in the united states , iron - deficiency anemia ( ida ) affects 1 - 2% of adults while iron deficiency without anemia ( i d ) is more prevalent , affecting 11% of childbearing age women , and it is estimated that 7.8 million women have iron deficiency . symptoms of ida usually include weakness , headache , irritability , fatigue , exercise intolerance and reduced exercise capacity , pagophagia , and restless legs syndrome . they are often not specific and no clear clinical correlation has been shown between the degree of anemia and clinical manifestations . however , it has previously been shown that iron supplementation should be discussed in women with unexplained fatigue whose ferritin levels are less than 50  g / l , even in the absence of anemia . parenteral iron treatments are increasingly used because of their higher efficacy and fewer gastrointestinal side effects compared to oral iron therapy . in europe , ferric carboxymaltose ( fcm ) and iron sucrose ( fs ) are frequently used in this context . phosphate homeostasis is maintained via the bone - kidney endocrine axis , which is mainly regulated by the parathyroid hormone ( pth ) , vitamin d , and a group of hormones called phosphatonins , including fibroblast growth factor 23 ( fgf23 ) . in 2008 , the fda has reported that 2.1% of patients treated with fcm injection developed hypophosphatemia but profound hypophosphatemia was rare . however , we have recently reported the case of a patient with profound and sustained hypophosphatemia due to phosphate diabetes   after fcm administration , a complication which has also been reported by others [ 911 ] , and some patients , including those with history of bariatric surgery , are more likely to develop hypophosphatemia . phosphate plays an important role in the organism and hypophosphatemia , especially when severe , is associated with various complications including fatigue , seizures , osmotic demyelination syndrome , myocardial depression , ventricular tachycardia , proximal myopathy , rhabdomyolysis , and hemolytic anemia . the aim of this study was to retrospectively assess the impact of intravenous iron formulations on the phosphate level in clinical practice . the medical records of all patients treated with parenteral iron formulation ( either fcm or fs ) in the department of general internal medicine , centres hospitaliers jolimont , belgium ( 800 beds ) , between january 2012 and december 2014 were retrospectively reviewed . biological parameters including hemoglobin , ferritin , plasma phosphate , creatinine , pth , and vitamin d levels were assessed before and after iron injection . hypophosphatemia was considered moderate when the phosphate level ranged between 0.32 and 0.80  mmol / l and severe when the level was less than 0.32 one hundred and four cases were excluded due to the absence of phosphate assessment before or after iron injection . finally , 130 patients were included : 52 were treated with fs injection ( 17 men , 35 women ) and 78 with fcm injection ( 24 men , 54 women ) . among the 52 fs - treated patients , the mean dose of fs was 701  mg ( quartile 200800 ) . iron was prescribed by hematologists ( 5 patients ) , geriatricians , gastroenterologists , nephrologists , oncologists , internists , pediatricians , and gynecologists . indications for fs injection were ida in 40 cases and i d in 6 cases and 3 patients had no anemia and no i d . moreover , 3 patients received fs injection while their hemoglobin level and iron status were not assessed . forty patients were asymptomatic , 12 presented with fatigue , and 3 complained of dyspnea . the mean hemoglobin level before injection was 10.1  1.99  gr / dl and it increased to 11.5  2.3  gr / dl after iron administration ( p = 0.02 ) . the mean ferritin level rose from 64  g / l ( quartile : 661  g / l ) to 133  g / l ( 34139  g no difference in ferritin level or in hemoglobin level was noted between patients with and without fatigue ( p = 0.63 and p = 0.6 for the ferritin and hemoglobin level , resp . ) . before intravenous injection , 42% of patients had taken oral iron formulation which was ineffective and led to digestive intolerance in 54% and 31% of cases , respectively . mmol / l and it did not change significantly following fs administration ( 1.00  0.29  mmol / l ; p = 0.37 ) . before injection , 4 patients had moderate hypophosphatemia and none had severe hypophosphatemia . after injection , 22% of patients developed hypophosphatemia with a phosphate level less than 0.80  mmol / l ( they were all within normal range before injection ) . after injection , the phosphate level did not correlate with the initial hemoglobin level ( rs = 0.153 , p = 0.5 ) , ferritin level ( rs = 0.05 , p = 0.82 ) , or cumulated injected iron doses ( rs = 0.2 , p = 0.37 ) . among the 78 fcm - treated patients , the mean dose of fcm was 2123  mg ( quartile : 10002000  mg ) . various physicians prescribed the drug , including haematologists ( 6 cases ) , gastroenterologists , oncologists , general internists , nephrologists , pneumologists , endocrinologists , geriatricians , surgeons , and emergency physicians . ninety percent of patients had ida , 4% had i d , and 6% had history of ida but did not have anemia or i d at the time of the injection . before injection , 52% of patients had taken oral iron which was associated with gastrointestinal side effects in 20% of cases . the initial hemoglobin level was 9.6  1.6  gr / dl and it increased to 11.5  1.7  gr / dl after injection ( p < 0.001 ) . the ferritin level was also significantly higher after injection ( from 63  g / l ( 855 ) to 408  g / l ( 128536 ) ) . no difference in hemoglobin level was observed between patients with and without symptoms of fatigue ( 9.6  1.8  gr / dl versus 9.7  1.7  gr / dl , resp . ) . mmol / l and it decreased to 0.82  0.29  mmol / l following iron administration ( p < 0.0001 ) . after injection , 13% of patients had a phosphate level < 0.32  mmol / l and 51% had a phosphate level < 0.80 no difference in hypophosphatemia severity was noted between patients with history of bariatric surgery and the other patients . patients with severe hypophosphatemia were questioned about their symptoms , including 62% by phone interview . among them , 55% had fatigue improvement and 30% complained of fatigue worsening while the remaining patients had no change in fatigue . in the group with fatigue worsening , the mean phosphate level was 0.55  mmol / l ( 0.320.76 the mean hypophosphatemia duration was 6 months ( 29 months ) , a long period of time which was due to the fact that patients often received other injections during the follow - up . some patients never reached a normal phosphate level during the entire study period ( 2 years ) . it plays a central role in hemoglobin synthesis and in many cellular processes , including oxygen transport and storage , generation of energy through oxidative phosphorylation , and enzyme activity affecting the intracellular metabolism . ida is commonly found in clinical practice , affecting 1 - 2% of adults in the united states   and accounting worldwide for 65.5 million years lived with disability . classical symptoms of ida reported in the literature include fatigue , headache , dyspnea , and sleep disturbance secondary to restless legs syndrome [ 2 , 22 ] . ida is also known to negatively impact the physical quality of life and cognitive functions [ 23 , 24 ] . however , the link between anemia and symptoms , for example , fatigue , has been poorly investigated in the literature . first , it is well known that patients may have acute or chronic profound anemia in the absence of symptoms [ 25 , 26 ] . the study by wood and elwood did not find a correlation between the hemoglobin level and the symptoms of anemia , including fatigue , dyspnea , and palpitations . most of the trials assessing the efficacy of intravenous iron formulations have shown a rapid increase in ferritin and hemoglobin levels , assessed as primary endpoints . some of them have also assessed clinical endpoints . a sponsored , randomized , placebo - controlled , single - blind study   has assessed the efficacy and safety of single - dose intravenous fcm on fatigue reduction in iron - deficient , premenopausal women with symptomatic , unexplained fatigue and normal or borderline hemoglobin level ( 115 they have shown that a single infusion of fcm improved the fatigue , mental quality of life , cognitive function , and erythropoiesis in these patients . in their study , 28% of related adverse events were observed in the treatment group versus 3.4% in the placebo group ( p < 0.0004 ) , including fever , urticaria , headache , and nausea . have shown an improvement in some clinical symptoms with fcm , including fatigue , lack of concentration , hair loss , dyspnea , and sleep disturbance in women with ida and i d . froessler et al .   