/day +2
>60gm/day −2
ALP:AST (or ALT) ratio >3 −2
1.5–3 0
<1.5 +2
Serum globulins or IgG (times above >2.0 +3
ULN) 1.5–2.0 +2
1.0–1.5 +1
<1.0 0
ANA, SMA, or anti-LKM-1 titers >1:80 +3
1:80 +2
1:40 +1
<1:40 0
AMA Positive −4
Parameter Feature Score
Principal parameters
Sex Female +2

16. Revised International Autoimmune Hepatitis Group diagnostic (IAIHG) scoring system (1999)
Histological features Interface hepatitis +3
Plasmacytic infiltrates +1
Rosettes +1
None of above −5
Biliary changes −3
Atypical changes −3
Concurrent immune illness Thyroiditis UC etc +2
Seropositivity for other defined
autoantibodies
Anti-SLA/LP, actin, LC1, atypical p-ANCA +2
HLA DR3 or DR4 +1
Response to therapy complete +2
Relapse +3
Interpretation of aggregate scores
Pre-treatment
Definite AIH >15
Parameter Feature Score
Principal parameters
Probable AIH 10–15
Post-treatment
Definite AIH >17
Probable AIH 12–17

17. Simplified criteria for the diagnosis of autoimmune hepatitis (2008)
Variable Cut-off Points
ANA or SMA 1:40 +1
≥1:80 +2
Or Anti-LKM1 (alternative to ANA and SMA) ≥1:40 +2
Or Anti-SLA (alternative to ANA, SMA and LKM1) Positive +2
IgG or γ-globulins level >ULN +1
>1.10 times ULN +2
Liver histology Compatible with AIH +1
Typical of AIH +2
Absence of viral hepatitis Yes +2
6 probable AIH
≥7 definite AIH
 Less reliable in children and atypical groups of AIH patients (seronegative disease, normal IgG levels) and
those with co-existing chronic viral hepatitis

18. Typical AIH: 2 points
Typical and compatible histology for the diagnosis of AIH in the 2008 simplified criteria
Diagnostic category Histological features
• Interface hepatitis with lymphocytic or lymphoplasmacytic
portal inflammatory infiltrates extending into the lobule
• Emperipolesis
• Hepatocyte rosette formation
Compatible with AIH: 1 point
Chronic hepatitis with lymphocytic infiltration without all the
features considered typical
Atypical 0 points Evidence of another diagnosis

19. • Revised diagnostic criteria (1999):
• More accurate for diagnosis of AIH
in patients with complex or unusual
features, multiple medications or
alcohol use
• The simplified diagnostic criteria
(2008):
• Preferred with typical biochemical,
serological and histological features
100%
73%
82%
95%
90%
92%
60%
65%
70%
75%
80%
85%
90%
95%
100%
105%
Sensitivity Accuracy
Specificity
Revised Simplified

20. Limitations of the revised original and
simplified scoring systems
• Lack of validation
• Lack of accuracy in the setting of concurrent PSC, PBC, NAFLD/NASH,
LT
, or fulminant liver failure
• Failure to include other serological markers, such as anti‐SLA

21. LIVER BIOPSY
• Histopathology :
• diagnosis,
• exclusion
• monitoring
• response.
INVESTIGATIONS
No single histological feature is specific or pathognomonic for AIH
de Boer et al Histopathology 2015
TYPICAL histology: Two out of Three. IAHG
Hennes EM, Zeniya M, Czaja AJ, et al, Hepatology 2008

23. Histological activity index for chronic hepatitis
HAI 1-3: minimal hepatitis or remission.

 HAI 4-8: mild hepatitis.
 HAI 9-12: moderate hepatitis.
 HAI 13-18: severe hepatitis

24. Noninvasive Fibrosis Assessment
FIBROSCAN
• After 6 months of treatment: accuracy is excellent in the detection of
advanced fibrosis.
Hartl J et al. J Hepatol 2016
• MR ELASTOGRAPHY
• MRE correlate strongly with fibrosis stage
• Accuracy (97%), sensitivity (90%), specificity (100%), positive predictive value
(100%), and negative predictive value (90%)
Wang J et al. World J Gastroenterol 2017

25. 2019
50

26.  TPMT activity:
• Test for thiopurine methyltransferase activity to detect patients with zero or
near‐zero TPMT activity (0.3-0.5%) to avoid AZA severe myelosuppression.
 Vaccines:
• Recombinant and inactivated vaccines.
• Avoid live, attenuated vaccines in persons on high doses of immunosuppression.
• HAV and HBV vaccination before treatment.
• Response to vaccines is relatively slow.
PRE TREATMENT EVALUATION

27.  Bone Maintenance:
 Baseline DEXA scan and then every 2- 3 years.
 Measure Vit D
 On Steroids: 1-1.2g elemental calcium and 800 IU vitamin D.
 Osteoporosis: bisphosphonate.
 Metabolic syndrome.
 Steroids increases DM and cardiovascular diseases.
 Assessment for all features of metabolic syndrome.

28. ABSOLUTE RELATIVE NONE
Clinical ֍ Symptoms (fatigue, arthralgia, ֍ Asymptomatic
jaundice, abdominal pain)
Laboratory ֍ AST ≥ 10 ULN or AST ≥ 5 ULN and ֍ AST or IgG less than absolute ֍ Normal or near normal AST and
IgG ≥ 2 ULN criteria IgG
Histology ֍ Bridging necrosis or multiacinar ֍ Interface hepatitis ֍ Inactive cirrhosis or mild portal
necrosis on histology HAI >4 hepatitis
֍ Incapacitating symptoms ֍ Osteopenia, emotional instability,
hypertension, diabetes, or cytopenia
(white blood cell counts ≤2.5 ×109/L
or platelet counts ≤50 ×109/L)
֍ Severe cytopenia (WBCs <2.5
×109/L or platelet counts <50 ×109/L)
or known complete deficiency of
TPMT activity precludes treatment
with azathioprine
֍ Vertebral compression, psychosis,
brittle diabetes, uncontrolled
hypertension, known intolerances to
prednisone or azathioprine.
Indications for treatment of autoimmune hepatitis
2010

29. EASL Clinical Practice Guidelines: Autoimmune hepatitis. Journal of Hepatology 2015; 63:971-1004.
with AIH are
All patients
candidates for therapy except
individuals with inactive disease by
clinical, laboratory, and histological
assessment.
New
Concept
2019
2015

30. Different Guideline Protocols
AASLD 2010 EASL 2015
Monotherapy Combined Therapy Combined Therapy
Week
Prednisolone
mg/day
Prednisolone
mg/day
AZA mg/day or
mg/kg/day
Prednisolone
or Budesonide
mg/day
AZA mg/day
1 60 30 50 or 1-2 60 (1mg/kg) 9 0
2 40 20 50 or 1-2 50 9 0
3 30 15 50 or 1-2 40 6 50
4 30 15 50 or 1-2 30 6 50
5 20 10 50 or 1-2 25 6 100 (1-2mg/kg)
6 20 10 50 or 1-2 20 6 100
7+8 20 10 50 or 1-2 15 6 100
8+9 20 10 50 or 1-2 12.5 6 100
from week
10
20 and below 10 50 or 1-2 10 and below 6 and below 100
For EASL if the patient is not 60kg use initial weight based formula Prednisolone 1mg/kg and AZA 1-2mg/kg

31. 2019

33. EASL Clinical
EASL.
Practice Guidelines:
Autoimmune hepatitis.
Journal of Hepatology
2015; 63:971-1004.
2015
Therapeutic strategy in autoimmune hepatitis.

34. Figure 1
Budesonide Induces Remission More Effectively Than Prednisone in a Controlled Trial of Patients With
Autoimmune Hepatitis Michael P. Manns et al Gastroenterology 2010

35. 0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
Complete Biochemical
Remission At 6 months
SSSE
Prednisolone Budesonide

37. 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Biochemical Response Side Effects
Predinisolone Budesonide

38. Pape S, Gevers TJG, Belias M, Mustafajev IF, Vrolijk JM, van Hoek B, Bouma G, van Nieuwkerk CMJ, Hartl J, Schramm C, Lohse
AW, Taubert R, Jaeckel E, Manns MP, Papp M, Stickel F, Heneghan MA, Drenth JPH. Predniso(lo)ne Dosage and Chance of
Remission in Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol. 2019

39. Pape S, Gevers TJG, Belias M, Mustafajev IF, Vrolijk JM, van Hoek B, Bouma G, van Nieuwkerk CMJ, Hartl J, Schramm C, Lohse
AW, Taubert R, Jaeckel E, Manns MP, Papp M, Stickel F, Heneghan MA, Drenth JPH. Predniso(lo)ne Dosage and Chance of
Remission in Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol. 2019

40. Predictors of Treatment Response
• AST and ALT improvement within 2 weeks.
• Patients ≥60y and HLA DRB1*04:01 : Rapid response
• 6-months biochemical remission decreases risk of progression to cirrhosis.
• ELEVATED Ferritin >2.1‐fold ULN.
• IgG <1.9‐fold ULN
• Vit D def : histological severity, poor treatment response, progression to cirrhosis

41. Duration of therapy & drug withdrawal
• AASLD 2019:
• Sustained normal liver functions, IgG
• At least 2 years.
• Liver biopsy before drug withdrawal is preferred but not mandatory in adults
• EASL 2015:
• At least 3 years
• And at least 24 months after complete normalization of ALT AST and IgG levels

