Anion gap

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Pathophysiology sample values
BMP/ELECTROLYTES:
Na+ = 140 Cl− = 100 BUN = 20 /
Glu = 150
\
K+ = 4 CO2 = 22 PCr = 1.0
ARTERIAL BLOOD GAS:
HCO3− = 24 p a CO2 = 40 p a O2 = 95 pH = 7.40
ALVEOLAR GAS:
p A CO2 = 36 p A O2 = 105 A-a g = 10
OTHER:
Ca = 9.5 Mg2+ = 2.0 PO4 = 1
CK = 55 BE = −0.36 AG = 16
SERUM OSMOLARITY/RENAL:
PMO = 300 PCO = 295 POG = 5 BUN:Cr = 20
URINALYSIS:
UNa+ = 80 UCl− = 100 UAG = 5 FENa = 0.95
UK+ = 25 USG = 1.01 UCr = 60 UO = 800
PROTEIN/GI/LIVER FUNCTION TESTS:
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:
CSF alb = 30 CSF glu = 60 CSF/S alb = 7.5 CSF/S glu = 0.6

The anion gap [1] [2] (AG or AGAP) is a value calculated from the results of multiple individual medical lab tests. It may be reported with the results of an electrolyte panel, which is often performed as part of a comprehensive metabolic panel. [3]

Contents

The anion gap is the quantity difference between cations (positively charged ions) and anions (negatively charged ions) in serum, plasma, or urine. The magnitude of this difference (i.e., "gap") in the serum is calculated to identify metabolic acidosis. 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. [4] [5] [6] [7]

Calculation

The anion gap is a calculated measure. It is computed with a formula that uses the results of several individual lab tests, each of which measures the concentration of a specific anion or cation.

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−] + [HCO−
3]) = 20 mEq/L

Without potassium

Because potassium concentrations are very low, they usually have little effect on the calculated gap. Therefore, omission of potassium has become widely accepted. This leaves the following equation:

= [Na+] - ([Cl−] + [HCO−
3])

Normal AG = 8-16 mEq/L

Expressed in words, the equation is:

Anion Gap = sodium - (chloride + bicarbonate)
which is logically equivalent to:
Anion Gap = (the most prevalent cation) minus (the sum of the most prevalent anions)

(Bicarbonate may also be referred to as "total CO2" or "carbon dioxide".) [3]

Uses

Calculating the anion gap is clinically useful because it helps in the differential diagnosis of a number of disease states.

The total number of cations (positive ions) should be equal to the total number of anions (negative ions), so that the overall electrical charge is neutral. However, routine tests do not measure all types of ions. The anion gap is representative of how many ions are not accounted for by the lab measurements used in the calculation. These "unmeasured" ions are mostly anions, which is why the value is called the "anion gap." [3]

By definition, only the cations sodium (Na+) and potassium (K+) and the anions chloride (Cl−) and bicarbonate (HCO−
3) are used to calculate the anion gap. (As discussed above, potassium may or may not be used, depending on the specific lab.)

The cations calcium (Ca2+) and magnesium (Mg2+) are also commonly measured, but they aren't used to calculate the anion gap. Anions that are generally considered "unmeasured" include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma).

Similarly, tests do often measure the anion phosphate (PO3−
4) specifically, but it isn't used to calculate that "gap," even if it is measured. Commonly 'unmeasured' anions include sulfates and a number of serum proteins.

In normal health there are more measurable cations than 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.

Normal value ranges

Different labs use different formulas and procedures to calculate the anion gap, so the reference range (or "normal" range) from one lab isn't directly interchangeable with the range from another. The reference range provided by the particular lab that performed the testing should always be used to interpret the results. [3] Also, some healthy people may have values outside of the "normal" range provided by any lab.

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. A normal anion gap is often defined as being within the prediction interval of 3–11 mEq/L, [8] with an average estimated at 6 mEq/L. [9]

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 [10] and 8–16 mEq/L. [11] [12]

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 HCO−
3 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 increased concentrations of unmeasured anions by proxy. Elevated concentrations of unmeasured anions like lactate, beta-hydroxybutyrate, acetoacetate, PO3−
4, and SO2−
4, which rise with disease or intoxication, cause loss of HCO−
3 due to bicarbonate's activity as a buffer (without a concurrent increase in Cl−). Thus, finding a high anion gap should result in a search for conditions that lead to excesses of the unmeasured anions listed above.

