Episode 11: Why can acetaminophen toxicity cause an anion gap acidosis?

For this episode of the podcast, we discussed the first in a series of questions Hannah has asked during the first-half of her intern year. As she noted the routine ‘first round’ differential for an anion gap metabolic acidosis typically includes lactic acidosis, keto-acids, and uremic acids (e.g., sulfuric and phosphoric acids). If one of these isn’t present, then one begins exploring the other items on the MUDPILES or GOLDMARK pneumotic.

For Hannah, reacquainting herself with these introduced her to acetaminophen-related anion gap metabolic acidosis.

Drug Metabolism Refresher

Recall that there are two phases of drug metabolism, the aptly named Phase I and Phase II. Phase I reactions include oxidation, reduction, and hydrolysis and are often carried out by cytochrome p450 enzymes. Phase II reactions conjugate drugs by adding stick an endogenous polar group on them, making them more permanently polar and therefore easily excretable by the kidney.

In the liver, the gamma-glutamyl cycle normally generates glutathione. Glutathione is a tripeptide molecule containing cysteine, glycine, and glutamate. It has several key biochemical functions, but the key for understanding acetaminophen-related acidosis is that is aids in Phase II conjugation.


When we consume small doses of acetaminophen most of it goes straight to glucuronidation in the liver. Only about 10% undergoes Phase I metabolism into a toxic molecule called N-acetyl-p-benzoquinone imine (NAQPI).

NAQPI is highly reactive and has the potential to bind several hepatic proteins. To neutralize this toxicity, the liver conjugates it to glutathione.

Here’s the key: in cases of acetaminophen overdose, the normal glucuronidation pathway is overwhelmed, so more NAQPI is generated and more glutathione is consumed.

Where’s the acidosis?

In the setting of acetaminophen overdose, the liver must regenerate glutathione stores. One of the metabolites of glutathione is 5-oxoproline, perhaps most famous as the “O” in the “GOLDMARK” mnemonic. 5-oxoproline (also known as pyroglutamic acid) is an unmeasured acid. When it accumulates it increases the anion gap.

While acute acetaminophen overdose causes metabolic acidosis via hepatic necrosis and a sharp rise in lactic acid, subacute or chronic high dose acetaminophen (e.g., a patient on standing acetaminophen through a weeks-long hospitalization) will eventually cycle through enough glutathione and develop very high serum and urine levels of 5-oxoproline levels.

The clinical significance of this form of anion gap metabolic acidosis remains unclear. Fortunately it is uncommon. Risk factors include severe malnutrition and renal failure. It has also been associated with widely variable total doses, including those as low as 650mg daily over 3 weeks in a patient with severe malnutrition.

Take Home Points

  1. Consider acetaminophen exposure in a hospitalized patients with a new anion gap metabolic acidosis.
  2. Chronic or subacute glutathione use causes buildup of 5-oxoproline via the gamma glutamyl cycle.

Learning Objectives

  1. Apply Phase I and Phase II drug metabolism to acetaminophen.
  2. Review the mechanism by which acetaminophen causes an anion gap metabolic acidosis and the risk factors for its development.


Click here to obtain AMA PRA Category 1 Credits™ (1.00 hours), Non-Physician Attendance (1.00 hours), or ABIM MOC Part 2 (1.00 hours).

Listen to the episode

Credits & Citation

◾️Episode written by Hannah Abrams
◾️Audio edited by Clair Morgan of nodderly.com
◾️Show notes by Tony Breu and Hannah Abrams

Abrams HR, Cooper AZ, Breu AC. How does acetaminophen cause an anion gap acidosis? The Curious Clinicians Podcast. October 14, 2020. https://curiousclinicians.com/2020/10/12/episode-11-how-does-acetaminophen-cause-an-anion-gap-acidosis/

Image credit: https://www.kireports.org/article/S2468-0249(20)30130-3/fulltext

Published by Tony Breu

Tony Breu, MD is an internist/hospitalist who loves asking ‘why’?

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