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Table of Contents
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 198-200

High anion gap metabolic acidosis as a result of 5-oxoproline

1 Department of Nephrology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
2 Department of Medicine, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India

Date of Submission15-Jan-2022
Date of Decision16-Feb-2022
Date of Acceptance21-Feb-2022
Date of Web Publication14-Jul-2022

Correspondence Address:
Dr. Suvika Patel
Department of Nephrology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_8_22

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High anion gap metabolic acidosis is a common acid–base disorder encountered in hospitalized patients and more so in the intensive care unit. The most common causes are accumulation of lactate, ketones, and urea and ingestion of certain toxins. In the absence of these, lesser-known etiologies such as accumulation of D-lactate or pyroglutamic acid (PGA) should be suspected. PGA (5-oxoproline) is an endogenous organic acid that can accumulate in serum to cause anionic gap metabolic acidosis. This can occur with inherited defects in enzymes that participate in the y-glutamyl cycle or can be acquired in association with therapeutic paracetamol use, malnutrition, sepsis, antibiotics, and renal impairment. Our case illustrates that prompt recognition of this entity and discontinuation of offending agents such as paracetamol result in rapid recovery, thus reducing the hospital stay.

Keywords: High anion gap metabolic acidosis, paracetamol, pyroglutamic acidosis, renal impairment

How to cite this article:
Patel S, Parikh F, Kulkarni N. High anion gap metabolic acidosis as a result of 5-oxoproline. Indian J Med Spec 2022;13:198-200

How to cite this URL:
Patel S, Parikh F, Kulkarni N. High anion gap metabolic acidosis as a result of 5-oxoproline. Indian J Med Spec [serial online] 2022 [cited 2023 Jan 30];13:198-200. Available from: http://www.ijms.in/text.asp?2022/13/3/198/350918

  Introduction Top

The anion gap (difference between easily measurable cations and easily measurable anions) remains a very important tool in the systematic approach to acid–base disorders. Relatively uncommon etiologies of high anion gap metabolic acidosis (HAGMA) such as pyroglutamic acid often get overlooked. We hereby present our case of persistent severe HAGMA due to accumulation of 5-oxoproline that promptly responded to discontinuation of paracetamol.

  Case Report Top

A 70-year-old female was admitted to our hospital with reduced level of consciousness, low-grade fever, and bilateral lower limb weakness after a fall at home. She has been known to be diabetic for the past 7 years. She was hospitalized for moderate COVID-19 infection 6 months back when she received remdesevir and steroids. High-resolution computed tomography chest showed endobronchial nodules, which was not consistent with typical findings of COVID-19 infection. Further evaluation led to a diagnosis of pulmonary tuberculosis, for which she was started on isoniazid + rifampicin + pyrazinamide + ethambutol (HRZE). Isoniazid and pyrazinamide were temporarily replaced with levofloxacin 2 months back in view of drug-induced hepatitis, which was subsequently reintroduced.

In the last 10 months, she had a history of recurrent urinary tract infection, uterine prolapse, and a perineal abscess requiring incision and drainage along with the use of higher antibiotics.

Ten days before current hospitalization, she was given nitrofurantoin, cefuroxime, and paracetamol for fever and burning micturition by her family physician. However, because of persistent fever along with deterioration in sensorium, she was admitted to our hospital and started on intravenous fluids, paracetamol, and cefoperazone/sulbactam.

Three days into hospitalization, the patient remained somnolent and her blood workup as shown in [Table 1] indicates a HAGMA with normal osmolar gap and without any abnormalities in ketones or lactates.
Table 1: Biochemical parameters

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In view of the persistent HAGMA without a clear etiology, her urine sample was analyzed for the presence of any organic acids. This showed very high levels of 5-oxoproline (479.38 with cutoff value being 10.48), confirming the diagnosis of pyroglutamic acidosis.

Paracetamol has been reported to have a causative link with pyroglutamic acidosis, which was discontinued along with the administration of N-acetyl cysteine and intravenous fluids. The patient showed a steady improvement in her condition. Her blood workup after treatment showed a significant improvement [Table 2].
Table: 2: Biochemical parameters after treatment

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  Discussion Top

Metabolic acidosis that is caused by 5-oxoproline results from disruption of the y-glutamyl cycle. Several inherited enzyme defects that have been characterized are extremely rare and usually present at a very early age with neurologic and hematologic abnormalities. Glutathione synthetase (GS) deficiency[1] is an autosomal recessive disorder and is characterized by mental retardation, ataxia, hemolytic anemia, and chronic metabolic acidosis. With GS deficiency, reduced glutathione levels increase γ-glutamyl cysteine synthetase activity and the resulting high γ-glutamyl cysteine levels are partially converted to 5-oxoproline. 5-Oxoprolinase deficiency[2] is another rare autosomal recessive disorder that presents with 5-oxoprolinuria and is known to develop kidney stones at a young age.

Acquired 5-oxoprolinuria has been described in adults. Several contributory factors[3] such as malnutrition, pregnancy, strict vegetarian diet, and renal impairment have been identified [Figure 1]. Limited glycine availability may be a common precipitating cause. Severe 5-oxoproline aciduria and acidemia have been described in patients exposed to certain medications.[4],[5] These include acetaminophen (paracetamol), vigabatrin, and antibiotics such as flucloxacillin. Glycine deficiency along with other predisposing conditions may result in depletion of glutathione. This critically important tripeptide that contains glutamic acid, cysteine, and glycine has major antioxidant effects and detoxifies many drugs and poisons. The liver has highest contents of glutathione and it is known that hepatic glutathione stores are depleted in patients with acetaminophen toxicity. HAGMA has been noted in some patients on therapeutic doses of acetaminophen.[6] It should be emphasized that acetaminophen ingestion alone probably does not generate clinically significant 5-oxoprolinuria or metabolic acidosis. In most cases, synergistic interaction between acetaminophen ingestion and multiple other factors exists. A reduction of kidney function will reduce urine excretion of 5-oxoproline and therefore may cause greater systemic accumulation. Urine 5-oxoproline excretion in the acetaminophen group was higher than that in the control group, although still much lower than that which occurs in patients with inherited GS deficiency.
Figure 1: Various factors act to cause accumulation of 5-oxoproline, either by depleting glutathione (green) or by inhibiting the clearance of 5-oxoproline by 5-oxoprolinase or its renal excretion (red)

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We believe that treatment[7] of this unusual form of metabolic acidosis should focus on the early recognition of its presence and cessation of acetaminophen intake. The importance of treatment of sepsis and renal and/or hepatic dysfunction is self-evident. N-acetyl cysteine has been used with some effectiveness in patients with GS deficiency because it is thought to increase the low intracellular glutathione and cysteine concentrations. In view of N-acetyl cysteine's low toxicity and theoretical benefit, its use seems reasonable until better studies become available.

  Conclusion Top

Pyroglutamic acidosis is reasonably common in hospitalized patients[8] but is almost certainly underdiagnosed. It should be suspected in patients taking long-term paracetamol in therapeutic doses in the presence of additional risk factors (malnutrition, infection, multiple antibiotic use, pregnancy, and renal failure). It can be detected as metabolic acidosis with an elevated anion gap in the absence of an elevated L-lactate or ketones. Treatment involves cessation of paracetamol (and any other causative agent) and bicarbonate supplementation. N-acetyl cysteine has been used in some cases to accelerate recovery.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Meister A, Larsson A. Glutathione synthetase deficiency and other disorders of the gamma-glutamyl cycle. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Basis of Inherited Metabolic Disease. 7th ed. New York: McGraw-Hill; 1995. p. 1461-77.  Back to cited text no. 1
Larsson A, Mattsson B, Wauters EA, van Gool JD, Duran M, Wadman SK. 5-oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers – A new inborn error of the gamma-glutamyl cycle. Acta Paediatr Scand 1981;70:301-8.  Back to cited text no. 2
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.  Back to cited text no. 3
Pitt J. Association between paracetamol and pyroglutamic aciduria. Clin Chem 1990;36:173-4.  Back to cited text no. 4
Bonham JR, Rattenbury JM, Meeks A, Pollit RJ. Pyroglutamic aciduria from vigabatrin. Lancet 1989;1:1452-3.  Back to cited text no. 5
Humphreys BD, Forman JP, Zandi-Nejad K, Bazari H, Seifter J, Magee CC. Acetaminophen-induced anion gap metabolic acidosis and 5-oxoprolinuria (pyroglutamic aciduria) acquired in hospital. Am J Kidney Dis 2005;46:143-6.  Back to cited text no. 6
Mårtensson J, Gustafsson J, Larsson A. A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5-oxoprolinuria). J Inherit Metab Dis 1989;12:120-30.  Back to cited text no. 7
Mizock BA, Belyaev S, Mecher C. Unexplained metabolic acidosis in critically ill patients: The role of pyroglutamic acid. Intensive Care Med 2004;30:502-5.  Back to cited text no. 8


  [Figure 1]

  [Table 1], [Table 2]


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