High anion gap

The anion gap is affected by changes in unmeasured ions. In uncontrolled diabetes, there is an increase in ketoacids due to metabolism of ketones. Raised levels of acid bind to bicarbonate to form carbon dioxide through the Henderson-Hasselbalch equation resulting in metabolic acidosis. 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.

Causes of high anion gap metabolic acidosis (HAGMA):

Note: a useful mnemonic to remember this is MUDPILES – Methanol, Uremia, Diabetic Ketoacidosis, Paraldehyde, Infection, Lactic Acidosis, Ethylene Glycol and Salicylates

Normal anion gap

In patients with a normal anion gap the drop in HCO−
3 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 HCO−
3 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 other causes).
2. Low aldosterone may be due to adrenal disorders or ACE inhibitors.
3. Low response to aldosterone maybe due to potassium-sparing diuretics, trimethoprim/sulfamethoxazole, 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 often due to hypoalbuminemia. Albumin is an anionic protein and its loss 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.

The anion gap is sometimes reduced in multiple myeloma, where there is an increase in plasma IgG (paraproteinaemia). [14]

Correcting the anion gap for the albumin concentration

The calculated value of the anion gap should always be adjusted for variations in the serum albumin concentration. [15] For example, in cases of hypoalbuminemia the calculated value of the anion gap should be increased by 2.3 to 2.5 mEq/L per each 1 g/dL decrease in serum albumin concentration (refer to Sample calculations, below). [9] [16] [17] Common conditions that reduce serum albumin in the clinical setting are hemorrhage, nephrotic syndrome, intestinal obstruction and liver cirrhosis. Hypoalbuminemia is common in critically ill patients.

The anion gap is often employed as a simple scanning tool by clinicians at the bedside to detect the presence of anions such as lactate, which can accumulate in critically ill patients. Hypoalbuminemia can mask a mild elevation of the anion gap, resulting in failure to detect an accumulation of unmeasured anions. In the largest study published to date, featuring over 12,000 data sets, Figge, Bellomo and Egi [18] demonstrated that the anion gap, when used to detect critical levels of lactate (greater than 4 mEq/L), exhibited a sensitivity of only 70.4%. In contrast, the albumin-corrected anion gap demonstrated a sensitivity of 93.0%. Therefore, it is important to correct the calculated value of the anion gap for the concentration of albumin, particularly in critically ill patients. [18] [19] [20] Corrections can be made for the albumin concentration using the Figge-Jabor-Kazda-Fencl equation to give an accurate anion gap calculation as exemplified below. [17]

Sample calculations

Given the following data from a patient with severe hypoalbuminemia suffering from postoperative multiple organ failure, [21] calculate the anion gap and the albumin-corrected anion gap.

Data:

Calculations:

In this example, the albumin-corrected anion gap reveals the presence of a significant quantity of unmeasured anions. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Bicarbonate</span> Polyatomic anion

In inorganic chemistry, bicarbonate is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula HCO−
3.

<span class="mw-page-title-main">Arterial blood gas test</span> A test of blood taken from an artery that measures the amounts of certain dissolved gases

An arterial blood gas (ABG) test, or arterial blood gas analysis (ABGA) measures the amounts of arterial gases, such as oxygen and carbon dioxide. An ABG test requires that a small volume of blood be drawn from the radial artery with a syringe and a thin needle, but sometimes the femoral artery in the groin or another site is used. The blood can also be drawn from an arterial catheter.

Alkalosis is the result of a process reducing hydrogen ion concentration of arterial blood plasma (alkalemia). In contrast to acidemia, alkalemia occurs when the serum pH is higher than normal. Alkalosis is usually divided into the categories of respiratory alkalosis and metabolic alkalosis or a combined respiratory/metabolic alkalosis.

<span class="mw-page-title-main">Electrolyte imbalance</span> Medical condition

Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance, oxygen delivery, acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte. Examples of electrolytes include calcium, chloride, magnesium, phosphate, potassium, and sodium.

