5-Oxoprolinuria is an underreported metabolic aberration which is easy to diagnose and treat. We report the case of a 72-year-old woman who was admitted to the ICU with slowly progressive dyspnoea and severe metabolic acidosis. We obtained her written informed consent to report the case.
Two months earlier she was admitted to the hospital with a traumatic cruris fracture. Recovery was complicated by Staphylococcus aureus wound infection for which she received intravenous flucloxacillin in the 3 weeks preceding ICU admission. Concurrently, she was taking carbasalate calcium, paracetamol and metformin.
Physical examination showed a lethargic and tachypnoeic patient with Kussmaul respiration. Her vital signs were as follows: blood pressure 153/92 mmHg, atrial fibrillation of 111 beats/min and temperature of 35.4°C. Auscultation of heart, lungs and abdomen were unremarkable as were her extremities besides the scar on the left lower leg. Diuresis was normal. Blood gas analysis while breathing 5 l of oxygen showed pH 7.16, pCO2 2.0 kPa, HCO3− 5 mmol l−1, base excess (BE) −21.5 mmol l−1, sat 1.0, pO2 19.7 kPa. Laboratory tests revealed values for haemoglobin 6.2 mmol l−1, urea 5.2 mmol l−1, creatinine 96 μmol l−1, creatine kinase 28 U l−1, sodium 136 mmol l−1, potassium 3,2 mmol l−1, chloride 115 mmol l−1, albumin 19 g l−1, lactate 0.44 mmol l−1, C-reactive protein 27 mg l−1, glucose 10.4 mmol l−1, plasma osmolality 297 mosmol kg−1 (calculated osmol-gap 9 mosmol kg−1), normal liver function tests and absence of ketones in urine. Urine pH was 5. Chest radiography showed no infiltrates or pulmonary congestion. Toxicology screen was negative. When corrected for the hypoalbuminemia, the anion gap was increased at 21. Although a diagnosis was lacking, she received sodium bicarbonate to correct the metabolic acidosis. Other medication included amiodarone for atrialfibrillation. Carbasalate calcium, paracetamol and metformin were ceased. Despite continuous sodium bicarbonate infusion, the metabolic acidosis persisted but was less severe. Blood gas analysis while breathing 1 l of oxygen showed pH 7.45, pCO2 3.7 kPa, HCO3− 19 mmol l−1, BE −4.2 mmol l−1, sat 99%, pO2 14 kPa. At that time, 5-oxoprolinuria was suspected and flucloxacillin was switched to cefazolin, after which the blood gas normalised (pH 7.44, pCO2 4.0 kPa, HCO3− 20 mmol l−1, BE −3.3 mmol l−1, pO2 11.7 kPa). Urine samples were analysed for urinary organic acids by gas chromatography-mass spectrometry and showed strong increases in 5-oxoproline (pyroglutamate) levels at 25 mmol l−1 (normal <50 μmol l−1). After switching flucloxacillin to cefazolin medication, the 5-oxoproline concentration in urine normalised within 3 days. The patient was clinically improving and in good condition was discharged to the general ward.
To determine the cause of a metabolic acidosis determination of the anion gap is helpful. The anion gap is the difference between the sums of positively and negatively charged molecules (cations and anions) in serum and refers to the concentration of unmeasured anions. The anion gap is calculated as (Na+)−(Cl− + HCO3−). In a normal situation, equal quantities of cations and anions are present in serum. However, not all cations and anions are measured by routine laboratory analysis. Chloride and bicarbonate are the most important anions, and sodium the most important cation analysed in serum. Unmeasured plasma cations are calcium, magnesium, potassium and gamma globulins. Unmeasured plasma anions are albumin, sulphate, phosphate, lactate and other organic anions. Because there are more unmeasured anions than cations, the ‘anion gap’ equation is always positive (normal value 8–16 mmol l−1). The anion gap can help to differentiate between the possible causes of metabolic acidosis. A high anion gap is associated with the presence of endogenous or exogenous acids, whereas a normal anion gap is associated with the loss of HCO3− from the kidney or gastrointestinal tract, or the failure of the kidney to excrete H+. The causes of metabolic acidosis are shown in the following list.
- Increased anion gap
- Increased endogenous acid
- Lactic acidosis
- Ketoacidosis (starvation, diabetic, alcoholic)
- Decreased renal acid excretion
- Chronic renal failure
- Exogenous acid
- Metformin, paracetaldehyde, ethylene glycol, methanol, toluene, salicylates
- Normal anion gap
- Gastrointestinal HCO3− loss
- Renal tubular acidosis
- Chloride retention or administration
- Heavy metals
- Carbonic anhydrase inhibitors
Several mnemonics have been used to remember the major causes of the high-gap metabolic acidoses. GOLD MARK is one of these mnemonics representing Glycols (ethylene and propylene), Oxoproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, and Ketoacidosis.1
Besides the known inherited causes of high 5-oxoproline (5-oxoprolinase and gluthatione synthetase deficiency), transient 5-oxoproline acidaemia is a rare cause of high anion gap metabolic acidosis which is suggested to be related to malnutrition, sepsis, chronic alcohol use, liver disease, renal insufficiency and drugs like flucloxacillin, paracetamol, netilmicin and vigabatrin. The majority of the reported cases are women which may reflect the sex-related aspect of the glutathione metabolism.2–5 5-oxoproline is an intermediate of the γ-glutamyl cycle. It plays a role in synthesis and metabolism of glutathione, transport of glutathione out of the cell and uptake of amino acids into the cell.3,6 Paracetamol depletes the glutathione store and activates γ-glutamyl cysteine synthetase which results in overproduction of γ-glutamyl cysteine, a substrate of γ-glutamyl cyclotransferase which produces 5-oxoproline. Flucloxacillin inhibits 5-oxoprolinase activity, resulting in 5-oxoproline acidaemia (Fig. 1). Diagnosis can be made by 5-oxoproline measurement in plasma or urine using gas chromatography-mass spectrometry. Treatment consists of supportive therapy, administration of sodium bicarbonate and withdrawing potential causes, in this case flucloxacillin and paracetamol.3,4
It was concluded that this patient suffered from 5-oxoprolinuria due to the combination of flucloxacillin and paracetamol. Because flucloxacillin and paracetamol are frequently used concomitantly, we believe 5-oxoproline acidemia is undervalued and underrecognised.
None of the authors declared any conflict of interest in relation to this case report.
1. Mehta AN, Emmett JB, Emmett M. GOLDMARK: an anion gap mnemonic for the 21st century. Lancet
2. Dempsey GA, Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamicacidemia: a cause of high anion gap metabolic acidosis. Crit Care Med
3. Pitt JJ, Hauser S. Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects. Clin Chem
4. Fenves AZ, Kirkpatrick HM, Patel VV, et al. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for paracetamol. Clin J Am Soc Nephrol
5. Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis
6. Pitt JJ, Brown GK, Clift V, Christodoulou J. Atypical pyroglutamic aciduria: possible role of paracetamol. J Inherit Metab Dis