The anion gap (AG) is a measure of acid-base balance. Your body maintains balance by holding onto or releasing carbon dioxide through the lungs (acid) or bicarbonate through the kidneys (base). Cations are positive (base) and anions are negative (acid). The anion gap is the difference between the number of cations versus anions. An anion gap can be high, normal, or low (rare). A high anion gap indicates the presence of more anions than cations, or acidosis. When bicarbonate is used up to correct the acid-base balance, the gap widens (Kraut and Madias, 2007). Normal anion gap metabolic acidosis is also called hyperchloremic acidosis because the kidneys reabsorb chloride instead of reabsorbing bicarbonate (Emmett and Szerlip, 2019).

The normal value for the serum anion gap is approximately three to 10 mEq/L (averaging six mEq/L) but may vary according to your lab (Kraut and Madias, 2007). Remember that when calculating the anion gap, the CO₂ value from a patient’s basic metabolic panel is often used as an equivalent value for the HCO₃^- from an arterial blood gas. The total CO₂ content includes the serum bicarbonate as well as available forms of carbon dioxide, and the serum HCO₃^- comprises about 95% of the total CO₂ content. Therefore, it is common to use this measurement to estimate the serum HCO₃^- level.

Causes

High anion gap acidosis may be caused by:

• ketoacidosis
• lactic acidosis
• renal failure
• toxic ingestions

Normal anion gap acidosis may be caused by:

• gastrointestinal or renal bicarbonate losses
• impaired renal excretion

Signs and symptoms

While mild acidemia is typically asymptomatic, symptoms and signs of high anion gap acidosis may include:

• nausea
• vomiting
• malaise
• hyperpnea (long, deep breaths at a normal rate)
• fatigue
• cardiac dysfunction with hypotension, shock, ventricular arrhythmias 

Diagnosis

The cause of high anion gap acidosis may be obvious as in diabetic ketoacidosis, hypovolemic shock, or missed hemodialysis. Other data that is helpful in determining the cause include arterial blood gas (ABG), serum electrolytes, lactate and possible toxins. Elevation in anion gap indicates a metabolic acidosis. A normal anion gap with a low HCO₃^- (< 24 mEq/L) and high serum chloride indicates a non-anion gap (hyperchloremic) metabolic acidosis.
 
If a high anion gap acidosis is present, a delta ratio is calculated to help determine its cause, and Winters’ formula is applied to determine whether respiratory compensation is present or whether there is a second acid-based disorder.

• Delta ratio = Delta anion gap/Delta HCO₃^- = [AG -12] ÷ [24 - HCO₃^-]
• Winters’ formula: PCO₂ = (1.5 x HCO₃^-) + 8 ± 2

Treatment

Treatment is directed at reversing the underlying cause. Hemodialysis is required for renal failure and sometimes for ethylene glycol, methanol and salicylate poisoning. When metabolic acidosis results from loss of bicarbonate, as in normal anion gap acidosis, bicarbonate therapy is usually safe and effective. However, treatment with sodium bicarbonate for high anion gap acidosis is controversial and is typically used only in cases of severe metabolic acidosis when the bicarbonate is very low and the pH is below 7.1 (Emmett and Szerlip, 2019).

Mnemonics

Here are some helpful ways to remember the causes of high anion gap acidosis.
The most common mnemonics are:

• KUSMALE
  • Ketoacidosis
  • Uremia
  • Salicylate poisoning
  • Methanol
  • Aldehyde
  • Lactate
  • Ethylene glycol
• MUD PILES
  • Methanol
  • Uremia
  • Diabetes
  • Paraldehyde
  • Iron/Isoniazid
  • Lactate
  • Ethylene glycol
  • Salicylate

A newer mnemonic takes into account the new organic anion gap generating acids and precursors that have been recognized in recent years, and replaces paraldehyde which has become exceedingly rare (Mehta, Emmett & Emmett, 2008).

• GOLD MARK
  • Glycols
  • Oxoproline
  • L-lactate
  • D-lactate
  • Methanol
  • Aspirin
  • Renal failure
  • Ketoacidosis

How do you apply anion gap in clinical practice?  
In the hospital setting, you may hear the phrase “the anion gap is closed.” This often refers to the patient who is admitted to the hospital with ketoacidosis from uncontrolled diabetes. Typically, IV fluids and an insulin drip are administered until the gap is closed, and then a maintenance regimen may begin. In what other instances have you heard discussion about a patient’s anion gap? Have you ever had to use the calculation?
 

References:
Albert, M., Dell, R., & Winters, R. (1967). Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis. Annals of Internal Medicine, 66 (312-322). doi: 10.7326/0003-4819-66-2-312
 
Emmett, M. & Szerlip, H. (2019). Approach to the adult with metabolic acidosis. UptoDate. Retrieved from https://www.uptodate.com/contents/approach-to-the-adult-with-metabolic-acidosis
 
Gabow, P. (1985). Disorders associated with an altered anion gap. Kidney International, 27(2). doi:  10.1038/ki.1985.34

Kraut, J. & Madias, N. (2007). Serum anion gap: its uses and limitations in clinical medicine. Clinical Journal of the American Society of Nephrology, 2(1). doi: 10.2215/CJN.03020906

Mehta, A., Emmett, J., & Emmett, M. (2008). GOLD MARK: an anion gap mnemonic for the 21^st century. The Lancet, 372 (9642). doi: 10.1016/S0140-6736(08)61398-7

Rastegar, A. (2007). Use of Delta AG/DeltaHCO3- Ratio in the Diagnosis of Mixed Acid-Base Disorders. Journal of the American Society of Nephrology, 18.9 (2429-2431).