Pyroglutamic acidosis has been the subject of several SAQs, which - some might say- places it upon a pedestal of undeserved importance in the mind of the trainee. It is a ridiculous rare problem, which occurs due to glutathione depletion in patients who are already glutathione-depleted, and who receive flucloxacillin or vigabatrin  together with paracetamol.

SAQs involving this disorder have appeared every year for the last 4 years.

 

Mechanism

  • Pyroglutamic acid is produced from γ-glutamyl cysteine by the enzyme γ-glutamyl cyclotransferase
  • When glutathione levels are low, the activity of γ-glutamyl cyclotransferase is increased, resulting pyroglutamic acid accumulation.
  • Glutathione is acutely depleted by paracetamol and sepsis; it can also be chronically depleted in liver disease and malnutrition.

 

A much more detailed exploration of this ridiculously rare disorder is carried out in a dedicated chapter on pyroglutamic acidosis. The three-line answer above is the expected minimum.

 

The diagnosis of pyroglutamic acidosis depends upon the detection of 5-oxoproline; this is either a urinary or a serum level. Usually, an adult ICU needs to send this sample to a paediatric centre, where detailed analysis of weird metabolites is more likely to be available.

 

Management consists of

  • The cessation of the causative agents (flucloxacillin and paracetamol)
  • Glutathione repletion (with N-acetylcysteine)
  • Protection of satisfactory diuresis (5-oxoproline is cleared renally)

 

Factors which predispose patients to pyroglutamic acidosis

This was asked about in Question 23 from the second paper of 2014.

 

Depletion of glutathione

  • Paracetamol
  • Severe sepsis
  • Chronic alcoholism
  • Chronic liver failure of any cause
  • Weird diet, or malnutrition in general

 

Dysfunction of 5-oxoprolinase

 

Diminished 5-oxoproline clearance

  • Renal failure

 

The college also like to include old age as a risk factor. This association is known from case reports, as it seems most of the reported-on patients are elderly, but the mechanism is not well explained. Likely there are simultaneous issues of malnutrition, decreased hepatic glutathione reserves, diminished enzyme activity, and poor renal clearance.

References

Dempsey GA Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis. Crit Care Med. 2000Jun;28(6):1803-7.

 

Duewall, Jennifer L., et al. "5-Oxoproline (pyroglutamic) acidosis associated with chronic acetaminophen use." Proceedings (Baylor University. Medical Center) 23.1 (2010): 19.

 

Akhilesh Kumar and Anand K. Bachhawat Pyroglutamic acid: throwing light on a lightly studied metabolite ,SPECIAL SECTION: CHEMISTRY AND BIOLOGY. CURRENT SCIENCE, VOL. 102, NO. 2, 25 JANUARY 2012. 288

 

Amer, H. "Flucloxacillin/paracetamol interaction Metabolic acidosis in elderly patients: 2 case." Reactions 1373 (2011): 15.