Hindawi Publishing Corporation
Hepatitis Research and Treatment
Volume 2011, Article ID 390916, 11 pages
AutoimmuneHepatitis:A Review ofCurrent
Ashima Makol,1KymberlyD. Watt,2andVaidehiR.Chowdhary1
1Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
2Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine,
Rochester, MN 55905, USA
Correspondence should be addressed to Vaidehi R. Chowdhary, email@example.com
Received 13 November 2010; Revised 15 February 2011; Accepted 3 March 2011
Academic Editor: Mikio Zeniya
Copyright © 2011 Ashima Makol et al.This isanopen access articledistributed under theCreative CommonsAttribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Autoimmunehepatitis(AIH)isachronicinflammatorydisordercharacterized byperiportal inflammation,elevatedimmunoglob-
ulins, autoantibodies, and a dramatic response to immunosuppression. An environmental agent is hypothesized to trigger an
immune-mediated attack directed againstliver antigens in genetically predisposed individuals. A plethora of clinical presentations
can be seen ranging from chronic indolent disease to fulminant hepatic failure, and diagnosis requires exclusion of other causes
of liver disease. Corticosteroid therapy must be instituted early and modified in an individualized fashion. Treatment decisions
are often complicated by the diverse clinical manifestations,uncertainty about natural history, evolving ideas about treatment end
points,and a multitudeof alternative immunosuppressiveagents. Achievingnormalliver tests andtissueis the ideal treatment end
point,butneeds tobe weighed againsttheriskofsideeffects. Decompensated patientsmaybenefit fromearlylivertransplantation.
ofitsclinicalpresentation,riskfactors,immunopathogenesis,up-to-date diagnosticcriteria,currentupdates intherapywithabrief
discussion of AIH in pregnancy, and long-term implications for cirrhosis and hepatocellular carcinoma in AIH patients.
Autoimmune hepatitis (AIH) is a chronic inflammatory
disease of unknown etiology characterized by the presence
of circulating autoantibodies, hypergammaglobulinemia,
necroinflammatory changes on hepatic histology, and a
dramatic response to immunosuppressive therapy. Earliest
descriptions include those by Amberg in 1942  and
Leber in 1950  describing a form of chronic liver disease
prevalent among young women and characterized by an
excessive increase in serum protein and gamma-globulins.
In 1951, Kunkel et al. termed the condition “hypergam-
maglobulinemic chronic hepatitis” . Since then, it has
been known by various names including chronic active
hepatitis, chronic aggressive hepatitis, plasma cell hepatitis,
and autoimmune chronic active hepatitis. Cowling and
Mackay coined the term “lupoid hepatitis” after they noted
the association of this entity with autoimmune syndromes
and the LE cell phenomenon .
The disease is rare with a mean incidence of 1-2 per
100,000 and a point prevalence of 11–17 per 100,000 [5, 6].
Although more frequently seen in young women (sex ratio
3.6:1), it can affect children and adults of all ages and eth-
nicities [7, 8]. A minority of patients may present with acute
ity, the prognosis of AIH is good and mostly determined
by response to corticosteroid therapy. In general, long-
term survival and average life expectancy are excellent and
estimated to be comparable to the normal population .
The classification of AIH into different types is based on
serum autoantibody profiles. Type I AIH is characterized by
the presence of antinuclear antibody (ANA), anti-smooth
muscle antibody (SMA), or both and constitutes 80% of
AIH cases. About 25% have cirrhosis at presentation, and
association with other autoimmune diseases is common
2 Hepatitis Research and Treatment
Table 1: HLA associationsin autoimmunehepatitis.
(i) European and North American
Increases susceptibility to AIH Type I
(ii) HLA-DR3 associated with younger
age at presentation, diminished
response to therapy and more frequent
liver failure requiring liver
transplantation as compared to
European and North American
I 11945% 23%
(celiac disease, ulcerative colitis, autoimmune thyroid dis-
ease) [10, 11]. Type 2 AIH is characterized by the presence
of anti-liver kidney microsomal (LKM) 1 and/or anti-LKM3
and/or anti-liver cytosol 1 (LC1) [12, 13] antibodies. Most
patients are children, acute severe presentation can occur,
and progression to cirrhosis commonly ensues .
In patients who are negative for conventional antibodies
and AIH is strongly suspected, additional tests can be done
including perinuclear antineutrophil cytoplasmic antibodies
(pANCA), actin (anti-actin), soluble liver antigen (anti-
SLA), asialoglycoprotein receptor (anti-ASGPR), chromatin,
and liver cytosol type 1 (anti-LC1). In our experience,
10–15% patients do not have either ANA, SMA, or anti-
LKM1 at presentation, but 25% of these will have detectable
conventional antibodies later in their course. Another 10–
20% of the seronegative patients at presentation will have
pANCAoranti-SLA.Overall, approximately5% will haveno
currently available markers long term.
unknown, AIH, like many autoimmune diseases, is thought
to be caused by environmental triggers and failure of
immune tolerance mechanisms in a genetically susceptible
cases have an unknown trigger. Triggers may share epitopes
that resemble self-antigens, and molecular mimicry between
foreign antigens and self-antigens is the most frequently
proposed initiating mechanism in type 2 AIH where the
autoantigen is known. Repeated exposures to the triggering
antigen, in turn, may trigger autoreactive organ-specific
2.2. Genetic Associations. AIH is a complex polygenic disease
and different populations may have different genetic and
environmental triggers and genetic association varies in
study populations. The human leukocyte antigen (HLA)
genes on chromosome 6 are the most commonly described
have been summarized in Table 1. HLA may be associated
with age at presentation, disease severity, and response to
therapy. How the HLA genes predispose to disease is not
exactly known but is likely due to their role in autoreactive T
cell selection and autoantigenic peptide presentation. Differ-
ent susceptibility alleles like HLA DRβ1∗0301, DRβ1∗0401,
DRβ1∗0404, and DRβ1∗0405 share a “common motif,”
namely, amino acids LLEQKR or LLEQRR at position 67-
72 of class II HLA, whereas the resistant alleles DRβ1∗1501
encodes ILEQAR [20, 21]. In contrast, HLA-DRβ1∗1501,
encodes for the ILEQAR motif  and is associated with
protection from AIH. Substitution of a lysine or arginine to
alanine at position 71 is postulated to change the polarity
and charge of the peptide binding groove of the major his-
tocompatibility complex thereby influencing autoantigenic
peptide presentation. However, these associations are not
absolute and significant geographic differences exist, for
example, in Japan DR2(DRB1∗1501) is a weak susceptibility
rather than a resistance allele  and in South American
children DRB1∗1301 is a strong susceptibility allele .
Furthermore, patient numbers in many HLA studies are low.
