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HIGH ANIONIC GAP METABOLIC ACIDOSIS- UNCOMMON CAUSES 2: PYROGLUTAMIC ACIDOSIS

"Heard melodies are sweet,
those unheard are sweeter"
                      - John Keats

Pyroglutamic acid (5-oxoproline) is an intermediate metabolite of gamma glutamyl cycle. Gamma glutamyl cycle is responsible for glutathione synthesis and degradation.

Glutathione (gamma glutamyl cysteinyl glycine-GSH) is an antioxidant substance, involved in many biological function, including inactivation of free radicals.
Glutathione is synthesized by glutamate, glycine and cysteine.

Glutamate and cysteine is converted to gamma glutamyl cysteine, by gamma glutamyl cysteine synthetase (GCS), which then reacts with glycine, in the presence of glutathione synthetase, to produce glutathione.

Glutathione is degraded by gamma glutamyl transpeptidase (GGT) and gamma glutamyl cyclotransferase to pyroglutamic acid (5-oxoproline).

Pyroglutamic acid (5-oxoproline) is catalyzed by 5-oxoprolinase to glutamate, which enters into gamma glutamyl cycle.

Glutathione synthesis is kept under control by, negative feedback of glutathione, over gamma glutamyl cysteine synthetase (GCS). In other words glutathione inhibits gamma glutamyl cysteine synthetase.
Second mechanism of this control is, that excess gamma glutamyl cysteine is converted into pyroglutamic acid (5-oxoproline), by gamma glutamyl cyclotransferase.

PATHOPHYSIOLOGY: Glutathione deficiency, leads to disinhibition of gamma glutamylcysteine synthase (GCS). This results in unchecked production of gamma glutamyl cysteine, which is further converted into pyroglutamic acid (5-oxoproline).

Some of the pyroglutamic acid is catalyzed into glutathione. But persistently disinhibited gamma glutamyl cysteine synthetase, by deficient glutathione, results in accumulation of pyroglutamic acid, producing high anionic gap metabolic acidosis.

Glycine deficiency may also results in excess gamma glutamyl cysteine, and excess production and accumulation of pyroglutamic acid.

Genetic enzyme deficiency or acquired enzymatic inhibition, may also cause excess pyroglutamic acid production and accumulation.

Glutathione deficiency is seen in chronic paracetamol abuse, chronic ethanol abuse, malnutrition, pregnancy, hepatic and renal impairment, sepsis and vigabatrin toxicity.

Flucloxacillin and netilmycin inhibit enzyme 5-oxoprolinase.

DIAGNOSIS: Pyroglutamic acidosis should be suspected if other causes of HAG metabolic acidosis is ruled out, and established by high serum or urine 5-oxoproline level.

5-oxoproline level is not readily available, therefore PYROGLUTAMIC acidosis should be suspected in a patient with no explainable cause for HAG metabolic acidosis, and conditions predisposing to glutathione deficiency.

MANAGEMENT: 5-oxoproline is water soluble. IV fluid and diuresis leads to rapid resolution in 24-48 hours.

Removal of causative agents like drugs, or correction of causative factor like sepsis, malnutrition and glutathione repletion (N acetyl cysteine), is the cornerstone of therapy.

normal gamma-glutamyl cycle

Gamma Glutamyl Cycle

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