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Case Report  |   September 2010
5-Oxoproline–Induced Anion Gap Metabolic Acidosis After an Acute Acetaminophen Overdose
Author Notes
  • From the Division of Medical Toxicology and the Department of Emergency Medicine at the University of Virginia School of Medicine in Charlottesville, Virginia. 
  • Address correspondence to Nathan P. Charlton, MD, Division of Medical Toxicology, University of Virginia School of Medicine, P.O. Box 800774, Charlottesville, VA 22908-0774. E-mail: npc8a@virginia.edu 
Article Information
Cardiovascular Disorders / Emergency Medicine / Gastroenterology / Hypertension/Kidney Disease / Neuromusculoskeletal Disorders / Obstetrics and Gynecology / Psychiatry
Case Report   |   September 2010
5-Oxoproline–Induced Anion Gap Metabolic Acidosis After an Acute Acetaminophen Overdose
The Journal of the American Osteopathic Association, September 2010, Vol. 110, 545-551. doi:10.7556/jaoa.2010.110.9.545
The Journal of the American Osteopathic Association, September 2010, Vol. 110, 545-551. doi:10.7556/jaoa.2010.110.9.545
Abstract

Metabolic acidosis after acute acetaminophen overdose is typically attributed to either transient lactic acidosis without evidence of hepatic injury or hepatic failure. High levels of the organic acid 5-oxoprolinuria are usually reported in patients with predisposing conditions, such as sepsis, who are treated in a subacute or chronic fashion with acetaminophen. The authors report a case of a 40-year-old woman who developed anion gap metabolic acidosis and somnolence after an acute acetaminophen overdose. Substantial hepatic damage did not occur, which ruled out acetaminophen-induced hepatic insufficiency as a cause of the patient's acidosis or altered mental status. Urinalysis revealed elevated levels of 5-oxoproline, suggesting that the patient's acute acetaminophen overdose was associated with marked anion gap metabolic acidosis due solely to 5-oxoproline without hepatic complications. The acidosis fully resolved with N-acetylcysteine treatment and supportive care including hydration.

Anion gap metabolic acidosis occurs after acute and chronic acetaminophen poisoning.1 Data suggest that acute acetaminophen overdose can lead to mitochondrial poisoning that results in lactic acidosis, a cause of anion gap metabolic acidosis.2-4 Reports also suggest that after chronic poisoning, high levels of the organic acid 5-oxoproline (pyroglutamic acid) may result in anion gap acidosis.5-7 However, this process has not been documented after acute acetaminophen overdose. We present a case of a woman who overdosed on acetaminophen and developed clinically significant anion gap metabolic acidosis due to high levels of 5-oxoproline. 
Report of Case
A 40-year-old woman with a history of ethanol abuse presented to the emergency department (ED) after an acute acetaminophen overdose. The patient's boyfriend called emergency medical services (EMS) after finding the patient in her home at 5:00 pm, poorly responsive on her couch, with an open bottle of rum and an open 200-count bottle of 500-mg acetaminophen tablets. Pill count revealed 93 acetaminophen tablets remaining. A bottle of topiramate was also found in the patient's home; the topiramate had been prescribed for the treatment of ethanol abuse. The patient did not have a history of seizure disorder. Pill count revealed an appropriate number of topiramate pills in the bottle, consistent with the amount prescribed. 
The patient was last seen in a normal state by her boyfriend at 8:00 am the same day as presentation. In addition, the patient's boyfriend indicated the patient did not sound inebriated or ill when he spoke with her on the phone at noon. Seizure activity was not witnessed by the patient's boyfriend, EMS staff, or emergency department personnel. The patient displayed no evidence of tongue biting or incontinence. 
The patient arrived at the ED somnolent but arousable, complaining only of nausea. She confirmed ingesting an unknown amount of acetaminophen and ethanol and denied taking topiramate in overdose that day, but otherwise she refused to answer physician questions regarding medical history or events surrounding her presentation. The exact time of acetaminophen intake was unknown. According to the medical records, the patient's medical history included ethanol abuse, depression, bipolar disorder, and multiple suicide attempts. 
Her vital signs at presentation were as follows: body temperature (taken orally), 36.2°C; blood pressure, 141/92 mm Hg; pulse, 104 beats per minute; and respiratory rate, 24 breaths per minute. The patient's pupils were 3 mm in diameter in both eyes, and she had bilateral horizontal nystagmus. The oropharynx was unobstructed, without lesions, with moist mucous membranes and an odor of ethanol. The patient moved all of her extremities spontaneously with patellar reflexes 3+ and biceps reflexes 2+ and equal. No clonus was present. She was oriented to person only. The rest of her complete physical examination was unremarkable. 
Results of the patient's initial laboratory evaluation were as follows: chloride, 107 mmol/L; sodium, 140 mmol/L; bicarbonate, 15 mmol/L (anion gap, 18 mmol/L); creatinine, 0.8 mg/dL; aspartate aminotransferase, 43 U/L; alanine aminotransferase, 60 U/L; total bilirubin, 0.2 mg/dL; lactic acid, 5.2 mmol/L; ethanol level, 118 mg/dL; salicylate level, undetectable; and acetaminophen, 430 μg/mL (Table). Urinalysis results showed no presence of calcium oxalate crystals. An electrocardiogram showed a sinus rhythm of 99 beats per minute, a normal QRS interval of 80 milliseconds, and a prolonged QTc interval at 508 milliseconds (Table). Complete blood cell count findings showed no abnormalities. 
Table
Anion Gap Metabolic Acidosis After Acetaminophen Overdose in a 40-Year-Old Woman: Laboratory and Additional Findings