Hyperchloremia is an electrolyte disturbance in which there is an elevated level of chloride ions in the blood. The normal serum range for chloride is 96 to 106 mEq/L, therefore chloride levels at or above 110 mEq/L usually indicate kidney dysfunction as it is a regulator of chloride concentration. As of now there are no specific symptoms of hyperchloremia; however, it can be influenced by multiple abnormalities that cause a loss of electrolyte-free fluid, loss of hypotonic fluid, or increased administration of sodium chloride. These abnormalities are caused by diarrhea, vomiting, increased sodium chloride intake, renal dysfunction, diuretic use, and diabetes. Hyperchloremia should not be mistaken for hyperchloremic metabolic acidosis as hyperchloremic metabolic acidosis is characterized by two major changes: a decrease in blood pH and bicarbonate levels, as well as an increase in blood chloride levels. Instead those with hyperchloremic metabolic acidosis are usually predisposed to hyperchloremia.

Hypochloremia is an electrolyte disturbance in which there is an abnormally low level of the chloride ion in the blood. The normal serum range for chloride is 97 to 107 mEq/L.

<span class="mw-page-title-main">Metabolic acidosis</span> Medical condition

Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys to excrete excess acids. Metabolic acidosis can lead to acidemia, which is defined as arterial blood pH that is lower than 7.35. Acidemia and acidosis are not mutually exclusive – pH and hydrogen ion concentrations also depend on the coexistence of other acid-base disorders; therefore, pH levels in people with metabolic acidosis can range from low to high.

<span class="mw-page-title-main">Respiratory acidosis</span> Medical condition

Respiratory acidosis is a state in which decreased ventilation (hypoventilation) increases the concentration of carbon dioxide in the blood and decreases the blood's pH.

<span class="mw-page-title-main">Ringer's lactate solution</span> Fluid used for resuscitation after blood loss

Ringer's lactate solution (RL), also known as sodium lactate solution,Lactated Ringer's, and Hartmann's solution, is a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. It is used for replacing fluids and electrolytes in those who have low blood volume or low blood pressure. It may also be used to treat metabolic acidosis and to wash the eye following a chemical burn. It is given by intravenous infusion or applied to the affected area.

Osmol gap in medical science is the difference between measured serum osmolality and calculated serum osmolality.

<span class="mw-page-title-main">Metabolic alkalosis</span> Medical condition

Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

In physiology, base excess and base deficit refer to an excess or deficit, respectively, in the amount of base present in the blood. The value is usually reported as a concentration in units of mEq/L (mmol/L), with positive numbers indicating an excess of base and negative a deficit. A typical reference range for base excess is −2 to +2 mEq/L.

Hyperchloremic acidosis is a form of metabolic acidosis associated with a normal anion gap, a decrease in plasma bicarbonate concentration, and an increase in plasma chloride concentration. Although plasma anion gap is normal, this condition is often associated with an increased urine anion gap, due to the kidney's inability to secrete ammonia.

Acid–base homeostasis is the homeostatic regulation of the pH of the body's extracellular fluid (ECF). The proper balance between the acids and bases in the ECF is crucial for the normal physiology of the body—and for cellular metabolism. The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.

Normal anion gap acidosis is an acidosis that is not accompanied by an abnormally increased anion gap.

<span class="mw-page-title-main">High anion gap metabolic acidosis</span> Medical condition

High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap. Metabolic acidosis occurs when the body produces too much acid, or when the kidneys are not removing enough acid from the body. Several types of metabolic acidosis occur, grouped by their influence on the anion gap.

The urine anion gap is calculated using measured ions found in the urine. It is used to aid in the differential diagnosis of metabolic acidosis.

Chloride is an anion in the human body needed for metabolism. It also helps keep the body's acid-base balance. The amount of serum chloride is carefully controlled by the kidneys.

<span class="mw-page-title-main">Distal renal tubular acidosis</span> Medical condition

Distal renal tubular acidosis (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct of the distal nephron. This failure of acid secretion may be due to a number of causes. It leads to relatively alkaline urine, due to the kidney's inability to acidify the urine to a pH of less than 5.3.

Delta ratio, or "delta-delta", is a formula that can be used to assess elevated anion gap metabolic acidosis and to evaluate whether a mixed acid–base disorder is present. The anion gap (AG) without potassium is calculated first and if a metabolic acidosis is present, results in either a high anion gap metabolic acidosis (HAGMA) or a normal anion gap acidosis (NAGMA). A low anion gap is usually an oddity of measurement, rather than a clinical concern.

