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Overview of autoimmune hepatitis

Author: Michael A Heneghan, MD, MMedSc, FRCPI
Section Editor: Sanjiv Chopra, MD, MACP
Deputy Editor: Kristen M Robson, MD, MBA, FACG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2020. | This topic last updated: Feb 27, 2019.

INTRODUCTION

Autoimmune hepatitis is a chronic, inflammatory disease of the liver that is characterized by

circulating autoantibodies and elevated serum globulin levels. The disease may start as acute
hepatitis and progress to chronic liver disease and cirrhosis.

Although this disorder had been known by a variety of names, including lupoid hepatitis, plasma cell
hepatitis, and autoimmune chronic active hepatitis, the International Autoimmune Hepatitis Group
determined that autoimmune hepatitis was the most appropriate term for this disease [1].

An overview of autoimmune hepatitis will be provided here. Variant forms of autoimmune hepatitis
(ie, overlap syndromes) are discussed separately. (See "Autoimmune hepatitis variants: Definitions
and treatment".)

INCIDENCE AND EPIDEMIOLOGY

Autoimmune hepatitis can present at any age and in all ethnic groups, but it occurs predominantly in
women [2-5]. For type 1 autoimmune hepatitis, the female to male ratio is 4:1, but for type 2
autoimmune hepatitis, the ratio is 10:1 [6,7]. (See 'Autoantibodies' below.)

The worldwide incidence of autoimmune hepatitis ranges from 0.7 (southern Israel) to 2 (Canterbury,
New Zealand) per 100,000 population, while the prevalence ranges from 4 (Singapore) to 25
(Canterbury, New Zealand) per 100,000 [8-10]. In studies from Europe, the incidence is 0.9 to 2 per
100,000 population per year, with a prevalence of 11 to 25 per 100,000 population [4,8,11,12]. No
prevalence data on autoimmune hepatitis exists for the United States.
PATHOGENESIS

One theory for pathogenesis is that the disease is caused by an environmental trigger in a genetically
predisposed individual. The exact relationships between genes and the autoimmune process remain
largely undefined, but at the molecular level, they are thought to involve the autoantigen, the major
histocompatibility complex, and the T-cell receptor. (See "Autoimmune hepatitis: Pathogenesis".)

CLINICAL FEATURES

Patterns of clinical presentation — Autoimmune hepatitis has a variety of clinical phenotypes;

therefore, it is included in the differential diagnosis for patients with abnormal liver biochemical tests,
acute hepatitis, cirrhosis, or acute liver failure [13]. It may present as either an acute or chronic
disease with a fluctuating pattern [14,15]. However, the spectrum of presentation also includes
asymptomatic patients. At its extreme, patients can present with considerable and sometimes
debilitating symptoms (eg, anorexia, fatigue, weight loss). Furthermore, long periods of subclinical
disease may occur before or after presentation.

Physical findings range from a normal physical examination to findings suggestive of cirrhosis or liver
failure (eg, jaundice, ascites, splenomegaly). (See "Cirrhosis in adults: Etiologies, clinical
manifestations, and diagnosis", section on 'Clinical manifestations'.)

Asymptomatic patients may be identified when they undergo screening examinations, such as those
required for insurance, for employment, or prior to blood donation. In this setting, the finding of an
elevated aminotransferase level may be the only sign of liver disease. On occasion, the asymptomatic
patient is discovered when abdominal surgery is performed for some other reason and the surgeon
notes an abnormal, sometimes cirrhotic-appearing liver.

At the far end of the spectrum are those patients who present with acute liver failure, jaundice, and
coagulopathy, but such a presentation is generally uncommon [16-18]. (See "Acute liver failure in
adults: Etiology, clinical manifestations, and diagnosis".)

However, for some patients with acute liver failure of unknown etiology, autoimmune hepatitis is
determined to be the cause upon further review. In a study including 303 patients with acute liver
failure of unclear etiology, 34 patients (11 percent) were thought to have underlying autoimmune
hepatitis as the cause after a committee review which was guided by etiology-specific algorithms
[19].

In addition to asymptomatic disease and an acute presentation, some patients present with a range
of mild to severe, nonspecific symptoms, such as fatigue, anorexia, nausea, abdominal pain, and
itching. Arthralgia involving the small joints or a transient erythematous rash may also be present [6].

