Serum Ferritin Levels Research Articles

Amlodipine Therapy in β-Thalassemia Patients: A Systematic Review and Meta-Analysis on Ferritin Levels and Liver MRI T2*

Background and aim: We conducted a review to determine the efficacy of amlodipine alongside iron chelators on serum ferritin levels and liver T2-weighted magnetic resonance imaging (MRI T2*) in β-thalassemia patients. Methods: Systematic search was conducted in multiple databases, including Web of Science, PubMed, Scopus, Embase, Cochrane Library, ClinicalTrials.gov, the Iranian Registry of Clinical Trials (IRCT), ProQuest, OpenGrey, and Web of Science Conference Proceedings Citation Index. The search was closed in January 2023. Primary outcomes were comprised of liver MRI T2* (millisecond (msec)) and serum ferritin levels (ng/mL). Results: Seven studies (n = 227) were included in the study. The pooled Cohen’s d for serum ferritin was estimated at −0.46, 95% confidence interval (CI) −1.11 to 0.19 and p = 0.16 (I2 86.23%, p < 0.0001). The pooled mean difference for serum ferritin was −366.44 ng/mL, 95% CI −844.94 to 112.05, and p = 0.13 (I2 81.63%, p < 0.0001). After a meta-regression based on the length of using amlodipine, a coefficient for the mean difference was also −23.23 ng/mL and 95% CI −155.21 to 108.75. The coefficient obtained from a meta-regression as per the amlodipine dose at 5 mg/day than 2.5 to 5 mg/day anchored at −323.49 ng/mL and 95% CI −826.14 to 1473.12. A meta-regression according to the baseline values of serum ferritin discovered a coefficient of 1.25 ng/mL and 95% CI 0.15 to 2.35. Based on two included studies (n = 96), the overall Cohen’s d for liver MRI T2* was 2.069, 95% CI −0.896 to 5.035, and p = 0.17 (I2 96.31%, p< 0.0001). The synthesized mean difference for liver MRI T2* was 8.76 msec, 95% CI −4.16 to 21.67, and p = 0.18 (I2 98.38%, p < 0.000). Conclusion: At a very low level of evidence, probably using amlodipine at a dose of 2.5 to 5 mg a day, up to a year, alongside iron chelators slightly decreases serum ferritin levels in iron-overloaded thalassemia cases by nearly 366 ng/mL (23 ng/mL per month). The liver MRI T2* might also rise to 8.76 msec upon co-therapy with amlodipine.

Exploring The Effect of Wheat Grass Juice on Thalassaemia: A Comprehensive Review

Thalassemia is a hereditary blood disorder characterized by a deficiency in the oxygen-carrying protein (haemoglobin) and a reduced number of red blood cells in the body compared to normal. Mild forms of thalassemia may not necessitate treatment, while severe cases may require blood transfusions or a stem-cell transplant from a donor. Wheatgrass extract is seen as a supplementary treatment option for thalassemia, although research in this field is still in its early stages. Wheatgrass is a low-calorie substance but rich in essential nutrients, including antioxidants like glutathione, vitamin C, and vitamin E that plays a crucial role in combating harmful free radicals in the body, reducing oxidative stress, and providing protection against conditions such as arthritis, cancer, and neurodegenerative diseases. The proposed mechanism behind wheatgrass extract involves the swift absorption of chlorophyll and its action at the cellular level in the bone marrow, facilitating heme production. Treatment with wheatgrass tablets has been found to maintain serum ferritin levels and increase HbF levels in children with thalassemia who undergo frequent blood transfusions. However, it does not appear to reduce the frequency of blood transfusions required. Wheatgrass tablets also contribute to an improved quality of life for children with thalassemia. The present study aims to investigate the effectiveness of wheatgrass therapy in patients with transfusion-dependent anemia, further extensive studies involving a larger patient population would be necessary.

Hyperferritinemia among very-low-birthweight infants in Thailand: a prospective cohort study.

To determine the incidence of hyperferritinemia in VLBW infants, and its association with neonatal morbidity. Prospective cohort study in a tertiary-level hospital in Bangkok, from March 2022 to January 2023. Serum ferritin (SF) was measured in VLBW infants at one month and repeated monthly for those with hyperferritinemia (SF > 300 ng/mL). Gestational age and birth weight were 29.7 ± 2.4 weeks (mean ± SD) and 1100 g (IQR, 830, 1340). Hyperferritinemia was identified in 30.1% (95% CI, 20.8-41.4). After adjustment, only packed red cell transfusion >15 mL/kg was associated with hyperferritinemia (RR 3.1; 95% CI, 1.5-6.4). All elevated SF levels returned to normal within four months. Hyperferritinemia was associated with severe bronchopulmonary dysplasia (RR 2.3, 95% CI, 1.0-5.4) and retinopathy of prematurity (RR 3.5, 95% CI, 1.4-8.6). Hyperferritinemia is common among our VLBW infants, particularly after transfusion, and is associated with severe BPD and ROP.

Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis. Although the aetiology and pathology remain unclear, increasing evidence suggests that viral infection is a potential trigger of MDA5-DM. Multiple factors, including T cells, B cells, neutrophils and macrophages, are implicated in the pathophysiology of MDA5-DM. Distinctive skin rashes, rapidly progressive interstitial lung disease, peripheral lymphopenia and elevated serum ferritin levels are the most prominent clinical and laboratory features of MDA5-DM. Concomitant infection is a common complication of MDA5-DM. The proper evaluation of patients with MDA5-DM requires knowledge of the disease heterogeneity and clinical course variability. Several biomarkers, including serum levels of anti-MDA5 antibodies and biomarkers related to macrophage activation, have been identified as useful tools for monitoring disease activity and prognosis. MDA5-DM shows a poor response to conventional glucocorticoid and immunosuppressant therapy and has a poor overall prognosis. Therefore, there is an urgent need to explore the key pathogenic mechanisms of MDA5-DM and develop novel therapeutic options for patients. This Review discusses recent clinical progress and pathogenic findings of MDA5-DM.

Association of serum iron and serum calcium levels in children with febrile seizures

Objectives: The current case–control study was conducted to investigate the relationship of iron deficiency anemia and calcium levels with febrile seizures (FSs) in children. Materials and Methods: The study included 200 children ranging in age from 6 to 60 months. One hundred cases had FSs, including simple FSs and rest; 100 controls had a short history of febrile illness (<3 days) without seizures. A statistical analysis of the data was carried out using Statistical Package for the Social Sciences version 23. Results: The mean weight, height, and head circumference of cases and controls are 9.73 ± 2.51 kg and 10.63 ± 3.34 kg, 79.66 ± 11.08 cm and 85.43 ± 15.55 cm, and 46.37 ± 2.79 cm and 46.83 ± 3.72 cm, respectively. As per the Indian Academy of Pediatrics, 27% of cases and 37% of controls had protein energy malnutrition (PEM). In cases and controls, the mean hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and red cell distribution width values were 9.23 ± 1.30 and 10.78 ± 1.60 gm/dL, 68.83 ± 8.86 and 78.59 ± 9.82 fl, 25.40 ± 3.47 and 28.50 ± 3.60 pg, and 18.73 ± 1.77 and 16.44 ± 1.76, respectively, and are statistically significant. Patients had lower serum ferritin levels than controls. The mean blood calcium levels in cases and controls were 9.13 ± 0.64 and 9.05 ± 0.93 mg/dL, respectively (P = 0.507). Iron deficiency anemia was found in 26% of cases and 7% of controls (P value <0.001). Hypocalcemia was reported in only 18% of patients and 23% of controls (P = 0.38). Conclusion: There is a clear correlation between FSs and iron deficiency. The majority of data suggests that hypocalcemia is unlikely to be the cause of FSs. Early detection and intervention of iron deficiency in children could help in the prevention and recurrence of FSs.

Association Between Serum Ferritin Levels in Early Pregnancy and Thyroid Function and Pregnancy Outcomes in Chinese Population.

The relationship of iron deficiency and thyroid hormone has been researched a lot among pregnant or other healthy population. However, invisible iron deficiency, namely shortage of serum ferritin (sFer) level, has been barely investigated among Chinese pregnant women. This study aimed to explore the effects of sFer status on thyroid function and pregnancy outcomes in a population-based upper first-class hospital. A total of 781 singleton pregnant women of gestation in Shanghai General Hospital took part in this retrospective cohort study. The participants were divided into four groups by quartiles of serum ferritin levels (Q1-4). Binary logistic regressions were used to examine the strength of association between the different traits and the serum ferritin (sFer) quartiles separately, where Q1 (lowest ferritin quartile) was taken as the base reference. One-way ANOVA was adopted to compare the averages of the different variables across sFer quartiles. Categorical measures were compared by Fisher exact test or chi-square test. As the sFer concentration rises, incidence of premature birth (15.8%vs 12.3% vs 9.20% vs 6.20% p = 0.016) as well as threatened miscarriage (14.8% vs 7.2% vs 8.70% vs 6.70% p = 0.021) presented a downward trend. Compared with the other sFer group, subjects of the low sFer group were older, more often to be found to have lower serum γT3 and FT4 levels in early pregnancy but not in middle pregnancy. sFer concentration in the first trimester can affect thyroid function. The correction of invisible iron deficiency with inadequate sFer status prior to pregnancy or during early pregnancy is imperative, not only to prevent anemia, but also for maintaining optimum thyroid function and normal fetal development. For clinicians, sFer status of pregnant women should be attached great importance apart from attention to iron level.

