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Anion gap
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Uses [edit]
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
(Mg 2+ ). 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 (HCO 3 − ) and phosphate (H2 PO4 − ),
while commonly 'unmeasured' anions include sulphates 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 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.
The average anion gap for healthy adults is 8-12 mEq/L. As typical in medicine, abnormal values are
defined as 2 standard deviations over or under the average level; hence, the upper limit of normal is
12 mEq/L. [4] In the past, methods for the measurement of the anion gap consisted of colorimetry for
[HCO 3 − ] 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 [5] and 8–16 mEq/L. [6][7] Modern analyzers make use
of 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
between 3–11 mEq/L. [8]
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 certain proportion of normal individuals
may have values outside of the 'normal' range provided by any lab.
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 leukocyte cellular metabolism 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 is loss of HCO3 − without a concurrent increase in Cl − .
Electroneutrality is maintained by the elevated levels of anions like lactate, beta-hydroxybutyrate and
acetoacetate, PO4 − , and SO4 − . These anions are not part of the anion-gap calculation and therefore
a high anion gap results. Thus, the presence of a high anion gap should result in a search for
conditions that lead to an excess of these substances.
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: a useful mnemonic to remember this is MUDPILES (methanol, uremia, diabetic ketoacidosis,
propylene glycol, isoniazid, lactic acidosis, ethylene glycol, salicylates). A newer mnemonic CUTE
DIMPLES includes C for Cyanide and T for Toluene. Historically, the "P" in MUDPILES was for
paraldehyde. As paraldehyde is no longer used medically, the "P" in the MUDPILES mnemonic
currently refers to propylene glycol, a substance common in pharmaceutical injections such as
diazepam or lorazepam. Accumulation of propylene glycol is converted into lactate and pyruvate,
which causes lactic acidosis.
In patients with a normal anion gap the drop in HCO3 − is compensated for almost completely by an
increase in Cl − and hence is 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 and joel intoxication(RTA) also known as
type 2 RTA)
Renal dysfunction (i.e. distal renal tubular acidosis also known as type 1 RTA)
Ingestions
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)
Note: a useful mnemonic to remember this is FUSEDCARS (fistula (pancreatic), uretogastric
conduits, saline administration, endocrine (hyperparathyroidism), diarrhea, carbonic anhydrase
inhibitors (acetazolamide), ammonium chloride, renal tubular acidosis, spironolactone)
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 anion gap is reduced from between 2.5 to 3 mmol/L per g/dL decrease in
serum albumin. [9] 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).[10]
Corrections can be made for hypoalbuminemia to give an accurate anion gap. [11]
References [edit]
1. ^ "Urine Anion Gap: Acid Base Tutorial, serum anion gap". Archives of Internal
University of Connecticut Health Center" . Medicine 150 (2): 311–3.
Retrieved 2008-11-14. doi:10.1001/archinte.150.2.311 .
2. ^ "Urine anion and osmolal gaps in metabolic PMID 2302006 .
acidosis" . Retrieved 2008-11-14. 9. ^ Feldman M, Soni N, Dickson B (December
3. ^ Kirschbaum B, Sica D, Anderson FP (June 2005). "Influence of hypoalbuminemia or
1999). "Urine electrolytes and the urine anion hyperalbuminemia on the serum anion gap".
and osmolar gaps". The Journal of Laboratory The Journal of Laboratory and Clinical
and Clinical Medicine 133 (6): 597–604. Medicine 146 (6): 317–20.
doi:10.1016/S0022-2143(99)90190-7 . doi:10.1016/j.lab.2005.07.008 .
PMID 10360635 . PMID 16310513 .
4. ^ Serum Anion Gap: Its Uses and Limitations in 10. ^ Lolekha PH, Lolekha S (1 February 1983).
Clinical Medicine "Value of the anion gap in clinical diagnosis
5. ^ Physiology at MCG 7/7ch12/7ch12p51 and laboratory evaluation" . Clinical
6. ^ "The Anion Gap" . Retrieved 2008-10-04. Chemistry 29 (2): 279–83. PMID 6821931 .
7. ^ "Anion Gap: Acid Base Tutorial, University of 11. ^ Figge J, Jabor A, Kazda A, Fencl V
Connecticut Health Center" . Retrieved 2008- (November 1998). "Anion gap and
10-04. hypoalbuminemia" . Critical Care Medicine
8. ^ Winter SD, Pearson JR, Gabow PA, Schultz 26 (11): 1807–10. PMID 9824071 .
AL, Lepoff RB (February 1990). "The fall of the
Cl − Hyperchloremia · Hypochloremia
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