Low Ferritin Levels Research Articles

INDOLENT SYSTEMIC MASTOCYTOSIS MASQUERADING AS CHRONIC ANEMIA IN ULCERATIVE COLITIS: A CASE STUDY

Abstract BACKGROUND Anemia is a frequent systemic/extra-intestinal manifestation of inflammatory bowel disease (IBD). It has a complex multifactorial etiology which suppresses erythropoiesis due to pro-inflammatory mediators, myelosuppression, iron and micronutrient deficiency. It significantly impacts quality of life (QoL) and increases hospitalizations, length of hospital stays and mortality rates. It Is commonly thought to arise as a consequence of IBD or it’s related therapy. Current strategies are aimed at correction of anemia with low priority towards identifying a specific cause. Here, we represent a case of UC with chronic anemia secondary to systemic mastocytosis (SM). CASE A 41 y/o female with UC presents to the outpatient clinic with complaints of fatigue. Further questioning revealed a baseline of 1-2 formed bowel movements per day. She did not report any hematochezia or weight loss. She was managed on 300 mg of vedolizumab every 4 weeks. Prior failure to medications includes anti-tumor necrosis factor inhibitors and tofacitinib. Labs were consistent with albumin 4.5 mg/dL and CRP < 1 mg/dL. Iron studies revealed low iron, TIBC and ferritin levels. Fecal calprotectin measurements were not available due to patient non-compliance. Patient (Pt) was thought to have experienced a UC flare and colonoscopy was recommended. Colonoscopy was unrevealing with no sign of active disease on examination (Mayo Endo 0). Pt was referred to hematology where she underwent a bone marrow biopsy revealing multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) expressing CD2+ and CD 25+ with 25% showing atypical morphology in bone marrow biopsies. KIT D816V mutation was also positive. The serum tryptase level in this pt was 47.1ug/L. She was then placed on anti-histamines, proton pump inhibitors and steroid therapy. CONCLUSION SM is a clonal disorder of MC that infiltrates one or more organs. It almost always involves the bone marrow. Gastrointestinal (GI) symptoms are present in up to 80% patients. These symptoms are secondary to systemic effects of MC mediators. Incidence of SM in UC has never been established. SM has been shown to mimic Crohn’s disease and is difficult to differentiate based on clinical and endoscopic features. Furthermore, little is known regarding histopathological features of GI involvement in SM. The presence of chronic anemia despite adequate therapy in a clinically/endoscopically inactive UC patient should raise suspicion of other pathologic causes of anemia. Our case highlights the importance of diagnosing the specific cause of anemia in IBD as it may lead to inaccurate clinical judgements of disease flares leading to undue alteration in therapy.

Anaemia among school children of different socioeconomical status in a city of Southern Brazil

Background: Iron deficiency is one of the leading causes of anaemia, with those most affected being children and women of childbearing age, in Brazil there is a scarcity of studies involving the local prevalence of anaemia. Aim: To evaluate anaemia and associated factors in schoolchildren in Santa Cruz do Sul through the analysis of biochemical and haematological markers and parasitological examination of faeces. Subjects and methods: School children from 10 to 12 years of age were evaluated through complete blood count, serum ferritin, C-reactive protein and stool parasitological examination, as well as socio-demographic characteristics and prophylaxis with ferrous sulphate in childhood. Results: It was found that 13.0% of the population was anaemic, girls were very slightly overrepresented among the anaemic children. Only 5.3% had altered haematocrit levels; 26.6% had low Mean Corpuscular Volume levels; 18.4% had low ferritin levels; 2.4% had increased C-reactive protein levels, and 21.7% had altered eosinophils. As for the socioeconomic level, classes A2 and D presented lower haemoglobin levels, as well as class D presenting lower ferritin levels, although without statistical significance. Only 6.0% of the population presented iron-deficiency anaemia and 46.0% of the schoolchildren had used ferrous sulphate supplementation in childhood. Conclusion: The prevalence of anaemia in the studied municipality is low, probably due to the high municipal human development index. Epidemiological studies are essential to characterise the population in a systematic form, to prevent future problems.

Is nociplastic pain, a new pain category, associated with biochemical, hematological, and inflammatory parameters?

