Elevated levels of circulating CDH5 and FABP1 in association with human drug‐induced liver injury

Mikus, Maria; Drobin, Kimi; Gry, Marcus; Bachmann, Julie; Lindberg, Johan; Yimer, Getnet; Aklillu, Eleni; Makonnen, Eyasu; Aderaye, Getachew; Roach, James; Fier, Ian; Kampf, Caroline; Göpfert, Jens; Perazzo, Hugo; Poynard, Thierry; Stephens, Camilla; Andrade, Raúl J.; Lucena, M. Isabel; Arber, Nadir; Uhlén, Mathias; Watkins, Paul B.; Schwenk, Jochen M.; Nilsson, Peter; Schuppe-Koistinen, Ina

doi:10.1111/liv.13174

Cited by 28 publications

(29 citation statements)

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“…Proteomics investigations revealed elevated levels of cadherin 5 (CDH5) and fatty acid-binding protein (FABP) as protein biomarkers for DIH (Mikus et al, 2016). However, the detection of idiosyncratic hepatotoxicants with the currently available in vitro methods remains challenging, as idiosyncratic drug reactions are unpredictable and mostly immune mediated (Van Summeren et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV-and ARV-ATDinduced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G/A, R919Q, p = 1.4 · 10 -6 , odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH ( p = 5.3 · 10 -7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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“…• FABP1 has superior characteristics regarding tissue distribution and kinetics compared to ALT. Wu et al, 2016b;Karvellas et al, 2017;Mikus et al, 2017;Wu et al, 2017 CDH5…”

Section: High Mobility Group Box-1 Protein (Hmgb1)mentioning

confidence: 99%

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Jiang

et al. 2020

Front. Pharmacol.

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Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.

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“…(28) Recently, FABP1 has been shown to be a diagnostic marker of liver injury in patients with hepatitis C infection (29) and to be associated with drug-induced liver injury. (30) However, to date FABP1 has not been evaluated as a prognostic marker in these conditions or ALF. FABP1 has physiological properties that could potentially make it advantageous as a prognostic biomarker.…”

Section: Comparison With the Literaturementioning

confidence: 99%

Elevated FABP1 serum levels are associated with poorer survival in acetaminophen‐induced acute liver failure

et al. 2017

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Background/Aim Acetaminophen (APAP)-induced Acute Liver Failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Hypothesis: Serum Liver-type Fatty Acid Binding Protein (FABP1) early (day 1) or late (day 3–5) levels are associated with 21-day mortality in the absence of liver transplant. Methods Serum samples from 198 APAP-ALF patients (nested case control study with 99 survivors, 99 non-survivors) were analyzed by ELISA methods and assessed with clinical data from the US Acute Liver Failure Study Group (ALFSG) Registry (1998–2014). Results APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 vs. 690.8 ng/ml, p <0.0001) and late (148.4 vs. 612.3 ng/ml, p <0.0001) compared with non-survivors. FABP1 > 350 ng/ml was associated with significantly higher risk of death at early (p=0.0004) and late (p<0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio (OR) 1.31, p=0.027) and late (log FABP1 OR 1.50, p =0.005) were associated with significantly increased 21-day mortality after adjusting for significant covariates (MELD, vasopressor use). Areas under the receiver-operating curve (AUROC) for early and late multivariable models were 0.778 and 0.907 respectively. AUROC of the King’s College Criteria (KCC) (Early: 0.552 alone, 0.711 with FABP1; Late: 0.604 alone, 0.797 with FABP1) and ALFSG prognostic index (Early: 0.686 alone, 0.766 with FABP1; Late: 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (p <0.002 for all). Conclusion In patients with APAP-ALF, FABP1 may have good potential to discriminate survivors from non-survivors and may improve models currently used in clinical practice. Validation of FABP1 as a clinical prediction tool in APAP-ALF warrants further investigation.

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Elevated levels of circulating CDH5 and FABP1 in association with human drug‐induced liver injury

Cited by 28 publications

References 29 publications

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Elevated FABP1 serum levels are associated with poorer survival in acetaminophen‐induced acute liver failure

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