Re: Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report

Abstract

We read with great interest the case report by Bartko and colleagues (1) concerning a patient with osteomalacia due to longstanding hypophosphatemia after long-term intravenous (iv) iron administration. We would like to add our experience regarding a similar case of a male patient with Hirschsprung disease suffering from severe hypophosphatemia due to continuous iv iron administration. A 31-year-old man with extensive Hirschsprung disease (involving the colon and the distal one-third of ileum) was referred to our department suffering from insufficiency fractures and severe hypophosphatemia. Disease onset was on the second day after birth with meconium ileus. By the age of 2 years, he underwent near total colectomy and excision of the distal one-third of the ileum by the Duhamel retrorectal transanal technique. Since then, he suffered from mild iron-deficiency anemia (IDA) and B12 and vitamin D deficiency, managed with oral iron treatment (OIT) and B12 and D2 im injections. Serum phosphate levels were within normal range (1.065 to 1.227 mmol/L). At the age of 26 years, IDA became refractory to OIT because of multiple bleeding ulcers at the site of rectal anastomosis. At that time, monthly ferric carboxymaltose (FCM) iv injections were administered for the management of IDA along with occasional need for blood transfusions. At the age of 29 years, he suffered multiple insufficiency fractures (4th left metatarsal and bilateral rib fractures). Laboratory evaluations performed on several occasions revealed severe hypophosphatemia (as low as 0.355 mmol/L) and secondary hyperparathyroidism. At presentation, the patient had diffuse skeletal pain, gait disturbance, and progressive loss of mobility. Laboratory evaluation revealed severe hypophosphatemia (0.419 mmol/L), mild hypocalcemia (2.09 mmol/L), and secondary hyperparathyroidism (parathyroid hormone [PTH] 104.8 pg/mL). 25 (OH) D levels were normal (77.25 nmol/L), whereas 1,25 (OH) 2 D levels were at the low normal level (24 pg/mL). Urinary calcium excretion was low (1.28 mmol/24 hr), whereas phosphate excretion was elevated (32.16 mmol/24 hr, tubular maximum reabsorption of phosphate to glomerular filtration rate [TmP/GFR] 0.2827 mmol/L [reference range 1.00-1.35]; Table 1). Intact FGF-23 level (Kainos Laboratories, Inc., Tokyo, Japan) was elevated (96 pg/mL [reference range 10-50] (2) ). Dual-energy X-ray absorptiometry (DXA) revealed a low BMD at the lumbar spine (LS) (0.92 mg/cm 2 , Z-score -2.7) and the femoral neck (FN) (0.725, Z-score -2.1). These results pointed to a combined defect: FGF-23 mediated hypophosphatemia due to FCM iv injections, leading to renal phosphate wasting and low calcitriol levels, and calcium and phosphate malabsorption due to low calcitriol and short bowel syndrome. Secondary hyperparathyroidism amplified phosphate wasting.The patient was treated with calcium citrate (500 mg tid) and alphacalcidol (1 mcg bid), was instructed to increase milk intake, and switched to oral iron therapy (ferric hydroxide polymaltose). He was referred to a te...

Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets

“…There are several reports describing such resulting hypophosphatemic osteomalacia after iron infusion, particularly with ferric polymaltose and ferric carboxymaltose. (24)(25)(26)(27) Thus, for safety reasons, we chose to focus on oral iron supplementation to avoid the risk of acutely worsening intact FGF23 and hypophosphatemia. Such an effect might be worse in a patient with ADHR, having a mutation that already impairs cleavage of the FGF23 produced from one allele, if iron infusions were to also impair the cleavage of FGF23 produced from the normal allele.…”

Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside

“…If hypophosphatemia is severe, potential complications include respiratory failure, rhabdomyolysis, haemolysis and left ventricular dysfunction . Additionally, an increasing number of published case reports have shown that prolonged hypophosphatemia can result in osteomalacia …”

“…26 Additionally, an increasing number of published case reports have shown that prolonged hypophosphatemia can result in osteomalacia. [9][10][11][12][27][28][29][30][31][32][33] The aim of this study was to investigate the rate of hypophosphatemia after infusion of a single dose of intravenous iron (1000 mg) in adults with IBD treated with either ferric carboxymaltose or iron isomaltoside.…”

A Pooled Analysis of Serum Phosphate Measurements and Potential Hypophosphataemia Events in 45 Interventional Trials with Ferric Carboxymaltose

“…However, these reductions in serum PO 4 3− levels are of a short duration with a nadir at 2 weeks and resolution by about 12 weeks, and a correlation between HP and severe clinical outcomes was not observed. Severe clinical outcomes have been reported in individual case reports, specifically in patients with prolonged exposure to repeated high-dose administrations and pre-existing risk factors for HP (such as underlying disorders causing phosphate malabsorption or vitamin D deficiency) [43][44][45][46][47][48][49][50]. In studies, laboratory findings of HP are generally asymptomatic [28] or adverse drug reactions not observed [41] or clinical outcomes have not been measured [40].…”