A form of AIH can be seen in 20% of patients with
dystrophy (APECED) syndrome. APECED is a monogenic,
autosomal recessive disorder characterized by hypoparathy-
roidism, adrenal insufficiency, and chronic mucocutaneous
candidiasis. APECED is caused by mutations in a tran-
scription factor relevant to immune tolerance called AIRE
(autoimmune regulator) on chromosome 21q223. AIRE is
expressed in medullary epithelial and dendritic cells within
the thymus and regulates clonal deletion of autoreactive
T cells. The liver autoantigens associated with APECED
are cytochrome P450 (CYP) 1A2, CYP2A6, and CYP2D6
[24–26]. This is the only syndrome involving AIH that
exhibits a Mendelian pattern of inheritance, and genetic
testing and counseling for the patient and family members
are warranted .
Hepatitis Research and Treatment3
2.3. Immunopathogenesis. Full insight into the pathogenesis
of AIH remains elusive. The liver is part of the lymphoid sys-
temwith the normal lymphocyte populationmainly residing
in the portal tracts. AIH is an inflammatory disorder of the
liver involving multiple components of the immune system
including T cells, B cells, and cytokines. Hepatocytesisolated
from AIH patients are coated with immunoglobulins and
are susceptible to antibody-dependent cellular cytotoxicity
(ADCC) when exposed to autologous mononuclear cells
bearing Fcreceptors . CYP2D6, an important cytoplas-
mic enzyme is targeted by anti-LKM1 antibodies and plays a
crucial role in liver damage. Mice immunized with plasmid
containing human CYP2D6 antigenic region and human
formiminotransferase cyclodeaminase (another autoanti-
gen), have established a murine model for autoimmune
hepatitis type 2 . These mice develop autoantibodies,
elevation in transaminases, along with portal and periportal
inflammatory infiltrate. Another model using adenovirus
vector containing human CYP2D6 infection of CYP2D6
transgenic mice had focal hepatocyte necrosis and hepatic
fibrosis . These models will aid the developmentof more
therapeutic options in the management of autoimmune
Studies have demonstrated presence of cytotoxic cells
in both T and non-T cell compartment of peripheral blood
from AIH patients. This cytotoxic activity is higher in
patients with active disease but seen in only 40% of patients
in remission . Patients with AIH have a ten fold higher
frequency of liver-specific T cells compared to normal
subjects . In patients with predisposing HLA allele
DRβ1∗0701, CD4 T cells are able to recognize autoantigen
CYP2D6 and secrete interferon-γ . In addition CD8+ T
cells have been isolated from portal tract infiltrate. CD8 T
cellshave cytotoxiccapability,are capable ofsecreting IFN-γ,
and their responses correlate with disease activity .
Defects in numbers and function of regulatory cells (T
regs) have been demonstrated in AIH . T regulatory cells
normally control or limit immune responses by acting as
immunoregulators, preventing the proliferation and effector
function of autoreactive T cells. In patients with AIH, T-
regs are defective both in number and function. The number
of T regs is decreased more so at disease presentation than
at drug-induced remission. Their level correlates inversely
with levels of anti-SLA and anti-LKM-1 autoantibody titers
. The T reg numbers and function improve during
remission but are never normal. Longhi et al. in their study
demonstrated that Tregs generated under CYP2D6-specific
conditions and cocultured with semimature dendritic cells
are highly effective at controlling autoreactive T cells, thus
providing a potential tool for immunotherapy in type 2
AIH . T regs may, therefore, be an attractive therapeutic
target, but more studies are needed to elucidate this better.
2.4. Environmental Factors. Several drugs have also been
implicated as triggers for AIH including Infliximab ,
Minocycline , Atorvastatin , diclofenac,isoniazid, α-
methyldopa, nitrofurantoin, and propylthiouracil and Hep-
atitis A vaccine . Herbal agents such as black cohosh and
dai-saiko-to have been proposed to induced AIH . The
exact reason for drug-induced AIH is not known but may
be due to hepatotoxic effect of these chemicals, upregulation
of proteins expression (P450s, immunoregulatory proteins),
or related to the drug acting as a hapten by modifying the
hepatic protein, making them immunogenic. Drug-induced
AIH may improve after discontinuation of offending agent,
thus initial observation is warranted.
Viruses such as hepatitis A, B, or C, in addition to
measles have been implicated as triggers for AIH. ANA
and SMA can occur in diverse causes of acute and chronic
hepatitis including alcoholic, nonalcoholic fatty liverdisease,
and viral hepatitis. They are usually low titer, background
reactivities that should not alter diagnosis or management.
If clinical concern for autoimmune hepatitis exists, antiactin
antibodies can be checked as they increase the specificity
of SMA testing for diagnosing AIH . Anti-LKM1 has
been found in as many as 10% of patients with chronic
hepatitis C and is different from the anti-LKM1 found in
classic autoimmune hepatitis . Molecular mimicry at
the B-cell level between a structural motif of CYP2D6 and
HCV proteins could explain the production of anti-LKM1
antibodies in HCV-infected patients .
Women constitute at least 70% of cases, and 50% are
younger than 40 years; however, age at onset may range from
infancy to the elderly. AIH has diverse presentations with
25–34% of patients presenting with asymptomatic liver test
abnormalities. Forty percent of patients may present with an
acute onset, but the presentation of severe fulminant hepatic
failure is rare . Children or elderly more commonly
present with cirrhosis. Presenting symptoms may include
fatigue, lethargy, malaise, arthralgia of small joints, anorexia,
nausea, abdominal pain, and dark urine. These symptoms
are nonspecific and contribute to the delay in diagnosis.
Asymptomatic patients commonly become symptomatic,
and thus need to be monitored. Clinical manifestations
may vary by ethnicity; the presentation is acute and icteric
in Alaskan  native patients, cholestatic in Aboriginal
North American, African, Asian, and Arab patients, mild in
Japanese patients , but severe and rapidly progressive in
Somali patients . Cirrhosis occurs in as many as 85% of
black North American patients . Differences in etiologic
agents and genetic factors may account for this variation.
Physical examination may be normal, but may also
reveal hepatomegaly, splenomegaly, jaundice, and stigmata
of chronic liver disease. Findings such as acne, hirsutism,
obesity, and amenorrhea in young women are rarely seen.
Other autoimmune diseases such as Hashimoto thyroiditis,
type 1 diabetes, rheumatoid arthritis, systemic lupus erythe-
matosus, ulcerative colitis/Crohn’s disease, and celiac disease
can be seen in 20% of patients .
Chung et al. described a novel subtype of AIH character-
ized by infiltration of IgG4-positive plasma cells . This
subtype is associated with higher serum levels of IgG, AIH
severity scores, and, more importantly, an excellent response
to prednisone therapy for induction and maintenance of
remission. Positive IgG4 staining is suggested by the authors
4 Hepatitis Research and Treatment
as a surrogate marker for the subtype of AIH that may
respond well to corticosteroid therapy alone. Whether this
is a form of classic AIH or a distinct entity awaits a more
extensive description of its clinical and immunohistological
The diagnosis of AIH requires the presence of characteristic
clinical features and exclusion of other chronic liver condi-
tions, such as viral hepatitis, drug-induced hepatitis, fatty
liver disease, alcohol related liver disease, Wilson’s disease,
alpha 1 antitrypsin deficiency, or hemochromatosis.
