Autoimmune Liver Disease

Autoimmune hepatitis,
primary biliary cirrhosis/cholangitis,
primary sclerosing cholangitis and
overlap syndrome

Susanto H Kusuma
Div. Of Gastroentero-Hepatology, Dept of Internal
Medicine, Faculty of Medicine, Hasanuddin Unversity
Autoimmune liver disease

 Represent about 5% of all chronic liver disease

 Sub-category
 Autoimmune hepatitis (AIH)
 Primary biliary cirrhosis (PBC)
 Primary sclerosing cholangitis (PSC)
 IgG4-associated cholangitis
 Etc…
 Pathogenesis: unknown
 Diagnosis
 Based on reasonable exclusion + compatible findings
 No single test (eg., pathology) confirms thediagnosis

Jeong SH, KASL meeting 2011:S44

AIH: Definitions

 Autoimmune hepatitis is a chronic liver disease characterized by

inflammation and hepatocellular necrosis with unknown causes,
usually accompanied by fibrosis which tends to progressive towards
cirrhosis and liver failure.
 AIH: pathogenesis

INNATE IMMUNE ADAPTIVE

SYSTEM IMMUNE SYSTEM

• Neutrophils Cell B (humoral cell T (cellular

• Macrophages immunity) immunity)
• Interferon
• Natural killer cells
• Complement • Plasma cells
• Cell B memory
system • CD8 Cells (Cytotoxic T cells)
• CD4 cells (Helper T cells)
• T cell memory

Sherwood L, Fisiologi Manusia dari sel ke sistem, ECG. 2009

 Presentation of a nonclassical clinic in
autoimmune hepatitis

Asymptomatic
Acute Onset
• Frequency, 25-34% • Frequency, 25-75%
• Histological features similar to symptomatic patiens • Newly developed or exacerbated pre-
• Become symptomatic in 26-70% existent disease
• Survival without treatment possible

Acute severe (Fulminant) onset Overlap syndrome

• Frequency, 25-75% • Mixed features AIH
• Onset encephalophaty ≤ 26 weeks + PBC or PSC
• Classical features may be absent • Paris citeria for AIH
• Centrilobular necrosis in 86% + PBC
• Lymphoplasmacytic infiltrates and interfaves
hepatitis in 50%-90%
• Heterogeneous hypoattenuated regions by
unenhanced CT

Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver. 2016;10(2):177-203.
Czaja, A. J. (2013). "Challenges in the diagnosis and management of autoimmune hepatitis." CanJ Gastroenterol; 27(9);531-539.
 Subclassification of AIH
Sub-type Features
AIH-1 • Almost 90% of AIH cases • Usually excellent treatment
• Detection of ANAs, SMAs or anti-SLA/LP response, but variable
• Association with HLA DR3, DR4 and DR13 relapse rates after drug
• Any age at onset withdrawal and need for
• Variable clinical and histopathological long-term maintenance
severity therapy
AIH-2 • Up to 10% of AIH cases • Sometimes failure of
• Anti-LKM1, anti-LC1 and rarely anti-LKM3 treatment and frequent
• Association with HLA DR3 and DR7 relapse rates after drug
• Onset usually in childhood/young adulthood withdrawal; need for
• Clinical and histopathological severity long-term maintenance
commonly acute and advanced therapy very common
AIH-3 • Up to 10% of cases • Lifelong immuno-
• Only SLA/LP positive suppression in most, if not
• Otherwise very similar to AIH-1* all patients
• Often Ro52-antibody positive
*Possibly more severe
EASL CPG AIH. J Hepatol 2015;63:971–1004
Suggested diagnostic algorithm for AIH

Liver disease of unknown origin

IFL autoantibody test on

rodent tissue sections
+ SLA/LP (ELISA or blot)

LKM1/ SLA/ Test

ANA+ SMA+
LC1+ LP+ Negative

Clinical suspicion*
Consider AIH* remains

Repeat testing in Negative

Liver specialty lab Consider alternate
biopsy (including pANCAs and specific diagnoses or
immunoassays for LKM1, LKM3, Autoantibody-
LC1, SLA/LP, F-actin, Ro52, negative AIH
gp210†, sp100†)

