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This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with undernourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal. [ABSTRACT FROM AUTHOR]

Glutathione synthetase (GSS) deficiency is a rare disorder, occurring with a frequency of less than 1 in 100,000 individuals worldwide. The clinical presentation may vary from mild to severe, and manifestations include hemolytic anemia, hyperbilirubinemia, metabolic acidosis, neurological problems, and sepsis. Herein, we present a case of a newborn boy with the most severe phenotype of GSS deficiency, diagnosed based on clinical features and increased urinary 5-oxoproline levels determined via gas chromatography mass spectrometry (GCMS) testing. [ABSTRACT FROM AUTHOR]

Acetaminophen and flucloxacillin both interfere with the ?-glutamyl cycle. Long-lasting concomitant use of flucloxacillin and acetaminophen can lead to 5-oxoproline accumulation and severe high anion gap metabolic acidosis. Females and patients with sepsis, impaired kidney and/or liver function, malnutrition, advanced age, congenital 5-oxoprolinase deficiency and supratherapeutic acetaminophen and flucloxacillin dosage are associated with increased risk. Therefore, a critical attitude towards the prescription of acetaminophen concomitant with flucloxacillin in these patients is needed. We present the case of a 79-year-old woman with severe 5-oxoprolinaemia after long-lasting treatment with flucloxacillin and acetaminophen, explaining the toxicological mechanism and risk factors, and we make recommendations for acetaminophen use in patients with long-lasting flucloxacillin treatment.

Résumé On retient parmi les causes classiques d’acidose métabolique à trou anionique augmenté (AMTAA) les acidoses lactiques ou cétosiques, la réduction néphronique (insuffisance rénale sans acidose tubulaire) et certaines intoxications. Néanmoins, le clinicien peut être confronté à certains cas d’AMTAA inexpliqués, nécessitant la recherche d’étiologies plus rares. Nous décrivons le cas d’un patient de 79 ans ayant présenté une acidose liée à l’accumulation de 5-oxoproline (acide pyroglutamique) secondaire à la prise chronique de paracétamol. La physiopathologie de ce trouble est liée à des anomalies du cycle du gamma-glutamyl causées par la prise de paracétamol sur un terrain de comorbidités sévères, conduisant à l’accumulation de 5-oxoproline. Devant une AMTAA chez un patient présentant des comorbidités et dont le traitement comporte du paracétamol, une acidose à l’acide pyroglutamique devrait être suspectée quand les causes usuelles ont été écartées. Ce diagnostic, bien que rare, devrait être présent à l’esprit du clinicien car le simple arrêt du paracétamol permet la résolution de cette anomalie. The most common causes of high anion gap metabolic acidosis (HAGMA) are lactic acidosis, ketoacidosis, and intoxications. Nevertheless, clinicians can be faced with unexplained HAGMA, with a need to look for less common etiologies. We describe a case of 5-oxoproline (pyroglutamate) acidosis due to chronic acetaminophen ingestion at therapeutic dose in a 79-year-old inpatient. The pathophysiology of this condition is detailed, with abnormalities in the gamma-glutamyl cycle due to acetaminophen ingestion and severe chronic morbidities, resulting in glutathione and cysteine deficiency and then accumulation of 5-oxoproline. In HAGMA, when usual causes have been excluded, 5-oxoproline acidosis should be suspected in patients with chronic morbidities and acetaminophen ingestion. This diagnosis should be kept in mind because it generally resolves quickly with cessation of acetaminophen and administration of intravenous fluids. [ABSTRACT FROM AUTHOR]

High anion gap metabolic acidosis frequently complicates acute paracetamol overdose and is generally attributed to lactic acidosis or compromised hepatic function. However, metabolic acidosis can also be caused by organic acid 5-oxoproline (pyroglutamic acid). Paracetamol’s toxic intermediate, N-acetyl- p -benzoquinoneimine irreversibly binds to glutathione and its depletion leads to subsequent disruption of the gamma glutamyl cycle and an excessive 5-oxoproline generation. This is undoubtedly an underdiagnosed condition because measurement of serum 5-oxoproline level is not readily available. A simple, cost effective, and fast capillary electrophoresis method with diode array detection (DAD) for simultaneous measurement of both paracetamol (acetaminophen) and 5-oxoproline in serum was developed and validated. This method is highly suitable for clinical toxicology laboratory diagnostic, allowing rapid quantification of acidosis inducing organic acid 5-oxoproline present in cases of paracetamol overdose. The calibration dependence of the method was proved to be linear in the range of 1.3–250 μg mL −1 , with adequate accuracy (96.4–107.8%) and precision (12.3%). LOQ equaled 1.3 μg mL −1 for paracetamol and 4.9 μg mL −1 for 5-oxoproline. [ABSTRACT FROM AUTHOR]

Unlabelled: Transient 5-oxoprolinuria is a phenomenon that is well recognised in adults. We illustrate an unusual paediatric case of transient 5-oxoprolinuria presenting during an episode of severe sepsis with concomitant paracetamol use. The 15-month-old patient had an extremely high anion gap metabolic acidosis. Adequate resuscitation failed to correct the biochemical disturbance, and high levels of 5-oxoproline were identified. A combination of haemofiltration, replenishment of glutathione stores with N-acetylcysteine and cessation of paracetamol administration resulted in the resolution of the acidosis. Subsequent testing following treatment of the sepsis revealed no ongoing 5-oxoprolinuria.Conclusion: Transient 5-oxoprolinuria has been previously reported in the adult population during episodes of severe sepsis and various pharmaceutical interventions. This case illustrates that it is a phenomenon that should be considered in paediatric patients where a very high anion gap metabolic acidosis exists that cannot be explained by the biochemical indices.What Is Known: • 5-oxoprolinuria in the paediatric population is usually secondary to an inborn error of metabolism. • Transient 5-oxoprolinuria is well recognised in adults during episodes of severe glutathione depletion.What Is New: • Transient 5-oxoprolinuria is a phenomenon rarely reported in the paediatric population. • It highlights the importance of investigating a high anion gap such that unusual diagnoses are not missed. [ABSTRACT FROM AUTHOR]

The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of "MUDPILES" (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen. [ABSTRACT FROM AUTHOR]

Introduction: Profound metabolic acidosis in critically ill adults sometimes remains unexplained despite extensive evaluation. Case Report: A 58-year-old female presented in a confused state to the emergency department; she had been confused for several days. Laboratory evaluation revealed a high anion gap metabolic acidosis and modestly elevated acetaminophen level. Lactic acid was only modestly elevated. There was no evidence of ketoacids, salicylate, methanol, or ethylene glycol. A urine sample submitted on day 1 of hospitalization revealed a markedly elevated level of 5-oxoproline. Discussion: Originally described in children with an inherited defect of glutathione synthetase, 5-Oxoproline is an unusual cause of metabolic acidosis. More recently this disturbance has been recognized in critically ill adults without a recognized inherited metabolic disorder. In most of these cases there has been the concomitant use of acetaminophen. Any causal relationship between acetaminophen and this disturbance is speculative. Conclusion: In critically ill adults with unexplained metabolic acidosis, 5-Oxoproline should be considered in the differential. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 77-year-old male with stable chronic kidney disease stage 3, type 2 diabetes and peripheral vasculopathy. He was taken to the hospital for treatment of a badly healing diabetic ulcer on the right hallux. Topics include maintenance therapy, percutaneous transluminal angioplasty of the right external iliac artery and abdominal computed tomography-angioscan.