Case 46: Diagnosis & Conclusions

Case 46 Index
Case Published: July 2020
Case Submitted By: Stephen West

Diagnosis: 5- oxoproline or pyroglutamic acidosis (5-oxoprolinemia or 5-oxoprolinuria)

Case Summary: 

Strong work. In this case, we’re presented with a patient initially with septic shock in the setting of S. aureus infection – who has now developed an elevated anion-gap metabolic acidosis despite improvement in hemodynamics and clearance of blood cultures.

Let’s get into the acid-base problem here. From the arterial blood gas and basic metabolic panel, we determine that this patient has an acidemia, with an elevated anion-gap metabolic acidosis. Let’s take a moment to review our approach to acid-base disturbances:

A trick to solving every acid/base problem:  pLACO

The normal range for arterial blood pH is 7.35 – 7.45. Looking at the pH will help identify the primary acid/base disturbance:
< 7.35 = acidemia          >7.45 = alkalemia
Looking at both the pCO2 and HCO3 will identify the primary process that led to the pH change. For an acidemia: If the pCO2 is elevated pCO2 (>45) , the primary process is a respiratory acidosis. If the HCO3 is low (<22), the primary process is a metabolic acidosis. For an alkalemia: If the pCO2 is decreased pCO2 (<35) , the primary process is a respiratory alkalosis. If the HCO3 is high (>32), the primary process is a metabolic alkalosis.
Anion gap
Use the bicarbonate from the chemistry panel to calculate the AG, or unmeasured anions (AG = Na – Cl – HCO3). Be sure to estimate the patient’s expected/normal anion gap using the serum albumin.
*The anion gap should be checked even in the absence of an acidemia as a metabolic acidosis may be hiding!
Once the primary process has been identified, use the appropriate formulas (follow the link to Acid/Base below) to see if the patient is compensating. If compensation is inadequate, then there may be another process going on!
Other processes
Patients can have up to 3 acid-base disorders – an anion gap metabolic acidosis may coexist with a metabolic alkalosis OR non-gap metabolic acidosis AND 1 respiratory disorder (you can only hyperventilate or hypoventilate).
Calculate the delta gap, Δ/Δ = (Anion gap – normal anion gap) / (Pt’s HCO3 – normal HCO3)
If the ratio above is > 2, then there is a concomitant metabolic alkalosis. If it is < 1, then there is a concomitant metabolic alkalosis.

For more on pLACO, check out our  Acid/Base tutorial.

Time to identify the culprit. A useful mnemonic for the differential diagnosis of a high anion gap metabolic acidosis is  GOLDMARK


Other follow up testing helps us narrow down our differential diagnosis here. The absence of an osmolal gap (calculate it here) makes glycol or methanol toxicity less likely (lorazepam infusion can lead to propylene glycol toxicity). The normal lactate level makes  type A lactic acidosis (due to hypoperfusion) or type B lactic acidosis unlikely. Take a look at etiologies for type B lactic acidosis here. Ketoacidosis is lower on our differential given the absence of ketones in the serum or urine.  Salicyate or aspirin toxicity seems unlikely as the patient hasn’t been received any during her hospital stay.

So we’re left with the “O” in GOLDMARK, oxoproline – what is that anyway?

Accumulation of 5-oxoproline (or pyroglutamic acid) can lead to pyroglutamic acidosis.  5-oxoproline accumulates because of disruption to the γ-glutamyl cycle (Figure 1 below). This cycle maximizes amino acid absorption from the gut and proximal tubule,  and is also used by the liver for chemical detoxification. Glutathione depletion from sepsis and acetaminophen use leads to increased 5-oxoproline production. Penicillins further worsen the situation by inhibiting the action of 5-oxoprolinase preventing 5-oxoproline breakdown.

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The γ-glutamyl cycle (Source)


Risk factors for pyroglutamic acidosis (click!)
Elderly woman
Penicillin use
Liver impairment (gluthiaione depletion)
Decreased kidney clearance of 5-oxoproline
Acetaminophen use

Diagnosis is done by detecting urine or serum 5-oxoproline. Treatment consists of minimizing risk factors when possible and administering N-acetylcysteine. Kidney replacement therapy may be required, but will not correct the underlying problem.

Acetaminophen toxicity has been associated with high anion gap metabolic acidosis attributed to 5-oxoproline (Click here to read more), though is less commonly associated with a respiratory alkalosis.

Case 46 Index
Case 46 Introduction
Case 46 Physical Exam
Case 46 Diagnostic Testing