Autoimmune Hepatitis

1. Autoimmune Hepatitis: Update
2021
Brian McMahon MD
Liver Disease and Hepatitis Program
Alaska Native Medical Center

2. Disclosures and Conflicts of
Interest
• None

3. Goals and Objectives
• To understand the epidemiology of
autoimmune hepatitis (AIH) in the Alaska
Native Population
• To understand the ways patients with AIH
can present
• To understand the laboratory tests to
obtain to make the diagnosis of AIH
• To understand general principles of
treatment and monitoring of AIH

4. New 2019 Guidelines for AIH
from the Liver Society: AASLD
• Download at aasld.org
• Then click on Practice Guidelines and
select Autoimmune Hepatitis

5. Case Study # 1
•72 y.o. Alaska Native woman presented with acute hepatitis, jaundice,
feeling poorly, dark urine, nausea and vomiting.
•No recent Tylenol, no street drug use.no alcohol.
•No offending medicines:
•Past LFTs normal
• ALT 1482, AST 1377, Alk Phos 281, Alb 4.1, T Bili 7.6
WBC 5.4, Hgb 14.5, PLT 351, PT 12.2, INR <1.0
RUQ ultrasound non specific.

6. Clinical Presentation
• Acute hepatitis (ALT > 10 times ULN: 25 in
females, 35 U/L in males) with or without
jaundice in approximately 50%
• Chronic hepatitis: ALT >2 < 10 times ULN
without jaundice but may have synthetic liver
dysfunction (elevated INR, T Bili or low
albumin)

7. Work–up
ANA Negative
IgG 4400 (ULN 1618)
Actin smooth muscle Ab 73 (normal <20)
AMA negative
IgM 61
Anti-HCV neg, Anti-HAV neg, HBsAg neg, Anti-HBc neg,
Anti-HBs 80.20 (immune)
HIV negative

8. Role of Liver Biopsy
• Since no combination of markers are
diagnostic for AIH, biopsy is necessary to:
– Confirm diagnosis since long-term treatment with
drugs with lots of side effects will be needed
– To determine level of liver fibrosis
• If advanced fibrosis or cirrhosis is present,
hepatocellular carcinoma surveillance (HCC) is needed
– Liver ultrasound and AFP every six months
– To determine if liver steatosis is present which
could result in progression of fibrosis

9. Liver Biopsy
5/15/14 -
• A very aggressive acute hepatitis with marked severe portal
inflammation in all portal tracts, mixed cellular infiltrate with
neutrophils , plasma cells and lymphocytes, severe interface hepatitis
in all portal tracts, areas of bridging necrosis, and lobular hepatitis.
• Hepatic activity index is approximately 14-15/18. A couple of areas of
early bridging fibrosis on the trichrome stain, which would give her a
fibrosis score on the Ishak scale of 3/6 or Metavir 3 fibrosis stage.
• No increased iron in the biopsy and no fat.
Course of Disease/Treatment
5/12/14 - Total bilirubin peaked at 9.0
5/15/14 – Started methylprednisolone at 16mg qd
5/29/14 – TPMT Enzyme Activity Level returned at 37.8, azathioprine
started at 25mg qd

10. Liver biopsy

14. Date
Month/Day
ALT AST Total
Bili
Medication
6/11 32 23 0.6 AZA 50mg, methylpred
14mg, Folic Acid 1mg
5/29 120 37 1.3 AZA 25mg, methylpred
16mg
5/20 559 219 2.7 methylpred 16mg
5/15 1088 1055 7.7 methylpred 16mg qd
5/12 1362 1287 9.0
5/9 1482 1377 7.6
3/28 34 40
3/6 18 24

15. Case Study # 2
 65 y.o Alaska Native woman presented with mild fatigue and was
incidentally found to have elevated LFTs. No other symptoms.
 Medical history: Hypertension, on Lisinopril
 BMI 32; No jaundice.
 No alcohol for 30 years.
 No history of liver disease.
Labs/Course of Treatment
11/30/09 – ALT 157, AST 133, Alk Phos 85 (PCP did elevated LFT work-up)

