A rare and underestimated cause of anion gap metabolic acidosis in a pediatric patient

Abstract Recognized causes of anion gap metabolic acidosis include methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, iron, lactic acidosis, ethylene glycol, and salicylates, which is taught as the mnemonic, MUDPILES. While this mnemonic can be a useful learning tool, it is important to consider other, atypical causes. Here, we present the case of a 9-year-old male patient with a complex medical history, including trisomy 21 and Lennox-Gastaut syndrome who presented to the emergency department (ED) in hypotensive shock. Upon admission, he was noted to have a distended abdomen, evidence of acute pancreatitis and possible sepsis. Of note, his initial labs revealed an anion gap of 30.1 mmol/L, a whole blood lactate of 4.4 mmol/L, a pH of 7.2, and a normal pCO2, indicting an anion gap metabolic acidosis. Importantly, methanol, ethylene glycol, ketones, and salicylates were not detected, and renal function was normal. However, he did have an extensive medication history, including several antiepileptic drugs (AEDs). Over the coming weeks, he recovered from the acute pancreatitis, but developed fluid overload, electrolyte derangements (hypernatremia and hypokalemia), a worsening metabolic acidosis with an anion gap up to 54.6 mmol/L, and hyperammonemia (plasma NH3 of 232 μmol/L). At this point, the metabolism team was contacted for concerns regarding the rising ammonia levels, which subsequently responded to a combination of lactulose and Rifaximin. An inborn error of metabolism (IEM) was considered, and plasma amino acid analysis was performed (Waters Acquity MassTrak AAA solution) but was not diagnostic. Notably, the patient developed a significantly elevated gamma glutamyl transpeptidase (GGT) up to 4088 U/L, suggesting glutathione depletion, however, transaminases and alkaline phosphatase were normal. The laboratory was contacted by the metabolism providers for other possible causes of metabolic acidosis and it was suggested that the patient undergo urine organic acid testing. Urine specimens were analyzed using gas chromatography/mass spectrometry (GC/MS) (Aligent system). The results were notable for marked excretion of pyroglutamic acid (5-oxoproline), which is typically associated with acetaminophen, however, the patient’s acetaminophen levels were less than 5 μg/mL, indicating another, atypical cause of increased pyroglutamic acid. In this case, vigabatrin, an anticonvulsant known to cause glutathione depletion and secondary pyroglutamic aciduria was suspected, and subsequently withdrawn. The patient was also started on a trial of N-acetylcysteine (NAC) to replenish glutathione, which resolved the pyroglutamic aciduria and anion gap, and corrected the metabolic acidosis. This case highlights the importance of recognizing pyroglutamic acid as a rare cause of anion gap metabolic acidosis, even in the setting of normal acetaminophen levels, and the importance of organic acid testing in the work-up of such patients. Wider use of the mnemonic GOLD MARK, where the “O” stands for oxoproline, may help in the differential diagnosis of anion gap metabolic acidosis.