PATHOLOGICA 2021;113:185-193;

DOI: 10.32074/1591-951X-241

Review

Pathology of autoimmune hepatitis

Claudia Covelli1, Diana Sacchi2, Samantha Sarcognato2, Nora Cazzagon3, Federica Grillo4,
Francesca Baciorri , Daniela Fanni5, Matilde Cacciatore2, Valeria Maffeis2, Maria Guido2,6
2

1
 Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; 2 Pathology
Department Azienda ULSS 2 Marca Trevigiana, Treviso, Italy; 3 Department of Surgery, Oncology and
Gastroenterology, University of Padova, Padova, Italy; 4 Unit of Anatomic Pathology, Department of Surgical
Sciences and Integrated Diagnostics (DISC), University of Genova and Ospedale Policlinico San Martino
IRCCS, Genoa, Italy; 5 Pathology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy;
6
 Department of Medicine-DIMED, University of Padova, Padova, Italy

Summary
Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which
mainly affects women. It is characterized by hypergammaglobulinemia, circulating autoan-
tibodies, interface hepatitis on liver histology and a favourable response to immunosup-
pression. The putative mechanism for the development of autoimmune hepatitis is thought
to be the interaction between genetic predisposition, environmental triggers and failure of
the native immune system.
AIH still remains a major diagnostic and therapeutic challenge, mainly because it is a
very heterogeneous disease. Prompt and timely diagnosis is crucial since, if left untreated,
AIH has a high mortality rate. Histological demonstration of hepatitis is required for the
diagnosis of AIH and, therefore, liver biopsy is mandatory in the initial diagnostic work-up,
before treatment. In this review, we summarize the histological features of AIH with the
main aim of highlighting the most important clinical-pathological hallmarks useful in the
routine diagnostic practice.

Received and accepted: December 14, 2020 Key words: autoimmune hepatitis, histology, liver biopsy, interface hepatitis

Correspondence
Claudia Covelli
Fondazione IRCCS Casa Sollievo della Soffe-
Introduction
renza, 71013, San Giovanni Rotondo, Italy
Tel.:+39 0882 835505 Autoimmune hepatitis (AIH) is a chronic progressive liver disease of un-
Fax: +39 0882 410411 known etiology. The pathogenesis of AIH is complex and involves inter-
E-mail: [email protected] actions between tolerant liver, environmental triggers, and dysregulated
Conflict of interest immunological mechanisms. Genetic factors influence an individual’s
The Authors declare no conflict of interest. susceptibility to developing AIH 1,2.
Originally considered a disease of young women, AIH may also occur
How to cite this article: Covelli C, Sacchi D, in children and the elderly (about 30% of cases occur over 60 years of
Sarcognato S, et al. Pathology of autoimmune age). Both sexes (about 30% are males) and all ethnic groups are in-
hepatitis. Pathologica 2021;113:185-193.
https://doi.org/10.32074/1591-951X-241 volved, and recent epidemiological studies indicate an increasing trend
in AIH prevalence worldwide, especially in men 3. If untreated, AIH leads
© Copyright by Società Italiana di Anatomia Pato- to cirrhosis and associated complications, with a small (1-2% per year)
logica e Citopatologia Diagnostica, Divisione Itali-
ana della International Academy of Pathology but significant risk of hepatocellular carcinoma development 4,5. Charac-
teristic laboratory features include hypergammaglobulinemia, with ele-
OPEN ACCESS vation of immunoglobulin G (IgG) in the majority of cases, and presence
of non-organ specific autoantibodies 6.
This is an open access journal distributed in accordance
with the CC-BY-NC-ND (Creative Commons Attribution- Diagnosis is often challenging, since no single feature is reliable. There-
NonCommercial-NoDerivatives 4.0 International) license: the fore, careful clinical-pathological integration is required for the exclusion
work can be used by mentioning the author and the license,
but only for non-commercial purposes and only in the original of other causes of liver disease and a confident diagnosis of AIH. An
version. For further information: https://creativecommons. early diagnosis is, however, critical for timely initiation of life-saving im-
org/licenses/by-nc-nd/4.0/deed.en
munosuppressive therapy.
186 C. Covelli et al.

Current guidelines recommend liver biopsy as a pre- also in patients with Non-alcoholic fatty liver disease
requisite for the diagnosis of AIH 1. Liver biopsy is also (NAFLD): in a multicenter study in United States, sig-
useful for treatment management, to determine dis- nificant titers of autoantibodies were detectable in
ease severity and distinguish acute vs. chronic pres- 21% of adult NAFLD patients, with no association with
entation. advanced histological features or presence of steato-
This review focuses on the current role of liver biop- hepatitis 21.
sy and describes characteristic histological lesions The spectrum of clinical presentation of AIH ranges
which contribute to AIH diagnosis. from asymptomatic elevation of serum liver enzymes,
to fulminant hepatitis. The most common clinical pres-
entation is characterized by a slow disease onset and
Overview on laboratory and clinical progression with non-specific complaints such as fa-
features tigue and malaise, which explains why AIH is in ad-
vanced stages of fibrosis at the time of diagnosis in
Liver function tests typically show a hepatocellular around a third of patients. Acute onset of AIH occurs in
pattern of injury, with an increase in aminotransferas- about one third of patients. It may represent an acute
es, that can be mildly elevated or up to 50 times the exacerbation of unrecognized AIH with pathological
upper normal value. Alanine aminotransferase (ALT) evidence of chronic hepatitis or a genuine newly de-
is typically higher than Aspartate aminotransferase veloped acute AIH, without previous clinical-patholog-
(AST). Cholestatic enzymes are usually normal or ical findings of chronic liver disease. Acute onset is
mildly elevated unless there is an overlap with primary clinically indistinguishable from acute hepatitis of oth-
biliary cholangitis (PBC) or primary sclerosing chol- er causes  22-24. Moreover, in some of these patients,
angitis (PSC)  7-13. Increase in serum globulins (serum IgG levels may be within the normal range and ANA
γ-globulin or IgG level) is evident in 90% of patients. and/or SMA may be negative at the first screening 10,25-
This prevalence seems to be lower in patients with 28
, thus leading to a challenging diagnosis.
an acute onset, among which a proportion of cases,
ranging from 25 to 39%, has normal IgG levels  14,15.
IgA and IgM are usually normal, and their increased The role of liver biopsy in AIH
levels should prompt the exclusion of different etiolo-
gies, such as alcoholic steatohepatitis and PBC, re- Liver biopsy is recommended by the American Asso-
spectively1. ciation for the Study of Liver diseases (AASLD) and
Circulating autoantibodies are considered the hall- the European Association for the Study of the Liver
mark of AIH and have been used to subclassify AIH (EASL) guidelines to help establish the diagnosis, ex-
into type 1, or classic autoimmune hepatitis, and type clude other causes of liver disease, and guide treat-
2. Type 1 AIH is defined by the presence of antinuclear ment choice 1,26.
antibody (ANA) and/or anti-smooth muscle antibody The diagnostic criteria for AIH have been codified in
(ASMA). Antibody titers more than 1:40 are consid- 1993, revised in 1999 by the International Autoimmune
ered significant in adults. Type 2 AIH is less common Hepatitis Group (IAHG) 7,8 and more recently simplified
and mainly affects pediatric patients. It is character- for clinical use (Table I)  9. In the simplified system, as
ized by the presence of antibodies against liver/kid- in the previous ones, liver histology is included among
ney microsomes (LKM1) and/or liver cytosol antigen the parameters required to confirm clinical diagnosis
(LC1). The validity of such subclassification in clinical of AIH. Indeed, the system comprises four parame-
practice has been questioned  1. Autoantibodies may ters: autoantibodies, serum IgG, results of viral hep-
not be detected, particularly in cases of severe acute atitis work-up and AIH histology, which is coded as
presentation (autoantibody negative AIH)16. Notewor- absent, typical or compatible (Table II).
thy, is that the presence of autoantibodies always Once a diagnosis of AIH is made, liver biopsy is the
needs careful interpretation, as they can be found in gold standard for grading and staging AIH and pro-
healthy patients as well as in other, non-autoimmune, vides crucial information for patient management and
hepatopathies. In asymptomatic blood donors, ANA treatment decisions29. Persistence of any degree of in-
prevalence of any titer has been found to vary be- flammation, particularly interface hepatitis, and pres-
tween 4% and 26%, with nearly 15% of cases positive ence of plasma cells in biopsy samples taken under
at a 1:40 dilution, and up to 10% of pregnant women treatment, are strong predictors of AIH- relapse if im-
are ANA positive 17-19. ANA are found in approximately munosuppression is stopped.
5% of individuals with HCV, showing titers more than Liver biopsy is particularly important for the differen-
1:100  20. The presence of autoantibodies is common tial diagnosis of AIH, as it may lead to an alternative
AUTOIMMUNE HEPATITIS 187

