Serum Ferritin Iron Research Articles

Pancreatic Iron and Bone Health in Thalassemia Major

Background. It has been shown that serum ferritin and heart iron content are good indicators of bone mineral density (BMD) in patients with beta thalassemia major (TM). In the present study we explored for the first time the relationship between pancreatic iron and BMD and bone markers in TM.Methods. We considered 135 TM patients (68 M, mean age 37.79±7.74 years) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) Network. BMDs of the lumbar vertebrae (L1-L4) and femoral neck were measured by dual X-ray absorptiometry (DEXA) and were expressed as T-scores. Pancreatic iron overload was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. Blood samples were collected for the measurement of bone formation markers (procollagen 1 amino-terminal propeptide-P1NP, osteocalcin and bone-specific-BAP alkaline phosphatise), bone resorption marker (carboxy-terminal telopeptide of type I collagen-CTX), calcium, and vitamin D.Results. Pancreatic T2* values were significantly associated to lumbar T-scores (R=0.207, P=0.017) as well as to femoral T-scores (R=0.242, P=0.005). The correlations remained significant also in patients without diabetes. Pancreatic iron (global pancreas T2*<26 ms) was detected in 8 patients. Patients with pancreatic iron showed significant lower lumbar T-scores (-2.61±0.89 vs -1.60±0.89; P=0.031) as well as femoral T-scores (-2.12±1.17 vs -1.03±0.97; P=0.009) and 7 of them (87.6%) had lumbar and femoral T-scores indicating osteopathy (osteopenia or osteoporosis).As regards as the markers, pancreatic T2* values were negatively correlated to BAP (R=-0.196 P=0.031) and positively correlated to vitamin D (R=0.220, P=0.014).Conclusion. A significant correlation, although not strong, was detected between pancreatic iron overload and bone disease. From a different point of view, our results support the role of endocrinopathies in thalassemic osteopathy and underline the critical role of a multi-disciplinary intervention in preventing bone complications. DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Transfusion- Related Iron Overload (TRIO) Is Associated with Delayed Engraftment and Increased Non Relapse Mortality (NRM) in Patients Undergoing Umbilical Cord Blood (UCB) Hematopoietic Cell Transplantation (HCT)

▪TRIO has been shown to be associate with higher risk of morbidity (infections, venocclusive disease and hepatic dysfunction) and mortality after allogeneic HCT. A high transplant iron score (>25 red cell unit transfused prior to HCT, serum ferritin > 1000 ng/ml and a bone marrow (BM) iron stain of +6) was associated with 50% decrease in survival at one year (Storey J. Hem & Oncol 2009). TRIO in BM macrophages can generate free radicals resulting in oxidant stress thereby altering the hematopoietic microenvironment. This could have adverse effects on hematopoiesis and affect engraftment after HCT. To date, limited data are available on the effect of TRIO on outcomes of UCB HCT. We examined whether TRIO quantified based on serum ferritin (sF) and BM iron score (MIS) impact outcomes of UCB HCT, particularly with regards to engraftment.We reviewed 150 consecutive patients (pts) who underwent UCB HCT between March 2006 and September 2015 at City of Hope. Median age at time of HCT was 33.5 years (yrs) (range: 0-70 years) with 55% male and 23% < 18 yrs of age. sF was available within 30 days before HCT for 65%, and MIS was assessed on the pre-HCT BM biopsy for 40% of pts. HCT indications included bone marrow failure (n=13), hemoglobinopathies (n=2), lymphoma (n=23), acute leukemia (n=104), and chronic leukemia (n=8). Disease risk index (DRI) was high/very-high in 38% and 20% of pts had HCT comorbidity index of more than 2. One cord graft was received for 20% of pts. Median TNC of 4.9X10^7/kg (range: 1.8-26.6) and median CD34 count of 1.8X10^5/kg (range: 0.2-122.4). HLA match status was 4/6, 5/6, 6/6 in 93, 48, and 9 pts. Almost 60% of pts received myeloablative conditioning regimen (MAC) and 80% had calcineurin inhibitor/mycophenolate mofetil for graft versus host disease (GVHD) prophylaxis.With a median follow-up of 48.1 months (range: 5.8- 119.6), 2- and 5-yrs progression free survival (PFS) were 41% and 35.5% while 2- and 5-yrs OS were 47% and 36%, respectively. Cumulative incidence (CI) of NRM at 2 and 5 yrs were 35.7 and 40.6% and CI of relapse at 2- and 5-yrs were 23 and 24%, respectively. Day 100 grade II-IV and grade III/IV aGvHD were 56.7% and 28.7%. 2 yrs CI of cGvHD was 51.7% with 38.8% extensive cGvHD. DRI was found to be significant factor for relapse (HR 1.74 95%CI 0.88-3.45 p<0.001) and conditioning regimen significantly affect OS (HR= 1.92 95%CI 1.24-2.96; p=0.003), PFS (HR= 2.12 CI 1.39-3.24; p<0.001) and relapse rate (HR= 4.07 CI 1.95-8.49; p<0.001) when non-myeloablative/reduced intensity conditioning was compared with MAC. However, day 100 grade II-IV and III/IV aGVHD was increased in pts with MAC (65.1% vs 45.3%; p=0.006 and 37.2% vs 17.2%; p=0.005; respectively) with no significant effect seen on the NRM (p=0.9).In multivariable analysis, sF <1000 ng/ml independently predicted for shorter OS (HR=0.49; CI 0.27-0.88 p=0.015). When the impact of sF was examined by quartiles, pts in the highest sF quartile (>1948 ng/ml) had shorter OS (HR=3.05, 95%CI: 1.40-6.66; p=0.03) and higher NRM (HR=2.79, 95%CI: 1.16-6.72; p=0.03) compared to those in the lowest quartile (<530 ng/ml) (Fig 1a and b). There was no statistically significant difference in regards to disease relapse, or incidence of acute or chronic GVHD across sF groups.Patients in the highest sF quartile had delayed platelet engraftment compared to those in the lowest quartile (HR=0.46, 95%CI: 0.24-0.89, p=0.03). A trend towards delayed neutrophil engraftment was also observed between these 2 groups (HR=0.57, 95%CI: 0.33-0.99; p=0.055) (Fig 1c and d). No significant difference was seen in neutrophil (p=0.67) or platelet engraftment (p=0.92) based on MIS. But there was a statistically significant increase of grade II-IV aGVHD in pts with MIS of 3-4 (63.8% vs 30.8% at day 100; p=0.04). This however did not translate into worse OS, NRM or relapse.In conclusion, TRIO measured by sF has an adverse impact on OS and NRM in recipients of UCB HCT. Elevated sF is also associated with delay in platelet and neutrophil engraftment after UCB HCT. MIS was not associated with time to engraftment, however, this value was available in only 40% of pts. Therefore, TRIO should be considered as a risk factor for adverse outcome and poor graft function after UCB HCT. [Display omitted] DisclosuresNademanee:seattle Genetics: Speakers Bureau.

