Metabolic Acidosis - Anion Vs Non Anion Gap


Jun 8, 2020
Interesting about the salicylate acid leading to anion gap metabolic acidosis. Of course lactate, -ols, and iron does too.

He says CAI can cause non-anion gap acidosis this seems contrary to the research- take B1 for example.



Thread starter
Jun 8, 2020
All the B1 derivatives? Or would Benfotiamine and TTFD be exempt from this?
My understanding is all forms of B1 are CA2I.

CA is the enzyme that takes H2O and CO2 to bicarbonate. So if he says all -ates increase the NAGAP then this does follow. However, a B1 deficiency will causes a large increase in lactate relative to bicarbonate among other issues. So while bicarbonate might increase the NAGAP, compared to what lactate does I think the benefits outweigh the downsides.

Tyw has a great writeup here:
Carbonic Anhydrase Is A Key Driver Of Aging; Inhibiting It Is Beneficial


Sep 10, 2014
Not Uganda
It depends on how the anion is dealt with. In normal conditions, lactate can be processed, returned to cellular respiration and yield carbon dioxide, which will then increase hydrogen carbonate; it's 'metabolizable' and is eventually converted into something else. The same won't happen with salicylate or chloride that will be elevated in circulation prior to clearance.

The 'hydrogen carbonate' thing may seem pedantic and is irritating, but it's because bicarbonate is confusing and ainn't accurate. For example, I doubt that many people associate sulfuric acid with protonated sulfate, whereas if we referred to it as dihydrogen sulfate, it would be instant. But to make it worse, what about bisulfate to hydrogen sulfate? It's equivalent to referring to hydrogen carbonate as bicarbonate:

- Sulfate - Wikipedia

"The conjugate base of sulfuric acid (H2SO4)—a dense, colourless, oily, corrosive liquid—is the hydrogen sulfate ion [HSO4(−)], also called the bisulfate ion.[*] Sulfuric acid is classified as a strong acid; in aqueous solutions it ionizes completely to form hydronium ions (H3O+) and hydrogen sulfate [HSO4(−)]. In other words, the sulfuric acid behaves as a Brønsted–Lowry acid and is deprotonated. Bisulfate has a molar mass of 97.078 g/mol. It has a valency of 1. An example of a salt containing the HSO4(−) group is sodium bisulfate, NaHSO4. In dilute solutions the hydrogen sulfate ions also dissociate, forming more hydronium ions and sulfate ions [SO4(2−)]."

[*] "The prefix "bi" in "bisulfate" comes from an outdated naming system and is based on the observation that there is twice as much sulfate [SO4(2−)] in sodium bisulfate (NaHSO4) and other bisulfates as in sodium sulfate (Na2SO4) and other sulfates. See also bicarbonate."​

- carbonic acid/dihydrogen carbonate, hydrogen carbonate, carbonate
- sulfuric acid/dihydrogen sulfate, hydrogen sulfate, sulfate

Both being diprotic acids when fully protonated. But it's sulfite species that contain 3 oxygen atoms per molecule like carbonate.​

Taking salicylate with sodium is a way of increasing opposites together, should be less disturbing than just salicylate, even more so if it also provides hydrogen carbonate (baking soda). If the neutralization occurs in the stomach, the body might be able to hold onto some of the carbon dioxide instead of losing it to the environment.

Potassium citrate when dissociated is handled by the cell, both ions, whereas the hydrogen carbonate form remains outside the cell prior to metabolism. This may give an advantage for potassium citrate over hydrogen carbonate. I remember reading that a great portion of dietary citrate is processed in the liver, which mitigates complexation with desirable nutrients in other organs. However, some escapes, otherwise it wouldn't protect against kidney stones.

Regarding thiamine, if anything, inhibition would require pharmacological doses.

Each inhibitor has its specificitawaifties towards variants of carbonic anhydrase. If it happens to target a variant that acts where there's a large amount of either carbonic acid or carbon dioxide, the response might vary because the enzyme is disposed to convert the metabolite that's high, otherwise how to explain the presence of the enzyme? Where there are large amounts of carbon dioxide, the the enzyme should be there to convert it into carbonic acid.

Contrary to carbon dioxide, hydrogen carbonate doesn't move freely in and out of the cell. On the left is pee; middle, kidney cell; and right, blood:

- Type 2 renal tubular acidosis and acetazolamide | Deranged Physiology

Note forms of carbonic anhydrase.

"Carbonic anhydrase converts the filtered bicarbonate [now in urine] into easily resorbed CO2, and then traps it again inside the cell. The filtered bicarbonate is essentialy completely reabsorbed."

"The concentration of chloride in the tubule is therefore expected to increase if the bicarbonate has been reabsorbed, more chloride must remain in the tubule to maintain electroneutrality."

They is exchanged:


"However, the failure of carbonic anhydrase [or its inhibition] results in bicarbonate remaining trapped in the urine. This, of course, means that electroneutrality of the tubule is maintained without the excretion of any further chloride.

Chloride retention results."


"Thus, the chloride which would otherwise be excreted, is retained."

Since carbonic acid won't be decomposed in the cell into hydrogen carbonate and hydrogen ions to recover the former (serum) and excrete the latter (urine) in exchange of sodium (top left), sodium concentration in the urine will increase and hydrogen ion decrease, which will decrease the amount of carbonic acid formed feed the cycle where hydrogen carbonate isn't being reclaimed. Water will follow sodium (Medicosis) and chloride will make up for the hydrogen carbonate that hasn't been recovered elsewhere.

- Acetazolamide - Wikipedia

"[..]urinary Na+ and bicarbonate HCO3− are increased, and urinary H+ and Cl− are decreased. Inversely, serum Na+ and bicarbonate (HCO3−) are decreased, and serum H+ and Cl− are increased. H2O generally follows sodium, and so this is how the clinical diuretic effect is achieved, which reduces blood volume and thus preload on the heart to improve contractility and reduce blood pressure, or achieve other desired clinical effects of reduced blood volume such as reducing edema or intracranial pressure."

"In the prevention or treatment of mountain sickness, acetazolamide forces the kidneys to excrete bicarbonate, the conjugate base of carbonic acid. Increasing the amount of bicarbonate excreted in the urine causes the blood to become more acidic. As the body equates acidity of the blood to its CO2 concentration, artificially acidifying the blood fools the body into thinking it has an excess of CO2, and it excretes this perceived excess CO2 by deeper and faster breathing, which in turn increases the amount of oxygen in the blood. Acetazolamide is not an immediate cure for acute mountain sickness; rather, speeds up (or, when taking before traveling, forces the body to early start) part of the acclimatization process which in turn helps to relieve symptoms."​
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