Positive

Consider AIH

*Test also for elevated IgG levels; †These antibodies are highly specific for PBC diagnosis EASL CPG AIH. J Hepatol 2015;63:971–1004
Scoring system for AIH

Manns et al., AASLD practice guideline 2010

 Differential diagnosis of AIH

AIH should be considered in any patient with acute or

chronic liver disease
Particularly if hypergammaglobulinaemia is present and if the patient has features of other
autoimmune diseases

Other autoimmune liver diseases

• Primary biliary cirrhosis • IgG4-associated cholangitis
• Primary sclerosing cholangitis*

Chronic viral hepatitis

• Chronic hepatitis B  HDV
Other conditions
• Cholangiopathy due to HIV infection
• Alcoholic liver disease
• Drug-induced liver injury
• Granulomatous hepatitis
• Haemochromatosis
• Chronic hepatitis C
• Non-alcoholic steatohepatitis
• α1-antitrypsin deficiency
• Wilson disease
• Systemic lupus erythematosus
• Coeliac disease

*Including small duct primary sclerosing cholangitis

EASL CPG AIH. J Hepatol 2015;63:971–1004
PBC:pathogenesis

Damage and loss of

biliary epithelial cells
lining small intrahepatic
bile ducts

Chronic
cholestatic liver
disease
Jones Gut 2007;56:1615
Diagnosis

1. Biochemical evidence of cholestasis based mainlyon

alkaline phosphatase elevation.
2. Presence of AMA
3. Histologic evidence of nonsuppurative destructive
cholangitis and destruction of interlobular bile ducts

 When two of the three criteria are met, the diagnosis of

PBCcan be established

Lindor et al., AASLD Practice guideline, 2010

Primary Sclerosing Cholangitis (PSC)

Is one of the cholestatic liver disorders

Cholestasis (“a standing still of bile”) is defined
clinically as jaundice and/or itching and
biochemically by varying degrees of elevation in
alkaline phosphatase and bilirubin

Chronic cholestatic liver disease characterized by

diffuse inflammation and fibrosis of both intra-
and extra-hepatic bile ducts
May lead to liver cirrhosis, portal hypertension,
and liver failure
Primary Sclerosing Cholangitis (PSC)
Etiology and pathogenesis of PSC

Exact causes of PSC –unknown, however believed to

be multifactorial
Data supporting genetic predisposition
Familial occurrence of PSC
Association of certain haplotypes (HLA chrom 6p21, HLA B*08,
HLA-DRB1) with the disease
Genome wide assoc studies – 16 risk loci
Data supporting Immune-mediation
Presence of autoantibodies (ANCA, ANA, ASMA, and others)
Association with other autoimmune disorders
Clinical Presentation of PSC

Most patients are asymptomatic at diagnosis

Cholestatic biochemical profile found incidentally in a
patient with known IBD
Hypergammaglobulinemia (elevated IgG levels)
Positive ANA, ASMA, pANCA may be found
Symptomatic patients
Most common initial symptoms are abdominal pain
(20%), itching (10%), jaundice (6%) and fatigue (6%)
Symptoms of bacterial cholangitis or infection in bile ducts
(fever, chills, Abd pain, jaundice)
Diagnosis of PSC

Cholestatic biochemical profile

Characteristic cholangiography (multifocal strictures
with segmental dilatations)
Exclusion of secondary causes
Choledocholithiasis, previous biliary surgical trauma, HIV, ischemic
stricture post cholesistectomy, histiocytosis X, ischemic
Autoantibodies have no role in the diagnosis of PSC
Case scenario

32 y/o male presents with fatigue, pruritus,

abdominal pain, diarrhea. Physical examination
unremarkable except for abdominal discomfort.

ALT 43, AST 39, Alk Phosphatase 700, T bili 1.2, INR
1.0, albumin 4.2, AMA negative, ANA negative.
Ultrasound shows mild diffuse intrahepatic biliary
dilatation, no obvious masses.

What is the next best diagnostic test?

