Hypophosphatemia After Iron Infusions: A Formulation-Specific Complication
Iron infusions cause hypophosphatemia through a formulation-dependent mechanism, with ferric carboxymaltose (FCM) causing severe hypophosphatemia in 47-75% of patients, while alternative formulations like ferric derisomaltose, iron sucrose, and ferumoxytol cause hypophosphatemia in less than 10% of patients. 1
Mechanism and Pathophysiology
The hypophosphatemia occurs through a specific mechanism related to the physicochemical properties of certain iron formulations, particularly FCM. 1
FCM triggers a sharp increase in intact fibroblast growth factor 23 (iFGF23), a phosphaturic hormone that causes renal phosphate wasting through hyperphosphaturic hypophosphatemia. 1, 2
This cascade leads to low 1,25(OH)2 vitamin D, hypocalcemia, and secondary hyperparathyroidism, which has been associated with osteomalacia, fractures, and other bone deformities. 1
The mechanism relates to the molecules complexed to the iron rather than the iron itself. 1
Incidence by Formulation
The risk varies dramatically by formulation:
Clinical Presentation and Timing
Hypophosphatemia occurs within the first 2 weeks after administration and can be severe and prolonged. 1
Symptoms by Severity:
- Mild hypophosphatemia (phosphate <2.5 mg/dL): Often asymptomatic 1
- Moderate hypophosphatemia (<2.5-2.0 mg/dL): Fatigue, proximal muscle weakness, bone pain (symptoms that can mimic iron deficiency anemia itself) 1, 3
- Severe hypophosphatemia (<2.0-1.0 mg/dL): Asthenia, myopathy 1, 3
- Life-threatening (<1.0 mg/dL): Respiratory failure 1, 3
Duration:
- FCM-induced hypophosphatemia can persist for up to 6 months, though the true duration remains unknown. 1
- Most episodes are biochemically moderate (0.32-0.64 mmol/L) and asymptomatic, resolving without intervention. 1
High-Risk Patients Who Should Avoid FCM
The following patients should NOT receive FCM and should be given alternative formulations: 2
- Patients with recurrent or ongoing blood loss requiring repeat infusions 1, 2
- Malabsorptive disorders 1, 2
- Normal or high glomerular filtration rate (GFR) - higher GFR correlates with greater phosphorus excretion 1
- Severe iron deficiency requiring repeat infusions 2
- Low baseline serum phosphate 2, 4, 5
- Elevated parathyroid hormone at baseline 2, 4, 5
- Pre-existing vitamin D deficiency 4, 5
- Malnourished patients 6
Important note: Patients with impaired kidney function have a lower risk of developing hypophosphatemia due to reduced GFR, which limits filtered phosphate and therefore limits urinary excretion. 1
Monitoring Recommendations
Selective monitoring is recommended rather than universal screening. 2
Who to Monitor:
- Patients with clinical symptoms of hypophosphatemia 2
- Patients with risk factors for chronic low phosphate 2
- Those requiring repeat treatment 2
- Anyone receiving a second course within 3 months 2
- Those receiving long-term or multiple high-dose infusions of FCM (per UK Medicines and Healthcare products Regulatory Agency 2020 recommendation) 1
When to Monitor:
- Symptoms lasting more than a few days after infusion should prompt evaluation, as they may indicate hypophosphatemia rather than typical delayed infusion reactions. 1
Management Algorithm
1. Immediate Action - Discontinue FCM:
If hypophosphatemia develops after FCM, immediately discontinue FCM and switch to an alternative formulation (ferric derisomaltose, iron sucrose, or ferumoxytol) for any future iron therapy needs. 2
2. Treatment Based on Severity:
Asymptomatic mild hypophosphatemia:
- Observation only 2
Symptomatic or moderate-to-severe hypophosphatemia:
- Vitamin D supplementation to mitigate secondary hyperparathyroidism 2, 3
- This addresses the downstream metabolic consequences
3. Critical Management Pitfall:
DO NOT use phosphate supplementation for FCM-induced hypophosphatemia. 2, 3
- Phosphate supplementation is refractory and counterproductive in this setting 2
- It raises parathyroid hormone levels, which worsens phosphaturia and ultimately exacerbates the hypophosphatemia 2
- This is the most important management principle to avoid 2, 3
Prevention Strategies
The only effective prevention is choosing an alternative iron formulation for high-risk patients. 2
Prophylactic vitamin D supplementation before FCM does NOT reduce hypophosphatemia risk and is therefore ineffective as a preventive strategy. 2
For patients requiring total dose iron infusion, prefer ferric derisomaltose, low molecular weight iron dextran, or ferumoxytol over FCM, especially in high-risk patients. 1, 2
Clinical Importance and Long-Term Consequences
While most episodes are asymptomatic and self-limited, the clinical importance should not be underestimated:
- Rare but serious association with hypophosphataemic osteomalacia prompted regulatory warnings. 1
- Persistent hypophosphatemia can cause debilitating diseases including myopathy, osteomalacia, and fractures. 7
- Severe cases may require months of management - one case required 16 weeks of phosphorus supplementation despite the known futility of this approach. 8
Practical Recommendations
For new patients requiring IV iron:
- Assess risk factors for hypophosphatemia before selecting formulation 2
- Choose ferric derisomaltose, iron sucrose, or ferumoxytol over FCM for high-risk patients 2
- If FCM must be used, counsel patients about potential delayed symptoms (fatigue, muscle weakness, bone pain) that may develop days to weeks after infusion 1
For patients who develop hypophosphatemia after FCM: