I Had an Iron Infusion and Felt Better the Day After but Teo Dats Later I Feel Tired Again

Endocrinol Diabetes Metab Case Rep. 2019; 2019: 19-0065.

Symptomatic hypophosphataemia after intravenous iron therapy: an underrated adverse reaction

Eseoghene Ifie

ⁱNuffield Department of Clinical Neurosciences, John Radcliffe Infirmary, Oxford, Britain

Samson O Oyibo

²Department of Endocrinology, Peterborough City Hospital, Peterborough, Great britain

Hareesh Joshi

²Department of Endocrinology, Peterborough City Hospital, Peterborough, United kingdom

Olugbenro O Akintade

³Department of Elderly Intendance Medicine, Peterborough City Hospital, Peterborough, UK

Received 2019 Jun 26; Accepted 2019 Jul 8.

Summary

Fe (ferric carboxymaltose) infusion therapy is used to treat severe iron deficiency which is not responding to the first-line oral atomic number 26 therapy. However, it can also cause severe renal wasting of phosphate resulting in severe hypophosphataemia in some patients. Despite the growing number of case reports, this side effect is not well known to healthcare professionals. The product labelling information sheet does mention that hypophosphataemia can exist a side effect, but also says that this side result is unremarkably transient and asymptomatic. We report a challenging case of a patient who developed astringent, symptomatic and prolonged hypophosphataemia after an intravenous iron infusion for severe iron deficiency.

Learning points:

• Clinicians prescribing ferric carboxymaltose (Ferinject^®) should be aware of the common side effect of hypophosphataemia, which could be mild, moderate or severe.

• Patients receiving fe infusion should be educated concerning this potential side effect.

• Pre-existing vitamin D deficiency, depression calcium levels, low phosphate levels or raised parathyroid hormone levels may be risk factors, and these should be evaluated and corrected before administering intravenous iron.

• Patients may require phosphate and vitamin D replacement along with monitoring for a long period later on iron infusion-induced hypophosphataemia.

• Every incident should exist reported to the designated body and so that the truthful prevalence and management thereof tin can exist ascertained.

Background

Iron deficiency is an important cause of anaemia affecting patients with chronic kidney disease, inflammatory bowel disease, intestinal malabsorption syndromes and women who accept heavy menstrual haemorrhage. Not all cases are associated with anaemia. In the absenteeism of anaemia, iron deficiency withal produces symptoms such as fatigue, irritability, aloofness and depression. Therefore, iron replacement therapy is unremarkably commenced, while the patient is undergoing investigations for the underlying cause.

Oral iron supplementation is the usual first-line therapy for iron deficiency, but this has a high charge per unit of gastrointestinal side effects, low bioavailability and non-adherence to handling is common (ane). For this reason, the parenteral route was developed and is now the preferred route, as this allows the administration of large amounts of fe (yard mg) in one single infusion (1).

The product labelling information sheet for the iron infusion (ferric carboxymaltose) does mention that it tin crusade hypophosphataemia and that it is usually transient and asymptomatic. This side result is besides mentioned under common or very mutual in the British National Formulary. However, this is not widely acknowledged by healthcare professionals who prescribe this iron product.

Ferric carboxymaltose infusion therapy causes renal wasting of phosphate. It has been suggested that this iron compound increases serum levels of fibroblast growth gene 23 (FGF23) by inhibiting FGF23 degradation. FGF23 is a peptide secreted by both osteoclasts and osteoblasts in response to raised phosphate levels. Its role is to limit phosphate reabsorption in the renal tubules, maintaining phosphate homeostasis. Therefore, the resultant excess serum FGF23 causes hypophosphataemia by inappropriately decreasing phosphate reabsorption in the proximal renal tubules fifty-fifty in the presence of connected depression serum phosphate levels. Additionally, FGF23 has been reported to inhibit the production of calcitriol which is needed for phosphate absorption in the intestines (2).

Nosotros study a challenging case of a patient who developed severe, symptomatic and prolonged hypophosphataemia after an intravenous iron infusion.

Example presentation

A 43-year-onetime Caucasian lady presented to the emergency department with a 3-day history of palpitations and chest discomfort. At that place was a past medical history of chronic atomic number 26 deficiency secondary to heavy uterine bleeding being treated with oral fe tablets (ferrous sulphate). She had poor adherence to taking the iron tablets considering of gastrointestinal side furnishings and the fact that she did non like taking tablets. Serum ferritin levels had been beneath 30 μg/50 for the past 2 years. Every bit a effect of not-response to prolonged oral iron supplementation and a serum ferritin level nevertheless low at 17 µg/50, the patient received an intravenous infusion of ferric carboxymaltose (Ferinject^®) half-dozen days prior to this presentation. The patient was scheduled to receive a k mg dose made upwards to 270 mL with 0.9% sodium chloride solution to run over xxx min, but tolerated only half of the infusion, because of a astringent feet attack. Examination revealed no aberrant features. Her electrocardiogram was normal. Initial blood results were normal autonomously from the serum phosphate level beingness slightly low at 0.half dozen mmol/L (normal range: 0.8–1.five mmol/L). She was reassured and sent home with effervescent phosphate tablets (Sandoz Phosphate®).

