Autoimmune Hepatitis

Robert G. Gish MD

Case Presentation
A 47 year old woman with a past medical history
of Grave disease presents with two months of
gradually worsening right upper quadrant pain,
fatigue and anorexia. She denies any history of
alcohol, tobacco or drugs
Unremarkable physical exam
Lab Values:
Normal CBC, Chem 7
AST/ALT > 5 X upper limit of normal (ULN)

?
Could this patient have Autoimmune
Hepatitis (AIH)?
How does AIH present?
How do you diagnose it?
How do you treat it?

Background
First described in the late 1940s by Harold
Percival Himsworth
Chronic active hepatitis described by
Waldenstrom in 1950
Lupoid hepatitis discussed in the Lancet by Ian
Mackay in 1956
Plasma cell hepatitis
Idiopathic chronic hepatitis
In 1992, the International Autoimmune Hepatitis
Group settled on the term Autoimmune
Hepatitis (AIH)
Developed probable vs. definite scoring system
1. Mackay IR et al., Ann N Y Acad Sci 1965; 124: 767-780
2. Himsworth HP. Lectures on the Liver and its Diseases. Oxford: Blackwell, 1947: 158-161
3. Waldenstrom JL: Blutproteine und Nahrungseiweiss. Dtsch Ges Verdau Stoffwechselkr 1950: 15: 113-119
4. Mackay IR et al., Lupoid Hepatitis. Lancet, 1956: 271: 1323-1326
5. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993; 18: 998-1005

Background
The incidence of autoimmune hepatitis
(AIH) estimated 0.1-1.9 per 100,000 people
Accounts for 6% of liver transplantations in
the U.S.
Accounts for 3% of liver transplantations in
Europe

Background
OLD Definition: Chronic, unresolving
inflammation of the liver, due to unknown
causes
NOW: Characteristics: plasmacytic
necroinflammatory liver dz,
hypergammaglobulinemia and presence of
one or more autoantibodies
Women affected more than men (~ 70% of
cases are women) although both affected at
all ages

Background
Increased coexistence of other autoimmune disease

Rheumatoid arthritis
Diabetes
Thyroiditis
Uveitis
Celiac Sprue
Ulcerative Colitis
Lupus
Psoriasis
Others

Why does AIH Occur?

Genetic susceptibility
HLA association
AIH type 1: B8, DR3, DR4
AIH type 2: B14, DR3, C4AQ0
AIH type 3: unknown

Different HLA class II genes confer AIH susceptibility at different

ages, even within the same ethnic population
HLA-DRB1*1301 conferred susceptibility in Argentine children1
HLA-DRB1*0405 conferred susceptibility in Argentine adults1
Are there different antigenic stimuli at different stages in life?

Why are women significantly more susceptible than men?

Why cirrhosis in African Americans & Native Alaskans with AIH?
GWAS to predict susceptibility ?

1. Pando M., et al. Hepatology 1999 Dec;30(6):1374-80

Pathophysiology
Complicated interaction of genetics and
environmental factors (viral: measles? HSV?
Hepatitis? EBV? chemicals? UTIs?)
The autoantigens responsible for initiating the
cascade of events in type 1 AIH have yet to be
identified (ASGPR?)
Cytotoxic T-cell mediated immunological attack
against hepatocytes
Aberrant display of HLA class II on the surface of
normal hepatocytes facilitates this.
Antigen processing cells then stimulate the clonal
expansion of cytotoxic T lymphocytes which
infiltrate and destroy hepatocytes.

