Intravenous Ferric Carboxymaltose-Induced Hypophosphatemia in a Patient with Systemic Lupus Erythematosus: Case Report

Abstract

Anemia is the most frequently observed hematological alteration in patients with systemic lupus erythematosus. Parenteral iron infusion is a highly effective treatment for the commonly encountered condition of iron deficiency. We report a case of an iron-deficient patient who developed severe symptoms due to hypophosphatemia following the administration of intravenous ferric carboxymaltose. These symptoms included feelings of dizziness and muscle cramping. The necessity to inform doctors and patients about this potential consequence has intensified. With this case report, we hope to raise awareness of the start of screening for this complication in the United Arab Emirates. Patients should also notify the doctor for follow-up if their fatigue worsens or if they develop any new musculoskeletal problems.

Keywords

ferric carboxymaltose - IDA - iron-induced hypophosphatemia - hypophosphatemia - SLE

Introduction

In contrast to anemia of chronic disease and autoimmune hemolytic anemia, iron deficiency is more prevalent. Intravenous iron infusions are frequently used to treat iron deficiency anemia (IDA), particularly in individuals who are unable to tolerate oral iron supplements due to gastrointestinal adverse effects. Intravenous ferric carboxymaltose (FCM) is a colloidal iron hydroxide complex commonly used in the clinical setting, allowing the administration of 750 to 1000 mg of elemental iron per infusion over a 15-minute infusion. Hypophosphatemia occurs when plasma phosphate levels are less than 2.0 mg/dL. The proposed mechanism in FCM-treated patients is an acute increase in plasma levels of intact fibroblast growth factor-23 (FGF-23) leading to increased urinary phosphate excretion. FGF-23 secretion is also associated with calcitriol deficiency which in turn leads to reduced gastrointestinal calcium and phosphate absorption, and increased parathyroid hormone secretion, further augmenting urinary phosphate losses.[1] [2] [3]

We report a case of a patient diagnosed with systemic lupus erythematosus (SLE) and iron deficiency anemia (IDA) who received intravenous ferric carboxymaltose (FCM). Ten days later, the patient developed symptomatic hypophosphatemia, which was successfully managed with oral phosphate supplements.

Case Presentation

A 47-year-old Emirati lady who is a known case of SLE (2014), cutaneous lupus (biopsy proven in 2017), alopecia areata, and hypothyroidism presented to the rheumatology clinic for a follow-up visit. Active medications were hydroxychloroquine 200 mg daily, levothyroxine, and oral iron supplements. Her IDA was secondary to uterine fibroids associated with menorrhagia. She had diffuse hair thinning, recurrent headaches, and muscle aches as a result of her IDA. Despite these symptoms, she was unable to comply with oral iron pills due to chronic constipation. Plasma iron profile was indicative of IDA with a ferritin level 12 mcg/L (reference range: 18–180 mcg/L) and iron level of 8.5 micromol/L (reference range: 5.8–34.5 micromol/L). She received intravenous FCM 750 mg in 0.9% NaCl 250 mL intravenously over 15 minutes which was well tolerated.

Ten days later, the patient contacted the rheumatology clinic, reporting nausea, lightheadedness, and muscle cramps. The patient was instructed to visit the emergency department due to concerns about a possible lupus flare. During the evaluation, her serum phosphate level was found to be critically low at 0.2 mmol/L (reference range: 0.81–1.45 mmol/L), with elevated parathyroid hormone levels of 7.7 pmol/L (reference range: 1.6–6.9 pmol/L). Serum creatinine, calcium, and magnesium levels were within normal limits. She was diagnosed with severe hypophosphatemia and was commenced on effervescent phosphorus 500 mg supplements twice daily for 1 week followed by once daily for 1 month. There was a significant clinical improvement, as well as an improvement in serum phosphorus levels after 4 weeks (0.77 mmol/L; [Table 1]). After 3 months of receiving the intravenous iron infusion, the serum phosphorus levels returned to normal (0.85 mmol/L).

Table 1 Plasma levels of phosphorus, ferritin, and iron were assessed before and after intravenous iron infusion from September to December 2020

	Reference range	September 2020	November 2020	December 2020
Phosphorus	0.81–1.45 mmol/L	0.89	0.20 (LL)	0.77 (L)
Ferritin	18–180 µg/L	12 (L)	800 (H)	339 (H)
Iron	5.8–34.5 µmol/L	11.4	19.8	14.6

Abbreviations: H, high; L, low; LL, very low.

