What side effects can occur from acute or chronic excessive iron supplementation?

Side Effects of Excessive Iron Intake

Taking too much iron causes gastrointestinal symptoms with oral supplementation and can lead to serious organ damage, cardiovascular events, infections, and death with chronic high-dose intravenous iron or acute toxic overdose.

Oral Iron Side Effects (Most Common)

Gastrointestinal Effects

• Nausea occurs in 29-63% of patients taking oral iron supplements, compared to 28-65% in control groups, with oral ferrous sulfate causing significantly more GI side effects than placebo (OR 2.32) or parenteral iron (OR 3.05) 1, 2
• Constipation affects 4-29% of iron-supplemented patients versus 1.6-28% in controls, making it one of the most common reasons for discontinuation 1, 2
• Diarrhea and abdominal discomfort are also frequent complaints, though most GI side effects are transient and not serious 2
• Discontinuation rates due to adverse events range from 0-40% in real-world settings, despite being lower (0-24%) in clinical trials 1

Key Pitfall to Avoid

The absence of a dose-effect relationship over the range of 50-400 mg elemental iron per day means that taking higher doses does not improve absorption but significantly increases side effects 1. Starting with 50-100 mg once daily or alternate-day dosing minimizes symptoms while maintaining efficacy 2.

Intravenous Iron Side Effects

Acute Reactions

• Hypersensitivity-type and infusion reactions occur in approximately 0.5% of patients, which is more common than with oral iron but still uncommon with modern preparations 1
• Serious adverse reactions including anaphylaxis-like reactions with dyspnea, hypotension, chest pain, and angioedema occur in fewer than 1% of administrations 1
• Loin pain, intense upper gastric pain, flushing, and hypotension have been reported, particularly with iron gluconate 1
• Fatalities are rare with iron dextran and have not been reported with iron gluconate 1

Metabolic Complications

• Hypophosphataemia occurs in 58% of patients receiving ferric carboxymaltose, compared to only 4% with iron derisomaltose and 1% with iron sucrose 1
• Most episodes are biochemically moderate (serum phosphate 0.32-0.64 mmol/L) and asymptomatic, but rare cases of hypophosphataemic osteomalacia have been reported 1
• The UK Medicines and Healthcare products Regulatory Agency recommends monitoring serum phosphate in patients with risk factors or those receiving long-term/multiple high-dose infusions of ferric carboxymaltose 1

Chronic Iron Overload (High-Dose IV Iron)

Cardiovascular and Mortality Risks

• Monthly IV iron doses of 300-399 mg increase mortality risk by 13% (HR: 1.13), and doses ≥400 mg/month increase it by 18% (HR: 1.18) in hemodialysis patients followed for 1.7 years 1
• High-dose IV iron (>200 mg/month) dramatically increases acute cardiocerebrovascular disease risk (HR: 6.02) and hospitalization (HR: 2.77) 1, 3
• Cumulative doses of 840-1600 mg over 6 months increase mortality 3.1-fold and cardiovascular events 3.5-fold compared to those receiving <820 mg/6 months 1

Infection Risk

• High-dose IV iron (>200 mg/month) increases infection risk 5.2-fold (HR: 5.22), while even low-dose IV iron (≤200 mg/month) increases infection risk 1.78-fold 1
• Iron maintenance therapy at 200 mg/month is not associated with increased short-term infection risk, contrasting sharply with bolus monthly doses of 700 mg 1, 3
• Caution is advised with parenteral iron in acute and chronic infection contexts, and it should be withheld in ongoing bacteremia 1

Organ Damage from Chronic Overload

• High ferritin levels (consistently >100 µg/L) are associated with increased risk of acute cardiocerebrovascular disease (HR: 2.22), infections (HR: 1.76), and death (HR: 2.28) 1, 3
• Iron overload disrupts cellular homeostasis through oxidative stress and inflammation, disrupting iron-regulating hormones like hepcidin and FGF-23 1, 3
• Most iron accumulation in dialysis patients occurs in reticuloendothelial cells with minimal parenchymal cell damage, unlike primary hemochromatosis 1
• Diabetic dialysis patients (40% of all dialysis patients) face higher risk, as even slight iron store increases worsen macrovascular and microvascular complications 1, 3

Acute Iron Toxicity (Overdose)

Life-Threatening Complications

• Acute iron ingestions >60 mg/kg are potentially serious and can cause multi-organ failure and death 4, 5, 6
• Severe acute iron overdose causes hemorrhagic shock, coagulopathy, necrotizing gastroenteritis, and cardiovascular collapse 4, 6
• Acute hepatic necrosis with aminotransferases >4,000 U/L can occur within 48 hours, even with serum iron levels as low as 340 µg/dL, though levels >1,700 µg/dL are typically associated with hepatotoxicity 4, 7
• Central nervous system effects include coma, and metabolic effects include severe hyperglycemia and metabolic acidosis 6

Clinical Course

The clinical presentation of severe acute iron overdose is fairly non-specific, and the length and type of treatment may alter the clinical course 4. Peak serum iron levels help differentiate acute toxicity from chronic overload states 4. Gastric iron encrustations visible at endoscopy or autopsy are specific for acute ingestion when present 4.

Emergency Management

Treatment requires immediate supportive care, GI decontamination with lavage (potentially with deferoxamine and sodium bicarbonate solution), whole-bowel irrigation with polyethylene glycol-electrolyte solution, and chelation therapy with deferoxamine by continuous IV infusion 6. Iron poisoning may have an additive toxic effect in drug-induced acute liver failure and worsen outcomes 5.

High-Risk Populations

• Young dialysis patients with repeated graft failure and long cumulative dialysis vintage face particular risk for long-term iron overload complications 1, 3
• Patients with pre-existing liver diseases (viral hepatitis B or C, non-alcoholic steatohepatitis) may experience worsening with iron accumulation 3
• Patients with multiple drug allergies have increased risk of acute iron dextran reactions 1