This type of acidosis has at least three main causes.

Acid-gaining acidosis. Hydrogen ions not included in the CO2 system are added to the blood. The common situations are:

1. Direct administration, such as treatment with ammonium chloride, or the late effects of salicylate poisoning. Ammonium chloride (NH4Cl) releases H+ ions and Cl– ions as the liver utilizes this compound for NH3 to synthesize urea. Aspirin is acetylsalicylic acid, which in large quantities will eventually add enough H+ ions to cause acidosis, even though in the early stages there is respiratory alkalosis (to be discussed later).

2. Excess metabolic acid formation is found in diabetic ketoacidosis, starvation, or severe dehydration. These conditions cause utilization of body protein and fat for energy instead of carbohydrate, with production of ketone bodies and various metabolic acids.

The results of acid-gaining acidosis are a decrease in free HCO–3, which is used up trying to buffer the excess H+. Thus, the numerator of the Henderson-Hasselbalch equation is decreased, the normal 20:1 ratio is decreased, and the pH is, therefore, decreased. The CO2 content (CO2 combining power) is also decreased because the bicarbonate which it measures has been decreased as a primary response to the addition of excess acid.

Base-losing acidosis. Base-losing acidosis is caused by severe intestinal diarrhea, especially if prolonged or in children. Diseases such as cholera or possibly ulcerative colitis or severe dysentery might cause this. The mechanism is direct loss of HCO–3 from the lumen of the small intestine. Normally, HCO–3 is secreted into the small intestine, so that the contents of the small intestine are alkaline in contrast to the acidity of the stomach. Most of the HCO–3 is reabsorbed; however, prolonged diarrhea or similar conditions could mechanically prevent intestinal reabsorption enough to cause significant HCO–3 loss in the feces. In addition, the H+ ions that were released from H2CO3 in the formation of HCO–3 by carbonic anhydrase are still present in the bloodstream and help decrease pH. However, the primary cause is the direct loss of HCO–3; the numerator of the Henderson-Hasselbalch equation is decreased, the 20:1 ratio is decreased, and the pH is decreased. Naturally, the CO2 content is also decreased.

Renal acidosis. Renal acidosis occurs in kidney failure that produces the clinical syndrome of uremia. As mentioned previously, the kidney has the major responsibility for excreting large excesses of H+. In uremia, H+ from metabolic acids that normally would be excreted this way is retained in the bloodstream due to loss of renal tubular function. As in acid-gaining acidosis, the excess H+ must be buffered; therefore, part of the available body fluid HCO–3 is used up. This decreases the numerator of the Henderson-Hasselbalch equation, decreases the normal 20:1 ratio, and therefore decreases pH. Again, the CO2 content is decreased.