Autoimmune Targets

Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer

zum Buschenfelde KH, et al. Identification of target antigen for
SLA/LP autoantibodies in autoimmune hepatitis. Lancet
2000;355:1510-1515
Costa M, Rodriguez-Sanchez JL, Czaja AJ, Gelpi C. Isolation
and characterization of cDNA encoding the antigenic protein of
the human tRNP(Ser)Sec complex recognized by
autoantibodies from patients with type-1 autoimmune hepatitis.
Clin Exp Immunol 2000;121:364-374
Volkmann M, Martin L, Baurle A, Heid H, Strassburg CP,
Trautwein C, et al. Soluble liver antigen: isolation of a 35-kd
recombinant protein (SLA-p35) specifically recognizing sera
from patients with autoimmune hepatitis. Hepatology
2001;33:591-59

Target Antigens
Type 1 AIH:
nuclear antigens

Type 2 AIH:
Cytochrome P450 (CYP) 2D6
UDP-glucuronosyltransferase
UGTIA

Type 3 AIH:
UGA-suppressor (tRNA)-associated protein

PBCholangitis
PDH

Presentation
History variable
Asymptomatic patients often discovered with elevated
liver enzymes
Can present with mild-moderate symptoms (fatigue,
arthralgia, abdominal discomfort, etc)
25% of cases present with acute hepatitis
Can also present with fulminant hepatitis or with
decompensated cirrhosis (~25%)

Physical Examination:
variable
May present with no abnormalities
May present with hepatosplenomegaly, jaundice and
stigmata of chronic liver disease.

Diagnosis
First Step: exclusion of conditions that resemble AIH
Hereditary (Wilson, antitrypsin deficiency)
Infectious ( Hep A, B and C as well as HEV)
Drug induced liver injury (INH, nitrofurantoin, etc)

Next step: Laboratory abnormalities

Autoantibodies present (ANA, ALKM-1,

F-actin, etc)

Do not order ASMA

Elevated aminotransferase > Bili/Alkaline phosphatase (maybe

more difficult to ascertain in overlap syndromes)
AST/ALT (may be in the 30-40 range or as high as 100-1,000)
Bili (above ULN: if 3-10mg/dL eval for severe liver disease)

Elevated Gamma Globulins (>2.5g/dL)

May be manifest as elevation in total protein
qIgG is the preferred way to evaluate hypergammaglobunemia

Autoantibodies

ANA (anti nucleic antibodies)

Homogeneous staining pattern
Titers of at least 1:80

ASMA (Anti-Smooth Muscle Antibodies)

Non specific
Titers of at least 1:320

AAA/F-actine (antiactin antibodies)

Generally much more specific

ALKM-1 (Anti Liver Kidney Microsome)

Directed against P450 IID6

Anti-SLA (Soluble Liver Antigen)

Directed against a UGA suppressor or tRNA-associated protein
Not widely available

p-ANCA
Atypical p-ANCA

ALC-1 (anti liver cytosol antibody)

Generally occur with ALKM
Not widely available

Difficult Diagnosis
International Autoimmune Hepatitis Group
developed scoring system in 1992:
Composite score to define patients with probable or
definite autoimmune hepatitis.
Based on clinical and lab findings:

gender
Degree of Hypergammaglobulinemia
ANA levels
Exposure to hepatotoxic agents (alcohol, medications,etc)

However, cumbersome and questionable accuracy

Met again in 1999 for revisions to differentiate

AIH from autoimmune biliary diseases and DILI
Pre-Rx Score: >15 (Definite) ; 10-15 (Probable)

Diagnostic criteria should be applied to all patients

If the diagnosis of AIH is not clear, scoring system should be used

Difficult Diagnosis
Recently, attempts have been made to introduce a newer,
simplified scoring system geared for clinical practices
Hennes et al. introduced a new scoring system
studied two cohorts of patients: a training set and a validation
set
The training set: 250 patients with definite AIH and 193 controls
with other well-defined liver diseases
The validation set: 109 with AIH and 284 controls

Stepwise logistic regression identified the best predictors

for AIH to be ANA and SMA titers, IgG levels, and liver
histology

Simplified method

Questions of the new system

Remains somewhat arbitrary
Has not been compared to the existing scoring
system
Does emphasize the importance of excluding viral
hepatitis, HAV, HBV, HCV, HEV
Will clinicians use it anymore than the previous
scoring system?
No overlap patients in the validation set?
Does it help differentiate overlap syndromes?

