Pyroglutamic acidosis

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.

• Question 23 from the second paper of 2014
• Question 18.3 from the second paper of 2013
• Question 3.2 from the second paper of 2012
• Question 3.1 from the second paper of 2011

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

• Flucloxacillin
• Vigabatrin
• Netilmicin (but apparently not any other aminoglycosides)
• Inherited enzyme deficiency (known only from case reports)
• Gender-specific difference in enzyme activity (women seem more prone to this acidosis)

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.