Transfusion‐dependent thalassemia patients develop cognitive impairment with gut dysbiosis

AbstractBackgroundThalassemia is an auto‐recessive hemoglobinopathy affecting populations worldwide. Although life expectancy of thalassemia patients has been increasing due to therapeutic advancements, neurocognitive complications have been continuously reported among transfusion‐dependent thalassemia (TDT). Interestingly, the relationships among cognitive decline, systemic iron burden, and gut microbial alterations in TDT patients remain to be determined.MethodTwenty‐eight participants, including 14 TDT patients and 14 heathy controls, were recruited to evaluate a cognitive function using the Mental State Examination T10 (MSET10) test. Serum ferritin was employed to reflect a severity of systemic iron burden. Stool was collected to determine a gut microbial profile using a next‐generation sequencing of bacterial 16s rRNA V3‐V4 regions.ResultTDT patients had the cognitive impairment, higher systemic iron burden, and gut dysbiosis when compared with the controls. TDT patients also had lower MSET10 scores than the controls (Figure 1A). In addition, an increase in serum ferritin was observed in the TDT, indicating that there was the iron burden in the TDT (Figure 1B). Moreover, gut dysbiosis in TDT patients as indicated by higher bacterial diversity and different microbial compositions in comparison with the controls were observed (Figure 1C and 1D). The MSET10 scores were negatively correlated with the levels of serum ferritin and gut microbial diversity (Figure 1E and 1F). Interestingly, the levels of serum ferritin were positively correlated with the gut microbial diversity (Figure 1G).ConclusionThese findings suggest that a systemic iron burden may involve in an alteration of gut microbiota, and the systemic iron burden together with the gut dysbiosis may concurrently deteriorate a cognitive function in TDT patients. Therefore, an iron reduction with a gut microbial manipulation, such as a combined usage of an iron chelator with a probiotic supplement, should provide benefits to prevent neurodegeneration as well as gut microbial disturbance in TDT patients.

Association Between the Polymorphism of Angiotensin-Converting Enzyme Gene and Interleukin-1 Beta Gene and the Response to Erythropoietin Therapy in Dialysis Patients with Anemia.

The polymorphism of the angiotensin-converting enzyme (ACE) gene and interleukin-1 beta (IL-1b) gene could be associated with resistance in the treatment of anemia in dialysis patients with recombinant human erythropoietin (rHuEPO). The aim of the study was to evaluate the association between the polymorphism of the ACE and IL-1b genes and the response to rHuEPO therapy in dialysis patients with anemia. The study investigated 69 patients on dialysis with anemia treated with recombinant human erythropoietin for 12 months. Genotyping of ACE and IL-1b polymorphism was done in all study patients at the initiation of the study. The patient's demographic characteristics, dialysis vintage, and laboratory parameters were also evaluated as factors associated with rHuEPO resistance. The erythropoietin resistance index (ERI) was calculated as the weekly rHuEPO dose per kg of body weight, divided by the hemoglobin (Hb) concentration in g/dl. The Hb ≥ 110 g/l was registered in 37 (53.6%) patients. Patients with Hb ≥ 110 g/l were characterized by significantly higher serum levels of albumin, cholesterol, and iron than those with Hb < 110 g/l. The serum level of the CRP, the weekly dose of rHuEPO, and ERI were significantly higher in patients with Hb < 110 g/l compared to patients with Hb ≥ 110 g/l. The ERI value of ≥ 10 IUkg/weekly/g/dl was present in 27 (39.1%) patients. The serum levels of ferritin and CRP, and weekly dose of rHuEPO were significantly higher in patients with ERI value ≥ 10 IU kg/weekly/g/dl compared with the patients with ERI value < 10 IUkg/weekly/g/dl. There was no significant association between the ERI and polymorphism of the ACE and IL-1b genes in study patients. The polymorphism of the ACE and IL-1b genes was not significantly associated with the response to erythropoietin therapy in dialysis patients with anemia. Iron deficiency, malnutrition, and inflammation were factors associated with anemia and resistance to erythropoietin therapy in dialysis patients.

Выявление и профилактика железодефицитного состояния у доноров крови (компонентов крови)

The problem of iron deficiency among donors is relevant and directly affects the provision of hemocomponents to the blood service. Donors, being a risk group for the development of iron deficiency, are examined before donation, including a study of hemoglobin levels. However, there is no information about the state of iron stores, when depleted, iron deficiency anemia develops. In turn, anemia is a contraindication to donation and, therefore, leads to medical exemptions from donation. The purpose of the study was to evaluate the main indicators of iron metabolism in donors of blood and (or) blood components at risk of developing latent iron deficiency. The examination of 174 donors included a hemogram, assessment of the level of hemoglobin, serum ferritin (SF), transferrin, and soluble transferrin receptors. When assessing the intensity of changes in reserve and transport iron indicators, 228 deviations from the reference range were analyzed. The criterion for the risk of developing iron deficiency was hemoglobin values at the lower limit of normal (130–135 g/l in men and 120–125 g/l in women) and the threshold level of ferritin (30 μg/l in male donors and 20 μg/l in women). The risk group included 58.3% of young donors — women who donate blood 1–2 times during the year (p &lt; 0.01) and 66.6% (p &lt; 0.01) of donors — men who donate blood regularly throughout 4 and &gt; years. The average ferritin level in male donors was 27.37 μg/l (p &lt; 0.02) and lower than the reference values. It is concluded that it is advisable to assess the indicators of iron metabolism in donors in the case of borderline hemoglobin levels, in women of reproductive age after 2 blood donations and in men with the number of donations ≥ 10. To replenish the iron depot in the body, when iron deficiency is detected in donors, it is necessary to consider the issue of prevention.

