This is a rare form of high anion gap metabolic acidosis, associated with the use of paracetamol, flucloxacillin and vigabatrin.

In summary, pyroglutamic acidosis occurs due to glutathione depletion in patients who receive flucloxacillin or vigabatrin  together with paracetamol. The key feature is loss of feedback inhibition because of glutathione depletion, which results in overproduction of pyroglutamic acid.

Normal gamma-glutamyl cycle

The purpose of this cycle is to bring amino acids (and various peptides, as well as xenobiotic drugs) into the cell, and then to replenish the glutathione, recycling it.

normal gamma-glutamyl cycle

The rate of glutathione synthesis is kept under check by negative feedback. Glutathione levels inhibit the function of gamma-glutamyl cysteine synthase.

Effect of glutathione depletion by paracetamol or sepsis

glutathione depletion in pyroglutamic acidosis

Let us imagine glutathione is depleted by some process, eg. paracetamol metabolism or sepsis. There is still plenty of cysteine and glutamate around. A disinhibition of gamma-glutamyl cysteine synthase results in frantic overproduction of gamma-glutamyl cysteine, the substrate for gamma-glutamyl cyclotransferase. Certainly, some is also turned into glutathione, but this glutathione continues to be eaten up by the depleting process, and gamma-glutamyl cysteine synthase remains disinhibited. The resulting excess of 5-oxoproline produces the acidosis.

Effect of 5-oxoprolinase inhibition by flucloxacillin

In a much more straightforward pattern, the acidosis results from a buildup of 5-oxoproline when the enzye responsible for its breakdown is inhibited.

5-oxoprolinase inhibition in pyroglutamic acidosi

Ample stores of glutamate and cysteine exist, because they do not depend on breakdown of 5-oxoproline, and the cycle continues - but 5-oxoproline buildup cannot resolve while the 5-oxoprolinase remains inhibited.

Diagnosis of pyroglutamic acidosis

A plasma assay (by gas chromatograph mass spectrometry) and a urine assay (by same method) is the only diagnostic modality mentioned in the papers. I imagine this is not available everywhere. A high anion gap without a good explanation may be one's only guide.

One must be aware of the fact that only the L-isoform of 5-oxoproline is produced by the human organism. An unxpected excess of dextro-5-oxoproline is therefore probably the effect of bacterial activity.

Predisposing risk factors

With an acid-base disturbance so freakishly rare, one ought to have some strong pre-test reasons to order all this expensive bichemistry.

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

Old age is also associated with pyuroglutamic acidosis. 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.

Management of pyroglutamic acidosis

5-oxoproline is cleared renally. Its solubility in water makes it easily dialysed, if it comes to that. If one is for some reason unable to correct the abnormality in the gamma-glutamyl cycle, one can rely on diuresis to clear it. Otherwise, the cessation of the causative agents (flucloxacillin and paracetamol) and glutathione repletion (with N-acetylcysteine) are the most important management strategies. It would be wonderful to have some sort of recombinant oxoprolinase, but we haven't got one.

Historical approaches to the management of pyroglutamic acidosis have included cheating with a sodium bicarbonate infusion. A case series from 2000 describes three case reports, of whom all received a correcting dose of NaHCO3. There were two survivors.

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

 

Fenves, Andrew Z., et al. "Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen." Clinical Journal of the American Society of Nephrology 1.3 (2006): 441-447.

 

Kortmann, W., et al. "5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors." Neth J Med 66.8 (2008): 354-357.

 

Larsson, A., et al. "5‐OXOPROLINURIA DUE TO HEREDITARY 5‐OXOPROLINASE DEFICIENCY IN TWO BROTHERS–A NEW INBORN ERROR OF THE γ‐GLUTAMYL CYCLE." Acta Paediatrica 70.3 (1981): 301-308.

 

Pitt, James J., and Simon Hauser. "Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects."Clinical chemistry 44.7 (1998): 1497-1503.

 

Brooker, G., et al. "High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition." Annals of clinical biochemistry 44.4 (2007): 406-409.

 

Oakley, Aaron J., et al. "The Identification and Structural Characterization of C7orf24 as γ-Glutamyl Cyclotransferase AN ESSENTIAL ENZYME IN THE γ-GLUTAMYL CYCLE." Journal of Biological Chemistry 283.32 (2008): 22031-22042.

 

Lv, Haitao, et al. "Ingenuity pathways analysis of urine metabonomics phenotypes toxicity of gentamicin in multiple organs." Molecular Biosystems6.10 (2010): 2056-2067.