Accepted Manuscript Chronic Acetaminophen use Associated with Anion-gap Metabolic Acidosis Hassan Kamran, MD, Nalini Ram, MD PII:
To appear in:
The American Journal of Medicine
Received Date: 8 February 2016 Accepted Date: 8 February 2016
Please cite this article as: Kamran H, Ram N, Chronic Acetaminophen use Associated with Anion-gap Metabolic Acidosis, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.02.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Chronic Acetaminophen use Associated with Anion-gap Metabolic Acidosis
Hassan Kamran, MDa, Nalini Ram, MDb a
Resident, Internal Medicine, Baylor College of Medicine, 1 Baylor Plaza,
Houston, Tx, USA
Associate Professor Medicine-Endocrinology, Baylor College of Medicine, 1
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Baylor Plaza, Houston, Tx, USA
Nalini Ram, MD, Baylor College of Medicine
One Baylor Plaza, ABBR 6th Floor, Division of Diabetes, Endocrinology and
Metabolism, Houston, Texas 77030, United States. Mail Stop: BCM185 Email: [email protected]
Funding source: None
Conflicts of interest: None All authors had access to data and role in writing the manuscript
Article type: Clinical Communications to the Editor Key words: Acetaminophen, anion-gap acidosis, 5-oxoproline To the Editor,
Introduction: Metabolic acidosis is a common finding in hospitalized patients. In the case of
high anion gap metabolic acidosis, multiple mnemonics such as MUDPILES have been popularized which list the possible etiologies. However, there are a few
conditions that are not accounted for in the classic mnemonics1. We present a
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oxoproline due to acetaminophen ingestion.
case of high anion gap metabolic acidosis caused by accumulation of 5-
A 25-year-old Caucasian female with a history of intravenous drug use presented with 1 week of fever, fatigue, and diffuse myalgia. She was found to have MSSA
endocarditis of the tricuspid and pulmonic valves and started on Nafcillin with documented clearance of blood cultures within 3 days. She was in severe pain from numerous septic emboli that was not well controlled on morphine; however,
higher doses were not tolerated due to sedation. She was thus also started on hydrocodone-acetaminophen with better control. Three weeks into treatment the
patient continued to have pain and intermittent fevers despite negative cultures. The patient then developed a high anion gap metabolic acidosis on her labs. She remained alert and oriented at her baseline status with an unchanged physical exam and vitals. Labs were significant for decreasing serum bicarbonate, reaching a nadir of 16 mEq/L. Her chloride was 107 mEq/L and her sodium was 139 mEq/L. The calculated anion gap was 16 mEq/L. A venous
blood gas revealed a pH of 7.42, pCO2 22.5 mm Hg, and HCO3 14.3 mEq/L. Serum lactate and beta-hydroxybutyrate were normal. Liver and renal function tests were also normal. Urinalysis was negative for leukocyte esterase, nitrites,
or ketones. Repeat blood and urine cultures showed no growth. It was noted that she had received nearly 2.5 grams of acetaminophen per day for several days for her pain control and fever. A urine organic acid analysis screen was sent. In the
meantime, all sources of acetaminophen were discontinued and she was placed on fentanyl with resolution of her anion gap acidosis. The urine organic acid
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analysis screen revealed a large elevation on 5-oxoproline, confirming the diagnosis 5-oxoproline anion gap acidosis from chronic acetaminophen use.
This case highlights the consideration of less common etiologies of high anion gap acidosis. 5-oxoproline accumulation with chronic acetaminophen use is an uncommon but likely underdiagnosed cause of high anion gap metabolic
acidosis. This acquired form should especially be considered in hospitalized females who have risks factors such as sepsis, malnutrition, liver disease,
pregnancy, or renal failure2. Acetaminophen is metabolized into acetaminophen cysteine and also hydroxylated into N-acetyl-p-benzoquinone imine, a highly reactive oxidizing agent that is conjugated and reduced by glutathione. Chronic acetaminophen use reduces both cysteine and glutathione levels. Cysteine is required in the production of glutathione and in the depletion of both a 5oxoproline intermediate is produced. This 5-oxoproline cycle depletes ATP and
over time results in an accumulation of 5-oxoproline and the subsequent anion gap acidosis3. This accumulation of 5-oxoproline has resulted in clinical presentations ranging from asymptomatic acidosis to coma 4. Acetaminophen
levels are usually not in toxic range. This is usually responsive to discontinuing acetaminophen and hydration. In severe cases, N-acetyl cysteine therapy has
also been given, though the data on its efficacy is limited.
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Mehta AN, Emmett JB, Emmett M. GOLD MARK: an anion gap mnemonic for the 21st century. Lancet. 2008;372:892.
Critchley JA, Nimmo GR, Gregson CA, Woolhouse NM, Prescott LF. Inter-
subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol. 1986;22:649-657. 3.
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;9:191-200. 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;23:19-20.
Author Information Dr. Hassan Kamran, Baylor College of Medicine
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Dr. Nalini Ram, Baylor College of Medicine