Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans

Llewellyn, Heather P.; Vaidya, Vishal S.; Wang, Zhenyu; Peng, Qinghai; Hyde, Craig; Potter, David M.; Zong, Qing; Arat, Seda; Martin, Matt; Masek-Hammerman, Katherine; Warner, Roscoe L.; Johnson, Kent J.; Kullak‐Ublick, Gerd A.; Aithal, Guruprasad P.; Dear, James W.; Ramaiah, Shashi K.

doi:10.1093/toxsci/kfab003

Cited by 25 publications

(12 citation statements)

References 32 publications

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“…Keratin 18 is expressed in epithelial tissue. Circulating levels of keratin 18 predict drug induced liver injury (Llewellyn et al, 2021), act as diagnostic and prognostic biomarker for acute alcoholic hepatitis (Vatsalya et al, 2020), and are associated with hepatic steatosis in elderly T2D patients (Morling et al, 2014). Keratin 18 had weak positive associations with several metabolic risk factors (glucose, HbA1c, BMI, waist, triglycerides) in elderly T2D patients (Morling et al, 2014).…”

Section: Igfbp2/ Insulin Like Growth Factormentioning

confidence: 99%

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

et al. 2021

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Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding of the inflammatory dynamics and to monitor them on the individual level. To this end, blood-based biomarkers reflecting the tissue-specific inflammatory dynamics would be of great value. Here, we describe an in silico approach to select candidate biomarkers for tissue-specific inflammation by using a priori mechanistic knowledge from pathways and tissue-derived molecules. The workflow resulted in a list of candidate markers, in part consisting of literature confirmed biomarkers as well as a set of novel, more innovative biomarkers that reflect inflammation in the liver and adipose tissue. The first step of biomarker verification was on murine tissue gene-level by inducing hepatic inflammation and adipose tissue inflammation through a high-fat diet. Our data showed that in silico predicted hepatic markers had a strong correlation to hepatic inflammation in the absence of a relation to adipose tissue inflammation, while others had a strong correlation to adipose tissue inflammation in the absence of a relation to liver inflammation. Secondly, we evaluated the human translational value by performing a curation step in the literature using studies that describe the regulation of the markers in human, which identified 9 hepatic (such as Serum Amyloid A, Haptoglobin, and Interleukin 18 Binding Protein) and 2 adipose (Resistin and MMP-9) inflammatory biomarkers at the highest level of confirmation. Here, we identified and pre-clinically verified a set of in silico predicted biomarkers for liver and adipose tissue inflammation which can be of great value to study future development of therapeutic/lifestyle interventions to combat metabolic inflammatory complications.

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Section: Igfbp2/ Insulin Like Growth Factormentioning

confidence: 99%

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

et al. 2021

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“…2013 ). Interestingly, the combination of miR-122-5p and K18 (along with glutamate dehydrogenase) demonstrated superiority over other approaches (including ALT) for the diagnosis of drug-induced liver injury in humans ( Llewellyn et al. 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Cave

Pinkston

Shesh

et al. 2022

Environ Health Perspect

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Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. Methods: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. Results: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor were well integrated within the top identified networks. Discussion: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467

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“…Recently, it was also demonstrated that a combined model comprising GLDH, K-18 and miR-122 was able to accurately detect paracetamol-induced liver injury and differentiate between DILI, healthy volunteers, and patients with non-hepatocellular organ damage [ 60 ]. However, when looked at individually, these three markers did not show superior diagnostics accuracy when compared to ALT [ 60 ]. These findings are questioning the results mentioned above that demonstrate high diagnostic accuracy also for the individual measurement of miR-122, GLDH and K18 [ 50 , 53 ].…”

Section: Biomarkers In Dili—promising Diagnostic Candidatesmentioning

confidence: 99%

Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

Weber

Gerbes

2022

IJMS

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Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.

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Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans

Cited by 25 publications

References 32 publications

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

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