Anion Gap: A Comprehensive Guide for Clinicians

The anion gap is an important lab test for understanding and diagnosing metabolic conditions. As a diagnostic tool used by healthcare providers to identify abnormalities in the body’s acid-base balance, the anion gap offers valuable insights into a range of metabolic disorders. 

In this article we will break down the anion gap in while providing important information to support its application in practice.

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What is the Anion Gap?

The anion gap represents the difference between positively charged ions (cations; primarily sodium, Na+, and potassium, K+) and negatively charged ions (anions; primarily bicarbonate, HCO3-, and chloride, Cl-) in the blood.

While the body maintains a delicate balance of these charged particles, or electrolytes, certain medical conditions can disrupt this equilibrium, leading to metabolic acidosis or alkalosis.

Why Is The Anion Gap Important?

The anion gap helps clinicians determine the underlying cause of metabolic acidosis—a condition where excess acid accumulates in the body or bicarbonate (a base) is lost. 

By identifying whether the acidosis involves excess acids (high anion gap) or a loss of bicarbonate (normal anion gap), healthcare providers can make more accurate diagnoses and treatment decisions.

What is Metabolic Acidosis?

Metabolic acidosis is a condition where there is too much acid in the blood, leading to a low level of bicarbonate (HCO₃-) and an acidic blood pH below 7.35. It is not a disease on its own but a sign of an underlying issue that needs to be addressed to prevent serious complications. 

The condition can occur for several reasons including increased acid production, reduced acid excretion, ingestion of acids, or loss of bicarbonate through the kidneys or gastrointestinal tract. It is classified into two main types: high anion gap metabolic acidosis (HAGMA) and non-gap metabolic acidosis (NAGMA).

High Anion Gap Metabolic Acidosis vs. Non-Gap Metabolic Acidosis

In high anion gap metabolic acidosis (HAGMA), the body accumulates unmeasured acids like lactate or ketoacids, which can happen with conditions such as diabetic ketoacidosis, lactic acidosis, or toxin ingestion (e.g., antifreeze or methanol). 

In contrast, non-gap metabolic acidosis (NAGMA) results from bicarbonate loss, typically through diarrhea or kidney issues like renal tubular acidosis. The decrease in bicarbonate is  accompanied by a corresponding chloride increase.

Urine vs. Blood Anion Gap Testing

The serum anion gap and urine anion gap are both used to evaluate acid-base and electrolyte imbalances but serve different purposes. 

The serum anion gap focuses on detecting metabolic acidosis and identifying unmeasured acids in the blood. It is calculated using sodium, chloride, and bicarbonate levels (and sometimes potassium levels as well) and is commonly used to identify conditions like lactic acidosis, ketoacidosis, or bicarbonate loss due to diarrhea or kidney issues. 

In contrast, the urine anion gap helps determine whether the kidneys or non-renal factors are causing metabolic acidosis. It is calculated using sodium, potassium, and chloride levels in urine. 

A positive urine anion gap often points to bicarbonate loss from the kidneys, while a negative gap suggests bicarbonate loss from other causes, like diarrhea. 

In short, the serum anion gap evaluates overall metabolic issues, while the urine anion gap helps determine the kidney's role in acid-base disturbances. Most often when people refer to the anion gap, they are speaking of the anion gap blood test.

How is the Anion Gap Calculated?

The formula to calculate the anion gap is straightforward:

Anion Gap = [Sodium (Na+) + Potassium (K+)] − [Chloride (Cl-) + Bicarbonate (HCO₃-)]

Some labs include potassium, and some do not. Exclusion is common in routine clinical practice because the concentration of potassium in the blood is relatively small compared to sodium. Therefore, it has minimal impact on the overall anion gap calculation.

Normal Range

The normal range for the anion gap varies depending on the lab, and on whether potassium is included in the calculation. 

• A lab that includes potassium will generally have a reference range of 16 ± 4 mEq/L

• A lab that excludes potassium will generally have a reference range of 12 ± 4 mEq/L 

Correcting for Albumin

Because albumin, a negatively charged protein, significantly impacts the anion gap, a correction is necessary in patients with low albumin levels.  

Adjusting the anion gap for albumin levels is important because albumin is the main unmeasured anion in the calculation. When albumin levels are low (a condition called hypoalbuminemia), the anion gap decreases, which can hide serious issues like high anion gap metabolic acidosis. 

