Plasma Ferritin Levels Research Articles

Deferasirox limits cartilage damage following haemarthrosis in haemophilic mice.

Joint bleeds in haemophilia result in iron-mediated synovitis and cartilage damage. It was evaluated whether deferasirox, an iron chelator, was able to limit the development of haemophilic synovitis and cartilage damage. Haemophilic mice were randomly assigned to oral treatment with deferasirox (30 mg/kg) or its vehicle (control) (30 mg/kg). Eight weeks after start of treatment, haemarthrosis was induced. After another five weeks of treatment, blood-induced synovitis and cartilage damage were determined. Treatment with deferasirox resulted in a statistically significant (p< 0.01) decrease in plasma ferritin levels as compared to the control group (823 ng/ml ± 56 and 1220 ng/ml ±114, respectively). Signs of haemophilic synovitis, as assessed by the Valentino score [range 0 (normal) - 10 (most affected)], were not different (p=0.52) when comparing the control group with the deferasirox group. However, deferasirox treatment resulted in a statistically significant (p< 0.01) reduction in cartilage damage, as assessed by the loss in Safranin O staining [range 0 (normal) - 6 (most affected)], when comparing the deferasirox group with the control group: score 2 (65.4 % vs 4.2 %), score 3 (26.9 % vs 4.2 %), score 4 (7.7 % vs 20.8 %), score 5 (0 % vs 54.2 %), and score 6 (0 % vs 16.7 %). Treatment with deferasirox limits cartilage damage following the induction of a haemarthrosis in haemophilic mice. This study demonstrates the role of iron in blood-induced cartilage damage. Moreover, these data indicate that iron chelation may be a potential prevention option to limit the development of haemophilic arthropathy.

High dose intravenous iron, mineral homeostasis and intact FGF23 in normal and uremic rats.

BackgroundHigh iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats.MethodsIron was administered iv as a single high dose of 80 mg/kg bodyweight and the effects on plasma levels of iFGF23, phosphate, Ca2+, PTH, transferrin, ferritin and iron were examined in short and long term experiments (n = 99). Blood samples were obtained at time 0, 30, 60, 180 minutes, 24 and 48 hours and in a separate study after 1 week. Uremia was induced by 5/6-nephrectomy.ResultsNephrectomized rats had significant uremia, hyperparathyroidism and elevated FGF23. Iron administration resulted in significant increases in plasma ferritin levels. No significant differences were seen in plasma levels of iFGF23, phosphate and PTH between the experimental groups at any time point within 48 hours or at 1 week after infusion of the iron compounds compared to vehicle.ConclusionsIn non-iron depleted normal and uremic rats a single high dose of either of two intravenous iron preparations, iron isomaltoside 1000, and ferric carboxymaltose, had no effect on plasma levels of iFGF23 and phosphate for up to seven days.

Design of Long Circulating Nontoxic Dendritic Polymers for the Removal of Iron in Vivo

Patients requiring chronic red blood cell (RBC) transfusions for inherited or acquired anemias are at risk of developing transfusional iron overload, which may impact negatively on organ function and survival. Current iron chelators are suboptimal due to the inconvenient mode of administration and/or side effects. Herein, we report a strategy to engineer low molecular weight iron chelators with long circulation lifetime for the removal of excess iron in vivo using a multifunctional dendritic nanopolymer scaffold. Desferoxamine (DFO) was conjugated to hyperbranched polyglycerol (HPG) and the plasma half-life (t1/2) in mice is defined by the structural features of the scaffold. There was a 484 fold increase in t1/2 between the DFO (5 min) versus the HPG-DFO (44 h). In an iron overloaded mouse model, efficient iron excretion by HPG-DFO in the urine and feces was demonstrated (p = 0.0002 and 0.003, respectively) as was a reduction in liver, heart, kidney, and pancreas iron content, and plasma ferritin level (p = 0.003, 0.001, 0.001, 0.001, and 0.003, respectively) compared to DFO. Conjugates showed no apparent toxicity in several analyses including body weight, serum lactate dehydrogenase level, necropsy analysis, and by histopathological examination of organs. These findings were supported by in vitro biocompatibility analyses, including blood coagulation, platelet activation, complement activation, red blood cell aggregation, hemolysis, and cell viability. This nanopolymer-based chelating system would potentially benefit patients suffering from transfusional iron overload.

