An Under Recognised Cause of Metabolic Acidosis

The MUDPALES mnemonic for raised anion gap acidosis was drilled into me from medical school.  However recently after working through each category I became stumped when nothing ticked the box to identify the cause. 

The lady I had been asked to see was in her 80s and had fractured her hip.  On admission she had normal renal function and acid base status.  Post-operatively she was started on regular analgesia including paracetamol (acetaminophen) and developed a Staphlococcus Aureus wound cellulitis treated with flucloxacillin.  Over the following 2 weeks she developed a raised anion gap acidosis and positive urinary anion gap.  Renal function, lactate and ketones were normal.    

A cause of metabolic acidosis not in MUDPILES is pyroglutamic acidosis.  Pyroglutamic acid (also called 5-oxoproline) is a by-product in the gamma-glutamyl cycle.  This pathway is involved in the synthesis of glutathione, and is shown above from a recent paper.

Glutathione provides negative feedback on the cycle by inhibiting the enzyme gamma-glutamyl-cysteine synthase.  An acquired deficiency in glutathione, as with alcohol or paracetamol, results in loss of this negative feedback and increased production of 5-oxoproline leading to a metabolic acidosis.  Other drugs affect the cycle at different points including flucloxacillin which inhibits 5-oxoprolinase similarly resulting in build-up of 5-oxoproline. 

Urine amino acid screens show high levels of 5-oxoproline, though this test is not always available.  Our patient improved with withdrawal of paracetamol and flucloxacillin and oral bicarbonate which was stopped after a week.  Some cases have been treated with N-acetylcysteine to replenish glutathione levels. 

I think this is probably an under-recognised cause of metabolic acidosis with many of the risk factors being prevalent in our inpatients (poor nutrition, chronic alcohol use, renal failure, infection, paracetamol use).  A different mnemonic for causes of raised anion gap metabolic acidosis may be helpful like GOLD MARK:

·         G – glycols (ethylene and propylene)

·         O – 5-oxoproline (pyroglutamic acid)

·         L – L-lactate

·         D – D-lactate

·         M – methanol, ethanol

·         A – aspirin/salicylates

·         R – renal failure

K – ketones 

Post by Ailish Nimmo