Presentation

2 Hours After Presentation

24 Hours After Presentation

2 Days After Presentation

Reference Range
▪ Laboratory Findings
□ Anion gap, mmol/L 18 23 14 11 8-12
□ Chloride, mmol/L10710411010798-107
□ Sodium, mmol/L 140 141 140 138 136-145
□ Bicarbonate, mmol/L1514162122-29
□ Creatinine, mg/dL 0.8 0.7 0.7 0.6 0.1-0.4
□ Aspartate aminotransferase, U/L43NA2421<35
□ Alanine aminotransferase, U/L 60 NA 38 33 <55
□ Total bilirubin, mg/dL0.2NA0.50.200.3-1.2
□ Lactic acid, mmol/L 5.2 2.1 NA NA <2.2
□ Ethylene glycol, mg/dLNANDNANA>30
□ Methanol, μg/mL NA ND NA NA <200
□ Ethanol, mg/dL118NANANA<2
□ Salicylate, μg/mL ND NA NA NA 150-300
□ Acetaminophen, μg/mL430NA5ND10-30
▪ Additional Findings
□ Electrocardiogram findings
- Sinus rhythm, beats/min 99 NA NA NA NA
- QRS interval, milliseconds80NANANANA
- QTc interval, milliseconds 508 NA NA NA NA
□ Estimated glomerular filtration rate, mL/min/1.73 m2>60>60>60NA>60
 Abbreviations: NA, not available; ND, not detected.
Table
Anion Gap Metabolic Acidosis After Acetaminophen Overdose in a 40-Year-Old Woman: Laboratory and Additional Findings



