5-Oxoprolinuria as a Cause for Metabolic Acidosis

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One of the rare (but potentially underdiagnosed) causes of anion gap metabolic acidosis is acquired 5-oxoprolinuria due to excessive Tylenol ingestion.  To explain how this works, you need to familiarize yourself briefly with the gamma-glutamyl cycle, a series of enyzmes and reactions involved in the metabolism of glutathione, an amino-acid derivative which appears to be important in the prevention of oxidative injury.  This cycle is shown below, taken from a 2005 AJKD paper by Humphreys et al.


You can see that acetaminophen inhibits glutathione.  Normally, glutathione performs a type of negative feedback control on the cycle by inhibiting gamma-glutamyl cysteine synthetase.  Without glutathione, then, this feedback inhibition is removed, and there is an upregulation of this enzyme, resulting in increased amounts of gamma-glutamyl cysteine, which itself is a precursor to the organic acid 5-oxoproline.  One of the key aspects of diagnosing this disorder, aside from having a clinical suspicion in the setting of anion gap metabolic acidosis without another explanation, is the detection of 5-oxoproline in the urine.  The disorder appears to be more common in elderly women or individuals with multiple comorbidities, in whom glutathione levels may already be low.  Although there is not much data in support of it, it makes sense that Mucomyst (N-acetyl cysteine, which augments glutathione levels) might work.
From the genetics angle, there are some pediatric, congenital causes of 5-oxoprolinuria which not surprisingly involved defects in enzymes of the gamma-glutamyl cycle (in particular, mutations in glutathione synthetase and 5-oxoprolinase have been identified in these patients). 

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