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Anion gap

Pathophysiology sample values
Na+ = 140 Cl = 100 BUN = 20 /
Glu = 150
K+ = 4 CO2 = 22 PCr = 1.0 \
HCO3 = 24 paCO2 = 40 paO2 = 95 pH = 7.40
pACO2 = 36 pAO2 = 105 A-a g = 10
Ca = 9.5 Mg2+ = 2.0 PO4 = 1
CK = 55 BE = −0.36 AG = 16
PMO = 300 PCO = 295 POG = 5 BUN:Cr = 20
UNa+ = 80 UCl = 100 UAG = 5 FENa = 0.95
UK+ = 25 USG = 1.01 UCr = 60 UO = 800
LDH = 100 TP = 7.6 AST = 25 TBIL = 0.7
ALP = 71 Alb = 4.0 ALT = 40 BC = 0.5
AST/ALT = 0.6 BU = 0.2
AF alb = 3.0 SAAG = 1.0 SOG = 60
CSF alb = 30 CSF glu = 60 CSF/S alb = 7.5 CSF/S glu = 0.4

The anion gap[1][2] is the difference in the measured cations (positively charged ions) and the measured anions (negatively charged ions) in serum, plasma, or urine. The magnitude of this difference (i.e., "gap") in the serum is often calculated in medicine when attempting to identify the cause of metabolic acidosis, a lower than normal pH in the blood. If the gap is greater than normal, then high anion gap metabolic acidosis is diagnosed.

The term "anion gap" usually implies "serum anion gap", but the urine anion gap is also a clinically useful measure.[3][4][5][6]


The concentrations are expressed in units of milliequivalents/liter (mEq/L) or in millimoles/litre (mmol/L).

With potassium

The anion gap is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium and potassium (cations):

= ([Na+] + [K+]) − ([Cl-] + [HCO3])

Without potassium (daily practice)

Omission of potassium has become widely accepted, as potassium concentrations, being very low, usually have little effect on the calculated gap. This leaves the following equation:

= [Na+] − ([Cl] + [HCO3]) =16 mEq/L


Anion gap is an 'artificial' and calculated measure that is representative of the unmeasured ions in plasma or serum (serum levels are used more often in clinical practice).

Commonly measured cations include sodium (Na+), potassium (K+), calcium (Ca2+) and magnesium (Mg2+). Cations that are generally considered 'unmeasured' include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma). Likewise, commonly 'measured' anions include chloride (Cl), bicarbonate (HCO3) and phosphate (</sub>PO4−3), while commonly 'unmeasured' anions include sulfates and a number of serum proteins.

By definition, only Na+, Cl and HCO3 (+/- K+) are used when calculating the anion gap.

In normal health there are more measurable cations compared to measurable anions in the serum; therefore, the anion gap is usually positive. Because we know that plasma is electro-neutral (uncharged), we can conclude that the anion gap calculation represents the concentration of unmeasured anions. The anion gap varies in response to changes in the concentrations of the above-mentioned serum components that contribute to the acid-base balance. Calculating the anion gap is clinically useful, as it helps in the differential diagnosis of a number of disease states.

Normal value ranges

Modern analyzers use ion-selective electrodes which give a normal anion gap as <11 mEq/L. Therefore, according to the new classification system, a high anion gap is anything above 11 mEq/L and a normal anion gap is often defined as being within the prediction interval of 3–11 mEq/L,[7] with an average estimated at 6 mEq/L.[8]

In the past, methods for the measurement of the anion gap consisted of colorimetry for [HCO3] and [Cl] as well as flame photometry for [Na+] and [K+]. Thus normal reference values ranged from 8 to 16 mEq/L plasma when not including [K+] and from 10 to 20 mEq/L plasma when including [K+]. Some specific sources use 15[9] and 8–16 mEq/L.[10][11]

A reference range provided by the particular lab that performs the testing should be used to determine if the anion gap is outside of the normal range. A proportion of normal individuals may have values outside of the 'normal' range provided by any lab.

Interpretation and causes

Anion gap can be classified as either high, normal or, in rare cases, low. Laboratory errors need to be ruled out whenever anion gap calculations lead to results that do not fit the clinical picture. Methods used to determine the concentrations of some of the ions used to calculate the anion gap may be 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 HCO3 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 that there are, usually due to disease, elevated levels of anions like lactate, beta-hydroxybutyrate and acetoacetate, PO43−, and SO42−. These anions are not part of the anion-gap calculation and therefore a high anion gap results. There is a secondary loss of HCO3 which is a buffer, without a concurrent increase in Cl. Electroneutrality is therefore maintained. Thus, the presence of a high anion gap should result in a search for conditions that lead to an excess of these anions.

High anion gap

The anion gap is affected by changes in unmeasured ions. A high anion gap indicates acidosis. In uncontrolled diabetes, there is an increase in ketoacids due to metabolism of ketones. Ketoacids are unmeasured anions, so there is a resulting increase in the anion gap. 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.

