High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition

Brooker, G; Jeffery, Jinny; Nataraj, T; Sair, Mark; Ayling, Ruth M

doi:10.1258/000456307780945769

Cited by 28 publications

(24 citation statements)

References 8 publications

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“…Acetaminophen-related 5-oxoprolinemia/5-oxoprolinuria is usually associated with long-term outpatient use of the drug, although it has also been reported after inpatient therapeutic dosing (14,16,18,20,21,26). Acetaminophen blood levels are usually therapeutic.…”

Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Emmett

2014

Clinical Journal of the American Society of Nephrology

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SummaryThe acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the g-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.

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Section: Acetaminophen and Acquired 5-oxoprolinemia/ 5-oxoprolinuriamentioning

confidence: 99%

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Emmett

2014

Clinical Journal of the American Society of Nephrology

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“…Inherited metabolic diseases, underlying infection, malnutrition, and drugs in particular are the main causes. 5,6 Among these, acetaminophen, via its hepatic metabolite (the N-acetylp-benzoquinone imine), is a wellknown cause of depleted GSH stores. 10 Observations of acetaminophenacquired 5-oxoprolinuria are regularly reported in literature, attesting to its deleterious effect.…”

Section: Discussionmentioning

confidence: 99%

“…3 GSH depletion can be constitutive (genetic defect) 4 or induced by different trigger factors (eg, drugs, severe sepsis, malnutrition). 5,6 Hereditary glutathione synthetase deficiency (GSD) is classified into 3 phenotypes, from a mild form with isolated HA to a severe form with HA, constant 5-oxoprolinuria, metabolic acidosis, abstract Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern.…”

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confidence: 99%

Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

et al. 2016

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Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern. We report a rare case of red blood cell enzyme defect in a male infant, who presented during his first months of life with recurrent and isolated neonatal hemolysis. All main causes were ruled out. At 6.5 months of age, the patient presented with gastroenteritis requiring hospitalization; fortuitously, urine organic acid chromatography revealed a large peak of 5-oxoproline. Before the association between HA and 5-oxoprolinuria was noted, glutathione synthetase deficiency was suspected and confirmed by a low glutathione synthetase concentration and a collapse of glutathione synthetase activity in erythrocytes. Moreover, molecular diagnosis revealed 2 mutations in the glutathione synthetase gene: a previously reported missense mutation (c.[656A>G]; p.[Asp219Gly]) and a mutation not yet described in the binding site of the enzyme (c.[902T>C]; p.[Leu301Pro]). However, 15 days later, a control sample revealed no signs of 5-oxoprolinuria and the clinical history discovered administration of acetaminophen in the 48 hours before hospitalization. Thus, in this patient, acetaminophen exposure allowed the diagnosis of a mild form of glutathione synthetase deficiency, characterized by isolated HA. Early diagnosis is important because treatment with bicarbonate, vitamins C and E, and elimination of trigger factors are recommended to improve long-term outcomes. Glutathione synthetase deficiency should be screened for in cases of unexplained newborn HA.

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“…There are no strong evidence supporting its use, but it was shown to be effective in several cases reports [9][10][11][12] . Previous reports of aquired pyroglutamic acidemia in pediatric patients also found that this condition was associated with the use of acetaminophen 5,6 .…”

Section: Discussionmentioning

confidence: 99%

Case Report of Acquired Pyroglutamic Acidemia in a Pediatric Patient

Bischoff¹,

Dornelles²,

Azevedo³

et al. 2015

cbr

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Pyroglutamic acid (also known as 5-oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle. Accumulation of pyroglutamic acid is a rare cause of high anion gap metabolic acidosis. In the pediatric population, the congenital form of pyroglutamic acidemia has been extensively described. However, there are scarce reports of the acquired form of this condition in children. The urine test for organic acids confirms the diagnosis of pyroglutamic acidemia. We report the case of a 16-month-old girl who developed transient 5-oxoprolinemia associated with malnutrition and the use of acetaminophen and ampicillin for the treatment of acute otitis media and abdominal pain. The patient received 21-hour course of n-acetylcysteine with improvement of metabolic acidosis. This report highligts the need of considering pyroglutamic acidemia in the differencial diagnosis for high anion gap metabolic acidosis in pediatric patients with malnutrition and other risk factors.

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High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition

Abstract: Addresses

Cited by 28 publications

References 8 publications

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

Case Report of Acquired Pyroglutamic Acidemia in a Pediatric Patient

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