4.1. Laboratory Features. Laboratory studies typically show
elevation of aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels, but levels are generally
<500U/L, but on rare occasions can range between 500–
1000U/L. Some patients may have high conjugated bilirubin
atic biliary obstruction, cholestatic forms of viral hepatitis,
drug-induced disease, primary biliary cirrhosis (PBC), and
primary sclerosing cholangitis (PSC). The alkaline phos-
phatase rarely exceeds 4 X normal and generally remains <2
times normal. Another characteristic laboratory feature of
AIH is hypergammaglobulinemia, with a selective increase
in IgG, which is 1.2–3.0 times higher than the upper level
of normal . It should be noted that HLA typing has not
been endorsed as a diagnostic or prognostic tool.
4.2. Autoantibodies. The characteristic circulating autoan-
tibodies seen in AIH include ANA, SMA, and (LKM-1)
autoantibodies. A list of the important autoantibodies and
their autoantigenic targets is summarized in Table 2 .
They are helpful in diagnosis as well as for classification of
AIH into type 1 and type 2 diseases. The reader is referred to
excellent reviews for description of methodology, sensitivity,
and assay performance [27, 39, 64]. Except for pANCA,
which is readily available and can be positive in 50–90%
of type I AIH, only antiactin can be easily in measured in
some laboratories. Recently, antibodies to cyclic citrullinated
peptides (CCP) have been described in 9–11% of patients
with AIH in absence of rheumatoid arthritis. These patients
have a propensity to develop cirrhosis and liver failure
. Antimitochondrial antibodies are sometimes present in
patientswith AIH and an overlap syndrome of AIHand PBC
should be considered in these patients .
4.3. Diagnostic Scoring System. A diagnostic system was
proposed by the International AutoimmuneHepatitis Group
(IAIHG) in 1993 and subsequently updated in 1999 [66, 67].
In 2008, they proposed a simplified set of diagnostic criteria
to facilitate early recognition and initiation of adequate
ence of specific autoantibodies (ANA, SMA, LKM antibody,
SLA antibody) in moderate to high titers, hypergammaglob-
ulinemia, typical histological pattern on liver biopsy, and
Figure 1: Interface hepatitis demonstrated by infiltration of
lymphoplasmacytic infiltrate into the hepatic parenchyma typical
of autoimmune hepatitis.
exclusion of viral hepatitis. These criteria have a lower sensi-
tivity (85% versus 100%) but higher specificity (99% versus
93%) than the original criteria and are good at identifying
[69, 70]. However, Miyake et al. showed that 30% of males,
23% of patients with acute clinical presentation, and 46%
patients negative for ANA were not diagnosed with AIH by
simplified criteria even though they met the original criteria
.Therefore, itfails toadequatelyidentifycaseswith atyp-
ical features which is an important point to keep in mind.
4.4. Histological Diagnosis. The histologic hallmark of AIH
is a lymphoplasmacytic periportal infiltrate invading the
limiting plate, also called piecemeal necrosis or “interface
hepatitis” (Figure 1) that eventually progresses to lobular
hepatitis. There is often an abundance of plasma cells and
eosinophilsare frequentlypresent.The portal lesiontypically
spares the biliary tree. A lobular, or panacinar hepatitis is
also frequently observed. Fibrosis is present in all but the
mildest forms of AIH. It causes distortion of the hepatic
lobule and the appearance of regenerative nodules, resulting
in cirrhosis . Many patients with acute presentation may
have chronic features on liver biopsy indicating a subclinical
phase of disease and several patients with mild clinical
disease may have advanced fibrosis on biopsy. Of important
note is the fact that the fibrosis and even cirrhosis in AIH
is reversible to a significant degree with immunosuppressive
therapy unlike in other chronic liver diseases.
4.5. Radiology. There are no specific imaging techniques
to confirm the diagnosis of autoimmune hepatitis. In
adults with both AIH and IBD, cholangiographic changes
suggestive of PSC are present in up to 44% patients and
may affect therapy and prognosis . In children with AIH,
autoimmune sclerosing cholangitis can be present with or
without inflammatory bowel disease .
5.1.Indications forTreatment. AIHisatreatablechronicliver
disease in the majority of the cases. Untreated patients with
Hepatitis Research and Treatment5
Table 2: Autoantibodies in autoimmune hepatitis.
Antiliver kidney microsomal
Molecular target Prognostic valueReference
Cytochrome 450 2D6 Diagnostic for AIH type 2
Actin and non-actin
7% of patients with AIH associated with
viral hepatitis C
Antismooth muscle antibody Diagnostic marker for type 1 AIH
Antiactin Polymerized F-actin
(1) Subset of smooth muscle antibodies
(2) Children: treatment dependence and
progression to liver failure
(3) Adults: early onset and severe disease
(4) Severe clinical and histological disease if
reactive to actin and α-actinin, anti-ss DNA
antibodies can be seen as well.
(1) High specificity, may be present when
other markers are absent
(2) Predictor of relapse and treatment
(3) Associated with DRB1∗0301
(4) Higher frequency of death from liver
(1) Present when other markers like ANA,
SMA, LKM1 absent
(2) Early age of onset and concurrent
(3) Marked liver inflammation and rapid
progression to cirrhosis
Anti-soluble liver antigen
Antiliver cytosol type 1 (LC1)
Antibody to histone and
double stranded DNA
Asialoglycoprotein receptor (1) Correlate with histological activity
(1) Patients with anti-dsDNA fail
corticosteroid treatment more frequently
(1) Occur in association with ANA
(2) May define a subset of ANA positive
patients that are treatment dependent
(3) Predictor of relapse after drug
(4) Higher levels of γ globulin and IgG at
Seen in type 1 AIH may help in diagnosis if
other tests are negative.
active histologic inflammation have worse overall survival.
Histologic presence of bridging or multilobular necrosis is
associated with progression to cirrhosis in 82% cases and a
tomatic patients with inactive cirrhosis (defined as no or
limited inflammation), corticosteroidtherapy has not shown
to improve survival. Patients without cirrhosis who undergo
treatment have a 10–20 year survival probability more than
80%, similar to the general population . Retrospective
analysis of patients with mild disease has demonstrated
the possibility of long-term survival without treatment,
but very careful follow-up is required. Untreated patients
may, rarely, recover spontaneously, but improvement is less
common than treated patients, and long-term survival is
lower . AIH can have unpredictable and varying disease
activity and ultimately the majority of patients with active
inflammation willwarrant therapy.Indicationsfortreatment
are listed in Table 3 and are based on the presence and
severity of hepatic inflammation. The indications are also
reflective of risk factors for disease progression as severely
abnormal liver enzyme elevation, incapacitating symptoms,
histological presence of interface hepatitis, bridging necrosis,
or multiacinar collapse portend a worse prognosis without
6 Hepatitis Research and Treatment
Table 3: Indications for treatment of autoimmune hepatitis.