Prevalence of Serological Autoimmune Markers

in Subjects With Selected Liver Diseases and
Controls
% positive (no positive/total)
Liver disease
chronic HCV
chronic HBV
acute HBV
AIH
cryptogenic
cirrhosis
alcohol-induced
liver disease
Wilson disease
controls
(no liver disease)

SMA

ANA

AMA

15% (62/413)
14% (7/48)
0% (0/10)
69% (154/223)
36% (12/33)

34% (126/366)
9% (4/47)
74% (63/85)
80% (174/217)
33% (10/33)

0.7% (2/269)
0% (0/270)
0% (0/406)
14% (41/298)
18% (12/65)

5% (1/19)

13% (215)

0% (0/16)

25% (5/20)
6% (12/200)

25% (5/20)
3% (7/228)

ND
3% (26/850)

Clifford et al., Hepatology 1995;21:617

Gregorio et al., Clin Exp Immunol 1998;112:472

Role of Liver Biopsy

Determines diagnosis, type of AIH and severity
Aminotransferase/gamma globulin do not
accurately predict the level of necrosis/damage
Can also detect AIH overlap syndromes (primary
sclerosing cholangitis, Primary biliary cirrhosis,
etc.)

Biopsy can provide alternative diagnosis

(steatosis, iron overload, etc.)
New scoring system condenses the liver
histology into 3 categories: typical, compatible
and atypical

Autoimmune Overlap/Variant Syndromes

PBC =
Primary
Biliary
Cholangitis

AMA neg
PBC
polyarteritis
with
normal ERCP

Microscopic PeriCholangio- cholangitis

pathy

PBC

Autoimmune
cholangitis
10%

10%

Giant Cell Hepatitis

Drug induced
AIH
hepatitis

Granulomatous
Hepatitis
Mild
idiopathic
ductopenia
of adulthood

IgG 4
ASC

2-8%

PSC

6-25%

Classic

AIH
11%

Autoantibody
Cryptogenic
negative
hepatitis
Fatty Liver idiopathic
hepatitis
with
autoantibodies

Vanishing Bile
Duct Syndrome

1-2%

HCV
HBV

MastCell
cholangiopathy

Eosinophilic Hepatitis

Central Venulitis

Histology
Typical
Interface hepatitis, lymphoplasmacytic infiltrates in the portal
tracts, emperipolesis
2 points

Compatible
Chronic hepatitis with lymphocytic infiltrate
1 point

Atypical
0 points

No deduction for findings of steatosis, iron overload or

biliary changes (new)

Histology

Interface hepatitis (piecemeal necrosis)

Portal plasma cell infiltration
Some degree of fibrosis usually present
Bile duct usually spared (to differentiate)

Interface hepatitis and bridging necrosis in severe type 1 autoimmune hepatitis

Plasma cell infiltration of the portal tracts in type 1 autoimmune hepatitis

Mott Cell , a full engorged

Plasma cell
DX: AIH

Central Perivenulitis

Severe hepatitis with extensive inflammation extending from the

portal tract (PT) into the lobule, with marked loss of hepatocytes.
Note the prominent hepatocyte loss and inflammation around the
central vein (CV), central perivenulitis. (Inset) Higher magnification
of central perivenulitis highlighted by plasma cells surrounding and

Classification
AIH is classified by the type of autoantibody present
Type 1 (classic): antibodies to nuclei (ANA) and/or smooth muscle
(ASMA) or antiactin antibodies (AAA)
Bimodal distribution
Occasionally, antimitochondrial antibodies present
Most common

Type 2: antibodies to liver/kidney microsomes (ALKM-1) and/or

antibodies to liver cytosol antigens (ALC-1)
Predominately younger women
More common in Europe and South America

Type 3?: Antibodies against soluble liver antigen (anti-SLA)

Predominately older patients
No longer considered an independent entity
10% of type 1 AIH have SLA

Overlap syndromes
Patients with AIH may also have features of other autoimmune liver disease
Primary Biliary Cholangitis
7-14% of PBCholangitis patients will have AIH

Primary sclerosing cholangitis (in children)

Autoimmune cholangitis
MCC or peri-cholangitis

Suspect it when a patient with AIH has:

Pruritus
UC
Bile duct abnormalities on biopsy
Marked elevation in alkaline phosphatase

Despite revisions of the criteria for the diagnosis, remains difficult to

correctly diagnose overlap syndromes
Cholangiography?