Serum Ferritin Underestimates Liver Iron Concentration in Patients with Homozygous Alpha-0 Thalassemia

Background: Homozygous α0-thalassemia (Hemoglobin Bart's hydrops fetalis, HBHF) results from deletion of all α-globin genes. Similar to patients with transfusion-dependent beta-thalassemia (TDT-β), survivors of HBHF require life-long transfusions which over time will inevitably lead to significant tissue iron overload (IO). We have recently reported that the underlying disease process in HBHF is different from that of TDT-β (Amid A. et al. Blood, 2016). Unlike TDT-β, hemolysis is the major pathophysiologic process in HBHF and chronically transfused HBHF patients continue to have significant erythropoietic activity and tissue hypoxia (with increased serum erythropoietin) due to the indegenous nonfunctional hemoglobin-H. In addition, almost all survivors of HBHF would have commenced their transfusion therapy in-utero, potentially resulting in earlier IO compared to their TDT-β counterparts. Considering these differences, we hypothesized that the pattern of IO in patients with HBHF would likely differ from those with TDT-β.Methods: Following research ethics board approval, we retrospectively collected longitudinal data on transfusion and chelation history, serum ferritin, and liver iron concentration (LIC) measured by MRI or biopsy, in 7 HBHF (5 males; mean age: 7.3 years) and 14 TDT-β (8 males; mean age: 11.1 years) patients. None of the HBHF or TDT-β patients were splenectomized. Corresponding pairs of serum ferritin and LIC assessment (defined as measurements of not more than two weeks apart with no transfusions in between) were used to calculate ferritin-to-LIC ratios. All patients were treated with the same transfusion protocol to maintain pre-transfusion hemoglobin of >90 g/L and LIC of <5 mg/g of dry liver weight, until 2014. Since April 2014, five patients with HBHF have been commenced on a more aggressive transfusion strategy to decrease the nonfunctional HbH, suppress erythropoiesis, increase tissue oxygenation, and reduce hemolysis. We used linear mixed models to assess the associations between serum ferritin, LIC, and ferritin-to-LIC ratio with age, disease type (HBHF vs. TDT-β), chelation type, and method of LIC assessment. Correlations within a subject and between different ages were effectively accounted for in this model.Results: At 12 month of age, chelation-naïve HBHF patients had significantly higher serum ferritin level reflecting earlier IO compared to chelation-naïve TDT-β patients [1242.4 μg/dL (SD 419.4) vs. 418.3 μg/dL (SD 113.3), p<0.001]. On longitudinal assessments in both chelated HBHF and TDT-β patients, ferritin was significantly correlated with LIC (ρ = 0.88, p <0.001 and ρ = 0.46, p <0.001, respectively). Serum ferritin was significantly lower in HBHF vs. TDT- β [849 μg/dL (SD 573) vs. 2036 μg/dL (SD 1495), p<0.001] but there was no difference in LIC between the two groups [9.68 mg/g (SD 5.73) vs. 8.63 mg/g (SD 7.99), p=0.48]. Consequently, HBHF patients had significantly lower ferritin-to-LIC ratios [86.8 (SD 33.2) vs. 308.5 (SD 182.4), p<0.0001]. In addition, in the HBHF patients, serum ferritin-to-LIC ratio was corrolated with reticulocyte count (ρ = 0.41, p <0.042). In two mixed model analyses that included age, disease type, and method of LIC assessement or chelation type as variable of interset, disease type remained a highly signifiant predictor of serum ferritin-to-LIC ratio (p<0.0001). However, after the implementation of aggressive transfusion strategy (and suppression of erythropoeitic activity and improvement of tissue oxygenation) in HBHF patients, ferritin-to-LIC ratios were significantly higher [304.2 (SD 121.5) vs. 86.87 (SD 33.2), p=0.0003], becoming similar to ratios in TDT-β patients (p=0.88).Conclusion: Patient with HBHF are at-risk of significant IO early in life which poses potential challenges with iron chelation at an early age. Furthermore, in these patients, ferritin significantly underestimates LIC. This finding has important implications for clinical care and surveillance of IO in these patients, especially in areas with limited resources where non-invasive assessement of LIC (MRI) may not be widely available. The lower ferritin-to-LIC ratio observed in HBHF patients and its relation to erythropoietic activity indirectly suggest that in addition to transfusional iron loading, increased gastrointestinal absorption of iron due to suppressed hepcidin may also contribute to siderosis in these patients. DisclosuresNo relevant conflicts of interest to declare.

Optimizing the Management of Iron Overload in Patients with Hemoglobin Disorders in Centers with Limited Access to Magnetic Resonance Imaging

Background:Transfusion therapy for severe chronic anemias is a major cause of iron overload. Patients with hemoglobin disorders are often transfused, either chronically or occasionally, and if iron overload is suspected, it is currently recommended they are subjected to so-called “iron studies” and determination of liver iron content (LIC) and heart T2* by magnetic resonance imaging (MRI). It remains common practice to request both laboratory and imaging tests, even for patients already undergoing iron chelation, despite the unreliability of laboratory markers such as ferritin in the presence of concurrent inflammatory conditions, which do not affect results from MRI scans. Since MRI is not widely available in most underdeveloped and developing countries, we aimed to assess the contribution of laboratory tests to the management of patients with hemoglobin disorders with iron overload by analyzing a cohort of patients who managed to undergo MRI during a period of limited access to MRI scans in our center.Methods: In this single-center, retrospective analysis, data were collected from digital MRI, laboratory information system, and electronic chart databases, upon approval of the local ethics board. Since access to MRI was limited during the period of time studied, physicians used the following criteria to indicate MRI scans to define clinical suspicion of iron overload: patient already undergoing chelation therapy based on previous laboratory tests and clinical assessment, current or previous chronic transfusion therapy, or elevated ferritin with transferrin saturation (TSAT) above 45%.Results and Discussion: From April 2014 to September 2016, 27 patients (17 with sickle cell disease - SCD, 10 with beta thalassemia - BT), median age 35 years (15-62), 9 male (33%), were evaluated at 34 different occasions with MRI and conventional iron studies. Patients with BT had significantly higher levels of serum iron and TSAT than patients with SCD (BT median 266ug/dL, range 93-328 and 0.94, range 0.41-1.00; SCD median 157ug/dL, range 58-264, and 0.64, range 0.21-1.00, P=0.004 and P=0.0138), which reflects a higher percentage of BT patients on chronic transfusions (8/11 vs. 6/17) and the higher transfusion volume for BT in comparison to what is needed for exchange transfusions in SCD. Four patients had normal MRI scans: 1 with SCD not in transfusion, 1 with SCD that had been treated with iron chelation, and 2 BT major in chronic transfusion and optimal response to iron chelation (ferritin <500ng/mL). Only one SCD and one BT patient were diagnosed with cardiac iron overload, with a T2* of 7.5ms and 2.95ms, respectively, in patients with extreme hyperferritinemia (11,567 and 7,090ng/mL) and low compliance to iron chelation. MRI liver iron concentration correlated positively with serum ferritin and total iron binding capacity (TIBC) measurements (r=0.67, 95% CI 0.41-0.83, P <0.0001, and r=-0.49, 95% CI -0.72 to -0.17, P <0.004, respectively) but no serum biomarkers correlated with myocardial iron concentrations. Receiver operating characteristic (ROC) curve analysis showed that ferritin levels performed best in our population as predictor of any increase of LIC above 2mg/g (area under curve 0.9753, P=0.0003), with a cutoff value of 731.6ng/mL with a sensitivity of 96.3% and specificity of 100% to discriminate for the presence of any increase in hepatic iron. In addition, a ferritin cutoff value of 1649ng/mL yielded 76.2% sensitivity and 91.7% specificity to detect a LIC above 5mg/g, comprising 17 (50%) of the MRI scans. Only one patient in this group had less than moderate liver iron overload, but still with an abnormal LIC of 3.5mg/g.Conclusions: Our data suggest that conventional iron studies cannot predict cardiac siderosis, but earlier evaluation with MRI may be warranted in the presence of clinical risk factors such as history of chronic transfusion along with low compliance to iron chelation, independently from laboratory tests. In settings with limited access to MRI, ferritin levels may be useful in pre-screening for hepatic iron overload, so postponing probable negative scans for patients undergoing iron chelation with optimal response or probable positive scans for those with certain levels of hyperferritinemia (e.g.>1649mg/dL) could be appropriate criteria to manage referrals to MRI scans and help prioritize patients with undetermined indication of iron chelation. DisclosuresFertrin:Alexion Pharmaceuticals: Consultancy.

