Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid)

Abstract

The endogenous organic acid metabolic acidoses that occur commonly in adults include lactic acidosis; ketoacidosis; acidosis that results from the ingestion of toxic substances such as methanol, ethylene glycol, or paraldehyde; and a component of the acidosis of kidney failure. Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid). Reported are four patients with this syndrome, and reviewed are 18 adult patients who were reported previously in the literature. Twenty-one patients had major exposure to acetaminophen (one only acute exposure). Eighteen (82%) of the 22 patients were women. Most of the patients were malnourished as a result of multiple medical comorbidities, and most had some degree of kidney dysfunction or overt failure. The chronic ingestion of acetaminophen, especially by malnourished women, may generate high anion gap metabolic acidosis. This undoubtedly is an underdiagnosed condition because measurements of serum and/or urinary 5-oxoproline levels are not readily available.

Drug-induced acid-base disorders

“…Penicillins Rarely, penicillins may cause a disturbance in the gamma glutamyl cycle, with decreased 5-oxoproline and pyroglutamate, analogous to acetaminophen, causing metabolic acidosis with elevated AG [68][69][70].…”

Drug-induced metabolic acidosis

“…The resulting accumulation of pyroglutamic acid (5-oxoproline) causes high anion gap metabolic acidosis. Although a rare cause of metabolic acidosis, it is important due to its association with two widely used drugs, paracetamol and flucloxacillin, 34,35 and because it is often unrecognised. Chronic paracetamol therapy contributes to the risk of pyroglutamic acidosis through depletion of glutathione stores, while flucloxacillin inhibits 5-oxoprolinase, the enzyme responsible for metabolising pyroglutamic acid to glutamic acid.…”

Pyroglutamic acidosis in association with therapeutic paracetamol use

“…Depletion of intracellular glutathione is thought to be key to the pathogenesis of pyroglutamic acidosis; N-acetylcysteine has been used in other cases in an attempt to restore glutathione stores. 2 Flucloxacillin may have been causative in case 3; this was therefore converted to ceftriaxone (and rifampicin) and continued so that antibiotic therapy was given for 6 weeks in total. Although flucloxacillin may also have been causative in cases 2 and 5, a clinical decision was made to continue with flucloxacillin therapy.…”

“…[1][2][3][4][5][6][7][8] All had chronic exposure to paracetamol at therapeutic doses; all were malnourished due to either alcohol excess or prolonged illness in hospital; four were female; all had received antibiotics (flucloxacillin for Staphylococcus septicaemia in three); three had renal failure. Our cases emphasise that multiple risk factors (particularly nutritional deficiency plus chronic paracetamol use) are universally present.…”

“…1 Chronic paracetamol use contributes to both glutathione and cysteine depletion and is exacerbated by nutritional deficiencies in cysteine precursors and glycine. 1,2 The evidence that paracetamol ingestion causes pyroglutamic acidosis comes from case series demonstrating a strong clinical association, and also from an experimental rat model. 10 Interestingly, the urinary excretion of pyroglutamate is increased (although not to levels that cause systemic acidosis) in children exposed to paracetamol, suggesting that asymptomatic (non-acidaemic) pyroglutamic aciduria may be a common feature of therapeutic paracetamol use.…”