Associated extrahepatic disorders — Patients with autoimmune hepatitis may present with a

coexisting extrahepatic disorder, which may also be autoimmune-mediated. For example, associated
common autoimmune disorders include autoimmune thyroiditis, rheumatoid arthritis, type 1 diabetes
mellitus, ulcerative colitis, celiac disease, and systemic lupus erythematosus (table 1) [20-25]. While
asthma and some skin disorders (eg, acne) have been reported in association, these are not regarded
as autoimmune in nature and may reflect the bias of larger referral centers.

Celiac disease is a common extrahepatic condition, and prevalence varies from approximately 3 to 6
percent [26-28]. In a cohort study involving 460 patients with autoimmune hepatitis from the
Netherlands, the prevalence of celiac disease was approximately 10 times higher compared with the
general population (2.8 versus 0.35 percent) [28].

Skin conditions can occur at any time during the course of the disease. At initial presentation, rashes
are seen in 8 to 17 percent of patients and most commonly appear as a transient and nonspecific
maculopapular rash, particularly over the face, trunk, and upper arms [4,5]. Associated skin lesions
also include psoriasis [4], vitiligo [5,21], urticaria [29], acne [21], lichen planus [29], erythema nodosum
[5], and pyoderma gangrenosum [30,31].

Laboratory features

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.

Most of the data on autoantibodies are based upon results obtained by immunofluorescence. By
contrast, commercial laboratories tend to measure autoantibodies by ELISA, and thus it is possible
that results may differ from those reported in the literature. For adults with suspected autoimmune
hepatitis, higher antibody titers (>1:160) provide greater support for the diagnosis compared with
lower titers.

Patterns in children are described below. (See 'Children' below.)

Imaging — There are no characteristic imaging features for autoimmune hepatitis, and imaging
studies are not routinely obtained in all patients [49]. (See 'Diagnostic evaluation' below.)

Histology — Autoimmune hepatitis can be characterized histologically by the following findings,

although they are nonspecific:

● A portal mononuclear cell infiltrate (generally lymphoplasmacytic, often with occasional

eosinophils), invades the sharply demarcated hepatocyte boundary (limiting plate) surrounding
the portal triad and infiltrates into the surrounding lobule and beyond (picture 1).
 ● The periportal lesion, sometimes referred to as piecemeal necrosis or interface hepatitis,
essentially spares the biliary tree but may involve more of the lobule (picture 2). There may also
be centrizonal necrosis [50].

● Bile duct changes (eg, destructive and nondestructive cholangitis, ductal injury, and ductular
reaction) are increasingly recognized in patients with autoimmune hepatitis [51]. In particular,
ductal injury and ductular reaction may be seen in over 80 percent of patients at the time of
diagnosis. Granulomas are uncommonly seen, but if present, should prompt an evaluation for
another diagnosis such as PBC or sarcoidosis.

● A plasma cell infiltrate, rosettes of hepatocytes, and multinucleated giant cells, may be seen
(picture 3). The presence of infiltrate in the portal areas and plasma cell infiltrates can help
distinguish such patients from those with other forms of acute hepatitis [52,53].

● Some degree of fibrosis is usually present in all but the mildest forms of autoimmune hepatitis.
Advanced fibrosis connects portal and central areas (bridging), which ultimately, by architectural
distortion of the hepatic lobule and the appearance of regenerating nodules, results in cirrhosis.

DIAGNOSTIC EVALUATION

Autoimmune hepatitis is a diagnosis of exclusion, and for patients with suspected disease, we
proceed with testing in a stepwise fashion. This approach is largely consistent with guidelines issued
by the American Association for the Study of Liver Diseases [2].

For adults with any serum aminotransferase elevation, we initially measure the following serum
globulins and serologic markers:

● Antinuclear antibody

● Anti-smooth muscle antibody

● Anti-liver-kidney microsomal-1 antibodies

● Antimitochondrial antibody

● Immunoglobulin G (IgG) or gamma globulin level

For adult patients who are negative for the conventional autoantibodies outlined above, we obtain
additional autoantibodies:

● Anti-liver cytosol antibody-1

 ● Anti-soluble liver antigen/liver pancreas antibody

● Atypical perinuclear antineutrophil cytoplasmic antibodies

We obtain magnetic resonance cholangiopancreatography in the following adult patients to exclude

primary sclerosing cholangitis [49]:

● Patients with an established diagnosis of inflammatory bowel disease.