Awareness and practices in preventing maternal iron deficiency among pregnant women living in urban slum areas in Makassar City, Indonesia.

During pregnancy, the body requires more complex nutritional intake. Therefore, problems with fulfilling nutrition during pregnancy occur often. One of the most common nutritional problems in pregnancy is iron deficiency anemia, the most widespread micronutrient problem and the most difficult to overcome worldwide. This study aimed to determine awareness and prevention behavior associated with the incidence of iron deficiency in pregnant women living in urban slum areas. This was a cross-sectional study. The data collection used KoboToolbox, an Android-based tool. Iron status was examined by serum ferritin level assay using ELISA at the Microbiology Laboratory Unit of Hasanuddin University Hospital. The prevalence of pregnant women who experienced iron deficiency was 78%. The logistic regression analysis showed that poor awareness (AOR = 3.03, CI 95% 1.26-7.29, P = 0.013) and practices in taking iron enhancers (AOR = 2.85, CI 95% 1.18-6.92, P = 0.020) became the main factors associated with iron deficiency among pregnant women. Poor awareness and practices regarding consuming iron enhancers increased the risk of iron deficiency among pregnant women living in urban slum areas. Iron deficiency is a major health concern for pregnant women, especially those living in slum settlements, which must be addressed. A more optimal healthcare system for pregnant women may reduce the incidence of iron anemia in pregnancy by improving health promotion and optimizing healthcare services.

Are serum ferritin levels an indicator of cardiovascular risk in individuals with type 2 diabetes?

Are serum ferritin levels an indicator of cardiovascular risk in individuals with type 2 diabetes?

Serum ferritin level is an effective prognostic factor for lung cancer immunotherapy

ABSTRACT Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X2 = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X2 = 6.475, P = .011). However, the “integrated factor”, which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.

Serum Iron, Ferritin, Erythroferrone and their Inter-Correlation In Adult Cigarette Smokers: A Case-Control study

Cigarette smoking is one of the leading causes of lung and blood cancers worldwide. A higher risk of pulmonary injury is associated with elevated lung iron and ferritin levels. Erythroferrone (ERFE) is a newly discovered tumor necrosis factor (TNF) superfamily member produced by erythroblasts during erythropoiesis. Eventually, it suppresses hepcidin during enhanced erythropoietic activity. The current study investigated the relationship between serum ferritin, iron, and erythroferrone concentrations among adult smokers. This study included 76 selected adult cigarette smokers and 48 healthy individuals (non-smokers) as a control group. The enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay (CLIA) biochemical techniques were used to accurately measure serum iron, ferritin, and erythroferrone. Cigarette smokers (CS) had a mean age of 42.75±2.92 years, while healthy control (HC) subjects had a mean age of 37.36±2.7 years. The findings have shown a significant increase in serum iron, ferritin, and EREF levels in CS (119± 4.30, 131.1±6.58, and 75.02±2.09) compared with HC (98.67±7.84, 85.50±4.12, and 65.74±2.25) respectively. This study has shown a significant positive correlation between serum EREF (P=0.0072, r=0.4089) and the duration of smoking &lt;20 years and a moderate association between serum iron (P=0.1907, r=0.4511) and the duration of smoking &lt;40 years. For the first time, this outcome shows increased serum EREF and overexpression by erythroblasts in subjects associated with smoking habits, along with increased serum iron and ferritin levels. An indicative correlation is found between EREF overexpression, iron overload, and hyperferritinemia with reference to the duration of smoking. The study also illustrates the interconnection between iron metabolism perturbations and ERFE overexpression induced by cigarette smoking.

Hereditary hyperferritinemia cataract syndrome with iron deficiency : a case report

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. HHCS is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. In this case report, we aimed to present a young female patient with a history of cataracts in herself and her family members. Our patient had the dilemma of iron deficiency anemia and hyperferritinemia. As in our patient, patients with HHCS apply to many outpatient clinics and have difficulty in diagnosis. For this reason, we prepared our case to raise awareness.

Nearly Half of Extreme Preterm Infants Are Iron Deficient at 4-6 Months of Corrected Age Despite Prophylactic Iron Supplementation