Table I. Simplified diagnostic criteria for autoimmune hepatitis (from Hennes et al., 2009, adapt.) 9.
Feature Cutoff Points
ANA or SMA ≥ 1:40 1
ANA or SMA ≥ 1:80  2*
or LKM ≥ 1:40
or SLA Positive  
IgG > Upper normal limit 1
  > 1.10 times upper normal limit 2
Liver histology (evidence of hepatitis is a necessary condition) Compatible with AIH 1
Typical AIH 2
Absence of viral hepatitis Yes 2
Interpretation of aggregated scores: ≥ 6: probable AIH; ≥ 7: definite AIH
*Addition of points achieved for all autoantibodies (maximum, 2 points).
ANA, Antinuclear antibody; SMA, smooth muscle antibody; LKM, liver-kidney microsomal antibody; SLA/LP, soluble liver antigen/liver
pancreas antibody, AIH, autoimmune hepatitis.

Table II. Histological categories for grading histology in the simplified system for autoimmune hepatitis (from Hennes et al.,
2009, adapt.) 9.
Histological Categories Morphological features
Typical for AIH Interface hepatitis, with lymphocytic/lymphoplasmocytic infiltrate in portal tracts extending into the lobule
Emperipolesis
Hepatic rosette formation
(All three features have to be present)
Compatible with AIH Chronic hepatitis pattern of injury with lymphocytic infiltration
Lack of all the features considered typical
Atypical for AIH Signs suggestive of other diagnosis
AIH, Autoimmune hepatitis.

etiology  30. Moreover, it may identify possible concur-

rent disorders, especially fatty liver disease, consid-
ering the epidemic proportion of risk factors for the
metabolic syndrome. Finally, liver biopsy is consid-
ered mandatory in cases of AIH with overlapping fea-
tures of autoimmune biliary disorders. Liver biopsy at
presentation should be performed prior to beginning
treatment since immunosuppression may rapidly clear
inflammation on liver biopsy, with the risk of a “false
negative” diagnosis.

Histopathology of AIH
Despite the pivotal role of liver biopsy for diagnosis, no
morphological feature is pathognomonic of AIH. How- Figure 1. Severe portal inflammation, mainly composed of
ever, there is a characteristic picture in many patients lymphocytes, and interface hepatitis. Several necro-inflam-
before treatment. The typical aspect of AIH is that of a matory foci are visible in the adjacent lobular parenchyma
severe chronic hepatitis with intense portal and lobu- (H&E; original magnification 40x).
lar inflammation, severe interface hepatitis, and much
hepatocyte damage.
Portal inflammation is composed of mononuclear
cells, mainly lymphocytes, with a variable amount of make a diagnosis since they are rare/absent in about
plasma cells. Some eosinophils and neutrophils may one third of cases. However, detection of plasma cells
be seen (Fig. 1). Plasma cells are considered typical in clusters (Fig.  2) is highly suggestive of AIH. In a
for AIH, but they are neither sufficient nor necessary to recent critical appraisal concerning the histological
188 C. Covelli et al.