have also shown an improved quality of life related to fcm injections in pregnant women with anemia but they did not assess fatigue with a validated scale and they reported 20% of side effects . in patients with inflammatory bowel disease , evstatiev et al . have shown that the quality of life remained unchanged after fcm administration in nonanemic patients with low serum ferritin level . in heavy uterine bleeding , van wyck et al . have compared fcm to oral ferrous sulfate in 325 women with postpartum ida with hemoglobin levels less than 10  gr / l . they have shown that both treatment groups presented similar improvements in terms of quality of life scores . another study by the same group   has also shown an improved quality of life in acute anemic patients . finally , improved quality of life , functional capacity , or six - minute walk test has been reported in patients with chronic heart failure [ 34 , 35 ] . in terms of efficacy , our study was similar to prospective studies showing a rapid elevation in hemoglobin and ferritin levels [ 36 , 37 ] . regarding side effects , in clinical trials , serious anaphylactic / anaphylactoid reactions have been reported in 0.1% of patients treated with fcm . other serious reactions potentially related to hypersensitivity , including pruritus , rash , urticaria , wheezing , or hypotension , were experienced by 1.5% of cases versus 3.8% of patients with hypertension . hypophosphatemia is not systematically assessed in clinical trials but when done its rate is about 2.1% , while other studies have reported higher rates . in the study assessing the effect of a single dose of fcm in fatigued women , favrat et al . have indeed found that 86% of patients had a phosphate level < 0.8  mmol / l at day 7 which resolved spontaneously before the end of the study in almost all fcm - treated patients ; however , no data on the risk of profound hypophosphatemia ( < 0.32  mmol / l ) , fatigue persistence , and hypophosphatemia development were reported . iron - induced hypophosphatemia could play a role given that the results of some cognitive function tests do not improve after treatment . in patients with chronic kidney disease ( ckd ) and ida , macdougall et al . mmol / l at week 4 from baseline value but returned to normal value at week 52 . in 2010 , mani et al .   has reported a case of profound hypophosphatemia after fcm injection in a stable renal transplant recipient . some case reports have been published since then [ 911 ] and we have recently published the case of a patient with severe hypophosphatemia due to phosphate diabetes secondary to fcm injection . in our study , 22% of patients developed hypophosphatemia after fs treatment but none of them developed severe hypophosphatemia . we found only two case reports of hypophosphatemia after iron sucrose injection [ 41 , 42 ] . , new insights into the regulation of the phosphate metabolism have been obtained , including growing evidence suggesting that factors other than the pth and vitamin d are involved in maintaining the phosphate balance . a new class of phosphate - regulating factors , the so - called  phosphatonins ,  has also been shown to play a role in phosphate - wasting diseases . among them , fgf23 is involved in various diseases , including autosomal dominant hypophosphatemic rickets / osteomalacia ( adhr ) or tumor - induced osteomalacia . true hypophosphatemia can be induced by a decrease in intestinal absorption , increase in urinary phosphate excretion , or acute movement of extracellular phosphate into the cells . then , the normal renal response to phosphate depletion is to increase phosphate reabsorption , leading to the virtual abolition of urinary phosphate excretion . most of the filtered phosphate is reabsorbed in the proximal tubule by the sodium - phosphate cotransporter in the luminal membrane . mmol / l ) can be deleterious because it can lead to cardiac arrest and severe hypophosphatemia can lead to metabolic encephalopathy and could therefore contribute to the development of central and extrapontine myelinolysis [ 13 , 14 , 16 ] . in this study , 13% of patients developed severe and prolonged hypophosphatemia after fcm injection . we did not find any risk factor for the development of severe hypophosphatemia and we showed that a vitamin d level initially low did not correlate with the phosphate level following injection . the mechanism underlying the development of hypophosphatemia is not known but many arguments suggest a role of fgf23 . per se , the fgf23 level is increased in i d [ 46 , 47 ] but , in our retrospective study , no correlation was found between the initial ferritin level and the postinjection hypophosphatemia severity . in a prospective trial , schouten et al . have shown that intravenous iron polymaltose injection is followed by a rapid increase in fgf23 level and a drop in phosphate and 1,25(oh)2d tubular reabsorption that persisted 3 weeks after injection . the increased fgf23 level found in their study was very high and similar to that seen in adhr . we found no difference between patients developing hypophosphatemia and nonhypophosphatemic patients except for the iron cumulative dose . to the best of our knowledge , there are no published studies conducted in patients without ckd in which the impact of fcm injection on phosphate metabolism has been assessed . however , in a post hoc study , prats et al . have