Understanding how to calculate the anion gap is a daunting task at the medical student level and even for many physicians. This is understandable. The equation can have exceptions, the causes of anion gap abnormalities are a lot, and acid-base disorders are not straightforward. If you find it difficult, don’t feel bad about that. It is totally okay.
Anion gap calculation is the first step in the evaluation of metabolic acidosis. It can help us narrow the list of the possible causes of metabolic acidosis in every case. This is because some conditions can lead to normal anion gap metabolic acidosis, and some others can lead to high anion gap metabolic acidosis.
The blood is neutral. So, the concentration of positive molecules is equal to the concentration of negative molecules. The dissociation of organic acids produces H+ and unmeasured anions; this is when anion gap abnormalities can occur.
The issue here is that there are some other concepts that you need to be aware of when tackling anion gap problems. This is why we are here. If you feel confused or not confident enough, don’t worry; this article will make you master this concept. Ready? Let’s get started.
What is anion gap?
The anion is defined as the difference between measured cations (positively charged cations like sodium Na+) and measured anions (negatively charged anions like HCO3- and Cl-). Here is the anion gap formula:
Serum anion gap = [Na+] – ([Cl-] + [HCO3-]) Where:
- [Na+] is the concentration of sodium in plasma in mEq/L.
- [Cl-] is the concentration of chloride in plasma in mEq/L.
- [HCO3-] is the concentration of bicarbonate in plasma in mEq/L/.
Anion gap normal range: 6–12 mEq/L
A deeper dive
Understanding the equation is great but understanding how we came up with it is very helpful. Let’s go through it a step by step:
If the blood is neutral and all anions equal to cations, then:
Total serum anions = Total serum cations
Therefore: Na + All unmeasured cations = Cl + HCO3 + All unmeasured anions
Rearranging: Na – (Cl + HCO3) = All unmeasured anions – All unmeasured cations = Serum anion gap
By estimating the concentration of measured cations (like Na+) and anions (like Cl- and HCO3-), we can estimate the difference between the unmeasured ones.
High anion gap occurs when there is an increased concentration of organic acids such as ketone bodies, lactate, formic acid, etc., with no compensatory increase in chloride. The dissociation of these organic acids produces H+ and unmeasured anions. The H+ atoms neutralize the HCO3- molecules leading to a decrease in HCO3- concentration.
In normal anion gap metabolic acidosis, the issue is not due to the accumulation of organic acids. The problem here is the loss of bicarbonate. Now you may wonder, isn’t that similar to high anion gap metabolic acidosis? Both lead to a decrease in bicarbonate. While this is true, there is a difference here.
In normal anion gap metabolic acidosis, the loss of bicarbonate is compensated by increased chloride concentration. Most of our cells have (especially in the kidney in the alpha intercalated cell), we have a chloride/bicarbonate transporter. It allows for bicarbonate excretion and reabsorption of chloride (the compensatory increase in chloride). Therefore, we can say that there is a kidney compensation in normal anion gap metabolic acidosis by increased chloride reabsorption.
What are the causes of anion gap abnormalities?
Now you have a good understanding of the concept of the anion gap. Let’s make it clearer by dissecting the different causes of anion gap metabolic acidosis and understanding why they lead to a high anion gap.
Causes of high anion gap metabolic acidosis
High serum anion gap can be caused by either accumulation of endogenous organic acids or exogenous organic acids.
- Lactic acidosis: When there is hypoperfusion to the tissues due to hypotension, cells convert from aerobic energy production to anaerobic energy production, leading to lactic acid production.
- Ketoacidosis: Ketoacidosis occurs in cases of uncontrolled type 1 diabetes. In this case, absolute insulin deficiency makes the body start breaking down adipose tissue to produce fatty acids. Excessive fatty acids stimulate the ketone body synthesis pathway, hence, ketoacidosis.
- Chronic kidney disease (CKD): In CKD, there is damage to the renal nephrons. This leads to inability to excrete organic acids that are produced in the body as a result of metabolic processes.
- Ingestion of exogenous organic acids like methanol, polyethylene glycol, ethylene glycol, salicylates, and iron.
Causes of normal anion gap metabolic acidosis
In addition to the causes of high serum anion gap metabolic acidosis, knowledge of the causes of normal anion gap metabolic acidosis is also essential. Here is a list of the most important ones:
- Diarrhea
- Hyperchloremia due to excessive saline infusion
- Addison disease
- Renal tubular acidosis
Final trick: Some conditions can lead to abnormally low anion gap without metabolic acidosis. This happens in cases of hypoalbuminemia. Hypoalbuminemia → ↓ unmeasured anions → ↓ anion gap.
How to recognize anion gap metabolic acidosis?
The anion gap is the way we can know whether we are dealing with an anion gap metabolic acidosis or not. However, in metabolic acidosis, there are other biochemical changes that occur that you should be aware of. This will help you know whether you are dealing with metabolic acidosis or not before you use the anion gap. Here is a summary of these changes.
| Metabolic acidosis | |
| pH | ↓ |
| PCO2 | ↓ |
| HCO3- | ↓ |
| Mechanism | Production and/or ingestion of H+ or loss of bicarbonate |
How to calculate compensatory changes in high anion metabolic acidosis?
Compensation is the physiologic change that occurs in the body in acid-base disorders to maintain normal body pH. Sometimes, the compensation can be abnormal. This means that you have another concomitant acid-base disorder present in the one you are already dealing with.
The equation used in cases of metabolic acidosis is winter’s formula: Expected PCO2 (mm Hg) = (1.5 × HCO3-) + 8 ± 2
- Measured PCO2 > expected PCO2: respiratory acidosis in addition to metabolic disturbance
- Measured PCO2 < expected PCO2: respiratory alkalosis addition to metabolic disturbance
Discordance between the measured compensatory response and the expected compensatory response means that there is a secondary acid-base disturbance.
How to approach high anion gap metabolic acidosis problems?
Now you have a good understanding of the anion gap and metabolic acidosis. It is time to apply. There are many ways you can solve acid-base problems, but here is our suggested method:
- Evaluate blood pH
- Evaluate PCO2
- Evaluate Bicarbonate (HCO3)
If pH is < 7.35: You have a primary acidosis
- ↓ pH and ↓ HCO3-: metabolic acidosis
- ↓ pH and ↑ PCO2: respiratory acidosis
If metabolic acidosis is present:
- Check if compensation is appropriate using Winter’s formula
- Calculate the anion gap using this equation: Serum anion gap = [Na+] – ([Cl-] + [HCO3-])
- Narrow down your differential diagnosis
Conclusion
Metabolic acidosis is a pathologic process where there is an increase in the concentration of hydrogen ions. In some cases, this increase is accompanied by an elevated anion gap. Therefore, we have two types of metabolic acidosis: Elevated anion gap metabolic acidosis and normal anion gap metabolic acidosis.
Assessment of the anion gap can help identify the cause of acidosis. It can be calculated using this equation: Serum anion gap = [Na+] – ([Cl-] + [HCO3-]). Causes of elevated anion gap metabolic acidosis include Lactic acidosis, ketoacidosis, chronic kidney disease, and ingestion of organic acids like methanol. Causes of normal anion gap metabolic acidosis include diarrhea, hyperchloremia, Addison disease, and renal tubular acidosis.