16. Liver biopsy done 1/1/10
 Mild portal inflammation with fibrous expansion of the portal tracts.
 Lymphocytes and some plasma cells in majority of portal tracts but
sparse in tracts with fibrous expansion.
 Piecemeal necrosis in a minority of periportal areas.
 Patchy mild intralobular inflammation.
 Early bridging fibrosis.
 HAI = 7, Knodell fibrosis = 3, Ishak fibrosis = 3.
1/13/10
 TPMT Enzyme Activity = 22.6 (normal >20)
 Azathioprine started at 25mg qd

17. 12/4/09 –Total Bili 1.1, Alb 3.5
 Gamma globulin 2.5 (ULN 1.6)
 ANA 1:640
 Actin antibody 40
 Hepatitis screen negative for chronic and acute viral hepatitis
 Immune to hepatitis A
 RUQ US showed mild increased echogenicity.
12/15/09 –
 Patient was started on methylprednisolone 20mg qd.
 Biopsy recommended to confirm diagnosis.

18. AIH Pathology

19. AIH: Plasma Cells

20. Jan 2010 to Sept 2010
 Methylprednisolone gradually tapered to 7mg qd
 Azathioprine gradually increased to 75mg qd
9/27/10 – Patient reports low energy and nausea. Feels it is from the
azathioprine. Azathioprine was decreased to 50mg qd.
10/12/10 – ALT 11, AST 29, WBC 2.1, ANC 1.0, Hgb 5.8, PLT 116
(previously on 8/9/10- WBC 3.8, ANC 2.9, Hgb 12, PLT 181)
Pancytopenia – Azathioprine D/C’d. Admitted and given 2 units of PRBCs.
CBC gradually improved.
10/12/10 – 2/24/11 – Remission maintained with only methylprednisolone
at 7mg qd.

21. 2/24/11 – ALT 179, AST 165, WBC 3.8, Hgb 13, PLT 149.
 Flared on 7mg mpred.
 Tacrolimus started at 0.5mg bid, gradually increased to 1mg bid
 Remission achieved, methylpred slowly tapered
2/10/12 – Flared again on Tacrolimus 1mg bid and methylprednisolone 4mg
qd.
 Methylpred was increased to 10mg
 Tacrolimus was increased to 2mg bid.
2/3/14 – Finally tapered off of prednisone (>4 years after starting). Maintained
on tacrolimus 2mg bid.
Additional challenges: lives in the rural community, providers frequently
changing.

22. Global Prevalence of AIH
• Range from 4/100,000 in Singapore to
42.9/100,000 in Alaska Native people in 2000
• Incidence from 0.67 to 2.0/100,000

23. Prevalence of Autoimmune
Hepatitis
• Autoimmune Hepatitis
– Norway: 16.9/100,000
– Alaska Natives:
43/100,000
• Calculated in 2014
Hurlburt K. Am J Gastroenterol
2002;97:2402-7
• Prevalence: 58.6/100,000 (95%
CI = 47.3-72.5)
• (2002 AK Native people prevalence
=42.9/100,000 (95% CI = 31-57.7)
• Alaska area user population for
2012 population 143,389
• The female to male ratio for
Alaska Native People is 13:1

24. AIH in Alaska Native Persons
• Crude Prevalence: 117/100,000
• Alaska area user population for
2019 population 160,000
• Total Number of AN patients
diagnosed as of :
– 23 (14%) with overlap syndrome
• Total AIH patients alive as of
12/31/20: 175
• The female to male ratio for
Alaska Native People is 13:1

25. Autoimmune Liver Disease in Alaska
Native People Followed by Liver
Program Statewide: 2021
Autoimmune Liver
Disease: Juneau Count
AIH and Overlap 175
AIH 152
Overlap 23
PBC & AIC
98
Total Autoimmune Liver
Disease 273

26. Results Cont. 2016 not Updated
•Mean age of death 63.1 years old
•Life expectancy for Alaska Native
population 70.5 yo
•Life expectancy for Alaska White
population 77.7 yo
•Life expectancy for U.S. White
population 78.3 yo
* Death Outcomes includes 2 patients who died in 2012