Background: Iron deficiency (ID) is the most prevalent micronutrient deficiency globally and has been associated with negative neurodevelopmental and behavioral outcomes in infants and young children. Susceptibility to ID is heightened in preterm infants due to lower iron reserves at birth, rapid growth during the initial weeks of life, immature erythropoiesis, and frequent blood samplings during hospitalization. To mitigate this problem, international bodies recommend prophylactic iron therapy from 2-6 weeks of age until at least 6-12 months in preterm infants. Currently, the literature regarding iron status in extremely preterm infants (EPI, infants born less than 28 weeks gestational age) who receive prophylactic iron supplementation after birth is limited. Considering the potential long-term detrimental effects of ID on the developing brain of these high-risk preterm infants, examining the prevalence and risk factors for ID are crucial to implement prevention strategies. Objective: To investigate the prevalence and risk factors associated with ID in EPI Methods: A retrospective cohort study was conducted using a population-based Provincial Perinatal Follow-Up database on all live EPIs born in Nova Scotia between 2005 and 2018. Infants with congenital malformations, chromosomal anomalies, blood disorders or those who died before outcome assessment were excluded. Prophylactic iron supplementation (2-3 mg/kg/day) starting at 2-4 weeks of chronological age was a standard of care for all included infants. Further, the dosage of iron was adjusted regularly during the hospital stay based on serum ferritin (SF) levels. Discharge instructions recommended continuing iron prophylaxis until 9-12 months corrected age (CA). At 4-6 months CA, all infants underwent blood tests to evaluate hemoglobin, and SF levels. ID was defined as SF levels below 20g/L or 12g/L at 4 and 6 months CA, respectively. A univariate analysis was performed by using a series of single-variable logistic regression models to identify the factors associated with presence of ID. Factors with a p-value &amp;lt; 0.20 in the univariate analysis were entered into a multivariable risk model using a backward selection procedure. Variables with a p-value &amp;lt; 0.05 were retained. Results: Among 146 infants, 67 (45.9%) had ID. Ferritin (16.4 µg/L vs 50.0 µg/L, p &amp;lt; .001) and reticulocyte hemoglobin equivalent (28.4pg vs 31.6pg, p &amp;lt; .001) were significantly lower in the ID group than non-ID group. The prevalence of ID decreased over time, from 59.7% in 2005-2011 to 40.3% in 2012-2018 (p = 0.52). Table 1 compares the antenatal and neonatal characteristics of the ID and non-ID groups. Table 2 compares sociodemographic variables and clinical variables at 4-6 months CA between two groups. Breastfeeding (exclusive or partial) versus formula alone at a 4-6 months CA was identified as an independent factor protective for ID (Odds: 0.2 (0.1 - 0.6), p = 0.003). Iron therapy at follow-up was also protective for ID but did not remain significant in the final model. Of note, iron therapy was stopped in 40 (27.4%) EPI before 4-6 months CA. Supplemental iron intake at 4-6 months CA was significantly lower in the infants receiving exclusive formula feeding (66.1%) compared with those breastfed (99.1%, p = 0.006). Conclusion(s): Despite prophylactic iron supplementation, nearly half of the EPI had ID at 4-6 months CA, and iron therapy was discontinued in roughly a quarter of all EPI before 4-6 months CA. Breastfeeding at 4-6 months follow-up was found to be protective for ID. High prevalence of ID in EPI highlights the need for further research in this area to avert the negative neurodevelopmental consequences of ID on the developing brain of these high-risk infants. Closer monitoring of iron status and early identification of children at high risk for ID is imperative to maximize the benefits of prophylactic iron supplementation in EPI. Further, there is lack of sufficient data for iron requirements in EPI leading to a variability in iron therapy recommendations by different professional organizations. Future prospective studies to investigate specific iron requirements of EPI as well as risk factors for ID in this high-risk vulnerable population are essential to optimize their neurodevelopmental outcomes.

Alterations of Gut Microbiota Related with Status of Iron-Overload in Thalassemia Patients: A Cross-Sectional Pilot Study

Background: Gut dysbiosis can cause an impaired gut-barrier function and may contribute to the pathogenesis of various diseases. Iron overload is a common complication in thalassemia patients and can result in numerous complications, including those affecting the cardiovascular, endocrine, and immune systems. However, it is unclear how iron overload affects the gut microbiota of patients with thalassemia. Objective: To characterize the profiles of the gut microbiome in thalassemia patients compared with healthy participants, as well as to determine the association of these profiles with iron status. Method: Transfusion-dependent thalassemia (TDT) patients and healthy controls aged ≥ 18 years old were enrolled in the study. Stool samples were collected prior to receiving regular blood transfusions in the thalassemia group. Paired-end sequencing of 16s rRNA bacterial DNA extracted from each stool sample was performed. Serum ferritin levels were assessed in each participant to reflect iron status. Results: A total of 14 adult TDT patients and 14 healthy controls were enrolled, with a similar proportion of age and sex. The TDT patients had a significantly higher iron overload status than the controls (median serum ferritin level = 1424 in the TDT group and 197 in the control group; p &amp;lt; 0.001). The Shannon diversity index demonstrated a significant increase in gut microbial diversity in TDT patients as compared to healthy controls (7.06 vs. 6.48; p = 0.001). The TDT group showed a higher abundance of several gram-negative bacterial phyla, such as Bacteroidota, but a reduction in the abundance of Actinobacteriota as compared to the control group. Serum ferritin levels showed a positive correlation with higher gut diversity index. Conclusions: Our study suggests that TDT patients develop gut dysbiotic characteristics compared to the healthy population, with gut diversity associated with serum ferritin levels. This association suggests that iron overload induces gut dysbiosis.

