From KSAP
A 70-year-old woman with a history of chronic low back pain, alcohol use, chronic obstructive pulmonary disease, and breast cancer presents with nausea, vomiting, and progressive mental deterioration over 5 days.
Her home medications include digoxin daily, furosemide twice daily, and acetaminophen/hydrocodone as needed for chronic back pain. She uses cigarettes and drinks alcohol but is unable to say how much.
On physical examination, her blood pressure is 110/60 mm Hg. Respirations are deep and rapid. Findings include cachexia, confusion, and lethargy.
Laboratory tests on admission:
Result Reference Range
Sodium 143 mEq/L 136–145
Potassium 4.7 mEq/L 3.5–5.0
Chloride 108 mEq/L 98–106
Total CO2 5 mEq/L 23–30
Blood urea nitrogen 20 mg/dL 8–20
Creatinine 1.2 mg/dL 0.5–1.1
Glucose 166 mg/dL 70–99 (fasting)
Osmolality 308 mOsm/kg 275–295
Arterial blood gas
pH 7.16 7.38–7.44
PaCO2 14 mm Hg 38–42
PaO2 111 mm Hg 75–100
Lactate 1.4 mmol/L 0.7–2.1
Which of the following tests is MOST likely to identify the cause of her acid-base disturbance?
A Ethylene glycol
B D-Lactate
C Pyroglutamic acid (5-oxoproline)
D β-hydroxybutyrate
E Methanol
Ansewer Key
C. Pyroglutamic acid (5-oxoproline)
This presentation is most consistent with metabolic acidosis due to accumulation of pyroglutamic acid, or 5-oxoproline. 5-Oxoproline is an intermediate in the γ-glutamyl pathway, which is responsible for generating glutathione. Under normal circumstances, increased glutathione levels lead to feedback suppression of this pathway. A lack of glutathione leads to accumulation of γ-glutamylcysteine and its conversion to 5-oxoproline through an alternative pathway. This ultimately results in an elevated anion gap metabolic acidosis (see approach to the acid-base disorder below). The diagnosis is established by identification of 5-oxoproline in the serum. Alternatively, 5-oxoproline can also be measured in the urine as part of an organic acid screen.
Although there are inherited forms of this disorder, these generally present early in life. Acquired 5-oxoprolinemia most commonly results from chronic acetaminophen ingestion, which depletes glutathione stores. Risk factors for 5-oxoprolinemia include female sex, advanced age, malnutrition, diabetes, and liver disease. The metabolic acidosis typically resolves when acetaminophen is discontinued.
D-Lactic acidosis most commonly occurs in individuals with small intestinal bacterial overgrowth. Glucose and other carbohydrates are metabolized in the colon to D-lactic acid, which is absorbed into the systemic circulation.
Ethylene glycol toxicity is characterized by an anion gap metabolic acidosis and a high osmolal gap. Patients typically present with AKI due to oxalate deposition. There was no osmolal gap present in this case. Methanol toxicity similarly presents with a high osmolar gap and high anion gap metabolic acidosis. Classically, patients will also complain of visual defects.
Serum β-hydroxybutyrate is elevated in patients with ketoacidosis, which is usally caused by diabetes, alcohol ingestion, or starvation. This patient had no history of diabetes or alcohol use, and the serum glucose level was not decreased on presentation, making starvation ketosis less likely.
An approach to the acid-base disorder is as follows:
1. The first step is to assess the pH and determine whether there is an acidemia or alkalemia. Because the pH is low, she has an acidemia.
2. The second step is to determine whether the acidemia is caused by a metabolic (low serum bicarbonate) or respiratory (high PaCO2) process. In this case, the serum bicarbonate is extremely low, and this is consistent with a metabolic acidosis.
3. The third step is to calculate the anion gap. Here, the anion gap is 143 – (108 + 5) = 30. Because the normal anion gap is approximately 10, this is consistent with an anion gap metabolic acidosis.
4. The next step is to determine the appropriateness of the respiratory response. Using Winter’s equation the predicted PaCO2 = (1.5 × serum HCO3) + 8 ± 2. In this case, (1.5 × 5) + 8 ± 2 = 16 ± 2 mmHg. This matches the observed PaCO2 of 14 mm Hg, so the respiratory response is appropriate. (This can also be calculated by multiplying the change in serum bicarbonate from normal (24 being normal) by 1.2, then subtracting this product from the normal paCO2 (40 being normal) giving the expected compensatory paCO2.)5. In patients with increased anion gap acidosis, the ratio of the change in anion gap to the change in bicarbonate (∆ AG ÷ ∆ bicarbonate) can also be used to assess whether there is a concurrent metabolic acid-base disturbance. The relationship between the rise in anion gap and the fall in the serum bicarbonate is typically between 0.7 and 1.7. The reason that the relationship is not simply 1:1 is because hydrogen ions are buffered both by extracellular bicarbonate and also by intracellular proteins, phosphates, and hemoglobin. A ratio of <0.7 suggests that bicarbonate has fallen more than expected based on the rise in anion gap and may reflect the presence of a concurrent normal anion gap metabolic acidosis, whereas a ratio of >1.7 may indicate the presence of metabolic alkalosis, because the bicarbonate decline is less than expected for the rise in anion gap.
In this case, ∆ AG ÷ ∆ bicarbonate = (30 – 10)/(24 – 5) = 20/19 = 1
This ratio is within the typical range for patients with an isolated anion gap acidosis.
References
Pitt JJ, Hauser S: Transient 5-oxoprolinuria and high anion gap metabolic acidosis: Clinical and biochemical findings in eleven patients. Clin Chem 44(7):1497–1503, 1998
Fenves AZ, Kirkpatrick HM III, Patel VV, Sweetman L, Emmett M: Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): A role for acetaminophen. Clin J Am Soc Nephrol 1(3): 441–447, 2006