1. Classification of Autoimmune Liver Diseases (AILD)
Autoimmune hepatitis (AIH)
Cholestatic AILD
Primary biliary cirrhosis cholangitis (PBC) 2015
Primary sclerosing cholangitis(PSC)
IgG4-associated cholangitis (IAC)
Overlap syndrome
AILD is classified into Autoimmune hepatitis, AIH and cholestatic AILD, which includes PBC, PSC, and IgG4 associated cholangitis.
In addition, there are some patients showing overlap of Autoimmune hepatitis and cholestatic AILD.

2. Frequency of Autoimmune Liver Diseases <2% of liver ds
Frequency of Autoimmune Liver Diseases <2% of liver ds. in liver clinic : Rare Disease
Chronic hepatitis
Liver cirrhosis
AILD is a rare disease in hepatology.
As shown in this slide, AILD occupies only 2% of the patients with chronic hepatitis, and 1% of liver cirrhosis patients in our hospital.
6,307 patients visited to a liver clinic in SNUBH, South Korea ( )
Lee SS, et al. Clin Mol Hepatol 2012;18;309

3. Definition of Rare Disease
No single definition but defined by prevalence
US: < 1/1,500 (<200,000 people in US) at any give time
Europe: <1/2,000 & life-threatening or chronically debilitating ds. that special combined efforts are needed to address them
Japan: < 1/2,500 (<50,000 people in Japan)
Korea < 20,000 people in South Korea
Orphan disease
a synonym for rare disease
A distinct legal meaning, “The orphan drug movement” or “Orphan Drug Act” Benefit for drug development (tax incentives, financial subsidies, lower cost for clinical trials of small sample size, enhanced patent protection…)
281 marketed orphan drugs, 600 drugs in clinical trials in 2014
AILD patients receive a healthcare benefit from government in many countries
Globally 300 million people are affected by a rare disease
5,000-7,000 rare diseases, only 400 have therapies
Although there is no single definition for rare disease,
it is defined by prevalence less than 1 among 2500 people in Japan, while it is defined by patient’s number less than 20 thousand in South Korea.
As a synonym for rare disease, the term of orphan disease has a distinct legal meaning such as tax incentives for drug development for rare disease.
The patients with AILD usually receive a healthcare benefit from government in most countries.

4. AIH: Diagnosis ↑AST/ALT, immunoglobulin G (IgG)
Autoantibodies are usually present
ANA, SMA, anti-LKM1
≥1:40 in adults, ≥ 1:20 in children
Liver biopsy is essential
Interface hepatitis, portal plasma cell infiltration
Biochemical markers not correlate with histological severity
Exclusion of other etiologies
Viral(A,B,C), alcohol (>25-50 g/d)
drug (minocycline, nitrofurantoin, interferon α, methyl dopa, et al)
hereditary liver diseases (ceruloplasmin, iron, ferritin, α1AT)..
Scoring systems
The diagnosis of AIH is usually based on the elevated levels of ALT and IgG, with presence of conventional autoantibodies, such as ANA, Anti-SM, anti-LiverKidneyMicrosome type1 Ab.
Liver biopsy is essential for the diagnosis and guiding therapeutic decisions, if there are no contraindications.
The exclusion of other etiologies of liver injury is a prerequisite diagnostic criteria.

5. AutoAntibodies in AIH Type 1 AIH Type 2 AIH
ANA (70-90%): speckled or homogeneous, IF
F-actin reactive SMA (60-80%), IF
Anti-SLA/LP (10-20%): Poor Px marker, ELISA
Type 2 AIH
Anti-LKM-1 (90%): CYP2D6(target Ag), IF or ELISA
Anti-LC-1(30%): IF
Helpful for Dx, but Nonspecific
(+) in nearly all kind of liver ds, even in healthy person
Type 1 AIH is the most common type in adult patients more than 75%. It is characterized by presence of ANA and ASM, both of which are detected by indirect immunofluorescence. However, these 2 abs can be detected in many other liver diseases or even in normal individuals. Therefore these are not specific for AIH.
Anti-SLA/LP(soluble liver antigen/or liver pancreas ag measured by ELISA method is the most specific Ab detected in type 1 AIH, however, it is found only in 10-20% of the patients. This ab reflects disease activity and relapse risk after Tx, and indicates a poor clinical outcomes. However, its availability in clinics is limited in many countries.
Type 2 AIH is characterised by anti-LKM1 which has a well defined antigenic target of Cyptochrome 2D6. It can be evaluated either by IF or ELISA.
Anti-Liver cytosol 1 ab also shows a high specificity for type 2 AIH, but low sensitivity.
Himoto T, Autoim Highlights 2013;4:39,

