An 80-year-old man was admitted under the orthopaedic team with a five-week history of progressive right hip pain. He had a background of a total hip replacement (THR) following a road traffic collision. His past medical history was significant for hypertension and type 2 diabetes with peripheral neuropathy. He had an excellent and independent functional baseline.

X-ray showed a loosening of the acetabular component of the previous THR and he was brought to theatre for a revision of THR. Intraoperatively, pus was noted on entering the joint capsule, and it was determined the loosening of THR was caused by a prosthetic joint infection. The intraoperative samples grew methicillin sensitive Staph aureus and he was commenced on a six week course of flucloxacillin after the joint was washed out during surgery.

On day 24 post op, he had a sudden deterioration. He become drowsy, hypotensive and tachypnoeic. Blood work revealed a metabolic acidosis with a pH of 7.203, unrecordable low pCO2, Po2 of 15 kPa, bicarbonate was 3.6. Anion gap was calculated at 35.2. He had an acute kidney injury with a creatinine of 151 (previous 108). The more common causes of metabolic acidosis were ruled out with a normal lactate, ketones, salicylate and ethanol levels.

He was treated with IV bicarbonate and N-acetyl cysteine which failed to correct the acidosis and subsequently the patient was brought to the intensive care unit for continuous venovenous haemodialysis (CVVHD). Due to the prolonged course of flucloxacillin and paracetamol, pyroglutamic acid toxicity was suspected. The patient improved quickly on haemodialysis; antibiotics were changed from flucloxacillin to ceftriaxone; and paracetamol was stopped. A week later the result of serum sample for pyroglutamic acid returned as markedly elevated.

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Discussion

Pyroglutamic acidosis is a rare cause of increased  anion gap metabolic acidosis. Metabolic acidosis due to high levels of 5-oxoproline (pyroglutamic acid) was first described in 1989, in a woman chronically taking paracetamol.¹ Previously, it had only been described in the context of genetic enzyme deficiencies, causing specific clinical manifestations of varying severity from the neonatal period.² 5-oxoproline accumulation occurs due to a defect in the γ-glutamyl cycle. This cycle is the pathway for synthesis and degradation of glutathione and certain hepatically metabolised drugs. Risk factors for development include female gender, chronic malnutrition, sepsis, liver failure and certain medications. Both paracetamol and flucloxacillin are known to affect this cycle. Chronic paracetamol ingestion depletes glutathione stores, and flucloxacillin inhibits 5-oxyprolinase, the enzyme that degrades pyroglutamic acid, causing its accumulation. Treatment includes supportive measures, discontinuation of any offending drugs and, in severe cases, haemodialysis can accelerate clearance of the acid. N-acetyl cysteine can be given to replenish stores of glutathione.³

Conclusion

This patient had a high anion gap metabolic acidosis secondary to pyroglutamic acid. He had several risk factors for development with chronic paracetamol, and long-term flucloxacillin use, as well as sepsis and malnutrition which had developed during his prolonged hospital stay. This condition is rare but likely underdiagnosed since testing is not widely available, and it would be missed if using the classic mnemonic of MUDPILES to investigate causes of metabolic acidosis: M – methanol; U – uraemia (chronic kidney failure); D – diabetic ketoacidosis; P – paracetamol, propylene glycol; I – infection, iron, isoniazid, inborn errors of metabolism; L – lactic acidosis; E – ethylene glycol (ethanol sometimes included also); and S – salicylates. It is important to think of metabolic acidosis because the treatment is straightforward but if left untreated can have fatal consequences.

References

1. Creer MH, Lau BWC, Jones JD, Chan K-M. Pyroglutamic acidemia in an adult patient. Clin Chem 1989; 35:684-686
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 
3. Lanoy C, Bouckaert Y. J Med Case Reports 2016; 10:184. https://doi.org/10.1186/s13256-016-0964-x