The patient presented once more 3 days later with symptoms of painful cramps in both legs, dizziness, fatigue and nausea and was establish to take a serum phosphate level of 0.43 mmol/L. The patient could not tolerate the effervescent phosphate tablet because it acquired astringent nausea and painful indigestion. There was no past history of undernutrition or intake of any medications that would interfere with phosphate metabolism.

Investigation

Other blood results were normal, and the serum ferritin level was accordingly raised in response to the recent intravenous iron administration (Table i). Urinalysis demonstrated a fractional excretion of phosphate (FEPO₄) of 24.two%, which confirmed severe renal wasting of phosphate in the presence of severe hypophosphataemia (FEPO_iv should exist less than v% in the presence of hypophosphataemia). Urinalysis for aminoaciduria ruled out underlying renal tubular disorders. Blood tests washed 4 months prior to the iron infusion revealed normal serum creatinine, calcium, phosphate (0.94 mmol/Fifty) and vitamin D levels. This ruled out any form of underlying or pre-existing hypophosphataemia or problems with phosphate and calcium metabolism. Moreover, FGF23 levels were raised at 225 RU/ml (normal <100 RU/ml).

Table 1

Haematology and biochemistry results (with normal values) prior to the iron infusion and at presentation.

Blood parameters (units)	Normal ranges	Patient'south results
		4 months prior to iron infusion	At presentation (after atomic number 26 infusion)
Haemoglobin (1000/50)	115–165	153	140
White blood cells	four.0–11.0	8.8	7.0
Platelets (10nine/L)	150–400	265	242
Sodium (mmol/Fifty)	132–145	141	142
Potassium (mmol/L)	3.4–v.1	four.five	4.iv
Creatinine (µmol/L)	45–84	78	67
Adjusted calcium (mmol/L)	2.20–2.60	2.27	2.35
Phosphate (mmol/Fifty)	0.80–i.50	0.94	0.43
25-hydroxy vitamin D (nmol/L)	>fifty	76	59
Magnesium (mmol/Fifty)	0.7–1.0	–	0.74
Parathyroid hormone (pmol/Fifty)	i.four–six.2	–	6.0
Alkaline Phosphatase (U/L)	xxx–130	88	89
Ferritin (µg/L)	30–400	thirteen	481

Treatment

The patient was admitted and given an intravenous infusion of Phosphate Polyfusor^®, 150 mL infused over 12 h (containing fifteen mmol of phosphate). The patient could not tolerate the effervescent phosphate tablets, which gave her astringent breast and epigastric discomfort. Because of recurrent low serum phosphate levels and symptoms the patient required fifteen doses of intravenous Phosphate Polyfusor^® over a 4-week infirmary stay period. The patient was also given calcitriol 0.25 µg daily, vitamin D3 800 units daily, a phosphate-rich diet and a bespoke syrup phosphate (sodium dihydrogen phosphate fifteen mmol three times a day) which the patient was just most able to tolerate. The calcitriol dose was afterward increased to 0.25 µg twice a day. The patient's serum calcium, magnesium, phosphate and creatinine levels were monitored throughout the treatment period.

The last phosphate infusion was administered on day 26 and the patient was discharged on day 30 on a regimen of calcitriol 0.25 µg twice a day, vitamin D3 800 units daily, syrup sodium dihydrogen phosphate xv mmol 3 times a day, and some effervescent phosphate tablets. The serum phosphate levels are shown in Fig. one.

Graph demonstrates the serum phosphate levels at presentation, during admission and afterwards discharge. The sodium dihydrogen phosphate syrup was started on twenty-four hour period 17. The last dose of intravenous phosphate therapy was administered on twenty-four hours 26. Patient was discharged home on twenty-four hour period thirty. The phosphate supplements were stopped on solar day 42.

Effect and follow-up

The patient'due south serum phosphate levels remained in the normal range while on a reducing dose of phosphate supplements, during outpatient monitoring (Fig. 1). A repeat serum ferritin level was much lower (67 µg/L) and the patient was advised to recommence oral iron tablets. On the 42nd day, the patient was able to finish taking phosphate supplements altogether and the patient's serum phosphate levels remained in the normal range thereafter.

