From the Guidelines
An elevated anion gap is primarily caused by conditions such as methanol, uremia, diabetic ketoacidosis, lactic acidosis, ethylene glycol, and salicylates, which can be remembered using the mnemonic MUDPILES. The anion gap is calculated as the difference between measured cations (primarily sodium) and measured anions (chloride and bicarbonate) in the blood, and it exceeds the normal range of 8-12 mEq/L in these conditions 1.
Causes of Elevated Anion Gap
- Methanol poisoning
- Uremia (kidney failure)
- Diabetic ketoacidosis
- Lactic acidosis
- Ethylene glycol poisoning
- Salicylate toxicity
- Other causes such as propylene glycol, isoniazid/iron, and paraldehyde ingestion
Diagnosis and Management
The diagnosis of an elevated anion gap involves calculating the anion gap and identifying the underlying cause. Management includes identifying and treating the underlying cause while supporting vital functions. For toxic ingestions like methanol or ethylene glycol, fomepizole (15 mg/kg loading dose, then 10 mg/kg every 12 hours) or ethanol infusion may be needed to block toxic metabolite formation 1. Sodium bicarbonate (1-2 mEq/kg IV) may be administered for severe acidosis (pH < 7.1) to temporarily stabilize the patient. Hemodialysis is often required for severe cases of toxic alcohol ingestion, uremia, or refractory acidosis.
Clinical Indications for Extracorporeal Treatment
In patients presenting with ethylene glycol poisoning, extracorporeal treatment (ECTR) is recommended if the anion gap is > 27 mmol/L (strong recommendation, very low-quality evidence) and suggested if the anion gap is 23-27 mmol/L (weak recommendation, very low-quality evidence) 1. The anion gap is a useful surrogate marker for glycolate and correlates linearly with glycolate and is associated with clinical outcomes 1.
Key Considerations
Prompt identification and treatment of the underlying cause is essential to prevent serious complications. The elevated anion gap represents accumulation of acids that donate hydrogen ions, causing metabolic acidosis, which can lead to impaired cardiac function, altered mental status, and respiratory compensation through increased breathing rate. Other clinical manifestations such as respiratory failure and pulmonary edema would occur after already stated indications for ECTR 1.
From the Research
Causes of Elevated Anion Gap
The causes of an elevated Anion Gap (AG) can be attributed to various factors, including:
- Metabolic acidosis, which can be caused by the presence of organic anions such as beta-hydroxybutyrate, acetoacetate, and lactate 2
- Lactic acidosis, ketoacidosis, and impaired renal function, which are frequent causes of high anion gap metabolic acidosis (HAGMA) 3, 4
- Severe increases in concentration of phosphorus, which can cause hyperphosphatemic acidosis 4
- Diabetic ketoacidosis, which can lead to an increased anion-gap caused by the presence of organic anions 2, 4
- Renal failure, which is a common cause of high AG acidosis 4
- Sepsis, hyperglycaemia, prior gastric bypass surgery, decreased renal perfusion, and paracetamol intake, which can contribute to the development of HAGMA 3
- Toxic alcohols, such as methanol, ethylene glycol, diethylene glycol, propylene glycol, or isopropanol, which can cause an increase in serum osmolality and serum osmolal gap with or without high-anion-gap metabolic acidosis 5
- Diabetic or alcoholic ketoacidosis, acute kidney injury, chronic kidney disease, and lactic acidosis, which can cause high-anion-gap metabolic acidosis associated with an increased serum osmolal gap 5
Common Causes of Increased Anion Gap
The most common causes of increased anion gap include:
- Hypertensive disease
- Chronic renal failure
- Malignant neoplasms
- Diabetes mellitus
- Heart diseases 6