From the Guidelines
Acute iron toxicity results in high anion gap metabolic acidosis primarily due to the toxic effects of iron on cellular metabolism, leading to increased lactic acid production, impaired lactate clearance, and accumulation of other organic acids. The mechanisms underlying this process involve the direct damage of mitochondria by free iron ions, disrupting cellular respiration and causing a shift to anaerobic metabolism, which increases lactic acid production 1. Iron also damages the liver and other organs, impairing lactate clearance and further contributing to lactic acidosis. Some key points to consider in the context of high anion gap metabolic acidosis include:
- The presence of lactic acidosis, which can be suggested by clinical history and measurement of blood lactate levels
- Ingestion of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde, which can also cause high-anion gap metabolic acidosis
- Chronic renal failure, which is more typically associated with hyperchloremic acidosis, but can also present with high-anion gap metabolic acidosis in certain cases
- The importance of clinical history in distinguishing between different causes of high-anion gap metabolic acidosis, including previous drug intoxications or metformin use The corrosive effects of iron on the gastrointestinal tract can cause hemorrhagic gastroenteritis with fluid losses, contributing to hypoperfusion and further accumulation of lactic acid. Iron toxicity also interferes with electron transport chain function, reducing ATP production and promoting metabolic acidosis. These combined mechanisms result in significant lactate and other organic acid accumulation, creating the characteristic high anion gap metabolic acidosis seen in acute iron poisoning, as suggested by the presence of anion gap >10 in certain metabolic disorders 1.
From the Research
Causes of High Anion Gap Metabolic Acidosis
- High anion gap metabolic acidosis can occur due to the accumulation of endogenous acids that consume bicarbonate, such as lactic acidosis, ketoacidosis, and renal failure 2
- Intoxication with certain substances, including ethylene glycol, methanol, salicylate, and less commonly pyroglutamic acid (5-oxoproline), can also cause high anion gap metabolic acidosis 2, 3
- Other causes of high anion gap metabolic acidosis include toxin/drug-induced acidosis, such as methanol, ethylene glycol, and salicylates 3
Relationship Between Iron Toxicity and High Anion Gap Metabolic Acidosis
- There is no direct evidence in the provided studies that links acute iron toxicity to high anion gap metabolic acidosis
- However, it is known that high anion gap metabolic acidosis can occur in critically ill patients, and iron toxicity can lead to severe illness and potentially metabolic acidosis 4, 5
Treatment and Diagnosis of High Anion Gap Metabolic Acidosis
- The treatment of high anion gap metabolic acidosis depends on the underlying cause, and cessation of acid production via improvement of tissue oxygenation is often the most effective approach 2
- Diagnosis of high anion gap metabolic acidosis can be challenging, and consideration of the clinical presentation, laboratory results, and potential causes is necessary 3, 6