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Suspected pyroglutamic acidosis in a complex patient: A case report
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Received: ,
Accepted: ,
How to cite this article: Al Ali AA, Al-Shaaili KS. Suspected pyroglutamic acidosis in a complex patient: A case report. World Adv Renal Med. doi: 10.25259/WARM_33_2025
Abstract
We present the case of a 35-year-old female with multiple co-morbidities who developed unexplained high anion gap metabolic acidosis (HAGMA) despite marked improvement in sepsis parameters and other clinical conditions. Given the presence of known predisposing factors such as chronic therapeutic paracetamol (acetaminophen) use, chronic kidney disease, female gender, acute serious illness, undernutrition, and a dramatic improvement in acidosis following discontinuation of paracetamol without other overt explanations, we suspect acquired pyroglutamic acidosis (5-oxoproline acidosis) despite a lack of laboratory confirmation of 5-oxoproline. This case underlines the importance of recognizing this underdiagnosed cause of HAGMA.
Keywords
Chronic kidney disease
High anion gap metabolic acidosis
5-Oxoproline
Paracetamol
Pyroglutamic acidosis
INTRODUCTION
High anion gap metabolic acidosis (HAGMA) is a common acid-base disturbance, most often due to lactic acidosis, ketoacids, uremic toxins, or ingestion of toxic agents. However, one less frequently recognized cause is the accumulation of pyroglutamic acid (5-oxoproline) in the γ-glutamyl (glutathione) cycle.[1] This acquired form of pyroglutamic acidosis typically occurs in adults exposed to chronic therapeutic doses of acetaminophen (paracetamol), especially when other predisposing conditions are present.[2]
CASE REPORT
A 35-year-old Omani woman was admitted to the hospital with a severe diabetic foot infection that could not be managed by conservative management, so she required sequential surgical debridement and amputations. Initially, she underwent infected wound debridement and antibiotic coverage. Then, the patient suffered from severe sepsis, and her wound was not healing well, so she underwent right-sided transmetatarsal amputation. She started on broad-spectrum antibiotics (pipracillin-tazobactam), but after wound cultures showed Klebsiella Oxytoca and Citrobacter Braakii, treatment was switched to meropenem based on sensitivity. A couple of days later, her wound deteriorated with signs of wet gangrene and osteomyelitis, so finally, she underwent right-sided below-knee amputation.
During this period, she received regular paracetamol (1 g, 3 times daily) over her hospitalization period for fever and pain control.
Her past medical history includes poorly controlled insulin-dependent diabetes mellitus complicated by micro and macrovascular complications and chronic kidney disease; her baseline serum creatinine is 168 µmol/L; estimated glomerular filtration rate (eGFR) by (modification of diet in renal disease [MDRD]) ~ 31.7 mL/min/1.73 m2, and a history of ischemic stroke 2 years back with residual right-sided weakness.
Two weeks after admission, and despite better control of sepsis evidenced by resolution of fever, improving inflammatory markers, better wound healing, and blood cultures revealed no microbial growth, the patient developed persistent metabolic acidosis, manifested clinically by respiratory distress requiring non-invasive ventilation. She was afebrile with a temperature of 36.4°C, blood pressure of 142/87 mmHg, pulse 96 beats/min, and respiratory rate 27 breaths/min. Other physical examination was unremarkable, with normal vesicular sounds on chest auscultation and scattered basal crackles.
Blood test results
Arterial blood gases; pH 7.31, pCO2 24 mmHg, PO2 81 mmHg, bicarbonate 10 mmol/L; lactate 0.7 mmol/L, renal function tests revealed creatinine 246 µmol/L, urea 16.6 mmol/L, eGFR (MDRD) 20.4 mL/min/1.73 m2, sodium 142 mmol/L, potassium 3.8 mmol/L, chloride 111 mmol/L, base excess – 14.3 mmol/L, normal alanine transaminase 7U/L and aspartate transaminase 10U/L, but low albumin 22 g/L, albumin-corrected anion gap was 25.5 mEq/L. Complete blood count findings showed hemoglobin of 8.2 g/dL, white blood cells of 8 × 109/L, and platelets of 365 × 109/L. Blood glucose 8.8 mmol/L was controlled on insulin.
Given the presence of unexplained HAGMA, the nephrology team raised suspicion of pyroglutamic acidosis. We immediately discontinued paracetamol and recommended switching to opioid pain killers for pain management, prescribed N-Acetylcysteine 600 mg twice daily, and gave sodium bicarbonate intravenous (IV) 50 mmol, 3 times daily for 2 days.