References

  1. ↑ Oh MS, Carroll HJ (1977). "The anion gap". N. Engl. J. Med. 297 (15): 814–7. 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): 854–8. doi:10.1056/NEJM198010093031505. PMID   6774247.
  3. 1 2 3 4 "Electrolytes: Common Questions: What is anion gap?". Lab Tests Online. American Association for Clinical Chemistry. 24 February 2015. Retrieved 10 November 2015.
  4. ↑ Emmett M.; Narins R.G. (1977). "Clinical use of the anion gap". Medicine. 56 (1): 38–54. doi:10.1097/00005792-197701000-00002. PMID   401925.
  5. ↑ "Urine Anion Gap: Acid Base Tutorial, University of Connecticut Health Center". Archived from the original on 21 November 2008. Retrieved 14 November 2008.
  6. ↑ "Urine anion and osmolal gaps in metabolic acidosis" . Retrieved 14 November 2008.
  7. ↑ Kirschbaum B, Sica D, Anderson FP (June 1999). "Urine electrolytes and the urine anion and osmolar gaps". The Journal of Laboratory and Clinical Medicine. 133 (6): 597–604. doi:10.1016/S0022-2143(99)90190-7. PMID   10360635.
  8. ↑ 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): 311–3. doi:10.1001/archinte.150.2.311. PMID   2302006.
  9. 1 2 Kraut JA, Madias NE (2006). "Serum Anion Gap: Its Uses and Limitations in Clinical Medicine". Clinical Journal of the American Society of Nephrology. 2 (1): 162–174. doi: 10.2215/CJN.03020906 . PMID   17699401.
  10. ↑ Nosek, Thomas M. "Section 7/7ch12/7ch12p51". Essentials of Human Physiology. Archived from the original on 23 May 2016.
  11. ↑ "The Anion Gap" . Retrieved 4 October 2008.
  12. ↑ "Anion Gap: Acid Base Tutorial, University of Connecticut Health Center". Archived from the original on 21 November 2008. Retrieved 4 October 2008.
  13. ↑ Sabatine, Mark (2011). Pocket Medicine . Lippincott Williams Wilkens. p.  4–3. ISBN   978-1-60831-905-3.
  14. ↑ Lolekha PH, Lolekha S (1 February 1983). "Value of the anion gap in clinical diagnosis and laboratory evaluation". Clinical Chemistry. 29 (2): 279–83. doi:10.1093/clinchem/29.2.279. PMID   6821931.
  15. ↑ Berend K, de Vries A, Gans R (9 October 2014). "Physiological approach to assessment of acid-base disturbances". The New England Journal of Medicine. 371 (15): 1434–45. doi:10.1056/NEJMra1003327. PMID   25295502. S2CID   1675324 .
  16. ↑ 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. doi:10.1016/j.lab.2005.07.008. PMID   16310513.
  17. 1 2 Figge J, Jabor A, Kazda A, Fencl V (November 1998). "Anion gap and hypoalbuminemia". Critical Care Medicine. 26 (11): 1807–10. doi:10.1097/00003246-199811000-00019. PMID   9824071.
  18. 1 2 Figge J, Bellomo R, Egi M (13 October 2017). "Quantitative relationships among plasma lactate, inorganic phosphorus, albumin, unmeasured anions and the anion gap in lactic acidosis". Journal of Critical Care. 44: 101–10 [Epub ahead of print]. doi: 10.1016/j.jcrc.2017.10.007 . PMID   29080515. Open Access logo PLoS transparent.svg
  19. ↑ Chawla L, Shih S, Davison D, Junker C, Seneff M (16 December 2008). "Anion gap, anion gap corrected for albumin, base deficit and unmeasured anions in critically ill patients: implications on the assessment of metabolic acidosis and the diagnosis of hyperlactatemia". BMC Emergency Medicine. 8 (18): 18. doi: 10.1186/1471-227X-8-18 . PMC   2644323 . PMID   19087326. Open Access logo PLoS transparent.svg
  20. ↑ Mallat J, Michel D, Salaun P, Thevenin D, Tronchon L (March 2012). "Defining metabolic acidosis in patients with septic shock using Stewart approach". American Journal of Emergency Medicine. 30 (3): 391–8. doi:10.1016/j.ajem.2010.11.039. PMID   21277142.
  21. 1 2 Fencl V, Kazda A, Jabor A, Figge J (December 2000). "Diagnosis of metabolic acid-base disturbances in critically ill patients". American Journal of Respiratory and Critical Care Medicine. 162 (6): 2246–51. CiteSeerX   10.1.1.322.2433 . doi:10.1164/ajrccm.162.6.9904099. PMID   11112147. Open Access logo PLoS transparent.svg
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