Acetaminophen, the missing anion gap in the patient with metabolic acidosis

Acetaminophen intake is well-known but an often missed cause of high anion gap (AG) metabolic acidosis, and physicians must understand the metabolic pathway which increases the AG. Multiple mnemonics for common causes of metabolic acidosis have been developed and are widely taught in medical schools. Some of them, such as MUDPILES and KUSMAE, may not lead to an adequate workup and miss the diagnosis for the acidosis. More recently developed memory tools, such as GOLDMARK, provide a complete differential diagnosis for high AG metabolic acidosis. Pyroglutamic acid accumulates after alterations of the gamma-glutamyl cycle mediated by acetaminophen and glutathione deficiency in some patients. The lower capacity of 5-oxiprolinase to metabolize pyroglutamic acid into glutamate results in the gradual accumulation of oxoproline/pyroglutamic acid. Treatment is mainly supportive with the major aim of restoring glutathione levels, optimizing nutrition, and using N-acetylcysteine as needed. Different modalities of renal replacement therapy have also been used in these patients.