AST ≥ 10 fold
AST ≥ 5 fold
HG ≥ 2 fold
AST or HG less
Normal or near
normal AST and
cirrhosis or mild
∗Relative Contraindications to immunosuppressant therapy-Osteopenia,
Emotional Lability, Hypertension, Diabetes, Mild Cytopenia
pression, Psychosis, Uncontrolled hypertension, Brittle Diabetes, Severe
Cytopenia (WBC count < 2.5 × 109/L, Platelet count < 50 × 109/L),
Complete deficiency of Thiopurine methyl-transferase enzyme, Known
intolerance to prednisone or azathioprine
AST-Aspartate aminotransferase HG-Hypergammaglobulinemia ULN-
Upper limit of normal.
taper down to 20mg daily in 4 weeks) or at a lower dose
(30mg with taper down to 10mg daily in 4 weeks) in
combination with azathioprine (50mg daily) is the most
effective treatment regimen studied in randomized clinical
trials . The preferred regimen is listed in Table 4. Both
regimens are similarly effective and differ only in the fre-
quency of side effects. Histologic improvement lags behind
clinical and laboratory resolution by 3 to 8 months, and
therapy should be continued for at least 3–6 months beyond
this point of improvement. Treatment is often maintained
for at least 2 years before withdrawal of drug therapy is
considered. The end points for treatment include remission,
treatment failure, incomplete response, or development of
drug toxicity. Their criteria and subsequent intervention are
summarized in Figure 2.
Prednisone is used alone in patients with severe cytope-
nias, active malignancy, pregnant or contemplating preg-
nancy, and those with complete thiomethylpurine trans-
ferase (TPMT) enzyme deficiency. Combination therapy is
associated with lesser side effectsand is preferred when treat-
mentisexpected to bemore than 6 monthsand in patientsat
risk of side effects including postmenopausal women, brittle
diabetics, labile hypertensive, and osteoporotic patients.
side effects must be taken into consideration. Corticos-
teroids can cause weight gain, central obesity, moon facies,
prominent supraclavicularfat pad, acne, bruising, cutaneous
striae, cataracts, glaucoma, peptic ulcers, deterioration of
hypertension and diabetic control. Long-term side effects
include increased risk of fractures secondary to osteoporosis
and avascular necrosis of bone. Patients with brittle dia-
betes, severe osteoporosis, vertebral compression fractures,
psychosis, obesity, and uncontrolled hypertension should be
carefully evaluated for a treatment benefit before starting
corticosteroids. If severity of disease necessitates corticos-
teroid therapy, adequate measures should be instituted to
control the comorbid conditions . In patients with
mild disease or relative contraindications to prednisone,
budesonide 3mg TID (in place of prednisone) is an option
to reduce overall treatment side effects with no impairment
of efficacy [77, 78]. Its benefitsare derived from the 90% first
pass metabolism which results in less steroid-induced side
effects while maintaining efficacy.
5.3. Alternative Treatments. Alternative regimens must be
considered in several circumstances: after treatment failure
with prednisone (60mg daily) or prednisone (30mg daily)
and azathioprine (150mg daily), incomplete response to
Mycophenolate mofetil (2g daily) has shown improvement
in 39–84% patientswho were unable to tolerate azathioprine
but use was limited by side effects (nausea, vomiting, rash,
pancreatitis, diarrhea, cytopenia) [79–81]. Patients in these
studies were also treated with steroids in conjunction with
Mycophenolate mofetil. There are studies demonstrating
benefit to the use of cyclosporine (in conjunction with
prednisone) for patients refractory to standard therapy. In
addition, a report suggests some benefit to tacrolimus, but
risk of toxicity must be weighed with these and other agents.
Ursodeoxycholic acid has been studied in randomized trials
and unfortunately was not found to be of benefit .
5.4. Treatment of Relapse. Relapse is characterized by an
increase in the serum aminotransferase levels to at least
threefold normal. Relapse occurs in 50% to 86% of patients,
most often during the first 6 months after the termination of
be retreated with a combination of prednisone plus azathio-
prineatthesame treatment regimenaswiththeinitialcourse
of therapy and then tapered to monotherapy with either
azathioprine (2mg/kg daily) as a long-term maintenance
therapy or indefinite low-dose prednisone (10mg daily) in
maintenance therapy maybe attemptedagain afteratleast 24
months of treatment and continued normal serum AST or
ALT level only after careful benefit risk evaluation in patients
been associated with worse outcomes .
5.5. Liver Transplantation (LT). AIH is the underlying cause
for 4%–6% cases of liver transplants done in the Western
world [85, 86]. It usually results from a failure to diagnose
and treat AIH as an etiology of cirrhosis, inadequate
response or intolerance to immunosuppressive therapy, or
noncompliance with treatment. Treatment failure requiring
transplant is more often associated with the HLA genotype
Hepatitis Research and Treatment7
Corticosteroids (CS) and
-Absence of symptoms
-Normal serum transaminases
-Normal γ globulin level
-Normal histology or inactive
-Some or no improvement in
clinical, laboratory and
histological features despite
compliance with therapy for
2–3years, without worsening
Failure of therapy
and histological features
despite compliance with
therapy or development of
jaundice, ascites or hepatic
-Development of symptomatic
osteopenia, emotional instability,
poorly controlled hypertension,
brittle diabetes, progressive
cytopenia, or pancreatitis
over 6 weeks
-AST, ALT, total bilirubin and
Gradual taper of prednisone
taper and every 3–6months after
2.5 mg/month until lowest level
possible (≤10 mg daily) to
prevent worsening of serum AST
or ALT abnormalities or
azathioprine (2mg/kg daily)
High dose prednisone
Reduction in dose or
Restart CS and AZA
Monitor lab tests
Reduction in prednisone dose by
± high dose
γ globulin every 3weeks during
Figure 2: Endpoints for Immunosuppressive treatment with course of action in AIH.
Table 4: Treatment regimen for autoimmunehepatitis.
60mg × 1 week
40mg × 1 week
30mg × 2 weeks
20mg maintenance dose
30mg × 1 week
20mg × 1 week
15mg × 2 weeks
10mg maintenance dose
in patients with AIH and acute liver failure, decompen-
sated cirrhosis with a MELD score ≥15, or hepatocellular
carcinoma meeting criteria for transplantation . LT for
AIH is very successful with 10-year patient survivals of
approximately 75% . A combination of prednisone and
a calcineurin inhibitor (tacrolimus more frequently than
cyclosporine) is the most common immunosuppression
regimen after LT. Despite this, AIH can recur in transplanted
liversoroccurde novoin livertransplants done fornon-AIH
conditions, but discussion of this is beyond the scope of this
6.Other Important Dimensionsof AIH
6.1. Pregnancy and AIH. AIH can improve during preg-
nancy, and this may enable reduction in immunosuppressive
8 Hepatitis Research and Treatment
therapy. The greatest risk is prematurity, but fetal mortality
has been reported to be as high as 21% . Occurrence of
adverse outcome of any type is 26%. Perinatal mortality is
4%, and maternal mortality 3% . Maternal antibodies
to SLA and extractable nuclear antigens (Ro/SSA) have
been associated with a more complicated pregnancy .