Impact of baseline serum ferritin and supplemental iron on altitude-induced hemoglobin mass response in elite athletes.

The present study explored the impact of pre-altitude serum (s)-ferritin and iron supplementation on changes in hemoglobin mass (ΔHbmass) following altitude training. Measures of Hbmass and s-ferritin from 107 altitude sojourns (9-28days at 1800-2500m) with world-class endurance athletes (males n=41, females n=25) were analyzed together with iron supplementation and self-reported illness. Altitude sojourns with a hypoxic dose [median (range)] of 1169 (912) km·h increased Hbmass (mean±SD) 36±38g (3.7±3.7%, p<0.001) and decreased s-ferritin -11 (190) µg·L-1 (p=0.001). Iron supplements [27 (191) mg·day-1 ] were used at 45 sojourns (42%), while only 11 sojourns (10%) were commenced with s-ferritin <35µg/L. Hbmass increased by 4.6±3.7%, 3.4±3.3%, 4.2±4.3%, and 2.9±3.4% with pre-altitude s-ferritin ≤35µg·L-1 , 36-50µg·L-1 , 51-100µg·L-1 , and >100µg·L-1 , respectively, with no group difference (p=0.400). Hbmass increased by 4.1±3.9%, 3.0±3.0% and 3.7±4.7% without, ≤50mg·day-1 or >50mg·day-1 supplemental iron, respectively (p=0.399). Linear mixed model analysis revealed no interaction between pre-altitude s-ferritin and iron supplementation on ΔHbmass (p=0.906). However, each 100km·h increase in hypoxic dose augmented ΔHbmass by an additional 0.4% (95% CI: 0.1-0.7%; p=0.012), while each 1g·kg-1 higher pre-altitude Hbmass reduced ΔHbmass by -1% (-1.6 to -0.5; p<0.001), and illness lowered ΔHbmass by -5.7% (-8.3 to -3.1%; p<0.001). In conclusion, pre-altitude s-ferritin or iron supplementation were not related to the altitude-induced increase in Hbmass (3.7%) in world-class endurance athletes with clinically normal iron stores.

Correlation of Serum Ferritin and Liver Iron Concentration with Transient Liver Elastography in Adult Thalassemia Intermedia Patients with Blood Transfusion.

IntroductionIron overload is a common feature of thalassemia intermedia due to regular blood transfusion and increased gastrointestinal iron absorption. Early detection and adequate iron chelator can decrease morbidity and mortality from iron overload. Liver iron concentration (LIC) by MRI T2* is the best non-invasive way to measure body iron stores. However, this method is expensive and not available nationwide in Indonesia. The aim of this study was to identify liver iron overload and correlation of transferrin saturation, serum ferritin, liver MRI T2* and LIC with transient liver elastography in adult thalassemia intermedia patients.MethodsThis is a cross-sectional study of 45 patients with thalassemia intermedia with blood transfusion and with and without iron chelator therapy. The study was conducted at Cipto Mangunkusumo Hospital from August through October 2016. We performed measurements of transferrin saturation, serum ferritin level, transient liver elastography and liver MRI T2*. Pearson and Spearman correlation tests were used to evaluate the correlation between transient liver elastography with transferrin saturation, serum ferritin, liver MRI T2*and LIC.Results and DiscussionThis study showed that 64.4% of study subjects are β-Hb E thalassemia intermedia. Furthermore, 84.4% of study subjects have regular transfusion. Based on liver MRI T2*all subjects suffered from liver iron overload, 48.9% had severe degree. Median value of liver MRI T2* was 1.6 ms. Mean serum ferritin was 2831 ng/mL, with median transferrin saturation of 66%. Mean of LIC corresponding to liver MRI T2* and mean liver stiffness measurement was 15.36±7.37 mg Fe/gr dry weight and 7.7±3.8 kPa, respectively. Liver stiffness correlated with serum ferritin (r=0.651; p=0.000), liver MRI T2* (r=−0.357; p=0.016), and LIC (r=0.433; p=0.003). No correlation was found between liver elastography and transferrin saturation (r=0.204; p=0.178).ConclusionSerum ferritin, liver MRI T2*and LIC correlated with liver elastography. No correlation was found between transferrin saturation and liver elastography.

Evaluation of Corneal Epithelial Thickness and Dry Eye Disease Tests in Thalassemic Adolescents.