Abstract B57: Premenopausal plasma ferritin levels, HFE polymorphisms, and risk of breast cancer in the Nurses' Health Study II

Abstract Background: Evidence from the Nurses' Health Study II (NHSII) suggests that red meat consumption is associated with increased breast cancer risk in premenopausal women. Iron may be responsible by contributing to oxidative stress or effects on immune function. Methods: We conducted a case-control study nested within the NHSII examining prediagnostic plasma ferritin (n=795 cases, 795 controls), 15 hemochromatosis gene (HFE) SNPs (n=772 cases, 1,368 controls), and breast cancer risk. Cases were diagnosed with cancer after providing blood samples between 1996 and 1999. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for ferritin levels by conditional logistic regression and for HFE SNPs by unconditional logistic regression. Results: We did not observe a significant association between ferritin levels and breast cancer (top vs. bottom quartile multivariate OR: 1.05, 95% CI: 0.77-1.45, P-value for trend: 0.77). Results did not change when restricted to women who were premenopausal at blood draw, and were similar when cases were examined by hormone receptor status and menopausal status at diagnosis. No HFE SNPs were significantly associated with breast cancer in a log-additive manner. Among controls, ferritin levels were nominally associated with SNPs rs9366637 (P-value for trend: 0.04), rs6918586 (P-value for trend: 0.06) and rs13161 (P-value for trend: 0.07), but results did not remain significant after adjusting for multiple testing. Conclusions: Ferritin levels and HFE SNPs were not associated with breast cancer risk in this population. Components of red meat other than iron are likely responsible for its positive association with breast cancer in premenopausal women. Citation Format: Rebecca E. Graff, Cho Eunyoung, Sara Lindström, Peter Kraft, Walter C. Willett, A Heather Eliassen. Premenopausal plasma ferritin levels, HFE polymorphisms, and risk of breast cancer in the Nurses' Health Study II. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B57.

RISCO DE ANEMIA FERROPRIVA EM CRIANÇAS COM BAIXOS NÍVEIS DE FERRITINA

Em crianças pré-escolares a anemia ferropriva pode comprometer a capacidade de aprendizagem, além de produzir efeitos comportamentais como a falta de atenção, fadiga e cansaço que podem levar ao baixo rendimento escolar. O objetivo deste estudo foi verificar o número de crianças de 02 a 06 anos que realizaram as dosagens de ferritina, ferro sérico e hemograma, com suspeita de anemia ferropriva, num laboratório clínico, no primeiro semestre de 2011, buscando avaliar os resultados dos referidos exames e estabelecer a prevalência de anemia ferropriva nos indivíduos estudados. Foi conduzido um estudo observacional descritivo do tipo transversal. Através do software SADIG-BI, utilizado para gerenciamento de dados, foram selecionadas 363 crianças de 02 a 06 anos que realizaram os exames ferritina, ferro sérico e hemograma no período de 01/01/2011 a 31/07/2011. As crianças do sexo masculino apresentaram níveis plasmáticos de ferritina significativamente mais baixos quando comparadas com as crianças do sexo feminino (p&lt;0,05). Com relação aos parâmetros ferro sérico e hemoglobina, não foram observadas diferenças significativas entre os participantes dos dois sexos. Das 363 crianças estudadas, 9 (2,5%) apresentavam anemia ferropriva (Hb ≤11,0 g/dL e Ferritina ≤12 ng/mL). Foi observada uma baixa prevalência de anemia ferropriva nas crianças estudadas. O achado mais importante deste estudo foi o risco quase cinco vezes maior do desenvolvimento de anemia ferropriva em crianças que apresentaram níveis plasmáticos de ferritina menores ou iguais a 12 ng/mL, sugerindo que este valor pode ser considerado o melhor ponto de corte para a população estudada.