Natural History of Disease

Morbidity and mortality are high:
Failure of Bilirubin to improve within 2 weeks is a poor prognostic
indicator
Without treatment, 40-50% of patients with severe AIH will die within 5
years
Cirrhosis develops >40% of survivors who are untreated with severe AIH
54% of those develop esophageal varices within two years
20% of those with varices die from hemorrhage

Patients with milder AIH may still develop cirrhosis:

50% within 15 years if untreated
Death from hepatic failure in >10%

Risk of hepatocellular cancer is rare

(0.5% in one study), surveillance every 12 months advised

Natural History of Disease

Severity of symptoms vary but can include:

Fatigue
RUQ pain
Mild pruritus
Cushingoid features (usually with steroids) /
arthralgias / hirsuitism / amenorrhea

Fluctuating course
Spontaneous exacerbations
Spontaneous remissions

Initiating Treatment
Generally IS is started (AASLD recommendations):
With aminotransferase levels greater than 10 times ULN
Or with aminotransferase 5 times ULN and serum gamma
globulin level 2 times ULN
Necrosis or extensive fibrosis on histology
(In children) at time of diagnosis
Severe symptoms

Treatment is often withheld in inactive, burned-out

cirrhosis, if co-morbid conditions or questionably low
ANA titers and normal or near normal liver enzymes.

Choice of Treatment
AASLD recommends either treatment with
corticosteroids alone or with lower dose steroids
and azathioprine
Three randomized, controlled trials between 1971
and 1974 clearly displayed the benefits of steroids
Generally felt that high dose steroids alone and
combo therapy are equal
Combo therapy allows lower dose steroids, and
lower frequency of side effects
However, there is limited data showing equal
efficacy of high dose steroids vs. low dose and
azathioprine

Initiating Treatment
In the Real World
With aminotransferase levels greater than ULN
do biopsy
Interface hepatitis with any extraportal fibrosis
on histology
(In children) at time of diagnosis
Severe symptoms
Use prednisone and Imuran in combination

Treatment Monitoring
A therapeutic response is seen in 80% of patients, with
prednisone and Imuran
However, does not necessarily prevent the eventual
progression to cirrhosis
Improvement of symptoms happens within days to weeks
Improvement of lab values occurs over weeks to months
ALT needs to be less than 30 for men and less than 20 for
women to be on target
Plan to do a liver biopsy, even if normal liver enzymes
every 2-3 years

Immunosuppressive Therapy
for AIH
Prednisone 60mg/d tapering to maintenance of 510mg/d if prednisone used alone or 30 mg tapering to
5-10 if combination therapy plus:
Azathioprine 50-100mg/d (steroid sparing)

Remission in ~70-80% (ALT/AST normal or ~normal)

Remission for 2-3 years consider steroid cessation, continuing
AZP and pursue biochemical + histological monitoring.

Second line alternatives

Cyclosporine
Tacrolimus (Prograf or FK-506)
Mycophenolate- Best
Budesonide

Choice of Treatment
Advanced cirrhosis can impair hepatic conversion
of prednisone to prednisolone (no proof of
increased benefit from use of prednisolone)
Pts with advanced cirrhosis respond as well as
those milder disease to therapy
Some recommend use of 6-MP as opposed to
Azathioprione to by-pass hepatic conversion (not
proven)
Follow 6 TP for therapy, 6 MMP for toxicity risk;
levels to determine if therapeutic dose is correct

Check PPD in patients prior to treatment!