PurposeTo assess dry eye disease (DED) in thalassemic adolescents by evaluating corneal epithelial thickness (CET) and various dry eye clinical tests and correlate them to tissue iron overload.MethodsThe study included 120 Beta-thalassemia patients (11 to 18 years) and 120 matched controls. CET maps were captured using anterior segment optical coherence tomography. OSDI questionnaire was completed. Dry eye tests included Schirmer test, tear film breakup time ‎‎ (TBUT), and ocular surface staining (OSS) with fluorescein and lissamine green. We recorded serum ferritin ‎level, and liver iron concentration (LIC) measured by magnetic resonance imaging.ResultsSuperior and inferior CET was thinner, while map standard deviation (MSD) was higher in thalassemics compared to controls (all P‎<0.001‎). Thalassemic group also showed higher OSDI scores‎ (P‎<0.001), shorter TBUT ‎‎(P‎<0.001‎), and higher OSS grades (P‎<0.001‎). Both superior and inferior CET was correlated positively with TBUT, and negatively with OSS (all P < 0.001). Serum ferritin and LIC showed negative correlations with CET (superior and inferior, both P< 0.001), positive correlations with MSD, P< 0.001, as well as with TBUT (P< 0.001), OSS ‎(P< 0.001), and OSDI scores (P< 0.001).ConclusionThalassemic adolescents had thinner CET with higher thickness’ variability, shorter TBUT and more marked OSS‎ than controls. Correlation of higher serum ferritin and hepatic iron overload with irregular epithelial thinning and more affected dry eye tests results supports our hypothesis that high tissue iron levels could play a pivotal role in DED pathogenesis in thalassemic patients.

Evaluation of Punarnavadi Mandura for haematinic activity against mercuric chloride-induced anemia in albino rats.

Punarnavadi Mandura, a compound Ayurvedic formulation, is one of the most commonly used medicine in the treatment of anemia (Pandu) in Ayurveda. The safety profile of this formulation is well established; however, no pharmacological study has been reported to provide the scientific basis for its use in the treatment of anemia. To evaluate the hematinic effect of Punarnavadi Mandura against mercuric chloride-induced anemia in albino rats. The test drug (Punarnavadi Mandura) was suspended in distilled water and administered orally in a dose of 450 mg/kg for 30 days in rats. Anemia was induced by simultaneous administration of mercuric chloride (9 mg/kg) for 30 consecutive days. Body weight was noted for each animals. At the end, haematological parameters, anaemia markers like serum iron, ferritin, and total iron binding capacity (TIBC), as well as relative weight of organs and histopathology investigation, were examined. Exposure of mercuric chloride to rats for 30 days resulted in a significant decrease of body weight, an increase in the weight of the liver and kidney and a decrease in hemoglobin content. It also decreased serum ferritin to a significant extent and increased serum TIBC. Histopathology of the liver shows macro fatty changes, vacuolization, marked necrosis, and severe degenerative changes, while the kidney shows cell infiltration. All these changes were significantly attenuated by the administration of Punarnavadi Mandura. The present data indicate that Punarnavadi Mandura has possessing marked cytoprotective activity, significantly attenuated the HgCl2-induced adverse changes on red blood cell related parameters, and showing hematinic activity in albino rats.

Effect of Different Complementary Feeding on Iron Deficiency Anemia and Growth in Breastfed Infants: Home-Made VS Commercial

After approximately 6 months of age, term breastfed infants are increasingly depend on other sources of iron to avoid iron deficiency anemia, due to the depletion of the low concentration of iron in human milk. The appropriate complementary feeding must include a balance composition of foods containing an adequate amount of macro- and micronutrients to avoid iron deficiency anemia. This study aimed to compare the risk of iron deficiency and growth in breastfeed infants receiving commercial fortified complementary foods or home-made. A cross-sectional study was held on April-June 2016 to evaluate infants aged 6-24 months with breast feeding intake for 6 month of life. Complementary feeding practices were determined by questionnaire; an unquantified food frequency and feeding practices questionnaire was used to determine usual food intake. Biochemical assessment of haemoglobin (Hb), serum ferritin (SF) and serum iron (SI) level were measured. Anthropometric were assessed using WHO Child Growth Standard 2005. Statistical analysis used were Chi-square Test. Thirty eight infants were enrolled, mean age of 16.2 (SD 10.5) months. 17 infants consumed commercial complementary foods and 21 infants use home-made. Infants with home-made had lower Hb level, SF and SI than those receiving commercial complementary food, and had higher risk of underweight, stunted and wasted. Infants with home-made complementary food had lower haemoglobin, serum feritin and serum iron levels than those in fortified complementary food CF; and a higher risk of stunted and wasted than children with commercial fortified CF.

The serum ferritin levels and liver iron concentrations in patients with alpha-thalassemia: is there a good correlation?

