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Tandem Mass Tag-Based Quantitative Proteomic Profiling Identifies Novel Serum Biomarkers of Drug-Induced Liver Injury in Humans

ABSTRACT: Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. In this study we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in a cohort of patients with DILI at onset (DO; n = 133) and follow-up (DF; n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (NDF; n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase; argininosuccinate synthase; carbamoylphosphate synthase, fumarylacetoacetase; fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieves near complete separation (range: 0.94 - 0.99) of DO and HV. In addition, we show that FBP1 alone or in combination with glutathione S-transferase A1 and leukocyte cell derived chemotaxin 2 could potentially assist in clinicla diagnosis by distinguishing NDO from DO (AUC range: 0.65 – 0.78), but further technical and clinical validation of these candidate biomarkers is needed.

ORGANISM(S): Homo Sapiens

SUBMITTER: Joel Federspiel

PROVIDER: PXD034882 | panorama | Thu Jan 26 00:00:00 GMT 2023

REPOSITORIES: PanoramaPublic

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Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of histological findings, from simple steatosis to steatohepatitis (NASH), the latter presenting a higher risk of cardiovascular and kidney diseases, type 2 diabetes and end-stage liver disease. NAFLD is seen as the hepatic manifestation of the metabolic syndrome and affects up to 70-80% of obese patients. There are currently no approved pharmacological therapies for NASH, thus the only option is lifestyle intervention or bariatric surgery in order to lose weight and to improve insulin resistance. Although surgical intervention has allowed collections of liver biopsies, transcriptomic data from livers are still scarce and especially follow-up data to evaluate the impact of weight loss intervention on the liver. Therefore we studied hepatic transcriptomic data in a large cohort of obese patients assessed for presence of NASH at baseline and 1 year follow-up. Patients visiting the obesity clinic of the Antwerp University Hospital for a problem of being overweight (BMI above 25 to 29.9 kg/m²) or obese (BMI above 30 kg/m²) were prospectively recruited and underwent a hepatic work-up. Patients were excluded from further analysis in case of significant alcohol consumption (>20 g/day), history of bariatric surgery, diagnosis of another liver disease, pre-existing diabetes. Patients who were, however, diagnosed with de novo diabetes at baseline or at follow-up were not excluded. If NAFLD was suspected, liver biopsy was proposed. For patients undergoing bariatric surgery (BS), a liver biopsy was proposed regardless of the criteria. Patients were reassessed after 1 year. Liver biopsy was performed percutaneously (16G Menghini) or peri-operatively (14G Tru-Cut). The different histological features of NAFLD were assessed using the NASH Clinical Research Network (NASH CRN) Scoring System. The presence of NASH was defined according to Chalasani et al. necessitating the combined presence of steatosis, ballooning and lobular inflammation.

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Tandem Mass Tag-Based Quantitative Proteomic Profiling Identifies Novel Serum Biomarkers of Drug-Induced Liver Injury in Humans

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