Overlap syndromes

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Overlap syndromes A complicated issue in
hepatology
Mohssen Nassiri Toosi,MD Associate Professor of
Intrnal Medicine Imam Khomini Hospital Tehran
University of Medical Sciences mohsen_nasiri_at_yaho
o.com
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A 57-year-old woman referred for evaluation of
abnormal serum liver tests. She reported fatigue
and slight pruritus, but was otherwise in good
general health. Six months before, elevated
serum liver tests were detected for the first
time when she went for a routine medical
examination. At presentation, serum liver tests
revealed elevated Alk.Ph and gamma-GT (3 x N),
elevated transaminases (AST 2.5 x N, ALT 5.5 x
N), and normal bilirubin. Serum AMA (13840) and
ASMA were positive, whereas ANA, LKM1 and ANCA
were all negative. Her immunoglubulins showed
elevated IgG (23.2 g/L) and IgM (3.3 g/L).
Metabolic and viral liver diseases were ruled
out. A liver biopsy disclosed an interface
hepatitis and mild portal fibrosis without
evidence of cirrhosis.
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Diagnosis of Autoimmune liver disease
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Diagnosis of Autoimmune liver disease
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Autoimmune liver disease (ALD) well-defined
entities since 50 years ago continuous spectrum
of diseases (AIH, PBC, PSC) but obscure etiology
and possible environmental triggers So, not
diagnostic hallmark
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• What are outlier, overlap, sequential syndromes?
• Heterogeneous group of autoimmune liver diseases
  (ALD) not fit into one diagnostic category
• Atypical ALD differing in some patterns ?
• Variant or outlier syndrome such as
  AMA-negative PBC
• Two coincident autoimmune diseases ?
• One distinct disease entities ?
• Transitions from one autoimmune to another ?
• Sequential syndromes
• PBC ltgt AIH and AIH ltgt PSC

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Why do we have to know overlap syndromes? Diagnos
tic implications To distinguish them from fit
autoimmune liver disease Need high index of
suspicion of gastroenterologist and pathologist
is often necessary to make the diagnosis of
overlap syndrome Clinical implications Different
natural course Therapeutic implications
Different treatment
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What are overlap syndromes? Relatively rare
disorders (low prevalence) Lack of standard
definition and diagnostic criteria and
terminology No defined diagnostic criteria
Difficulty in comparability of studies No define
prevalence No controlled trials Is not it a
complicated issue?
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What are overlap syndromes? No classic
presentation Presented with both hepatitic and
cholestatic presentation No defined diagnostic
criteria May have worse clinical outcomes
(Treatment?) Unknown natural course Probably
progressive course towards liver cirrhosis and
liver failure without treatment Treatment No
controlled trials (empiric therapy) including
anticholestatic therapy (UDCA) combined with
immunosuppressive therapy with corticosteroids
and/or azathioprine in both AIH-PBC and AIH-PSC
overlap syndromes
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Overlap syndrome classifications Outlier
syndrome such as AMA-negative PBC
(AIC) Overlap syndrome AIH-PBC overlap
syndrome The most common form in adults (10 AIH
or PBC) AIH-PSC overlap syndrome Predominantly
in children, adolescents and young adults
AIH-AIC overlap syndrome Reported in Single
cases PBC-PSC overlap syndrome Reported in
Single cases Sequential syndromes
Transitions from one ALD (PBC) to other one
(AIH) in their course (AIH-PBC overlap syndrome)
sequentially PBC ltgt AIH and AIH ltgt PSC AIH
became cholestatic and/or resistant to
immunosuppressive therapy PBC or PSC with flares
of hepatitis and/or resistant to UDCA therapy
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AIH Variants
Cholestatsis
Hepatitis
J. WOODWARD, HEPATOLOGY 2001 33, No. 4,