Presentation

2 Hours After Presentation

24 Hours After Presentation

2 Days After Presentation

Reference Range
▪ Laboratory Findings
□ Anion gap, mmol/L 18 23 14 11 8-12
□ Chloride, mmol/L10710411010798-107
□ Sodium, mmol/L 140 141 140 138 136-145
□ Bicarbonate, mmol/L1514162122-29
□ Creatinine, mg/dL 0.8 0.7 0.7 0.6 0.1-0.4
□ Aspartate aminotransferase, U/L43NA2421<35
□ Alanine aminotransferase, U/L 60 NA 38 33 <55
□ Total bilirubin, mg/dL0.2NA0.50.200.3-1.2
□ Lactic acid, mmol/L 5.2 2.1 NA NA <2.2
□ Ethylene glycol, mg/dLNANDNANA>30
□ Methanol, μg/mL NA ND NA NA <200
□ Ethanol, mg/dL118NANANA<2
□ Salicylate, μg/mL ND NA NA NA 150-300
□ Acetaminophen, μg/mL430NA5ND10-30
▪ Additional Findings
□ Electrocardiogram findings
- Sinus rhythm, beats/min 99 NA NA NA NA
- QRS interval, milliseconds80NANANANA
- QTc interval, milliseconds 508 NA NA NA NA
□ Estimated glomerular filtration rate, mL/min/1.73 m2>60>60>60NA>60
 Abbreviations: NA, not available; ND, not detected.
×
A loading dose of 150 mg/kg N-acetylcysteine was initiated intravenously over 60 minutes followed by the standard 20-hour protocol. In addition, the patient was given 100 mg of thiamine. The diagnosis of anion gap acidosis secondary to high levels of lactic acid was considered and, due to the initial lack of another unifying diagnosis, was attributed to a possible seizure or to volume depletion. However, because of the patient's history of ethylene glycol poisoning, an electrolyte panel was repeated 1.5 hours after the initial blood test revealed a decrease in the bicarbonate level to 14 mmol/L, an increase in the anion gap to 23 mmol/L, and a decrease in the concomitant lactic acid level to 2.1 mmol/L (normal level). Ethylene glycol and methanol were not detected. Because of these negative laboratory values, the diagnosis of 5-oxoprolinuria seemed more plausible and urine was sent for gas chromatography/mass spectroscopy (GC/MS) evaluation of 5-oxoproline. 
The patient was admitted to a monitored general internal medicine floor bed and continued to receive N-acetylcysteine. Her transaminase levels returned to a normal range by the next morning. Bicarbonate levels and the anion gap gradually improved during the next 24 hours of admission (Table). The patient's creatinine level, estimated glomerular filtration rate, coagulation profile, and bilirubin concentration remained normal. Two days after the patient presented, her acetaminophen levels were undetectable and the N-acetylcysteine therapy was discontinued. Her urine 5-oxoproline levels were markedly elevated compared with those in a normal urine specimen; both samples were normalized for creatinine. Urine drug screening revealed the presence of benzodiazepines and ethanol. 
Analysis of 5-Oxoproline
5-Oxoproline is an organic acid that requires GC/MS for detection. In the present case, urine organic acid qualitative analysis was performed using Agilent Technologies' Gas Chromatograph 6890N and Mass Selective Detector 5973N (Santa Clara, California). A urine specimen was collected from the patient during initial presentation. The volume of urine required for sample preparation was normalized to 1 μmol/L urine creatinine. The level of urine creatinine was determined using a picric acid method (AU400 Chemistry Analyzer, Olympus Diagnostic Systems Group, Center Valley, Pennsylvania). 
The normalized sample was acidified and then reacted with pentafluorobenzylhydroxylamine hydrochloride to form pentafluorobenzyl oximes of oxyacids, aldehydes, and ketones. Urine pentafluorobenzyl oximes were extracted with ethyl acetate, neutralized, and evaporated to dryness under nitrogen. The sample was then derivatized with bis-(trimethylsilyl) trifluoro-acetamide (TRISIL Reagent) to form volatile trimethylsilyl derivatives and analyzed using GC/MS. The extracted ion chromatograms were scaled with multiplication factors, integrated to obtain peak retention times. Data were analyzed using Agilent Technologies' MSD ChemStation software, which compared fragmented ions to the following spectral libraries: NIST Mass Spectral Library (Rev D 03.00), Wiley Mass Spectral Library (Rev D 03.00), and UVA Medical Labs San Diego Library (Pitt, July 2007). Semiquantitative analysis was performed by determining the ratio of the chromatographic peak height for 5-oxoproline in the patient sample with the peak in a normal urine specimen. The ion fragmentation fingerprint detected at a 24.39-minute retention time was 99% identical between the patient's urine specimen and the normal urine specimens. Quantitative analysis was not performed because 5-oxoproline controls and calibrators have not been validated for the GC/MS method at this facility. 
The 5-oxoproline chromatographic peak was detected at a retention time of 24.39 minutes (Figure 1). The GC/MS method used to screen for 5-oxoprolinuria in these samples is qualitative. Compared with baseline peak height of 5-oxoproline levels observed in non-oxoprolinuria patient samples (relative abundance approximately 1×106, Figure 1A), the observed peak height at a 24.39-minute retention time was approximately 30 times greater (relative abundance approximately 3.5 × 107, Figure 1B). The ion fragment fingerprint at a 24.39-minute retention time was identical to 5-oxoproline ion fingerprints stored in the spectral libraries (Figure 1C). 