Objective The aim of the study was to evaluate the relationship between biochemical, hematological, and inflammatory parameters and pain in patients with nociplastic pain. Methods In this cross-sectional study, a total of 8632 patients, aged between 20 and 65, were evaluated according to the nociplastic pain diagnosis criteria determined by IASP. Excluding individuals who did not meet the criteria for nociplastic pain, the study included a total of 660 participants. The biochemical, hematological, and inflammatory parameters of all individuals were examined. The pain levels of the patients were assessed using the Visual Analogue Scale (VAS). The patients were categorized based on nociplastic pain types and pain regions for evaluation. Results In this study, the female gender was more prevalent both in all nociplastic pain categories and in all pain region groups (p < 0.05). In the nociplastic pain categories, it was observed that vitamin D levels were lower in patients with chronic widespread pain, while ferritin and C-reactive protein levels were higher in patients with chronic primary musculoskeletal pain. Among patients with chronic widespread pain with low hemoglobin and/or ferritin levels, the Visual Analog Scale activity score was higher. For patients with chronic widespread pain and low vitamin D levels and/or high erythrocyte sedimentation rate levels, the Visual Analog Scale rest score was higher. In patients with fibromyalgia and high parathyroid hormone levels, the Visual Analog Scale activity score was higher. For patients with fibromyalgia and high Neutrophil/Lymphocyte ratio levels, the Visual Analog Scale rest score was higher. In patients with chronic primary musculoskeletal pain and high erythrocyte sedimentation rate and/or C-reactive protein levels, the Visual Analog Scale activity score was higher. While vitamin B12 levels were found to be lower in patients with widespread pain, no significant relationship was identified between electrolytes, other blood count results, and nociplastic pain. Conclusion In our study, it was observed that levels of vitamin D in individuals with nociplastic pain were low, while erythrocyte sedimentation rate, C-reactive protein, and Neutrophil/Lymphocyte ratio were high, and hemoglobin and ferritin levels were elevated. Furthermore, these findings were found to be associated with both the presence of pain and the severity of pain assessed using the visual analog scale.

A study of the correlation between magnesium and ferritin levels and the severity of the disease and sleep quality in restless legs syndrome

Background/Aim: Restless legs syndrome (RLS) is a chronic neurological disease that impairs sleep quality, causes emotional stress and affects daily activities. While the association between disease severity and low iron and ferritin levels is known, the magnesium (Mg) results are contradictory. This study aimed to investigate the influence of low Mg and ferritin levels on the severity of the disease and sleep quality. Methods: A case-control study included 50 RLS patients aged 18–78 years and 50 healthy control patients. Mg and ferritin levels were measured, considering values below &lt;1.8 mg/dL and 75 ng/mL as low. Both groups completed the International Restless Legs Syndrome Severity Rating Scale (IRLSSG) to assess the severity of RLS, as well as the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) to evaluate subjective sleep quality. Results: The mean age of RLS patients and the control group was 47.06 (13.35) years and 43.30 (15.43) years, respectively (P=0.196). The RLS patients had an IRLSSG score of 25.16 (6.85). The PSQI total scores, subscale scores, and ESS scores of RLS patients were significantly higher than those of the control group. However, no significant difference was observed in the IRLSSG score, PSQI, and ESS scores based on Mg and ferritin levels. Sleep latency was found to be shorter in individuals with Mg deficiency. Conclusion: Sleep disorders are prevalent among RLS patients. No correlation was found between Mg and ferritin levels and disease severity or sleep disorders. Furthermore, Mg deficiency did not appear to exacerbate the IRLSSG score or sleep disorder scores.

Association of iron deficiency with chronic suppurative otitis media in adults

Background Chronic suppurative otitis media (CSOM) is a prevalent chronic inflammatory disease globally. Current research suggests a possible association between anaemia and the development of CSOM. Objectives The objective of this trial was to investigate the relationship between iron metabolism and chronic suppurative otitis media (CSOM) in adults aged 20–60 years. Materials and methods A consecutive sampling case-control study was used. The study participants were divided into a case group (42 children diagnosed with CSOM) and a control group (42 children with normal ears). Haemoglobin (Hb), Hematocrit (Hct), mean corpuscular volume of erythrocytes (MCV), serum iron level (SI), unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin (TF), ferritin (Fer) were tested in all the participants, and the results were compared with the normal ranges of the World Health Organization (WHO). The comparative analysis of cases and controls was performed using the Fisher extract test, independence t-test, or Mann–Whitney U test. p-value <.05 was considered statistically significant for correlation. Results There were 61 patients with CSOM and 61 controls included in the study. In the case group, 16 out of 61 patients (26.2%) had low ferritin levels and in the control group, 1 out of 61 patients (1.6%) had low ferritin levels (p < .001). In the case group, 6 (9.8%) of 61 patients had IDA, and in the control group, there were no patients with IDA among 61 patients (p = .027). There were significant differences in SI, UIBC, and Fer parameters between the groups. Conclusions In adult patients, the incidence of iron deficiency was higher in CSOM patients than in controls. Iron deficiency may be considered a potential risk factor for chronic suppurative otitis media, and serum iron parameters should be evaluated in these CSOM patients and further studies should be conducted to better understand the potential link between iron deficiency and CSOM.

Association between Body Iron Status and Cognitive Task Performance in a Nationally Representative Sample of Older Adults.

