sPeCIAL ARTI CLE severe hypophosphataemia after intravenous iron administration A. Blazevic, J. Hunze, J.M.M. Boots* Department of Internal Medicine and Nephrology, Maasstad Hospital, the Netherlands, *corresponding author: tel.: +31 (0)10-2911833, e-mail: [email protected] a B s t r a C t Currently, in many centres, intravenous administration of iron is becoming increasingly popular because of What was known on this topic? higher efficacy and decreased side effects, mainly gastro- Intravenous iron supplements are highly effective in intestinal, compared with oral iron therapy. Studies of treating iron deficiency anaemia. Besides a transient, intravenous ferric carboxymaltose administration in the asymptomatic hypophosphataemia, there are few postpartum setting and in patients with non-dialysis- adverse effects of these intravenous preparations dependent chronic kidney disease revealed a decrease in compared with oral iron supplements. serum phosphate levels that was generally asymptomatic and transient. What does this add? Here, we report four cases of severe and symptomatic This article emphasises the importance of hypophosphataemia after intravenous iron administration. determining pre-existent disorders in phosphate All patients received this as therapy for iron deficiency homeostasis and continuous monitoring of anaemia due to heavy menstrual bleeding. In most cases, a serum phosphate levels after intravenous ferric pre-existent disorder in the phosphate homeostasis existed, carboxymaltose administration as the provoked such as a secondary (cases 3 and 4) or tertiary hyperpara- hypophosphataemia can be severe, prolonged and thyroidism (case 1). However, in the second case there potentially life-threatening. were no risk factors for a dysregulation of the phosphate homeostasis. Based on these findings, we conclude that severe and symptomatic hypophosphatemia can occur as a side effect of the deficiency, symptoms can be relieved by iron of intravenous iron administration and can persist for supplements, which can be either orally or intravenously months after administration. Especially patients with administered. Oral iron supplementation is often poorly low phosphate levels prior to therapy due to concomitant tolerated due to a high rate of gastrointestinal side effects, disorders in phosphate homeostasis (e.g. hyperparath- which leads to dose reduction or non-adherence to yroidism, vitamin D deficiency) are at risk. treatment.1-3 Recently, intravenous iron supplements were developed that allow administration of large amounts of iron by one simple infusion. These iron supplements are K e YW o r d s more effective in achieving haemoglobin level increases and have less drug-related adverse effects.4 Adverse effects, ferric compounds, hypophosphaetemia, However, some studies of intravenous ferric intravenous iron administration/supplementation carboxymaltose administration reported a decrease in serum phosphate levels. The induced hypophos- phataemia was generally asymptomatic and transient.5-8 INTRODUCTION In non-dialysis dependent chronic kidney patients, serum phosphate levels decreased in 3.8% of the patients Iron deficiency is one of the most common causes of receiving intravenous iron supplementation and did anaemia and is frequently encountered in patients with not reach a clinically important level.8 However, in this chronic kidney disease. Besides investigating the cause paper it is demonstrated that a severe and potentially © Van Zuiden Communications B.V. All rights reserved. january 2014, vol. 72, no 1 49 life-threatening hypophosphataemia can be provoked by tingling in both hands. Again, profound hypophosphataemia intravenous administration of iron supplements. (P 0.17 mmol/l) and continued inappropriate phosphate fractional excretion of 33.3% were found. Moreover, plasma levels of fibroblast growth factor 23 (FGF23) were elevated CASE REP ORT at 202 RU/ml (normal <125 RU/ml). The patient was re-admitted to the hospital for short-term intravenous Case 1 phosphate repletion, sodium glycerophosphate 20 ml twice A 45-year-old female of Asian origin received an unrelated daily, and within one day the serum phosphate level rose living donor kidney allograft in May 2008 for end-stage to 0.55 mmol/l. As the symptomatic hypophosphataemia renal failure due to diabetes mellitus type I. The resolved, treatment was continued with oral phosphate postoperative course was complicated by a delayed graft repletion (1 ml = 67 mg P), 20 ml three times a day. function. Four years later, she has a good transplant The patient was discharged with stable serum phosphate function (estimated glomerular filtration rate (eGFR) levels and within six weeks oral phosphate repletion was of 60 ml/min/1.73 m2) on a dual