susceptible to very specific errors. For example, if the blood sample is not processed immediately after it is collected, continued cellular metabolism by leukocytes (also known as white blood cells) may result in an increase in the HCO concentration, and result in a corresponding mild reduction in the anion gap. In many situations, alterations in renal function (even if mild, e.g., as that caused by dehydration in a patient with diarrhea) may modify the anion gap that may be expected to arise in a particular pathological condition. A high anion gap indicates increased concentrations of unmeasured anions by proxy. Elevated concentrations of unmeasured anions like lactate, beta-hydroxybutyrate, acetoacetate, PO, and SO, which rise with disease or intoxication, cause loss of HCO due to bicarbonate's activity as a buffer (without a concurrent increase in Cl−). Thus, finding a high anion gap should result in a search for conditions that lead to excesses of the unmeasured anions listed above. High anion gap The anion gap is affected by changes in unmeasured ions. In uncontrolled diabetes, there is an increase in ketoacids due to metabolism of ketones. Raised levels of acid bind to bicarbonate to form carbon dioxide through the Henderson-Hasselbalch equation resulting in metabolic acidosis. In these conditions, bicarbonate concentrations decrease by acting as a buffer against the increased presence of acids (as a result of the underlying condition). The bicarbonate is consumed by the unmeasured cation(H+) (via its action as a buffer) resulting in a high anion gap. Causes of high anion gap metabolic acidosis (HAGMA): Lactic acidosis Ketoacidosis Diabetic ketoacidosis Hazardous alcohol use Toxins: Methanol Ethylene glycol Propylene glycol Lactic acid Uremia Aspirin Phenformin (no longer on market in U.S. since 1978 due to severe lactic acidosis, but still a problem globally. "Old metformin") Iron Isoniazid Cyanide, coupled with elevated venous oxygenation Kidney failure, causes high anion gap acidosis by decreased acid excretion and decreased HCO reabsorption. Accumulation of sulfates, phosphates, urate, and hippurate accounts for the high anion gap. Note: a useful mnemonic to remember this is MUDPILES – Methanol, Uremia, Diabetic Ketoacidosis, Paraldehyde, Infection, Lactic Acidosis, Ethylene Glycol and Salicylates Normal anion gap In patients with a normal anion gap the drop in HCO is the primary pathology. Since there is only one other major buffering anion, it must be compensated for almost completely by an increase in Cl−. This is therefore also known as hyperchloremic acidosis. The