Figure 2. A cluster of plasma cells is visible close to the Figure 4. Ductular reaction (arrows) around an inflamed por-
portal tract (H&E; original magnification 40x). tal tract (immunostain for CK7; original magnification 20x).

features of AIH  31, the presence of plasma cell clus- ally more prominent compared to interface hepatitis
ters (defined as a collection of ≥  5 plasma cells) in of other causes  33. According to the 2008 simplified
the lobule was the most sensitive diagnostic finding. criteria, the presence of interface hepatitis, even in the
Immunohistochemical stains for multiple myeloma-1 absence of all the other typical features, is in agree-
(MUM-1) or CD38 may help to highlight number and ment with the diagnosis of AIH 9.
distribution pattern of plasma cells (Fig. 3) 32. Severe portal and interface hepatitis are usually asso-
Although not specific, interface hepatitis is considered ciated with ductular reaction (DR). It consists of bile
the hallmark of AIH. It is characterized by the exten- ductules with poorly defined lumina at the portal-pa-
sion of portal inflammation beyond the limiting plate renchymal interface, arranged in anastomosing cords,
into the adjacent lobule with damage and progres- and lined by small CK7-positive cells (Fig. 4). Ductular
sive loss of hepatocytes at the portal-lobular interface reaction is a regenerative phenomenon, which repre-
(Fig. 1). It is observed in up to 98% of AIH and is usu- sents proliferation and bidirectional differentiation of
facultative hepatic stem cells in a variety of acute and
chronic liver diseases. In AIH, DR correlates with the
severity of portal-periportal inflammation, as in other
liver diseases 34.
Lobular changes are dominated by necro-inflamma-
tory damage, ranging from spotty to confluent ne-
crosis. Apoptotic bodies are commonly seen. Multi-
ple necro-inflammatory foci may be associated with
hepatocyte ballooning and sinusoidal inflammation,
giving the appearance of lobular disarray (Fig.  5)
which resembles what is seen in patients with acute
viral hepatitis. Bridging necrosis (portal to portal and
portal to central) is not uncommon and may repre-
sent the deep extension of interface hepatitis into the
lobules. Confluent necrosis and inflammation may be
seen in perivenular areas. In most cases, it is associ-
ated with the typical portal peri-portal inflammation.
Figure 3. Immunostain with CD38 helps in identifying a However, there are few patients affected by AIH in
cluster of plasma cells. This is a pediatric case with mild whom the major feature at presentation is the isolated
portal inflammation within an otherwise typical clinical pre- centrilobular necro-inflammation, with spared portal
sentation (original magnification 20x). tract (Fig.  6). This is thought to be an early feature
of AIH that precedes overt portal-dominant (classic)
AUTOIMMUNE HEPATITIS 189

Figure 5. Several foci of “spotty” necrosis, giving the ap- Figure 7. Typical hepatocyte rosette, representing a regen-
pearance of lobular disarray (H&E; original magnification erative phenomenon in a heavily inflamed liver (H&E; origi-
20x). nal magnification 60x).

Figure 6. Centrilobular necro-inflammation in a case of true Figure 8. Emperipolesis (arrow) appears as a lymphocyte
acute AIH presentation. Portal tracts were completely spared within the hepatocyte cytoplasm (H&E; original magnifica-
in this case. Toxic damage is the main differential diagnosis tion 60x).
(H&E; original magnification 40x).

represent a regenerative response to the necro-in-

AIH  35. Indeed, this pattern of necrosis is commonly flammatory damage. Emperipolesis is characterized
seen in patients with acute disease onset  36. In rare by the presence of a mononucleated inflammatory cell
cases, a massive-panlobular necrosis may occur, (lymphocyte or plasma cell) within the cytoplasm of
leading to liver failure. hepatocytes and it is reported in 65-78% of AIH cas-
Much emphasis has been given to the presence of es. Emperipolesis and rosette formation have been
rosettes (Fig. 7) and emperipolesis (Fig. 8) as classic considered better histological predictors of AIH, when
changes of AIH. Indeed, they have been considered compared to plasma cells and interface hepatitis  37.
as typical histological AIH-features in the 2008 simpli- However, such superiority is still controversial and
fied scoring system for adults and they are a required it has been shown that emperipolesis is associated
item to get score 2 (Tab. II)9. Rosettes are defined as with the severity of activity rather than the etiology 38.
hepatocytes arranged around a central lumen and Moreover, emperipolesis is difficult to be reliably as-
190 C. Covelli et al.

