scholarly journals Identification of Serum Biomarkers to Distinguish Hazardous and Benign Aminotransferase Elevations

2019 ◽  
Author(s):  
Joel H Vazquez ◽  
Melissa M Clemens ◽  
Felicia D Allard ◽  
Eric U Yee ◽  
Stefanie Kennon-McGill ◽  
...  
Keyword(s):  
Liver Injury ◽  
Drug Safety ◽  
Serum Biomarkers ◽  
High Dose ◽  
Hepatocellular Injury ◽  
Drug Induced ◽  
Safety Testing ◽  
Apap Overdose ◽  
High Dose Dexamethasone ◽  
Duct Ligation

Abstract The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected four (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosyhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all four were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation (BDL)-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury (DILI), in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve pre-approval drug safety assessment.

High-dose methotrexate-induced reversible grade 4 hyperbilirubinaemia and transaminitis in an adolescent with Burkitt Leukaemia

2021 ◽  
Vol 14 (1) ◽  
pp. e237512
Author(s):  
Sanjeev Khera ◽  
Randhir Ranjan ◽  
Sateesh Ramachandran ◽  
Ajay Beriwal
Keyword(s):  
Liver Injury ◽  
Clinical Significance ◽  
Short Latency ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Drug Induced ◽  
Common Cause ◽  
Drug Induced Liver Injury ◽  
Dose Methotrexate

Symptomatic drug-induced liver injury (DILI) is an uncommon problem. Direct DILI is dose-related, predictable with short latency (hour to days) and is generally associated with transient and reversible transaminitis without jaundice. Antimetabolites including methotrexate are a common cause for direct DILI. Hepatotoxicity associated with high-dose methotrexate (HD-MTX) is generally transient and includes reversible elevation of transaminase in up to 60% and associated hyperbilirubinaemia (≤grade 2) in 25% of courses and therefore is of no clinical significance. Severe grades of DILI with HD-MTX (grade ≥4) are extremely rare. We describe an adolescent with Burkitt leukaemia who had reversible grade 4 DILI including hyperbilirubinaemia postfirst course of HD-MTX. Rechallenge with two-third dose of HD-MTX in subsequent chemotherapeutic cycle did not cause recurrence of DILI.

scholarly journals TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Madison Davis ◽  
Brendan D. Stamper
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Chemical Exposure ◽  
Health Concern ◽  
Hepatocellular Injury ◽  
Drug Induced ◽  
Endogenous Factors ◽  
Drug Induced Liver Injury

In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-αtransgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine.

scholarly journals Predicting Drug-Induced Liver Injury Using Convolutional Neural Network and Molecular Fingerprint-Embedded Features

2021 ◽  
Author(s):  
TH Nguyen-Vo ◽  
L Nguyen ◽  
N Do ◽  
PH Le ◽  
TN Nguyen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Language Processing ◽  
American Chemical Society ◽  
In Vivo Studies ◽  
Drug Induced ◽  
Molecular Fingerprint ◽  
Molecular Fingerprints ◽  
Safety Testing ◽  
Drug Induced Liver Injury

© 2020 American Chemical Society. As a critical issue in drug development and postmarketing safety surveillance, drug-induced liver injury (DILI) leads to failures in clinical trials as well as retractions of on-market approved drugs. Therefore, it is important to identify DILI compounds in the early-stages through in silico and in vivo studies. It is difficult using conventional safety testing methods, since the predictive power of most of the existing frameworks is insufficiently effective to address this pharmacological issue. In our study, we employ a natural language processing (NLP) inspired computational framework using convolutional neural networks and molecular fingerprint-embedded features. Our development set and independent test set have 1597 and 322 compounds, respectively. These samples were collected from previous studies and matched with established chemical databases for structural validity. Our study comes up with an average accuracy of 0.89, Matthews's correlation coefficient (MCC) of 0.80, and an AUC of 0.96. Our results show a significant improvement in the AUC values compared to the recent best model with a boost of 6.67%, from 0.90 to 0.96. Also, based on our findings, molecular fingerprint-embedded featurizer is an effective molecular representation for future biological and biochemical studies besides the application of classic molecular fingerprints.