● Patients with a liver biochemical pattern that suggests cholestasis (predominantly elevated
alkaline phosphatase) (see "Approach to the patient with abnormal liver biochemical and
function tests", section on 'Patterns of liver test abnormalities').

Routine liver biopsy is not always necessary because the diagnosis of autoimmune hepatitis can be
strongly suspected based upon clinical features in patients with either a positive autoantibody and/or
elevated IgG or gamma globulin levels [54]. We prefer to obtain a liver biopsy in patients in whom
autoimmune hepatitis is suspected because histologic assessment can confirm the diagnosis and
help guide treatment. (See "Autoimmune hepatitis: Treatment".)

Histologic evaluation is particularly useful for evaluating patients who have few or atypical findings,
negative autoantibodies, and/or normal IgG levels. The decision to obtain a liver biopsy also involves
a discussion of the risks and benefits of biopsy and also depends on patient preferences. The risk of
adverse events related to liver biopsy is discussed separately. (See "Approach to liver biopsy", section
on 'Complications'.)

We use a standardized scoring system as part of the assessment. (See 'Histology' above and
'Diagnostic scoring systems' below.)

Of note, some guidelines require liver biopsy as part of the diagnostic evaluation, including 2015
guidelines from the European Association for the Study of the Liver [55].

DIAGNOSIS

Our diagnostic criteria — The diagnosis of autoimmune hepatitis can be made in a patient with a
compatible clinical presentation when the following features are present (see 'Patterns of clinical
presentation' above):

● A minimum of one elevated serum aminotransferase, typically (but not always) an aspartate
aminotransferase and/or alanine aminotransferase level at least two times the upper limit of the
reference range.
 ● A minimum of one positive laboratory test: increased total IgG or gamma-globulin levels, and/or
serologic markers (antinuclear antibodies, antismooth muscle antibodies at a titer of at least
1:40, anti-liver/kidney microsomal-1 antibodies, anti-LC antibody-1, or anti-soluble liver/liver
pancreas (anti-SLA/LP) antibodies.

● Exclusion of diseases that have a similar presentation, particularly viral hepatitis, drug-induced
liver injury, and alcoholic liver disease (see 'Differential diagnosis' below)

When a liver biopsy is obtained, the diagnosis can be confirmed by histology showing interface
hepatitis and/or a predominantly lymphoplasmacytic infiltrate. (See 'Histology' above and 'Diagnostic
evaluation' above.)

Disease classification — On the basis of the autoantibody profiles, patients can be categorized into
two disease subtypes: type 1 or type 2, but these subtypes have not been established as distinct
clinical or pathological entities (table 2) [2]. (See 'Autoantibodies' above.)

However, some patients lack circulating autoantibodies.

Type 1 autoimmune hepatitis — Autoantibodies characteristic of type 1 autoimmune hepatitis are:

● Antinuclear antibody (ANA).

● Anti-smooth muscle antibody (approximately 65 percent of patients).

● Antiactin antibodies.

● Antimitochondrial antibodies (rarely positive in patients without primary biliary cholangitis

overlap) (see 'Other types of autoimmune liver disease' below and "Autoimmune hepatitis
variants: Definitions and treatment").

● Anti-SLA/LP antigen (approximately 10 to 30 percent of adults).

● Anti-single-stranded and anti-double-stranded DNA (25 to 35 percent of patients) [43].

● Atypical perinuclear antineutrophil cytoplasmic antibodies [42].

Type 2 autoimmune hepatitis — Autoantibodies characteristic of type 2 autoimmune hepatitis are

antibodies to liver/kidney microsomes (ALKM-1) alone or accompanied by liver cytosol antigen (ALC-
1). Positive titers are defined as >1:20 for ANA and antismooth muscle antibody (ASMA), whereas
titers of 1:10 may be considered positive for ALKM-1. However, some patients have only ALC-1
antibodies [47]. In addition, approximately 10 to 30 percent of patients with type 2 disease will have
anti-SLA/LP antibodies [56]. Antibodies to LKM-3 are rarely seen in type 2 disease and are not useful
in clinical practice [55].
 Autoantibody negative autoimmune hepatitis — Approximately 20 percent of patients who present
with all the features of autoimmune hepatitis lack circulating ANA, ASMA, or ALKM-1 antibodies [6].
These patients are usually regarded as having autoantibody negative autoimmune hepatitis or
cryptogenic chronic hepatitis. A therapeutic response to anti-inflammatory therapy may be the only
indication that autoimmune hepatitis is the underlying disease in these patients. (See "Autoimmune
hepatitis: Treatment".)

