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Anion Gap: Low, Normal & High Levels + Causes, Symptoms

Written by Mathew Eng, PharmD | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Mathew Eng, PharmD | Last updated:

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The anion gap is a value calculated from the results of an electrolyte blood test which informs clinicians about the balance of positively and negatively charged particles in the blood. This is a useful measure to diagnose diseases and disorders associated with an acid/base imbalance in the body.

What Is the Anion Gap?

anion gap

The anion gap is a value that represents the difference between positively charged ions (cations) and negatively charged ions (anions) in the blood.

The anion gap cannot be directly measured, instead, it is calculated from the results of an electrolyte panel, another type of blood test.

The anion gap is calculated using the concentrations of the major anions in the blood, chloride and bicarbonate, and the major cations, sodium and potassium.

However, the concentration of potassium in the blood is usually much lower compared to sodium, chloride, and bicarbonate. Therefore, it is common practice to not use potassium when calculating the anion gap, as it usually has little effect [1].

In the body, the total positive charge from cations should equal the total negative charge from anions in the blood to maintain overall neutrality.

However, blood tests usually do not measure all types of ions. This means the anion gap gives us a picture of the unmeasured anions and cations in the blood. There are normally more unmeasured anions than cations, hence there is usually an anion gap [2].

Clinically, the anion gap value is primarily used to help evaluate acid-base disorders, which occur when the concentration of acids and bases in the blood becomes unbalanced [2].

Although the term anion gap usually refers to the concentrations of cations and anions in the blood, it can also refer to their concentrations in the urine, which is also clinically useful [3].

Normal Range

Normal ranges can vary between laboratories due to differences in equipment, techniques, and chemicals used. If your results are outside of the normal range, it may not necessarily mean there is something wrong. However, a normal result also doesn’t mean a particular medical condition is absent. Always talk with your doctor to learn more about your test results.

The value of the anion gap is reported in milliequivalents per liter (mEq/L).

Normal values are 3 to 11 mEq/L [4, 2].

Some older types of tests used different techniques to measure electrolytes, which give different results. The normal range for these older tests is 8 to 16 mEq/L [5, 6, 7].

High Anion Gap

Causes

It’s important to note that a number of factors may cause a high anion gap. Test results should be interpreted by a doctor who can take into account your medical history and other test results.

The anion gap is primarily used to determine the cause of metabolic acidosis, a condition where the body is producing too much acid or not enough acid is being removed from the body.

The list below details some potential causes of metabolic acidosis that is associated with a high anion gap. A normal anion gap during metabolic acidosis may indicate a different set of causes [8].

Disorders/Conditions

  1. Lactic acidosis – a condition where the body produces too much lactic acid [9, 10, 11]
  2. Diabetic ketoacidosis – a serious, life-threatening complication of diabetes resulting from excess production of ketones, which are byproducts of fat breakdown used as an alternative energy source [12, 13]
  3. Kidney failure – reduces the amount of acid removed from the body, while increasing the excretion of bicarbonate [14, 15]
  4. Uremia – the presence of urea in the blood is associated with kidney failure
  5. Thiamine (vitamin B1) deficiency [16, 17, 18]
  6. Hyperphosphatemia – High levels of phosphate ions in the blood [19, 2]
  7. Starvation [20]

Toxins

  1. Carbon monoxide [21, 22]
  2. Cyanide [23, 24]
  3. Ethylene glycol (antifreeze) poisoning [25, 26, 27]
  4. Propylene glycol [28]
  5. Isopropyl alcohol [28]
  6. Toluene [29, 30]
  7. Methanol [31]
  8. Paraldehyde [22]

Drugs

  1. Metformin [20]
  2. 5-Oxoproline/pyroglutamic acid – a byproduct of Tylenol (acetaminophen, paracetamol) [32, 33, 34, 35]
  3. Overdose with salicylates such as aspirin [20]
  4. Gamma-hydroxybutyrate (GHB) [36]
  5. Ibuprofen [28]

Other

  1. Iron overdose [28, 22]

Symptoms

A high anion gap itself does not produce symptoms, but it may indicate an imbalance in blood acid levels, such as metabolic acidosis. Some symptoms of metabolic acidosis include [9]:

  1. Nausea
  2. Vomiting
  3. Rapid and shallow breathing
  4. Fatigue
  5. Rapid/abnormal heartbeat
  6. Low blood pressure
  7. Confusion
  8. Headaches
  9. Lack of appetite

Treatment

Talk with your doctor if your anion gap test results are high. A high anion gap may indicate metabolic acidosis, which requires medical management.

The treatment of metabolic acidosis typically requires addressing the underlying cause. Some possible treatments for metabolic acidosis include detoxification if caused by drugs or toxins and insulin if the condition is caused by diabetes [9].

Low Anion Gap

Causes

Test results should always be interpreted by a doctor who can take into account your medical history and other test results.

The occurrence of a low anion gap value is very rare. When it is reported, the most common cause is a laboratory error.

In a study of over 67,000 calculations of the anion gap, the prevalence of a low anion gap value was found in only 304 (0.8%) out of the 39,360 patients whose electrolyte blood levels were studied, and only 19 of them had a repeatedly low anion gap [37].

Some other potential causes of a low anion gap are as follows [2, 38, 39]:

Disorders/Conditions

  1. Hypoalbuminemia – a condition where the levels of albumin in the body are low. Albumin is the most abundant of the circulating proteins. It is negatively charged, and hence, a drop in this protein may lower the anion gap value [40, 41]
  2. Monoclonal and polyclonal gammopathy – a condition where an overaccumulation of positively or negatively charged proteins at normal body pH is observed. Examples of such proteins include antibodies (IgG and IgA), where overproduction may lead to a decrease in the anion gap value [42, 41, 43]
  3. Hypercalcemia (high blood calcium) and hypermagnesemia (high blood magnesium) – a significant increase in positively charged ions, like calcium and magnesium in the body, may reduce the value of the anion gap [44]
  4. Pregnancy [45]
  5. Multiple myelomas – cancer of plasma cells, which are a type of white blood cell usually responsible for producing antibodies [46, 47, 48]

Drugs

  1. Bromide intoxication – bromide interferes with the calculation of the chloride ion concentration and thus, may cause a falsely low anion gap value. It is present in some sedative drugs, pyridostigmine bromide, and some herbal medications [49, 50, 51]
  2. Lithium overdose – lithium is a commonly prescribed treatment for bipolar disorder. Since lithium is a positively charged ion, it may lower the anion gap value when present in high concentrations in the body [52, 53, 54].

Symptoms and Treatment

A low anion gap may be caused by a number of different conditions. Symptoms will depend on the underlying cause.

Treatment will depend on the underlying cause as well. It is worthwhile to repeat the electrolyte blood test and recalculate the anion gap value to ensure that the low anion gap value is not an outcome of a laboratory error in measurement.

About the Author

Mathew Eng

Mathew Eng

PharmD
Mathew received his PharmD from the University of Hawaii and an undergraduate degree in Biology from the University of Washington.
Mathew is a licensed pharmacist with clinical experience in oncology, infectious disease, and diabetes management. He has a passion for personalized patient care and believes that education is essential to living a healthy life. His goal is to motivate individuals to find ways to manage their chronic conditions.

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