DOI: 10.7860/JCDR/2017/25193.

10242
Case Report

Autoimmune Hepatitis –
Internal Medicine Section

Primary Biliary Cirrhosis

Overlap Syndrome
INDIRA BAIRY1, ANUPAM BERWAL2, SHUBHA SESHADRI3

ABSTRACT
Autoimmune Hepatitis (AIH) and Primary Biliary Cirrhosis (PBC) are important immune mediated liver diseases. They are usually differentiated
based on clinical, biochemical, serological and histological parameters. The presence of autoantibodies, clinical and serological findings
can sometimes occur in different combinations leading to overlap syndromes, which is rare. Early recognition of such overlap syndromes
is clinically significant from treatment point of view. Here, we report a case of AIH-PBC overlap syndrome with a brief review of literature
on overlap syndromes.
Keywords: Antinuclear antibodies, Antimitochondrial antibodies, Immunofluorescence, Primary sclerosing cholangitis

CASE REPORT for which patient was receiving tablet pantoprazole 40  mg twice
A 50-year-old female was admitted to the medicine department daily. The clinical, biochemical, serological and histopathological
with complaint of hematemesis for past 10  days. Her personal findings were suggestive of direct hyperbilirubinemia with raised
medical history revealed that she is a known case of hypertension levels of ALP with hyperglobulinemia, strongly AMA-M2 and ANA
since five years and diabetes mellitus since six  months and on positive, histopathological examination was compatible with PBC.
regular medications (β-blocker and insulin). There was no history A diagnosis of PBC-AIH overlap syndrome was made depending
of alcohol consumption, drug abuse or relevant family history of on these findings.
liver disease. The patient was treated by Ursodeoxycholic Acid (UDCA) – 150 mg
On physical examination, vitals were within normal limits. Her skin BD and her condition improved gradually. Then, the patient reported
and sclera were icteric. On examination of abdomen, a nontender after six months and her condition was still the same.
hepatomegaly was evident 6 cm below the right costal margin and
splenomegaly, palpable 3 cm below the left costal margin. Other DISCUSSION
systemic examinations such as of the central nervous system, The major autoimmune disorders of the liver are AIH, PBC and
cardiovascular system and respiratory system were found to be Primary Sclerosing Cholangitis (PSC); variants are called overlap
normal. syndromes. The overlap syndromes occur in 3%-7% of patients
Laboratory tests showed: Serum bilirubin: Total - 3.4 mg/ with autoimmune liver disease and the frequency of each overlap
dl, direct - 2.7 mg/dl, indirect - 0.7 mg/dl, alkaline phosphatase combination (outside PBC and PSC) are similar, regardless of the
(ALP) - 541 IU/L (normal <130 IU/L), alanine aminotransferase predominant disease component [1]. AIH and PBC both are the
- 49 IU/L (normal <40 IU/L), aspartate aminotransferase - 137 most common hepatopathies. Although the mechanism of both
IU/L (normal <40 IU/L), international normalized ratio was 1.01, is same, they can be differentiated based on clinical features,
erythrocyte sedimentation rate - 60 mm/h, serum albumin - 4.8 biochemical tests, serological markers, histopathology, course of
g%, immunoglobulin G (IgG) level - 4.8 g/dl, hemoglobin - 9.3 g/ the disease and treatment outcomes. AIH is a chronic inflammatory
disease of the liver of unknown aetiology. It usually affects females
dl, total white blood cell - 7400/mm3, differential count - P 68.3/L
of all age groups. Pathogenic mechanisms include environmental
23.3/E 1.1/M 6.6%, platelet count - 210000/mm3 and serological
triggering factors (e.g.,  alcohol consumption and drug-induced
tests for viral hepatitis B and C were negative.
hepatotoxic drugs), failure of immune tolerance mechanisms and
Antinuclear Antibody (ANA) immunofluorescence on HEP-2 and rat genetic predisposition. All these factors collectively initiate a T-cell-
liver cells as shown in [Table/Fig-1,2] showed mixed pattern ANA mediated immune attack on liver antigens, leading to progressive
and anticytoplasmic antibodies. It was strongly positive with a titer inflammatory and fibrotic changes [2]. PBC is a chronic cholestatic
of >1:3200 showing positive for nuclear membrane with nucleus disease of autoimmune aetiology that affects mainly females of
dotted (+++) and antimitochondrial antibodies (AMA) (+++). The middle age. AMA is a significant serologic marker of the disease,
ANA profile and liver profile also showed AMA-M2 (+++); Anti which is present in at least 90% of the patients [3]. In patients with
neutrophil cytoplasmic antibody (ANCA) was negative. a diagnosis of AIH, possibility of an overlap syndrome should be
Ultrasonography was suggestive of hepatosplenomegaly and ruled out if cholestatic features are present.
cirrhosis of the liver with portal hypertension. A liver biopsy showed
moderate mixed portal and mild lobular inflammation with mild Autoimmune Hepatitis
interface activity, mild reduction in interlobular bile ducts, periportal AIH is a chronic inflammatory disorder characterized by periportal
Mallory’s hyaline with xanthomatous transformation, significant inflammation, hypergammaglobulinemia, circulating autoantibodies
stainable copper-associated protein deposits and moderate portal and necrosis of the liver. It can affect any age group. It mainly affects
and periportal focal bridging fibrosis. Histological features were young females. The majority of patients have autoantibodies such
suggestive of a chronic cholestatic process. Upper gastrointestinal as ANA, soluble liver antigen and liver kidney microsomal antibody.
endoscopy was suggestive of small and large esophageal varices, In hypergammaglobulinemia, mainly IgG levels are raised. On
which was managed by endoscopic variceal ligation. Gastric histopathological examination, interface hepatitis is hallmark of the
biopsy specimen showed Helicobacter pylori induced gastritis, disease but the finding may differ depending upon course of the
Journal of Clinical and Diagnostic Research. 2017 Jul, Vol-11(7): OD07-OD09 7
 Indira Bairy et al., Autoimmune Hepatitis – Primary Biliary Cirrhosis Overlap Syndrome www.jcdr.net