Iron is an essential micronutrient that is necessary for proper cognitive function. However, the dose-response relationship between body iron status and cognitive function remains unclear. The objective of this study was to investigate the association between serum ferritin concentrations, an indicator of body iron status, and cognitive function in older adults. Based on the National Health and Nutrition Examination Survey (NHANES) 1999 -2002 in the United States, nationally representative data was collected from 2,567 adults aged 60 years and older who had objectively measured serum ferritin levels and cognitive performance. High ferritin levels were defined as a serum ferritin level >200 ng/mL in women and >300 ng/mL in men. Low ferritin levels were defined as a serum ferritin level <30 ng/mL. The digit symbol substitution test (DSST) was employed to assess cognitive function. Multivariable logistic regression analyses with survey weights were performed after the DSST was dichotomized at the median score. The weighted prevalence of adults with normal, low, and high serum ferritin levels were 73.98%, 9.12%, and 16.91%, respectively. A U-shaped association between serum ferritin concentrations and cognitive task performance was observed. After adjusting for demographic, socioeconomic, lifestyle, and C-reactive protein factors, the odds ratio (95% confidence intervals) for lower cognitive performance was 1.39 (1.11, 1.74) in adults with high ferritin levels and 1.38 (0.86, 2.22) in adults with low ferritin levels, compared with those with normal ferritin levels. The association between serum ferritin levels and lower cognitive performance was stronger in adults aged 60 to 69 years old than those aged 70 years and older. In conclusion, in a nationally representative sample of older adults in the United States, a high serum ferritin level was significantly associated with worse cognitive task performance. Thus, the relationship between low serum ferritin concentrations and cognitive task performance warrants further investigation.

Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study

BackgroundWhether iron deficiency contributes to incident heart failure (HF) and cardiac dysfunction has important implications given the prevalence of iron deficiency and the availability of several therapeutics for iron repletion. ObjectivesThe aim of this study was to estimate the associations of plasma ferritin level with incident HF overall, HF phenotypes, and cardiac structure and function measures in older adults. MethodsParticipants in the ongoing, longitudinal ARIC (Atherosclerosis Risk In Communities) study who were free of prevalent HF and anemia were studied. The associations of plasma ferritin levels with incident HF overall and heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were estimated using Cox proportional hazards regression models. Linear regression models estimated the cross-sectional associations of plasma ferritin with echocardiographic measures of cardiac structure and function. ResultsThe cohort included 3,472 individuals with a mean age of 75 ± 5 years (56% women, 14% Black individuals). In fully adjusted models, lower ferritin was associated with higher risk for incident HF overall (HR: 1.20 [95% CI: 1.08-1.34] per 50% lower ferritin level) and higher risk for incident HFpEF (HR: 1.28 [95% CI: 1.09-1.50]). Associations with incident HFrEF were not statistically significant. Lower ferritin levels were associated with higher E/e′ ratio and higher pulmonary artery systolic pressure after adjustment for demographics and HF risk factors but not with measures of left ventricular structure or systolic function. ConclusionsAmong older adults without prevalent HF or anemia, lower plasma ferritin level is associated with a higher risk for incident HF, HFpEF, and higher measures of left ventricular filling pressure.

Computational recognition of regulator genes and signature for ferroptosis with implications on immunological properties and clinical management of atopic dermatitis.

Atopic dermatitis (AD) is a common chronic dermatitis of autoimmune origin that considerably affects the quality of life of patients. Ferroptosis, a newly regulated form of cell death, is essential for inflammation-related damage-associated molecular patterns (DAMPs). In this study, we aimed to identify ferroptosis regulators relevant to AD pathogenesis and reveal the mechanisms by which ferroptosis regulates the pathogenesis of AD. We analyzed the GEO AD cohorts (GSE16161, GSE32924, GSE107361, and GSE120721), identifying AD-related differentially expressed genes (DEGs) using edgeR. Co-expression and STRING database analyses were used to elucidate the interactions between DEGs and ferroptosis markers. Through functional enrichment analysis, we defined potential biological functions within the protein-protein interaction (PPI) network and developed FerrSig using LASSO regression. The utility of FerrSig in guiding the clinical management of AD was evaluated using the GSE32473 cohort. Subsequently, our in silico findings were confirmed, and mechanistic insights were expanded through both in vitro and in vivo studies, validating the relevance of FerrSig. In the GEO AD cohort, 278 DEGs were identified, including seven ferroptosis signature genes. Co-expression analysis and STRING database review revealed a 63-node PPI network linked to cell cycle and pro-inflammatory pathways. Four ferroptosis genes (ALOXE3, FABP4, MAP3K14, and EGR1) were selected to create FerrSig, which was significantly downregulated in samples collected from patients with AD. In addition, immune-related signaling pathways were significantly differentially enriched between the stratifications of samples collected from patients with AD with high and low ferritin levels, whereas in the GSE32473 cohort, FerrSig was significantly increased in cohorts effectively treated with pimecrolimus or betamethasone. Finally, in vitro and in vivo models showed a notable FerrSig decrease in patients with AD versus healthy control. Treatment with betamethasone and tacrolimus restored FerrSig, and the magnitude of the increase in FerrSig was higher in samples collected from patients with AD with better efficacy assessments. In addition, FerrSig was significantly positively correlated with the ferroptosis inhibitors GPX4 and SLC7A11 and negatively correlated with reactive oxygen species (ROS) levels and p-STAT3/STAT3. This implies that the FerrSig signature genes may regulate ferroptosis through the JAK/STAT3 signaling pathway. Our study further explored the pathogenesis of AD, and FerrSig could serve as a potential biomarker for identifying AD morbidity risks and determining treatment efficacy.

