Anion Gap

OVERVIEW

Anion Gap = Na+ – (Cl- + HCO3-)

• The Anion Gap (AG) is a derived variable primarily used for the evaluation of metabolic acidosis to determine the presence of unmeasured anions
• The normal anion gap depends on serum phosphate and serum albumin concentrations
• An elevated anion gap strongly suggests the presence of a metabolic acidosis
• The normal anion gap varies with different assays, but is typically 4 to 12mmol/L (if measured by ion selective electrode; 8 to 16 if measured by older technique of flame photometry)
• If AG > 30 mmol/L then metabolic acidosis invariably present
• If AG 20-29mmol/L then 1/3 will not have a metabolic acidosis
• K can be added to Na+, but in practice offers little advantage

ALBUMIN AND PHOSPHATE

• the normal anion gap depends on serum phosphate and serum albumin
• the normal AG = 0.2 x [albumin] (g/L) + 1.5 x [phosphate] (mmol/L)
• albumin is the major unmeasured anion and contributes almost the whole of the value of the anion gap.
• every 1g/L decrease in albumin will decrease anion gap by 0.25 mmoles
• a normally high anion gap acidosis in a patient with hypoalbuminaemia may appear as a normal anion gap acidosis.
• this is particularly relevant in ICU patients where lower albumin levels are common

HIGH ANION GAP METABOLIC ACIDOSIS (HAGMA)

HAGMA results from accumulation of organic acids or impaired H+ excretion

Causes (LTKR)

• Lactate
• Toxins
• Ketones
• Renal

Causes (CATMUDPILES)

• CO, CN
• Alcoholic ketoacidosis and starvation ketoacidosis
• Toluene
• Metformin, Methanol
• Uremia
• DKA
• Pyroglutamic acidosis, paracetamol, phenformin, propylene glycol, paraladehyde
• Iron, Isoniazid
• Lactic acidosis
• Ethylene glycol
• Salicylates

Effects of albumin

• Anion gap may be underesitmated in hypoalbuminaemia, because if albumin decreased by 1g/L then the anion gap decreases by 0.25 mmol
• To overcome the effects of the hypoalbuminaemia on the AG, the corrected AG can be used which is AG + (0.25 X (40-albumin) expressed in g/L

Lab tests to consider include:

• lactate, glucose, creatinine and urea, urinary ketones, serum levels of methanol, ethanol, paracetamol, salicylates and ethylene glycol

NORMAL ANION GAP METABOLIC ACIDOSIS (NAGMA)

NAGMA results from loss of HCO3- from ECF

Causes (CAGE)

• Chloride excess
• Acetazolamide/Addisons
• GI causes – diarrhea/vomiting, fistulae (pancreatic, ureters, billary, small bowel, ileostomy)
• Extra – RTA

Causes (ABCD)

• Addisons (adrenal insufficiency)
• Bicarbonate loss (GI or Renal)
• Chloride excess
• Diuretics (Acetazolamide)

Calculate the urinary anion gap to differentiate between a GI and renal cause of a normal anion gap acidosis

• urinary anion gap = (Na+ + K+) – Cl-
• The remaining significant unmeasured ions are NH4+ and HCO3-
  • renal causes increased urinary HCO3- excretion thus increased urinary AG
  • GI causes increased NH4+ excretion thus decreased urinary AG

LOW ANION GAP

Causes

• Non random analytical errors (increased Na+, increased viscosity, iodide ingestion, increased lipids)
• Decrease in unmeasured anions (albumin, dilution)
• Increase in unmeasured cations (multimyeloma (cationic IgG paraprotein), hypercalcaemia, hypermagnesaemia, lithium OD, polymixin B)
• bromide OD (causes falsely elevated chloride measurements)

ADVANTAGES AND DISADVANTAGES OF THE ANION GAP

Advantages

• simple to measure and evaluate acid-base disturbance
• can be done at bed side

Disadvantages

• reduced anions (ie hypoalbuminaemia) which is common in critical illness will reduce AG and may mask an elevated AG
• unmeasured cations such as lithium and hyperglobulinaemia will reduce AG
• hypercalcaemia and hypermagnesemia will reduce the AG
• calculation of AG involves the measurement of electrolyte therefore is depends on the accuracy of measurement process.

References and Links

LITFL

• Acid-Base: ABG analysis – Anion Gap – SID – NAGMA
• Metabolic acidosis: Overview – evaluation – DDx
• Metabolic alkalosis: Overview – evaluation – DDx
• Respiratory acidosis: Overview – DDx
• Respiratory alkalosis: Overview – DDx
• Metabolic Muddle 007 — HAGMA, LTKR, and CATMUDPILES

Journal articles

• Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162-174. [PMID 17699401]

FOAM and web resources

• Renal Fellow Network — Low Anion Gap