disease. These cases have favorable response to steroid therapy

resulting in better prognosis [3].

Primary Biliary Cirrhosis

PBC, also known as chronic nonsuppurative destructive cholangitis,
is a disease mainly involving intrahepatic bile ducts. Its diagnosis
is based on cholestatic serum enzyme pattern, serum AMA and
PBC-specific AMA-M2 and a compatible histology (which includes
bile duct lesions). Treatment of the patient with UDCA can slow
down the course of the disease, but till today, no drug is available
which can stop the progression of PBC [3].

Primary Biliary Cirrhosis/Autoimmune Hepatitis

Overlap
Overlap syndrome is the term used for patients presenting with
features of disorders within the spectrum of autoimmune liver
diseases (i.e.,  AIH, PBC and PSC). Overlap syndrome lacks
specific definitions [4]. [Table/Fig-1]: Antinuclear antibody immunofluorescence on HEP-2 cell line showing
nucleus dotted andcytoplasm coarse granular ().
The AIH-PBC overlap syndrome is accepted when two or three
criteria for PBC and AIH are fulfilled [Table/Fig-3] [5].
In the present case for AIH - the criteria met included serum IgG
levels two times the upper limit of normal (ULN), strong positive for
ANA and liver biopsy showing interface hepatitis.
For PBC, the criteria met included serum tests strongly positive for
AMA-M2 and nuclear membrane and liver biopsy showing bile duct
lesions. For these reasons, overlap syndrome was diagnosed.
PBC in genetically predisposed patients of AIH can flare up
autoimmune destruction of bile ducts which results in mixed clinical
presentation of AIH and PBC in such patients.
PBC enhances the autoimmune mechanism and genetic
predisposition along with resulting inflammatory hepatitis with most
of the features of AIH [6].
However, it is not sure whether this categorization is clinically
significant or not. One study has suggested that PBC patients with
superimposed features of AIH progress rapidly to cirrhosis and liver
failure [5]. Whereas, another study found that patients with overlap
[Table/Fig-2]: Antinuclear antibody immunofluorescence on rat liver cell showing
syndromes were more likely to develop esophageal varices,
nuclear membrane pattern ().
ascites, liver failure compared to patients with typical PBC  [7]. In
the present case study, we observed both the findings. Study of
more cases is required to find whether these groups have different AIH (2 out of 3 criteria)
1. ALT levels>5× ULN value
natural history and response to treatment.
2. Serum IgG levels>2× ULN or a positive test for ASMA
Diagnosing an overlap syndrome has therapeutic implications. 3. Liver biopsy showing moderate or severe periportal or periseptal lymphocytic
Immunosuppression is considered as standard effective therapy piecemeal necrosis
OR
for AIH and UDCA is recommended to slow down the progression Liver biopsy showing interface hepatitis ‑ a typical finding of AIH [4].
of PBC [4]. A  complete clinical and biochemical response is PBC (2 out of 3 criteria)
achieved in patients after using combination therapy of UDCA and 1. ALP levels>2 × or GGT levels>5 × ULN
corticosteroids [5,8]. 2. Positive test for AMA
3. Liver biopsy specimen showing florid bile duct lesions
Study done by Angulo P et al. showed that administration of oral [Table/Fig‑3]: Diagnostic criteria of AIH‑PBC overlap syndrome proposed by
steroids in patients with PBC is associated with systemic side Chazouilleres et al., in 1998 [5].
