From the Guidelines
The anion gap is elevated due to accumulation of unmeasured anions in the blood, primarily caused by metabolic acidosis conditions, with the main causes including Methanol, Uremia, Diabetic ketoacidosis, Propylene glycol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, and Salicylates, as supported by the most recent study 1.
Causes of Increased Anion Gap
The causes of an increased anion gap can be remembered using the mnemonic MUDPILES:
- Methanol poisoning, which produces toxic metabolites like formic acid and oxalic acid 1
- Uremia (kidney failure), leading to retention of phosphates, sulfates, and organic acids 1
- Diabetic ketoacidosis, resulting in accumulation of ketone bodies (acetoacetate and beta-hydroxybutyrate) 1
- Propylene glycol, Isoniazid/Iron, and other medications or substances that can cause metabolic acidosis 1
- Lactic acidosis, occurring with tissue hypoxia, sepsis, or liver failure 1
- Ethylene glycol poisoning, which produces toxic metabolites like glycolate and oxalate 1
- Salicylate overdose, causing both respiratory alkalosis and metabolic acidosis 1 Other causes include alcoholic ketoacidosis, starvation ketoacidosis, and certain medications like metformin 1.
Anion Gap Calculation
The anion gap represents the difference between measured cations (primarily sodium) and measured anions (chloride and bicarbonate), with normal values typically between 8-12 mEq/L 1. When unmeasured anions increase, the gap widens, reflecting the body's attempt to maintain electroneutrality in the presence of these additional negative charges.
Clinical Implications
The anion gap is a critical parameter in diagnosing and managing metabolic acidosis, and its elevation can indicate serious underlying conditions, such as poisoning or kidney failure 1. Prompt recognition and treatment of the underlying cause are essential to prevent morbidity and mortality.
Key Findings
A recent systematic review and recommendations from the EXTRIP workgroup 1 highlight the importance of considering the anion gap in the diagnosis and management of ethylene glycol poisoning, and provide guidance on the use of extracorporeal treatments in this setting.
Recommendations
In patients with a suspected increased anion gap, it is essential to promptly investigate and address the underlying cause, and to consider the use of extracorporeal treatments, such as hemodialysis, in severe cases, as recommended by the EXTRIP workgroup 1.
From the Research
Causes of Increased Anion Gap
The causes of an increased anion gap can be divided into several categories, including:
- Lactate accumulation, which can be caused by decreased oxygen delivery or defective oxygen utilization 2
- Ketoacid production, which can be caused by diabetes, alcohol, or starvation 2, 3
- Toxin or drug ingestion, such as methanol, ethylene glycol, or salicylates 2, 4, 5
- Uremia, which can cause a mild acidosis secondary to decreased ammonia secretion and an anion gap caused by the retention of unmeasured anions 2
- Other causes, such as 5-oxoproline acidosis or starvation ketosis 5, 6
Specific Causes
Some specific causes of increased anion gap include:
- Diabetic ketoacidosis, which is usually secondary to diabetes 2, 3
- Alcoholic ketoacidosis, which is usually secondary to alcohol consumption 2, 3
- Lactation ketoacidosis, which can occur in young and otherwise healthy lactating women who do not meet the high energy requirements of breastfeeding with adequate carbohydrate intake 3
- Toxic alcohol ingestion, such as methanol or ethylene glycol, which can cause severe acidoses and elevated osmolar gaps 2, 4, 5
- Salicylate toxicity, which can cause a mild metabolic acidosis and a respiratory alkalosis 2