27. AUTOIMMUNE HEPATITIS
Features
• Up to 14% to 44% have other Autoimmune
condition: Should be vigilant for these and screen
– Autoimmune thyroid most common
– 2.8 to 3.5% have celiac disease
• A family history of an autoimmune disorder in a 1st
degree relative
– Sjogrens most common
– Autoimmune thyroiditis
– RA
– SLE

28. AUTOIMMUNE HEPATITIS
• In general females Predominate 8-10:1 F:M
• Occurs At Any Age
• May Be Symptomatic Or Asymptomatic
– Can present as acute icteric hepatitis
• Acute onset in 25%-75% of patients
– Can present as asymptomatic or minimally
symptomatic abnormal LFTs (25%-34%)
• Most develop symptoms one to 10 years later
• In original Mayo Clinic study 70% progressed to End
Stage Liver Disease without treatment within 2-3
years

29. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and
Guidelines From the American Association for the Study of Liver Diseases
Hepatology, Volume: 72, Issue: 2, Pages: 671-722, First published: 21 December 2019, DOI: (10.1002/hep.31065)

30. 2/7/2024 ANMC Viral Hepatitis Program
AUTOIMMUNE HEPATITIS
TYPES
• Type 1: 60-70%
– Anti-Smooth Muscle (Actin) Antibody (ASMA)
And/Or Anti-Nuclear Antibody (ANA) positive
• Type 2: 4%-20%
– Anti Liver/Kidney Microsomal (Anti-LKM) Antibody
positive:
– Younger females, frequent in Mediterranean area
– Occasionally associated with HCV
• Type 3: 10%-30%. Is a variant of Type 1
– Anti-SLA (Soluble Liver Antigen); variant of type 1
– Elevated IgG may be only positive lab test

31. AUTOIMMUNE HEPATITIS
DIAGNOSIS
• Laboratory
– ANA > 1:40
– ASMA > 1:40 or Actin > 30 (20-30 intermed)
– Anti-LKM if ANA, ASMA negative: antibody to
short linear sequence CYP2D6
– Elevated globulin, gamma globulin or IgG
– Genetic: HLA B8-DR3 or DR4

32. Other Autoimmune Antibodies
• Anti-SLA: sole marker in 14% to 20% of
AIH
– Associated with severe disease and with
relapse after medication withdrawal
• pANCA: 50%-92%
• Anti-LKM mostly found in type 2 AIH, more
frequently in children

33. AIH in Alaska Natives: Unique
Autoantibodies and HLA Associations
• Compared to other populations AN with AIH
– Had a higher prevalence of
• Antibodies to double stranded DNA (47.9%)
• Anti-neutrophil cytoplasmic antibodies (38%)
– Had a lower prevalence of
• Anti-Ro antibodies (15.5%)
• Anti-SLA (only one person):
• No association between anti-Ro and anti-SLA
– A positive association was found between:
• HLA DR3 and anti-double stranded DNA
• HLA DR14 and anti-cytoplasmic antibodies
– No association between autoantibodies and clinical
outcome
Ferucci et al. Liver International 2013

34. HLA and Antibody Associations
in AN Persons with AIH
• At least one allele of HLA DR4 was found in
80% of AN persons with AIH
• 14 of 71 patients in this study had a
concurrent rheumatic diagnosis
• The presence of HLA DR4 and absence of
HLA DR3 was significantly found in more AN
persons with AIH who had a concurrent
rheumatic disease
– Neutropenia was more common in persons with
concurrent rheumatic disease while not on meds
Ferucci ED et al. Liver International 2013: ISSN 1478-3223

35. Other Antibodies in AIH
• pANCA: common in AIH, lack specificity
• Anti-ASGPR:
– directed against transmembrane glycoprotein
on hepatocyte surface
– Coexists with SMA and ANA
– Correlates with histological activity
– Disappears with remission
– Reappears with relapse

36. Other Antibodies in AIH
• Anti-SLA/LP
– Highly specific
– Targeted to 50-kd cytosolic protein
– Predict relapse with treatment withdrawal
• Anti-LCI
– High prevalence in patients with AIH <20
years old
– Rare in persons > 40 years old

37. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and
Guidelines From the American Association for the Study of Liver Diseases
Hepatology, Volume: 72, Issue: 2, Pages: 671-722, First published: 21 December 2019, DOI: (10.1002/hep.31065)

38. Differential Diagnosis
• Rule out:
– Viral hepatitis A, B and C
– Drug Induced
• Immune Check Point Inhibitors
– NAFLD
– Alcohol associated liver damage

40. Role of Liver Biopsy
• Guidelines recommend liver biopsy to
confirm diagnosis and assess degree of
fibrosis and concurrent steatosis
• Reasons
– No pattern of tests are diagnostic of AIH
– False positive ANA and Actin Smooth Muscle
antibody elevations are common and increase
with age
– IgG may be elevated due to another immune
disorder such as RA of Sjogren's

41. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and
Guidelines From the American Association for the Study of Liver Diseases
Hepatology, Volume: 72, Issue: 2, Pages: 671-722, First published: 21 December 2019, DOI: (10.1002/hep.31065)

42. Concurrent Liver Diseases in
Patients with AIH
• Histologic features of NAFLD are present
in 17% to 30% of patients with AIH on liver
biopsy

43. AUTOIMMUNE HEPATITIS
Features
• >90% respond to treatment;
Corticosteroids with or without
azathioprine
• Spontaneous remissions can occur
• Relapse >70% in patients off medications
or if corticosteroids tapered to rapidly
(common mistake we have made)

44. AIH in Pregnancy
• Always treat persons with acute autoimmune
hepatitis (ALT > 10 X ULN with or without
jaundice)
• For persons with mild/moderate ALT elevation
liver biopsy to:
– Confirm diagnosis
– Stage fibrosis
– Determine need for treatment with liver biopsy
Manns et al. AASLD Guideline AIH. Hepatology 2010;51:1-31
Free download at aasld.org on practice guidelines tab

45. AIH in Pregnancy

46. Drugs for AIH in Pregnancy
• Azathioprine: No increased risk in pregnancy
found small amounts found in breast milk
• Mycophenolate (MMF): Contraindicated in
pregnancy
– Increased risk of 1st trimester pregnancy loss and
birth defects
• Council patients about risks in pregnancy and
if they plan to get pregnant, adjust
medications appropriately and monitor

47. FibroScan in AIH
• May be useful to follow patients with cirrhosis as
increasing values may predict portal hypertension,
risk of esophageal variceal bleed and risk of liver
failure
• May be also useful to follow improvements or
worsening of fibrosis over time
• One caveat is when LFTs are elevated, FibroScan
score will be higher with liver inflammation
• Best to wait few months after remission to perform
FibroScan testing, then every 2-3 years thereafter
to determine if fibrosis is improving or resolving
– Also useful for detecting steatosis and NAFLD

48. Fig. 1. Time-course of liver stiffness (A) and serum alanine aminotransferase levels (ALT, B). Within the first months of
immunosuppressive treatment. (This figure appears in colour on the web.)
Johannes Hartl, Ulrike Denzer, Hanno Ehlken, Roman Zenouzi, Moritz Peiseler, Marcial Sebode, Sina Hübener, Nadine
Pannicke, Christina Weiler-Normann, Alexander Quaas, Ansgar W. Lohse, Christoph Schramm
Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis
Journal of Hepatology, Volume 65, Issue 4, 2016, 769–775
http://dx.doi.org/10.1016/j.jhep.2016.05.023

49. Thiopurine S-Methyltransferase
(TPMT)
• Azathioprine converted to 6-MP in liver
• 6-MP converted to 6-TGN by hypoxanthine
phosphoribosyl transferase and 6-MMP by
TPMT Tyrosine Phosphate Methyl Transferase
• TPMT genotype in Caucasians
– Homozygous normal 89%
– Heterozygous 11%
– Homozygous recessive 0.3%
• TPMT genotype in Alaska Native Population is
similar

