Acetaminophen-Induced Anion Gap Metabolic Acidosis and 5-Oxoprolinuria (Pyroglutamic Aciduria) Acquired in Hospital

doi:10.1053/j.ajkd.2005.04.010

American Journal of Kidney Diseases

Volume 46, Issue 1, July 2005, Pages 143-146

https://doi.org/10.1053/j.ajkd.2005.04.010 Get rights and content

A rare cause of high anion gap acidosis is 5-oxoproline (pyroglutamic acid), an organic acid intermediate of the γ-glutamyl cycle. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We report the case of a patient with lymphoma who was admitted for salvage chemotherapy. The patient subsequently developed fever and neutropenia and was administered 20.8 g of acetaminophen during 10 days. During this time, anion gap increased from 14 to 30 mEq/L (14 to 30 mmol/L) and altered mental status developed. After usual causes of high anion gap acidosis were ruled out, a screen for urine organic acids showed 5-oxoproline levels elevated at 58-fold greater than normal values. Predisposing factors in this case included renal dysfunction and sepsis. Clinicians need to be aware of this unusual cause of anion gap acidosis because it may be more common than expected, early discontinuation of the offending agent is therapeutic, and administration of N-acetylcysteine could be beneficial.

Section snippets

Case Report

A 41-year-old man with a history of autosomal dominant polycystic kidney disease and follicular B-cell lymphoma with transformation to aggressive large cell lymphoma was admitted for salvage chemotherapy. He previously had undergone 3 separate chemotherapy regimens, but had progressive disease with malignant pericardial and pleural effusions. Baseline creatinine level was 1.5 mg/dL (133 μmol/L), and he had minimal liver involvement with normal liver function test results. The patient was

Discussion

This patient’s anion gap began increasing after he had been administered approximately 8 g of acetaminophen during 4 days and continued to increase with subsequent acetaminophen intake (Fig 1). The temporal correlation between acetaminophen intake and increase in anion gap provides strong evidence for causality. The development of altered mental status within this time frame also is highly suggestive of 5-oxoprolinemia because this symptom accompanies acidosis in most cases. It has been

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Cited by (46)