Evaluation of the relationship of digital phototrichogram findings of patients with diffuse hair loss with blood TSH, ferritin and vitamin B12 levels.

Telogen effluvium (TE) is a type of alopecia that is frequently seen in women. Among factors resulting in hair loss, many reasons such as endocrine diseases, nutrition disorders, stress, anemia, low ferritin levels, vitamin B12 deficiency, and thyroid diseases are found. A digital phototrichogram is one of the non-invasive methods of diagnosis in the evaluation of alopecia. In this study, it was aimed to compare biochemical parameters of female patients with diffuse hair loss with phototrichogram findings. 108 female patients with diffuse hair loss were included in the study. Patients were divided into two groups: acute and chronic TE, and a hair pull test was applied. Total blood count, blood biochemistry, iron, iron binding capacity, ferritin, thyroid stimulating hormone (TSH), sT3, sT4, folic acid, and vitamin B12 levels were examined. The telogen/anagen ratios and hair densities of patients were determined with a phototrichogram. The serum biochemical parameters (aspartate aminotransferase, alanine aminotransferase, urea, creatinine), TSH, sT3, sT4, and folic acid levels of patients were within normal limits. Telogen ratio, anagen ratio, hair density, number of shed hairs, family history, blood ferritin, TSH, and vitamin B12 levels were found to be similar between groups having acute and chronic TE. In our study, while mean anagen and telogen ratios with trichoscan were similar to literature data, no statistically significant correlation was determined between patients' ages and examined trichoscan findings (p>0.05). The hair pull test positivity of patients with chronic TE was higher compared to patients with acute TE (p<0.05). In patients with positive hair pull tests, the telogen ratio and hair density were found to be higher. In the group with <40 ng/mL ferritin level, the mean telogen ratio was detected to be significantly higher than the mean anagen ratio (p<0.05). No significant correlation was determined between vitamin B12 and TSH levels in patients and phototrichogram findings (p>0.05). The findings of this study showed that ferritin has an important role in diffuse hair loss, and the phototrichogram method is an auxiliary method for the physician in the diagnosis of TE.

Micronutrient status in patients with diabetic foot ulcers: A cross-sectional study in Saudi Arabia.

Patients with diabetes are at risk for developing diabetic foot ulcers (DFUs). It is recognized that type 2 diabetes (T2D) is distinguished by the loss of vitally important micronutrients because of the metabolic nature of this disease and its associated complexities. This study was performed to determine the level of micronutrients in patients with DFUs in Saudi Arabia. From February to May 2022, this descriptive study was conducted, adopting the cross-sectional design and a group of 88 patients with T2D. Applying the convenience sampling method, this study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. Data collection was conducted through a standard questionnaire, and details regarding the demographic variables and micronutrient deficiency were collected. Among the nutritional deficiencies identified, the one with the highest frequency was vitamin D, observed in 43.2% of the patient population; after vitamin D, in order of descent, were low ferritin levels (29.5%), B12 (13.6%), and the folic acid deficiency (12.5%). Folic acid showed a statistically significant difference among patients with cardiovascular disease (CVD) (P = 0.041). Moreover, vitamin B12 showed a significant association among patients who have charcot foot (P = 019) and previous amputation (P = 0.029). Vitamin B12 deficiency is significantly associated with patients who had an amputation; having charcot foot and folic acid revealed a vital relationship among patients with DFUs having CVD. Comprehensive research is a pressing need to enable deeper awareness of micronutrient deficiencies in patients with diabetes.

Serum ferritin levels in chronic spontaneous urticaria in association with autologous serum skin test: A cross-sectional study

Abstract BACKGROUND: Chronic spontaneous urticaria (CSU) is a common clinical condition presenting with wheals or along with angioedema. It has a complex pathogenesis having a considerable impact on quality of life. In patients with chronic spontaneous urticaria (CSU) exhibiting poor response to conventional treatments, the presence of hyposiderinemia suggests that oral iron therapy could potentially lead to resolution of the urticaria symptoms. OBJECTIVES: (1). To estimate serum ferritin levels in patients with CSU. (2) To assess the correlation between urticarial activity score, autologous serum skin test (ASST), and serum ferritin levels in CSU. MATERIALS AND METHODS: This prospective study enrolled 37 cases of clinically diagnosed CSU attending the dermatology outpatient department from December 2019 to November 2020 after Institutional Ethics Committee approval. ASST and serum ferritin level estimation were done on all patients. The severity of urticaria was calculated using the Urticaria Activity Score. Statistical analysis was done by frequency, standard deviation, and Chi-square test. RESULTS: Among ASST-positive patients, only 4 (19%) had low ferritin levels. No association was found between ASST and serum ferritin levels (P = 0.342). Mean serum ferritin levels in ASST-positive patients were high 91.34 ± 87.24 μg/L which was statistically significant compared to mean serum ferritin levels in ASST-negative patients 49.64 ± 46.91 μg/L. There was significant involvement of palms and soles in ASST-positive patients (P = 0.038). CONCLUSION: Although there was no significant correlation of serum ferritin levels with CSU, oral iron supplementation may be considered an add-on treatment in case of refractory urticaria.

