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:
| Venous Sample | ||
| 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 |
| FiO2 | 0.3 | |
| 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 |
| Lactate | 1.0 mmol/L | <1.5 |
| Urinalysis | |
| Parameter | Patient Value |
| 5-Oxoproline (Pyroglutamic acid) | > 3+ (16 mmol/mmol creatinine) |
| 3-Hydroxybutyrate | 1+ |
| Acetoacetate | 1+ |
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.
a)
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)]
b)
High levels of PGA imply that this is the cause of her underlying HAGMA
Low levels of ketones relate to relative starvation
c)
Predisposing factors in this patient are:
Elderly patient
Sepsis
Malnutrition
Renal impairment
May have had concomitant treatment with paracetamol and/or flucloxacillin
Liver function not given but liver dysfunction also predisposing factor
Congenital enzyme deficiencies unlikely
d)
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
e)
Management strategies
Supportive care and monitoring - oxygen, haemodynamic and renal support as indicated
Cease culprit drugs
Treat sepsis (appropriate antibiotics and surgical debridement)
Improve nutritional status
N-acetyl cysteine
a)
Let us dissect these results systematically.
b)
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.
c)
Pyroglutamic acidosis is discussed in greater detail elsewhere, and there is also a brief summary of this topic for revision. For a much deeper discussion, one can turn to Kortmann's 2008 article.
In brief, the predisposing factors to pyroglutamic acidosis in general are as follows:
Risk factors for depletion of glutathione
Risk factors for dysfunction of 5-oxoprolinase
Risk factors for diminished 5-oxoproline clearance
The college also include old age as a risk factor.
d)
Specific management consists of addressing the synthesis and clearance of 5-oxoproline.
Thus:
Dempsey GA Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis. Crit Care Med. 2000Jun;28(6):1803-7.
Duewall, Jennifer L., et al. "5-Oxoproline (pyroglutamic) acidosis associated with chronic acetaminophen use." Proceedings (Baylor University. Medical Center) 23.1 (2010): 19.
Akhilesh Kumar and Anand K. Bachhawat Pyroglutamic acid: throwing light on a lightly studied metabolite ,SPECIAL SECTION: CHEMISTRY AND BIOLOGY. CURRENT SCIENCE, VOL. 102, NO. 2, 25 JANUARY 2012. 288
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.
Pitt, James J., and Simon Hauser. "Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects." Clinical chemistry 44.7 (1998): 1497-1503.