sessed in routine practice with light microscopy, and it

is best evaluated by electron microscopy.
Bile duct injury can be identified in up to 83% of AIH
patients  34,39,40, often in a PBC-like pattern, even af-
ter the exclusion of an overlap syndrome. Therefore,
some degree of biliary involvement in AIH does not
necessarily lead to a change in diagnosis! A major
problem is that how much bile duct damage is diag-
nostic of biliary disease is still not established. In rou-
tine practice, it is reasonable to suggest a possible
concomitant biliary disease when bile duct damage is
seen in the majority of portal tracts. The bile ducts are
not the target of damage in AIH, and probably their in-
flammatory damage represents collateral injury of the
conspicuous inflammatory process, as demonstrated
by their subsiding after immunosuppressive therapy 34. Figure 9. Giant cell transformation in autoimmune hepatitis
Therefore, an evident bile duct destruction (ductope- (H&E; original magnification 40x).
nia) is not a feature of AIH and warrants consideration
of primary biliary cholangitis. Moreover, copper-asso-
ciated protein accumulation and/or CK7-positive peri-
portal hepatocytes are recognized features of chronic sociated protein/CK7 stains, and demonstrated high-
cholestasis and their presence should prompt to con- er sensitivity for the diagnosis of AIH. These results
sider an alternative diagnosis or an overlap condi- should be validated in prospective series.
tion. It is noteworthy to highlight that these features Cholestasis is usually not observed in AIH, but a mild
of chronic cholestasis no longer have their diagnostic degree may be seen in cases with marked lobular in-
value when severe fibrosis or cirrhosis is present. In flammation.
such cases, nonspecific copper-associated protein Giant cell transformation may be rarely seen in adults
accumulation and CK7 positivity can be seen, not- with AIH (Fig. 9). This represents an unusual regener-
withstanding the etiology. The practical value of taking ative or degenerative hepatocyte reaction to various
in consideration results of copper-associated protein injuries, and it is a common response in the newborn
and CK7 stains in the histological features has been liver diseases. Post infantile giant cell hepatitis is a
evaluated in a recent study 41. In this study, histological rare, non-specific subtype of hepatitis, which can be
criteria codified in the 2008 simplified score proposed seen in a wide variety of inflammatory and cholestatic
by the IAHG (Tab. II) were reviewed and new param- liver diseases, among which AIH represents the most
eters were proposed. The new criteria (Tab. III) were common cause 42.
based on interface/lobular inflammatory activity, num- Recently, PAS positive-diastase resistant hyaline
ber of plasma cells, biliary features, and copper-as- droplets in Kupffer cells, resembling Russell bodies of

Table III. Proposed criteria for the histologic scoring of autoimmune hepatitis (from Balitzer et al., 2017, adapt.) 41.
Histologic score Morphological features
Score 0 Features not observed in AIH (e.g. florid duct lesion, bile duct loss, or copper/CK7 positivity, if applicable*)
Score 1** 1. Hepatitis with mild or moderate necro-inflammatory activity, with any of the following:
(a) Ishak A2 (mild/moderate interface activity)
(b) Ishak B1 (focal confluent necrosis)
(c) Ishak C2 (2-4 foci of lobular activity x 10)
2. CK7 and copper stains negative (if applicable*)
Score 2 Hepatitic pattern with any of the following:
1. Plasma cells numerous or in clusters
2. High necroinflammatory activity with at least one of the following:
(a) Ishak score A3 or higher (at least moderate interface activity)
(b) Ishak B2 or higher (confluent necrosis in zone 3 or beyond)
(c) Ishak C3 or higher (5 or more foci of lobular activity x 10)
*Applicable only in cases without any bridging fibrosis.
**Both 1 and 2 are necessary for histologic score 1, except in cases with acute presentation.
AIH, Autoimmune hepatitis.
AUTOIMMUNE HEPATITIS 191