Pyroglutamate acidosis 2023. A review of 100 cases
2024, Clinical Medicine, Journal of the Royal College of Physicians of London
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 under-nourishment 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.
Acetaminophen induced 5-oxoproline acidosis: An uncommon case of high anion gap metabolic acidosis
2018, Revue de Medecine Interne
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.
The Many Shades of Dyspnea
2018, American Journal of Medicine
High anion gap metabolic acidosis secondary to chronic paracetamol (acetaminophen) poisoning
2015, Toxicologie Analytique et Clinique
L’acidose métabolique à trou anionique élevé (AMTAE) est couramment rencontrée dans la pratique médicale. Elle est le plus souvent associée à l’acide lactique, l’insuffisance rénale, à l’acidocétose diabétique et aux intoxications par le méthanol, les paraldéhydes, le fer, l’éthylène glycol ou les salicylates, étiologies rappelées par la mnémonique anglaise « MUDPILES » qui, dans le cadre de l’urgence, suffit généralement pour étiqueter l’AMTAE. Cependant, elle ne tient pas compte de nombreuses autres étiologies. Certaines causes rares sont en rapport avec l’accumulation d’acides organiques ou inorganiques. Les déficits enzymatiques, tels que les troubles du cycle γ-glutamyl, décrits plus fréquemment chez les enfants, provoquent une AMTAE par accumulation de 5-oxoproline (5-OxP) (ou acide pyroglutamique). L’AMTAE induite par l’acétaminophène (AC) est peu connue. Elle est alors généralement attribuée à l’acidose lactique transitoire sans lésion ni insuffisance hépatique. Dans ce contexte de consommation d’AC, des taux urinaires élevés de 5-OxP sont rapportés principalement chez des malades de sexe féminin, ayant des facteurs prédisposant tels que malnutrition, maladie hépatique, grossesse ou insuffisance rénale. Nous présentons ici le cas d’une patiente de 40 ans qui a présenté une AMTAE suite à l’accumulation de 5-OxP dans un contexte de malnutrition et d’ingestion chronique d’AC. Le traitement d’une AMTAE à 5-OxP en cas de surdosage en AC comprend l’arrêt de la substance en cause, l’administration de bicarbonates et de N-acétylcystéine (NAC) même si aucune preuve de l’efficacité de ces thérapeutiques n’a été démontrée.
High anion gap metabolic acidosis (HAGMA) is commonly encountered in medical practice. It is most often associated with lactic acid, renal failure, diabetic ketoacidosis and poisoning by methanol, paraldéhydes, iron, ethylene glycol or salicylates, etiologies recalled by the English mnemonic “MUDPILES” which, as part of the emergency, is usually sufficient to label the HAGMA. However, it does not take into account many other etiologies. Some rare cases of HAGMA are related to the accumulation of organic or inorganic acids. The enzyme defects, such as γ-glutamyl cycle disorders, described frequently in children, cause HAGMA by accumulation of 5-oxoproline (5-OxP) (or pyroglutamic acid). The HAGMA induced by acetaminophen (AC) is little known. It is then usually attributed to transient lactic acidosis without injury or liver failure. In this context of AC consumption, high urinary 5-OxP are reported mainly in female patients, who have predisposing factors such as malnutrition, liver disease, pregnancy or renal impairment. We present the case of a 40-year-old patient who presented a HAGMA following the accumulation of 5-OxP in the context of malnutrition and chronic ingestion of AC. The treatment of a 5-OxP acidosis in this context of AC overdose includes stopping the drug involved, the administration of bicarbonate and N-acetylcysteine (NAC), although no evidence of the effectiveness of these therapies has been proven.
Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies
2015, Brain and Development
Citation Excerpt :
A novel mutation, c.1252C>T was detected in one patient, although p.418R is not conserved, it leads to a premature termination codon which results in a truncated protein, which is very likely to be deleterious. Early treatment with vitamin C (ascorbic acid, 100 mg/kg/day), vitamin E (alpha-tocopherol, 100–300 mg/day) [24], N-acetylcysteine and bicarbonate are recommended to improve antioxidant capacity, raise the glutathione content, correct high-anion gap acidosis and normalize microtubule assembly and polymorphonuclear leukocyte function [25]. The therapy was proved effective for three patients in this study, as demonstrated by the much decreased urine 5-oxoproline levels after treatment.
5-Oxoprolinuria is a rare inherited metabolic disorder caused by a defective gamma-glutamyl cycle resulting from mutations in the genes encoding 5-oxoprolinase (OPLAH) and glutathione synthetase (GSS). No inherited 5-oxoprolinuria case has been reported in mainland China until now. In this study, clinical, biochemical, and genetic aspects of five Chinese 5-oxoprolinuria patients with OPLAH or GSS gene mutations were investigated.
Three boys and two girls from five unrelated Chinese families with symptomatic 5-oxoprolinuria were identified within the past 3 years in Peking University First Hospital. OPLAH and GSS genes were analyzed.
Patients were hospitalized between the age of 13 days to 1 year and 3 months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia. All patients had significantly elevated urine 5-oxoproline. Three novel mutations (c.1904G>A and c.2813_2815delGGG in Patient 1, c.2978G>T in Patient 2) on OPLAH, on GSS, one novel mutation (c.1252C>T in Patient 3) and a reported mutation (c.491G>A in Patients 3–5) were detected. Patient 4 has homozygous mutation c.491G>A, the others are heterozygous. After treatment by l-carnitine, vitamin E, B1, B2 and coenzyme Q₁₀, three patients with GSS deficiency improved, but the two 5-oxoprolinase-deficient patients did not respond to treatment.
5-Oxoprolinase deficiency and GSS deficiency share some clinical and biochemical features. Genetic analysis is important for the deferential diagnosis. In this study, five Chinese patients had severe central nervous system damage. Antioxidant treatments were proved effective for the three patients with GSS deficiency but not for the two patients with 5-oxoprolinase deficiency.
Diagnosis and Management of Acid-Base Disorders
2014, Hospital Medicine Clinics

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: Originally published online as doi:10.1053/j.ajkd.2005.04.010 on June 7, 2005.

: Supported in part by National Research Service Award grant no. F32 DK069037-01 (B.D.H.).

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Case reportAcetaminophen-Induced Anion Gap Metabolic Acidosis and 5-Oxoprolinuria (Pyroglutamic Aciduria) Acquired in Hospital

Section snippets

Case Report

Discussion

Lancet

J Pediatr

Pyroglutamic aciduria—A new inborn error of metabolism

Scand J Clin Lab Invest

5-Oxoprolinuria in patients with and without defects in the gamma-glutamyl cycle

Eur J Pediatr

Pyroglutamic acidemia in an adult patient

Clin Chem

Transient 5-oxoprolinuria and high anion gap metabolic acidosisClinical and biochemical findings in eleven subjects

Clin Chem

Pyroglutamic acidemiaA cause of high anion gap metabolic acidosis

Crit Care Med

Case report
Acetaminophen-Induced Anion Gap Metabolic Acidosis and 5-Oxoprolinuria (Pyroglutamic Aciduria) Acquired in Hospital