assessed the effect of fcm injection on the serum phosphate and c - terminal fgf23 levels in nondialysis ckd patients and no difference between hypophosphatemic and nonhypophosphatemic patients was found in terms of initial 25(oh)d , ferritin , and hemoglobin levels . our study has some limitations , in particular its retrospective design and the fact that the value of the fgf23 level was not recorded . however , if hypophosphatemia is secondary to the increase in fgf23 as demonstrated in other studies , hypophosphatemia duration , several months in some cases , raises questions about the long - term side effects of the drug on bone . indeed , recent reports suggest that fgf23 may have a phosphate - independent effect on bones   with suppression of the osteoblast differentiation and matrix mineralization in a fetal rat calvaria cell line overexpressing fgf23 . these consequences have been validated by two case reports of osteomalacia induced by intravenous iron sucrose administration [ 51 , 52 ] . it is well known that metabolic bone disease is a concern during the follow - up of these patients   and an evolving concept of bariatric osteomalacia has emerged recently . in our study , a history of bariatric surgery was not a risk factor for developing hypophosphatemia , but 60% of patients with history of bariatric surgery developed hypophosphatemia which , over the long term , could contribute to bone - specific complications . moreover , 30% of our patients with fcm - induced hypophosphatemia complained about fatigue worsening . it is not known , however , if correcting hypophosphatemia could improve their symptomatology . at least , practitioners should keep in mind that it is indicated for i d . indeed , in our study 3.8% of patients received iron formulations without hemoglobin or ferritin level evaluation . blood test should be performed before injection and the phosphate level assessed both before and after injections . parenteral iron formulations are increasingly prescribed but their long - term side effects remain unknown , in particular the long - term bone impact of hypophosphatemia ( 13% in our study ) . in cystic fibrosis patients , respiratory deterioration has been reported after treatment   and intravenous iron seems to have deleterious effects on mononuclear cells , oxidative stress , and apoptosis . in conclusion , we found that parenteral fcm injection is often followed by hypophosphatemia which may be profound and last a long time without immediate clinical consequences except fatigue in some cases . studies evaluating oral phosphate supplementation and its long - term consequences are needed because the biological change in phosphate homeostasis after injection is similar to that observed in diseases such as tumor - induced osteomalacia   or x - linked hypophosphatemic rickets .
introduction . 
 parenteral iron formulations are frequently used to correct iron deficiency anemia ( ida ) and iron deficiency ( i d ) . 
 intravenous formulation efficacy on ferritin and hemoglobin level improvement is greater than that of oral formulations while they are associated with lower gastrointestinal side effects . 
 ferric carboxymaltose- ( fcm- ) related hypophosphatemia is frequent and appears without clinical significance . 
 the aim of this study was to assess the prevalence , duration , and potential consequences of hypophosphatemia after iron injection . 
 patients and methods . 
 the medical records of all patients who underwent parenteral iron injection between 2012 and 2014 were retrospectively reviewed . 
 pre- and postinjection hemoglobin , ferritin , plasma phosphate , creatinine , and vitamin d levels were assessed . 
 patients who developed moderate ( range : 0.320.80 
 mmol / l ) or severe ( < 0.32 
 mmol / l ) hypophosphatemia were questioned for symptoms . 
 results . during the study period , 
 234 patients received iron preparations but 104 were excluded because of missing data . among the 130 patients included , 52 received iron sucrose ( fs ) and 78 fcm formulations . among fs - treated patients , 
 22% developed hypophosphatemia versus 51% of fcm - treated patients , including 13% who developed profound hypophosphatemia . 
 hypophosphatemia severity correlated with the dose of fcm ( p = 0.04 ) but not with the initial ferritin , hemoglobin , or vitamin d level . 
 mean hypophosphatemia duration was 6 months . 
 no immediate clinical consequence was found except for persistent fatigue despite anemia correction in some patients . 
 conclusions . 
 hypophosphatemia is frequent after parenteral fcm injection and may have clinical consequences , including persistent fatigue . further studies of chronic hypophosphatemia long - term consequences , especially bone assessments , are needed .