50. Azathioprine Metabolic Pathway
Azathioprine
6-MP
6-MMP
TPMT
6-MP 6-MP
HGPRT
6-Thiosinonine
5 mono-PO4
XO
6-Thiouric
Acid
IMPDH
TPMT
6-MMP
6-TGN

51. Use of TPMT in Management of
Autoimmune Hepatitis
• TPMT phenotype (enzyme activity level) or
genotype in persons starting azathioprine
– At least 8 abnormal genotypes of TPMT
• Metabolite levels of TPMT and hypoxanthine
phosphoribosyl transferase in persons on
Azathioprine to adjust dosage
– 6-TGN associated with response
– Levels of 6-TGN > 400 associated with neutropenia
– Levels of 6-MMP > 6000 associated with hepatitis

52. Usefulness of Measuring
Azathioprine Metabolite In AIH
• Study of the usefulness of measuring 6-TGN
and 6-MMP in AIH Alaska Native patients,
Hispanics and African American patients taking
azathioprine (AZA)
• No association between these levels and leukopenia
developing on AZA
• No association between 6-TG level, the active
metabolite of AZA, and remission
• Conclusion: Measure TPMT enzyme level to
identify abnormal enzyme in homozygotes and
to guide starting dose of AZA but not 6-TG
Ferucci et al. Canadian J Gastroenterology 2011;25: 21-7

53. Investigational Findings:
Neutropenia in AIH in AN
People
• Abnormalities found in the enzyme that
metabolizes azathioprine: Thiopurine
methyl-transferase (TPMT)
– 19.3% (1in 5) AN persons with AIH had
heterozygous abnormality: 1*/3A compared to
one in eight persons in other populations
• However, neutropenia was still common in
persons with normal TPMT genotype or
enzyme activity
Ferucci ED et al Can J Gastrenterol 1011;25:21-27

54. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and
Guidelines From the American Association for the Study of Liver Diseases
Hepatology, Volume: 72, Issue: 2, Pages: 671-722, First published: 21 December 2019, DOI: (10.1002/hep.31065)

55. AIH TREATMENT
• Initial induction therapy based on 3
randomized controlled trials in early 1970s
– Prednisone 20-40 mg/day, budesonide 9mg/day or methyl
prednisolone 16-32 mg/day. Improvement within 2-weeks
expected; Taper rapidly: Goal ALT normalization
– Azathioprine after checking TPMT, start 25mg, increase to
50mg/day then increase to 1.5 to 2.0 mg/kg/day if tolerated
• Do not use in decompensated cirrhosis
• Maintenance Therapy
– Azathioprine (AZA) 1-2 mg/kg/day with or without
prednisone 4-6mg/day. Both may be needed
– Or prednisone 10-12.5 mg/day
– Mycophenolate or Tacrolimus as alternative drugs

56. AIH Treatment
• Salvage Therapy: For persons not
tolerating steroids and/or Azathioprine or
on maximum therapy not able to bring ALT
<1.5 X ULN: No randomized trials done
– Cyclosporin: need to monitor trough levels
– Tacrolimus: need to monitor trough levels
– Mycophenolate: monitor CBC and diff
• 89% achieve remission
– Rituximab, Infliximab, Thioguanine

57. Budesonide
• Non-halogenated glucocorticoid
• 90% metabolized by liver during 1st pass
• Glucocorticoid activity of two metabolites are<
10% that of other corticosteroids
• 15-20 times higher glucocorticoid binding activity
in liver than other corticosteroids
• May be as effective as 1st line treatment
• Fewer side effects than other corticosteroids
• Initial dose: 9mg/day-
• AASLD now recommends Budesonide in children
and adults without cirrhosis

58. Initial Monitoring of Patients with
AIH after Starting Treatment
• Initial management:
– Frequent ALT and CBC with diff (if on AZA or
mycophenolate)
– Gradually increase azathioprine every 2-4
weeks to between 1-2 mg/kg (max 3mg/kg);
check CBC w/diff 2 weeks after start and after
each increase
– If TPMT enzyme is intermediate level, go very
slowly on Azathioprine increases