Preconceptional counseling is advised and immunosuppres-
sive therapy should be modified if possible. Azathioprine
is an FDA category D drug and safety in pregnancy has
not been well established in human studies. Although
increased number of birth defects have not been reported
in neonates of women receiving this treatment and no
adverse consequences of breast feeding have been noted by
treated mothers [91, 92], congenital malformations have
been reported in pregnant mice, and, thusthere isa potential
risk for teratogenicity. This justifies exercising caution when
using in pregnancy, thus the mainstay of treatment in
pregnancy is prednisone at as low dose as possible. AIH
commonly exacerbates following delivery, therefore therapy
must be resumed (if stopped) or increased 2 weeks prior
to anticipated delivery and continued in the postpartum
Women with advanced cirrhosis and portal hypertension
are at high risk for variceal hemorrhage during pregnancy
. Pregnancy should be avoided and effective contracep-
tion should be advised in these patients.
6.2. AIH, Cirrhosis, and Hepatocellular Carcinoma (HCC).
AIH is associated with chronic inflammation that may
proceed to cirrhosis and end-stage liver disease which also
puts AIH patients at risk of developing HCC. However,
unlike other cohorts of cirrhotic patients, the majority of
patients with AIH respond well to immunosuppression and
in those whom enter a sustained remission, the potential
exists to retain a near normal life expectancy. However, the
interactions of disease activity, response to treatment, and
other factors in relation to the risk of HCC development
in AIH are unknown. Although the development of HCC
in patients with AIH and cirrhosis is considered a rare
occurrence, the true incidence remains unknown due to
the paucity of published data addressing this issue. A large
prospectively obtained cohort at a single center (n = 243)
determined a rate of HCC development of 1.1% per year,
with equal proportions among men and women . The
median duration from time of confirmed cirrhosis to a
diagnosisofHCCwas 102.5months (range12–195months).
Not surprisingly, HCC was found to occur more frequently
in patients with cirrhosis at presentation (9.3% versus 3.4%,
P = .048) or history of variceal bleed as the index presenta-
tion of AIH (20% versus 5.3%, P = .003). Median survival
in patients whose HCC was diagnosed on surveillance was
higher (19 months versus 2 months) compared with patients
presenting symptomatically (P = .042). The majority of
patientsdevelopHCCafter having cirrhosis for an averageof
9 years, and although the incidence of HCC is less common
than in other chronic liverdiseases, the risk may be sufficient
to undertake surveillance in all patients with cirrhosis with
AIH who are candidates to undergo curative therapies.
Autoimmune hepatitis is one of the few liver diseases with
excellent response to therapy. On the other hand, it still
remains a liver disease with many unanswered questions,
particularly in respect to its etiology and pathogenesis. There
is significant heterogeneity in its presentation that may mask
its identity, affect its clinical behavior, and confound its
management. It may start with a fulminant course, and
the diagnosis should not be overlooked when dealing with
patients with acute liver failure. Alternatively, it may behave
as a slowly progressing disease, and it is still controversial
whether those patients need immunosuppressive treatment
at all. There is no prescribed minimum or maximum
duration of treatment. Over the last decade, remarkable
progress has been made in understanding and clarifying
the areas of diagnosis with introduction of classification
criteria, and broadening therapeutic options, with trial of
several new medications likebudesonideand mycophenolate
mofetil, and more in the pipeline. Management, however,
still faces several other important issues, such as in children,
the elderly, in males, and during the preconception period,
pregnancy, and lactation. A key to successful management is
 S. Amberg, “Hyperproteinemia associated with severe liver
damage,” Mayo Clinic Proceedings, vol. 17, pp. 360–362, 1942.
 W. J. Leber, “Blutproteine und Nahrungseeiweisse,” Dtsch
Gesellsch Verd Stoffw, vol. 15, pp. 113–119, 1950.
 H. G. Kunkel, A. E. Eisenmenger, A. M. Bougiovanni, and R.
J. Slater, “Extreme hypergammaglulinemia in young women
with liver disease of unknown etiology,” Journal of Clinical
Investigation, vol. 30, pp. 654–659, 1951.
 I. Mackay, L. I. Taft, and D. C. Cowling, “Lupoid Hepatitis,”
The Lancet, vol. 268, no. 6957, pp. 1323–1326, 1956.
 K. M. Boberg, E. Aadland, J. Jahnsen, N. Raknerud, M. Stiris,
and H. Bell, “Incidence and prevalence of primary biliary
cirrhosis, primary sclerosing cholangitis, and autoimmune
hepatitis in a norwegian population,” Scandinavian Journal of
Gastroenterology, vol. 33, no. 1, pp. 99–103, 1998.
 M. Werner, H. Prytz, B. Ohlsson et al., “Epidemiology and
the initial presentation of autoimmune hepatitis in Sweden:
a nationwide study,” Scandinavian Journal of Gastroenterology,
vol. 43, no. 10, pp. 1232–1240, 2008.
 T. Al-Chalabi, J. A. Underhill, B. C. Portmann, I. G. McFar-
lane, and M. A. Heneghan, “Impact of gender on the long-
term outcomeand survival of patients with autoimmunehep-
atitis,” Journal of Hepatology, vol. 48, no. 1, pp. 140–147, 2008.
 A. J. Czaja and P. T. Donaldson, “Gender effects and
synergisms with histocompatibility leukocyte antigens in type
1 autoimmune hepatitis,” American Journal of Gastroenter-
ology, vol. 97, no. 8, pp. 2051–2057, 2002.
 S. Kanzler, H. L¨ ohr, G. Gerken, P. R. Galle, and A. W. Lohse,
“Long-term management and prognosis of autoimmune
hepatitis (AIH): a single center experience,” Zeitschrift fur
Gastroenterologie, vol. 39, no. 5, pp. 339–348, 2001.
 M. P. Manns and D. Vergani, “Autoimmune hepatitis,”
Seminars in Liver Disease, vol. 29, no. 3, pp. 239–240, 2009.
Hepatitis Research and Treatment9
 D. Vergani, M. S. Longhi,D. P. Bogdanos,Y. Ma, and G. Mieli-
Vergani, “Autoimmune hepatitis,” Seminars in Immunopath-
ology, vol. 31, no. 3, pp. 421–435, 2009.