The relation between body iron stores and adipose tissue function in patients with manifest vascular disease

We investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights. In a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers. Increasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without (β -0·13; 95% CI -0·30 to 0·04) or with the metabolic syndrome (β -0·04; 95% CI -0·17 to 0·10). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30μm Fe(III)-citrate vs. control (500±98pg/mL vs. 194±31pg/mL, P=0·03). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30μm Fe(III)-citrate did not influence adiponectin secretion compared with control. In patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron.

Deferoxamine Reduces Neuronal Death and Hematoma Lysis After Intracerebral Hemorrhage in Aged Rats

Intracerebral hemorrhage (ICH) is primarily a disease of the elderly. Deferoxamine (DFX), an iron chelator, reduces long-term neurological deficits and brain atrophy after ICH in aged rats. In the present study, we investigated whether DFX can reduce acute ICH-induced neuronal death and whether it affects the endogenous response to ICH (ferritin upregulation and hematoma resolution) in aged rats. Male Fischer 344 rats (18 months old) had an intracaudate injection of 100 μL autologous whole blood into the right basal ganglia and were treated with DFX (100 mg/kg) or vehicle 2 hours post-ICH and then every 12 hours up to 7 days. Rats were euthanized 1, 3, or 7 days later for neuronal death, ferritin and hematoma size measurements. Plasma ferritin levels and behavioral outcome following ICH were also examined. DFX treatment significantly reduced ICH-induced neuronal death and neurological deficits. DFX also suppressed ferritin upregulation in the ipsilateral basal ganglia after ICH and hematoma lysis (hematoma volume at day 7: 13.2±4.9 vs. 3.8±1.2 mm3 in vehicle-treated group, p<0.01). However, effects of DFX on plasma ferritin levels after ICH did not reach significance. In conclusion, DFX reduces neuronal death and neurological deficits after ICH in aged rats. It also affects the endogenous response to ICH.

Hepcidin, iron status, and inflammation variables among healthy pregnant women in the Turkish population

Purpose: To investigate hepcidin levels in each trimester and their association with other haematological variables and inflammation markers during normal pregnancy among low-risk pregnant women in rural Turkey.Method: The series comprised 103 healthy Turkish primigravida women with a normal pregnancy. Blood samples were obtained at 11–14, 24–28 and 30–34 weeks of gestation. Haemoglobin, hematocrit, red cell indices, white blood cell count, platelet count, iron status indicators (plasma iron, transferrin, ferritin levels and iron binding capacity), serum hepcidin, interleukin-6 and C-reactive protein levels were analysed. The proportions were compared using Pearson’s χ2 test or Friedman’s test.Results: The mean serum hepcidin concentrations at 11–14, 24–28 and 30–34 weeks of gestation were as follows: 7.8 ± 3.4 ng/mL, 8.6 ± 3.1 ng/mL and 7.3 ± 3.0 ng/mL, respectively. The mean serum ferritin concentrations with median values at each trimester were 14.2 (11.5), 9.5 (8.8) and 11.2 (9.3), respectively. The mean serum CRP values at each trimester were 5.1 (4.0), 5.5 (4.6) and 6.0 (5.5), respectively. The serum hepcidin levels were not related to iron status or the haemoglobin, IL-6 or C-reactive protein levels.Conclusions: There was no association between serum hepcidin and serum ferritin, IL-6 or CRP concentrations in each trimester among low-risk pregnant women.

Correlation ofhemochromatosisgene mutations and cardiovascular disease in hemodialysis patients

BACKGROUND AND OBJECTIVESCardiovascular disease (CVD) is a major cause of death in hemodialysis (HD) patients. Hemochromatosis (HFE) gene mutations are reported to be associated with CVD. The present study aims to investigate the association of HFE gene polymorphism with CVD in HD patients.DESIGN AND SETTINGSCross-sectional case-control.METHODSC282Y/H63D mutations of HFE gene were evaluated in 560 HD patients and 480 healthy controls from 4 HD centers in North China. The results obtained from this evaluation process were correlated with biochemical parameters including iron status (serum iron, ferritin, and transferrin concentration), cardiovascular disease, and inflammation marker CRP, IL-6, TNF-α.RESULTSNo C282Y mutations were detected in HD patients or healthy controls in this study. The genotype of H63D heterozygous mutation was similar in HD patients with CVD, HD patients without CVD, and controls. H63D homozygous mutation was 7.4% (19/257), 3.1% (9/303), and 1.0% (5/480) for the 3 groups, respectively. Compound heterozygosity was not found in this study. The relative risk for CVD in HD patients with H63D homozygous mutation was 2.59 (95% CI: 1.15–5.84). H63D homozygous mutation had significantly higher serum ferritin concentrations compared with wild-type individuals. Moreover, HD patients had significantly higher levels of inflammatory biomarkers such as CRP, IL-6, and TNF-α. The multivariate logistic regression analysis revealed that H63D mutation instead of ferritin level was an independent risk factor of CVD for HD patients.CONCLUSIONSOur study demonstrates for the first time that there was an association between H63D homozygous mutations and CVD in HD patients. Elevated serum CRP, IL-6, and TNF-α levels were also related to CVD in HD patients.

Laboratory variables for assessing iron deficiency in REDS-II Iron Status Evaluation (RISE) blood donors.

Iron deficiency is common in regular blood donors. We evaluated the diagnostic sensitivity and specificity of red blood cell (RBC) hematology analyzer indices to assess iron status as a part of donor management. A total of 1659 male and female donors from the Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation (RISE) study who were either first-time/reactivated (FT/RA; no donations for 2 years) or frequent donors were recruited into a longitudinal study of regular donation of RBCs. Of these, 1002 donors returned 15 to 24 months later for a final assessment. Absent iron stores (AIS) was defined as plasma ferritin level of less than 12 μg/L. Logarithm of the ratio of soluble transferrin receptor to ferritin of at least 2.07 (≥97.5% in FT/RA males) was used to define iron-deficient erythropoiesis (IDE). Receiver operating characteristics analysis was performed to assess selected RBC indices (e.g., percentage of hypochromic mature RBCs, proportion of hypochromic mature RBCs [HYPOm], and hemoglobin [Hb] content of reticulocytes [CHr]) in identifying AIS and IDE. HYPOm and CHr detected IDE with comparable sensitivity, 72% versus 69%, but differed in specificity: HYPOm 68% and CHr 53%. For detecting AIS, sensitivity was improved to 85% for HYPOm and 81% for CHr but specificity was reduced for both. Venous Hb had high specificity but poor sensitivity for IDE and AIS. A plasma ferritin level of less than 26.7 μg/L was a good surrogate for assessing IDE. RBC indices correlate with AIS and IDE and are more informative than Hb measurement, but lack sufficient sensitivity and specificity to be used as diagnostic tools in blood donors at risk for iron deficiency.

The Plasma Concentration of Copper and Prevalence of Depression Were Positively Correlated in Shift Nurses

Several studies have reported the prevalence of depression in shift nurses to be 15%, and in some cases it may even be as high as 23%. Depression is a major cause of poor sleep quality and can impede efforts to overcome the chronic fatigue that commonly affects shift nurses. Adverse mental health issues have been confirmed in shift nurses, but few studies have investigated the underlying cause of poor mental health in different shift-nurse populations. Therefore, the aim of this study was to investigate the relationship of serum trace element levels to mental health and the tendency toward depression in shift nurses. We collected blood samples from 90 shift nurses (day, evening, and night shift) who worked in intensive care units and asked them to complete a general data questionnaire as well as the Chinese version of the Beck Depression Inventory, second edition. The night-shift nurses showed mild-to-moderate depression levels, which were significantly higher than those of the control group and other shift nurses. Night-shift nurses also had higher levels of plasma copper, ferritin, interleukin (IL)-6, and alanine aminotransferase (p < .05) than the control group and other nurses. Elevated concentrations of ferritin and IL-6 are considered important markers for the onset of depression. The results of this study suggest that plasma copper concentrations in nurses should be monitored.

