Anion gap

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Overview

• The anion gap is used to aid in the differential diagnosis of metabolic acidosis; (The cause of metabolic acidosis is determined by the anion gap).
• Chloride and bicarbonate comprise 85% of the anions in the serum

  • The remaining anions are called the anion gap

• Reference range: 8-16 mmol/l

Calculation

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

Anion Gap = ( [Na⁺]+[K⁺] ) - ( [Cl^-]+[HCO₃^-] )

However, for daily practice, the potassium is frequently ignored, leaving the following equation:

Anion Gap = ( [Na⁺] ) - ( [Cl^-]+[HCO₃^-] )

Uses

The anion gap is representative of the unmeasured anions in the plasma, and these anions are affected differently based on the type of metabolic acidosis. The primary function of the anion gap measurement is to allow a clinician to narrow down the possible causes of a patient's metabolic acidosis. For example, if a patient presents with metabolic acidosis, but a normal anion gap, then conditions that cause a high anion gap can be ruled out as being the cause of the acidosis.

Normal value ranges

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 mmol/L plasma when not including [K⁺] and from 10 to 20 mmol/L plasma when including [K⁺]. Some specific sources use 15 and 8-16 mEq/L.

Modern analysers make use of ion-selective electrodes which give a normal anion gap as <11 mmol/L. Therefore according to the new classification system a high anion gap is anything above 11mmol/L and a normal anion gap is between 3-11 mmol/L.

Interpretation and causes

Anion gap can be classified as either high, normal or, in rare cases, low. A high anion gap indicates that there is loss of HCO₃^- without a subsequent increase in Cl^-. Electroneutrality is maintained by the increased production of anions like ketones, lactate, PO₄^-, and SO₄^-; these anions are not part of the anion-gap calculation and therefore a high anion gap results. In patients with a normal anion gap the drop in HCO₃^- is compensated for by an increase in Cl^- and hence is also known as hyperchloremic acidosis.

High anion gap

The bicarbonate lost is replaced by an unmeasured anion and thus you will see a high anion gap.

• Hyperosmolar hyperglycemic nonketotic coma
• Lactic acidosis
• Ketoacidosis
  • Alcohol ketoacidosis
  • Diabetic ketoacidosis
  • Starvation ketoacidosis
• Renal failure (acute/chronic)

• Toxins or drugs:
  • Ethanol
  • Ethylene glycol
  • Lactic acid
  • Methanol
  • Paraldehyde
  • Aspirin
  • Cyanide, coupled with elevated venous oxygenation
  • Iron
  • isoniazid

The mnemonic "MUDPILES" is used to remember the causes of a high anion gap.

M - methanol/metformin
U - uremia
D - diabetic ketoacidosis
P - paraldehyde/propylene glycol
I - Infection/ischemia/isoniazid
L - lactate
E - ethylene glycol/ethanol
S - salicylates/starvation

Some people, especially those not in the emergency room, find the mnemonic KIL-U easier to remember and also more useful clinically:

K - Ketones
I - Ingestion
L - lactic acid
U - uremia

All of the components of "mudpiles" are also covered with the "KIL-U" device, with the bonus that these are things that can kill you.

Ketones: more straightforward than remembering diabetic ketosis and starvation ketosis, etc.

Ingestion: methanol, metformin, paraldehyde, propylene glycol, isoniazid, ethylene glycol, ethanol, and salicilates are covered by ingestion. These can be thought of as a single group: "ingestions" during the initial consideration, especially when not triaging a patient in the emergency room.

Lactate: including that caused by infection and shock

Normal anion gap (hyperchloremic acidosis)

Usually the HCO₃^- lost is replaced by a chloride anion, and thus there is a normal anion gap.

• Alcohol (such as ethanol) can effect anion gap by inducing alcohol dehydrogenase enzyme.
• Ammonium chloride and Acetazolamide
• Arginine and lysine during total parenteral nutrition
• Carbonic anhydrase inhibitors
• Drugs
• Enteral bicarbonate loss: diarrhea (note: vomiting causes hypochloraemic alkalosis)
• Fluid loss with pancreatitis
• Ileal stoma
• Pancreatic fistula
• Recovery from diabetic ketoacidosis
• Renal loss of HCO₃^- (i.e. proximal renal tubular acidosis)
• Renal dysfunction (i.e. renal failure, hypoaldosteronism, distal renal tubular acidosis)
• Some cases of ketoacidosis, particularly during insulin treatment
• Ureteroenterostomy

Low anion gap

A low anion gap is relatively rare but may occur from the presence of abnormal positively charged proteins, as in multiple myeloma, or in the setting of a low serum albumin level.

Differential Diagnosis

Decreased Anion Gap

• Bromism
• Dilution
• Hypercalcemia
• Hypermagnesemia
• Hypernatremia
• Hyperviscosity
• Hypoalbuminemia
• Increased unmeasured cations
• Lithium toxicity
• Multiple Myeloma
• Paraproteinemia
• Pheochromocytoma
• Underestimation of serum sodium

Increased Anion Gap

• Alcoholic ketoacidosis
• Diabetic Ketoacidosis
• Drugs, toxins
• Hyperosmolar hyperglycemic nonketotic coma
• Lactic acidosis
• Renal failure (acute/chronic)
• Starvation ketoacidosis

Normal Anion Gap

• Arginine and lysine during parenteral nutrition
• Carbonic anhydrase inhibitors
• Drugs
• Enteral bicarbonate loss: diarrhea
• Fluid loss with pancreatitis
• Ileal stoma
• Pancreatic fistula
• Recovery from diabetic ketoacidosis
• Renal Tubular Acidosis
• Ureteroenterostomy

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

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