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2018 ; 13
(3
): e0193960
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Evaluation of classical and novel autoantibodies for the diagnosis of Primary
Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome (PBC-AIH OS)
#MMPMID29554146
Nguyen HH
; Shaheen AA
; Baeza N
; Lytvyak E
; Urbanski SJ
; Mason AL
; Norman GL
; Fritzler MJ
; Swain MG
PLoS One
2018[]; 13
(3
): e0193960
PMID29554146
show ga
BACKGROUND AND AIMS: Up to 20% of Primary Biliary Cholangitis (PBC) patients are
estimated to have features that overlap with Autoimmune Hepatitis (AIH). Patients
with PBC-AIH overlap syndrome (PBC-AIH OS) have been reported to exhibit
suboptimal responses to ursodeoxycholic acid therapy, and are more likely to
progress to cirrhosis. Anti-double stranded DNA (anti-dsDNA) and anti-p53 have
been previously suggested to be potential autoantibodies for identifying patients
with PBC-AIH OS. In our well defined PBC patient cohorts, a comprehensive
assessment of various classical and novel autoantibodies was evaluated for their
utility in identifying PBC-AIH OS patients. METHODS: PBC-AIH OS was classified
according to the Paris criteria and PBC as per the European Association for the
Study of the Liver guidelines. Biobanked serum samples from 197 patients at the
University of Calgary Liver Unit and the University of Alberta were analyzed for
classical and novel autoantibodies. Anti-dsDNA was measured by the Crithidia
luciliae immunofluorescence (CLIFT) assay (1:20 dilution) and chemiluminescence
(CIA: QUANTA Flash®, Inova Diagnostics, San Diego). Anti-p53, anti-Ro52/TRIM21,
anti-YB 1, anti-GW182, anti-Ge-1, and anti-Ago 2 were measured by either an
addressable laser bead immunoassay (ALBIA) or line immunoassay (LIA).
Autoantibodies against MIT3, gp210, sp100, LKM1, SLA, and the novel
autoantibodies Hexokinase-1 (HK-1), and Kelch like protein 12 (KLHL-12) were
measured using QUANTA Lite® ELISA assays. We applied non-parametric methods to
compare the biomarkers frequencies between study groups. We used multivariate
adjusted models and AUROC to compare the diagnostic accuracy of the different
autoantibodies alone or in combination with serum biochemistry. RESULTS: 16 out
of 197 PBC patients (8.1%) were classified as PBC-AIH OS. Compared to PBC
patients, PBC-AIH OS patients were similar in age (median: 59 vs. 63, P = 0.21)
and female predominance (94% vs. 89%, P = 1.00). Anti-dsDNA-by CLIFT (37.5% in
PBC-AIH OS vs 9.9% in PBC alone, P <0.01) was the only autoantibody associated
with PBC-AIH OS; a finding consistent with previous reports. Significant
elevation in serum ALT (62 IU/L in PBC-AIH OS vs 37 IU/L in PBC alone, P < 0.01),
and serum IgG (17.6 g/L in OS vs 12.1 g/L in PBC alone, P <0.01) were observed in
patients with PBC-AIH OS receiving medical/immunosuppressive therapy. In a
multivariate model, positive anti-dsDNA by CLIFT, ALT and IgG were significant
predictors of PBC-AIH OS with an area under the receiver operator curve (AUROC)
value of 0.84. CONCLUSIONS: Consistent with previous findings, the presence of
anti-dsDNA by CLIFT is associated with PBC-AIH OS. Contrary to previous reports,
anti-p53 was not associated with PBC-AIH OS. Our comprehensive evaluation of
various classical and novel autoantibody biomarkers including Ro52/TRIM21,
anti-p53, anti-KLHL-12 and anti-HK-1 were not significantly associated with
PBC-AIH OS. Our findings highlight the ongoing need for the research and
development of new autoantibody biomarkers to aid in the diagnosis of PBC-AIH OS.
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