Iron Deficiency in Young Children Beyond Anemia: Clinical Features, Maternal Factors, and the Predictor for Neuropsychomotor Development Delay

Introduction: Iron deficiency (ID) is the most common micronutrient deficiency in children and is prevalent in young children, especially in those with long-term exclusive breastfeeding (BF). Iron deficiency anemia (IDA), the most common type of pediatric anemia, while it is not the only clinical manifestation of ID. In Taiwan, prevalence of IDA was up to 23% in child-bearing women. It was reported that the iron levels in the breast milk of IDA mothers were markedly lower than that of non-IDA mothers. ID alone in young children can cause neurocognitive development symptoms, including inattention, psychomotor delay, cognition impairment, pica, etc, in children. However, clinical reports on ID, not IDA, are relatively few. We aimed to investigate the clinical features and influencing factors of ID in young children. Methods and Materials: There were 33 young children diagnosed as ID at outpatient department at Taipei Medical University Hospital from 2017 to 2019. The charts were retrospectively reviewed and clinical data were collected, including diagnostic age, initial symptoms, periods of breast-feeding (BF), hemoglobin (Hb), mean corpuscular volume (MCV), serum ferritin (SF), serum iron, total iron binding capacity (TIBC), zinc levels, thalassemia survey, duration of iron supplement, and laboratory improvement after iron supplement. Whether there were neuropsychomotor (NPMD) delay depended on the chart record of doctors of pediatric rehabilitation. Results: The median age of ID diagnosis was 2.5 years (range: 5 month－7.17 years). There were 31 (94%) of ID children initially presented with either koilonychias, picky eating, or poor appetite. 24 (72.7%) were found to have koilonychias, and among them, 18 (54.5%) had flat nails and 6 (18.2%) had spoon nails. 17 (51.5%) were picky eaters, 16 (48.5%) had poor appetite, 7 (21.2%) had pale nails, and 3 (9.1%) had pica. 11 (33.3%) had NPMD delay. The median duration of BF was 10.8 months (range: 0 to 36). There were 12 (36.4%) children whose mother had IDA. The median Hb was 11.2 g/dL (IQR: 10－12.65), median MCV was 76.45 fL, median SF level was 25 ng/mL (IQR: 13.25－45.5), and median transferrin saturation was 9.25% (IQR: 7－12.88). The median serum zinc level at diagnosis of ID was 66.4 μg/dL. In addition, 21 (63.6%) has concurrent zinc deficiency, 10 (30.3%) had pediatric IDA, and 2 (6.3%) had combined thalassemia trait. The median (IQR) duration of iron supplement is 3 (3-6) months. After treatment, patients' data revealed a significant increase in median Hb of 12.6 mg/dL, median MCV of 78.7 fL, median SF of 47 ng/mL, and median transferrin saturation of 15.35%. By correlation analysis, breastfeeding duration was also moderately correlated to SF level (Pearson rank=-0.5224). Maternal IDA history also had a negative correlation to SF level in ID children (Pearson rank=-0.4053). By multivariate linear regression (MVLR) analysis, breastfeeding duration and maternal IDA history were identified as significantly inverse predictors for SF levels in ID children. ID children with NPMD delay had significantly higher rate of concurrent zinc deficiency. By MVLR analysis, serum zinc level was identified as a significant inverse predictor for NPMD delay among ID children (Odd's ratio: 0.89, 95%CI: 0.799-0.991, p-value=0.0336*). Conclusion: Our results highlighted the clinical features of ID in infants and children. A high proportion of ID children had maternal IDA history (36.4%) and NPMD delay (33.3%). Iron supplementary was effective to improve ID. Breastfeeding duration and maternal IDA history can negatively impact SF level in ID children. Good levels of serum zinc in ID children can predict lower risk of NPMD delay. Disclosures : No relevant conflicts of interest to declare.

Efficacy of Vitamin C with Iron Supplementation in Iron Deficiency Anemia Patients: A Systematic Review and Meta-Analysis