Cholangiography
 Diagnosis of PSC: Imaging

MRCP: Sensitivity is around 90% and specificity is

around 95%
ERCP is the gold-standard for diagnosis
Role of liver biopsy:
Not routinely necessary for the diagnosis of PSC
Often nonspecific, false negatives may occur
Helpful in cholestasis in IBD with normal cholangiogram
Useful in determining stage of fibrosis
Presence of overlap such as autoimmune hepatitis
 Autoimmune hepatitis/PSC overlap

Present at a younger age (35% of children with PSC, 5% of

adults) and have a worse prognosis when compared to PSC
alone
Consider in patients with:
mixed elevation of liver tests + imaging consistent with PSC and
serologic suggestive of autoimmune hepatitis (+ANA, + anti-smooth
muscle antibody and/or +anti-LKM), elevated IgG levels
Need a liver biopsy for diagnosis
lymphoplasmacytic portal based infiltrates with at least moderate
interface hepatitis
Algorithm for the diagnosis of PSC

AASLD Guidelines Hepatology 2010;51:660-678

Overlap syndrome

PBC

8%

Autoimmune
Cholangitis 10% 6%
PSC
Autoimmune
hepatitis

11% 13%

Chronic Cryptogenic
Hepatitis C

Czaja et al., Ann Intern Med 1996;125:588

AIH-PBC overlap syndrome

AIH PBC

 AIH  PBC
 ALT> 5 XUNL  AP> 2 XUNL or rGT > 5 XUNL
 IgG > 2 XUNL, SMA(+)  AMA ≥ 1:40
 Compatible liver biopsy  Compatible liver biopsy
 Autoimmune Hepatitis Test

Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis--Update 2015. J Hepatol. 2015;62(1 Suppl):S100-11.
High-dose UDCA

 28-30 mg/kg/day for treatment

Lindor et al., Hepatology 2009;50:808

Overlap with viral hepatitis

 61/F
 8 years ago, chronic hepatitis Cdiagnosed
 Rheumatoid arthritis
 Lab
 Genotype 2a/2c
 RNA: 30,780 copies/ml
 Peg-interferon + Ribavirin for 24 weeks
 Course
IgG = 3441 mg/dl
FANA= 1:320
Anti-SM = positive
AMA =negative
Bx = Active cirrhosis, etiology undetermined, marked
activity
Peg-IFN + RBV
500 Steroid +AZA

400

300
AST
200 ALT

100

0
Pre_Tx ETR SVR 1m 4 years
Variant forms of AIH
Syndrome
Overlap syndromes
AIH & PBC
AIH & PSC
AIH & viral hepatitis
Outlier syndrome
Autoimmune cholangitis
Cryptogenic chronic hepatitis
Distinguishing features
Mitochondiral antibodies
Histologic cholangitis
Cholestatic laboratory changes
Responsiveness to corticosteroid therapy
Ulcerative colitis
Histologic cholangitis
Cholestatic laboratory changes
Abnormal cholangiogram
High autoantibody titer (AIH)
Interface hepatitis, plasma cells(AIH)
Low autoantibody titer (viral)
Portal lymphoid aggregates, steatosis, bile duct injury (viral)
AMA negative
ANA, anti-SM positive
Histologic features of bile ductinjury
Cholestatic laboratory changes
Normal cholangiogram
Absence of autoantibodies
Histologic findings identical to AIH
Responsiveness to cortocosteroid therapy
Czaja et al., Ann Intern Med 1996;125:588
Consecutive PBC/AIH
Take home message

 Tools are used to differentiate

 History, lab pattern, autoantibodies, biopsy
 Clinical course

 Clinical suspicions is most important step inthe

differentiation!
Seorang wanita 46 tahun datang ke poliklinik penyakit dalam dengan
keluhan mata kuning, mudah merasa lelah, gatal-gatal di kulit sejak 1
minggu sebelumnya. BAK dengan urine seperti teh tua, dan BAB dengan
tinja berwarna pucat. Tidak ada riwayat demam sebelumnya. Riwayat
transfusi darah sebelumnya juga disangkal. Tidak ada keluhan nyeri
perut. Penggunaan narkoba suntik disangkal. Pada pemeriksaan fisik
dalam batas normal, dan berat badan pasien 55 kg dengan tinggi badan
160 cm. Pada laboratorium didapatkan Hb. 12,3 g/dl. Leukosit 10.200
/mm3, trombosit 210.000. peningkatan ALP dan gamma GT, enzim hati
dalam batas normal, bilirubin indirek 2,4. Bilirubin direk 4,3.