Note: the classic mnemonic physicians use to remember the causes of anion gap metabolic acidosis is MUDPILES (methanol, uremia, diabetic ketoacidosis, propylene glycol, iron poisoning or isoniazid, lactic acidosis, ethylene glycol, salicylates). Variations include MUDPILERS with an "R" for rhabdomyolysis; MUDPALES with the "A" representing alcoholic ketoacidosis. However, these are outdated and include low yield items that are no longer in use. Historically, the "P" in these mnemonics stood for paraldehyde. As paraldehyde is no longer used medically, the "P" often refers to propylene glycol. Additionally, three “new” organic anion-gap-generating acids and acid precursors have been recognized since the initial acronym was created. D-lactic acidosis occurs in patients with short bowel syndromes; 5-oxoproline (or pyroglutamic acid) is associated with chronic acetaminophen use by malnourished women; and propylene glycol infusions, often used as the solvent for several parenteral medications including lorazepam, phenobarbital, and others is metabolised to D-lactate and L-lactate. These changes and additions required an update to the mnemonic. Thus, GOLD MARK has been suggested for use by nephrologists in the 21st century.[12] This acronym represents glycols (ethylene glycol and propylene glycol), oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure, and ketoacidosis. Finally, another mnemonic CUTE DIMPLES includes cyanide, toluene, and a second "E" for ethanol (alcoholic ketoacidosis) (cyanide, uremia, toluene, ethanol, diabetic ketoacidosis, isoniazid, methanol, propylene glycol, lactic acidosis, ethylene glycol, salicylates). Perhaps the easiest mnemonic is KULT: ketones, uremia, lactate and toxins, because these are the most common causes of a high anion gap metabolic acidosis (HAGMA). The mnemonic for the (rare, in comparison) toxins is ACE GIFTs: aspirin, cyanide, ethanolic ketosis, glycols (ethylene and propylene), isoniazid, ferric iron, toluene.

Normal anion gap

In patients with a normal anion gap the drop in HCO3 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 HCO3 lost is replaced by a chloride anion, and thus there is a normal anion gap.

There are three types.
1. Low Renin may be due to diabetic nephropathy or NSAIDS (and others causes).
2. Low aldosterone may be due to adrenal disorders or ACE inhibitors.
3. Low response to aldosterone maybe due to potassium sparing diuretics, Bactrim, or diabetes (and other causes).[13]

Note: a useful mnemonic to remember this is FUSEDCARS (fistula (pancreatic), uretero-enterostomy, saline administration, endocrine (hyperparathyroidism), diarrhea, carbonic anhydrase inhibitors (acetazolamide), ammonium chloride, renal tubular acidosis, spironolactone)

Low anion gap

A low anion gap is frequently caused by hypoalbuminemia. Albumin is a negatively charged protein and its loss from the serum results in the retention of other negatively charged ions such as chloride and bicarbonate. As bicarbonate and chloride anions are used to calculate the anion gap, there is a subsequent decrease in the gap.

In hypoalbuminaemia the normal anion gap is decreased with 2.5 to 3 mmol/L per 1 g/dL decrease in serum albumin.[14] Common conditions that reduce serum albumin in the clinical setting are hemorrhage, nephrotic syndrome, intestinal obstruction and liver cirrhosis.

The anion gap is sometimes reduced in multiple myeloma, where there is an increase in plasma IgG (paraproteinaemia).[15]

Corrections can be made for hypoalbuminemia to give an accurate anion gap.[16]


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  8. Kraut JA, Madias NE (2006). "Serum Anion Gap: Its Uses and Limitations in Clinical Medicine" (PDF). Clinical Journal of the American Society of Nephrology 2 (1): 162–174. PMID 17699401. doi:10.2215/CJN.03020906. 
  9. Physiology: 7/7ch12/7ch12p51 - Essentials of Human Physiology
  10. "The Anion Gap". Retrieved 4 October 2008. 
  11. "Anion Gap: Acid Base Tutorial, University of Connecticut Health Center". Retrieved 4 October 2008. 
  12. Mehta AN, Emmett JB, Emmett M (13 September 2008). "GOLD MARK: an anion gap mnemonic for the 21st century.". The Lancet 372 (9642): 892. PMID 18790311. doi:10.1016/S0140-6736(08)61398-7. Retrieved 2/3/2013.  Check date values in: |accessdate= (help)
  13. Sabatine, Mark (2011). Pocket Medicine. Lippincott Williams Wilkens. p. 4-3. ISBN 978-1-60831-905-3. 
  14. Feldman M, Soni N, Dickson B (December 2005). "Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap". The Journal of Laboratory and Clinical Medicine 146 (6): 317–20. PMID 16310513. doi:10.1016/j.lab.2005.07.008. 
  15. Lolekha PH, Lolekha S (1 February 1983). "Value of the anion gap in clinical diagnosis and laboratory evaluation". Clinical Chemistry 29 (2): 279–83. PMID 6821931. 
  16. Figge J, Jabor A, Kazda A, Fencl V (November 1998). "Anion gap and hypoalbuminemia". Critical Care Medicine 26 (11): 1807–10. PMID 9824071. doi:10.1097/00003246-199811000-00019. 

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