Anti-kelch-like 12 and anti-hexokinase 1: Novel autoantibodies in primary biliary cirrhosis

Gary L. Norman, Chen Yen Yang, Heather P. Ostendorff, Zakera Shums, Mark J. Lim, Jinjun Wang, Amany Awad, Gideon M. Hirschfield, Piotr Milkiewicz, Donald B. Bloch, Kenneth J. Rothschild, Christopher Bowlus, Iannis Adamopoulos, Patrick S Leung, Harry J. Janssen, Angela C. Cheung, Catalina Coltescu, M. Eric Gershwin

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Using high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC. Initial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 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-KLHL12 and anti-HK1 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-HK1 and anti-KLHL12 with available markers (MIT3, gp210 and sp100), increased the diagnostic sensitivity for PBC. Most importantly, anti-KLHL12 and anti-HK1 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-KLHL12 and anti-HK1 antibodies to AMA and ANA serological assays significantly improves efficacy in the clinical detection and diagnosis of PBC, especially for AMA-negative subjects.

Original languageEnglish (US)
Pages (from-to)642-651
Number of pages10
JournalLiver International
Volume35
Issue number2
DOIs
StatePublished - Feb 1 2015

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Hexokinase
Biliary Liver Cirrhosis
Autoantibodies
Anti-Idiotypic Antibodies
Enzyme-Linked Immunosorbent Assay
Antibodies
Biomarkers
Protein Array Analysis
Serum
Recombinant Proteins

Keywords

  • Diagnostics
  • Liver
  • Serology

ASJC Scopus subject areas

  • Hepatology

Cite this

Anti-kelch-like 12 and anti-hexokinase 1 : Novel autoantibodies in primary biliary cirrhosis. / Norman, Gary L.; Yang, Chen Yen; Ostendorff, Heather P.; Shums, Zakera; Lim, Mark J.; Wang, Jinjun; Awad, Amany; Hirschfield, Gideon M.; Milkiewicz, Piotr; Bloch, Donald B.; Rothschild, Kenneth J.; Bowlus, Christopher; Adamopoulos, Iannis; Leung, Patrick S; Janssen, Harry J.; Cheung, Angela C.; Coltescu, Catalina; Gershwin, M. Eric.

In: Liver International, Vol. 35, No. 2, 01.02.2015, p. 642-651.

Research output: Contribution to journalArticle

Norman, GL, Yang, CY, Ostendorff, HP, Shums, Z, Lim, MJ, Wang, J, Awad, A, Hirschfield, GM, Milkiewicz, P, Bloch, DB, Rothschild, KJ, Bowlus, C, Adamopoulos, I, Leung, PS, Janssen, HJ, Cheung, AC, Coltescu, C & Gershwin, ME 2015, 'Anti-kelch-like 12 and anti-hexokinase 1: Novel autoantibodies in primary biliary cirrhosis', Liver International, vol. 35, no. 2, pp. 642-651. https://doi.org/10.1111/liv.12690
Norman GL, Yang CY, Ostendorff HP, Shums Z, Lim MJ, Wang J et al. Anti-kelch-like 12 and anti-hexokinase 1: Novel autoantibodies in primary biliary cirrhosis. Liver International. 2015 Feb 1;35(2):642-651. https://doi.org/10.1111/liv.12690
Norman, Gary L. ; Yang, Chen Yen ; Ostendorff, Heather P. ; Shums, Zakera ; Lim, Mark J. ; Wang, Jinjun ; Awad, Amany ; Hirschfield, Gideon M. ; Milkiewicz, Piotr ; Bloch, Donald B. ; Rothschild, Kenneth J. ; Bowlus, Christopher ; Adamopoulos, Iannis ; Leung, Patrick S ; Janssen, Harry J. ; Cheung, Angela C. ; Coltescu, Catalina ; Gershwin, M. Eric. / Anti-kelch-like 12 and anti-hexokinase 1 : Novel autoantibodies in primary biliary cirrhosis. In: Liver International. 2015 ; Vol. 35, No. 2. pp. 642-651.
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abstract = "Background & Aims: Using high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC. Initial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 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-KLHL12 and anti-HK1 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-HK1 and anti-KLHL12 with available markers (MIT3, gp210 and sp100), increased the diagnostic sensitivity for PBC. Most importantly, anti-KLHL12 and anti-HK1 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-KLHL12 and anti-HK1 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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T2 - Novel autoantibodies in primary biliary cirrhosis

AU - Norman, Gary L.

AU - Yang, Chen Yen

AU - Ostendorff, Heather P.

AU - Shums, Zakera

AU - Lim, Mark J.

AU - Wang, Jinjun

AU - Awad, Amany

AU - Hirschfield, Gideon M.

AU - Milkiewicz, Piotr

AU - Bloch, Donald B.

AU - Rothschild, Kenneth J.

AU - Bowlus, Christopher

AU - Adamopoulos, Iannis

AU - Leung, Patrick S

AU - Janssen, Harry J.

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