REVIEW

Overlap Syndromes
Albert J. Czaja M.D.

Patients with autoimmune hepatitis (AIH) may have fea- Diagnosis

tures of primary biliary cirrhosis (PBC) or primary sclerosing
cholangitis (PSC).1,2 Similarly, patients with classic features of
PBC or PSC may have features of AIH. The diagnostic boun-
daries between these diseases are porous, and clinical, labora-
tory, and histological features can be shared (Fig. 1). AIH has
the least disease-specific clinical findings, and it is the most
common component of the overlap syndromes. In contrast,
PBC and PSC have the most disease-specific clinical features,
and they rarely constitute an overlap syndrome. The overlap
syndromes occur in 3% to 17% of patients with autoimmune
liver disease, and the frequencies of each overlap combination
(outside PBC and PSC) are similar, regardless of the predomi-
nant disease component.1,2
Pathogenic Hypotheses
The overlap syndromes may simply be variants or atypical
forms of classic diseases. The features of AIH are not
disease-specific, and their occurrence in patients with PBC
or PSC may simply denote an inflammatory form of the
classic disease.1,2 The overlap syndromes could be transi-
tion stages in the evolution of classic diseases. The observed
transitions between the diseases may exemplify these
diverse evolutionary pathways.1-3 The overlap syndromes
could represent concurrent diseases in the same individual.
This hypothesis is possible but unlikely because two dis-
eases with highly specific features, PBC and PSC, rarely
coexist.1-3 Lastly, the overlap syndromes could be separate
pathological entities with their own distinctive pathogenic
mechanisms and clinical outcomes.1,2
The predominant disease component determines the
nature and behavior of the overlap syndrome.4 An overlap
syndrome should be suspected in all patients with predomi-
nant manifestations of AIH, PBC, or PSC who have atypical
findings (Fig. 2). Patients with laboratory, serological, and
histological features that denote inflammatory or cholestatic
changes outside the classic phenotype, individuals refractory
to conventional treatment regimens, and patients with con-
current inflammatory bowel disease are prime candidates
for an overlap syndrome.1,2
The Paris criteria provide an objective basis for making
the diagnosis of the overlap syndrome of AIH and PBC5
(Table 1). The Paris criteria have a sensitivity of 92% and a
specificity of 97% with clinical judgment as the gold stand-
ard.1,2 These criteria have been endorsed by the European
Association for the Study of the Liver (EASL) with the stip-
ulation that all patients have interface hepatitis on histologi-
cal examination.4,6 Patients outside the Paris criteria may
have less severe forms of the AIH-PBC overlap syndrome,
and they should not be excluded from the diagnosis.1,2
The diagnosis of the overlap syndrome of AIH and PSC
requires features of AIH, an absence of anti-mitochondrial
antibodies (AMAs), and an abnormal cholangiogram with
focal bile duct strictures and dilations typical of PSC1,2
(Table 1). Patients may also have features of AIH and a cho-
lestatic phenotype in the absence of classic features of PSC
or PBC1,2 (Table 1). These patients lack AMAs, and they
have a normal cholangiogram. The histological findings of

Abbreviations: AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AMA, anti-mito-
chondrial antibody; ANA, anti-nuclear antibody; AP, alkaline phosphatase; AST, aspartate aminotransferase; CUC, chronic ulcerative colitis; EASL, European
Association for the Study of the Liver; ERC; endoscopic retrograde cholangiography; GGT, gamma-glutamyltransferase; IgG, immunoglobulin G; MRC, or
magnetic resonance cholangiography; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibody; UDCA, ursodeoxy-
cholic acid; ULN, upper limit of normal.
From the Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
The author reviewed the literature, selected the pertinent studies, drafted the manuscript, created the figures, critically reviewed and revised its content,
typed the document, approved the final version, and submitted the manuscript for review. He received no writing or research assistance.
Potential conflict of interest: This review did not receive financial support from a funding agency or institution, and the author has no conflict of interests to
declare.
View this article online at wileyonlinelibrary.com
C 2013 by the American Association for the Study of Liver Diseases
V