plasma cells, have been described as specific feature tibodies associated to AIH are frequently found dur-
in AIH  43. However, little information is known on this ing acute HEV infection. Clinicians and pathologists
and, therefore, it is still controversial to consider this should be aware of this and always exclude HEV in-
feature as a reliable histological sign of AIH. fection before diagnosing and treating AIH, as immu-
nosuppression can lead to chronic HEV disease  47. A
broad and highly variable spectrum, related to the clin-
Histological grading and staging ical context, of histopathological findings can be ob-
served in livers of patients infected with HEV, making
Since no specific grading and staging systems for AIH the histopathological diagnosis very challenging  48.
have been developed, grading of the inflammatory Immunohistochemistry for HEV pORF2 protein is a
activity and staging of the fibrosis can be performed helpful histopathological tool 49.
borrowing the systems used for chronic viral hepatitis
such as the Scheuer  44, Ishak  45, and Metavir  46 sys- Drug induced liver injury
tems. This is reasonable since both chronic viral hepa- Drug induced liver injury (DILI) represents the most
titis and AIH have a similar pattern of necro-inflamma- challenging differential diagnosis, not only because it
tory damage and share the morphogenesis of fibrosis. can mimic the clinical, biochemical, serological and
The choice of grading/staging system is arbitrary and morphological phenotype of AIH (AIH-like-DILI), but
depends on the pathologist’s preference and tradition, also because drugs may trigger latent or induce a de
and on agreement with the local hepatologists. As novo AIH  50-53. The distinction between DILI and AIH
in viral hepatitis, it is important to clearly specify the by histology can be extremely difficult (sometimes
name of the used system in the final histological re- impossible), due to the absence of histological fea-
port, without which the scores lose their significance. tures pathognomonic of either DILI or AIH. Severe
Patients often consult different clinicians; therefore, portal plasma cell-rich inflammation, prominent in-
this information is crucial for a proper interpretation of tralobular plasmacells and eosinophils, rosette forma-
the histological report. tion, absence of cholestasis and presence of fibrosis
Grading and staging have prognostic and therapeu- have been suggested as features that are in favor of
tic implications and are required, since ALT values do the diagnosis of AIH  54. The absence of cirrhosis, or
not properly correlate with the disease severity and advanced fibrosis, at presentation mainly suggests
non-invasive tests for the assessment of fibrosis have AIH-like DILI. A detailed clinical information is crucial,
not been fully validated in AIH 1. and the patient’s history should focus on recent expo-
According to EASL guidelines, treatment withdrawl is sure to drugs that can induce AIH-DILI. Fortunately,
considered when biochemical remission is reached, AIH-DILI usually responds to high doses of steroids as
but it requires histological remission, defined as nor- severe AIH usually does, but differently from true AIH
mal histology or minimal hepatitis (Hepatitis Activity that always relapses, steroid treatment can be discon-
Index score/HAI < 4 or equivalent) 1. tinued without a DILI relapse 1.

Primary biliary cholangitis

Differential diagnosis Differential diagnosis between AIH and classical PBC
is not difficult. PBC is a chronic cholestatic syndrome
Since the pattern of injury and typical features of AIH showing a distinctive serological profile of positive an-
are non-specific, the spectrum of histological differen- timitochondrial antibodies (AMAs), often associated
tial diagnosis is very broad and an accurate integra- with intense pruritus. Increase in serum IgM and alka-
tion with all clinical and laboratory features is required line phosphatase (ALP) levels with a normal or slightly
to reach a correct diagnosis. elevated bilirubin level and only a mild elevation of ALT
is typically observed at earlier stages. PBC may show
Viral hepatitis moderate to severe portal inflammatory infiltrate with
All acute and chronic viral hepatitis can appear similar many plasma cells and even interface hepatitis, but
to AIH and neither plasma cells nor the other histolog- prominent florid duct lesions and bile duct loss (not
ic findings, which are more typically seen in AIH, are seen in AIH) are typically found in liver biopsies. More-
sensitive or specific enough. However, viral infection over, PBC does not show a hepatitic pattern of lobular
can be easily excluded by serological testing which injury, which is common in AIH. AMA-negative PBC
are mandatory in all patients in whom a diagnosis of may occur in about 10% of cases, but the histological
AIH is considered. A special attention should be paid scenario does not differ from the typical AMA-positive
to hepatitis E virus (HEV), since non-specific autoan- PBC. As already highlighted, stains for copper-asso-
192 C. Covelli et al.

ciated protein and/or CK7 may be useful to recognize 6

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