An uncommon cause of highanion gap metabolic acidosis after repeated supratherapeutic paracetamol ingestion. [Clinical Toxicology]

Abstract

Objective: High-anion gap metabolic acidosis (HAGMA) most commonly results from excess urea, lactate, ketones and exposure to toxins such as salicylate and toxic alcohols. Accumulation of pyroglutamic acid (PGA) is a rare cause of HAGMA. The exact incidence of HAGMA caused by PGA accumulation is unknown. A recent prospective study reported that high urine PGA concentrations were associated with 10% of patients with HAGMA. PGA is processed by the glutamate-glutathione cycle. The commonest cause of PGA accumulation is glutathione depletion. This causes the loss of negative feedback on gamma-glutamylcysteine (PGA precursor) production. Other causes include malnutrition, alcoholism, liver failure and sepsis. Though rare, deficiency of either glutathione synthetase causing gamma-glutamylcysteine (PGA precursor) accumulation or 5-oxoprolinase resulting in reduced PGA metabolism, also cause PGA accumulation. We describe a case of confirmed PGA accumulation after repeated supratherapeutic paracetamol use. Case report: A 32-year-old female presented with ongoing pain from shingles despite having taken 96 x 665 mg modified-release paracetamol caplets over the preceding two days. Two years prior, she suffered a gastric ulcer perforation following excessive ibuprofen use for dysmenorrhea. She subsequently ceased using NSAIDs and substituted these with regular use of four modifiedrelease paracetamol tablets every 3-4 hours. On presentation vital signs were normal except a respiratory rate of 24/min. Venous blood gas showed pH 7.04, bicarbonate 5.0mmol/L, pCO2 19 mmHg, lactate 1.4mmol/L, sodium 150mmol/L, chloride 117 mmol/L and anion gap 28, indicating a partially compensated HAGMA. Serum ketones were 2.8mmol/L, salicylate undetected and normal osmolar gap. Serum paracetamol was 312 mumol/L, 2.5 hours after the last dose. Liver function, INR and creatinine were normal. PGA accumulation from chronic paracetamol misuse and glutathione depletion was suspected. Acetylcysteine was infused for 20 hours to replenish glutathione. Other treatment included intravenous crystalloids and sodium bicarbonate infusion. Metabolic acidosis resolved completely over 36 hours. Serum ALT and INR remained normal. She was discharged after three days. A qualitative urine assay was positive for PGA (5-oxoproline). Conclusion(s): In this case, chronic excessive paracetamol use compounded by a staggered paracetamol overdose most likely lead to glutathione depletion and PGA accumulation. Treatment included ceasing paracetamol and glutathione replenishment with acetylcysteine therapy. In the absence of enzyme deficiencies, HAGMA from PGA accumulation is unlikely to recur once glutathione is replenished. PGA accumulation should be considered in the differential diagnosis of unexplained HAGMA, especially with a history of excessive supratherapeutic paracetamol use.