Pyroglutamic acidosis by glutathione regeneration blockage in critical patients with septic shock

Yenifer Gamarra,José Castaño,Felipe C Santiago,Jorge Molina-López,Elena Planells,Lourdes Herrera-Quintana,Álvaro Domínguez

doi:10.1186/s13054-019-2450-5

Abstract

AimThe aim of this study was to evaluate oxidative stress from glutathione depletion in critically ill patients with a septic shock through the abnormal presence of pyroglutamic acid (PyroGlu) in the urine (indirectly) and through its serum level (directly).MethodsThis was a prospective analytical study of 28 critically ill patients with a septic shock who were monitored from admission (initial) to 3 days of stay (final) in the intensive care unit (ICU). Data collected included PyroGlu and glutamic acid (Glu) using liquid chromatography/mass spectrometry, and glutathione peroxidase (GPX) activity with a colorimetric assay. The differences in Glu, PyroGlu, and GPX activity between the septic shock group and healthy control group serving as reference values were evaluated using the Mann–Whitney test. The correlations between Glu, PyroGlu, and GPX activity and clinical outcomes were determined using Spearman’s correlation coefficient.ResultsIn patients with septic shock, serum and urine PyroGlu levels were higher, erythrocyte GPX activity/gr Hb was lower, and urine Glu levels were lower compared to healthy control reference values, for both initial and final values. Initial serum Glu levels were also lower. Serum PyroGlu levels had a correlation with both initial and final serum Glu levels; levels also correlated in the urine. Initial serum Glu correlated with the days of mechanical ventilation (P = 0.016) and the days of ICU stay (P = 0.05). Urine Glu/mg creatinine correlated with APACHE II (P = 0.030). This positive correlation observed for serum Glu was not observed for PyroGlu.ConclusionsThe current study found that septic patients have higher levels of PyroGlu, lower levels of Glu, and lower erythrocyte GPX activity, suggesting that these biomarkers could be used as an indicator of glutathione depletion. In addition, Glu is related to severity parameters. This study can guide future studies on the importance of monitoring the levels of pyroglutamic acidosis in critical patients with septic shock in order to preserve the oxidative status and its evolution during the stay in the ICU.

Highlights

Septic shock is the leading cause of death in the intensive care unit (ICU), and despite increased knowledge about the pathogenesis of sepsis, its mortality rate remains high, approximately 20 to 80% [1,2,3]
The current study found that septic patients have higher levels of pyroglutamic acid (PyroGlu), lower levels of glutamic acid (Glu), and lower erythrocyte glutathione peroxidase (GPX) activity, suggesting that these biomarkers could be used as an indicator of glutathione depletion
The increase in PyroGlu could be due to three key points: (I) the catabolism of glutathione is in the reduced form (GSH) through gamma-glutamyl transpeptidase, (II) and/or to a limiting factor in the second step of gamma-glutamylcysteine synthetase (III) or a limiting factor in the following step involving glutathione synthetase. (II) The gamma-glutamylcysteine synthetase enzyme is the main rate-limiting step in this cycle, and this reaction is non-allosterically inhibited by physiologic concentrations of glutathione. (III) The impact of a pre-existing ATP depletion in the successive step causes GSH not to be synthesized through glutathione synthetase, which can be caused by glycine deficiency

Summary

Introduction

Septic shock is the leading cause of death in the intensive care unit (ICU), and despite increased knowledge about the pathogenesis of sepsis, its mortality rate remains high, approximately 20 to 80% [1,2,3]. The excess oxidative stress in sepsis is produced by both an excess production of free radicals and a deficit in antioxidant defenses (scavengers). One of the most important and most abundant defensive antioxidant systems is the GPX enzyme family (GPX). These enzymes require reduced glutathione (GSH) for its action. One member of the GPX enzyme family is cellular glutathione peroxidase (GPX1), whose function is to detoxify peroxides in the cell. GPX1 is found in the cytoplasm of cells, especially red blood cells, and its main function is to protect hemoglobin from the action of free radicals. Other enzymatic families with an important role in antioxidant defense are the thioredoxin reductase

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