 J. C. Homberg, N. Abuaf, O. Bernard et al., “Chronic active
type 1: a second type of “autoimmune”hepatitis,” Hepatology,
vol. 7, no. 6, pp. 1333–1339, 1987.
 E. Martini, N. Abuaf, F. Cavalli, V. Durand, C. Johanet,
and J. C. Homberg, “Antibody to liver cytosol (anti-LC1) in
patients with autoimmune chronic active hepatitis Type 2,”
Hepatology, vol. 8, no. 6, pp. 1662–1666, 1988.
 G. Porta, L. C. Da Costa Gayotto, and F. Alvarez, “Anti-liver-
kidney microsome antibody-positive autoimmune hepatitis
presenting as fulminant liver failure,” Journal of Pediatric Gas-
troenterology and Nutrition, vol. 11, no. 1, pp. 138–140, 1990.
 D. G. Doherty, P. T. Donaldson, J. A. Underhill et al., “Allelic
sequence variation in the HLA class II genes and proteins in
patients with autoimmune hepatitis,” Hepatology, vol. 19, no.
3, pp. 609–615, 1994.
 M. N. V´ azquez-Garc´ ıa, C. Al´ aez, A. Olivo et al., “MHC class
H sequences of susceptibility and protection in Mexicans with
autoimmune hepatitis,” Journal of Hepatology, vol. 28, no. 6,
pp. 985–990, 1998.
 T. Seki, M. Ota, S. Furuta et al., “HLA class II molecules and
autoimmune hepatitis susceptibility in Japanese patients,”
Gastroenterology, vol. 103, no. 3, pp. 1041–1047, 1992.
 P. L. Bittencourt, A. C. Goldberg, E. L. R. Canc ¸ado et al.,
“Genetic heterogeneity in susceptibility to autoimmune
hepatitis types 1 and 2,” American Journal of Gastroenterology,
vol. 94, no. 7, pp. 1906–1913, 1999.
 M. Manns, K. Mergener, G. Gerken et al., “HLA class I–III in
autoimmunehepatitis type 2 and its associationwith hepatitis
C virus infection,” Journal of Hepatology, vol. 16, supplement
1, p. 16, 1991.
 A. J. Czaja, M.D. J. Strettell, L. J.Thomsonet al.,“Associations
between alleles of the major histocompatibility complex and
type 1 autoimmune hepatitis,” Hepatology, vol. 25, no. 2, pp.
 M. D. J. Strettell, P. T. Donaldson, L. J. Thomsonet al., “Allelic
basis for HLA-encoded susceptibility to type 1 autoimmune
hepatitis,” Gastroenterology, vol. 112, no. 6, pp. 2028–2035,
 M. Ota, T. Seki, K. Kiyosawa et al., “A possible association
between basic amino acids of position 13 of DRB1 chains and
autoimmune hepatitis,” Immunogenetics, vol. 36, no. 1, pp.
 M. Pando, J. Larriba, G. C. Fernandez et al., “Pediatric and
adult forms of type I autoimmune hepatitis in Argentina:
evidence for differential genetic predisposition,” Hepatology,
vol. 30, no. 6, pp. 1374–1380, 1999.
 J. Aaltonen, P. Bjorses, L. Sandkuijl, J. Perheentupa, and L.
Peltonen, “An autosomal locus causing autoimmune disease:
autoimmune polyglandular disease type I assigned to chro-
mosome21,” Nature Genetics, vol. 8, no. 1, pp. 83–87, 1994.
 P. Obermayer-Straub, J. Perheentupa, S. Braun et al.,
Gastroenterology, vol. 121, no. 3, pp. 668–677, 2001.
 M. G. Clemente, A. Meloni, P. Obermayer-Straub, F. Frau,
M. P. Manns, and S. De Virgiliis, “Two cytochromes P450
are major hepatocellular autoantigens in autoimmune
polyglandular syndrome type 1,” Gastroenterology, vol. 114,
no. 2, pp. 324–328, 1998.
 A. J. Czaja, “Autoantibodies as prognostic markers in auto-
immune liver disease,” Digestive Diseases and Sciences, vol. 55,
no. 8, pp. 2144–2161, 2010.
 A. Csepregi, E. Nemes´ anszky, B. Luettig, P. Obermayer-
Straub, and M. P. Manns, “LKM3 autoantibodies in hepatitis
C cirrhosis: a further phenomenon of the HCV-induced
autoimmunity,” American Journal of Gastroenterology, vol. 96,
no. 3, pp. 910–911, 2001.
 G. Maggiore, F. Veber, O. Bernard et al., “Autoimmune
hepatitis associated with anti-actin antibodies in children
and adolescents,” Journal of Pediatric Gastroenterology and
Nutrition, vol. 17, no. 4, pp. 376–381, 1993.
 A. J. Czaja, F. Cassani, M. Cataleta, P. Valentini, and F. B.
Bianchi, “Frequency and significance of antibodies to actin in
type 1 autoimmune hepatitis,” Hepatology, vol. 24, no. 5, pp.
 Y. Renaudineau, G. N. Dalekos, P. Gu´ eguen, K. Zachou,
and P. Youinou, “Anti-α-actinin antibodies cross-react with
anti-ssDNA antibodies in active autoimmune hepatitis,”
Clinical Reviews in Allergy and Immunology, vol. 34, no. 3, pp.
 Y. Ma, M. Okamoto, M. G. Thomas et al., “Antibodies to
conformational epitopes of soluble liver antigen define a
severe form of autoimmune liver disease,” Hepatology, vol. 35,
no. 3, pp. 658–664, 2002.
 A. J. Czaja, P. T. Donaldson, and A. W. Lohse, “Antibodies
to soluble liver antigen/liver pancreas and HLA risk factors
for type 1 autoimmune hepatitis,” American Journal of Gast-
roenterology, vol. 97, no. 2, pp. 413–419, 2002.
 N. Abuaf, C. Johanet, P. Chretien et al., “Characterization of
the liver cytosol antigen type 1 reacting with autoantibodies
in chronic active hepatitis,” Hepatology, vol. 16, no. 4, pp.
 L. Bridoux-Henno, G. Maggiore, C. Johanet et al., “Features
and outcome of autoimmune hepatitis type 2 presenting with
troenterology and Hepatology, vol. 2, no. 9, pp. 825–830, 2004.
 I. G.McFarlane, C.G. McSorley,andJ.E. Hegarty, “Antibodies
to liver-specific protein predict outcome of treatment
withdrawal in autoimmune chronic active hepatitis,” The
Lancet, vol. 2, no. 8409, pp. 954–956, 1984.
 A. J. Czaja, S. A. Morshed, S. Parveen, and M. Nishioka,
“Antibodies to single-stranded and double-stranded DNA in
antinuclear antibody-positive type 1-autoimmune hepatitis,”
Hepatology, vol. 26, no. 3, pp. 567–572, 1997.
 A. J. Czaja, Z. Shums, W. L. Binder, S. J. Lewis, V. J. Nelson,
and G. L. Norman, “Frequency and significance of antibodies
to chromatin in autoimmune hepatitis,” Digestive Diseases
and Sciences, vol. 48, no. 88, pp. 1658–1664, 2003.
 K. Zachou, E. Rigopoulou, and G. N. Dalekos, “Autoantibod-
in clinical practice and to study pathogenesis of the disease,”
Journal of Autoimmune Diseases, vol. 1, no. 1, p. 2, 2004.
 D. Vergani, G. Mieli-Vergani, M. Mondelli, B. Portmann, and
A. L. W. F. Eddleston, “Immunoglobulin on the surface of
isolated hepatocytes is associated with antibody-dependent
cell-mediated cytotoxicity and liver damage,” Liver, vol. 7, no.
6, pp. 307–315, 1987.
 P. Lapierre, I. Djilali-Saiah, S. Vitozzi, and F. Alvarez, “A
murine model of type 2 autoimmune hepatitis: xenoimmuni-
zation with human antigens,” Hepatology, vol. 39, no. 4, pp.
10 Hepatitis Research and Treatment
 U. Christen, E. Hintermann, and E. Jaeckel, “New animal
models for autoimmune hepatitis,” Seminars in Liver Disease,
vol. 29, no. 3, pp. 262–272, 2009.
 G. M. Vergani, D. Vergani, and P. J. Jenkins, “Lymphocyte
cytotoxicity to autologous hepatocytes in HBsAg-negative
chronic active hepatitis,” Clinical and Experimental Immun-
ology, vol. 38, no. 1, pp. 16–21, 1979.
 Y. Ma, D. P. Bogdanos, M. J. Hussain et al., “Polyclonal T-cell
responses to cytochrome P450IID6 are associated with disease
activity in autoimmune hepatitis type 2,” Gastroenterology,
vol. 130, no. 3, pp. 868–882, 2006.
 M. S. Longhi, M. J. Hussain, D. P. Bogdanos et al.,
responses mirror disease activity in autoimmune hepatitis
type 2,” Hepatology, vol. 46, no. 2, pp. 472–484, 2007.
 M. S. Longhi, Y. Ma, D. P. Bogdanos, P. Cheeseman, G.
Mieli-Vergani, and D. Vergani, “Impairment of CD4+CD25+
regulatory T-cells in autoimmune liver disease,” Journal of
Hepatology, vol. 41, no. 1, pp. 31–37, 2004.
 M. S. Longhi, M. J. Hussain, W. W. Kwok, G. Mieli-Vergani,
Y. Ma, and D. Vergani, “Autoantigen-specific regulatory T
cells, a potential tool for immune-tolerance reconstitution in
type-2 autoimmune hepatitis,” Hepatology, vol. 53, no. 2, pp.
 V. Germano, A. P. Diamanti, G. Baccano et al., “Autoimmune
hepatitis associated with infliximab in a patient with psoriatic
arthritis,” Annals of the Rheumatic Diseases, vol. 64, no. 10, pp.
 N. S. Goldstein, N. Bayati, A. L. Silverman, and S.
C. Gordon, “Minocycline as a cause of drug-induced
autoimmune hepatitis: report of four cases and comparison
with autoimmune hepatitis,” American Journal of Clinical
Pathology, vol. 114, no. 4, pp. 591–598, 2000.
 N. Pelli and M. Setti, “Atorvastatin as a trigger of autoimmune
hepatitis,” Journal of Hepatology, vol. 40, no. 4, p. 716, 2004.
 P. A. Berry and G. Smith-Laing, “Hepatitis A vaccine
associated with autoimmune hepatitis,” World Journal of
Gastroenterology, vol. 13, no. 15, pp. 2238–2239, 2007.
 T. Kamiyama, T. Nouchi, S. Kojima, N. Murata, T. Ikeda, and
C. Sato, “Autoimmune hepatitis triggered by administration
of an herbal medicine,” American Journal of Gastroenterology,
vol. 92, no. 4, pp. 703–704, 1997.
 V. Aubert, I. G. Pisler, and F. Spertini, “Improved diagnoses of
autoimmune hepatitis using an anti-actin ELISA,” Journal of
Clinical Laboratory Analysis, vol. 22, no. 5, pp. 340–345, 2008.
 F. Cassani, M. Cataleta, P. Valentini et al., “Serum
autoantibodies in chronic hepatitis C: comparison with
autoimmune hepatitis and impact on the disease profile,”
Hepatology, vol. 26, no. 3, pp. 561–566, 1997.
 A. R. Kammer, S. H. Van Der Burg, B. Grabscheid et al.,
“Molecular mimicry of human cytochrome P450 by hepatitis
C virus at the level of cytotoxic T cell recognition,” Journal of
Experimental Medicine, vol. 190, no. 2, pp. 169–176, 1999.
 M. P. Manns, A. J. Czaja, J. D. Gorham et al., “Diagnosis and
management of autoimmune hepatitis,” Hepatology, vol. 51,
no. 6, pp. 2193–2213, 2010.
 K. J. Hurlburt, B. J. McMahon, H. Deubner, B. Hsu-
Trawinski, J. L. Williams, and K. V. Kowdley, “Prevalence of
autoimmuneliver disease in Alaskanatives,” American Journal
of Gastroenterology, vol. 97, no. 9, pp. 2402–2407, 2002.
 K. Nakamura, M. Yoneda, S. Yokohama et al., “Efficacy
of ursodeoxycholic acid in Japanese patients with type
autoimmune hepatitis,” Journal of Gastroenterology and
Hepatology, vol. 13, no. 5, pp. 457–495, 1998.
 R. D’Souza, P. Sinnott, M. J. Glynn, C. A. Sabin, and G.
R. Foster, “An unusual form of autoimmune hepatitis in
young Somalian men,” Liver International, vol. 25, no. 2, pp.
 K. N. Lim, R. L. Casanova, T. D. Boyer, and C. J. Bruno,
“Autoimmune hepatitis in African Americans: presenting
features and response to therapy,” American Journal of Gastro-
enterology, vol. 96, no. 12, pp. 3390–3394, 2001.
 V. R. Chowdhary, C. S. Crowson, J. J. Poterucha, and K. G.
Moder, “Liver involvement in systemic lupus erythematosus:
case review of 40 patients,” Journal of Rheumatology, vol. 35,
no. 11, pp. 2159–2164, 2008.
 H. Chung, T. Watanabe, M. Kudo, O. Maenishi, Y. Wakatsuki,
and T. Chiba, “Identification and characterization of IgG4-
associated autoimmune hepatitis,” Liver International, vol. 30,
no. 2, pp. 222–231, 2010.
 A. J. Czaja, “Variant forms of autoimmune hepatitis,” Current
Gastroenterology Reports, vol. 1, no. 1, pp. 63–70, 1999.
