Anion gap

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	paCO2=40	paO2=95	pH=7.40
ALVEOLAR GAS:
	pACO2=36	pAO2=105	A-a g=10
OTHER:
Ca=9.5	PO4=1	Mg2+=2.0
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=0.4

The anion gap is used to aid in the differential diagnosis of metabolic acidosis.

Although the term "anion gap" usually implies "serum anion gap", the Urine anion gap is also a clinically useful measure.^[1][2][3]

Contents 1 Calculation 1.1 With potassium 1.2 Without potassium 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

Calculation

The concentrations are expressed in units of milliequivalents/liter (mEq/L).

With potassium

It is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium plus potassium (cations):

= ( [Na⁺]+[K⁺] ) − ( [Cl⁻]+[HCO₃⁻] )

Without potassium

However, for daily practice, the potassium is frequently ignored because potassium concentrations, being very low, usually have little effect on the calculated gap. This leaves the following equation:

= ( [Na⁺] ) − ( [Cl⁻]+[HCO₃⁻] )

Uses

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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). The 'measured' cations are sodium (Na⁺), Potassium (K⁺), Calcium (Ca²⁺) and Magnesium (Mg²⁺). The 'unmeasured' cations include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma). Likewise, the 'measured' anions are chloride (Cl⁻), bicarbonate (HCO₃⁻) and phosphate (PO₃⁻), with the 'unmeasured' anions being sulphates and a number of serum proteins (predominantly albumin).

By convention (and for the sake of convenience) only Na⁺, Cl⁻ and HCO₃⁻ are used for calculation of the anion gap as noted above especially in clinical settings.

In normal health there are more unmeasured anions (compared to unmeasured cations) in the serum, therefore the anion gap is usually positive. 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 helpful clinically, as it helps in the differential diagnosis of a number of disease states.

Normal value ranges

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 [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^[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 gap. A certain 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 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 an excess of these substances.

High anion gap

In these conditions, bicarbonate concentrations decrease, in response to the need to buffer the increased presence of acids (as a result of the underlying condition). The bicarbonate is replaced by the unmeasured anion resulting in a high anion gap.

• Lactic acidosis
• Ketoacidosis
  • Diabetic ketoacidosis
  • Alcohol abuse

• Toxins:
  • Ethylene glycol
  • Lactic acid
  • Methanol
  • Propylene Glycol
  • Phenformin
  • Aspirin
  • Cyanide, coupled with elevated venous oxygenation
  • Iron
  • isoniazid

Note: a useful mnemonic to remember this is MUDPILES (methanol, uremia, DKA, propylene glycol, INH, lactic acidosis, ethylene glycol, salicylates). Historically, the "P" in MUDPILES was for paraldehyde. Paraldehyde is no longer used medically, so 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.

Normal anion gap

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(RTA) also known as type 2 RTA)
• Renal dysfunction (i.e. renal failure, hypoaldosteronism, distal renal tubular acidosis also known as type 1 RTA)
• Ingestions
  • Ammonium chloride and Acetazolamide.
  • 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

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

Low anion gap

A low anion gap is largely associated with 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 1.5 and 2.5 mmol/L per g/dL decrease in serum albumin.^[9] Common conditions that reduce serum albumin in the clinical setting are haemorrhage, 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] This should not be confused with hyperalbuminaemia as an increase in albumin causes an increased anion gap.

In critical care corrections can be made for hypoalbuminemia to give an accurate anion gap.^[11]

References

External links

• Clinical Physiology of Acid-Base and Electrolyte Disorders by Rose, Post
• Intensive Care Medicine by Irwin and Rippe
• The ICU Book by Marino
• Calculator at mcw.edu

v • d • e Urinary system, physiology: renal physiology and acid-base physiology Filtration Renal blood flow · Ultrafiltration · Countercurrent exchange · Filtration fraction Hormones affecting filtration Antidiuretic hormone (ADH) · Aldosterone · Atrial natriuretic peptide Secretion/clearance Pharmacokinetics · Clearance of medications · Urine flow rate Reabsorption Solvent drag · Na+ · Cl- · urea · glucose · oligopeptides · protein Endocrine Renin · Erythropoietin (EPO) · Calcitriol (Active vitamin D) · Prostaglandins Assessing Renal function/ Measures of dialysis Glomerular filtration rate · Creatinine clearance · Renal clearance ratio · Urea reduction ratio · Kt/V · Standardized Kt/V · Hemodialysis product · PAH clearance (Effective renal plasma flow · Extraction ratio) Acid-base physiology Fluid balance · Darrow Yannet diagram · Body water: Intracellular fluid/Cytosol · Extracellular fluid · (Interstitial fluid · Plasma · Transcellular fluid) Base excess · Davenport diagram · Anion gap · Arterial blood gas · Winter's formula Buffering/compensation Bicarbonate buffering system · Respiratory compensation · Renal compensation Other Fractional sodium excretion · BUN-to-creatinine ratio · Tubuloglomerular feedback · Natriuresis urinary system navs: anat/physio/dev, noncongen/acid+base/congen/neoplasia, symptoms+signs/eponymous, proc

v • d • e Water-electrolyte imbalance and acid-base imbalance (E86-E87, 276) Volume status Volume contraction (Dehydration/Hypovolemia)  · Hypervolemia Electrolyte Na+ Hypernatremia · Hyponatremia (Hypotonic, Isotonic) K+ Hyperkalemia · Hypokalemia Cl− Hyperchloremia · Hypochloremia Acid-base Acidosis Metabolic: High anion gap (Ketoacidosis/Diabetic ketoacidosis, Lactic) · Normal anion gap (Hyperchloremic, Renal tubular) Respiratory Alkalosis Metabolic: Contraction alkalosis Respiratory Both Mixed disorder of acid-base balance urinary system navs: anat/physio/dev, noncongen/acid+base/congen/neoplasia, symptoms+signs/eponymous, proc