Following cessation of paracetamol, the patient’s general condition and acid-base status markedly improved over the subsequent 2 days, kidney function stabilized with serum creatinine 226 umol/L, urea 16 mmol/L, Na 131 mmol/L, chloride 96 mmol/L, bicarbonate 24 mmol/L, eGFR (MDRD) 22.5 mL/min/1.73 m2. It was observed that serum bicarbonate levels normalized and remained stable in the days following discontinuation of IV sodium bicarbonate infusion.
DISCUSSION
The mechanism of acquired pyroglutamic acidosis involves impairment of the γ-glutamyl cycle. Paracetamol metabolism depletes glutathione, and in predisposed individuals (with low cysteine/glutathione reserves), the cycle is diverted to generate 5-oxoproline, which accumulates and causes HAGMA. The vast majority of pyroglutamic acidosis cases in this context occur in hospital-admitted patients on regular and therapeutic doses of paracetamol.
We report a case in which the clinical picture strongly supports this diagnosis, illustrating the diagnostic reasoning and management considerations.
This case meets multiple features described in the literature for acquired pyroglutamic acidosis[3], like the presence of predisposing factors, including prolonged paracetamol use (3 g/day) over a sustained in-patient stay, female gender, acute kidney injury superimposed over CKD that leads to reduced glutathione reserve or metabolism, and critical illness due to sepsis and undernutrition.[4]
Unexplained HAGMA after exclusion of more frequent etiologies like lactic acidosis which was excluded by normal lactate level, no diabetic ketoacidosis as she has controlled blood glucose and absence of ketones in blood and urine, no evidence of a toxin/alcohol intake as the patient was in close observation allover her hospital stay due to her critical condition, and no salicylate ingestion as her acetylsalicylic acid medication was stopped on admission, these findings suggested the suspected diagnosis.[5]
In uremic acidosis, retention of unmeasured anions causes only a modest rise in the serum anion gap; a significantly elevated albumin-corrected anion gap suggests an additional cause of HAGMA. There is no validated formula for a “uremic anion gap,” and it cannot be predicted from blood urea nitrogen, as urea is neutral and the retained anions are variable.[6]
The cornerstones of management are to discontinue the offending agent (paracetamol), administer N-acetylcysteine or other glutathione-replenishing therapy in some cases, and provide supportive care to the underlying condition and acid-base status.
In this patient, the observed acid-base improvement following discontinuation of paracetamol presents strong clinical evidence for considering this a suspected case of pyroglutamic acidosis. Ideally, confirmation would be obtained through urine or plasma organic acid screening to detect elevated 5-oxoproline; however, such testing is often unavailable, and recent literature indicates that many reported cases are based solely on clinical assessment.[7] The absence of biochemical verification remains a significant limitation, and the existence of multiple potential contributing factors means alternative causes of HAGMA cannot be completely ruled out, although they were considered unlikely in this instance (normal lactate, no ketones in urine or blood, no evidence of drug/toxin ingestion, and the degree of renal failure not consistent with the high degree of change in anion gap [AG]).
It is important for clinicians to recognize that pyroglutamic acidosis is a rare cause of HAGMA relative to more prevalent etiologies. Common and treatable conditions, such as lactic acidosis, drug co-ingestion, and ketoacidosis, should be excluded before considering less frequent diagnoses.[8]
Learning points and key messages
In patients with HAGMA and no obvious cause, suspect pyroglutamic acidosis when predisposing factors exist.
Therapeutic (not necessarily overdose) doses of paracetamol may precipitate the condition in susceptible individuals.
Withdrawal of paracetamol can reverse the acid-base disturbance.
A well-documented clinical scenario may suffice to justify a “suspected” diagnosis for case-report purposes.
CONCLUSION
This case underscores the importance of considering acquired pyroglutamic acidosis in patients with unexplained HAGMA, especially when it is accompanied by other predisposing factors. Strong clinical suspicion and prompt withdrawal of the offending medications can lead to rapid improvement. Increased awareness of this condition may reduce the delay in diagnosis and hence improve outcomes.
Author contributions:
AAAA: Contributed to the conceptualization and study design, prepared the initial draft of the manuscript, conducted the literature search, acquired the data, performed data analysis and interpretation, and participated in manuscript review and editing. AAAA: Responsible for the integrity of the work from inception to publication; ASKS: Contributed to study conceptualization, responsible for patient care and the collection of clinical and laboratory data, and participated in manuscript review and editing.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as patients identity is not disclosed or compromised.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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