Dataset Information

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

ABSTRACT: Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.

SUBMITTER: Smith AK

PROVIDER: S-EPMC7292418 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Smith Andrew K AK Ropella Glen E P GEP McGill Mitchell R MR Krishnan Preethi P Dutta Lopamudra L Kennedy Ryan C RC Jaeschke Hartmut H Hunt C Anthony CA

PLoS computational biology 20200602 6

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related mod ...[more]

PMID: 32484845

Similar Datasets

Project description:UnlabelledBackgroundThe association between serum alanine aminotransferase (ALT) levels and hepatic insulin resistance (IR) has been evaluated with the hyperinsulinemic-euglycemic clamp. However, there is no information about the association of ALT with the Hepatic Insulin Resistance Index (HIRI). The aim of this study was to evaluate the association between serum ALT levels and HIRI in subjects with differing degrees of impaired glucose metabolism.MethodsThis cross-sectional study included subjects that had an indication for testing for type 2 diabetes mellitus (T2DM) with an oral glucose tolerance test (OGTT). Clinical and biochemical evaluations were carried out including serum ALT level quantification. HIRI was calculated for each participant. Correlation analyses and lineal regression models were used to evaluate the association between ALT levels and HIRI.ResultsA total of 324 subjects (37.6% male) were included. The mean age was 40.4?±?14.3?years and the mean body mass index (BMI) was 32.0?±?7.3?kg/m2. Individuals were divided into 1 of 5 groups: without metabolic abnormalities (n?=?113, 34.8%); with the metabolic syndrome (MetS, n?=?179, 55.2%), impaired fasting glucose (IFG, n?=?85, 26.2%); impaired glucose tolerance (IGT, n?=?91, 28.0%), and T2DM (n?=?23, 7.0%). The ALT (p?<?0.001) and HOMA2-IR (p?<?0.001) values progressively increased with HIRI quartiles, while ISI-Matsuda (p?<?0.001) progressively decreased. After adjustment for sex, age, and BMI, we identified a significant correlation between HIRI and ALT in persons with the MetS (r?=?0.22, p?=?0.003), IFG (r?=?0.33, p?<?0.001), IGT (r?=?0.37, p?<?0.001), and T2DM (r?=?0.72, p?<?0.001). Lineal regression analysis adjusting for age, HDL-C, TG and waist circumference (WC) showed an independent association between ALT and HIRI in subjects with the MetS (beta?=?0.07, p?=?0.01), IFG (beta?=?0.10, p?=?0.02), IGT (beta?=?0.09, p?=?0.007), and T2DM (beta?=?0.31, p?=?0.003). This association was not identified in subjects without metabolic abnormalities.ConclusionsALT levels are independently associated with HIRI in subjects with the MetS, IFG, IGT, and T2DM. The ALT value in these subjects may be an indirect parameter to evaluate hepatic IR.

Project description:Experiments were conducted with intact rat hepatocytes to identify inhibitors and incubation conditions that cause selective inhibition of alanine aminotransferase or aspartate aminotransferase. Satisfactory results were obtained by preincubating cells with L-cycloserine or L-2-amino-4-methoxy-trans-but-3-enoic acid in the absence of added substrates. When cells were incubated for 20 min with 50 microM-L-cycloserine, alanine aminotransferase activity was decreased by 90%, whereas aspartate aminotransferase was inhibited by 10% or less. On subsequent incubation, synthesis of glucose and urea from alanine was strongly inhibited, but glucose synthesis from lactate was unaffected. L-2-Amino-4-methoxy-trans-but-3-enoic acid (400 microM) in hepatocyte incubations caused 90-95% inactivation of aspartate aminotransferase, but only 15-30% loss of alanine aminotransferase activity. After preincubation with the inhibitor, glucose synthesis from lactate was almost completely blocked; with alanine as the substrate, gluconeogenesis was unaffected, and urea synthesis was only slightly decreased. By comparison with preincubation with inhibitors, simultaneous addition of substrates (alanine; lactate plus lysine) and inhibitors (cycloserine; aminomethoxybutenoic acid) resulted in smaller decreases in aminotransferase activities and in metabolic rates. Other compounds were less satisfactory as selective inhibitors. Ethylhydrazinoacetate inactivated the two aminotransferases to similar extents. Vinylglycine was almost equally effective in blocking the two enzymes in vitro, but was a very weak inhibitor when used with intact cells. Concentrations of DL-propargylglycine (4 mM) required to cause at least 90% inhibition of alanine aminotransferase in hepatocytes also caused a 16% decrease in aspartate aminotransferase. When tested in vitro, alanine aminotransferase was, as previously reported by others, more sensitive to inhibition by amino-oxyacetate than was aspartate aminotransferase, but in liver cell incubations the latter enzyme was more rapidly inactivated by amino-oxyacetate.

Project description:IntroductionAlterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV.MethodsAdult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy.ResultsAmong the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation.DiscussionSpontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Dataset Information

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Publications

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets