Common Laboratory (LAB) Values - Anion Gap

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Anion Gap

Question: Please define the Anion Gap and its utility in diagnosis and how it relates to osmolality.

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.

Side note:
some newer references will list the normal anion gap as
7 +/- 4. This lower level may represent a more accurate reflection of the true anion gap based on changes that have occurred in contemporary medical labs. In the past, electrolyte analysis was performed using predominantly flame photometer measurement compared to the modern day use of ion-selective electrodes. Previous measurement techniques tended to underestimate the value of chloride, which led to a higher calculated anion gap.

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
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.

Serum Osmolality

Osmolality refers to the number of particles of solute per kilogram of solvent. The normal range for the serum osmolality is 285-295 mOsm/kg. This value is determined solely by the number of particles, and not the size, shape, or weight of the individual particles.

Calculated serum osmolality =
    2[Na+] + glucose/18 + BUN/2.8

(Note: the serum sodium, glucose, and BUN account for the majority of the osmotically active particles in the blood.)

         The serum osmolality is not very useful by itself when combined with the anion gap to determine the etiology of a specific acid-base disorder. A more useful value would be the osmolar gap, which is defined as the serum osmolality minus the calculated osmolality. A normal value would be <10 mOsm/kg. The osmolar gap is particularly helpful in cases of metabolic acidosis associated with an elevated anion gap. If the osmolar gap is >10 mOsm/kg, this helps to confirm the presence of other osmotically active substances such as ethanol, ethylene glycol, mannitol, methanol, or other toxins. In this scenario, the osmolar gap is an effective screening tool for these various osmotically active substances.

Typical causes of an increased osmolar gap

acetone, decreased serum water, ethanol, ethylene glycol, glycerol, hyperlipidemia, hyperproteinemia, isopropyl alcohol,laboratory error, sorbitol


1) Janicic N. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am – 2003 Jun 01; 32(2): 459-81, vii.

2) Mycyk MB. A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med. 2003, Jul 01; 21(4): 333-5.

3) Peixoto AJ. Critical issues in nephrology. Clin Chest Med. 2003 Dec 01; 24(4): 561-81.

4) Rocktaeschel J. Unmeasured anions in critically ill patients: can they predict mortality? Crit Care Med. 2003 Aug 01; 31(8): 2131-6.

5) Sterns RH . Fluid, Electrolyte, and Acid-Base Disturbances. J Am Soc Nephrol. 2003 Jan; 2(1); 1-33.

6) Whittier WL. Primer on clinical acid-base problem solving. Dis Mon. 2004 Mar 01; 50(3): 122-62.
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