For every 1 g/dL drop in albumin, the anion gap lowers by about 2.3 mmol/L. This adjustment is especially important for patients in critical care, like those in the ICU, where low albumin is common. Without this correction, doctors might miss important acid-base problems.

The corrected anion gap can be calculated as:

Corrected Anion Gap = Measured Anion Gap + 2.5 × (Normal Albumin−Measured Albumin)

This adjustment ensures the anion gap reflects true acid-base disturbances in patients with hypoalbuminemia.

Other Factors That Can Affect the Anion Gap

Several factors can affect the outcome of this lab test. For example, 

mistakes during sample collection or processing can affect the electrolytes measured to calculate the anion gap. 

Issues like delays in testing, dilution mistakes, kidney problems, or not collecting enough blood can also cause errors. For example, if a sample isn’t processed quickly, white blood cells keep metabolizing and raise bicarbonate levels, which can distort the results.

The Delta Gap

Sometimes clinicians need more nuanced testing to understand why a patient’s metabolic shifts are occurring.

The delta gap helps uncover hidden (or mixed) acid-base problems that might not be obvious from the anion gap alone. By comparing how the anion gap and bicarbonate levels change, doctors can get a clearer picture of what’s going wrong in the body and provide the right treatment.

What the Delta Gap Reveals:

Positive Delta Gap (> +6): may indicate metabolic alkalosis, where the anion gap rises more than bicarbonate drops.

Negative Delta Gap (< -6): may point to hyperchloremic acidosis, where bicarbonate drops more than the anion gap rises.

Clinical Significance of the Anion Gap

The anion gap can signal important problems with a person’s acid-base balance.

High Anion Gap (HAGMA)

High anion gap metabolic acidosis (HAGMA) occurs when unmeasured acids build up in the blood, leading to an imbalance in the body’s acid-base system. Common causes include:

• Diabetic Ketoacidosis (DKA): this happens when the body lacks insulin, causing fat to break down into acidic ketone bodies like beta-hydroxybutyrate and acetoacetate, which increase blood acidity.

• Salicylate Poisoning: overdoses of substances like aspirin can cause metabolic acidosis along with hyperventilation, leading to mixed acid-base issues.

• Lactic Acidosis: often caused by low oxygen levels or sepsis, it results from excess production or reduced breakdown of lactic acid.

• Toxins: chemicals like methanol, ethylene glycol (found in antifreeze), and acetaminophen can cause acidosis by producing harmful acidic byproducts.

• Uremia: this occurs when kidney failure leads to the accumulation of waste products, contributing to acidity in the blood.

A helpful way to remember these causes is the mnemonic “CAT MUDPILES”:

C: Carbon monoxide, cyanide

A: Aminoglycosides

T: Theophylline

M: Methanol

U: Uremia

D: Diabetic ketoacidosis

P: Paracetamol/acetaminophen

I: Iron, isoniazid

L: Lactic acidosis

E: Ethanol, ethylene glycol

S: Salicylates

Non-Anion Gap Metabolic Acidosis (NAGMA)

Non-Anion Gap Metabolic Acidosis (NAGMA) is a type of metabolic acidosis where the blood bicarbonate level decreases, but the anion gap remains within the normal range. 

This occurs because the reduction in bicarbonate is balanced by an equivalent increase in chloride, leading to hyperchloremic acidosis. NAGMA is common when there is excessive bicarbonate loss (which can occur in diarrhea) or reduced acid excretion from the kidneys.

NAGMA is not the same as a low or normal anion gap. While NAGMA occurs due to metabolic acidosis with a normal anion gap, a low anion gap results from shifts in unmeasured ions or lab errors, and a normal anion gap indicates no underlying metabolic imbalance.

Causes of NAGMA

Causes of NAGMA include:

Loss of Bicarbonate:

• From the Digestive System: diarrhea or intestinal fistulas can remove too much bicarbonate from the body.

• From the Kidneys: conditions like proximal renal tubular acidosis (RTA, which is kidney dysfunction disrupting acid balance) or certain medications (like acetazolamide) reduce the kidneys' ability to reabsorb bicarbonate.

Too Much Chloride:

• Chloride-Rich IV Fluids: giving a lot of normal saline during resuscitation can dilute bicarbonate, leading to hyperchloremic acidosis.