6. Pathology of AIH Interface hepatitis, enlarged portal tract
The pathological findings of typical AIH are Interface hepatitis, Portal inflammation with plasma cells, lymphoid follicles and lobular activities.
The interface hepatitis shown in the left panel of this slide is formerly called as piecemeal necrosis, and it is ass with ds. Progression.
Lobular activity ranges from single cell necrosis to confluent massive necrosis with regenerating cell clusters, which is called as cobblestone appearance
Rt panel of this slide shows an Emperiopolesis, which means that one immune cell penetrates into a larger cell:
emperiopolesis was found in 70% of the Western patients, but 15% of Japanese pt.
Bile duct damage can be seen in AIH, but loss of bile duct or granulomatous cholangitis are not present in AIH.
Interface hepatitis,
enlarged portal tract
Emperiopolesis
Harada K, Hepatol Res 2017

7. Scoring System for Diagnosis of AIH 1999 IAHG
Category Factor Score
1) Gender Female +2
2) ALP/AST ratio <
1.5 –
>
3) Γ-globulin(IgG) levels
above normal >
1.5 –
<
4) ANA, SMA, anti-LKM1 titers 1: 1:
< 1:
5) AMA positive -4
6) Viral marker positive -3
negative +3
7) Drugs yes -4
no +1
Category Factor Score
8) Alcohol < 25 g/day +2
> 60 g/day -2
9) HLA DR3 or DR4 +1
10) Immune ds +2
thyroiditis, colitis, synovitis
11) liver-defined Ab +2
anti-SLA/LP
anti-actin, anti-LC1
pANCA
12) Histology interface hepatitis +3
plasma cells +1 rosettes +1
none of above -5
biliary change -3
other features -3
13) Tx. Response complete +2
relapse +3
This comprehensive scoring system, so called revised original scoring system, was published in 1999 by the international AIH group.
It is widely validated and used with high sensitivity but somewhat lower specificity.
However, this is too complex to use in clinics.
Sensitivity=100%
Specificity=73%
Predictability 82%
PreTx. Score: definite diagnosis >15, probable diagnosis: 10-15
PostTx. Score: “ “ >17, “ “ : 12-17
Wiegard C, Semin Liver Dis 2009

8. Simplified Diagnostic Criteria for AIH 2008 IAHG
variables
cutoff
points
ANA or SMA
≥ 1:40 1
≥ 1:80 2
or LKM
or SLA +
IgG
> UNL
> 1.1 x UNL
Liver histology
c/w AIH
Typical AIH
Absence of viral hepatitis
yes
Sensitivity 95%, Specificity 90%, Predictability 92%
Sensitivity ( %), positive predictive value ( %) for probable-definite Dx with revised scoring system
≥6: probable AIH
≥7: definitive AIH
Therefore, the same group proposed the simplified scoring system in 2008.
It is based on 4 parameters including antoAbs, IgG ,histology and exclusion of viral hepatitis.
In this criteria, anti SLA testing and liver biopsy are required.
However, anti-SLA ab testing is not available in many countries, and liver biopsy can not be done in some patients
Hennes et al, Hepatology 2008;48:170

9. Revised Original (1999) vs. Simplified (2008) Scoring System
Concordant rate=85%
Simplified scoring system: higher specificity with lower sensitivity
more likely to exclude the atypical cases (NAFLD, acute onset)
No scoring system can supplant clinical judgment
Those 2 scoring systems showed a concordant rate of 85%.
Compared to the revised original criteria, the simplified criteria has higher specificity with cost of lower sensitivity.
Therefore, It is more likely to exclude the atypical cases.
Therefore, No scoring system can supplant clinical judgment

10. Case 1. Female/ 54 Yr ALT 52 IU/L, GGT 102 IU/L, SAP 98 IU/L
ANA+(1:160), IgG 1900 mg/dL
No viral, alcohol, toxic etiology
Obesity with DM type 2
Revised original score: 15 (probable AIH)
Simplified score: 6 (probable AIH)
Japanese criteria: 3(1/2) (atypical AIH)
Liver Bx:
typical NASH cirrhosis, no evidence of AIH
Let’s see this 54 year-old female case that showed a mildly elevated ALT(52 units) with ANA positivity and elevated IgG.
Her score met the “probable AIH” criteria by revised original and simplified scoring system and classified as Atypical AIH by Japanese criteria.
However, her liver biopsy revealed a typical NASH cirrhosis without evidence of AIH.

11. NAFLD with AIH features
US study
225 biopsy proven NAFLD (Mayo Clinic)
23% had autoAb (ANA20%, SMA3%)
NAFLD with autoAb (88%, 45/51) fulfil Dx criteria of AIH prior to biopsy
 after biopsy, 4/51 (8%) were AIH
Japan study
212 bx proven NAFLD, ANA+ (33%)
AIH score≥ 10 (n=127, 60%): 97% of female/ 20% male pt
 after liver Bx, definite AIH only in 0.5%
It is very important to perform a liver biopsy to make a definitive diagnosis of AIH or NAFLD before Tx.
As shown in these 2 studies in United States and Japan, the biopsy proven NAFLD patients showed ANA or SMA positivity in 23% to 33%.
Among the NALFD patients who fulfilled the diagnostic criteria of AIH before liver biopsy, only 8% or less than 1% of the patients finally had AIH after liver biopsy.
Therefore, it is very important to perform a liver biopsy to make a definitive diagnosis of AIH or NAFLD before Treatment,
because corticosteroid therapy for AIH may be harmful to NAFLD. .
Admas LA, et al. Am J Gastro 2004;1316
Yatsuji S et al. J Gastro 2005;40:1130

