5-Oxoprolinuria as a cause of high anion gap metabolic acidosis

摘要: We report a case of high anion gap metabolic acidosis (HAGMA) caused by 5-oxoprolinuria resulting from chronic intermittent paracetamol therapy, malnutrition and concomitant moderate renal/hepatic dysfunction. A 36-year-old Caucasian woman was brought to our intensive care unit after intubation at another hospital. She initially presented with drowsiness tachypnoea. The initial working diagnosis bibasilar bronchopneumonia, she received dose ceftriaxone. Arterial blood gas (prior intubation) showed pH 6.99, partial pressure CO2 14 mmHg, O2 80 mmHg 92% saturation on oxygen 2 l min−1 via nasal cannulae. had past medical history migraine, seizures, depression, obstructive pulmonary disease, malnutrition, anaemia deranged hepatic transaminases for 4 years following prior suicide attempt paracetamol. marijuana, methamphetamine, dextromethorphan cold tablet ethanol abuse, in addition 40 pack-year smoking. Her prescription medications included divalproex sodium, levetiracetam, olanzapine, promethazine, mirtazapine, fenofibrate, lactulose, omeprazole as needed. On examination, malnourished (body mass index 17.9 kg m−2), pale, tachypnoeic (40 breaths min−1) tachycardic (hear rate 102 105/60 weak peripheral pulses. Further laboratory studies an 20, bicarbonate 5 mequiv l−1 creatinine 1.5 mg dl−1 (132.6 µmol l−1). Δanion gap/Δbicarbonate ratio = 0.42 suggested mixed non-anion acidosis. latter presumed be renal dysfunction. Other pertinent values were follows: haemoglobin 11.9 g (119 l−1), white cell count 000 mm−3 × 109 l−1) platelets 854 (854 Total bilirubin normal, aspartate aminotransferase 322 U (normal 5–40 alanine 101 7–56 alkaline phosphatase 296 38–126 international normalized 2.5, ammonia 78 µg (45.7 l−1; normal 17–60 dl−1), lipase 411 7–60 amylase 68 l−1, activated thromboplastin time 50 s valproate concentration 24 (subtherapeutic). Urinalysis drug abuse screen unremarkable. The causes negative: lactic acid 1.0 mmol <0.01 dl−1, methanol <5 isopropranolol ethylene glycol <10 propylene <0.04 salicylate 4.3 <1.2 ml−1 β-hydroxybutyrate 0.2 d-lactic acid, acetaldehyde, paraldehyde acetone not detected. The patient's did resolve over the next days, so started sodium infusion later switched continuous veno-venous haemodialysis, which proved very effective correcting her derangement. To explore other aetiologies HAGMA, urine organic sent sample, revealed markedly elevated excretion 5-oxoproline. A HAGMA secondary made. patient regained neurological state no acid–base disturbance, repeat discharge 7 days negative, indicating transient 5-oxoprolinuria. absence haemolytic makes existence genetic deficiency glutathione synthetase this unlikely. Excess 5-oxoproline (also known pyroglutamic acid) production is rare cause HAGMA. It intermediary γ-glutamyl cycle, facilitates transport tripeptide (glutamyl-cystinyl-glycine) its constituent amino acids across cellular membranes regenerates intracellularly. Reduced required detoxification minimization free-radical-induced oxidative stress. As shown Figure 1, excess generated cyclotransferase enzyme when deficient [1]. Glutathione depletion exerts negative feedback cysteine synthetase. This decreased situations depletion, thus increasing cysteine, acts substrate generate seen liver use, alcohol fad diets (e.g. low-protein diet), glycine deficiency, severe sepsis [1–4]. 5-Oxoproline cleared renally accumulates oxidized 5-oxoprolinase l-glutamate; however, certain drugs (flucloxacillin, netilmicin vigabatrin) can inhibit 5-oxoprolinase, hence preventing degradation [2, 5]. concentrations are also increased patients burns those total parenteral nutrition [1]. Figure 1 γ-Glutamyl cycle showing generation (pyroglutamic acid). AKI, acute kidney injury Our combination probably led depletion. Importantly, supratherapeutic/toxic do appear 5-oxoprolinuria, reported others 6, 7]. management involves discontinuing offending agents (antibiotics or antiepileptics) providing supportive care. Some authors suggest using N-acetylcysteine regenerate intravenous if <7.0 [5, 8, 9]. Physicians should consider screening common have been excluded, especially who taking