Background Oral iron supplementation is one of the mainstays of treatment for iron deficiency anemia (IDA) but can be complicated by poor absorption. Vitamin C is hypothesized to increase the acidity of the GI tract and enhance the conversion of non-absorbable ferric iron (Fe 3+) to its absorbable ferrous (Fe 2+) state for improved absorption and is often prescribed with iron. However, whether vitamin C supplementation translates to clinically relevant differences, such as sufficient improvements in hemoglobin, remains unclear and a synthesis of available evidence is lacking. Therefore, the present systematic review and meta-analysis aims to compare oral iron with or without vitamin C supplementation in patients with IDA. Methods MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched from database inception to July 2023 for randomized controlled trials (RCTs) and non-randomized studies (NRSs) that investigated the use of oral iron supplements with vitamin C compared to oral iron supplements only in patients with IDA. Title &amp; abstract, full text review and data extraction were conducted independently and in duplicate. The primary outcome was the change in serum hemoglobin levels in g/dL. Secondary outcomes include change in serum ferritin, change in transferrin saturation, change in reticulocyte percentage, and incidence of adverse events including constipation, nausea/vomiting, GI upset and poor taste. The Mantel-Haenszel fixed effects model was utilized for the meta-analysis. The calculated effect sizes were represented by odds ratios (OR) and mean differences (MD) for binary endpoints and continuous endpoints, respectively, with 95% confidence intervals (CI). Results 2231 studies were retrieved from electronic databases. 12 RCTs and one prospective cohort study comprising 2240 patients were included. There was a small but statistically significant increase in serum hemoglobin level (MD 0.14 g/dL [95%CI 0.08, 0.20]) and serum ferritin levels (MD 3.23 µg/L [95%CI 1.63, 4.84]) in the iron + vitamin C group compared to the iron only group. There was a greater reduction in serum transferrin saturation associated with vitamin C supplementation (MD -2.01% [95%CI -3.31, -0.71%]) but the pool of evidence consists of only two studies. Reticulocyte percentage (MD 0.22% [95%CI 0.08, 0.36]) was higher in the iron + vitamin C group than in the iron only group. There were no significant differences between the iron + vitamin C group and the iron only group in overall incidence of adverse effects (OR 0.71 [95%CI 0.50, 1.00]), constipation (odds ratio (OR) 0.83 [95%CI 0.35, 1.96]), or nausea/vomiting (OR 0.80 [95%CI 0.52, 1.24]). The risk of GI upset is lower in the iron + vitamin C group (OR 0.40 [95%CI 0.18, 0.92]). Nevertheless, only three primary studies reported on incidence of adverse events. Conclusion The addition of vitamin C to iron supplementation in the management of IDA was associated with a statistically significant, but likely clinically unimportant, increase in serum hemoglobin of 0.14 g/dL. Similarly, a statistically significant increase in serum ferritin levels by 3.23 µg/L was observed, but its clinical relevance remains uncertain. A strength of the present analysis is the number of RCTs included; however, its conclusions are limited by the heterogeneity of interventions (e.g. different formulations/dosage) across studies. Our results do not provide strong evidence for adding vitamin C to iron supplementation.

Day +3/Day 0 Ferritin Ratio: A Simple Point-of-Care Index Predictive of Severe Immune Effector Cell-Associated Neurotoxicity Syndrome after CD19 CAR T-Cell Therapy

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is transforming the management of patients with relapsed/refractory (R/R) B- and plasma-cell malignancies. However, a major limitation of CAR T-cell therapy is the development of severe, sometimes life-threatening, toxicities such as immune effector cell-associated neurotoxicity (ICANS) and cytokine release syndrome (CRS). While the management of CRS has dramatically improved with the early use of tocilizumab and corticosteroids, how to best predict and treat ICANS remains poorly understood, with up to 30% of patients developing severe ICANS after CD19 CAR T-cell therapy. Since we had previously observed features overlapping with hemophagocytosis lymphohistiocytosis in patients with severe CRS and ICANS, we hypothesized that the early kinetics of ferritin and soluble IL-2 receptor alpha [sIL-2Rα] post infusion could predict the development of severe ICANS. Methods: We retrospectively analyzed data from 195 patients with R/R B-cell malignancies previously treated on a phase I/II clinical trial (NCT01865617) of an investigational defined 1:1 CD8+:CD4+ composition CD19 CAR-T product (JCAR014; training set). CRS and ICANS severity were graded using Lee 2014 and CTCAE 4.03 criteria, respectively. Logistic regression was used to predict the occurrence of severe ICANS. Ferritin was measured using an enzyme immunoassay. sIL-2Rα was measured using Luminex®. Goodness of fit was assessed using the Akaike information criterion (AIC). Independent test set included 203 patients treated at our center with the standard-of-care CD19 CAR T-cell products axicabtagene or lisocabatagene maraleucel. Discrimination and calibration were assessed in both the training and test set. Results: In the training set (n=195), median age was 55 (range: 20-76). Disease type was as follows: acute lymphoblastic leukemia, n=64 (32.8%); B-cell non-Hodgkin lymphoma, n=82 (42.1%); chronic lymphocytic leukemia, n= 47 (24.1%). We observed any grade and grade ≥3 CRS in 134 (68.7%) and 27 (13.8%), respectively, and any grade and grade ≥3 ICANS in 72 (38.8%) and 37 (19.0%), respectively. Longitudinal analyses of serum ferritin (Figure 1) and sIL-2Rα values using locally estimated scatterplot smoothing suggested that the rate of increase of both analytes was markedly higher in patients with grade ≥3 ICANS compared to grade 0-2 ICANS. We applied univariate logistic regression to estimate the association between serum ferritin levels at early timepoints, select ratios of ferritin and sIL-2Rα values, and the occurrence of severe ICANS. The strongest association was observed between the ferritin day +3/day 0 ratio and severe ICANS (OR per log10 increase, 175; 95% CI, 19.1-2668; p &amp;lt; 0.001). We could further improve our model by modeling the ferritin day +3/day 0 ratio with a restricted cubic spline to allow for non-linear effects (unsplined model, AIC = 129, C-index, 0.74; splined model, AIC = 127, C-index, 0.78). Ferritin day +3/day 0 ratios of 3, 5, and 10 were associated with an 81%, 95%, and 99% probability of grade ≥3 ICANS, respectively (Figure 2). The splined model was associated with near-perfect calibration corrected for optimism using bootstrapping. We next evaluated the predictive ability of the ferritin day +3/day 0 ratio to predict severe ICANS in our independent test set. Predictions in the test set based on our splined model retained good discriminative ability with a C-index of 0.64, although with suboptimal calibration. In a refitted logistic regression model in the test set, the ferritin day +3/day 0 ratio remained strongly associated with the development of severe ICANS (OR = 18.8 per log10 increase, 95%CI, 2.48-142.01, p = 0.004). Conclusion: We validated the ability of a simple point-of-care index (day +3/day 0 ferritin ratio) to predict the development of severe ICANS after CD19 CAR T-cell therapy in our training and test set. Since serum ferritin levels can be quickly measured by most clinical laboratories, the day +3/day 0 ferritin ratio could become a practical and useful tool for practitioners taking care of CAR T-cell patients. The early identification of patients at high risk of developing severe ICANS days prior to symptoms onset could enable the evaluation of targeted prophylactic interventions in future clinical trials. We plan to refine our modeling approach to further improve the calibration in test set.