12. Case 2. Male/21 yr
Abnormal LFT on pretest at military recruitment, nausea+
: AST/ALT 698/2,236 IU/L, T. bilirubin 2.3 mg/dL, SAP 208 IU/L
Heavy alcohol drinking with history of alcohol withdrawal sx, smoking (3PY)
drug(-), sexual contact(+)
176cm/67kg, no remarkable abnormality on physical exam.
HAV IgM(-), HBsAg(-), sAb(+), anti-HCV(-), HCV RNA(-), anti-HEV IgM(-)
Ceruloplasmin 24.3, urine drug test: negative
Abdominal ultrasound: normal
ANA- ASM- anti-LKM1- AMA-, ANCA-, IgG/A/M 1400/157/78
EBV DNA(-), EBV VCA IgM(-), HSV IgM(equivocal positive), HSV IgG(+), CMV DNA(-), anti-HIV(-)
This young man was presented as ALT level higher than 2,000 IU/L on pretest at military recruitment.
Although he was past heavy drinker, his recent hepatitis was not supported by alcoholic history.
All of autoantibodies were negative and Immunoglobulin G level was normal.
Interestingly he has a history of recent sexual contact, and anti HSV ab type IgM was equiviocally positive.

13. Case 2. Male/ 21 Yr Liver Biopsy Report: Active lobular hepatitis
1) confluent hepatocytes necrosis
2) regenerating hepatocytes
3) mild portal inflammation
Note)
The possibility of acute hepatitis (viral, toxin/drug-induced etc.) could be suggested. Immunohistochemical staining for Herpes virus was negative.
His liver biopsy findings were active hepatitis with confluent necrosis and mild portal inflammation.
The both of the scoring systems indicated no diagnosis of AIH.
PreTx. Score (6) < 10: No diagnosis of AIH
Simplified score(2) : No diagnosis of AIH

14. Case 2. Male/ 21 Yr PostTx revised original score (13): Probable AIH
Liver Bx#1
2013/9/30
Liver Bx#2
2013/11/25
Acyclovir
10/2-10/25
Valacyclovir
12/13-12/30
Pd 30mg
2014/4/14
-2014/11/8
AZT 50mg
2014/4/21
-2016/9/8
2013
9/27
10/9
11/8
11/26
12/13
2014
1/5
3/13
4/14
6/9
2016
12/23
Albumin
4.7
3.9
4.5
4.2
4.4
5.0
Bilirubin
2.3
1.8
1.2
1.1
0.9
0.7
1.3
1.0
SAP
208
165
125
170
143
109 99 84 91
AST
698
395
221
326
123 31 37
333 17
ALT
2236
1353
541
1190
440 64
127
416 29 12
IgG
1310
1400
1430
1160 PT
90%
98%
86%
102%
96%
Because of concern on the aggravation of possible herpes simplex hepatitis by corticosteroid, we tried acyclovir first.
ALT level tends to decrease, but relapsed.
He underwent 2nd liver Biopsy, which showed a compatible finding with AIH. But still anti-HSV IgM was positive
He had no symptoms without jaundice, and we tried 2nd time of antiviral therapy targeting herpes simplex.
It was accompanied by rapid decrease of ALT.
However, after 6 month of initial presentation, hepatitis relapsed, and at this time, we began to corticosteroid therapy.
It resulted in a dramatic normalization of ALT, and finally he successfully discontinued the immunosuppressive therapy.
PostTx revised original score (13): Probable AIH
Japanese criteria (3[1/2]) : atypical AIH

15. Acute Onset AIH: Pathology & Clinical Characteristics
Centrilobular necrosis
Parenchymal collapse
Minimal portal inflammation
Cobblestone appearance(regenerating hepatocytes)
lower interface hepatitis, less lymphoplasmacytic infiltration
Low ANA titer,
Lower IgG
Lower AIH score
Higher HLA-DR9 & lower DR4
Similar Tx response
This case is compatible with Acute onset AIH.
Many Japanese researchers already reported it as atypical case characterized by Pathologically centrilobular necrosis with less portal hepatitis, and clinically
lower rate of autoab detection and normal IgG levels. This acute onset AIH cases respond well to the corticosteroid therapy, similar to typical AIH.
Awareness of this case is important for timely treatment, and intervention of progression to acute liver failure
Harada K. Hepatol Res 2017
Y Aizawa, Eur J Gastroenterol Hepatol 2016;28:391

16. Problems in Dx. of AIH No gold standard criteria for Dx
No scoring system can replace clinical decision-making: NASH, acute presentation
Timely therapeutic trial with corticosteroid in severe case is important
There is no gold standard criteria for the Dx. of AIH
No scoring system replace clinical judgment, especially in atypical cases.
Therefore, timely therapeutic trial with corticosteroid in severe cases is important.