Anion Gap and its utility in diagnosis

Anion Gap
The anion gap provides an estimation of the unmeasured anions in the plasma and is useful in the setting of arterial blood gas analysis. It is especially useful in helping to differentiate the cause of a metabolic acidosis, as well as following the response to therapy. Its basic premise is based on the fact that electroneutrality must exist in the body, or in other words the net charges of serum anions, which includes albumin, bicarbonate, chloride, organic acids and phosphate must equal the net charges of the serum cations, which includes calcium, magnesium, potassium and sodium.
In clinical practice, the anion gap is calculated using three lab values (Na+, Cl-, and HCO3-).

Anion Gap = Na+ – (Cl- + HCO3-)

[Occasionally, you may see an alternative equation:
Anion Gap = [Na+] + [K+] – [Cl-] – [HCO3-]. This equation is preferred by some nephrologists, because of the wide fluctuations that may occur with potassium in renal disease. ]

Serum sodium represents over 90 percent of the extracellular cations, whereas chloride and bicarbonate represent approximately 85 percent of the extracellular anions. It follows then, that the anion gap in normal conditions will be a positive number since the sum of the serum anions used in the calculation represent a smaller value compared to the serum sodium concentration. The normal value for the anion gap is 12 +/-4.

Application:
In order to grasp the utility of this equation, lets assume a patient has developed a lactic acidosis. The addition of an organic acid (anion) will automatically reduce the serum bicarbonate level based on a simple acid – base interaction. When we calculate the anion gap in this patient, we will notice that the anion gap has increased or in other words the unmeasured anions have increased relative to the measured anions. In clinical practice, we usually group the condition of metabolic acidosis into two groups: normal anion gap metabolic acidosis, and elevated anion gap metabolic acidosis.
Over the years, several useful tables have been developed to help differentiate these two conditions. Here are some examples:

Typical causes of an elevated anion gap metabolic acidosis
Methanol.
Uremia.
Diabetic ketoacidosis.
Paraldehyde, phenformin.
Iron, isoniazid, inhalants.
Lactic acidosis.
Ethylene glycol, ethanol (alcoholic ketoacidosis).
Salicylates, solvents, starvation.

Pneumonic: MUDPILES
Other causes of an elevated anion gap: Increased Unmeasured Anions: metabolic acidosis, dehydration, therapy with Na+ salts of unmeasured anions (Na citrate, lactate, acetate), alkalosis. Decreased unmeasured cations: hypocalcemia, hypokalemia, hypomagnesemia.

Typical causes of a normal anion gap metabolic acidosis
Gastrointestinal bicarbonate loss: diarrhea, Pancreatic fistula. Hyperalimentation. Posthypocapnia. Renal tubular acidosis. Ureteroenterostomy. Drugs: ammonium chloride, hydrochloric acid.
Typical causes of a low anion gap
hypoalbuminemia, hypercalcemia, hyperkalemia, hypermagnesemia, lithium toxicity, multiple myeloma.

Important tip: Always consider other factors that may affect the calculated anion gap. A perfect example would be a patient with ethylene glycol toxicity and hypoalbuminemia. In this case, the patient may have a normal anion gap even though toxic levels of ethylene glycol are present.

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