effects and significant worsening of osteoporosis; so, they should Abbreviations: ULN: Upper limit of normal, ASMA: Anti smooth muscle antibodies, GGT:
γ‑glutamyltranspeptidase, IgG: Immunoglobulin G, AIH: Autoimmune hepatitis, ALT: Alanine
be used cautiously [9]. On the other hand, studies have shown that
aminotransferase, PBC: Primary biliary cirrhosis,
UDCA is helpful in patients diagnosed only with AIH and patients of ALP: Alkaline phosphatase, AMA: Antimitochondrial antibodies
PBC with associated features of AIH [10].
Based on the risks and benefits of different treatment strategies,
the majority think that trial of corticosteroids is a genuine approach
in the treatment of patients with overlap syndrome. therapy employed for any autoimmune liver disease, leading to
overall improvement of survival and decrease the need of liver
Only a small number of patients will be benefitted with improvement transplantation [7].
of biochemical and histopathological parameters. Steroids should
be discontinued if serum level of liver enzymes does not improve
and then treatment should be started with UDCA [11].
CONCLUSION
AIH-PBC is one of the most common overlap syndromes and should
Treatment with UDCA may delay disease progression and prolong always be kept in mind by clinicians while diagnosing AIH. Neither
survival. the diagnostic criteria nor the treatment strategy for this variant of
Recognition of overlap syndromes could have a significant impact PBC is standardized, but early diagnosis of overlap syndrome can
in the treatment of patients who have inadequate response with lead to better prognosis of the patient. Till now treatment options
8 Journal of Clinical and Diagnostic Research. 2017 Jul, Vol-11(7): OD07-OD09
www.jcdr.net Indira Bairy et al., Autoimmune Hepatitis – Primary Biliary Cirrhosis Overlap Syndrome

available are UDCA, corticosteroids and liver transplantation. Last clinical features and response to therapy. Hepatology. 1998;28(2):296-301.
  [6] Lohse AW, Zum Büschenfelde KH, Franz B, Kanzler S, Gerken G, Dienes HP.
but not the least, early diagnosis and intervention of this condition
Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and
are required for the better outcome of the patient. autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically
susceptible individuals. Hepatology. 1999;29(4):1078-84.
  [7] Silveira MG. Overlap syndromes of autoimmune liver disease. J  Clin Cell
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Poupon  R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome:

PARTICULARS OF CONTRIBUTORS:
1. Professor, Department of Microbiology, Melaka-Manipal Medical College, Manipal University, Manipal, Karnataka, India.
2. Assistant Professor, Department of Microbiology, Melaka-Manipal Medical College, Manipal University, Manipal, Karnataka, India.
3. Professor, Department of Medicine, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.

NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:

Dr. Indira Bairy,
Professor, Department of Microbiology, Melaka-Manipal Medical College,
Manipal University, Manipal-576104, Karnataka, India.
E-mail: indira.bairy@manipal.edu Date of Submission: Nov 04, 2016
Date of Peer Review: Jan 10, 2017
Date of Acceptance: Apr 26, 2017
FINANCIAL OR OTHER COMPETING INTERESTS: None.
Date of Publishing: Jul 01, 2017

Journal of Clinical and Diagnostic Research. 2017 Jul, Vol-11(7): OD07-OD09 9