Amelioration of nephrotoxicity by targeting ferroptosis: role of NCOA4, IREB2, and SLC7a11 signaling.

Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.

Serum ferritin level in children with normal hemoglobin and low MCV and MCH in a hospital in Iraq

Background: Iron deficiency is common around the world, particularly in young people because of their elevated need for iron to grow and develop. Iron deficiency is demonstrated by low levels of serum ferritin. This research will investigate the level of serum ferritin in children with normal hemoglobin but low MCV and MCH, the purpose of this is to determine the degree to which subclinical iron deficiency is present and distinguish it from other causes of microcytosis. Method: 150 children with typical hemoglobin but low MCV and MCH were recruited recognizing subordinate iron deficiency. Blood samples and demographic information regarding sociological aspects were collected and assessed. A computerized hematology analyzer and an ELISA were both used to assess the level of haemoglobin in the blood and the serum level of ferritin. Results: Children with normal hemoglobin but low MCV and MCH had a mean hemoglobin level of 12.7±0.6 mg/ dl and a serum ferritin level of 86.5±7 ng/ ml, according to the study. The levels of serum ferritin and hemoglobin changed significantly, depending on the sociodemographic variables. Among the pediatric population, the levels of serum ferritin and hemoglobin were significantly higher (P-value 0.002). Conclusion: In children with typical hemoglobin, but low MCV and MCH, the sociodemographic factors are strongly associated with the hemoglobin and serum ferritin levels. Gender, birth order, and family size—children under the age of 10 years— had an effect on the serum level of ferritin. The age, birthdate, and the time of supplemental food consumption also had an effect on hemoglobin levels. These findings demonstrate the necessity of recognizing and treating iron deficiency early on in life.

Diagnosis and treatment of iron deficiency anemia

The causes of iron deficiency anemia include blood loss, increased demand, insufficient dietary intake, and disorders affecting iron absorption. In certain circumstances, atrophic gastritis, either autoimmune or due to Helicobacter pylori infection, may contribute. On very rare occasions, iron-refractory iron deficiency anemia can develop as a consequence of TMPRSS6 mutations. Iron deficiency anemia is diagnosed by identification of microcytic hypochromic anemia with low serum ferritin levels. In cases of chronic disorders such as chronic kidney disease, chronic heart failure, and chronic inflammatory disorders, the diagnosis may also incorporate transferrin saturation. Treatment of underlying diseases is recommended along with iron supplementation. While oral iron supplements are the first choice, intravenous iron may be considered when oral administration is impractical, iron absorption is impaired, or rapid iron replenishment is necessary. Recently, high-dose intravenous iron formulations became available in Japan, but their use requires caution due to potential risks of allergic reactions, hypophosphatemia/osteomalacia, iron overload, and vascular leakage. Notably, the benefits of high-dose intravenous iron for patients with heart failure and iron deficiency are recognized in the field of cardiology. This article provides an overview, incorporating recent developments in the field of iron deficiency anemia.

Evaluating for Iron Deficiency in Pediatric Patients Obtaining a Hemoglobinopathy Evaluation