Erythrocyte membrane fatty acid composition is related to overloaded plasma ferritin in Chinese males with angiographic coronary artery disease

Not only is iron deficiency an abnormal iron status, but iron overload is also harmful for human health. It has been reported that overloaded iron stores are positively associated with increased coronary artery disease (CAD) risk, which is called the "iron-heart hypothesis". Previous studies evaluating the relationships between fatty acids (FAs) and body iron status only focused on participants with iron deficiency. However, whether FA composition is related to overloaded iron remains unclear. Therefore, this study was designed to investigate the relationships between erythrocyte membrane FA (Ery-FA) composition and overloaded body iron status as measured by plasma ferritin levels in Chinese CAD patients. A total of 446 subjects with angiographically identified CAD (mean age 63.1 years, 76.9% males) were recruited in a hospital between 2009 and 2010. Ery-FAs were measured by gas chromatography and the activities of FA desaturases, which are involved in the de novo synthesis of unsaturated FAs, were evaluated by using FA product-to-precursor ratios. Results showed that the average iron status was a bit overloaded in the population (median ferritin levels of 234.1 ng mL(-1) and 40.4% males of overload). Moreover, in males, saturated FAs (SFAs) were positively correlated (22 : 0, r = 0.182, p = 0.001; 24 : 0, r = 0.214, p < 0.001), whereas monounsaturated FAs (MUFAs) and n-6 polyunsaturated FAs (PUFAs) were negatively correlated (18 : 1n-9, r = -0.120, p = 0.028; 18 : 2n-6, r = -0.216, p < 0.001) with plasma ferritin levels. A negative correlation (r < 0, p < 0.05) between stearoyl-CoA desaturase (SCD) activity and ferritin levels was also found in males. However, all the significant associations above were not observed in females. In conclusion, the Ery-FA composition was related to overloaded plasma ferritin levels only in Chinese males with angiographic CAD, which might be linked to the change of SCD activity. The results may contribute to the understanding of the mechanism of the iron-heart hypothesis.

Hypoplastic Anemia in Cartilage-Hair Hypoplasia—Balancing between Iron Overload and Chelation

To evaluate the severity of iron overload and the success of iron chelation therapy in patients with cartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators. Four of the 23 presently surviving Finnish patients with CHH under 18 years of age are dependent on regular red blood cell transfusions. Their hospital records were reviewed for history of anemia and chelation therapy. Cumulative iron load from transfusions was calculated. Efficacy of the chelation therapy was evaluated biochemically and by liver iron content assessments. At the introduction of iron chelation, the patients had received on average 99 (37-151) transfusions; the mean cumulative iron overload was 4640 (800-8200) mg, the annual iron accumulation rate 0.35 (0.25-0.41) mg/kg/d, and the mean plasma ferritin was 2896 (1217-6240) μg/L. Liver iron content, determined by biopsy in 3 patients, was on average 20.0 (6.6-30.0) mg/g liver dry weight. All patients, except 1 with Hirschsprung disease, tolerated deferoxamine, deferiprone, and deferasirox therapy well, showing only mild adverse effects typical for the agents. Plasma ferritin levels and liver magnetic resonance imaging T2* of iron overload showed successful chelation. Iron chelation is well tolerated in patients with CHH, with possible exception of patients with Hirschsprung disease. Successful chelation will prepare for hematopoietic stem cell transplantation in patients with CHH with persistent transfusion dependency.

