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Anion gap - Wikipedia, the free encyclopedia

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Anion gap
From Wikipedia, the free encyclopedia

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

Pathophysiology sample values

Na+ = 140

Cl = 100

BUN = 20


CO2 = 22

PCr = 1.0

Glu = 150



= 24 paCO2 = 40

paO2 = 95

pH = 7.40

pACO2 = 36 pAO2 = 105

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

Ca = 9.5

Mg2+ = 2.0

PO4 = 1

CK = 55

BE = 0.36

AG = 16

A-a g = 10

PMO = 300 PCO = 295

1 Calculation
1.1 With potassium
1.2 Without potassium (daily practice)
2 Uses
3 Normal value ranges
4 Interpretation and causes
4.1 High anion gap
4.2 Normal anion gap
4.3 Low anion gap
5 References
6 External links

POG = 5

BUN:Cr = 20

UNa+ = 80

UCl = 100

UAG = 5

FENa = 0.95


USG = 1.01

UCr = 60

UO = 800

= 25


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 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)

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Anion gap - Wikipedia, the free encyclopedia

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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/lit

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 (PO43), 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 311 mEq/L,[7] with an average estimated at 6
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 816 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

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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, betahydroxybutyrate 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.
Lactic acidosis
Diabetic ketoacidosis
Alcohol abuse
Ethylene glycol
Propylene glycol
Lactic acid
Cyanide, coupled with elevated venous oxygenation
Renal failure, causes high anion gap acidosis by decreased acid excretion and decreased HCO3
reabsorption. Accumulation of sulfates, phosphates, urate, and hippurate accounts for the 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;

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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.
Gastrointestinal loss of HCO3 (i.e., diarrhea) (note: vomiting causes hypochloraemic alkalosis)
Renal loss of HCO3 (i.e., proximal renal tubular acidosis(RTA) also known as type 2 RTA)
Renal dysfunction (i.e., distal renal tubular acidosis also known as type 1 RTA)
Renal Hypoaldosterone (i.e., renal tubular acidosis also known as type IV RTA) characterized by elevated
serum potassium.
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]
Ammonium chloride and acetazolamide, ifosfamide.
Hyperalimentation fluids (i.e. total parenteral nutrition)
Some cases of ketoacidosis, particularly during rehydration with Na+ containing IV solutions.
Alcohol (such as ethanol) can cause a high anion gap acidosis in some patients, but a mixed picture in
others due to concurrent metabolic alkalosis.
Mineralocorticoid deficiency (Addison's disease)

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

1. Oh MS, Carroll HJ (1977). "The anion gap". N. Engl. J. Med. 297 (15): 8147. doi:10.1056/NEJM197710132971507
( PMID 895822
2. Gabow PA, Kaehny WD, Fennessey PV, Goodman SI, Gross PA, Schrier RW (1980). "Diagnostic importance of an
increased serum anion gap". N. Engl. J. Med. 303 (15): 8548. doi:10.1056/NEJM198010093031505
( PMID 6774247
3. Emmett M., Narins R.G. (1977). "Clinical use of the anion gap.". Medicine (56): 3854.
4. "Urine Anion Gap: Acid Base Tutorial, University of Connecticut Health Center"
( Archived
p.html) from the original on 21 November 2008. Retrieved 14 November 2008.
5. "Urine anion and osmolal gaps in metabolic acidosis" (
topicKey=fldlytes/28741). Retrieved 14 November 2008.
6. Kirschbaum B, Sica D, Anderson FP (June 1999). "Urine electrolytes and the urine anion and osmolar gaps". The
Journal of Laboratory and Clinical Medicine 7604 133: 597604. doi:10.1016/S0022-2143(99)90190-7
( PMID 10360635
7. Winter SD, Pearson JR, Gabow PA, Schultz AL, Lepoff RB (February 1990). "The fall of the serum anion gap". Archives
of Internal Medicine 150 (2): 3113. doi:10.1001/archinte.150.2.311 (
PMID 2302006 (
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): 162174. doi:10.2215/CJN.03020906 (
PMID 17699401 (

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9. Physiology at MCG 7/7ch12/7ch12p51

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. doi:10.1016/S0140-6736(08)61398-7 (
PMID 18790311 ( 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): 31720. doi:10.1016/j.lab.2005.07.008
( PMID 16310513 (
15. Lolekha PH, Lolekha S (1 February 1983). "Value of the anion gap in clinical diagnosis and laboratory evaluation"
( Clinical Chemistry 29 (2): 27983.
PMID 6821931 (
16. Figge J, Jabor A, Kazda A, Fencl V (November 1998). "Anion gap and hypoalbuminemia"
( Critical Care Medicine 26 (11): 180710. doi:10.1097/00003246199811000-00019 ( PMID 9824071

External links
Clinical Physiology of Acid-Base and Electrolyte Disorders (
Intensive Care Medicine (
The ICU Book (
Calculator at (
Metabolic acidosis by Merck (
Retrieved from ""
Categories: Acidbase disturbances Electrolyte disturbances
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