Comment
Metabolic acidosis has been reported to occur after acetaminophen overdose.1,2,5-11 This condition is often secondary to hepatic damage; compromised hepatic function impairs adequate clearance of lactic acid and organic acids, and the accumulation of these metabolic products leads to acidosis.1 However, the medical literature also includes multiple reports of patients who experienced acidosis and altered mental status in the early period after massive acetaminophen ingestion but who did not develop hepatic injury.1,8-11 In one study, lactic acidosis occurred at two different times after acetaminophen poisoning: a transient elevation in serum lactate noted within 15 hours of acetaminophen ingestion and an elevated plasma lactate level observed in patients presenting after 15 hours and with deteriorating hepatic function.2 Early-onset acidosis is often attributed to lactic acidosis resulting from inhibition of mitochondrial respiration by acetaminophen or its metabolite N-acetyl-p-benzo-quinone imine (NAPQI). This effect has been shown in several experimental studies that tested the effects of acetaminophen and NAPQI on hepatic mitochondria in isolated rat livers.3,4 While elevated lactic acid levels have been documented in some cases of acetaminophen overdose, lactic acidosis may not be entirely responsible for high anion gap metabolic acidosis.1,12 
Metabolic acidosis can also be caused by the accumulation of the organic acid 5-oxoproline.5,13 This condition, called 5-oxoprolinuria, is typically caused by reduced glutathione (GSH) deficiency.15 5-Oxoproline is an intermediate in the gamma-glutamyl pathway, which is the metabolic cycle responsible for creating glutathione and shuttling amino acids into the cytosol.14 In this pathway, normal glutathione levels are necessary for feedback inhibition on the enzyme gamma-glutamylcysteine synthase, which regulates the activity of the cycle (Figure 2).15 
When glutathione levels are diminished, feedback inhibition ceases, causing an overproduction of gamma-glutamylcysteine, a portion of which is metabolized to 5-oxoproline (Figure 3).13,14 5-Oxoproline is primarily metabolized to glutamate by the enzyme 5-oxoprolinase but also may be renally excreted.13,14 
Several conditions can lead to a clinically significant accumulation of 5-oxoproline and subsequent development of anion gap acidosis. All conditions result in disruption of the gamma-glutamyl cycle. For example, glutathione-synthase deficiency causes the accumulation of gamma-glutamylcysteine, which is converted back to 5-oxoproline by gamma-glutamyl cyclotransferase.14 This process results in metabolic acidosis secondary to the accumulation of 5-oxoproline. Depending on the severity of glutathione-synthase deficiency, which is inherited through recessive genes, metabolic acidosis and hemolytic anemia may manifest in infants. Patients with severe glutathione-synthase deficiency typically develop progressive neurologic dysfunction and may die.15 
Figure 1.
Identification of the organic acid 5-oxoproline with gas chromatographic/mass spectroscopic analysis in the urine of a 40-year-old woman who presented with acetaminophen overdose. (A) This peak with the arrow demonstrates basal levels of 5-oxoproline observed in a non-oxoprolinuric patient sample. (B) The 5-oxoproline peak, identified with the arrow, was detected at a retention time of 24.39 minutes. (C) Spectrum of ion fragments (mass-to-charge ratio) corresponds to the 5-oxoproline compound eluting at a retention time of 24.39 minutes. This ion fragment fingerprint from the patient in the present report was more than 99% identical to the fingerprint of 5-oxoproline ion fragments stored in the spectral libraries.
Figure 1.
Identification of the organic acid 5-oxoproline with gas chromatographic/mass spectroscopic analysis in the urine of a 40-year-old woman who presented with acetaminophen overdose. (A) This peak with the arrow demonstrates basal levels of 5-oxoproline observed in a non-oxoprolinuric patient sample. (B) The 5-oxoproline peak, identified with the arrow, was detected at a retention time of 24.39 minutes. (C) Spectrum of ion fragments (mass-to-charge ratio) corresponds to the 5-oxoproline compound eluting at a retention time of 24.39 minutes. This ion fragment fingerprint from the patient in the present report was more than 99% identical to the fingerprint of 5-oxoproline ion fragments stored in the spectral libraries.
5-Oxoprolinuria can also be induced by circumstances that reduce the body's supply of glutathione. Both sepsis and acetaminophen have been found to cause glutathione depletion.5,16-19 Glycine deficiency has also been found to deplete glutathione.20 Conditions that may result in decreased glycine levels include pregnancy, severe burns, premature birth, and malnutrition.15,20 
Another potential cause of 5-oxoprolinuria is insufficient 5-oxoprolinase activity. Inhibition of 5-oxoprolinase can occur due to either an inborn enzyme deficiency or the presence of xenobiotics such as the antibiotic flucloxacillin.6,7,13,21-23 Vigabatrin has also been described as a cause of 5-oxoprolinuria in children.24 However, the mechanism for this process is unknown. 
