25 May 2021
by Susan Troup, Jonathan Vernazza

Pyroglutamic acidosis due to therapeutic paracetamol: an under-recognised cause of metabolic acidosis

Susan D Troup, Jonathan Vernazza

Pyroglutamic acidosis due to therapeutic paracetamol: an under-recognised cause of metabolic acidosis

Susan Troup (Clinical Biochemistry, South of Tyne and Wear Pathology Services, Gateshead Health NHS Foundation Trust, Gateshead, United Kingdom), Jonathan Vernazza (Clinical Biochemistry, South of Tyne and Wear Pathology Services, Gateshead Health NHS Foundation Trust, Gateshead, United Kingdom)

Elevated anion gap metabolic acidosis is a common finding in critical illness.  Causes include lactic acidosis, ketoacidosis, advanced renal failure and ingestion of toxic alcohols.  Here we report 2 cases of an under-recognised cause, accumulation of pyroglutamic acid (5-oxoproline).

Patient 1 was a 64 year old woman admitted with an adnexal mass which necessitated bilateral nephrostomies.  She had been on paracetamol throughout her admission and was being treated with flucloxacillin for suspected endocarditis.  On day 25 she developed a metabolic acidosis which was treated with sodium bicarbonate.  Paracetamol and flucloxacillin were stopped, but haemodialysis was required to resolve the acidosis.  Patient 2 was a 44 year old woman with suspected pancreatitis, starvation ketosis and profound metabolic acidosis.  She denied overdose yet had an elevated serum paracetamol and was treated with N-acetyl cysteine.  In both cases a urine sample was sent for organic acid analysis whereupon significant amounts of pyroglutamic acid were detected. 

The anti-oxidant glutathione is an intermediary in the g-glutamyl cycle which imports amino acids across cell membranes.  Paracetamol, even at therapeutic doses, can lead to depletion of glutathione, particularly in combination with sepsis, chronic alcoholism, chronic liver failure or malnutrition.  Depletion of glutathione removes negative feedback on the enzyme g-glutamyl cysteine synthase leading to a futile over-activation of this cycle and the build-up of pyroglutamic acid.  The antibiotic flucloxacillin inhibits another enzyme in this cycle, 5-oxoprolinase, whose role is to breakdown pyroglutamic acid.

Pyroglutamic acidosis should be considered as a possible cause of elevated anion gap metabolic acidosis in patients administered paracetamol +/- flucloxacillin particularly where other risk factors are present.  Detection of high levels of pyroglutamic acid in urine or plasma can confirm the cause.  Cessation of these causative agents, alongside glutathione repletion with N-acetyl cysteine, is the mainstay of treatment, although haemodialysis may be required.

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Authors

Susan Troup

Jonathan Vernazza

Clinical Biochemistry, South of Tyne and Wear Pathology Services, Gateshead Health NHS Foundation Trust