44. Acute Severe AIH or ALF due to AIH
Acute severe AIH Jaundice, INR > 1.5 < 2, no encephalopathy; no previously recognized liver disease
ALF
INR ≥ 2; hepatic encephalopathy within 26 weeks of onset of illness; no previously recognized
liver disease
 Acute severe AIH:
 Prednisolone: 0.5‐1 mg/kg/d.
 If no response after 2 weeks LT
 AIH and ALF:
 Steroids do not increase survival.
 MELD >40 :poor survival.
 Steroids may be deleterious in patients with severe decompensation.
 Refer for LT

45. DILI vs AIH
Definite Association Probable Association Possible Association
 Minocycline  Propylthiouracil  Ipilimumab (anti‐CTLA‐4)
 Nitrofurantoin  Isoniazid  Tremelimumab (anti‐CTLA‐4)
 Infliximab  Diclofenac  Nivolumab (anti‐PD‐1)
 Alpha‐methyldopa  Etanercept  Pembroluzimab (anti‐PD‐1)
 Adalimumab  Atorvastatin  Atezolizumab (anti‐PD‐L1)
 Halothane  Rosuvastatin  Black cohosh (herbal medicine)
 Oxyphenisatin  Clometacine  Dai‐saiko‐to (herbal medicine)
 Dihydralazine  Germander (herbal medicine)
 Tienilic acid  Hydroxycut (nutritional supplement)
 Trichloroethylene (toxin)
 Papaverine
 Indomethacin
 Imatinab

46. DILI vs AIH
Clinical Features Drug Induced AIH‐Like Injury AIH
Gender  Mainly women
 Female predominance, but men also
affected
Acute onset  Majority (>60%)  <20%
Hypersensitivity (fever, rash,
eosinophilia)
 Up to 30%  Unusual
Temporal relationship with drug  Positive  Negative
HLA DRB1*03:01 or DRB1*04:01
association
 None  Common
Concurrent autoimmune diseases  Unusual  Present in 14%‐44%
Cirrhosis at presentation  Rare  28%‐33%
Management  Stop offending drug ± glucocorticoids  Glucocorticoids with AZA
Relapse after drug withdrawal  Rare  60%‐87%
Progression to cirrhosis  Rare  7%‐40%
Survival without transplantation  90%‐100%  10‐year survival, 89%‐91%

47. DILI vs AIH
2015
 Stop offending drug and watch
recovery within 1-3 months.
 Fulfilled Hy’s criteria (>3fold
ULN ALTs and >2fold ULN
bilirubin) or deterioration
give steroids.
 Laboratory flare after steroid
withdrawal suggest classic AIH
2019

48.  Pregnancy:
 Pregnancy may be planned 1 year after remission.
 Patient education is mandatory.
 Continue Maintenance doses of glucocorticoids and/or AZA.
 AVOID: MMF before and after pregnancy.
 Varices in a cirrhotic patients should be screened before and during 2nd trimester of
pregnancy +/- EVL.
 Surveillance for flare in the 1st 6 months postpartum.

49. Medication Safety Reports in Pregnancy
Terlipressin Uterine ischemia
Octreotide No harmful effects noted
Beta‐blockers Fetal bradycardia, fetal growth retardation
Lactulose No harmful effects noted
Rifaximin No harmful effects noted but limited data
Corticosteroids Inconsistent association with cleft abnormalities
AZA No LBW/defects. Preterm birth.
MMF Birth defects, spontaneous abortion
TAC
Premature birth, transient neonatal renal
dysfunction

50. Categories Recurrent AIH De Novo AIH
Clinical findings Graft dysfunction at 2 months‐12 years Indication for LT other than AIH
Laboratory findings Increased serum AST, ALT, IgG levels Increased serum AST, ALT, IgG levels
Serological markers Same antibodies as pre‐LT AIH ANA, SMA, anti‐LKM1
ANA, SMA common
Anti‐LKM1 rare
Histologic findings Lobular hepatitis, focal necrosis, pseudorosettes (early) Interface hepatitis
Interface hepatitis, lymphoplasmacytic infiltration (late) Lymphoplasmacytic infiltrates
Lobular collapse, confluent/bridging necrosis (severe)
Treatment Predniso(lo)ne, 30 mg daily, and AZA, 1‐2 mg/kg daily  Same as recurrent AIH
Predniso(lo)ne dose reduction to 5‐10 mg daily in 4‐8 weeks
Predniso(lo)ne and AZA maintenance
Continue calcineurin inhibitor
Rescueregimens
(empiric)
MMF for AZA MMF for AZA
Switch calcineurin inhibitor Rapamycin
Rapamycin
Outcomes 5‐year patient survival, 86%‐100% Better in children than adults
Graft failure, 8%‐50% Biochemical remission, 86%
Retransplantation, 33%‐60% Retransplantation, 8%
Recurrent AIH in retransplanted liver, 33%‐100% Patient survival, 95%

51. THANK YOU