Background Low ferritin levels have been previously described to lower HbA 2 percentages on hemoglobinopathy evaluation. At our institution we have incorporated serum ferritin levels into an expanded panel test for thalassemia and hemoglobinopathy to assist with interpretation. There have been many critiques on the reference ranges used to define low ferritin in various pediatric ages. Lower ferritin levels, even in the absence of anemia or microcytosis, have been ascribed to nonspecific symptoms such as fatigue, weakness, difficulty concentrating, and decreased productivity that could be misconstrued as an attention-deficit disorder, especially in children. A hemoglobinopathy evaluation is often the first occasion for ferritin testing in patients; therefore, the hemoglobinopathy evaluation can serve as a key checkpoint to detect iron deficiency allowing for prompt treatment and amelioration of symptoms. Objective The purpose of this study was to evaluate the relationship between ferritin levels and the occurrence of hemoglobinopathies among pediatric patients in a single institution with the expectation that patients obtaining a hemoglobinopathy workup would be more likely to have a low ferritin (null hypothesis: there is no difference in the ferritin levels between patients receiving a hemoglobinopathy workup). The second hypothesis was that hemoglobinopathy testing would be done in a stepwise manner so at least 50% of patients obtaining a hemoglobinopathy workup would have prior interventions such as iron supplementation (null hypothesis: patients obtaining hemoglobinopathy evaluation have less prior interventions such as iron supplementation). Design/Method This retrospective, single center study included patients aged 0-18 years who had their first thalassemia and hemoglobinopathy testing for any indication between January 1, 2023 and July 28, 2023. Clinical variables were collected via review of the medical record. Low ferritin was defined as a ferritin level less than or equal to 25 mcg/L. Pearson's Chi Squared test and the Kruskal Wallis test were used for statistical analysis of categorical and continuous variables respectively. Results Seventy-seven total eligible patients were identified. Of those patients 35 were found to have low ferritin levels (45.5%). Among the patients with a low ferritin level, 15 patients also had a hemoglobinopathy present on their testing (41.7%) but there was no significant difference compared to those with normal ferritin levels (p value = 0.467). The patients with normal ferritin levels were of a significantly higher age compared to those with low ferritin levels 12.2 years vs 6.8 years (p value = 0.001) and 14 (42.4%) patients with low ferritin had no anemia and 29 (82.9%) never received prior iron supplementation. It was also noted that patients of Asian race were significantly more likely to have received prior iron supplementation 27.3% (p value = 0.004). Among patients with a hemoglobinopathy present the average age of their diagnosis was 9.1 years (95% Confidence Interval 6.6-11.7 years). Nine of the 10 patients with no hemoglobin values available were tested due to college sports participation and only 2 of those patients were found to have low ferritins. Conclusion Among our group of pediatric patients who underwent evaluation for thalassemia and hemoglobinopathy, there was no significant difference between those having a hemoglobinopathy present and lower or higher ferritin levels. Iron deficiency was more often noted among the younger patients even in the absence of anemia. It was important to note the majority of patients with iron deficiency detected on the hemoglobinopathy evaluation had never received prior iron supplementation until the time of their hemoglobinopathy evaluation. This also demonstrates that many providers may not do a stepwise workup but order all the evaluations at once. As there are many nonspecific symptoms of iron deficiency that can hinder the development of a child it is valuable to detect iron deficiency on hemoglobinopathy testing in order to intervene as soon as possible as iron deficiency can be masked by normal hemoglobin and normocytosis. Further investigation with larger study groups is warranted to better elucidate this relationship. Overall, our results suggest that enhanced characterization of iron deficiency parameters for patients receiving a hemoglobinopathy evaluation is warranted.

Dual nature of ferritin for hematologic, liver functional, and metabolic parameters in older diabetic patients

This study explored the association between ferritin with hematologic, liver functional, and metabolic parameters in older diabetic patients. A total of 210 diabetic patients aged 65 or older were classified into four groups according to the reference range of serum ferritin. Demographic variables and health-related lifestyle factors were obtained through the utilization of a standardized questionnaire. Anthropometric measures, blood pressure, hematology test, and biochemical assessment were also performed. Among all patients, 29.5% had anemia. The percentage of anemia in groups low ferritin (< 40 μg/L), lower side within the reference range (40–120 μg/L), higher side within the reference range (121–200 μg/L), and high ferritin levels (> 200 μg/L) were 50.0, 27.7, 20.5, and 24.2% (P = 0.025), respectively. Low ferritin levels had a higher risk of anemia and a high red blood cell distribution width (RDW). High ferritin levels were associated with a higher risk of high glutamate pyruvate transaminase, obesity, high fasting blood glucose (FBG), and high postprandial blood glucose. The higher side within the reference range of ferritin also showed a higher risk of high FBG and high glycated hemoglobin. Nevertheless, there was no significant association between ferritin and inflammation marker, serum lipids or blood pressure. Overall, ferritin demonstrates a dual nature in older diabetic patients: low ferritin levels are linked to anemia or elevated RDW, while high levels are linked to obesity, increased liver enzymes, and worse glycemia control.

Relationship between Iron Deficiency and Thyroid Function: A Systematic Review and Meta-Analysis.

Objective: Iron deficiency (ID) is the most prevalent nutritional deficiency worldwide. Low levels of serum ferritin (SF) could affect the thyroid gland and its functioning. The purpose of this systematic review and meta-analysis is to summarize the main currently available evidence and analyze data on the relationship between ID and thyroid function. Methods: This study included all articles evaluating the relationship between ID and thyroid function. Quality assessment was performed using Cambridge Quality Checklists. The search strategy included the following combination of Medical Subjects Headings terms and keywords: "iron deficiency", "thyroid function", "thyroid disease", "thyroid dysfunction", and "hypothyroidism". A meta-analysis was performed to evaluate whether thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels differed between patients with ID and healthy controls without ID. For statistical comparison between cases and controls, the mean difference (MD) was calculated, and a subgroup analysis of pregnant and non-pregnant women was performed. Cochran's Q testing and heterogeneity indices (I2) were used to assess statistical heterogeneity. Sensitivity analysis and publication bias analyses were also performed, both qualitatively and quantitatively. Finally, a meta-regression analysis was performed to evaluate the correlation between serum TSH or FT4 levels and SF in the study population. Results: Ten cross-sectional studies were identified and reviewed. Patients with ID showed TSH (MD: -0.24 mIU/L; 95% CI -0.41, -0.07; I2 = 100%, p = 0.005), FT4 (MD: -1.18 pmol/L; 95% CI -1.43, -0.94; I2 = 99%, p < 0.000001), and FT3 (MD: -0.22 pmol/L; 95% CI -0.32, -0.12; I2 = 99%, p < 0.00001) levels that were significantly lower. Subgroup analysis confirmed significantly lower TSH, FT4, and FT3 levels in pregnant women. Non-pregnant women showed significantly lower serum FT4 and FT3 levels but no difference in TSH values. Meta-regression analysis showed that serum TSH and FT4 levels were positively correlated with SF levels. Our systematic review of the literature found that ID significantly increases the prevalence of thyroid autoantibody (anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies) positivity both individually and collectively. Conclusion: Studies currently published in the literature indicate a possible relationship between ID, thyroid function, and autoimmunity, especially in some patient groups. Data analysis shows that thyroid hormone levels are lower in patients with ID and, in particular, in pregnant women. Further studies are needed to understand the role played by iron in thyroid metabolism.

