Cited by 87Liver Diseases and ImmunityAutoimmune Bullous Skin DiseasesPediatric Hepatobiliary Diseases and Treatments

Anti‐kelch‐like 12 and anti‐hexokinase 1: novel autoantibodies in primary biliary cirrhosis

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Norman, Gary L., Yang, Chen‐Yen, Ostendorff, Heather P., Shums, Zakera, Lim, Mark J., Wang, Jinjun, Awad, Amany, Hirschfield, Gideon M. +10 more·2015·Liver International

Abstract

Background & Aims: Using high‐density human recombinant protein microarrays, we identified two potential biomarkers, kelch‐like 12 (KLHL 12) and hexokinase‐1 (HK 1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti‐KLHL 12/HK 1 autoantibodies in PBC. Initial discovery used sera from 22 patients with PBC and 62 non‐PBC controls. KLHL 12 and HK 1 proteins were then analysed for immunoglobulin reactivity by immunoblot and enzyme‐linked immunosorbent assay (ELISA) in two independent cohorts of PBC and disease/healthy control patients. Methods: Serum samples from 100 patients with PBC and 165 non‐PBC disease controls were analysed by immunoblot and samples from 366 patients with PBC, 174 disease controls, and 80 healthy donors were tested by ELISA. Results: Anti‐KLHL 12 and anti‐HK 1 antibodies were each detected more frequently in PBC compared with non‐PBC disease controls (P < 0.001). Not only are both markers highly specific for PBC (≥95%) but they also yielded higher sensitivity than anti‐gp210 and anti‐sp100 antibodies. Combining anti‐HK 1 and anti‐KLHL 12 with available markers (MIT 3, gp210 and sp100), increased the diagnostic sensitivity for PBC. Most importantly, anti‐KLHL 12 and anti‐HK 1 antibodies were present in 10–35% of anti‐mitochondrial antibody (AMA)‐negative PBC patients and adding these two biomarkers to conventional PBC assays dramatically improved the serological sensitivity in AMA‐negative PBC from 55% to 75% in immunoblot and 48.3% to 68.5% in ELISA. Conclusions: The addition of tests for highly specific anti‐KLHL 12 and anti‐HK 1 antibodies to AMA and ANA serological assays significantly improves efficacy in the clinical detection and diagnosis of PBC, especially for AMA‐negative subjects.

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Authors
Norman, G. L., Yang, C., Ostendorff, H. P., Shums, Z., Lim, M. J., Wang, J., Awad, A., Hirschfield, G. M., Milkiewicz, P., Bloch, D. B., Rothschild, K. J., Bowlus, C. L., Adamopoulos, I. E., Leung, P. S. C., Janssen, H. J., Cheung, A. C., Coltescu, C., & Gershwin, M. E.
Affiliations
  • Inova Diagnostics San Diego CA USA
  • University of California, Davis (US)
  • AmberGen, Inc. Watertown MA USA
  • University of Birmingham (GB)
  • Medical University of Warsaw (PL)
  • Harvard University (US)
  • Shriners Hospitals for Children - Northern California (US)
  • University of Toronto (CA)
  • University Health Network (CA)
Corresponding author
Gershwin, M. Eric
Venue
Liver International
Publisher
Wiley
Published
2014-10-10
Volume
35
Issue
2
Pages
642-651
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
OpenAlex
W2044395170
Cited by
87
References
54
Citations by year
2026: 6 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 14 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 1
FWCI
3.36
Type
journal article
Language
en
Open access
Locations
  • Liver International (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders
  • SBIR (R44 AI052525)
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Autoimmune Bullous Skin Diseases
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
primary biliary cirrhosis, autoantibody biomarkers, antimitochondrial antibodies, serological diagnosis, diagnostic sensitivity, gp210, SP-100
MeSH terms
Autoantibodies, Enzyme-Linked Immunosorbent Assay, Hexokinase, Humans, Liver Cirrhosis, Biliary, Microfilament Proteins, Sensitivity and Specificity, Immunoblotting, Biomarkers, Protein Array Analysis, Adaptor Proteins, Signal Transducing

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