doi: 10.1002/cld.294

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 R E V I E W Overlap Syndromes Czaja

bile duct injury or loss suggest an overlap syndrome, and

they may have AMA-negative PBC or small-duct PSC.1,2
The various scoring systems for AIH should not be used
to diagnose the overlap syndromes.4 These systems were
not designed for this application, and their ability to dem-
onstrate AIH in patients with cholestatic liver disease is
poor (sensitivity 5 50%-62%). The liver biopsy examination
is the strongest independent predictor of an overlap syn-
drome, and clinical judgment is the gold standard for the
diagnosis.7

Treatment and Outcomes

FIGURE 1 Porous diagnostic boundaries and commonly shared features of
AIH, PBC, and PSC. ANAs and abnormalities in the serum levels of AP, GGT,
and gamma-globulin are among the laboratory changes that are commonly
shared between the diseases. Similarly, interface hepatitis, plasma cell infiltra-
tion, and cholangitis are frequently shared histological changes. PBC and PSC
have highly disease-specific features that rarely overlap.
The treatment of the overlap syndrome of AIH and PBC
is influenced by the relative strength of each disease compo-
nent, and all regimens are empirical.1,2,4 The medications
used to treat these syndromes are unlicensed for these clini-
cal applications. Corticosteroids in combination with urso-
deoxycholic acid (UDCA; 13–15 mg/kg daily) have been
recommended for patients who satisfy the Paris criteria4,6
(Table 2). This regimen has significantly improved labora-
tory findings, and it has prevented progressive hepatic fibro-
sis.5 Combination therapy has also been superior to

FIGURE 2 Diagnostic algorithm for the overlap syndromes. Patients with AIH, PBC, or PSC who have atypical hepatitic or cholestatic laboratory or histologic
findings have concurrent inflammatory bowel disease, or do not respond to conventional treatments should undergo ERC or MRC. The cholangiographic findings can
then be used in conjunction with the presence or absence of AMAs to distinguish between AIH and PBC (AIH-PBC), AIH and an indeterminate cholestatic disease
(AIH--indeterminate cholestasis), PBC and PSC (PBC-PSC), and AIH and PSC (AIH-PSC) in patients with the overlap syndromes. The clinical findings can also be
used to distinguish the predominant disease component in each overlap syndrome. The Paris criteria tend to define a syndrome with equivalent AIH and PBC compo-
nents (AIH 5 PBC). The other overlap syndromes of AIH and PBC can be either AIH-predominant (AIH > PBC) or PBC-predominant (PBC > AIH). Similarly, patients
with the overlap syndrome of AIH and PSC (AIH-PSC) can be either AIH-predominant (AIH > PSC) or PSC-predominant (PSC > AIH).

3 Clinical Liver Disease, Vol 3, No 1, January 2014 An Official Learning Resource of AASLD
 R E V I E W Overlap Syndromes Czaja

TABLE 1 Diagnostic Features of the Overlap Syndromes

Overlap Syndrome Laboratory Features Histological Findings

4-6
AIH-PBC (Paris criteria modified by EASL) AIH features (1 of 2): Interface hepatitis (required)
ALT  5-fold ULN
IgG  2-fold ULN or SMAs
PBC features (2 of 3, including histology): Florid duct lesions
AP  2-fold ULN or GGT  5-fold ULN
AMAs
AIH-PBC (outside Paris criteria)1,2,8 Predominant AST/ALT abnormalities Interface hepatitis and bile duct injury or loss (lym-
phocytic, pleomorphic, or destructive cholangitis)
AP < 2-fold ULN and GGT < 5-fold ULN
Hypergammaglobulinemia (IgG > ULN)
ANAs or SMAs
AMAs
AIH-PSC4,6,10 AIH features Interface hepatitis and portal edema, fibrosis, or duc-
topenia (obliterative fibrous cholangitis possible but
rare)
AMAs absent
Focal strictures and dilations by ERC or MRC
AIH--indeterminate cholestasis (possibly AIH features Interface hepatitis and bile duct injury or loss
AMA-negative PBC or AIH--small-duct PSC)1,2,8
AP  2-fold ULN or GGT > ULN
AMAs absent
Normal ERC or MRC