Penyebab ikterik pada pasien tersebut adalah :

a. Hepatitis B kronik
b. Sirosis bilier primer
c. Hepatitis autoimun
d. Anemia hemolitik
e. Pankreatitis akut
Seorang laki-laki 20th datang ke poli penyakit dalam dengan keluhan
demam sejak 3hari sebelum masuk rumah sakit. Kurang lebih satu
minggu ini ia menyatakan keluhan lesu, tidak nafsu makan dan pegal
pegal semua badan. Saat tadi pagi os bak keluhan warna kencing seperti
air teh, BAB tampak seperti dempul. Dikatakan OS dua teman kuliahnya
ada yang menderita sakit kuning 2 minggu yang lalu. Pada pemeriksaan
fisik didapatkan kesadaran kompos mentis, tekanan darah 110/70 mmHg,
nadi 88x/menit nafas 22x/menit dan suhu 38 ֩C, sklera tampak ikterik,
hepar 2 jari dibawah arcus costa. Tbil 8, Dbil 6 GPT 380 da ALP 285.
Kemungkinan diagnosis pada pasian ini adalah

a. Kolelitiasis
b. Hepatitis B
c. Hepatitis autoimun
d. Hepatitis C
e. Hepatitis A
Seorang wanita berusia 40 tahun, datang ke praktek dokter spesialis
penyakit dalam mengeluhkan lemas, badan dan mata agak kuning, gatal
di seluruh badan 1 bulan terakhir, rasa tidak nyaman perut kanan atas,
mulut dan mata sering terasa kering. Demam, sesak nafas, riwayat sakit
kuning sebelumnya disangkal. Riwayat konsumsi alkohol dan obat-obatan
rutin disangkal. Tekanan darah 120/80 mmHg, nadi 92x/menit, laju
napas 20x/menit, suhu 36,7oC. Pemeriksaan hepar didapatkan liver span
13 cm. Hasil laboratorium didapatkan AST 62 U/L, ALT 74 U/L, bilirubin
total 5,8 mg/dL, bilirubin direk 4,4 mg/dL, ALP 320 IU/L, Gamma GT 220
U/L, kolesterol total 256 mg/dl. Pemeriksaan ultrasonografi abdomen
menunjukkan hasil normal. Pemeriksaan antibodi anti-mitokondrial
didapatkan hasil 1:40 dan anti-smooth muscle antibody negatif. Apakah
diagnosis pada kasus ini?
a. Primary sclerosing cholangitis
b. Autoimmune hepatitis
c. Sirosis bilier primer
d. Kolangitis non supuratif subakut
e. PBC-AIH overlap syndrome
Liver biochemical and function tests —
In acute presentations, elevations in aminotransferases (alanine
aminotransferase [ALT] and aspartate aminotransferase [AST]) may exceed 10 to
20 times the upper limit of the reference range, and the ratio of alkaline
phosphatase to AST (or ALT) is often <1:5, and in some cases is <1:10 [32].
In patients with chronic symptoms or those with cirrhosis at initial presentation,
AST and ALT elevations are less profound, while the ratio of alkaline phosphatase
to AST (or ALT) is lower and approaches 1:2.

