Which of the following conditions is most commonly associated with an increased serum anion gap?

- The serum anion gap is a useful clinical tool to help differentiate the causes of metabolic acidosis.
It is calculated using the formula:
Anion Gap = [Na⁺] - ([Cl⁻] + [HCO₃⁻]).
A normal anion gap typically ranges from 8 to 12 mEq/L.

- Diabetic ketoacidosis (DKA) is most commonly associated with an increased serum anion gap.
- This occurs because of the accumulation of organic acids, primarily ketone bodies (acetoacetate and β-hydroxybutyrate), which are unmeasured anions.
- These organic acids decrease serum bicarbonate (HCO₃⁻) and increase the anion gap.


In contrast:
- Chronic diarrhea leads to a normal anion gap (hyperchloremic) metabolic acidosis because bicarbonate is lost from the gastrointestinal tract and replaced by chloride, which keeps the anion gap normal.

- Renal tubular acidosis type 1 (distal RTA) also causes a normal anion gap metabolic acidosis, as the kidney fails to excrete hydrogen ions properly but chloride increases to compensate.

- Hyperaldosteronism typically causes metabolic alkalosis due to increased hydrogen ion excretion; thus, it is not associated with an increased anion gap.


Key points:
- Increased anion gap acidosis results from the accumulation of unmeasured acids (e.g., ketoacids, lactate, toxins).
- DKA is a classic cause of increased anion gap metabolic acidosis.
- Normal anion gap acidosis occurs due to bicarbonate loss with chloride replacement, as seen in diarrhea and RTA type 1.
- Hyperaldosteronism results in alkalosis, not acidosis.

Reference: Harrison's Principles of Internal Medicine, 20th Edition, Volume 2, Chapter 337, p. 2308