Baylor University Medical Center Proceedings April 2017 - 170

Figure 1. Anion gap trend over the patient's hospital courses. Anion gap (mEq/L) is
represented on the y axis, and the timing of acetaminophen and N-acetylcysteine
(NAC) is marked on the plot.

creatinine was in the "normal" range, that value was likely
deceptive due to her low muscle mass and her recurrent episodes
of AKI requiring RRT suggestive of chronic kidney disease.
5-oxoproline is an organic acid intermediate of the γ-glutamyl
cycle (Figure 2), which produces the antioxidant glutathione.
5-oxoprolinemia and its resultant anion gap metabolic acidosis can
occur from both hereditary and acquired mechanisms. Hereditary
causes include rare deﬁciencies in two essential enzymes in the
γ-glutamyl cycle: glutathione synthetase and 5-oxoprolinase (5).
Acquired 5-oxoprolinemia results from longstanding depletion of

Figure 2. The γ-glutamyl cycle. Reprinted from Fenves et al, 2006 (2) with
permission from the American Society of Nephrology.
170

glutathione and cysteine stores that occurs due to malnutrition,
sepsis, and chronic acetaminophen use (6). The acetaminophen is
typically not in the toxic range and is more often due to chronic
use within the accepted therapeutic range. Reduced glutathione
levels eliminate the feedback inhibition of γ-glutamyl cysteine
synthetase (Figure 2), causing accumulation of γ-glutamyl cysteine that is subsequently metabolized to 5-oxoproline. Reduced
cysteine levels prevent conversion of γ-glutamyl phosphate to
γ-glutamyl cysteine despite the increased activity of γ-glutamyl
cysteine synthetase, as cysteine is required for this reaction. Instead, γ-glutamyl phosphate is converted to 5-oxoproline as part
of a futile ATP-depleting cycle (4).
The utility of NAC for acute acetaminophen toxicity is well
known (7). It has also been postulated that NAC may be of beneﬁt in cases of acquired 5-oxoprolinemia, as it has been shown to
increase glutathione and cysteine levels in patients with hereditary
glutathione synthetase deﬁciency (8). Theoretically, repletion of
glutathione stores should reestablish the feedback inhibition of
γ-glutamyl cysteine synthetase, thereby reducing the conversion
of γ-glutamyl cysteine to 5-oxoproline. Repletion of cysteine
stores should reestablish conversion of γ-glutamyl phosphate to
γ-glutamyl cysteine, thereby preventing conversion of γ-glutamyl
phosphate to 5-oxoproline and breaking the futile ATP-depleting
cycle. Reported evidence in the literature supporting NAC administration for 5-oxoprolinemia is limited (9, 10). Although the
profound anion gap metabolic acidosis persisted for a week in our
patient despite discontinuation of acetaminophen, the anion gap
metabolic acidosis rapidly resolved after NAC administration. We
suggest that NAC, along with discontinuation of acetaminophen,
is the preferred treatment for 5-oxoproline metabolic acidosis.
1.

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