immunosuppressive ceased. On subsequent controls, the serum phosphate levels regimen of tacrolimus (trough levels 5.5-10.5 mg/l) and remained stable within the normal range. mycophenolate mofetil (500 mg twice daily) and adequate glycaemic control with a basal-bolus insulin regimen (HbA1c Case 2 55 mmol/mmol). To treat the vitamin D deficiency, she A 42-year-old Caucasian female with known systemic received colecalciferol 400 IE, which resulted in sufficient lupus erythematosus since 1998 developed iron deficiency 25(OH)vitamin D levels (78 nmol/l, normal 50-150 nmol/l). anaemia (Hb 7.4 mmol/l, serum iron 5 mmol/l, serum However, the pre-transplant secondary hyperparathyroidism transferrin 68 mmolFe/l, serum ferritin 15 mg/l) due to did not resolve completely over time with serum parathyroid heavy menstrual bleeding, while on anticoagulant therapy hormone (PTH) levels remaining around 12.0 pmol/l consisting of calcium carbasalate and acenocoumarol for (normal 1.0-8.0 pmol/l) and near-normal serum phosphate antiphospholipid syndrome and repeated cerebrovascular (P) levels between 1.37 and 0.70 mmol/l (normal 0.80-1.40 accidents. On ultrasound, a persistent ovarian follicle and mmol/l). Furthermore, mild systolic hypertension remained endometrial hyperplasia were diagnosed. Initially, oral iron which was treated with a combination of amlodipine 10 mg supplements were prescribed to treat the iron deficiency once daily and irbesartan 150 mg twice daily. anaemia. However, the patient developed profound side Due to a benign endometrial polyp, the patient suffered from effects that led to discontinuation of oral treatment and heavy menstrual bleeding which led to the development subsequent administration of three infusions of 1000 mg of iron deficiency anaemia. Laboratory findings were: Hb ferric carboxymaltose with a six-week interval. Three days 6.0 mmol/l (normal 7.5-10.0 mmol/l), serum iron 4 mmol/l after the last infusion, the patient was diagnosed with (normal 10-25 mmol/l), serum transferrin 84 mmolFe/l deep hypophosphataemia (P 0.32 mmol/l) and inadequate (normal 35-65 mmolFe/l), serum iron saturation 5% (normal fractional excretion of phosphate (12.4%). Symptoms 20-45%), serum ferritin 5 mg/l (normal 8-252 mg/l). As attributable to hypophosphataemia were not present. oral iron supplements caused significant gastrointestinal Additional laboratory findings revealed normal values of side effects, she received a single infusion of 1000 mg serum parathyroid hormone (4.92 pmol/l) and 25(OH) ferric carboxymaltose (Ferinject®, Vifor Nederland BV, vitamin D (97 nmol/l) and resolved anaemia (Hb 8.6 the Netherlands). Eight days after initiating therapy, the mmol/l). The patient was advised to increase her dietary patient developed generalised weakness and nausea. A phosphate intake by increasing the intake of protein- deep hypophosphataemia was diagnosed (P 0.25 mmol/l) enriched meals and the phosphate levels were restored and inappropriate phosphaturia. The fractional excretion of to normal levels within four weeks. However, due to phosphate was 59%; with hypophosphataemia it should be continued heavy menstrual bleeding, the iron deficiency below 5%. There were no cardiopulmonary or haematological anaemia recurred (Hb 4.5 mmol/l). Upon this, the patient manifestations. The patient was admitted to hospital and was treated with a single infusion of 100 mg iron sucrose received 40 ml sodium glycerophosphate intravenously (1 ml (Venofer®, Vifor Nederland BV, the Netherlands). After = 1 mmol P, Glycophos®, Fresenius Kabi Nederland BV, the eight days, the patient once more developed a deep, Netherlands). Forty-eight hours later, the serum phosphate although again asymptomatic, hypophosphataemia (0.33 level rose to 0.43 mmol/l and her clinical condition improved mmol/l), which was resolved in a similar way by increasing rapidly. She was discharged with instructions to continue the dietary intake of phosphate. oral phosphate supplementation by sodium glycerophosphate 20 ml three times a day. Seventy-two hours after discharge, Case 3 the patient returned to the emergency department presenting A 33-year-old Hindu female underwent a laparoscopic with vertigo, nausea, diarrhoea, general weakness and Roux-Y gastric bypass in 2010 on account of obesity Blazevic et al. Severe hypophosphataemia after intravenous iron administration. january 2014, vol. 72, no 1 50 (body mass index 44 kg/m2). The postoperative course She presented with increased menstrual bleeding due to a was complicated by pneumonia, which was treated with small intramural fibroid, fatigue, headache and palpitations. amoxicillin-clavulate and ciprofloxacin, and one year later Additionally, she had hypothyroidism (TSH 22.4 mU/l, she underwent a laparoscopic cholecystectomy