Acetaminophen, the missing anion gap in the patient with metabolic acidosis
Acetaminophen intake is well-known but an often missed cause of high anion gap (AG) metabolic acidosis, and physicians must understand the metabolic pathway which increases the AG. Multiple mnemonics for common causes of metabolic acidosis have been developed and are widely taught in medical schools. Some of them, such as MUDPILES and KUSMAE, may not lead to an adequate workup and miss the diagnosis for the acidosis. More recently developed memory tools, such as GOLDMARK, provide a complete differential diagnosis for high AG metabolic acidosis. Pyroglutamic acid accumulates after alterations of the gamma-glutamyl cycle mediated by acetaminophen and glutathione deficiency in some patients. The lower capacity of 5-oxiprolinase to metabolize pyroglutamic acid into glutamate results in the gradual accumulation of oxoproline/pyroglutamic acid. Treatment is mainly supportive with the major aim of restoring glutathione levels, optimizing nutrition, and using N-acetylcysteine as needed. Different modalities of renal replacement therapy have also been used in these patients.
Tan EM, Kalimullah E, Sohail MR, Ramar K. Diagnostic challenge in a patient with severe anion gap metabolic acidosis. Case Rep Crit Care. 2015;2015:272914.
Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st century. Lancet. 2008;372(9642):892.
Kamran H, Ram N. Chronic acetaminophen use associated with anion-gap metabolic acidosis. Am J Med. 2016;129(8):e127-128.
Zein JG, Wallace DJ, Kinasewitz G, Toubia N, Kakoulas C. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med. 2010;28(7):798-802.
Fenves AZ, Kirkpatrick HM, Patel VV, Sweetman L, Emmett M. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):441-447.
Creer MH, Lau BW, Jones JD, Chan KM. Pyroglutamic acidemia in an adult patient. Clin Chem. 1989;35(4):684-686.
Mizock BA, Belyaev S, Mecher C. Unexplained metabolic acidosis in critically ill patients: the role of pyroglutamic acid. Intensive Care Med. 2004;30(3):502-505.
Verma R, Polsani KR, Wilt J, Loehrke ME. 5-Oxoprolinuria as a cause of high anion gap metabolic acidosis. Br J Clin Pharmacol. 2012;73(3):489-491.
Duewall JL, Fenves AZ, Richey DS, Tran LD, Emmett M. 5-Oxoproline (pyroglutamic) acidosis associated with chronic acetaminophen use. Proc (Bayl Univ Med Cent). 2010;23(1):19-20.
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.
Liss DB, Paden MS, Schwarz ES, Mullins ME. 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.
Villano JH, O'Connell CW, Ly BT, Schneir A. Case files from the University of California San Diego Health System Fellowship coma and severe acidosis: remember to consider acetaminophen. J Med Toxicol. 2015;11(3):368-376.
Abkur TM, Mohammed W, Ali M, Casserly L. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report. J Med Case Rep. 2014;8:409.
Vichot AA, Rastegar A. Use of anion gap in the evaluation of a patient with metabolic acidosis. Am J Kidney Dis. 2014;64(4):653-657.
Kanji HD, Mithani S, Boucher P, Dias VC, Yarema MC. Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity. J Popul Ther Clin Pharmacol. 2013;20(3):e207-211.
Armenian P, Gerona RR, Blanc PD, Wu AH, Mookherjee S. 5-oxoprolinemia causing elevated anion gap metabolic acidosis in the setting of acetaminophen use. J Emerg Med. 2012;43(1):54-57.
Lawrence DT, Bechtel LK, Charlton NP, Holstege CP. 5-oxoproline-induced anion gap metabolic acidosis after an acute acetaminophen overdose. J Am Osteopath Assoc. 2010;110(9):545-551.
Holman M, ter Maaten JC. [Severe metabolic acidosis as a result of 5-oxoproline in acetaminophen use]. Ned Tijdschr Geneeskd. 2010;154:A1838.
Rolleman EJ, Hoorn EJ, Didden P, Zietse R. Guilty as charged: unmeasured urinary anions in a case of pyroglutamic acidosis. Neth J Med. 2008;66(8):351-353.
Hodgman MJ, Horn JF, Stork CM, et al. Profound metabolic acidosis and oxoprolinuria in an adult. J Med Toxicol. 2007;3(3):119-124.
Tailor P, Raman T, Garganta CL, et al. Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid). Am J Kidney Dis. 2005;46(1):e4-10.
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