TABLE 2 Treatment Options for the Overlap Syndromes

Overlap Syndrome Predominant Component Treatment Regimen Outcomes

AIH-PBC PBC and AIH equivalent Corticosteroids and UDCA* Improves serum AP, GGT, and ALT5
by Paris criteria
Prevents progressive hepatic fibrosis5
Better than UDCA or corticosteroids
alone5
AIH-PBC PBC UDCA Same laboratory improvements found
for classic PBC9
AIH-PBC AIH Corticosteroids alone or with Laboratory and histological improve-
azathioprine ments as frequently as for classic
AIH (improvement, 81% versus 86%;
treatment failure, 14% versus
9%)1,2,8
AIH-PSC AIH or PBC Corticosteroids and UDCA† Variable responses (20%-100%) possi-
bly related to level of cholestasis1,2
AIH--indeterminate AIH or cholestatic Empirical and unendorsed Uncertain response1,2
cholestasis (including phenotype
AMA-negative PBC and
small-duct PSC)
Directed by predominant Anecdotal experience1,2
component: corticosteroids,
UDCA, or corticosteroids
and UDCA

*Endorsed by the EASL.4,6

†
Endorsed by the EASL and the AASLD.4,6,10

treatment with corticosteroids or UDCA alone in a small
subgroup analysis,5 and it has been endorsed by the EASL
with a recommendation that is not strongly evidence-
based.4,6 Treatment with corticosteroids or UDCA alone has
been effective in patients whose primary disease of AIH or
PBC has heavily outweighed the overlap component8,9
(Table 2).
Combination therapy with corticosteroids and UDCA has
been endorsed by the EASL4,6 and the American Association
for the Study of Liver Diseases (AASLD)4,10 for the overlap syn-
drome of AIH and PSC with a recommendation that is also not
strongly evidence-based (Table 2). Combination therapy has
been effective in 20% to 100% of patients, and the variability
of the responses probably reflects differences in diagnostic cri-
teria and dosing schedules.1,2,8 Corticosteroids alone have had
inconsistent results, mycophenolate mofetil has been ineffec-
tive, and calcineurin inhibitors have been rarely used.1,2,4
Patients with mixed syndromes of AIH and AMA-negative PBC
or small-duct PSC lack a recommended strategy, and treat-
ments include corticosteroids, UDCA (13–15 mg/kg daily), or
both; this depends on the predominant clinical component
and the treatment response1,2,8 (Table 2).

4 Clinical Liver Disease, Vol 3, No 1, January 2014 An Official Learning Resource of AASLD
 R E V I E W
Overview
Overlap syndromes are clinical descriptions, and their
principal clinical value is that they respond variably to con-
ventional treatment strategies.1,2,4,8 Diagnostic criteria and
treatment algorithms have not been codified. Off-label com-
bination therapy with corticosteroids and UDCA has been
recommended for most patients on the basis of weak clini-
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5 Clinical Liver Disease, Vol 3, No 1, January 2014
Overlap Syndromes Czaja
cal evidence.6,10 Treatments can be individualized, and they
should be directed at the predominant disease compo-
nent.1,2,4,8 n
CORRESPONDENCE
Albert J. Czaja, M.D., Division of Gastroenterology and Hepatology, Mayo
Clinic College of Medicine, 200 First Street Southwest, Rochester, MN
55905. E-mail: czaja.albert@mayo.edu.
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