Acetaminophen (see Acetaminophen, [[Acetaminophen]])
Epidemiology: usually associated with chronic acetaminophen use, rather than acute intoxication
Physiology
The acetaminophen metabolite N-acetylbenzoquinonimine reacts irreversibly with glutathione
Precursors accumulate as they are unable to be converted to glutathione because of depletion or inhibition of the rate-limiting enzyme glutathione synthetase
Therefore, in the absence of glutathione, N-acetylbenzoquinonimine forms hepatotoxic compounds
Female Sex
Flucloxacillin (see Flucloxacillin, [[Flucloxacillin]]): inhibits the 5-oxoprolinase enzyme, which converts pyroglutamic acid to glutamate
Hepatic Dysfunction
Pregnancy (see Pregnancy, [[Pregnancy]]): since glycine combines with gamma-glutamyl cysteine to form glutathione (catalyzed by glutathione synthetase), relative glycine deficiency may lead to accumulation of precursors (incuding gamma-glutamyl cysteine, glutamate and pyroglutamic acid)
Severe Burns with Relative Glycine Deficiency (see Burns, [[Burns]]): since glycine combines with gamma-glutamyl cysteine to form glutathione (catalyzed by glutathione synthetase), relative glycine deficiency may lead to accumulation of precursors (incuding gamma-glutamyl cysteine, glutamate and pyroglutamic acid)
Vigabatrin
Physiology
Background
Pyroglutamic Acid (5-Oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle
Pathophysiology
Likely Related to glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle: however, the exact pathophysiology is unclear
Cessation of Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
Intravenous Fluid Hydration
N-Acetlycysteine (Mucomyst) (see xxxx, [[xxxx]]): may accelerate resolution
Methionine: may accelerate resolution
References
5-oxoprolinemia causing elevated anion gap metabolic acidosis in the setting of acetaminophen use. J Emerg Med. 2012 Jul;43(1):54-7. doi: 10.1016/j.jemermed.2011.06.017. Epub 2011 Oct 5 [MEDLINE]
What is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure? Clin Toxicol (Phila). 2013 Nov;51(9):817-27. doi: 10.3109/15563650.2013.844822. Epub 2013 Oct 11 [MEDLINE]
Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report. J Med Case Rep. 2014 Dec 6;8:409. doi: 10.1186/1752-1947-8-409 [MEDLINE]
Use of anion gap in the evaluation of a patient. Am J Kidney Dis. 2014 Oct;64(4):653-7. doi: 10.1053/j.ajkd.2014.05.022. Epub 2014 Aug 15 [MEDLINE]
Pyroglutamic acid-induced metabolic acidosis: a case report. Acta Clin Belg. 2014 Jun;69(3):221-3. doi: 10.1179/2295333714Y.0000000022. Epub 2014 Apr 2 [MEDLINE]
Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other. Clin J Am Soc Nephrol. 2014 Jan;9(1):191-200. doi: 10.2215/CJN.07730713. Epub 2013 Nov 14 [MEDLINE]