Most reported cases of transient 5-oxoprolinuria are caused by repeated therapeutic acetaminophen doses, usually occurring in the setting of sepsis, pregnancy, malnutrition, or other conditions that can reduce glutathione levels.5,7,21,22 In one large case series,5 most patients had a predisposing condition and developed 5-oxoprolinuria while receiving therapeutic doses of acetaminophen. Only one patient in this series overdosed.5 Another patient who developed 5-oxoprolinuria while pregnant resumed therapeutic acetaminophen use after giving birth. The patient's osteomyelitis resolved, and on resuming acetaminophen use she did not develop elevated urinary 5-oxoproline.5 The authors of this study concluded that therapeutic acetaminophen use alone was not responsible for the high incidence of 5-oxoprolinuria observed. Rather, other factors, such as underlying medical conditions, were likely involved. In another case series,20 patients who developed 5-oxoprolinuria after therapeutic use of acetaminophen also had some degree of renal insufficiency. 
Figure 2.
Normal function of the gamma-glutamyl pathway, with glutathione providing normal feedback inhibition of gamma-glutamyl-cysteine synthase. Abbreviation: aa, amino acid.
Figure 2.
Normal function of the gamma-glutamyl pathway, with glutathione providing normal feedback inhibition of gamma-glutamyl-cysteine synthase. Abbreviation: aa, amino acid.
Other cases have been reported of patients without known predisposing conditions developing 5-oxoprolinuria after taking therapeutic doses of acetaminophen.25,26 Results of another study showed that rats will develop 5-oxoprolinuria after being chronically fed acetaminophen.27 Therefore, it appears that other predisposing factors may be involved in the pathogenesis of 5-oxoprolinuria; these could also be related to the depletion of glutathione. One consideration is that an estimated 1 out of 10,000 patients are heterozygous for glutathione synthase deficiency;25 these patients, when exposed to acetaminophen, could be more susceptible to developing glutathione depletion. 
On the basis of a review of the literature, Mizock et al28 reported that most patients with 5-oxoprolinuria had a history of acetaminophen exposure and altered mental status, and they suggested that the two are cardinal features of a diagnosis of 5-oxoprolinuria. Our review of the literature yielded similar results.7,21,29,30 However, in two reports involving patients with 5-oxoprolinuria, acetaminophen exposure was described in all patients but altered mental status was not reported in all patients or episodes.20,26 
Conclusion
In the present case, clinically significant anion gap metabolic acidosis developed after acute acetaminophen overdose. While the lactic acid level was originally elevated in this patient, it quickly returned to normal and the large peak of 5-oxoproline at GC/MS led us to determine that this organic acid was the primary source of acidosis. In this patient, the acidosis fully resolved with N-acetylcysteine and supportive care. 
Altered mental status with anion gap metabolic acidosis is a common patient presentation. 5-Oxoprolinuria should be added to the differential diagnosis for patients presenting with clinically significant acidosis after acute acetaminophen overdose. In addition, this diagnosis should also be considered in any patient with unexplained metabolic acidosis and a history of therapeutic acetaminophen use, particularly in patients with coexisting conditions such as sepsis, malnutrition, or pregnancy that may lead to a baseline glutathione deficiency. Treatment for this condition should include prompt discontinuation of medications that could exacerbate 5-oxoprolinuria—primarily acetaminophen but also vigabatrin and flucloxacillin—along with supportive care including hydration. Any underlying infection or medical condition must be identified and resolved. Administration of N-acetylcysteine is a reasonable treatment,5,20,26 and N-acetylcysteine will help to replete glutathione levels by providing cysteine necessary for glutathione synthesis.31 The increase in glutathione will reestablish feedback inhibition of the enzyme gamma-glutamylcysteine synthase, reducing the amount of gamma-glutamylcysteine available for metabolism to 5-oxoproline. Physicians can help patients quickly recover from anion gap metabolic acidosis with proper diagnosis and treatment. 
Figure 3.
The gamma-glutamyl pathway after glutathione depletion due to acetaminophen overdose. The removal of glutathione's feedback inhibition of gamma-glutamyl-cysteine synthase leads to an overaccumulation of gamma-glutamylcysteine. This overacculuation is converted to 5-oxoproline, which leads to 5-oxoprolinuria. Abbreviations: aa, amino acid; APAP, acetyl-para-aminophenol; NAPQI, N-acetyl-p-benzoquinone imine.
Figure 3.
The gamma-glutamyl pathway after glutathione depletion due to acetaminophen overdose. The removal of glutathione's feedback inhibition of gamma-glutamyl-cysteine synthase leads to an overaccumulation of gamma-glutamylcysteine. This overacculuation is converted to 5-oxoproline, which leads to 5-oxoprolinuria. Abbreviations: aa, amino acid; APAP, acetyl-para-aminophenol; NAPQI, N-acetyl-p-benzoquinone imine.
 Financial Disclosures: None reported.
 