Discussion

We accept reported a example of symptomatic hypophosphataemia occurring within a week later the patient received 519 mg of intravenous ferric carboxymaltose (Ferinject^®) for severe iron deficiency. The very high FEPO₄ indicated that the hypophosphataemia resulted from significant renal phosphate wasting, secondary to the iron infusion. Renal part, phosphate and calcium metabolism were normal prior to the fe infusion. Unfortunately, the patient could non tolerate oral phosphate supplements so required frequent intravenous phosphate replacement.

Hypophosphataemia secondary to intravenous atomic number 26 (notably ferric carboxymaltose) has been reported, merely this has been generally thought to be both asymptomatic and transient. However, recent reports accept noted that this side issue is non every bit asymptomatic and transient as previously thought (3, iv, 5). The prevalence of hypophosphataemia after loftier-dose intravenous iron therapy is not easy to define. A study reported that 51% of patients who received an infusion of ferric carboxymaltose developed hypophosphataemia, the severity of hypophosphataemia correlated with the dose administered, and the mean hypophosphataemia duration was six months (vi). The main symptom in this group of patients was fatigue.

Despite several case reports in the literature and the fact that this side effect is common, patients are not routinely warned about this potentially life-threatening adverse event earlier having their fe infusion. Incident reporting of any side furnishings of medicines to a designated body, fifty-fifty if previously known, is important so that the Medicines and Healthcare products Regulatory Agency (MHRA) or its equivalent can human activity, if necessary, to ensure that medicines are used in a mode that minimises risk, while maximising patient benefit (vii). This incident was reported appropriately.

The mechanism by which intravenous fe increases serum FGF23 levels is however not fully understood. Increased production and reduced degradation through various processes have been implicated (8). The carbohydrate moieties in some of the iron preparations (e.g., carboxymaltose in Ferinject®) have been implicated in altering the FGF23 protein and thereby inhibiting its degradation (8). At that place are several intravenous fe formulations available and not all crusade hypophosphataemia. However, ferric carboxymaltose was constitute to exist more stable, had a amend side effect contour, caused less anaphylactic reactions and was plant to exist well tolerated when compared to other formulations. Additionally, ferric carboxymaltose was initially adult for rapid, single, high-dose infusion (9). Newer preparations, for case, superparamagnetic atomic number 26 molecules independent inside semi-synthetic saccharide cores, have been developed and have been shown to exhibit less hypersensitivity, less anaphylaxis and rarely cause hypophosphataemia when compared to other atomic number 26 preparations (x). It is of import to note that many reactions to intravenous iron are incorrectly labelled as anaphylaxis, which is a potentially life-threatening allergic reaction that commonly develops rapidly and may cause expiry because of circulatory collapse or bronchospasm, and requires immediate treatment. Many of these reactions are mild, self-limiting hypersensitivity reactions (11).

The patient in this case report only had 519 mg of intravenous atomic number 26, which resulted in both symptomatic and severe hypophosphataemia within a week. Previous case reports reported hypophosphataemia occurring afterward administration of higher doses (yard–3000 mg) of intravenous atomic number 26 (iii, iv, 5, 6). Pre-existing disorders in phosphate homeostasis, including depression vitamin D, phosphate and calcium levels have been suggested as chance factors for developing clinically pregnant hypophosphataemia after intravenous ferric carboxymaltose administration (iii, 4, 5, half dozen). Therefore, measuring these levels prior to having an fe infusion and repeating the serum phosphate level a week after the infusion should exist considered for high-risk patients. However, our patient did not have whatsoever of these suggested run a risk factors (e.grand., pre-existing vitamin D deficiency, low calcium or low phosphate levels). The patient'southward vitamin D and calcium levels were also normal later the iron infusion, just we still prescribed calcitriol hoping that it volition aid to increase intestinal phosphate absorption and improve serum phosphate levels. Further studies are needed to assess these suggested risk factors. This case was likewise challenging in that the patient could non tolerate the usual effervescent phosphate tablets and was but nearly able to tolerate the bespoke syrup. This patient was e'er symptomatic once serum phosphate levels cruel beneath 0.6 mmol/50 and required multiple doses of intravenous phosphate to proceed up with the renal wastage.

Some other mutual feature to all the case reports and case serial is the fact that the serum ferritin levels were all in the supraphysiological range for some elapsing after the iron infusions before falling to the normal range (iii, 4, 5, six). Ane could speculate that the supraphysiological serum ferritin levels could exist a possible 'inflammatory co-cistron or co-culprit' agonizing FGF23 metabolism and whether the dose of the iron infusion needs to be altered in order to non produce the initial supraphysiological rise.

