The novel hexokinase 1 antibodies are useful for the diagnosis and associated with bad prognosis in primary biliary cholangitis

Reig, A.; Garcia, Maurício de Camargo; Shums, Zakera; Milo, Jay; Encabo, Susan; Bentow, Chelsea; Mahler, Manuel Alejandro; Romera, Mercedes; Viñas, Odette; Norman, G.L.; Parés, Albert

doi:10.1016/s0168-8278(17)31049-8

Cited by 5 publications

(3 citation statements)

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“…A key question remaining is whether, in addition to their value in diagnosis, these antibodies can be shown to be associated with particular clinical phenotypes or outcomes. Preliminary results, so far only presented in abstract form, suggest this may be the case for anti-HK-1 antibodies, where the presence of these antibodies at diagnosis was associated with significantly increased levels of alkaline phosphatase, alanine aminotransaminase, and gamma-glutamyl transpeptidase compared to anti-HK-1 negative patients, as well as with shorter transplant-free survival time (25). These results are potentially of important clinical interest, however additional validation and studies are now needed to confirm their significance.…”

Section: Discussionmentioning

confidence: 99%

The Prevalence of Anti-Hexokinase-1 and Anti-Kelch-Like 12 Peptide Antibodies in Patients With Primary Biliary Cholangitis Is Similar in Europe and North America: A Large International, Multi-Center Study

Norman

Reig

Viñas³

et al. 2019

Front. Immunol.

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Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is present worldwide. Autoantibodies, in particular anti-mitochondrial antibodies (AMA) detected by indirect immunofluorescence assays or newer solid phase immunoassays can detect most, but not all individuals with PBC. Detection of antibodies to the anti-nuclear antigens sp100 and gp210 can identify additional PBC patients, but some seronegative patients remain, often resulting in delayed diagnosis and treatment. Antibodies to kelch-like 12 (KLHL12) and hexokinase 1 (HK-1) were recently identified as new biomarkers for PBC and notably identify patients who are negative for conventional autoantibodies. To become globally adopted, it is important to validate these new biomarkers in different geographic areas. In the present study we evaluated the prevalence of anti-KLHL12 (measured by a KLHL12-derived peptide referred to as KL-p) and anti-HK-1 antibodies by ELISA at five sites within Europe and North America and demonstrated the presence of these antibodies in patients with PBC in all geographies.

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Section: Discussionmentioning

confidence: 99%

The Prevalence of Anti-Hexokinase-1 and Anti-Kelch-Like 12 Peptide Antibodies in Patients With Primary Biliary Cholangitis Is Similar in Europe and North America: A Large International, Multi-Center Study

Norman

Reig

Viñas³

et al. 2019

Front. Immunol.

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“…Both anti-KLHL 12 and anti-HK 1 have been described as being highly specific markers for PBC that can be used in conjunction with other biomarkers, including anti-gp210 and anti-sp100 [ 20 ]. Interestingly, there is emerging evidence suggesting that anti-HK1 may be a marker of poor prognosis in PBC patients, with increased risk in liver disease progression and lower transplant free survival [ 37 ]. In our study, we found similar frequencies of anti-KLHL 12 and anti-HK 1 antibodies in patients with PBC-AIH OS and those with PBC alone.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of classical and novel autoantibodies for the diagnosis of Primary Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome (PBC-AIH OS)

et al. 2018

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Background and aimsUp 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.MethodsPBC-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.Results16 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.ConclusionsConsistent 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 ...

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“…Other two autoantibodies directed against hexokinase 1 and a nuclear protein involved in the metabolism of collagen (KL‐p) have shown a consistent sensitivity and specificity in the detection of PBC. A recent study found a correlation between the presence of antibodies anti‐hexokinase 1 and disease progression, with lower LT‐free survival …”

Section: Current Tools For Risk Stratificationmentioning

confidence: 98%

Precision medicine in primary biliary cholangitis

Ronca

Gerussi

Cristoferi

et al. 2019

J of Digest Diseases

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For many years the one‐size‐fits‐all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second‐line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient‐centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second‐line disease‐modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.

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The novel hexokinase 1 antibodies are useful for the diagnosis and associated with bad prognosis in primary biliary cholangitis

Cited by 5 publications

References 0 publications

The Prevalence of Anti-Hexokinase-1 and Anti-Kelch-Like 12 Peptide Antibodies in Patients With Primary Biliary Cholangitis Is Similar in Europe and North America: A Large International, Multi-Center Study

The Prevalence of Anti-Hexokinase-1 and Anti-Kelch-Like 12 Peptide Antibodies in Patients With Primary Biliary Cholangitis Is Similar in Europe and North America: A Large International, Multi-Center Study

Evaluation of classical and novel autoantibodies for the diagnosis of Primary Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome (PBC-AIH OS)

Precision medicine in primary biliary cholangitis

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