A 72-year-old female, body mass index 17.5 kg/m2 , is admitted to the High Dependency Unit following a Medical Emergency Team call for tachypnoea and hypotension. She is known to have sepsis relating to a urinary tract infection and wound infection following extensive surgery for resection of a left thigh chondrosarcoma six weeks earlier.
Her biochemistry results are as follows:
|Parameter||Patient Value||Normal Adult Range|
|Sodium||139 mmol/L||134 – 146|
|Potassium||4.6 mmol/L||3.4 – 5.0|
|Bicarbonate||5.0 mmol/L*||22 – 32|
|Urea||11.2 mmol/L*||3.0 – 8.0|
|Creatinine||179 µmol/L*||45 – 90|
|Arterial Blood Gas|
|Parameter||Patient Value||Normal Adult Range|
|pH||7.18*||7.35 – 7.45|
|PCO2||14 mmHg (1.8 kPa)||35 – 45 (4.6 – 6.0)|
|PO2||104 mmHg (13.7 kPa)|
|Bicarbonate||5.0 mmol/L*||22 – 28|
|Base Excess||-22 mmol/L*||-2.0 – +2.0|
|Sodium||141 mmol/L||134 – 146|
|Potassium||4.3 mmol/L||3.4 – 5.0|
|Chloride||114 mmol/L*||98 – 108|
|Glucose||6.9 mmol/L*||3.0 – 5.4|
|5-Oxoproline (Pyroglutamic acid)||> 3+ (16 mmol/mmol creatinine)|
a) Interpret her acid-base status.
With reference to her urinalysis:
b) Explain the significance.
c) List the likely predisposing factors in this patient.
d) Briefly outline the underlying pathophysiology.
e) List your management strategies.
Mixed high anion gap and normal anion gap metabolic acidosis with respiratory compensation
(AG = 22 and delta gap = 0.4 – 0.8)
[SIDA abbreviated = Na + K – Cl = 31.3 (decreased SID, raised Cl)]
High levels of PGA imply that this is the cause of her underlying HAGMA
Low levels of ketones relate to relative starvation
Predisposing factors in this patient are:
May have had concomitant treatment with paracetamol and/or flucloxacillin
Liver function not given but liver dysfunction also predisposing factor
Congenital enzyme deficiencies unlikely
Pathophysiology relates to glutathione depletion (sepsis, liver dysfunction, paracetamol via NAPQI) resulting in loss of negative feedback on synthesis of gamma-glutamylcysteine with subsequent increased production of pyroglutamic acid; or 5-oxoprolinase inhibition (flucoxacillin) resulting in decreased conversion of PGA to glutamate
Supportive care and monitoring - oxygen, haemodynamic and renal support as indicated
Cease culprit drugs
Treat sepsis (appropriate antibiotics and surgical debridement)
Improve nutritional status
Let us dissect these results systematically.
- The A-a gradient is high; ~92.4mmHg
- There is acidaemia
- The PaCO2 is compensatory
- The SBE is -22, suggesting a severe metabolic acidosis
- The respiratory compensation is essentially complete - the expected PaCO2 (5 × 1.5) + 8 = 15.5mmHg, according to the Boston rules.
- The anion gap is (141) - (114 + 5) = 22, or 26.3 when calculated with potassium
The delta ratio, assuming a normal anion gap is 12 and a normal bicarbonate is 24, would therefore be (22 - 12) / (24 - 5) = 0.52
Thus, there is both a HAGMA and a NAGMA here.
The college rightly blames the high anion gap acidosis on pyroglutamic acid. The combined contribution from the ketones and lactate would not be enough to explain the anion gap.
In brief, the predisposing factors to pyroglutamic acidosis in general are as follows:
Risk factors for depletion of glutathione
- Severe sepsis
- Chronic alcoholism
- Chronic liver failure of any cause
- Weird diet, or malnutrition in general
Risk factors for dysfunction of 5-oxoprolinase
- Netilmicin (but apparently not any other aminoglycosides)
- Inherited enzyme deficiency (known only from case reports)
- Gender-specific difference in enzyme activity (women seem more prone to this acidosis)
Risk factors for diminished 5-oxoproline clearance
- Renal failure
The college also include old age as a risk factor.
Specific management consists of addressing the synthesis and clearance of 5-oxoproline.
- Replenishing glutathione:
- Adequate nutrition
- Avoidance of paracetamol
- Management of the sepsis
- Increasing 5-oxoprolinase activity:
- cessation of inhibitory drugs
- Improving 5-oxoproline clearance
- Fluid management of renal failure
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Kortmann, W., et al. "5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors." Neth J Med 66.8 (2008): 354-357.
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