An Under Recognised Cause of Metabolic Acidosis

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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

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