Pyroglutamic Acidosis

OVERVIEW

  • Pyroglutamic acidosis is a rare cause of high anion gap metabolic acidosis (HAGMA)
  • pyroglutamic acid is also known as 5-oxoprolinemia
    • produced from γ-glutamyl cysteine by the enzyme γ-glutamyl cyclotransferase
    • catabolised by 5-oxoprolinase
  • when glutathione levels are low, the activity of γ-glutamyl cyclotransferase is increased, resulting in pyroglutamic acid accumulation in glutathione-depleted states

CAUSE

Risk factors

  • elderly
  • paracetamol use (glutathione depletion by its metabolite NAPQI)
  • sepsis (depletion of glutathione)
  • flucloxacillin (inhibits 5-oxoprolinase)
  • hepatic and renal impairment
  • malnutrition
  • pregnancy
  • vigabatrin
  • congenital enzyme deficiencies (glutathione synthase deficiency)

Pyroglutamic acidosis results from disruption of the γ-glutamyl cycle

G Gcycle
Key: A = excess γ-glutamyl cysteine becomes a substrate for γ-glutamyl cyclotransferase, P = paracetamol, S = sepsis, F = flucloxacillin. From Dempsey et al, 2000
  • 5-oxoproline (aka pyroglutamic acid) is produced from γ-glutamyl cysteine by the enzyme γ-glutamyl cyclotransferase
  • γ-glutamyl cyclotransferase activity increases when glutathione levels are low, due to a loss of feedback inhibition from glutathione
  • accumulation of pyroglutamic acid is thought to be due to depletion of the glutathione, particularly when glutathione synthetase is inhibited
  • Decreased activity of 5-oxoprolinase, which breaks down pyroglutamic acid, may also play a role

CLINICAL FEATURES

  • manifestations of acidaemia
    • e.g. tachycardia, tachypnoea, altered level of consciousness
  • presence of risk factors
  • features of underlying cause

INVESTIGATIONS

  • high anion gap metabolic acidosis (HAGMA) on blood gas
  • normal osmolar gap
  • normal lactate
  • normal beta-hydroxybutyrate
  • high pyroglutamic acid (urine or blood)

MANAGEMENT

  • stop exacerbating factors
  • treat sepsis, including:
    • early and appropriate antibiotics
    • source control
  • supportive care and monitoring
    • intubation, ventilation, renal replacement therapy (RRT) as indicated
  • N-acetylcysteine
    • help replenish glutathione stores

References and Links

LITFL

Journal articles

  • Dempsey GA, Lyall HJ, Corke CF, & Scheinkestel CD (2000). Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis. Critical care medicine, 28 (6), 1803-7 [pubmed]
  • Mizock BA, & Mecher C (2000). Pyroglutamic acid and high anion gap: looking through the keyhole? Critical care medicine, 28 (6), 2140-1 [pubmed]
  • Peter JV, Rogers N, Murty S, Gerace R, Mackay R, & Peake SL (2006). An unusual cause of severe metabolic acidosis. The Medical journal of Australia, 185 (4), 223-5 [pubmed]
CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.