In conclusion, much remains to be understood about the mechanism, prevalence and adventure factors for developing hypophosphataemia after intravenous iron therapy. This example illustrates the potential severity of this agin reaction and the need for prescribers to be aware of this potential and occasionally serious complexity and the potential demand to monitor pre-handling vitamin D, phosphate, calcium and parathyroid hormone levels and post-treatment serum phosphate levels in patients who may exist susceptible. Further enquiry into this phenomenon is required to make up one's mind the true prevalence, machinery and chance factors for intravenous iron-induced hypophosphataemia.

Patient'due south perspective

I was very distressed by the fact that I was not fabricated aware of this serious side effect of having intravenous iron therapy. I was not told what to expect. I certainly was non expecting to end up in infirmary for 4 weeks afterwards, which was sorry for both myself and family.

I as well institute that non many healthcare professionals knew virtually this side upshot: I got most of the information from searching the Google website. The scary part was reading that the status could last for a long time. What made things worse was the fact that I could not tolerate the Sandoz Phosphate tablets, so I had to proceed having the phosphate through an intravenous baste.

My healthcare team read up on the topic and kept me updated throughout my admission and were finally able to get a syrup formulation for me in the end. The syrup still gave my indigestion symptoms.

Healthcare professionals need to be made more aware of this problem and accept a plan in place in case this happens to other people. Introducing a pre-screening test to decide the probability of hypophosphataemia occurring, for example, phosphate and vitamin D levels and post-screening phosphate levels. Other iron formulations need to be produced.

I certainly will non be having any iron infusions once more in the time to come.

Declaration of involvement

The authors declare that at that place is no conflict of interest that could be perceived as prejudicing the impartiality of thid case report.

Funding

This piece of work did not receive any specific grant from whatsoever funding bureau in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent has been obtained from the patient for publication of the submitted commodity and any accompanying images.

Author contribution statement

E Ifie and S O Oyibo wrote the initial draft of the article. East Ifie, S O Oyibo, H Joshi and O O Akintade all critically revised the paper and approved the final manuscript for submission. Southward O Oyibo identified the case and is likewise the named dr. for the patient.

References

ane. Moore RA, Gaskell H, Rose P, Allan J. Meta-analysis of efficacy and safe of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data. BMC Blood Disorders 2011. 11 four (10.1186/1471-2326-11-four) [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Shamida T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda South, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterisation of FGF23 as a causative factor of tumor-induced osteomalacia. PNAS 2001. 98 . (10.1073/pnas.101545198) [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Blazevic A, Hunze J, Boots JMM. Severe hypophosphataemia afterward intravenous iron assistants. Netherlands Periodical of Medicine 2014. 72 . [PubMed] [Google Scholar]

four. Anand Grand, Schmid C. Severe hypophosphataemia subsequently intravenous atomic number 26 administration. BMJ Case Reports 2017. 2017 bcr2016219160 (ten.1136/bcr-2016-219160) [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Klein One thousand, Asaad Southward, Econs 1000, Rubin JE. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose assistants. BMJ Case Reports 2018. 2018 bcr-2017-222851 (10.1136/bcr-2017-222851) [PMC costless article] [PubMed] [CrossRef] [Google Scholar]

half-dozen. Hardy S, Vandemergel X. Intravenous iron assistants and hypophosphatemia in clinical practice. International Journal of Rheumatology 2015. 2015 468675 (10.1155/2015/468675) [PMC free article] [PubMed] [CrossRef] [Google Scholar]

vii. Anderson C, Krska J, Potato E, Avery A. & Xanthous Carte Study Collaboration. The importance of directly patient reporting of suspected adverse drug reactions: a patient perspective. British Journal of Clinical Pharmacology 2011. 72 . (10.1111/j.1365-2125.2011.03990.x) [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]

viii. Wolf Thou, Koch TA, Bregman DB. Effects of iron deficiency anaemia and its handling on fibroblast growth gene 23 and phosphate homeostasis in women. Journal of Os and Mineral Research 2013. 28 . (ten.1002/jbmr.1923) [PubMed] [CrossRef] [Google Scholar]

9. Barish CF, Koch T, Butcher A, Morris D, Bregman DB. Safe and efficacy of intravenous ferric carboxymaltose (750 mg) in the treatment of iron deficiency anemia: two randomized, controlled trials. Anemia 2012. 2012 . (x.1155/2012/172104) [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]

10. Auerbach M, Chertow GM, Rosner M. Ferumoxytol for the treatment of iron deficiency anemia. Expert Review of Hematology 2018. 11 . (10.1080/17474086.2018.1518712) [PubMed] [CrossRef] [Google Scholar]

11. Kalra PA, Bhandari S. Safety of intravenous atomic number 26 utilize in chronic kidney disease. Electric current Opinion in Nephrology and Hypertension 2016. 25 . (ten.1097/MNH.0000000000000263) [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]

figueroakelp1966.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689119/

Share this post