Diagnostic scoring systems — A scoring system developed to standardize the diagnosis for
population-based studies and clinical trials has had limited value in individual patients [1,57,58]. A
less complicated system using simplified criteria for individual patients is based upon titers of
autoantibodies, IgG levels, liver histology, and the exclusion of viral hepatitis.

● Autoantibodies – Assign one point if the ANA or ASMA are 1:40 OR assign two points if the ANA
or ASMA are ≥1:80 (OR if the LKM ≥1:40 OR if the SLA is positive).

● IgG – Assign one point if the IgG is >the upper limit of normal OR assign two points if the IgG is
>1.10 times the upper limit of normal.

● Liver histology (evidence of hepatitis is a mandatory condition) – Assign one point if the
histological features are compatible with autoimmune hepatitis OR two points if the histological
features are typical of autoimmune hepatitis. Typical histologic features were defined as the
presence of interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in the portal tracts
and extending into the lobule, emperipolesis (active penetration of one cell into and through a
large cell), and hepatic rosette formation. Compatible features were defined as a picture of
chronic hepatitis with lymphocytic infiltration without all the features considered typical.

● Absence of viral hepatitis – Assign two points if viral hepatitis has been excluded. In the
validation study, patients were mainly tested for hepatitis B and C. However, other forms of
hepatitis should be considered depending upon the clinical setting.

A probable diagnosis of autoimmune hepatitis is made if the total points are 6, while a definite
diagnosis is made if the total points are ≥7.

In a validation study involving 11 international centers, the simplified scoring system had 88 percent
sensitivity and 97 percent specificity compared with a clinical and histologic reference standard when
using a cutoff of ≥6; the corresponding values were 81 and 99 percent, respectively, when using a
cutoff of ≥7 [58]. Sensitivity was somewhat lower, but specificity remained high in a later validation
study using a cutoff of ≥7 (70 and 100 percent, respectively) [59].

A potential limitation of the scoring system is the relative lack of standardization of some of the
autoantibody tests across testing facilities (ie, simplified criteria are based on autoantibodies
measured by immunofluorescence) [58]. Nevertheless, in the validation studies above, the local
standards for autoantibody testing at each center were used, suggesting that the model is relatively
robust to these differences.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of autoimmune hepatitis includes conditions associated with either acute
hepatitis or chronic inflammation that may accompanied by cirrhosis (table 2).

Other types of autoimmune liver disease — The distinction between autoimmune hepatitis and other
autoimmune liver diseases, including primary biliary cholangitis and overlap syndromes, is based
upon clinical, histologic, and immunologic features [60].

● Primary biliary cholangitis – The isolated presence of AMA with the M2 subtype usually signifies
primary biliary cholangitis (PBC), and further diagnostic evaluation is needed. (See "Clinical
manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)",
section on 'Diagnosis' and "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)",
section on 'Antimitochondrial antibodies'.)

AMA is rarely the sole autoantibody in patients with autoimmune hepatitis [2,60]. However, some
patients with autoimmune hepatitis and a positive AMA will develop PBC [61]. Primary biliary
cholangitis may be indistinguishable from autoimmune hepatitis on liver biopsy, but often has
features involving bile duct paucity, inflammation and/or damage, or peri-ductular fibrosis that
are not seen in autoimmune hepatitis (picture 4A-C).

● Overlap syndromes – The diagnosis of an overlap syndrome such as primary sclerosing

cholangitis/autoimmune hepatitis, can be difficult, but imaging may differentiate the disorders
[2,60]. (See 'Diagnostic evaluation' above.)

For example, patients with primary sclerosing cholangitis have characteristic multifocal
stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiogram, while
patients with autoimmune hepatitis have a normal-appearing biliary tree. The diagnosis of
overlap syndromes and primary sclerosing cholangitis is discussed in more detail separately.
(See "Autoimmune hepatitis variants: Definitions and treatment" and "Primary sclerosing
cholangitis in adults: Clinical manifestations and diagnosis".)

