Pyroglutamic acidosis in association with therapeutic paracetamol use

Abstract

Long-term use of paracetamol (at therapeutic doses) can cause the accumulation of endogenous organic pyroglutamate, resulting in metabolic acidosis with an elevated anion gap. This occurs in the presence of malnutrition, infection, antibiotic use, renal failure and pregnancy. Given the prevalence of these risk factors, this condition is thought to be relatively common in a hospitalised population but is probably significantly underdiagnosed. Prompt recognition is essential because the condition is entirely reversible if the causative agents are withdrawn.Here we describe five cases of pyroglutamic acidosis that we have encountered in a tertiary referral hospital. Together they illustrate the common clinical risk factors and the excellent prognosis, once a diagnosis is made. We describe how a rudimentary acid-base analysis (calculation of the anion gap) usually leads to the diagnosis but how a more nuanced approach may be required in the presence of mixed acid-base disorders.

Keywords: 5-oxoproline; acidosis; anion gap; paracetamol; pyroglutamate.

Fig 1.

The γ-glutamyl cycle. 5-oxoprolinase operates at low capacity and, therefore, 5-oxoproline will accumulate in the plasma when its rate of production is high. Various factors act to cause accumulation of 5-oxoproline, either by depleting glutathione (blue boxes) or by inhibiting the clearance of 5-oxoproline by 5-oxoprolinase or its renal excretion (green boxes). Enzymes are shown in red italics. EtOH XS = excessive intake of ethanol. Adapted from Humphreys et al.

Fig 2.

Modified ‘Gamblegram’ displaying serum and urine anion gaps for case 2. A – measured and unmeasured cations (red) and anions (green) in the serum. Numbers refer to ion concentrations in mM and as the quantities of the unmeasured ions are not known, the figure is deliberately not drawn to scale. AG = Na–Cl– HCO₃ = unmeasured anions. B – measured and unmeasured cations (red) and anions (green) in the urine. UAG = Na+K–Cl = unmeasured anions. AG = serum anion gap; flucox = flucloxacillin; ket = ketones; OAs = organic acids; prot = proteins; pyro = pyroglutamate; tit ac = titratable acids; UAG = urine anion gap. Adapted from Rolleman et al and Gabow.