ABSTRACT Introduction Liver iron overload is common in patients with thalassemia. In patients with beta-thalassemia, the correlation between serum ferritin and liver iron concentration is well established. The correlation between serum ferritin levels and liver iron concentrations in patients with alpha-thalassemia remains limited. Methods This is a cross-sectional study in patients with alpha-thalassemia aged ≥ 18 years old at Srinagarind Hospital, Khon Kaen University, Thailand. Liver iron concentration (LIC) was evaluated by the MRI-T2* technique. Linear logistic regression analysis was used to determine the correlation between serum ferritin levels and liver iron concentrations. Results One hundred and thirty-one of the MRI-T2* measurements from 65 patients with alpha-thalassemia were evaluated. Patients with non-deletional alpha-thalassemia had higher LIC compared to patients with deletional alpha-thalassemia. The serum ferritin levels were relatively low at the same levels of LIC in patients with non-deletional alpha-thalassemia compared to deletional alpha-thalassemia. Conclusions The correlation of serum ferritin levels and LIC was modest and different among alpha-thalassemia genotypes. A different serum ferritin threshold is needed to guide iron chelation therapy in patients with alpha-thalassemia. Evaluation of liver iron concentration is necessary for patients with alpha-thalassemia, especially in patients with non-deletional alpha-thalassemia.

Evidence of Genetic Transmission in African Iron Overload

AbstractIron overload in Africa was previously regarded as purely due to excessive iron in traditional beer, but we recently found evidence that transferrin saturation and unsaturated iron binding capacity may be influenced by an interaction between dietary iron content and a gene distinct from any HLA-linked locus. To determine if serum ferritin follows a genetic pattern and to confirm our previous observations, we studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was characterized with repeated morning measurements of serum ferritin, transferrin saturation, and unsaturated iron binding capacity after supplementation with vitamin C. For each measure of iron status, segregation analysis was consistent with an interaction between a postulated iron-loading gene and dietary iron content (P < .01). In the most likely model, transferrin saturation is 75% and serum ferritin is 985 ’g/L in a 40-year-old male heterozygote with an estimated beer consumption of 10,000 L, whereas the saturation is 36% and serum ferritin is 233 ’g/L in an unaffected individual with identical age, sex, and beer consumption. This segregation analysis provides further evidence for a genetic influence on iron overload in Africans.

Still’s Disease–A Case of Diagnostic Dilemma

Still’s disease is an auto-inflammatory multisystem disease characterized by high spiking fever, salmon-colored rash that comes and goes, arthritis and other varieties of systemic manifestations. The puzzling fever and leukocytosis and high serum level of procalcitonin mistakenly may lead to diagnosis of severe bacterial infection or sepsis. But use of broad-spectrum antibiotic fails to improve the condition. It may mimic other multisystem autoimmune rheumatic diseases, but autoantibodies are negative. It may resemble the malignancies like leukemia and lymphoma, but lymph node biopsy and bone marrow study does not support. We have reported a case of Still’s disease in a 14-year-old young boy. Initially he presented like a viral illness, but high fever persisted for more than 4 weeks associated with body ache and skin rash withoutany arthritis. He had cervical lymphadenopathy, mild hepatosplenomegaly, pleural and pericardial effusion. He had persistent leukocytosis, high serum procalcitonin and high serum ferritin but low serum iron. Bacterial infection and sepsis were excluded, hematologic malignancy was ruled out by lymph node biopsy and bone marrow examination. There was no conclusive evidence of tuberculosis. Still a therapeutic trial was given but failed to produce any benefit. After exclusion of all the possible differentials and basing on diagnostic criteria he was diagnosed as a case of Still’s disease. With the use of steroid and immunosuppressive agent his condition improved dramatically and now he is leading a normal life.&#x0D; JAFMC Bangladesh. Vol 15, No 2 (December) 2019: 240-242

Retraction to: Minocycline ameliorates osteoporosis induced by ovariectomy (OVX) and iron accumulation via iron chelation, bone metabolism regulation and inhibition of oxidative stress.

OBJECTIVE To investigate the effect and mechanism of minocycline on iron accumulation-related postmenopausal osteoporosis. METHODS The present study established a rat model of ovariectomy (OVX), gave rats ferric ammonium citrate (FAC) and treated them with minocycline, then examined the severity of osteoporosis and iron metabolism in rats. To further explore the mechanism, osteoblasts were treated with FAC and minocycline, then their effects on cell viability, apoptosis, alkaline phosphatase (ALP) activity, bone metabolism proteins, iron metabolism proteins, and oxidative stress in osteoblasts were measured. RESULTS In the animal study, OVX significantly decreased the serum estradiol level. Both OVX and FAC significantly increased the serum ferritin and tibial iron level, which was significantly decreased by minocycline (P < 0.05). Minocycline significantly increased the ratio of BV/TV, Tb.Th and Tb.N (P < 0.05), and the levels of BALP, BGP and CTX, but decreased the levels of TRAP and ratio of RANKL/OPG (P < 0.05 compared to OVX+FAC group). In the cell study, minocycline significantly decreased the cellular iron accumulation and induced cell death and apoptosis (P < 0.05). Minocycline significantly increased the ALP activity, the expression of Collagen I, Osteocalcin and OPG (P < 0.05). Minocycline significantly decreased the expression of Ferritin and hepcidin, and increased the expression of FPN) (P < 0.05). It also significantly decreased the cellular MD) and protein carbonyl level and RO) intensity, but increased the levels of SO) and GP) (P < 0.05). CONCLUSION Minocycline ameliorated osteoporosis induced by OVX and iron accumulation. The mechanism may involve iron chelation, regulation of bone and iron metabolism, and inhibition of oxidative stress.

Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique for its incomplete penetrance, variety of disease onsets, and waxing and waning phenotypes. Iron deficiency is a trigger of ADHR. This study aimed to clarify the role of iron deficiency in ADHR. Data of clinical manifestations and laboratory examinations were collected from patients among eight kindreds with ADHR. Multiple regression and Pearson's correlation tests were performed to test the relationships of serum phosphate levels and other laboratory variables during the patients' follow-ups. Among 23 ADHR patients with fibroblast growth factor 23 (FGF23) mutations, 14 patients presented with obvious symptoms. Ten patients had iron deficiency at the onset of ADHR, coinciding with menarche, menorrhagia, pregnancy, and chronic gastrointestinal bleeding. Two patients who did not have their iron status tested presented with symptoms after abortion and pregnancy in one patient each, which suggested that they also had iron deficiency at onset. Patients were treated with ferrous succinate tablets, vitamin C, and neutral phosphate and calcitriol. With correction of the iron status, the patients' symptoms showed notable improvement, with increased serum phosphate levels. Two patients' FGF23 levels also declined to the normal range. There were strong correlations between serum phosphate and serum iron levels (r = 0.7689, p < 0.0001), serum ferritin levels (r = 0.5312, p = 0.002), iron saturation (r = 0.7907, p < 0.0001), and transferrin saturation (r = 0.7875, p < 0.001). We also examined the relationships between serum phosphate levels and hemoglobin-related indices, which were significant (hemoglobin: r = 0.71, p < 0.0001; MCV: r = 0.7589, p < 0.0001; MCH: r = 0.8218, p < 0.0001; and MCHC: r = 0.7751, p < 0.0001). Longitudinal data of six patients' follow-up also showed synchronous changes in serum phosphate with serum iron levels. Iron deficiency plays an important role in triggering ADHR. Monitoring and correcting the iron status are helpful for diagnosing and treating ADHR. Iron metabolism parameters and hemoglobin-related parameters are positively correlated with serum phosphate levels in patients with ADHR and iron deficiency, and these might serve as good indicators of prognosis of ADHR.

Sympathetic Overactivation in Patients With Essential Hypertension and Hepatic Iron Overload.

Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P<0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P<0.03), transferrin saturation (r=0.47, P<0.03), and hepatic iron load (r=0.76, P<0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P<0.05). These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.

Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: a systematic review.

Attention deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with iron dysregulation in children. Although previous focus was on examining systemic iron status, brain iron content may be a more reliable biomarker of the disorder. This systematic review examines whether children with ADHD have lower serum as well as brain iron concentrations, compared with healthy control subjects (HCS). A systematic literature search was conducted in Medline via PubMed, the Cochrane Library, Web of Science, Embase. and Ovid for papers published between 2000 and June 7, 2019. Studies were included if the mean difference of iron concentration, measured as serum iron, serum ferritin, or brain iron, between children with ADHD and HCS was an outcome measure. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Risks of bias within and between studies were assessed using the quality assessment tools of the National Institutes of Health. Of 599 records screened, 20 case-control studies met the inclusion criteria. In 10 of 18 studies in which serum ferritin concentration was assessed, and 2 of 10 studies that assessed serum iron, a significant difference between children with ADHD and HCS was observed. Results of systemic iron levels were inconsistent. In 3studies in which brain iron concentration was assessed, a statistically significant, lower thalamic iron concentration was found in children with ADHD than in HCS. The evidence, though limited, reveals that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. Larger, longitudinal, magnetic resonance imaging studies are needed to examine any correlations of iron deficiency in specific brain regions and symptoms of ADHD.

Minocycline ameliorates osteoporosis induced by ovariectomy (OVX) and iron accumulation via iron chelation, bone metabolism regulation and inhibition of oxidative stress.

To investigate the effect and mechanism of minocycline on iron accumulation-related postmenopausal osteoporosis. The present study established a rat model of ovariectomy (OVX), gave rats ferric ammonium citrate (FAC) and treated them with minocycline, then examined the severity of osteoporosis and iron metabolism in rats. To further explore the mechanism, osteoblasts were treated with FAC and minocycline, then their effects on cell viability, apoptosis, alkaline phosphatase (ALP) activity, bone metabolism proteins, iron metabolism proteins, and oxidative stress in osteoblasts were measured. In the animal study, OVX significantly decreased the serum estradiol level. Both OVX and FAC significantly increased the serum ferritin and tibial iron level, which was significantly decreased by minocycline (P < 0.05). Minocycline significantly increased the ratio of BV/TV, Tb.Th and Tb.N (P < 0.05), and the levels of BALP, BGP and CTX, but decreased the levels of TRAP and ratio of RANKL/OPG (P < 0.05 compared to OVX+FAC group). In the cell study, minocycline significantly decreased the cellular iron accumulation and induced cell death and apoptosis (P < 0.05). Minocycline significantly increased the ALP activity, the expression of Collagen I, Osteocalcin and OPG (P < 0.05). Minocycline significantly decreased the expression of Ferritin and hepcidin, and increased the expression of FPN) (P < 0.05). It also significantly decreased the cellular MD) and protein carbonyl level and RO) intensity, but increased the levels of SO) and GP) (P < 0.05). Minocycline ameliorated osteoporosis induced by OVX and iron accumulation. The mechanism may involve iron chelation, regulation of bone and iron metabolism, and inhibition of oxidative stress.