Gamma globulins —
One characteristic laboratory feature of autoimmune hepatitis, although not
universally present, is an elevation in gamma globulins, particularly
immunoglobulin G (IgG) (figure 1). Hypergammaglobulinemia is generally
associated with circulating autoantibodies.
Levels of immunoglobulin A and immunoglobulin M are typically normal [33].
Autoantibodies — The major autoantibodies that may be present in patients
with autoimmune hepatitis are (table 2):
●Antinuclear antibodies – Antinuclear antibodies (ANA) are the most common
circulating autoantibodies in autoimmune hepatitis, and may be the only
autoantibody present. Titers regarded as positive are dependent in part upon the
methodology used and the age of the patient. In most laboratories, titers in the
range of 1:80 to 1:100 or greater are regarded as positive in adults.
(See "Measurement and clinical significance of antinuclear antibodies".)
●Anti-smooth muscle antibodies – Anti-smooth muscle antibodies (ASMA) are
more specific than ANA for autoimmune hepatitis, particularly when present in
titers of 1:80 or more in adults, but less prevalent.
●Antiactin antibodies – Antiactin antibodies (AAA) are more specific than ANA
for type 1 autoimmune hepatitis, but have not generally been measured in
laboratories in North America. ASMA titers of 1:320 or greater generally reflect
the presence of AAA and can serve as a surrogate marker for these antibodies.
AAA (IgG anti-F-actin) measured by enzyme-linked immunosorbent assay (ELISA)
are available and, in some laboratories, have replaced ASMA in autoantibody
profiles. They appear to be more sensitive and specific than ASMA measured by
immunofluorescence [34,35].
●Anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP) – Anti-
SLA/LP antibodies have been found in approximately 10 to 30 percent of adult
patients with type 1 autoimmune hepatitis [36,37]. Cloning and characterization
of the soluble liver antigen shows an enzyme that is identical to the liver-
pancreas antigen; thus, the designation SLA/LP was adopted [38,39].
(See "Autoimmune hepatitis: Pathogenesis".)
●Antineutrophil cytoplasmic antibodies – Antineutrophil cytoplasmic antibodies
are a group of autoantibodies that recognize neutrophil proteins, and atypical
peripheral antineutrophil cytoplasmic antibodies (p-ANCA) have been identified
in patients with type 1 disease [40,41]. Atypical p-ANCA have a perinuclear or
atypical staining pattern on immunofluorescence and appear to be directed
against a myeloid 50-kd nuclear envelope protein [42]. Atypical p-ANCA is also
found in patients with inflammatory bowel disease and primary sclerosing
cholangitis. (See "Clinical spectrum of antineutrophil cytoplasmic
autoantibodies" and "Primary sclerosing cholangitis in adults: Clinical
manifestations and diagnosis", section on 'Laboratory tests'.)
In one series, atypical p-ANCA was identified in 30 of 46 (65 percent) patients
with type 1 autoimmune hepatitis as defined by ANA and/or ASMA at titers of
1:40 or greater [40].
●Antimitochondrial antibodies – Antimitochondrial antibodies (AMA) can occur
in type 1 autoimmune hepatitis. The frequency of these autoantibodies is
generally <5 percent, given the increased sensitivity and specificity of AMA and
its M2 subtypes. (See 'Differential diagnosis' below.)
One report found no AMA in 125 type 1 patients, which was due at least in part
to a stricter definition of the autoimmune hepatitis/primary biliary cholangitis
overlap (variant) syndrome [15]. (See "Autoimmune hepatitis variants:
Definitions and treatment".)
●Anti-DNA antibodies – Antibodies to single-stranded DNA and double-stranded
DNA, which are most commonly associated with systemic lupus erythematosus,
can be found in patients with autoimmune hepatitis types 1 and 2 [43]. The
clinical significance of anti-DNA antibodies is discussed separately.
(See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)
●Anti-liver-kidney microsomal-1 antibodies – Anti-liver-kidney microsomal-1
(ALKM-1) antibodies, which are directed at the cytochrome P450 enzyme
CYP2D6, occur mostly in patients with type 2 disease [44,45].
●Anti-liver-kidney microsomal-3 antibodies – Anti-liver-kidney microsomal-3
antibodies (ALKM-3) are directed against uridine diphosphate-glucuronosyl
transferases and are found rarely in patients with type 2 disease [46].
●Anti-liver cytosol antibody-1 – Anti-liver cytosol antibody-1 (ALC-1) is a marker
of type 2 autoimmune hepatitis. They generally occur in conjunction with ALKM-
1, but may be the sole autoantibody [47]. The antigen recognized by ALC-1 is
formiminotransferase cyclodeaminase, a liver-specific 58-kd metabolic enzyme
[48]. Measurement of ALC-1 antibodies is not generally available in clinical
laboratories.