What is wrong in doing good?

Hypophosphataemia is a common side-effect in patients with iron deficiency anaemia treated with ferric carboxymaltose, which is not a class effect of all intravenous (IV) iron formulations. The report by Chu et al. shows that moderate and severe hypophosphataemia is common and can even require IV supplementation of phosphate with unknown long-term consequences. Commentary on: Chu et al. Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-a 3-year experience from a single institution in Singapore. Br J Haematol 2023;202:1199-1204.

Tissue iron distribution in patients with anemia of inflammation: Results of a pilot study.

Anemia of inflammation (AI) is frequently present in subjects with inflammatory disorders, primarily caused by inflammation-driven iron retention in macrophages. So far, only limited data on qualitative and quantitative estimates of tissue iron retention in AI patients exist. We performed a prospective cohort study analyzing splenic, hepatic, pancreatic, and cardiac iron content with MRI-based R2*-relaxometry in AI patients, including subjects with concomitant true iron deficiency (AI+IDA) hospitalized between 05/2020-01/2022. Control groups were individuals without inflammation. Spleen R2* values in AI patients with ferritin ≤200 µg/L (AI+IDA) were comparable with those found in controls. In AI patients with ferritin >200 µg/L, spleen (47.6 s-1 vs. 19.3 s-1 , p < .001) and pancreatic R2* values (32.5 s-1 vs. 24.9 s-1 , p = .011) were significantly higher compared with controls, while liver and heart R2*-values did not differ. Higher spleen R2* values were associated with higher ferritin, hepcidin, CRP, and IL-6 concentrations. Spleen R2* values normalized in AI patients after recovery (23.6 s-1 vs. 47.6 s-1 , p = .008), while no changes were found in patients with baseline AI+IDA. This is the first study investigating tissue iron distribution in patients with inflammatory anemia and AI with concomitant true iron deficiency. The results support the findings in animal models demonstrating iron retention in macrophages, which are primarily accumulating in the spleen under inflammatory conditions. MRI-related iron measurement may help to better characterize actual iron needs and to define better biomarker thresholds in the diagnosis of true ID in patients with AI. It may qualify as a useful diagnostic method to estimate the need for iron supplementation and to guide therapy.

Hypophosphatemia after high-dose intravenous iron treatment in patients with inflammatory bowel disease: Mechanisms and possible clinical impact.

BACKGROUND: High-dose intravenous iron is an effective treatment option for iron deficiency (ID) or ID anaemia (IDA) in inflammatory bowel disease (IBD). However, treatment with ferric carboxymaltose (FCM) has been associated with the development of hypophosphatemia. AIM: To investigate mechanisms behind the development of hypophosphatemia after intravenous iron treatment, and disclose symptoms and clinical manifestations related to hypophosphatemia short-term. METHODS: A prospective observational study of adult IBD patients with ID or IDA was conducted between February 1, 2017 and July 1, 2018 at two separate university hospitals in the southeast region of Norway. Patients received one dose of 1000 mg of either FCM or ferric derisomaltose (FDI) and were followed for an observation period of at least 7 wk. Blood and urine samples were collected for relevant analyses at baseline, week 2 and at week 6. Clinical symptoms were assessed at the same timepoints using a respiratory function test, a visual analogue scale, and a health-related quality of life questionnaire. RESULTS: A total of 106 patients was available for analysis in this study. The FCM treatment group consisted of 52 patients and hypophosphatemia was present in 72.5% of the patients at week 2, and in 21.6% at week 6. In comparison, the FDI treatment group consisted of 54 patients and 11.3% of the patients had hypophosphatemia at week 2, and 3.7% at week 6. The difference in incidence was highly significant at both week 2 and 6 (P < 0.001 and P < 0.013, respectively). We observed a significantly higher mean concentration of intact fibroblast growth factor 23 (P < 0.001), a significant rise in mean urine fractional excretion of phosphate (P = 0.004), a significant decrease of 1,25-dihydroxyvitamin D (P < 0.001) and of ionised calcium levels (P < 0.012) in the FCM-treated patients compared with patients who received FDI. No clinical symptoms could with certainty be related to hypophosphatemia, since neither the respiratory function test, SF-36 (36-item short form health survey) or the visual analogue scale scores resulted in significant differences between patients who developed hypophosphatemia or not. CONCLUSION: Fibroblast growth factor 23 has a key role in FCM induced hypophosphatemia, probably by inducing loss of phosphate in the urine. Short-term clinical impact of hypophosphatemia was not demonstrated.

Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease.