Economic Evaluation of Severe Anaemia: Review-Based Recommendations and a Conceptual Framework

Objective: Novel anaemia treatments have greatly improved patient outcomes in the last decade and have also undergone economic evaluations in various settings using heterogenous model structures, costs, and inputs. The objectives were to review published economic evaluation studies in major red blood cell disorders, identify limitations in the applied methodology, provide a set of recommendations, and produce a conceptual framework for future economic research in this disease area. Methods: A targeted search was conducted for economic literature evaluating treatments in major red blood cell disorders related to anaemia. Disorders included autoimmune haemolytic anaemia, β-thalassaemia, chemotherapy-induced anaemia, anaemia in chronic kidney disease, and severe aplastic anaemia. Budget impact models and cost-effectiveness and cost-utility analyses were considered. Modelling assumptions regarding the model structure, time horizon, perspective, and type of costs were reviewed and recommendations and a conceptual framework for future economic analyses were created. Results: A total of four budget impact models, nine cost-utility analyses, and four cost-effectiveness analyses were investigated. A major limitation was that the included costs varied significantly across studies. Costs which were rarely included, and generally should be considered, were related to adverse events, mortality, and productivity. Additionally, relationships between levels of serum ferritin, hepatic or total body iron, and haemoglobin with long-term complications and mortality were rarely included. Conclusion: Published economic analyses evaluating treatments for major red blood cell disorders frequently exclude vital costs. A set of recommendations and a conceptual framework will aid researchers in applying a more comprehensive approach for economic evaluations in major red blood cell disorders.

Hepatic and cardiac iron load as determined by MRI T2* in patients with congenital dyserythropoietic anemia type I.

Iron overload comprises one of the main complications of congenital dyserythropoietic anemia type I (CDA-I). When analyzing magnetic resonance imaging T2* (MRI T2*) results in CDA patients, two previous studies reported discordant results regarding iron load in these patients. To further understand iron loading pattern in this group of patients, we analyzed MRI T2* findings in 46 CDA-I patients. Mild to moderate hepatic iron overload was detected in 28/46 (60.8%) patients. A significant correlation was found between serum ferritin and liver iron concentration (LIC). A significant correlation (p value = 0.02) was also found between the patient's age and LIC, reflecting increased iron loading over time, even in the absence of transfusion therapy. Notably, no cardiac iron overload was detected in any patient. Transfusion-naive patients had better LIC and better cardiac T2* values. These results demonstrate that a high percentage of CDA-I patients have liver iron concentration above the normal values, risking them with significant morbidity and mortality, and emphasize the importance of periodic MRI T2* studies for direct assessment of tissue iron concentration in these patients, taking age and transfusional burden into consideration.

Reply: Iron chelation may harm patients with COVID-19

Cavezzi A, Troiani E, Corrao S (2020) COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract 10(2). https://doi.org/10.4081/cp.2020.1271 Garrick M, Ghio A (2020) Iron chelation may harm patients with COVID-19. Eur J Clin Pharmacol Herbert V, Jayatilleke E, Shaw S, Rosman A, Giardina P, Grady R et al (1997) Serum ferritin iron, a new test, measures human body iron stores unconfounded by inflammation. Stem Cells 15(4):291–296 Article Google Scholar Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli G, Shoenfeld Y et al (2020) COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res 68(4):213–224 Article Google Scholar Edeas M, Saleh J, Peyssonnaux C (2020) Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis 97:303–305 Article Google Scholar Liu W, Zhang S, Nekhai S, Liu S (2020) Depriving iron supply to the virus represents a promising adjuvant therapeutic against viral survival. Curr Clin Microbiol Rep 7(2):13–19 Article Google Scholar Shi S, Lai M (2005) Viral and cellular proteins involved in coronavirus replication. Curr Top Microbiol Immunol 287:95–131 PubMed PubMed Central Google Scholar Juang H (2004) Modulation of iron on mitochondrial aconitase expression in human prostatic carcinoma cells. Mol Cell Biochem 265(1/2):185–194 Article Google Scholar Download references Spire Fylde Coast Hospital, St Walburgas Road, Blackpool, FY3 8BP, UK Anis Abobaker You can also search for this author in PubMed Google Scholar Correspondence to Anis Abobaker. The author declares that he has no conflict of interest. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions Abobaker, A. Reply: Iron chelation may harm patients with COVID-19. Eur J Clin Pharmacol (2020). https://doi.org/10.1007/s00228-020-02988-9 Download citation Received: 12 August 2020 Accepted: 27 August 2020 Published: 01 September 2020 DOI: https://doi.org/10.1007/s00228-020-02988-9