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Croal BL, Glen AC, Kelly CJ, Logan RW. Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy. Clin Chem. 1998;44(2):336-340.
Brooker G, Jeffery J, Nataraj T, Sair M, Ayling R. High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition. Ann Clin Biochem. 2007;44(4):406-409.
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Koulouris Z, Tierney MG, Jones G. Metabolic acidosis and coma following a severe acetaminophen overdose. Ann Pharmacother. 1999;33(11):1191-1194.
Mendoza CD, Heard K, Dart RC. Coma, metabolic acidosis and normal liver function in a child with a large serum acetaminophen level. Ann Emerg Med. 2006;48(5):637 .
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Kortmann W, Van Agtmael MA, van Diessen J, Kanen BL, Jakobs C, Nanayakkara PW. 5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors. Neth J Med. 2008;66(8):354-357.
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Figure 1.
Identification of the organic acid 5-oxoproline with gas chromatographic/mass spectroscopic analysis in the urine of a 40-year-old woman who presented with acetaminophen overdose. (A) This peak with the arrow demonstrates basal levels of 5-oxoproline observed in a non-oxoprolinuric patient sample. (B) The 5-oxoproline peak, identified with the arrow, was detected at a retention time of 24.39 minutes. (C) Spectrum of ion fragments (mass-to-charge ratio) corresponds to the 5-oxoproline compound eluting at a retention time of 24.39 minutes. This ion fragment fingerprint from the patient in the present report was more than 99% identical to the fingerprint of 5-oxoproline ion fragments stored in the spectral libraries.
Figure 1.
Identification of the organic acid 5-oxoproline with gas chromatographic/mass spectroscopic analysis in the urine of a 40-year-old woman who presented with acetaminophen overdose. (A) This peak with the arrow demonstrates basal levels of 5-oxoproline observed in a non-oxoprolinuric patient sample. (B) The 5-oxoproline peak, identified with the arrow, was detected at a retention time of 24.39 minutes. (C) Spectrum of ion fragments (mass-to-charge ratio) corresponds to the 5-oxoproline compound eluting at a retention time of 24.39 minutes. This ion fragment fingerprint from the patient in the present report was more than 99% identical to the fingerprint of 5-oxoproline ion fragments stored in the spectral libraries.
Figure 2.
Normal function of the gamma-glutamyl pathway, with glutathione providing normal feedback inhibition of gamma-glutamyl-cysteine synthase. Abbreviation: aa, amino acid.
Figure 2.
Normal function of the gamma-glutamyl pathway, with glutathione providing normal feedback inhibition of gamma-glutamyl-cysteine synthase. Abbreviation: aa, amino acid.
Figure 3.
The gamma-glutamyl pathway after glutathione depletion due to acetaminophen overdose. The removal of glutathione's feedback inhibition of gamma-glutamyl-cysteine synthase leads to an overaccumulation of gamma-glutamylcysteine. This overacculuation is converted to 5-oxoproline, which leads to 5-oxoprolinuria. Abbreviations: aa, amino acid; APAP, acetyl-para-aminophenol; NAPQI, N-acetyl-p-benzoquinone imine.
Figure 3.
The gamma-glutamyl pathway after glutathione depletion due to acetaminophen overdose. The removal of glutathione's feedback inhibition of gamma-glutamyl-cysteine synthase leads to an overaccumulation of gamma-glutamylcysteine. This overacculuation is converted to 5-oxoproline, which leads to 5-oxoprolinuria. Abbreviations: aa, amino acid; APAP, acetyl-para-aminophenol; NAPQI, N-acetyl-p-benzoquinone imine.
Table
Anion Gap Metabolic Acidosis After Acetaminophen Overdose in a 40-Year-Old Woman: Laboratory and Additional Findings