The Effect of Ferritin Level on Respiratory Functions in Patients with β-Thalassemia Major

Introduction-Purpose β-thalassemia major (β-TM) is an autosomal recessive disorder caused by mutations in the β-globin gene of hemoglobin. The disease is characterized by splenomegaly due to ineffective erythropoiesis, iron accumulation signs in tissues as a result of increased iron absorption, bone expansion due to increased erythropoietic activity, and decreased tissue oxygenation. One of the effected organ can be the lungs due to excessive iron deposition in these patients. The current study aimed to investigate the effect of serum ferritin level, which is known as a marker of iron accumulation in tissues, on pulmonary function tests (PFT) in patients with β-TM. Methods and Materials Patients aged ≥6 years who were regularly followed in the pediatric hematology section of Mersin City Research and Training Hospital with a diagnosis of β-TM were included. All patients received regular blood transfusion and iron chelation therapy. Study participants underwent PFT prior to blood transfusion in the pediatric pulmonology section Results A total of 43 patients with β-TM were studied. Included patients were divided into two groups according to the mean annual ferritin level; low ferritin group if below 2000 ml/ng and high ferritin group if above 2000 ml/ng. The low ferritin group was consisted of 19 patients and the high ferritin group was consisted of 24 patients. The characteristics of these two groups are shown in Table 1. There were no statistical significance in age, gender, body mass index, age at diagnosis, mean annual hemoglobin, splenectomy, cardiac involvement and oxygen saturation among both groups, but the number of annual transfusion was significantly higher in the high ferritin group than lower ferritin group. When PFT parameters of both groups were compared, FVC (forced vital capacity) was statistically lower in the high ferritin group compared to the low ferritin group. Other parameters included FEV 1 (forced expiratory volume in 1 second), FEV 1/FVC ratio, PEF (peak expiratory flow) and FEF 25-75 (forced expiratory flow between 25% and 75% of vital capacity) were similar among groups. (Table 2) Discussion Patients with β-TM may accumulate iron in the interstitial area of the lungs which can lead fibrosis and impaired lung function over time. There are several studies investigated lung dysfunction and its etiology in these patients. Although the results of the studies are varied, the majority of them reported a restrictive pattern of respiratory dysfunction in thalassemia patients. Additionally, some studies showed the presence of mild or moderate obstruction in small airways and decrease in diffusion capacity with the increase of alveolar-capillary membrane thickness at advanced ages. In the present study, we found that patients with β-TM who had high ferritin level showed restrictive type lung function compared to those with low ferritin level. There were no difference among the groups in obstructive parameters (i.e. FEV 1, FEV 1/FVC, FEF 25-75) of PFT. In the literature, studies investigating PFT in patients with high ferritin levels had variable results, impaired or no change, in pulmonary status. In conclusion, loss of respiratory function and impaired tissue oxygenation in patients with β-TM may develop over time due to iron deposition in the interstitial area. PFT assessment of these patients is essential and recommended for the detection of early lung disease. Routine PFT follow in patients with β-TM of high ferritin values is highly important.

