High anion gap metabolic acidosis causes, sorted by the anion

High anion gap metabolic acidosis causes: same gap, different anions

Four patients arrive on one night, and every one has a high anion gap metabolic acidosis with an anion gap of 24. One is in septic shock, one has type 1 diabetes, one drank antifreeze and one overdosed on aspirin. The number is the same, but four different causes, with different anions behind them, are hiding inside it.^[1]

That is the point of this lesson. The causes of a high anion gap metabolic acidosis are easiest to remember, and to tell apart, when you sort them by the anion that is actually there.

Why the anion gap widens: who is A⁻?

When an acid, HA, enters the blood, bicarbonate buffers its H⁺, so bicarbonate falls. Its anion, A⁻, stays behind unmeasured, and the gap widens.^[1][3]

In the previous lesson, the kidney made new bicarbonate to replace what buffering uses up. But the gap itself only tells you that an anion has arrived, not which one. The rest of the work is naming A⁻.

Families 1 and 2: lactate and ketoanions

Lactate. Cells turn pyruvate into lactate. When oxygen delivery fails, in shock, sepsis or severe hypoxia, lactate piles up. That is L-lactate.^[1][2]

Its mirror image, D-lactate, comes from gut bacteria fermenting carbohydrate in short bowel syndrome. The routine lactate test measures only L-lactate, so it misses D-lactate.^[1][4]

Ketoanions are β-hydroxybutyrate and acetoacetate. When insulin is low, fat is broken down and the liver turns the fatty acids into ketoacids. This happens in diabetic ketoacidosis, in alcoholic ketoacidosis and, more mildly, in starvation.^[1][2]

In alcoholic ketoacidosis, alcohol and starvation lower insulin, and alcohol's extra NADH pushes acetoacetate toward β-hydroxybutyrate.^[2][5]

Families 3 to 5: toxic alcohols, salicylate and uraemic anions

Toxic alcohol metabolites. Alcohol dehydrogenase starts turning methanol into formic acid, so the anion is formate. Ethylene glycol, the antifreeze, becomes glycolic acid and then oxalic acid, so the anions are glycolate and oxalate. The osmolar gap and the rest of the toxic alcohol story come in the next lesson.^[1][6]

Salicylate. Salicylate itself, the anion aspirin becomes, adds only a little to the gap. Instead, salicylate uncouples oxidative phosphorylation in the mitochondria, and the body's own organic acids, such as lactate and ketoanions, build up and do most of the work.^[2][7][8]

Retained uraemic anions. In advanced kidney failure, sulfate, phosphate, urate and hippurate are not excreted well, so they build up in the blood. Earlier in kidney disease, the gap is often still normal.^[1][2]

One more anion: 5-oxoproline. It builds up with chronic acetaminophen use, linked to glutathione depletion, mostly in malnourished, chronically ill women.^[9][10]

GOLD MARK re-sorted by anion

GOLD MARK lists the causes of a high anion gap metabolic acidosis: glycols (ethylene and propylene), 5-oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure and ketoacidosis. Re-sorted by anion, the eight letters collapse into the families above.^[11][12]

Propylene glycol, used in some drug infusions, is metabolised partly to lactate, so it joins L and D in the lactate family.^[13]

Bedside work-up: hunt the anion directly

The four opening patients now sort cleanly: septic shock gives lactate, type 1 diabetes gives ketoanions, antifreeze gives glycolate, and the aspirin overdose gives salicylate-driven organic acids.

1. LactateLook for L-lactate.
2. KetonesLook for ketoanions, whatever the glucose.
3. CreatinineRetained uraemic anions need advanced kidney failure.
4. Salicylate levelLook for salicylate.
5. Still unexplained?If those don't explain a high gap, think toxic alcohols first, and remember D-lactate (short bowel), propylene glycol infusions and 5-oxoproline (chronic acetaminophen).

Methanol and ethylene glycol often cannot be measured locally, which is why the osmolar gap, the subject of the next lesson, matters.^[1]