What Is the Anion Gap?
The anion gap is a value that is calculated from the electrolyte blood test that represents the difference between positively charged ions (cations) and negatively charged ions (anions) in blood.
The value of the anion gap is calculated using the concentrations of the major anions, chloride and bicarbonate, and the major cations, sodium, and potassium in the blood.
However, the concentration of potassium in the blood remains low and fairly constant compared to sodium, chloride, and bicarbonate. Therefore, it is common practice to remove the potassium concentration from the calculation .
The total positive charges from the cations must be balanced out with the total negative charges from the anions in the blood to maintain overall neutrality. Since the electrolyte blood test does not measure all ions, in essence, the anion gap tells us about the unmeasured anions and cations in the blood. There are normally more unmeasured anions than cations, hence there is usually an anion gap .
The anion gap value is used clinically to determine and evaluate acid-base disorders if the value is too high or too low.
Although the term anion gap usually refers to the concentrations of cations and anions in the blood, it could also refer to their concentrations in the urine, which is a clinically useful measure .
The value of the anion gap is reported in milliequivalents per liter (mEq/L).
However, the average anion gap value and the range of normal anion gap values differ between laboratories and thus, it is essential to interpret the anion gap value according to the reference range used by the particular laboratory .
Deviations in the Anion Gap
The value of the anion gap is defined as low, normal, or high. Any deviations from the normal range of values are due to laboratory error in measuring ion concentrations, or change in the concentration of cations and anions in the patient’s blood.
High Anion Gap
If a high anion gap value is reported, it means that the patient’s blood is more acidic than normal and has more unmeasured anions.
High Anion Gap Causes
- Metabolic acidosis – a clinical condition where the body has an excess of acid, specifically due to overproduction of acid by the body (lactic acidosis) or inability of the kidneys to excrete excess acid [10, 11, 12]
- 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 [13, 14]
- Kidney failure – kidneys remove acid from the body at a slower rate, and also the rate at which base is reabsorbed is decreased [15, 16]
- Uremia – the presence of urea in the blood associated with kidney failure
- Thiamine (vitamin B1) deficiency [17, 18, 19]
- Hyperphosphatemia – High levels of phosphate ions in the blood [20, 2]
- Starvation 
- Carbon monoxide [9, 22]
- Cyanide [23, 24]
- Ethylene glycol (antifreeze) poisoning [25, 26, 27]
- Propylene glycol 
- Isopropyl alcohol 
- Toluene [28, 29]
- Methanol 
- Paraldehyde 
- Metformin 
- 5-Oxoproline/pyroglutamic acid – a byproduct of Tylenol (acetaminophen, paracetamol) [31, 32, 33, 34]
- Overdose with salicylates such as aspirin 
- Gamma-hydroxybutyrate (GHB) 
- Ibuprofen 
High Anion Gap Symptoms
The symptoms may include:
- Rapid and shallow breathing
- Rapid/abnormal heartbeat
- Low blood pressure
- Lack of appetite
High Anion Gap Treatment
The treatment would depend on correctly diagnosing the underlying cause. If the high anion gap is caused by toxin or alcohol poisoning, a period of detoxification under clinical care with the appropriate fluid therapy can be administered .
Low Anion Gap and Causes
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 .
- 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 lowers the anion gap value [42, 43]
- 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 will lead to a decrease in the anion gap value [44, 43, 45]
- Hypercalcemia (high blood calcium) and hypermagnesemia (high blood magnesium) – a significant increase in positively charged ions, like calcium and magnesium in the body, reduce the value of the anion gap 
- Pregnancy 
- Multiple myelomas – cancer of plasma cells, which are a type of white blood cell usually responsible for producing antibodies [48, 49, 50]
- Bromide intoxication – bromide is present in some sedative drugs, pyridostigmine bromide which is used in the treatment of myasthenia gravis, and some herbal medications. Although it is a negatively charged ion, like chloride, abnormal bromide levels in the blood actually reduce the anion gap value, instead of the expected increase. This is because bromide interferes with the calculation of the chloride ion concentration and thus, causes a falsely low anion gap value [51, 52, 53]
- Lithium overdose – lithium is a commonly prescribed treatment for bipolar disorder. Since lithium is a positively charged ion, it can lower the anion gap value when present in high concentrations in the body [54, 55, 56].
- Salicylate poisoning (aspirin) 
Low Anion Gap Symptoms
The symptoms may include:
- Irregular or abnormal heartbeat
- Muscle weakness
- Hypotension (low blood pressure)
- Edema/swelling/buildup of fluid in legs or face
- Lack of appetite
- Difficulty in breathing
- Mental confusion
Low Anion Gap Treatment
The treatment depends on detecting the underlying cause. 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.
In cases of hypoalbuminemia, human serum albumin is administered to compensate for the low levels of circulating albumin in the body; however, the use and effectiveness of this approach remains controversial [58, 59].
Irregular Anion Gap Levels?
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