Side Effects of Treatment

Steroids:
Acne
Dorsal Hump/truncal obesity
Osteoporosis
Diabetes
Cataract

Azathioprine (Imuran)
Cholestatic hepatitis
Pancreatitis
Nausea/vomiting
Bone marrow suppression

Treatment End Points

Remission is achieved (generally not achieved until
12 months)
Resolution of symptoms, improvement in lab values and histology
65% achieve initial remission by 18 months
>80-95% achieve initial remission by 3 years

Deemed a treatment failure

Worsening clinical presentation, lab values (aminotransferase
levels increase by 70%) and histology
5-10% of patients
Remain salvageable using mycophenolate and or tacrolimus

Development of a liver drug toxicity

Approximately <1% of patients

Prednisone side effects ~15% of patients

To take patients off therapy?

Normal liver biopsy

Immune Globulins at <1.5 gm/dL
AST and ALT < 30 in men, < 20 in women
ANA and F-actin negative

Remission
Sustained remission is achieved in 10-40% of
patients.
Sustained remission is defined as:
Resolution of symptoms
Decrease in ALT/AST to less than 0.5xULN = healthy
range
Normalization of bili/alk phos
Improvement in liver histology

Likelihood of relapse after cessation of therapy is

at least 80%
Great majority of patients will require maintenance
therapy

Treatment Failure
Increase the dosages prednisone and imuran?
Best:

Mycophenolate
Liver transplantation
Patients who deteriorate during or after steroid therapy
(development of encephalopathy, ascites, etc.)
Five year survival > 80%
Usually there is a disappearance of
autoantibodies/hypergammaglobulinemia within one year
Recurrent disease is generally manageable
AIH can occur in allografts de novo!

Liver transplantation

http://www.autoimmunehepatitis.co.uk/main.htm

Case Presentation
47 year old woman with a past medical history of
treated Graves disease presents to your office with
two months of gradually worsening right upper
quadrant pain, fatigue and anorexia. Rare alcohol,
no tobacco or drugs
Unremarkable physical exam
Lab Values:
Normal CBC, Chem 7
AST/ALT > 5 X upper limit of normal (ULN)
Mildly elevated bili/alk phos

Workup
Medications: Tylenol PRN
Family History: Unremarkable
Additional Lab values:
Hepatitis panel: negative
(+) ANA, (+) F-actin
Gamma globulin level 7g/dl ( > 2 X ULN )

Interval history:
Patient notes that symptoms of fatigue worsening
Now also with arthralgias

Follow up
Given aminotransferase elevation (greater than
5xULN) and hypergammaglobulinemia (greater than
2xULN)
The patient receives a liver biopsy Dx of AIH and
The patient was started on
Prednisone 30mg PO Qday and
Azathioprine 50mg PO Qday
With plan to gradually taper prednisone to 10mg PO qday
until end point reached and increase Aza to 150 mg per day,
follow 6MMP for toxicity risk and 6TG levels to target
therapeutic levels

What if?
What if patient had diabetes?
Not an absolute contraindication to use of steroids (even if
its brittle diabetes)
Low-dose prednisone and azathioprine
Close monitoring

What if patient pregnant?

Treatment deemed probably safe
AIH in pregnancy associated with higher risk of prematurity,
low birth weight and fetal loss

What if the patient is also infected with Hep C?

Treat HCV first with all oral DDA therapy and the reassess to
see if AIH

GWAS
GWAS is now being use to identify various
polymorphisms and genes to then consider
new therapeutic targets and who is at risk
for AIH and its variants

Summary
Consider AIH when patient has acute hepatitis or
acute liver disease particularly if other autoimmune
disease is present
Liver biopsy for confirmation and follow up in 1-3
years
Treatment with (rarely corticosteroids alone) or
best: combination therapy prednisone and Imuran,
which is commonly life saving and should be
instituted early in all patients esp those patients
with severe AIH