scholarly journals The Characteristics, Prevalence, and Risk Factors of Drug-Induced Liver Injury Among Brucellosis Inpatients in Xinjiang, China

2021 ◽  
Vol 12 ◽  
Author(s):  
Maermaer Tuohutaerbieke ◽  
Xinjie Li ◽  
Yue Yin ◽  
Wei Chen ◽  
Dongmei Wu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Liver Injury ◽  
Serum Albumin ◽  
Rating Scale ◽  
Normal Liver ◽  
Hepatocellular Injury ◽  
Drug Induced ◽  
International Consensus ◽  
Drug Induced Liver Injury ◽  
Drug Of Choice

Background: We investigated the prevalence, demographic and clinical features, and risk factors associated with drug-induced liver injury (DILI) during the treatment of brucellosis inpatients in a retrospective study.Methods: We collected the clinical data of 782 brucellosis inpatients admitted at the Shawan County People’s Hospital, Xinjiang, from 2015–2019. All cases were re-evaluated using the international consensus of DILI criteria and RUCAM rating scale. 71 patients were confirmed as DILI cases and compared with 523 other patients with normal liver function.Results: It was indicated that DILI occurred with a prevalence of about 9.08% among brucellosis inpatients receiving drug therapy. Hepatocellular injury was the most common type of DILI (61.97%, 95% confidence interval [CI] 50.34–72.37), followed by mixed (23.94%, 95% CI 15.52–35.04) and cholestatic types (14.08%, 95% CI 7.83–24.02). In addition, 13.64% of the hepatocellular DILI cases fulfilled Hy’s law criteria and only two cases (2.82%) progressed to severe DILI. Most patients adopted the combination of rifampicin, antipyretic analgesics, anti-infective agents, and traditional Chinese medicine for the treatment of brucellosis, with all the 71 patients taking rifampicin as the drug of choice. Multivariable logistic regression analyses indicated that obesity, regular alcohol intake, and decreased serum albumin were the independent risk factors of DILI in patients with brucellosis after adjusting for gender, age, and ethnicity.Conclusion: DILI occurred in a minority of inpatients diagnosed with brucellosis receiving rifampicin-based therapeutic regimen. In addition, obesity, alcohol abuse, and decreased serum albumin were valuable predictors of the risk of DILI in patients with brucellosis.

Prednisolone: role in amoxicillin–clavulanate-induced cholestatic liver injury

2021 ◽  
Vol 14 (4) ◽  
pp. e239488
Author(s):  
Melvin Qiyu Lee ◽  
Royale Chigozie ◽  
Irfan Khan ◽  
Gerard O'Mara
Keyword(s):  
Liver Injury ◽  
Liver Function Tests ◽  
Hepatocellular Injury ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
The Us ◽  
Common Causes ◽  
Amoxicillin Clavulanate ◽  
The Common ◽  
Cholestatic Liver Injury

A 68-year-old patient presented with symptoms of a urinary tract infection. A deterioration in the patient’s liver function tests (LFTs) was noted 1 week following completion of a course of amoxicillin–clavunalate. This progressively worsened, reaching its peak by day 30. Our investigations excluded other possible causes for deranged LFTs and there was no improvement of same despite reduced dosing of potentially hepatotoxic medications.A trial of 30 mg/day prednisolone was commenced, resulting in an immediate and progressive improvement in LFTs to baseline over a period of 22 days and an improvement in constitutional symptoms such as tiredness and poor appetite. Drug-induced liver injury (DILI) is one of the common causes of acute hepatitis and a leading cause of acute liver failure in the US and Europe. Patterns of DILI can be generally divided into: (1) hepatocellular injury, (2) cholestatic injury and (3) mixed injury.

