Severe Anion Gap Metabolic Acidosis From Acetaminophen Use Secondary to 5-Oxoproline (Pyroglutamic Acid) Accumulation

doi:10.1097/MAJ.0b013e318259bd45

The American Journal of the Medical Sciences

Volume 344, Issue 6, December 2012, Pages 501-504

https://doi.org/10.1097/MAJ.0b013e318259bd45 Get rights and content

Abstract

Anion gap metabolic acidosis (AGMA) is commonly encountered in medical practice. Acetaminophen-induced AGMA is, however, not widely recognized. We report 2 cases of high anion gap metabolic acidosis secondary to 5-oxoproline accumulation resulting from acetaminophen consumption: the first case caused by acute one-time ingestion of large quantities of acetaminophen and the second case caused by chronic repeated ingestion in a patient with chronic liver disease. Recognition of this entity facilitated timely diagnosis and effective treatment. Given acetaminophen is commonly used over the counter medication, increased recognition of this adverse effect is of important clinical significance.

Section snippets

CASE 1

A 19-year-old woman without any significant medical history presented to her local emergency department (ED) 20 hours after ingesting 225 tablets of 500 mg of acetaminophen (total dose of 112.5 g). The patient’s plasma acetaminophen level at the local ED was elevated at 216 μg/L (reference range < 50 μg/L). Arterial blood gas (ABG) results showed a pH of 7.0, $P_{O_{2}}$ of 133 mm Hg, $P_{{CO}_{2}}$ of 18 mm Hg and HCO₃ of 4 mmol/L. Aspartate aminotransferase was elevated at 475 U/L (8–43 U/L) and alanine aminotransferase

CASE 2

A 67-year-old woman with multiple comorbidities, including a long-standing history of alcohol abuse, alcoholic cirrhosis, chronic pancreatitis, recurrent cholecystitis and recurrent gastrointestinal (GI) bleeding, was admitted to the hospital for a severe GI bleed. The diagnostic workup revealed a GI stromal tumor that was resected surgically. Postoperatively on hospital day 4, she was started on oral acetaminophen (1000 mg every 6 hours). Her hospital course was complicated by acute wound

DISCUSSION

5-Oxoproline also known as pyroglutamic acid is an uncommon cause of severe AGMA and is often overlooked. 5-Oxoproline is a strong organic acid that readily dissociates upon formation⁸ and results in generation of hydrogen anion. It is a derivative of amino acids and has a similar composition to glutamic acid, except that it has a cyclic form.⁸ It is an intermediate metabolite of γ-glutamyl cycle, a cycle involved in transport of amino acids into the cells.

The γ-glutamyl cycle starts with the

CONCLUSION

5-Oxoproline accumulation after acetaminophen ingestion is a rare but important cause of AGMA. In 2008, a new mnemonic for AGMA known as GOLD MARK was proposed²¹ and stands for: glycols (ethylene and propylene), oxoproline, l-lactate, d-lactate, methanol, aspirin, renal failure and ketoacidosis. We encourage physicians to consider using this mnemonic as it takes into account all the important causes of AGMA encountered in this contemporary era of clinical practice.

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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.
Metabonomics screening of serum identifies pyroglutamate as a diagnostic biomarker for nonalcoholic steatohepatitis
2017, Clinica Chimica Acta
Citation Excerpt :
The level of pyroglutamate is often used to screen for glutathione synthetase deficiency in pediatric patients [23]. Children with deficiencies of either glutathione synthase or 5-oxoprolinase will present with metabolic acidosis or other abnormalities due to the accumulation of pyroglutamic acid [24–26]. When glycine is insufficiently available to support glutathione recovery via the renal gamma-glutamyl cycle, the rising level of pyroglutamate is regarded as an index of glycine insufficiency.
A key step in managing non-alcoholic fatty liver disease (NAFLD) is to differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis (SS).
Serum samples were collected from three groups: NASH patients (N = 21), SS patients (N = 38) and healthy controls (N = 31). High performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyse the metabolic profile of the serum samples. The acquired data were processed by multivariate principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA) to identify novel metabolites. The potential biomarkers were quantitatively determined and their diagnostic power was further validated.
A total of 56 metabolites were capable of distinguishing NASH from SS samples based on the OPLS-DA model. Pyroglutamate was found to be the most promising factor in distinguishing the NASH from SS groups. With an optimal cut-off value of 4.82 mmol/L, the sensitivity and specificity of the diagnosis of NASH were 72% and 85%, respectively. The area under the receiver operating characteristic (AUROC) of the pyroglutamate levels of NASH versus SS patients was more than those of tumor necrosis factor-α, adiponectin and interleukin-8.
These data suggest that pyroglutamate may be a new and useful biomarker for the diagnosis of NASH.
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.
Flucloxacillin and paracetamol induced pyroglutamic acidosis
2021, BMJ Case Reports
Acquired pyroglutamic acidosis due to long-term dicloxacillin and paracetamol use
2020, BMJ Case Reports
5-Oxoproline concentrations in acute acetaminophen overdose
2020, Clinical Toxicology

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Case ReportSevere Anion Gap Metabolic Acidosis From Acetaminophen Use Secondary to 5-Oxoproline (Pyroglutamic Acid) Accumulation

Abstract

Section snippets

CASE 1

CASE 2

DISCUSSION

CONCLUSION

Life Sci

Toxicol Lett

Am J Kidney Dis

J Nutr

J Emerg Med

Lancet

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

Eur J Pediatr

Biochemical heterogeneity in glutathione synthetase deficiency

J Clin Invest

Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis

Crit Care Med

Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects

Clin Chem

Case Report
Severe Anion Gap Metabolic Acidosis From Acetaminophen Use Secondary to 5-Oxoproline (Pyroglutamic Acid) Accumulation