Other causes of hepatitis — Some clinical features of autoimmune hepatitis (eg, elevated

transaminases) may be found in patients who present with inflammatory liver disease from a
different etiology.
● Viral hepatitis - In the acute setting, it is necessary to distinguish autoimmune hepatitis from
acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-
Barr virus; cytomegalovirus); other viral infections; or an acute exacerbation of chronic viral
hepatitis (hepatitis B). The laboratory evaluation for a patient with acute hepatitis is discussed in
more detail elsewhere. (See "Approach to the patient with abnormal liver biochemical and
function tests", section on 'Elevated serum aminotransferases'.)

With older testing methods, a nonspecific antibody response seen in some patients with
autoimmune hepatitis made it difficult to distinguish between autoimmune disease and chronic
hepatitis C virus infection. A false positive hepatitis C antibody can easily be confirmed by
obtaining a hepatitis C virus RNA level in these patients. (See "Screening and diagnosis of
chronic hepatitis C virus infection".)

● Drug-induced liver injury – Some forms of drug-induced liver disease (DILI) can resemble
autoimmune hepatitis histologically, so a liver biopsy is often indicated when this diagnosis is
suspected as certain histologic features (eg, portal neutrophils, which are more common in DILI)
can help distinguish between the two [62]. The clinical presentation and diagnosis of DILI is
discussed separately. (See "Drug-induced liver injury".)

● Nonalcoholic steatohepatitis – Establishing the diagnosis of autoimmune hepatitis in patients

with underlying nonalcoholic steatohepatitis may be difficult, especially in those with a positive
ANA [63]. Antibodies that are more specific for autoimmune hepatitis (eg, ASMA, LKM-1) are not
present in patients with liver disease due to nonalcoholic steatohepatitis. In addition, fatty
infiltration and the presence of polymorphonuclear leukocytes and central fibrosis on histology
points to steatohepatitis, which is discussed separately. (See "Epidemiology, clinical features,
and diagnosis of nonalcoholic fatty liver disease in adults".)

● SLE-associated liver disease – Autoantibodies may help to distinguish between autoimmune

hepatitis and liver disease associated with systemic lupus erythematous (SLE). Although ANA
can be seen in both conditions, ASMA and AMA are rarely present in patients with SLE. Thus,
either antibody suggests that the patient has autoimmune hepatitis. On the other hand, there is a
form of hepatitis that occurs in SLE which is distinct from autoimmune hepatitis. Its
pathogenesis may be related to antiribosomal P protein antibodies, which are discussed
separately. (See "Antiribosomal P protein antibodies".)

● Acute liver failure - Various autoantibodies (eg, AMA, anti-SLA/LP) have been described in
patients with acute liver failure [64,65]. Thus, autoantibodies alone in such patients does not
establish autoimmune hepatitis as the cause. The diagnostic evaluation of patients with acute
 liver failure is discussed separately. (See "Acute liver failure in adults: Etiology, clinical
manifestations, and diagnosis", section on 'Diagnosis'.)

● Iron overload - On occasion, an elevated serum ferritin, sometimes accompanied by elevated

transferrin saturation, occurs in autoimmune hepatitis. Iron overload from genetic
hemochromatosis can be excluded by testing for common mutations for hereditary
hemochromatosis (HFE C282Y and H63D) and by assessing hepatic iron content with magnetic
resonance imaging or liver biopsy. (See "Approach to the patient with suspected iron overload",
section on 'Sequence and interpretation of testing'.)

TREATMENT AND PROGNOSIS

The initial treatment for autoimmune hepatitis typically includes a glucocorticoid, with or without
azathioprine or 6-mercaptopurine (table 3 and algorithm 1). Induction therapy, subsequent therapy
and prognosis are discussed in detail separately. (See "Autoimmune hepatitis: Treatment".)

SPECIAL POPULATIONS

Children — The diagnostic evaluation for children with suspected autoimmune hepatitis is similar to
the evaluation in adults, although we obtain magnetic resonance cholangiopancreatography in all
children to exclude autoimmune sclerosing cholangitis. In addition, antibody titers of 1:20 or greater
(for all antibodies) are regarded as positive in children.

For children with any serum aminotransferase abnormality, we initially measure the following
serologic markers:

● Antinuclear antibody.

● Antismooth muscle antibody [44].

● Anti-Liver-kidney microsomal-1 antibodies.

● Antimitochondrial antibody.

● Immunoglobulin G or gamma-globulin level. Low immunoglobulin A levels can be seen in children

with type 1 and, more frequently, type 2 disease [15].

For children who are negative for these autoantibodies, we obtain additional autoantibodies:

● Anti-soluble liver antigen/liver pancreas antibody (commonly found in children with type 2
disease)
 ● Atypical perinuclear antineutrophil cytoplasmic antibodies

● Anti-liver cytosol antibody-1 (ALC-1)

In a study of 39 children and 14 adults with type 2 autoimmune hepatitis, ALC-1 antibodies were
present more often in children compared with adults (59 versus 29 percent) [26]. In addition, ALC-1
antibodies were the sole autoantibody detected in 14 children (36 percent) with type 2 autoimmune
hepatitis.

Almost exclusively a disease of children, Wilson disease can present as a chronic hepatitis or as fatty
liver disease that resembles autoimmune hepatitis. Approximately 85 to 90 percent of patients with
Wilson disease have low serum ceruloplasmin levels (<20 mg/dL or 200 mg/L) which can distinguish
it from autoimmune hepatitis. (See "Wilson disease: Diagnostic tests" and "Wilson disease:
Epidemiology and pathogenesis".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Autoimmune hepatitis".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Autoimmune hepatitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Autoimmune hepatitis is a chronic, inflammatory disease of the liver that occurs predominantly
in women and may present at any age. It is generally characterized by circulating autoantibodies
and elevated serum globulin levels. The disease may start as acute hepatitis and may progress
to chronic liver disease and cirrhosis. (See 'Introduction' above.)

● Autoimmune hepatitis has a heterogeneous and fluctuating nature, leading to marked variability
in its clinical manifestations. Its spectrum ranges from asymptomatic patients to those with
considerable and sometimes debilitating symptoms, and even to those with acute liver failure.
(See 'Patterns of clinical presentation' above.)

● Diagnosis is based upon characteristic serologic and histologic findings and exclusion of other
forms of chronic liver disease. It can often be strongly suspected based upon clinical and
laboratory features, and thus a liver biopsy is not always necessary in patients with typical
findings on noninvasive testing (see 'Diagnostic evaluation' above):

• For adults with compatible clinical or laboratory features, we obtain serum antinuclear
antibodies, anti-smooth muscle antibodies, antimitochondrial antibodies, anti-liver/kidney
microsomal-1 antibodies, and either an immunoglobulin G (IgG) or gamma globulin level. For
patients who are negative for these autoantibodies, we obtain anti-soluble liver antigen/liver
pancreas antibody, anti-actin antibodies, and atypical perinuclear antineutrophil cytoplasmic
antibodies.

• We prefer to obtain a liver biopsy in all patients in whom autoimmune hepatitis is suspected
because histologic assessment can confirm the diagnosis and help guide treatment.
Histologic evaluation is particularly useful as part of the diagnostic evaluation for patients
who have few or atypical findings, negative autoantibodies and/or normal IgG levels.

● The initial treatment for autoimmune hepatitis typically includes a glucocorticoid, with or without
azathioprine or 6-mercaptopurine (table 3 and algorithm 1). Induction therapy, subsequent
therapy, and prognosis are discussed in detail separately. (See "Autoimmune hepatitis:
Treatment".)

● The diagnostic evaluation for children with suspected autoimmune hepatitis is similar to the
evaluation in adults, although we obtain magnetic resonance cholangiopancreatography in all
children to exclude autoimmune sclerosing cholangitis. In addition, antibody titers of 1:20 or
greater are regarded as positive in children. (See 'Children' above.)

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REFERENCES

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3. Boberg KM, Aadland E, Jahnsen J, et al. Incidence and prevalence of primary biliary cirrhosis,
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Topic 3665 Version 31.0

GRAPHICS

Extrahepatic disorders associated with autoimmune hepatitis

Frequency among patients with AIH

Extrahepatic diseases
(%)

