pyroglutamic acidosis aka tylenol toxicity

  • related: Nephrology
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The most likely diagnosis is pyroglutamic acidosis. Pyroglutamic acidosis, which presents with mental status changes and an increased anion gap (without osmolar gap increase), occurs in selected patients receiving therapeutic doses of acetaminophen on a chronic basis. Susceptible patients are those with critical illness, poor nutrition, liver disease, or chronic kidney disease, as well as those on a strict vegetarian diet. In this context, acetaminophen leads to depletion of glutathione, altering the γ-glutamyl cycle to overproduce pyroglutamic acid (also known as 5-oxoproline). Diagnosis can be confirmed by measuring urine levels of pyroglutamic acid.

A high anion gap metabolic acidosis is often encountered in critically ill patients and is most often associated with diabetic, alcoholic, or starvation ketoacidosis and with lactic acidosis. This finding can also be seen with the accumulation of organic acids such as 5-oxoproline, an increasingly recognized etiology of severe, persistent acidosis as seen in this case.

Elevated 5-oxoproline (pyroglutamic acid) levels should be considered in patients using acetaminophen with conditions that place them at risk of glutathione depletion, including sepsis, chronic alcohol use disorder, chronic liver disease, and malnutrition. Other recognized risk factors include older age, pregnancy, female sex, and certain medications (including vigabatrin, flucloxacillin, and netilmicin). 

Glutathione is an important antioxidant, responsible for the metabolism and clearance of N-acetyl-p-benzoquinone imine (the highly reactive acetaminophen metabolite responsible for acute liver injury at high levels). Glutathione is formed through the adenosine triphosphate (ATP)-dependent binding of glutamate, cysteine, and glycine by γ-glutamylcysteine synthetase and glutathione synthetase. Cysteine (among other sulfated amino acids) binds to acetaminophen metabolites prior to renal excretion, especially in women. The resulting low cysteine level impairs glutathione production, and glutamate is instead converted to 5-oxoproline. In the setting of malnutrition and chronic illness, low levels of dietary glycine further increase 5-oxoproline production, and the energy-dependent conversion of this acid back to glutamate slows as ATP levels fall. Chronic acetaminophen ingestion consumes glutathione and creates conditions that impede further synthesis in favor of 5-oxoproline production, especially in women and malnourished patients with glutathione-deficient states.

5-Oxoproline should be considered as a cause for a persistent high anion gap metabolic acidosis in a consistent clinical setting when more common causes have been addressed or excluded. A systematic review of published case reports found a wide variation of acetaminophen dose, duration, and circumstances in this setting, often with normal acetaminophen and normal or elevated transaminase levels. Acute kidney injury with potassium and phosphate wasting due to renal tubular toxicity from acetaminophen can also occur in low ATP states and is further exacerbated by futile ATP-depleting 5-oxoproline metabolism. Elevated 5-oxoproline concentrations in blood or urine confirm the diagnosis but have not been correlated with clinical outcomes or mortality. Although the administration of N-acetylcysteine has theoretical benefit, its therapeutic role has not been objectively demonstrated in clinical trials.

Treatment is otherwise supportive, and patients with refractory acidosis may require renal replacement therapy. Paraldehyde is a CNS depressant, historically used to treat alcohol withdrawal, seizures, and cough. It is not commonly encountered in modern medical practice. D-lactate is the optical isomer of L-lactate and can be produced by intestinal bacteria in the setting of short bowel syndrome, bariatric surgery, or ingestion of large volumes of carbohydrates with malabsorption of any cause. D-lactate levels can also be increased with use of medications containing propylene glycol, such as IV lorazepam or phenobarbital. Severe high anion gap metabolic acidosis can occur, and a specific D-lactate level is necessary to make the diagnosis. In this case, the patient has no risk factors to suggest this diagnosis.123

Footnotes

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  2. Emmett M. Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle. Clin J Am Soc Nephrol. 2014;9(1):191-200. PubMed ↩

  3. Liss DB, Paden MS, Schwarz ES, et al. What is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure? Clin Toxicol (Phila). 2013;51(9):817-827. PubMed ↩