Abstract
Two patients with high anion gap metabolic acidosis (HAGMA) and 5-oxoprolinuria who had been taking therapeutic paracetamol (acetaminophen) and antibiotics were recently described in this journal (Ann Clin Biochem 2007;
Previous case reports of paracetamol-induced 5-oxoprolinuria describe a heterogeneous group of mainly adult patients with a range of symptoms and no common underlying chronic illnesses. The mechanism is unknown, but suggested contributing factors include underlying metabolic abnormalities such as lactic acidosis or ketosis, abnormal liver function, impaired glycine supply, heterozygosity for glutathione synthetase deficiency and malnutrition. 2–5 We describe a paediatric case of 5-oxoprolinuria following a standard dose of paracetamol and suggest a possible mechanism for the abnormal response to this commonly used analgesic.
An 11-year-old boy with a history of severe epilepsy had been on a standard ketogenic diet consisting of high fat, low carbohydrate (ratio 4:1) and 0.7–1.0 g/Kg/day protein for eight years, resulting in marked improvement in seizure control. Dietary review was required due to a recent growth spurt. He presented to the Emergency Department with vomiting, fever and increased seizure activity following a cold-like illness for which he had been given paracetamol at home, 500 mg 6–8 hourly for two days. On admission he had HAGMA, elevated liver transaminases and renal impairment. These results had been normal on a routine outpatient appointment two weeks previously (Table 1). Plasma paracetamol concentration was 30 mg/L. Urine organic acids showed grossly elevated 5-oxoproline with ketosis, lactic acidosis and increased paracetamol excretion. Plasma taurine and cystine were low (Table 2). On admission to hospital paracetamol was stopped and his transaminases fell rapidly, normalizing by day 12. The HAGMA persisted until day six. Urine excretion of 5-oxoproline halved by day nine and was normal on repeat testing on day 19. Plasma taurine, cystine and methionine fell and remained below the reference range after recovery and discharge from hospital. Plasma glycine was within the reference range. Review of previous investigations found that two years prior to this admission he had very low levels of some of the sulphur-containing amino acids (Table 2). The child was given methionine supplementation (250 mg/day) and his plasma amino acids have returned to normal values.
Results of biochemistry tests performed before and during admission (day 0)
Plasma amino acid results
On presentation, this child had evidence for several of the proposed precipitating risk factors for paracetamol-induced 5-oxoprolinuria, including chronic ketosis, low plasma protein intake, liver failure and lactic acidosis. In addition, he had evidence of long-term depletion of sulphur-containing amino acids. N-acetyl-P-benzoquinoneimine, a toxic intermediate of paracetamol metabolism, is stabilized and excreted by conjugation with glutathione. Glutathione is synthesized from glutamate, cysteine and glycine; deficiency of this tripeptide alters the γ-glutamyl cycle, resulting in increased 5-oxoproline synthesis. 6 It is possible that deficiency of sulphur-containing amino acids in this patient resulted in low glutathione stores, precipitating 5-oxoprolinuria in following paracetamol ingestion.
In conclusion, we have described a child who presented with severe illness, HAGMA and 5-oxoprolinuria following a standard dose of paracetamol. His long-term ketogenic diet, while successful in controlling his severe epilepsy, appears to have been deficient in methionine, causing impaired synthesis of sulphur-containing amino acids and possible depletion of glutathione stores. This adds evidence to the hypothesis that nutritional deficiency, in particular of essential amino acids, may be a contributing factor to the abnormal metabolic response to paracetamol of HAGMA and 5-oxoprolinuria.