Pulmonary disorders Fibrosing alveolitis <1

Pulmonary fibrosis <1

Sarcoidosis <1

Asthma 1 to 4

Hematological disorders Immune thrombocytopenia <1

Autoimmune hemolytic anemia <1

Pernicious anemia 1

Antiphospholipid syndrome 1

Neurologic disorders Multiple sclerosis <1

Mononeuritis multiplex <1

Miscellaneous Primary amenorrhoea 4

Glomerulonephritis 1

Cryoglobulinemia <1

Uveitis <1

Polyglandular autoimmune syndrome <1

Endocrine disorders Autoimmune thyroiditis 8 to 23

Diabetes (type 1) 1 to 10

Gastrointestinal disorders IBD (ulcerative colitis) 2 to 8

Celiac disease +/– IgA deficiency 1 to 6

Connective tissue disorders Rheumatoid arthritis 2 to 4

Sjögren's syndrome 1 to 7

Mixed connective tissue disease 1 to 2.5

Systemic lupus erythematosus 1 to 2.6

Systemic sclerosis/scleroderma/CREST <1

Polymyalgia rheumatica <1

Polymyositis <1

Dermatomyositis <1

Skin disorders Psoriasis 3

Vitiligo 1 to 2

Pyoderma gangrenosum <1

Acne <1

Urticaria <1

Lichen planus <1

Erythema nodosum <1

Dermatitis herpetiformis <1

AIH: autoimmune hepatitis; IBD: inflammatory bowel disease; CREST: calcinosis cutis, Raynaud phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasia.
Graphic 59606 Version 2.0
Polyclonal gammopathy

(A) Densitometer tracing of these findings reveals a broad-based peak of gamma mobility.
This pattern is most often due to the presence of an inflammatory or reactive process, such
as chronic liver disease, connective tissue disease, chronic infection, or a
lymphoproliferative disorder.
(B) A polyclonal pattern is seen on serum protein electrophoresis on agarose gel (anode on
left). The band at the right (red asterisk) is broad, and extends throughout the gamma
mobility area.

Reproduced with permission from: Kyle RA, Rajkumar SV. Plasma cell disorders. In: Cecil textbook of
medicine, 22nd ed, Goldman L, Ausiello DA (Eds), WB Saunders, Philadelphia 2004. p.1184. Copyright
© 2004 Elsevier.

Graphic 74708 Version 4.0

Classification of autoantibodies in autoimmune hepatitis

Antibody Disease subtype Additional features

Antinuclear antibody (ANA) Type 1 Most common antibodies in type 1 disease

Antismooth muscle antibody (ASMA) Type 1 ASMA titers of 1:320 or greater generally
reflect the presence of AAA

Antiactin antibody (AAA) Type 1 Not routinely measured in North American

laboratories

Antimitochondrial antibody (AMA) Type 1 More specific for primary biliary cholangitis

Atypical perinuclear antineutrophil Type 1 Also found in patients with primary

cytoplasmic antibody (p-ANCA) sclerosing cholangitis

Anti-soluble liver antigen/liver pancreas Type 1 and type 2 More common in children with type 2
antibodies (anti-SLA/LP) disease

Anti-DNA antibodies (single stranded DNA Type 1 and type 2 Anti-dsDNA antibody is commonly
[ssDNA] and double-stranded DNA [dsDNA]) associated with systemic lupus
erythematosus

Anti-liver kidney microsomal-1 antibody Type 2 Occurs mostly in type 2 disease

(ALKM-1)

Anti-liver cytosol-1 antibody (ALC-1) Type 2 May occur in conjunction with ALKM-1

Anti-liver kidney microsomal-3 antibody Type 2 Rarely present

(ALKM-3)

Graphic 65135 Version 6.0

Autoimmune hepatitis

Liver biopsy in autoimmune hepatitis showing portal and periportal mononuclear cell
infiltration.

Courtesy of Edward L Krawitt, MD

Graphic 67909 Version 1.0

Interface hepatitis

The portal tract is expanded by a mononuclear infiltrate; the limiting plate is disrupted; and
the inflammatory process extends into the acinus. Staining by hematoxylin-eosin; original
magnification x 200.

Reproduced with permission from the American Association for the Study of Liver Diseases.
Hepatology 2002; 36:479.

Graphic 67959 Version 1.0

Plasma cell infiltrate

Plasma cells are identified by their eccentric, clock-face nucleus and pale perinuclear
cytoplasmic crescent. They are characteristic of autoimmune hepatitis, but neither
pathognomonic of the disease or required for its diagnosis. Staining by hematoxylin-eosin;
original magnification x 400.

Reproduced with permission from the American Association for the Study of Liver Diseases.
Hepatology 2002; 36:479.

Graphic 69850 Version 1.0

Primary biliary cholangitis

Low power view of liver biopsy in primary biliary cholangitis. A damaged bile duct (BD) is
visible in the center of an intense inflammatory cell reaction in an enlarged portal triad. The
bile duct appears to be the target of this inflammatory reaction.