Presentation

2 Hours After Presentation

24 Hours After Presentation

2 Days After Presentation

Reference Range
▪ Laboratory Findings
□ Anion gap, mmol/L 18 23 14 11 8-12
□ Chloride, mmol/L10710411010798-107
□ Sodium, mmol/L 140 141 140 138 136-145
□ Bicarbonate, mmol/L1514162122-29
□ Creatinine, mg/dL 0.8 0.7 0.7 0.6 0.1-0.4
□ Aspartate aminotransferase, U/L43NA2421<35
□ Alanine aminotransferase, U/L 60 NA 38 33 <55
□ Total bilirubin, mg/dL0.2NA0.50.200.3-1.2
□ Lactic acid, mmol/L 5.2 2.1 NA NA <2.2
□ Ethylene glycol, mg/dLNANDNANA>30
□ Methanol, μg/mL NA ND NA NA <200
□ Ethanol, mg/dL118NANANA<2
□ Salicylate, μg/mL ND NA NA NA 150-300
□ Acetaminophen, μg/mL430NA5ND10-30
▪ Additional Findings
□ Electrocardiogram findings
- Sinus rhythm, beats/min 99 NA NA NA NA
- QRS interval, milliseconds80NANANANA
- QTc interval, milliseconds 508 NA NA NA NA
□ Estimated glomerular filtration rate, mL/min/1.73 m2>60>60>60NA>60
 Abbreviations: NA, not available; ND, not detected.
Table
Anion Gap Metabolic Acidosis After Acetaminophen Overdose in a 40-Year-Old Woman: Laboratory and Additional Findings



Presentation

2 Hours After Presentation

24 Hours After Presentation

2 Days After Presentation

Reference Range
▪ Laboratory Findings
□ Anion gap, mmol/L 18 23 14 11 8-12
□ Chloride, mmol/L10710411010798-107
□ Sodium, mmol/L 140 141 140 138 136-145
□ Bicarbonate, mmol/L1514162122-29
□ Creatinine, mg/dL 0.8 0.7 0.7 0.6 0.1-0.4
□ Aspartate aminotransferase, U/L43NA2421<35
□ Alanine aminotransferase, U/L 60 NA 38 33 <55
□ Total bilirubin, mg/dL0.2NA0.50.200.3-1.2
□ Lactic acid, mmol/L 5.2 2.1 NA NA <2.2
□ Ethylene glycol, mg/dLNANDNANA>30
□ Methanol, μg/mL NA ND NA NA <200
□ Ethanol, mg/dL118NANANA<2
□ Salicylate, μg/mL ND NA NA NA 150-300
□ Acetaminophen, μg/mL430NA5ND10-30
▪ Additional Findings
□ Electrocardiogram findings
- Sinus rhythm, beats/min 99 NA NA NA NA
- QRS interval, milliseconds80NANANANA
- QTc interval, milliseconds 508 NA NA NA NA
□ Estimated glomerular filtration rate, mL/min/1.73 m2>60>60>60NA>60
 Abbreviations: NA, not available; ND, not detected.
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