BACKGROUND & AIMS: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. METHODS: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. RESULTS: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. CONCLUSIONS: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

Intravenous iron supplementation therapy.

Intravenous infusions of iron have evolved from a poorly effective and dangerous intervention to a safe cornerstone in the treatment of iron deficiency. Modern iron formulations are composite nanoparticles composed of carbohydrate ferric oxy-hydroxides. Iron dextran, iron derisomaltose (formely known as iron isomaltoside 1000), ferric carboxymaltose, ferrumoxytol, iron sucrose and sodium ferric gluconate can be infused at different doses and allow correction of total iron deficit with single or repeated doses in 1-2 weeks depending on the specific formulation. All iron preparations are associated with a risk of severe infusion reactions. In recent prospective clinical trials, the risk of moderate to severe infusion reactions was comparable among all modern preparations affecting <1% of patients. Hence, intravenous iron therapy is reserved for iron deficiency anemia patients with intolerance or unresponsiveness of oral iron. As per European drug label, intravenous iron may also be preferred when rapid correction of the iron deficit is required. In patients with inflammation, iron-deficiency should also be suspected as anemia cause when transferrin saturation is low because serum ferritin can be spuriously normal. The main treatment target for i.v. iron is an improvement of the quality of life, for which hemoglobin is a surrogate marker. An emerging complication affecting 50-74% of patients treated with ferric carboxymaltose in prospective clinical trials is hypophosphatemia - or more accurately the 6H syndrome (hyperphosphaturic hypophosphatemia triggered by high fibroblast growth factor 23 that causes hypovitaminosis D, hypocalcemia and secondary hyperparathyroidism). These biochemical changes can cause severe and potentially irreversible clinical complications, such a bone pain, osteomalacia and fractures. Individual selection of the appropriate iron therapy and evaluation of treatment response are mandatory to safely deliver improved outcome through intravenous iron therapies.

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

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

BACKGROUND: Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease (IBD). In patients with moderate-to-severe anaemia, oral iron intolerance or ineffectiveness of oral iron, ferric carboxymaltose and iron isomaltoside are widely used. Hypophosphatemia is a side effect of both preparations. AIMS: To investigate the occurrence of hypophosphatemia in IBD patients with iron deficiency/iron deficiency anaemia treated with high-dose intravenous iron. METHODS: A prospective observational study of adult IBD patients with iron deficiency/iron deficiency anaemia was conducted at two study sites where patients received 1000 mg of ferric carboxymaltose or iron isomaltoside. At baseline, weeks 2 and 6, blood and faecal samples were collected. The primary endpoint was to determine the incidence of moderate-to-severe hypophosphatemia. Secondary endpoints included the total incidence of hypophosphatemia, possible risk factors for hypophosphatemia, and response to single-dose intravenous iron. RESULTS: One hundred and thirty patients were included. In the per-protocol set, 52 patients received ferric carboxymaltose and 54 patients received iron isomaltoside. Ferric carboxymaltose treatment had a significantly higher incidence of moderate-to-severe hypophosphatemia compared with iron isomaltoside at week 2 (56.9% vs 5.7%, P < 0.001) and a higher incidence at week 6 (13.7% vs 1.9%, P = 0.054).The overall incidence of hypophosphatemia was significantly higher with ferric carboxymaltose compared with iron isomaltoside treatment at weeks 2 (72.5% vs 11.3%, P < 0.001) and 6 (21.6% vs 3.7%, P = 0.013). CONCLUSIONS: In IBD patients with iron deficiency/iron deficiency anaemia, ferric carboxymaltose was associated with higher incidence, severity and persistence of hypophosphatemia compared with iron isomaltoside. The presence of moderate-to-severe hypophosphatemia beyond 6 weeks is a clinical concern that requires further investigation.

The dilemma to diagnose Wilson disease by genetic testing alone.

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of hepatic copper excretion. About sixty per cent of patients present with liver disease. WD is considered a fatal disease if undiagnosed and/or untreated but recent data indicate that disease penetrance may not be 100%. MATERIALS AND METHODS: All patients underwent liver biopsy as part of the diagnostic workup. Genetic testing for ATP7B was performed by Sanger sequencing. RESULTS: We report on a large family with multiple affected siblings. The first patient (male, 31 years) underwent orthotopic liver transplantation (OLT) because of fulminant WD. He was homozygous for p.G710A. One asymptomatic brother (37 years) had the same mutation. He is doing well on chelation therapy. Fifteen years later, a second-degree sibling (female, 16 years) presented with fulminant WD and underwent OLT. She was compound heterozygote (p.G710A/p.G710S). Further family screening revealed a third mutation (p.V536A) in a female (21 years) and male (16 years) compound-heterozygote sibling (p.G710A/p.V536A). In both, serum ceruloplasmin and 24-hour urinary copper excretion were normal. Liver biopsy showed normal histology and a quantitative hepatic copper content within the normal range or only slightly elevated (19 and 75 µg/g dry weight, respectively). No decoppering treatment was initiated so far. CONCLUSION: Genetic testing alone is not always sufficient to diagnose WD in asymptomatic patients, and human mutation databases should be used with caution. Even patients carrying two disease-causing mutations do not necessarily have demonstrable alteration of copper metabolism. Asymptomatic siblings diagnosed by genetic screening require further testing before initiating treatment.