Courtesy of Sanjiv Chopra, MD.

Graphic 54128 Version 2.0

Primary biliary cholangitis

High power view of liver biopsy in primary biliary cholangitis in the same patient showing a
marked mononuclear cell infiltrate surrounding and destroying a bile duct.

Courtesy of Sanjiv Chopra, MD.

Graphic 66904 Version 2.0

Primary sclerosing cholangitis

Medium power view of a liver biopsy in primary sclerosing cholangitis showing

mononuclear cell infiltration and charactertistic concentric fibrosis around a small bile duct.

Courtesy of Edward L Krawitt, MD.

Graphic 81040 Version 1.0

Oral treatment regimens for autoimmune hepatitis in adults [1]

Combination¶
  Prednisone only*¶, mg/day
Prednisone*, mg/day Azathioprine Δ, mg/day

Week 1 60 30 50

Week 2 40 20 50

Week 3 30 15 50

Week 4 30 15 50

Maintenance until end point 20 ◊ 10 § 50

Reasons for preference:

  Cytopenia Postmenopausal state

Thiopurine methyltransferase (TPMT) deficiency Osteoporosis

Pregnancy Brittle diabetes

Malignancy Obesity

Short course (≤6 months) Acne

  Emotional lability

Hypertension

* Orally administered prednisolone can be used in place of prednisone at the same doses. For patients with mild disease (eg, asymptomatic
patients with aminotransferase levels <10 times the upper limit of normal), lower dose prednisone monotherapy (20 mg per day) is an
alternative. 
¶ For patients on prednisone monotherapy for induction, the initial prednisone dose is typically 40 to 60 mg daily. In patients at increased risk of
side effects from glucocorticoids, a lower dose of prednisone monotherapy (eg, 30 mg daily) or combination therapy may be preferable to
prednisone monotherapy.
Δ TPMT phenotyping should be obtained before initiating azathioprine. In Europe, an azathioprine dose of 1 to 2 mg/kg/day is often used.
◊ Prednisone may be further tapered to an individual dose that maintains remission. A 10 mg/day maintenance dose may be achieved by
tapering the dose by 5 mg every week. A maintenance dose of 5 mg/day may be considered; in that case, the dose is tapered by 2.5 mg every
week. The maintenance prednisone regimen is continued until resolution of the disease, treatment failure, or drug-intolerance.
§ Prednisone may be further tapered to an individual dose that maintains remission by increments of 2.5 mg/day each week down to a dose of 5
mg/day. Dose adjustment recommendations for maintenance with either azathioprine or glucocorticoids alone are provided in the topic and
accompanying algorithm.

Reference:
1. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51:2193.

Graphic 77509 Version 10.0

Approach to induction therapy for adults with autoimmune hepatitis

* Refer to the topic on the treatment of autoimmune hepatitis for additional discussion of the indications for treatment and for details on the
treatment of special populations including patients with fulminant hepatitis, children, women who are pregnant, patients with cirrhosis,
patients with hepatitis C virus, and patients with variants of autoimmune hepatitis.
¶ Asymptomatic patient with aminotransferase levels <10 times the upper limit of normal.
Δ Refer to topic on the treatment of autoimmune hepatitis for detailed instruction on drug administration. Oral prednisolone is an alternative to
prednisone. Budesonide may also be an alternative to prednisone, particularly for patients at increased risk for glucocorticoid side effects.
Oral mercaptopurine is an alternative to azathioprine.
◊ Eg, brittle diabetes, osteoporosis, emotional lability, history of psychosis, poorly controlled hypertension.
§ In Europe, initial therapy is often with prednisone/prednisolone and oral azathioprine. If this treatment is chosen, go to Box A.
¥ Refer to the UpToDate topic on the treatment of patients with autoimmune hepatitis for details.

Graphic 99038 Version 7.0

Contributor Disclosures
Michael A Heneghan, MD, MMedSc, FRCPI Grant/Research/Clinical Trial Support: Intercept (PBC) Practice to
Policy Program. Consultant/Advisory Boards: Novartis [Autoimmune hepatitis]. Speaker's Bureau: Falk
[Autoimmune hepatitis, Primary biliary cirrhosis]. Sanjiv Chopra, MD, MACP Nothing to disclose Kristen M
Robson, MD, MBA, FACG Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

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