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Using the results of the comprehensive metabolic panel (CMP), the anion gap is the difference between measured cations (positively charged ions like Na+ and K+) and measured anions (negatively charged ions like Cl- and HCO3-). There are three types: serum, plasma, and urine anion gaps. The most common application of the anion gap is classifying cases of metabolic acidosis, states of lower than normal blood pH. Specifically, classifying into either those that do and those that do not have unmeasured anions in the plasma. The human body is electrically neutral; therefore, in reality, does not have a true anion gap. The calculation then finds utility in exposing variations in that balance. However, changes in albumin and bicarbonate concentrations warrant specific attention.[1][2]

General pathophysiology of anion gap revolves around derangements in concentrations of cations and anions. In terms of metabolic acidosis, no matter the cause, the inciting event involves a reduction in bicarbonate concentration. This reduction can be due to increased use as a buffer of abnormal acids, decreased production, or increased loss from the body. However, the law of electrochemical neutrality is never breached, so either chloride concentration increases in tandem, or, unmeasured anions increase. If it is chloride, one would have a normal anion gap metabolic acidosis because it is a measured anion.[3] However, if it is unmeasured anions, it would be reflected as an increased anion gap metabolic acidosis. Two of the most common and notable causes of increased anion gap metabolic acidosis High anion gap metabolic acidosis (HAGMA) conditions include diabetic ketoacidosis (DKA) and salicylate poisoning.[5] Descriptions of their pathophysiology are below. In DKA, the patient presents with rapid onset of vomiting, abdominal pain, increased urination, confusion, and in some cases, fruity odor to the breath. At the cellular level, the foundational error is a lack of insulin in the body. Decreased insulin and increased glucagon cause the liver to release glucose via glycogenolysis and gluconeogenesis. Increased glucose in the blood results in osmotic diuresis, taking water and solutes (sodium and potassium) with it. Most relevant is the lack of insulin leading to lipolysis (release of free fatty acids from adipose tissue). The free fatty acids undergo beta-oxidation in the liver and ketone bodies, acetoacetate and B-hydroxybutyrate form. While they provide energy in the absence of glucose, they have lower pKa, causing blood to turn acidic ultimately resulting in the myriad of symptoms discussed at the beginning.[6][7] In salicylate poisoning, classic symptoms include ear ringing, nausea, abdominal pain, and hyperventilation. Interestingly, in this case, we find a mixed disorder resulting through three phases: Through direct respiratory center stimulation, hyperventilation causes respiratory alkalosis and compensation through alkaluria. This phase lasts about 12 hours. After significant amounts of potassium lost, paradoxical aciduria results.

In salicylate poisoning, classic symptoms include ear ringing, nausea, abdominal pain, and hyperventilation. Interestingly, in this case, we find a mixed disorder resulting through three phases: Through direct respiratory center stimulation, hyperventilation causes respiratory alkalosis and compensation through alkaluria. This phase lasts about 12 hours. After significant amounts of potassium lost, paradoxical aciduria results. Eventually, dehydration, hypokalemia, and progressive metabolic acidosis results, which presents within 4 to 6 hours in an infant and typically greater than 24 hours for an adolescent or adult.[8][9][10]