Monitoring Iron Overload: Relationship between R2* Relaxometry of the Liver and Serum Ferritin under Different Therapies.

OBJECTIVE: The objective of this study was to evaluate the relationship between hepatic magnetic resonance imaging (MRI) with R2* relaxometry and serum ferritin in therapy monitoring of patients with iron overload. Further, a possible influence of the chosen therapy (phlebotomy or chelation) was assessed. MATERIALS AND METHODS: We retrospectively evaluated 42 patients with baseline and follow-up R2* relaxometry and determination of serum ferritin before and during therapeutic phlebotomy or iron chelation therapy or watchful waiting, respectively. Linear regression analysis was used to analyze the correlation between changes of R2* and serum ferritin. Regression lines for different groups were compared with analysis of covariance. RESULTS: We found a moderate positive statistical correlation (r = 0.509) between serum ferritin and R2*, a moderate positive correlation between absolute R2* changes and serum ferritin changes (r = 0.497), and a strong correlation for percentage changes (r = 0.712). The correlation analysis between relative changes of R2* and serum ferritin for the different therapies resulted in a strong correlation between phlebotomy and chelation (r = 0.855/0.727) and a moderate for no applied therapy (r = 0.536). In 22/92 paired examinations, a discordance of R2* and ferritin was found, particularly involving patients under chelation. CONCLUSIONS: Despite the good correlation between serum ferritin and R2* relaxometry in monitoring iron overload, treatment response may be misinterpreted when only serum ferritin is considered. Although ferritin is an acceptable and far cheaper tool for monitoring, MRI should be performed for confirmation, especially in case of unexpected ferritin changes, particularly under chelation therapy.

Iron-induced hypophosphatemia: an emerging complication.

PURPOSE OF REVIEW: Iron-induced hypophosphatemia is a well documented side-effect but associated complications are largely neglected, because the results from single dosing studies suggest that transient decreases in plasma phosphate concentrations are asymptomatic and fully reversible. However, an increasing number of case reports and case series suggest that some patients develop severe and symptomatic hypophosphatemia. Long-term complications from hypophosphatemia include osteomalacia and bone fractures, which can result from repeated intravenous administration of certain high-dose iron preparations. RECENT FINDINGS: Results from clinical trials suggest that the highest risk for the development of hypophosphatemia is associated with ferric carboxymaltose, iron polymaltose, and saccharated iron oxide. Clinical studies show that renal phosphate wasting mediated by increased fibroblast growth factor 23 causes hypophosphatemia after iron therapy. Impaired renal function therefore protects from hypophosphatemia, whereas the highest incidences and most severe manifestations have been reported in patients in whom the underlying cause of iron deficiency cannot be corrected. SUMMARY: Diagnosis of iron-induced hypophosphatemia requires clinical suspicion. Treatment is guided by the severity of hypophosphatemia, and most patients will require oral or intravenous phosphate substitution. Future treatment options could involve therapeutic anti-FGF23 antibody (KRN23). Prevention and correction of vitamin D deficiency represents a supportive treatment option.

Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk.

BACKGROUND: Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM. AIM: To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort. METHODS: Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included. RESULTS: The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM-OR = 20.8; 95% CI, 2.6-166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. CONCLUSION: Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

Iron metabolism in transplantation.

Recipient's iron status is an important determinant of clinical outcome in transplantation medicine. This review addresses iron metabolism in solid organ transplantation, where the role of iron as a mediator of ischemia-reperfusion injury, as an immune-modulatory element, and as a determinant of organ and graft function is discussed. Although iron chelators reduce ischemia-reperfusion injury in cell and animal models, these benefits have not yet been implemented into clinical practice. Iron deficiency and iron overload are associated with reduced immune activation, whose molecular mechanisms are reviewed in detail. Furthermore, iron overload and hyperferritinemia are associated with poor prognosis in end-stage organ failure in patients awaiting kidney, or liver transplantation. This negative prognostic impact of iron overload appears to persist after transplantation, which highlights the need for optimizing iron management before and after solid organ transplantation. In contrast, iron deficiency and anemia are also associated with poor prognosis in patients with end-stage heart failure. Intravenous iron supplementation should be managed carefully because parenterally induced iron overload could persist after successful transplantation. In conclusion, current evidence shows that iron overload and iron deficiency are important risk factors before and after solid organ transplantation. Iron status should therefore be actively managed in patients on the waiting list and after transplantation.