Iron overload, an immunosuppression marker in HIV‐infected patients

PurposeIron overload (IO) has been associated with increased cardiovascular risk (CVR) and metabolic syndrome (MS) in the general population; both elevated CVR and MS are frequent in HIV‐patients. Our aim was to analyze the prevalence of IO in a cohort of asymptomatic patients with HIV infection, and related factors.MethodsCross‐sectional study of a cohort of HIV outpatients in regular follow‐up. Demographic, epidemiological, clinical, analytical and therapeutic data were collected. Patients completed a questionnaire about CVR factors and 10‐year CV disease risk estimation (Framingham score), underwent a physical exam, and a fasting blood analysis. IO was defined as a plasma ferritin level higher than 200 μ/L in women and 300 μ/L in men.Results571 patients (446 men, 125 women), with a mean age of 43.2 years, sexual transmission of HIV in 68.5%, median CD4 count 474 cell/μL (IQR: 308–666), and 36.3% Aids cases. 86.2% were on antiretroviral therapy (ART), and 74.8% of them had undetectable HIV viral load. 14.6% met MS criteria, and mean CVR at 10 years was 6.67%. IO was detected in 11% of cases. Patients with IO were more immunosuppressed (CD4 count 369 vs 483/μL, p&lt;0.0001), presented a higher prevalence of detectable HIV viral load (17.6% vs 8.9%; p&lt;0.005), and of Aids cases (14.9% vs 8.7%; p&lt;0.023), and lower plasma levels of cholesterol, HDLc and LDLc (154 vs 183, 34 vs 43, 93 vs 110 mg/dL, respectively; p&lt;0.0001. In the multivariate analysis, the only related factor was CD4 count &lt;350 cell/μL (OR 2.86, 95% CI 1.6–4.9; p&lt;0.0001). IO was not associated with CVR nor with MS.ConclusionsIO is not uncommon in HIV patients, and it is only related with immunosuppression defined as CD4 count &lt;350 cell/μL, and in contrast to general population, it is not related with increased CVR nor with MS.

High serum ferritin levels are associated with metabolic risk factors in non‐obese Korean young adults: Korean National Health and Nutrition Examination Survey (KNHANES) IV

The purpose of this study is to investigate the relationship between serum ferritin levels and metabolic risk factors in nonobese Korean young adults. We analysed the fourth annual Korea National Health and Nutrition Examination Survey (KNHANES) in young adults (aged 19-39 years), conducted between 2007 and 2008. A total of 1542 nonobese [body mass index (BMI) <25 kg/m(2) ] young adults (684 men and 858 women) were enrolled. Using blood pressure and levels of serum triglycerides, plasma glucose and high-density lipoprotein (HDL) cholesterol, the Asian criteria for abdominal obesity (Waist circumference ≥90 cm in men or ≥80 cm in women) was used to identify individuals with metabolic syndrome. Data on anthropometry, fasting plasma glucose, insulin, lipid profile and ferritin levels were analysed. The prevalence of metabolic syndrome was 4·1% for men and 2·7% for women. High fasting glucose and the prevalence of metabolic syndrome increased progressively across three different tertiles of ferritin levels in men. However, high ferritin levels were associated with high triglycerides, low HDL cholesterol and metabolic syndrome in women. After adjustment for age, smoking, alcohol consumption, BMI and ALT levels, low HDL cholesterol (OR 1·66, 95% confidence interval (CI) 1·16-2·36) and the presence of metabolic syndrome (OR 3·87, 95% CI 1·34-11·2) were independently associated with high serum ferritin levels in Korean nonobese young women. Our results suggest that elevated serum ferritin levels may be employed as a marker of metabolic syndrome in nonobese young adult women.