Accuracy of Reticulocyte Hemoglobin for Diagnosing Iron Deficiency in Very Preterm Infants: A Population-Based Cohort Study

Background: Preterm born infants are at an increased risk of developing iron deficiency (ID) despite preventative iron supplementation, which can lead to long-term negative neurodevelopmental and behavioral outcomes. Serum ferritin (SF) is the commonly used test for diagnosing ID. However, SF is influenced by infection and inflammation, making it an unreliable marker in such situations. An alternative, reticulocyte hemoglobin equivalent (Ret-He), measures the iron content in newly produced red blood cells, providing an immediate assessment of iron availability. Unlike SF, Ret-He tests are automated, can be performed on the same blood sample as a complete blood count, and is not influenced by infection or inflammation like SF. However, there is limited literature on the reliability of Ret-He as an ID marker in very preterm infants (VPI) during their first year of life. This study aims to evaluate the diagnostic accuracy of Ret-He as an ID indicator in VPI at 4-6 months of corrected age (CA) compared to SF levels. Objective: To investigate the accuracy of Ret-He in detecting ID in VPI at 4-6 months CA Methods: A retrospective population-based cohort study was conducted using a population-based Provincial Perinatal Follow-Up (PFUP) database on all live VPIs born in Nova Scotia between 2012 and 2018. Infants with hematological disorders, chromosomal abnormalities, or major congenital anomalies were excluded. Prophylactic iron supplementation (2-3 mg/kg/day) starting at 2-4 weeks of chronological age was a standard of care for all included infants. Iron supplementation was recommended until 9-12 months CA. All infants underwent SF and CBC testing at either 4- or 6-months CA to assess iron stores and guide supplementation. In 2012, Ret-He was added as an additional marker of ID for clinical decision-making. Two definitions of ID were used. Definition one defined ID as SF level &amp;lt;20 mcg/L. Definition two defined ID as SF level &amp;lt;20 mcg/L at 4 months and &amp;lt;12 mcg/L at 6 months CA. Receiver operating characteristic curves were performed and the areas under the curves (AUC) were calculated to assess the accuracy of Ret-He in classifying patients with ID. The optimal cut-off point for Ret-He was determined using Youden's index, from which sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The Spearman correlation coefficient was calculated between SF and Ret-He. Statistical significance was set at a two-sided P value of &amp;lt; 0.05. Results: A total of 156 patients were included. Under definition one, 62 (39.7%) met the criteria for ID. Under definition two, 39 (25.0%) patients had ID. Baseline characteristics are provided in Table 1. The Spearman correlation coefficient between SF and Ret-He was 0.23 (p=0.004). Under definition one, the AUC of Ret-He for diagnosing ID was 0.64 (p=0.002) and 0.69 (p&amp;lt;0.001) under definition two (Figure 1). The optimal cut-off value for Ret-He in ID diagnosis was 29.4 pg irrespective of the definition. Sensitivity, specificity, PPV, and NPV for both definitions are reported in Table 1. Conclusion: Regardless of the ID definition used, the AUCs indicated a weak discriminatory ability of Ret-He for ID diagnosis. The study indicated a weak positive relationship between SF and Ret-He. Ret-He's low diagnostic accuracy in this study is comparable to other studies involving healthy pediatric populations but lower than studies involving children with chronic health conditions. Clinicians should use caution when relying on Ret-He alone to diagnose ID in VPI. Further research is needed to determine the optimal diagnostic approach for identifying ID in VPI as well as explore the clinical utility of Ret-He in combination with other ID biomarkers such as SF and transferrin saturation.