scholarly journals Predicting Drug-Induced Liver Injury Using Convolutional Neural Network and Molecular Fingerprint-Embedded Features

2021 ◽  
Author(s):  
TH Nguyen-Vo ◽  
L Nguyen ◽  
N Do ◽  
PH Le ◽  
TN Nguyen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Language Processing ◽  
American Chemical Society ◽  
In Vivo Studies ◽  
Drug Induced ◽  
Molecular Fingerprint ◽  
Molecular Fingerprints ◽  
Safety Testing ◽  
Drug Induced Liver Injury

© 2020 American Chemical Society. As a critical issue in drug development and postmarketing safety surveillance, drug-induced liver injury (DILI) leads to failures in clinical trials as well as retractions of on-market approved drugs. Therefore, it is important to identify DILI compounds in the early-stages through in silico and in vivo studies. It is difficult using conventional safety testing methods, since the predictive power of most of the existing frameworks is insufficiently effective to address this pharmacological issue. In our study, we employ a natural language processing (NLP) inspired computational framework using convolutional neural networks and molecular fingerprint-embedded features. Our development set and independent test set have 1597 and 322 compounds, respectively. These samples were collected from previous studies and matched with established chemical databases for structural validity. Our study comes up with an average accuracy of 0.89, Matthews's correlation coefficient (MCC) of 0.80, and an AUC of 0.96. Our results show a significant improvement in the AUC values compared to the recent best model with a boost of 6.67%, from 0.90 to 0.96. Also, based on our findings, molecular fingerprint-embedded featurizer is an effective molecular representation for future biological and biochemical studies besides the application of classic molecular fingerprints.

scholarly journals Aedes aegypti mosquito saliva ameliorates acetaminophen-induced liver injury in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245788
Author(s):  
Josiane B. Assis ◽  
Bruno Cogliati ◽  
Eliane Esteves ◽  
Margareth L. Capurro ◽  
Denise M. Fonseca ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aedes Aegypti ◽  
Serum Levels ◽  
Hepatic Necrosis ◽  
Protective Role ◽  
Bioactive Molecules ◽  
Drug Induced ◽  
Immunological Parameters ◽  
Apap Overdose

Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose is the most common cause of drug-induced liver injury (DILI). Although the primary hepatic damage is induced by APAP-derived toxic intermediates resulting from cytochrome P450 metabolism, immune components also play an important role in DILI pathophysiology. Aedes aegypti saliva is a source of bioactive molecules with in vitro anti-inflammatory and immunomodulatory activities. However, evidences on the therapeutic use of Ae. aegypti salivary preparations in animal models of relevant clinical conditions are still scarce. Thus, the present study was designed to evaluate the protective role of Ae. aegypti saliva in a murine model of APAP-induced DILI. C57BL/6 mice were exposed to Ae. aegypti bites 2 hours after APAP overdose. Biochemical and immunological parameters were evaluated in blood and liver samples at different time points after APAP administration. Exposure to Ae. aegypti saliva attenuated liver damage, as demonstrated by reduced hepatic necrosis and serum levels of alanine aminotransferase in APAP-overdosed mice. The levels of hepatic CYP2E1, the major enzyme responsible for the bioactivation of APAP, were not changed in Ae. aegypti exposed animals, suggesting no effects in the generation of hepatotoxic metabolites. On the other hand, mice treated with Ae. aegypti saliva following APAP overdose presented lower serum concentration of TNF-α, IL-6, IL-1β and IL-10, as well as reduced frequency of inflammatory cell populations in the liver, such as NKT cells, macrophages and dendritic cells. These findings show that Ae. aegypti saliva has bioactive molecules with therapeutic properties and may represent a prospective source of new compounds in the management of DILI-associated inflammatory disorders and, perhaps, many other inflammatory/autoimmune diseases.

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