Metabolic acidosis due to paracetamol (acetaminophen)

Metabolic acidosis is a common metabolic disturbance among the acutely/critically ill that has many possible causes. The condition is diagnosed by arterial blood gas analysis which reveals primary reduction in pH and bicarbonate, followed by secondary (compensatory) reduction in pCO₂. 

Abnormal accumulation of endogenous organic acids is one broad mechanism that gives rise to metabolic acidosis, which is differentiated from other mechanisms by being associated with high anion gap. The most common endogenous organic acid metabolic acidosis are: lactic acidosis (accumulation of lactic acid) and ketoacidosis (accumulation of ketoacids). 

Rarer causes of high anion gap metabolic acidosis due to organic acid accumulation are those that result from ingestion of a toxic substance whose metabolism involves production of an organic acid. For example, the toxicity of ethylene glycol is due in part to its metabolism to oxalic acid and the metabolic acidosis that results from accumulating oxalic acid. 

In recent years there has been increasing recognition that regular/frequent paracetamol use at recommended dosage is a risk factor for high anion gap metabolic acidosis because it can be associated with accumulation in blood of the organic acid, 5-oxoproline (alternative name pyroglutamic acid).

Two recently published papers contain three illustrative case histories. The first paper focuses on two similar case histories including that of a 63-year-old woman with mild chronic kidney disease admitted to intensive care following a 9-day history of unexplained lethargy, breathlessness and confusion. 

She had a long history of chronic back pain, and two weeks prior to admission had been prescribed 2 × 500 mg paracetamol tablets to be taken every 6 hours (the maximum recommended dose). Admission arterial blood gases revealed severe high anion gap metabolic acidosis (pH 7.03, bicarbonate 6.0 mmol/L, base excess –22.6 mmol/L and anion gap of 37 mmol/L). 

A normal plasma lactate excluded lactic acidosis and the finding of only trace amounts of ketones in urine excluded ketoacidosis. The presence of 5-oxoproline in urine suggested that paracetamol ingestion might be the cause, despite plasma paracetamol being within therapeutic limits. Paracetamol was withdrawn and the paracetamol antidote N-acetylcysteine was administered along with sodium bicarbonate. 

These measures resulted in “immediate resolution of her acid-base state”.

In discussion of these three case histories, which are broadly similar, the authors of the two papers discuss the proposed mechanism that gives rise to accumulation of 5-oxoproline following paracetamol ingestion. Predisposing factors include: female gender, poor nutrition and some degree of renal insufficiency. 

A take-home message of both papers is that for patients with high anion gap metabolic acidosis without evidence of lactic acidosis or ketoacidosis, paracetamol should be considered in the differential diagnosis. If there is a history of chronic paracetamol use, urine or plasma should be submitted for 5-oxoproline estimation.