A rare cause of osteonecrosis

IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disorder caused by mutations in the HFE gene, which increase intestinal iron absorption. The prevalence of C282Y homozygosity, which causes the disorder, is 0.5% in Caucasian populations. The clinical manifestations are related to excess iron in the tissues, especially the liver, heart, pancreas, pituitary, and skin. They include fatigue, loss of libido or impotence in males, liver disease, skin pigmentation, diabetes mellitus, cardiac enlargement—with or without heart failure, and conduction defects. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation (“bronze diabetes”) results from a combination of iron deposits and melanin. It occurs late in the disease, when the total body iron content is more than five times the normal value, about 20 grams. Left untreated, approximately half of all patients with HH eventually develop arthralgia or arthropathy. Chondrocalcinosis, chronic pseudo-osteoarthritis, and osteoporosis are the major rheumatic manifestations of HH. The cause of the arthropathy is still unknown. Iron deposits within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition, which stimulate immune complex formation and inflammation.Materials and methodsWe describe the case of a 48-year-old male suffering from chronic bilateral ankle pain.ResultsThe work-up revealed osteonecrosis of ankle. The patient also presented high plasma ferritin levels and homozygosity for the C282Y mutation. Other than HH, which was confirmed by liver biopsy, the patient had no other risk factors for osteonecrosis.DiscussionHH represents a rare cause of osteonecrosis, and there are no prior reports of aseptic osteonecrosis of the ankle in a patient with this disease. The pathogenetic mechanism remains unknown.

Relationship between Plasma Ferritin Level and Siderocyte Number in Splenectomizedβ-Thalassemia/HbE Patients

Introduction. In iron overload status, excess iron deposits in reticuloendothelial cells and tissues and can be detected using Prussian blue staining. The aim of this paper was to investigate the relationship between siderocyte numbers and plasma ferritin levels (a practically standard marker of iron overload) in the blood of the splenectomized and nonsplenectomized β-thalassemia/HbE patients, who are at risk of iron overload. Methods. EDTA blood samples from 64 patients with 35 splenectomized and 29 nonsplenectomized β-thalassemia/HbE patients, who received regular blood transfusions, and 20 normal individuals were investigated for siderocyte numbers, plasma ferritin levels, and complete blood counts. Results. The average percent siderocytes in splenectomized and nonsplenectomized β-thalassemia/HbE patients were 11.5% and 0.08%, respectively, and plasma ferritin levels of 2,332 μg/L and 1,279 μg/L, respectively. Percent siderocytes showed a good correlation with plasma ferritin levels only in splenectomized patients (r = 0.69, P < 0.001). A receiver operating curve analysis from splenectomized patients' data indicated that siderocytes at 3% cut-off are the best predictor for plasma ferritin level ≥1,000 μg/L with 92.9% sensitivity and 42.9% specificity. Conclusion. Circulating siderocyte numbers can be used as a screening test for the assessment of the iron overload in splenectomized β-thalassemia/HbE patients in the place where serum ferritin is not available.

Fortified juice drink improved iron and zinc status of schoolchildren.

Energy and micronutrient deficiency remain prevalent among Filipino children. Juice drinks are commonly consumed and could be a viable vehicle for fortification to supplement the nutrient gap. This study determined the effects of a newly developed non-carbonated fortified juice drink on the iron, zinc and nutritional status of schoolchildren. One hundred randomly selected anemic children were randomly allocated into two groups in a doubly-masked placebo controlled manner: Group 1 received the fortified juice, Group 2 received the non-fortified juice for 100 days, five days a week under strict supervision. The juice drink was fortified with vitamin A, zinc, iron, vitamin C and lysine. The non-fortified juice was fortified only with vitamin C. All children were dewormed prior to the intervention. Hemoglobin, plasma ferritin and plasma zinc, weight and height were assessed using standard methods before and after intervention. A two-day 24-hour food recall was also collected. The basal prevalence of anemia was significantly reduced in both the fortified group (100% to 13%) and the non-fortified group (100% to 40%) at endline. The mean plasma ferritin levels were similar in both groups at baseline and endline. At endline, mean plasma zinc in the fortified group has significantly increased by 20 μg/dL from a baseline value of 83.9 μg/dL to 103.9 μg/dL, while the non-fortified group remained at similar levels with baseline. Basal weight and height significantly increased among all children at endline. The fortified juice drink was effective in reducing the prevalence of anemia and improved the zinc status of children.