 D. P. Bogdanos, G. Mieli-Vergani, and D. Vergani, “Auto-
antibodies and their antigens in autoimmune hepatitis,”
Seminars in Liver Disease, vol. 29, no. 3, pp. 241–253,
 A. Montano-Loza, A. J. Czaja, H. A. Carpenter et al., “Freq-
uency and significance of antibodies to cyclic citrullinated
peptide in type 1 autoimmune hepatitis,” Autoimmunity, vol.
39, no. 4, pp. 341–348, 2006.
 P. J. Johnson and I. G. Mcfarlane, “Meeting report: interna-
pp. 998–1005, 1993.
 F. Alvarez, P. A. Berg, F. B. Bianchi et al., “International
Autoimmune Hepatitis Group Report: review of criteria for
diagnosis of autoimmune hepatitis,” Journal of Hepatology,
vol. 31, no. 5, pp. 929–938, 1999.
 E. M. Hennes, M. Zeniya, A. J. Czaja et al., “Simplified criteria
for the diagnosis of autoimmune hepatitis,” Hepatology, vol.
48, no. 1, pp. 169–176, 2008.
 Y. Miyake, Y. Iwasaki, H. Kobashi et al., “Clinical features of
autoimmune hepatitis diagnosed based on simplified criteria
of the International Autoimmune Hepatitis Group,” Digestive
and Liver Disease, vol. 42, no. 3, pp. 210–215, 2010.
 A. J. Czaja, “Performance parameters of the diagnosticscoring
systems for autoimmune hepatitis,” Hepatology, vol. 48, no. 5,
pp. 1540–1548, 2008.
 J. J. Feld, H. Dinh, T. Arenovich, V. A. Marcus, I. R. Wanless,
and E. J. Heathcote, “Autoimmune hepatitis: effect of
symptoms and cirrhosis on natural history and outcome,”
Hepatology, vol. 42, no. 1, pp. 53–62, 2005.
 R. Perdigoto, H. A. Carpenter, and A. J. Czaja, “Frequency
and significance of chronic ulcerative colitis in severe
corticosteroid-treated autoimmune hepatitis,” Journal of
Hepatology, vol. 14, no. 2-3, pp. 325–331, 1992.
 G. V. Gregorio, B. Portmann, J. Karani et al., “Autoimmune
childhood: a 16-year prospective study,” Hepatology, vol.
33, no. 3, pp. 544–553, 2001.
 S. W. Schalm, M. G. Korman, and W. H. J. Summerskill,
“Severe chronic active liver disease: prognostic significance of
initial morphologic patterns,” American Journal of Digestive
Diseases, vol. 22, no. 11, pp. 973–980, 1977.
 A. J. Czaja, “Features and consequences of untreated type 1
autoimmune hepatitis,” Liver International, vol. 29, no. 6, pp.
Hepatitis Research and Treatment 11
 W.H.J.Summerskill,M.G. Korman,H. V.Ammon,andA.H.
Baggenstoss, “Prednisone for chronic active liver disease: dose
titration, standard dose, and combination with azathioprine
compared,” Gut, vol. 16, no. 11, pp. 876–883, 1975.
 M. P. Manns, M. Woynarowski, W. Kreisel, R. Oren, and R.
Gunther, “Budesonide 3 mg tid is superior to prednisone
in combination with azathioprine in the treatment of
autoimmune hepatitis,” Journal of Hepatology, vol. 48, pp.
 J. Wiegand, A. Sch¨ uler, S. Kanzler et al., “Budesonide
in previously untreated
International, vol. 25, no. 5, pp. 927–934, 2005.
 A. J. Czaja and H. A. Carpenter, “Empiric therapy of autoim-
mune hepatitis with mycophenolate mofetil: comparison
with conventional treatment for refractory disease,” Journal of
Clinical Gastroenterology, vol. 39, no. 9, pp. 819–825, 2005.
 I. Inductivo-Yu, A. Adams, R. G. Gish et al., “Mycophenolate
mofetil in autoimmune hepatitis patients not responsive or
intolerant to standard immunosuppressive therapy,” Clinical
Gastroenterology and Hepatology, vol. 5, no. 7, pp. 799–802,
 M. M. Aw, A. Dhawan, M. Samyn, A. Bargiota, and G.
Mieli-Vergani, “Mycophenolate mofetil as rescue treatment
for autoimmune liver disease in children: a 5-year follow-up,”
Journal of Hepatology, vol. 51, no. 1, pp. 156–160, 2009.
 B. A. Aqel, V. Machicao, B. Rosser, R. Satyanarayana, D. M.
Harnois, and R. C. Dickson, “Efficacy of tacrolimus in the
of Clinical Gastroenterology, vol. 38, no. 9, pp. 805–809, 2004.
 A. J. Czaja, H. A. Carpenter, and K. D. Lindor, “Ursode-
oxycholic acid as adjunctive therapy for problematic type
1 autoimmune hepatitis: a randomized placebo-controlled
treatment trial,” Hepatology, vol. 30, no. 6, pp. 1381–1386,
 European Liver Transplant Registry, http://www.eltr.org/.
 Scientific Registry of Transplant Recipients, http://www
 A. J. Czaja, H. A. Carpenter, P. J. Santrach, and S. B. Moore,
“Significance of HLA DR4 in type 1 autoimmune hepatitis,”
Gastroenterology, vol. 105, no. 5, pp. 1502–1507, 1993.
 T. J. S. Cross, C. G. Antoniades, P. Muiesan et al., “Liver
transplantation in patiens over 60 and 65 years: an evaluation
of long-term outcomes and survival,” Liver Transplantation,
vol. 13, no. 10, pp. 1382–1388, 2007.
 C. Schramm, J. Herkel, U. Beuers, S. Kanzler, P. R. Galle, and
A. W. Lohse, “Pregnancy in autoimmune hepatitis: outcome
and risk factors,” American Journal of Gastroenterology, vol.
101, no. 3, pp. 556–560, 2006.
 L. Candia, J. Marquez, and L. R. Espinoza,“Autoimmune hep-
atitis and pregnancy: a rheumatologist’s dilemma,” Seminars
in Arthritis and Rheumatism, vol. 35, no. 1, pp. 49–56, 2005.
 M. Werner, E. Bj¨ ornsson, H. Prytz et al., “Autoimmune
hepatitis among fertile women: strategies during pregnancy
and breastfeeding?” Scandinavian Journal of Gastroenterology,
vol. 42, no. 8, pp. 986–991, 2007.
 R. R. Varma, N. H. Michelsohn, H. I. Borkowf, and J. D.
Lewis, “Pregnancy in cirrhotic and noncirrhotic portal
hypertension,” Obstetrics and Gynecology, vol. 50, no. 2, pp.
 A. D. Yeoman, T. Al-Chalabi, J. B. Karani et al., “Evaluation of
risk factors in the development of hepatocellular carcinoma
in autoimmune hepatitis: implications for follow-up and
screening,” Hepatology, vol. 48, no. 3, pp. 863–870, 2008.