Long-term outcomes of patients with Wilson disease in a large Austrian cohort.

BACKGROUND & AIMS: Wilson disease is an autosomal recessive disorder that affects copper metabolism, leading to copper accumulation in liver, central nervous system, and kidneys. There are few data on long-term outcomes and survival from large cohorts; we studied these features in a well-characterized Austrian cohort of patients with Wilson disease. METHODS: We analyzed data from 229 patients diagnosed with Wilson disease from 1961 through 2013; 175 regularly attended a Wilson disease outpatient clinic and/or their physicians were contacted for information on disease and treatment status and outcomes. For 53 patients lost during the follow-up period, those that died and reasons for their death were identified from the Austrian death registry. RESULTS: The mean observation period was 14.8 ± 11.4 years (range, 0.5-52.0 years), resulting in 3116 patient-years. Of the patients, 61% presented with hepatic disease, 27% with neurologic symptoms, and 10% were diagnosed by family screening at presymptomatic stages. Patients with a hepatic presentation were diagnosed younger (21.2 ± 12.0 years) than patients with neurologic disease (28.8 ± 12.0; P < .001). In 2% of patients, neither symptoms nor onset of symptoms could be determined with certainty. Most patients stabilized (35%) or improved on chelation therapy (26% fully recovered, 24% improved), but 15% deteriorated; 8% required a liver transplant, and 7.4% died within the observation period (71% of deaths were related to Wilson disease). A lower proportion of patients with Wilson disease survived for 20 years (92%) than healthy Austrians (97%), adjusted for age and sex (P = .03). Cirrhosis at diagnosis was the best predictor of death (odds ratio, 6.8; 95% confidence interval, 1.5-31.03; P = .013) and need for a liver transplant (odds ratio, 07; 95% confidence interval, 0.016-0.307; P < .001). Only 84% of patients with cirrhosis survived 20 years after diagnosis (compared with healthy Austrians, P =.008). CONCLUSION: Overall, patients who receive adequate care for Wilson disease have a good long-term prognosis. However, cirrhosis increases the risk of death and liver disease. Early diagnosis, at a precirrhotic stage, might increase survival times and reduce the need for a liver transplant.

Efficacy and safety of oral chelators in treatment of patients with Wilson disease.

BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.

Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management.

Pyruvate kinase deficiency is a chronic illness with age specific consequences. Newborns suffer life-threatening hemolytic crisis and hyperbilirubinemia. Adults are at risk for infections because of asplenia, pregnancy-related morbidity, and may suffer organ damage because of systemic iron overload. We describe 27 Old Order Amish patients (ages 8 months-52 years) homozygous for c.1436G>A mutations in PKLR. Each subject had a predictable neonatal course requiring packed red blood cell transfusions (30 ± 5 mL/kg) to control hemolytic disease and intensive phototherapy to prevent kernicterus. Hemochromatosis affected 29% (n = 4) of adult patients, who had inappropriately normal serum hepcidin (34.5 ± 12.7 ng/mL) and GDF-15 (595 ± 335pg/mL) relative to hyperferritinemia (769 ± 595 mg/dL). A high prevalence of HFE gene mutations exists in this population and may contribute to iron-related morbidity. Based on our observations, we present a strategy for long-term management of pyruvate kinase deficiency.

Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.

BACKGROUND & AIMS: Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin. RESULTS: A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of aceruloplasminemia in three affected siblings. Two siblings presented with movement disorders and diabetes. Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809-852 while preserving the open reading frame. Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver. Aceruloplasminemia was associated with severe brain and liver iron overload, where hepatic mRNA expression of the iron hormone hepcidin was increased, corresponding to the degree of iron overload. Hepatic iron concentration normalized after 3 and 5months of iron chelation therapy with deferasirox, which was also associated with reduced insulin demands. During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload. CONCLUSIONS: Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain. Iron accumulation in aceruloplasminemia is a result of defective cellular iron export, where hepcidin regulation is appropriate for the degree of iron overload. Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron.

Iron supplementation in athletes--first do no harm.

Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.