A Novel Composite Endpoint of Toxicity- and Progression-Free Survival after B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: BCMA-directed chimeric antigen receptor T-cell therapy (CAR T), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), are approved for patients with relapsed and/or refractory (R/R) multiple myeloma (MM). Pivotal KaRMMA and CARTITUDE-1 trials as well as real-world data demonstrated heterogeneity in toxicity and efficacy between ide-cel and cilta-cel. To account for such differences, we have established a novel composite endpoint of toxicity-free, progression-free survival within 3 months (TPFS3) after anti-BCMA CAR T therapy. We also studied factors associated with TPFS3 across ide-cel and cilta-cel and the impact of TPFS3 on overall survival (OS) after CAR T. Methods: We analyzed a retrospective cohort of 133 consecutive recipients of ide-cel or cilta-cel at Moffitt Cancer Center (05/2021-03/2023). TPFS3 was defined as absence of severe (Grade≥3) cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia(s), myeloma progression/stable disease (PD/SD), and non-relapse mortality (NRM) within 3 months after CAR-T infusion. CRS and ICANS were graded according to ASTCT Consensus grading. Cytopenias were graded according to CTCAE v5.0 and defined as two (or more) timepoint uni- or multilineage cytopenia, including any Grade≥2 cytopenia at post-CAR T Day 30 deepening to at least Grade≥3 at Day 60 and/or Day 90. Factors associated with TPFS3 were assessed via multivariate logistic regression analysis (MVA). Landmark Cox survival analysis at the 3-month timepoint examined the impact of TPFS3 on subsequent overall survival (OS). All analyses were performed using SAS and R. Results: In total, 48.1% (N= 64; median age=66 years [range, 45-82]; male=44%) of the patients were alive, toxicity- and progression-free by 3 months after CAR T infusion. TPFS3 components included PD/SD (N=30, 43.5%), severe cytopenias (N=26, 37.7%), ICANS (N=8, 11.6%), CRS (N=3, 4.3%), and NRM (N=2, 2.9%) (Figure 1A). In the univariate analysis, TPFS3 patients differed from the rest of the cohort according to lower marrow burden ( p=0.025), revised international staging system (R-ISS) (I/II vs III; p=0.015), CRP ( p=0.019) and ferritin ( p=0.002) levels at lymphodepletion (LD). The use of ide-cel (N=109) vs cilta-cel (N=24) was not significantly associated with TPFS3 ( p=0.119). In the MVA logistic regression, lower ferritin level (median cut off=228 ng/mL) at LD was associated with TPFS3 (odds ratio [OR]=0.37 [95%CI, 0.18-0.78], p=0.008] after adjusting for age, myeloma marrow burden, presence of extramedullary disease, R-ISS, CAR T product (all p&amp;gt;0.1), and CRP (median cut off=0.41mg/dL) at LD (OR=0.51 for lower vs higher, [95%CI, 0.25-1.05], p=0.069) included in the final model together with ferritin. In the landmark Cox survival analysis at 3 months, TPFS3 was associated with 6.54-fold superior OS (hazard ratio [HR]=0.15, 95%CI 0.05-0.52, p=0.003) (Figure 1B) after adjustment for potential confounders (age, gender, CRP, CAR-T product, marrow burden, R-ISS, extramedullary disease; all p&amp;gt;0.1). Other prognostic risks associated with inferior OS in the final model of the landmark analysis included the use of bridging therapy (HR=3.98 [95%CI, 1.30-12.20], p=0.016), ECOG≥2 at LD (HR=4.53 [95%CI, 1.57-13.07], p=0.005) and higher ferritin level at LD (HR=2.60 [95%CI, 0.95-7.13], p=0.063). Conclusions: We found that 48.1% of anti-BCMA CAR T recipients with R/R MM were alive and free of TPFS3-defining events. Myeloma response failure, cytopenias and severe ICANS were the top leading components of TPFS3 which was best predicted by ferritin level at LD. TPFS3 independently predicted long-term OS. Thus, TPFS3 may serve as an ideal composite safety and efficacy endpoint in future myeloma trials with BCMA-directed CAR T.

Association of mutations in hemochromatosis genes with clinical severity of calcium pyrophosphate arthritis

Aims: To study factors associated with the development of calcium pyrophosphate (CPP) arthritis and the severity phenotype. Methods: Transversal case-control study. Cases had to be confirmed by both X-ray chondrocalcinosis and CPP crystals in synovial fluid. Controls had neither chondrocalcinosis nor CPP crystals in synovial fluid. Patients and controls with hemochromatosis or primary hyperparathyroidism were not included. Mutations of hemochromatosis genes (HFE), magnesium (Mg), calcium (Ca), phosphate, iron (Fe), transferrin saturation, ferritin, parathyroid hormone (PTH), and calcifediol levels were studied. Results: Three hundred patients and 300 sex and age matched controls were compared. Lower serum Mg (sMg) and higher ferritin levels were found among patients. Hypomagnesemia (HypoMg) and HFE mutations were more frequent among patients. Involvement of over one joint was observed in 199 (66.4%) patients whereas persistent joint inflammation was retrieved in 154 (51.4%) of the patients. Initial analysis showed that the frequency of polyarticular and inflammatory phenotypes seemed to be progressively overrepresented in patients with HFE mutations. Further bivariate and multivariate analysis adjusted for the time from onset disclosed that the presence of genotypes with C282Y mutations was associated with polyarticular disease (hazard risk 3.501, 95% confidence interval 1.862–6.581, P &lt; 0.001). Although C282Y mutations also seemed to be associated with inflammatory patterns, the association did not reach statistical significance (P = 0.173). Conclusions: Low sMg and high ferritin levels are associated with CPP arthritis (CPPA). In patients without hemochromatosis, HFE mutations, and specifically C282Y mutations seem to associate with the polyarticular disease phenotype, and plausibly with the chronic inflammatory phenotype.