Low Activity of Cytochrome P450 1A2 (CYP1A2) Enzyme May Protect From Iron Accumulation in Children and Adults with Transfusion Depended β-Thalassemia Major

Abstract 2153In human, normal iron homeostasis fails to prevent the harmful accumulation of iron in patients who require regular blood transfusions. Some patients will progress to liver fibrosis and cirrhosis, but others, with the same degree of iron overload, would not express any liver damage. Cytochrome P450 1A2 (CYP1A2), a cytochrome enzyme with pivotal role in hepatic drug metabolism, was shown in a CYP1A2−/− mice to be essential for hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to iron load in children and adults with transfusion-depended β-thalassemia major (TM) using the 13C-methacetin breath test. Methods:13C-methacetin continuous online breath test (MBT, BreathID® Exalenz Bioscience) was performed in children and adults with transfusion-depended TM. MBT parameters including PDR peak (percent dose recovered per hour), cumulative percentage of 13C recovery at 20 minutes (CPDR20) after ingestion of methacetin and time to peak PDR (TTP) were correlated with various clinical, blood and MRI measures. The t-test was used to assess difference of normally distributed continuous data, Mann-Whitney test was used to assess difference of non-normally distributed continuous data and the Fisher’s exact test was used to assess differences of categorical data. The study was approved by the Institutional Review Board. Results:Thirty patients [Jewish Kurdistan origin (n=14), Arab origin (n=16)] were enrolled to the study. The median (range) age of participants was 30 (1–60) years. All patients were treated with regular blood transfusion and all but one patient, were treated with iron chelation therapy [Deferoxamine (n =4), Deferiprone (n=2), Deferasirox (n=15), Combinations (n=7)]. Time from starting regular transfusion ranged from 0.8–56 years. Mean red blood cell (RBC) transfused was 100 cc/kg/year. Plasma ferritin level < 1000 mcg/l was found in 14 patients, and was not associated with age, origin, time of initiation of regular blood transfusion and amount of RBC transfusion. The PDR peak and CPDR20 were significantly lower in patients with ferritin levels < 1000 mcg/l compared to those with ferritin levels > 1000 mcg/l (PDR peak, mean±SD: 24±8 vs. 31± 10, p=0.013; CPDR20: 3.9± 2 vs. 5.5± 2.2, p=0.045, t-test). During the study period, 21 patients had T2* MRI scans. Liver MRI was normal (T2* MRI > 6.3 milliseconds) in 8 patients, and was not associated with age, origin, time of initiation of regular blood transfusion and amount of RBC transfusion. As expected, plasma ferritin levels were significantly lower in patients with normal liver MRI (Ferritin, median (range): 376 (110–1506) vs.1349 (205–8223), p=0.008, Mann-Whitney test). Decreased activity of CYP1A2 (PDR peak < 20%/hour) was associated with normal liver MRI (Table 1). All patients with decreased activity of CYP1A2 and normal liver MRI were from Jewish Kurdistan origin. Conclusions:Our study is the first to show an association between low activity of CYP1A2 and low liver iron accumulation in transfusion depended TM patients. Similar to the murine model, this finding may suggest that primary low CYP1A2 activity protects from iron accumulation. The fact that CPY1A2 activity in most patients with liver iron accumulation is normal implies that decreasing dosage of various drugs is probably not warranted in patients with hepatic iron overload. Further larger studies and genetic testing are needed to confirm our observations.Table 1:Association between CYP1A2 activity and liver iron accumulationLiver T2* MRINormal (> 6.3 ms)Abnormal (< 6.3 ms)PDR peak < 20%/hr51PDR peak > 20%/hr312ms, milliseconds; hr, hour. p=0.014, Fisher Exact test Disclosures:No relevant conflicts of interest to declare.

A Phase 2 Clinical Study of HQK-1001 (2,2-dimethylbutyrate, sodium salt), a Fetal Hemoglobin Inducer, in Patients with Sickle Cell Disease

Abstract 1066▪▪This icon denotes a clinically relevant abstractFetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943).This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period. [Display omitted] Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events. Disclosures:Aiello:HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.