59. Intermediate Management of
AIH: Tapering Steroids
• No hard and fast rules about corticosteroid
tapering
• When ALT < 2 times ULN (60-80U/ml)
begin to taper steroids by 4 mg/2-4 weeks
until dose of methylprednisolone reaches
16mg then 2 mg q. 2-4 weeks until dose
reaches 10 mg, then by 1mg q 4 weeks

60. Definition of Remission
• Ideal: Normal ALT and AST (AST may be
more important than ALT for remission)
• Normal IgG (usually lags behind ALT/AST
normalization)
• Practical: some persons will not reach a
normal ALT/AST due to:
– Concurrence of another liver disease usually
NAFLD but could include HBV, HCV, alcohol,
overlap syndrome or other conditions
– Importence of immunosuppressive medications

61. Maintenance Therapy in AIH
• Follow-up when in remission and on stable
dose of therapy every 3-4 months
• Duration of maintenance therapy:
Indefinite?
– May try withdrawal when in remission for 2-5
years
– In persons withdrawn relapse occurs in 70%
within 6 months
– Late relapses can occur so lifetime monitoring
of ALT/AST every 3-6 months is imperative

62. Tests for Monitoring AIH after
Remission
• LFT’s every 3 to 4 months
• If on Azathioprine or Mycophenolate, CBC
with diff
• If on Tacrolimus, creatinine and GFR plus
Tacrolimus levels
• IgG yearly
• FibroScan every 2-3 years
• Baseline DEXA then every 2-3 years

63. Withdrawal of AIH Patients from
Immunosuppressive Therapy
• Requirements
– At least2 years in remission on maintenance
therapy: normal ALT and IgG
– No inflammation on liver biopsy but not
required
– 50%-87% of those withdrawn relapse

64. AUTOIMMUNE OVERLAP
AND OTHER SYNDROMES
• Autoimmune Cholangitis and AIH
– AMA negative cholangitis (AMA neg PBC)
– High ANA titers and elevated IgG
• PBC and Autoimmune Hepatitis (AIH)
– AMA + and high titer of ANA and/or SMA
– Features of cholangitis and hepatitis on
biopsy
• Both of these overlap syndromes may
respond to UCDA and corticosteroids

65. PBC: Florid Bile Duct Lesion

66. AUTOIMMUNE OVERLAP AND
OTHER SYNDROMES
• PBC and PSC
– AMA positive Cholangitis on biopsy plus
radiological features of PSC
• Autoimmune cholangitis and PSC
– AMA-, cholangitis on BX and radiological PSC
• AIH and Autoimmune Cholangitis
– ANA and/or SMA+, AMA- and features of
chronic hepatitis and cholangitis on biopsy.
Usually responds to UCDA

67. OUR ROLE IN MANAGEMENT
• AIH RN tracks patients
• Sends letter reminding patient to get blood draws
every 3-4 months if in remission; sends list of
patients needing testing to PCP to order tests
– LFTs
– CBC with differential if on azathioprine or
mycophenolate
– Tacrolimus trough level and creatinine if on
Tacrolimus
• Hepatitis clinic visits depends on control
– Every 6-12 months if in remission: yearly in field
clinics

68. Research in AIH: Here and
Beyond
• HCC in cirrhosis in AIH: q. 6-month US
• Epidemiology of AIH in AN/AI peoples
• AIH and environmental heavy metal
contaminants
• FibroScan as a tool to track liver fibrosis

69. Conclusions
• Alaska Native People have the highest
reported rate of AIH in the world
• Females outnumber males 13:1
• Majority of persons with AIH either have or
develop another autoimmune disorder or
have a 1st degree relative with an
autoimmune disorder

70. Conclusions Continued
• Untreated AIH mortality can be as high as
75% in 2-years
• Persons with AIH who are treated and go
into remission survive similar to those
without AIH
• Life expectancy in AIH is about 7-years
less than general AN population and 15
years earlier that the US White population
• 29% expire from a liver related event

71. Conclusions Continued
• All AN women with elevated LFTs should
be screened for AIH (ANA, Actin AB IgG,
AMA)
• AN men with any autoimmune disorder or
family history of autoimmune disorder
should also be screened
• A liver biopsy is necessary to confirm the
diagnosis