• Variant forms are common, and can change the
  treatment plan

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Overlap syndrome classifications
Exact classification may change as we learn more
about the pathophysiology of these
diseases. Over-and under-diagnosis of overlap
syndrome Overlap syndrome should not be
overused Typical cases of PBC with prominent
interface hepatitis typical of AIH (prominent
piecemeal necrosis, numerous plasma cells in the
inflammatory infiltrate, and lobular hepatitis,
without prominent bile duct destruction), and
liver tests favor a hepatitic process over
chronic cholestasis with low-titer
AMA-positive Overlapping vs overlap syndrome Do
not use term overlap syndrome for coexistence of
AIH and other chronic liver diseases like chronic
hepatitis C (overlapping)
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Auto-Immune Cholangiopathy AIC shares many
features with PBC Female preponderance Cholestati
c serum enzyme pattern Florid bile duct lesions
on histology Slowly progresses to fibrosis and
cirrhosis AMA negative and ANA and/or ASMA
positive Treatment response to UDCA (13-15
mg/kg daily) similar to PBC Outcome of LTX
similar to PBC AIC patients suffer from true
PBC, variants of one PBC only differing in serum
autoantibody pattern. (AMA-negative PBC)
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Overlap syndromes Usually presented with
Nonspecific symptoms fatigue, arthralgias, and
myalgias like autoimmune hepatitis with
characteristics of cholestasis Hepatitic
cholestatic laboratory changes
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic
form Overlap of two most frequent autoimmune
hepatopathies Europe prevalence 25-40/100 000,
US prevalence 17/100 000 Prevalence 8-10 among
patients with AIH or PBC Predominantly found
among adults
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic
form No common definition or uniformly accepted
diagnostic criteria Common clinical
features Female gender predominates in both AIH
(80) and PBC (90-95) Diverse Biochemical,
Serological and Histological features of both
diseases HLA type B8, DR3, or DR4 similar to
AIH Autoantibodies hallmark of AIH Good
response to corticosteroid treatment
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic
form Diagnostic criteria of AIH-PBC overlap
syndrome (Chazouillères et al, 1998) AIH (2
out of 3 criteria) (1) ALT gt 5 x ULN (2)
IgG gt 2 x ULN or a positive test for ASMA (3)
Liver biopsy showing moderate or severe
periportal or periseptal lymphocytic piecemeal
necrosis PBC (2 out of 3 criteria) (1) Alk.
Ph gt 2 x or GGT gt 5 x ULN (2) Positive test
for AMA (3) Liver biopsy specimen showing
florid bile duct lesions
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic form
IAHG scoring system Highly specific for
excluding AIH (92.3100) None of AIH/overlap
syndromes achieved a score above 15 (definite
AIH) Not sensitive in detection of AIH/overlap
syndromes 50
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic
form IAHG scoring system ANA in PBC are not a
marker of AIH-PBC overlap syndrome and often
found in PBC without further signs of AIH 20 of
AIH present without ANA, ASMA, or LKM-1 ANA is
the least specific autoantibodies for diagnosis
of chronic liver diseases (30 of elderly, 10 of
pregnant women, 30 with malignancies) Because
ANA are found in high rates in PBC patients, this
autoantibody is not considered a helpful marker
of overlap syndrome. SLA in PBC patients does
appear to correlate with overlap with AIH.
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic form
Complicating the issue Transient features of
AIH in PBC Possible role of AIH in the
deterioration of liver function in PBC patients
unless diagnosis is made early and steroid
therapy is administered. Transition of PBC to
AIH 6 mo to 13 years later with multiple flares
of hepatitis Response to UDCA may unmask
hepatitis component in overlap patients.
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AIH-PBC OVERLAP SYNDROME PBC, hepatitic
form Treatment UDCA (13-15 mg/kg daily) If
not induce adequate biochemical response in
appropriate time span (3 mo) In patients with
predominantly hepatitic serum liver tests add
corticosteroid (0.5 mg/kg daily) taper once ALT
levels show a response add azathioprine (1-1.5
mg/kg daily) as alternative in long-term
management other immunosuppressants such as
cyclosporine A for resistance cases
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AIH-PBC Overlap Syndrome (Treatment)
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(No Transcript)
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AIH Histology
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AIH-PSC OVERLAP SYNDROME Autoimmune sclerosing
cholangitis (ASC) Mainly in children,
adolescents and young adults Prevalence 1.4 8
No defined diagnostic criteria Criteria
meet diagnosis of AIH-PSC overlap
syndrome (1) Revised AIH score gt 15 (2) ANA or
ASMA present in a titre of at least
140 (3) Liver histology with piecemeal necrosis,
lymphocyte rosetting, moderate or severe
periportal or periseptal inflammation
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AIH-PSC OVERLAP SYNDROME Autoimmune sclerosing
cholangitis (ASC) Lower transaminases respect
to AIH and lower Alk.Ph respect to PSC (normal
Alk.Ph may be seen in children with this
disease) very subtle irregularities of bile
ducts, without overt stricture More commonly
suffered from IBD More often were positive for
pANCA Survival probability was better than
those with classical PSC
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AIH-PSC OVERLAP SYNDROME Autoimmune sclerosing
cholangitis (ASC) Treatment UDCA at higher
doses (gt 20 mg/kg daily) Combined with
prednisolone (0.5 mg/kg daily, tapered to 10-15
mg/d) and azathioprine 50-75 mg
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AIC-AIH OVERLAP SYNDROME AIC are AMA negative
and often ANA and/or ASMA positive Reported in
single cases Biochemical changes hepatitic and
cholestatic Histology interface hepatitis with
bile duct lesions Therapy combined treatment
with UDCA and immunosuppressors
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AIH and SLE overlapping Patients with AIH may be
at increased risk of developing systemic
connective tissue diseases (SLE). AIH may lead
to end stage liver disease Patients with SLE
with rare involvement of liver (SLE-associated
hepatitis) may be at an increased risk of
AIH. 25-50 of patients with SLE have abnormal
liver tests with associated portal inflammation
in a liver dysfunction and subclinical liver
disease. SLE may result in end stage renal
disease.
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AIH and SLE overlapping Both have features of
autoimmune disorder (polyarthralgia,
hypergammaglobulinemia, positive ANA, SMA, and
anticardiolipin antibodies) Whether to classify
the patient as having a primary liver disease
with associated autoimmune features or as having
liver disease as a manifestation of SLE. It is
important to distinguish AIH from SLE, since
complications and therapy are different. Reliance
on serologic criteria alone may lead to
diagnostic confusion.
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AIH and SLE overlapping Histological features
differentiate AIH from SLE Histology support AIH
(but do not exclude SLE) Cirrhosis or periportal
(interface) hepatitis Periportal piecemeal
necrosis associated variably with lobular
activity Rosette formation of liver cells
Inflammatory cells are mixed with plasma
cells But do not exclude SLE Histology
compatible with SLE lupus hepatitis (SLE
hepatitis) Only lobular hepatitis Inflammatory
infiltrate consists mainly of lymphocytes
Resemble to treated AIH Other Fatty
infiltration Atrophy and necrosis of the central
hepatic cells
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AIH and SLE overlapping Marker for
differentiating SLE associated hepatitis from
AIH Antiribosomal P antibody 44 with SLE
Absent in AIH SLE associate hepatitis respond
rapidly to steroid, and prognosis is generally
good. AIH could be resistance to steroid and
lead to liver cirrhosis