• Amino Acid Metabolism: the body can convert lysine or arginine into hydrochloric acid, which increases chloride levels.

Problems with Kidney Acid Excretion:

• Distal Renal Tubular Acidosis (RTA) (Type 1): the kidneys don’t get rid of hydrogen ions effectively.

• Hypoaldosteronism (Type 4 RTA): low levels of aldosterone lead to poor excretion of hydrogen and potassium ions.

Chronic Kidney Disease (CKD): damaged kidneys can’t remove acids, so they build up in the body.

Other Metabolic Issues:

• Toluene Intoxication or Ketoacidosis: these conditions may cause a mix of NAGMA and high anion gap acidosis depending on their stage.

Dilution Acidosis:

• Fluid Overload: rapid infusion of IV saline can dilute bicarbonate levels, causing acidosis.

Low Anion Gap

In contrast to NAGMA, or non-gap metabolic acidosis (normal anion gap despite high acids, usually due to bicarbonate loss being offset by an increase in chloride), a true low anion gap can also be seen. Low anion gap is less common, and it can signal a different set of causes: 

• Testing Errors: mistakes during sample collection, transport, or analysis can falsely lower the anion gap, making retesting essential.

• Low Albumin: as a major unmeasured anion, albumin decreases the gap when levels drop due to malnutrition, liver issues, or inflammation. Hypoalbuminemia can mask high anion gap metabolic acidosis unless corrected.

• Excess Positive Ions: increased positively-charged electrolytes like lithium (in toxicity), magnesium, or calcium can reduce the anion gap. Lithium toxicity requires quick diagnosis and treatment.

• Abnormal Proteins: disorders like multiple myeloma create excess positively charged proteins, lowering the gap. 

• Chloride Overestimation: substances like bromide or iodide can be mistaken for chloride in tests, causing false high chloride levels and a lower anion gap, which may hide issues like salicylate poisoning.

• Sodium Underestimation: high sodium levels (hypernatremia) or testing mistakes can lead to underreported sodium levels, which may cause a low anion gap.

Clinicians should systematically explore these causes, correct for albumin when necessary, and consult specialists for complex cases.

Diagnostic Approach for Clinicians

A systematic approach to evaluating the anion gap involves:

Assessing The Anion Gap

Classifying acidosis:

• High anion gap: investigate unmeasured acids.

• Normal anion gap: look for bicarbonate losses or chloride retention.

• Low anion gap: look first for testing errors or low albumin, and then assess for other causes. Calculate for low albumin if needed.

• Applying the delta gap: identify mixed acid-base disorders.

Considering Related Tests

• Lactate levels for lactic acidosis

• Ketones for ketoacidosis

• Toxicology screens for suspected poisonings

• Renal function tests for kidney-related causes

Diagnostic algorithms can simplify these steps, aiding in efficient and accurate decision-making.

Treatment Considerations

Treatments depend on the cause of the altered anion gap. 

High Anion Gap Acidosis

Treatment focuses on addressing the underlying cause:

• Lactic Acidosis: improve oxygen delivery and address the source of low oxygen

• Ketoacidosis: administer insulin and fluids to halt ketone production

• Toxins: use specific antidotes or dialysis to remove toxins

• Renal Failure: dialysis may be required to remove accumulated acids

Non-Gap Acidosis

For normal anion gap acidosis:

• Diarrhea: rehydrate and replenish bicarbonate losses.

• Kidney Problems Affecting Acid/Base Balance: Treat with alkali therapy (e.g., sodium bicarbonate) and address the underlying renal dysfunction.

Low Anion Gap

First confirm, and then treat the cause such as low albumin levels, toxicity, or excessive proteins.

Monitoring and Follow-Up

Regular monitoring of the anion gap and related electrolytes is essential to assess treatment effectiveness. Persistent abnormalities may indicate the need for further diagnostic evaluation.

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Key Takeaways and Clinical Pearls

• Adjust for Albumin Levels: correct the anion gap for low albumin to avoid underestimating how severe the acidosis is.

• Use Advanced Tools: tools like the delta gap can help pinpoint the exact problem.

• Focus on the Cause: fixing the underlying condition is key to restoring acid-base balance.

• Track Changes: monitor the anion gap regularly to see if treatment is working and to catch any hidden or mixed issues.