Discussion

Depending on the severity of iron deficiency anemia (IDA), multiple infusions may be necessary, with ferric carboxymaltose (FCM) infusions typically given at 1-week intervals. FCM administration has been associated with hypophosphatemia in up to 70% of patients with peak occurrence at 2 to 3 weeks posttreatment.[1] In two randomized open-label studies of 245 patients with IDA,[2] hypophosphatemia was seen over 35 days in 74% of IDA patients receiving two doses of FCM 750 mg 1 week apart, and 11% of patients experienced severe hypophosphatemia (plasma phosphate < 1.0 mg/dL). In contrast, only 8% of patients treated with a single dose of ferric derisomaltose 1,000 mg developed hypophosphatemia and none had severe hypophosphatemia.[2]

In a randomized double-blind controlled trial of almost 2,000 adults with IDA, treatment with two doses of FCM 750 mg 1 week apart was associated with hypophosphatemia of plasma phosphate < 2.0 mg/dL in 51% of patients and < 1.3 mg/dL in 10% of patients. Approximately 30% of patients had hypophosphatemia over the 5-week duration of the study. In contrast, the respective numbers of hypophosphatemia in ferumoxytol-treated patients were less than 1 and 0%.[3] While the majority of patients tend to have transient and asymptomatic hypophosphatemia, symptomatic and prolonged hypophosphatemia may occur after repeated FCM infusions especially in patients with low plasma phosphate at baseline and in patients at risk for hypophosphatemia due to preexisting medical conditions[4] [5] [6] ([Table 2]). It is advisable to monitor plasma phosphate levels and address phosphate deficiency in these patients, especially when repeated FCM infusions are scheduled.

Table 2 Conditions associated with hypophosphatemia

Mechanism of hypophosphatemia	Medical conditions
Shift into cells	Increased insulin secretion Increased catecholamine secretion Refeeding Acute respiratory alkalosis Hungry bone syndrome (after parathyroid surgery)
Decreased intake/intestinal absorption of phosphate	Inadequate dietary intake Inhibition of phosphate absorption (e.g., phosphate binders, antacids) Chronic diarrhea Vitamin D deficiency
Renal losses	Hyperparathyroidism Vitamin D deficiency Diabetes Alcoholism Hereditary hypophosphatemic rickets Oncogenic osteomalacia Fanconi syndrome Medications, e.g., chemotherapy agents, acetazolamide

Note: Adapted from Felsenfeld and Levine. [7]

Conclusion

This case underscores the critical need for thorough education of both infusion patients and clinicians regarding the administration of FCM for IDA treatment. It is crucial to discuss and be aware of the potential side effects that may occur soon after or later following the infusion. By understanding these risks and promptly addressing any exacerbating factors that could contribute to complications, healthcare providers can effectively manage and minimize adverse outcomes associated with FCM therapy.

Conflict of Interest

None declared.

Authors' Contributions

All authors contributed equally to the writing, editing, and review of the case report.

Compliance with Ethical Principles

None.

Patient Consent

Written informed consent has been obtained from the patient for publication of the submitted article.

• References

• 1 Glaspy JA, Wolf M, Strauss WE. Intravenous iron-induced hypophosphatemia: an emerging syndrome. Adv Ther 2021; 38 (07) 3531-3549
• 2 Wolf M, Rubin J, Achebe M. et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. JAMA 2020; 323 (05) 432-443
• 3 Wolf M, Chertow GM, Macdougall IC, Kaper R, Krop J, Strauss W. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight 2018; 3 (23) e124486
• 4 Blazevic A, Hunze J, Boots JM. Severe hypophosphataemia after intravenous iron administration. Neth J Med 2014; 72 (01) 49-53
• 5 Fierz YC, Kenmeni R, Gonthier A, Lier F, Pralong F, Coti Bertrand P. Severe and prolonged hypophosphatemia after intravenous iron administration in a malnourished patient. Eur J Clin Nutr 2014; 68 (04) 531-533
• 6 Anand G, Schmid C. Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep 2017; 2017: bcr2016219160
• 7 Felsenfeld AJ, Levine BS. Approach to treatment of hypophosphatemia. Am J Kidney Dis 2012; 60 (04) 655-661

Publication History

Article published online:
06 August 2024