Transferrin Saturation Values Research Articles

Prevalence of C282Y, H63D and S65C gene mutations in patients with hyperferritinemia undergoing therapeutic phlebotomy suspected of having hereditary hemochromatosis

Background: Hemochromatosis is an autosomal recessive disorder caused by excessive iron overload in parenchymal organs. In Brazil, the prevalence of hereditary hemochromatosis (HH) may vary compared to other countries due to different ethnical backgrounds according to the geographic region studied. The prevalence of C282Y mutation of the HFE gene ranges from three to eight times lower in Brazilians than in Caucasians of Northern European origin. Methods: A retrospective cross-sectional study was carried out in 222 patients submitted to therapeutic phlebotomy between March 2011 and July 2014 in a tertiary hospital blood center. The prevalence of HH was determined in 89 (47.3%) out of 188 (84.6%) patients presenting hyperferritinemia, and divided in two genotype groups: C282Y mutation and other mutations. The HH patients’ geographical and clinical characteristics, serum ferritin rate (SF) and transferrin saturation (TS) were analyzed. Results: The HH group consisted of 71 males (79.7%) and 18 (20.3%) females, with a median age of 51.5 ± 10.6 years. There were 36 (40.0%) symptomatic patients and 65 (73.0%) tested positive for the HFE mutation. The initial baseline TS values were significantly higher in primary HH patients (48.6%, IC 95% 43.2% - 55.7%) compared to those with secondary HH (35.0%, IC 95% 27.5% 41.8%, p=0.001). Conclusion: The prevalence of C282Y mutation was higher in this population from the South region compared to previous reports in the Brazilian population, yet inferior to that of Northern Europeans.

The association between transferrin saturation and all-cause mortality in chronic kidney disease: findings from Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease.

Transferrin saturation (TSAT) has been used as an indicator of iron deficiency. However, there is no consensus regarding its optimal range for patient with chronic kidney disease (CKD). We aimed to analyze the effect of TSAT on the prognosis of patients with non-dialysis CKD (NDCKD). From 2011 to 2016, 2157 NDCKD patients with baseline TSAT measurements were followed for 10 years. Patients were divided into three groups based on baseline TSAT values: <25%, ≥25% and <45%, and ≥45%. All-cause mortality and 4-point major adverse cardiovascular events (MACE) were analyzed using multivariable Cox regression analysis. Other iron biomarkers and mortality were also analyzed. During a mean follow-up of 7.1 ± 2.9 years, 182 of a total of 2,157 patients (8.4%) died. Compared with the TSAT ≥25% and <45% group, the TSAT <25% group showed significantly increased all-cause mortality (hazard ratio [HR], 1.44; 95% confidence interval (CI), 1.02-2.03; p = 0.04). The occurrence of 4-point MACE was significantly increased in univariable analysis in the TSAT <25% group (HR, 1.48; 95% CI, 1.02-2.15; p = 0.04), but it was not significant in the multivariable analysis (HR, 1.38; 95% CI, 0.89-2.15; p = 0.15). Tertile comparisons of the iron-to-log-ferritin ratio showed increased mortality in the first tertile group. TSAT <25% is an independent risk factor for all-cause mortality in patients with NDCKD and care should be taken to prevent TSAT values of <25%. Other indicators, such as serum iron and iron-to-log-ferritin ratio, may also be used to assess iron deficiency.

#2264 Efficacy and safety of oral iron supplementation with liposomal iron in non-dialysis chronic kidney disease patients with iron deficiency

Abstract Background and Aims Iron deficiency (ID) is very common in patients with non-dialysis dependent chronic kidney disease (NDD-CKD). In these patients, oral iron supplementation is recommended as first-line treatment for ID. However, the efficacy of oral iron supplementation is frequently impaired by a higher incidence of adverse gastrointestinal side effects. Liposomal iron is a compound with ferric pyrophosphate enclosed in a phospholipid nucleus, providing high gastrointestinal absorption and bioavailability and a lower incidence of side effects. However, few data are available on its efficacy in patients with NDD-CKD. Method This single-arm pilot study was carried out in in patients with NDD-CKD stages 1-5 and ID, defined as serum ferritin (SF)&amp;lt;100 ng/mL and/or transferrin saturation (TSAT)&amp;lt; 20%, consecutively seen in two Nephrology units (Naples and Bari) from 01/12/2022 to 01/04/2023. We assessed the efficacy of six months of liposomal iron therapy in correcting ID across three visits after baseline (month 1, 3 and 6). All patients received liposomal iron (30 mg/day twice daily for the first month followed by 30 mg daily for the remaining five months). The primary endpoints were the achievement of SF ≥100 ng/mL and TSAT ≥20%. Secondary outcomes were hemoglobin (Hb) changes and safety of liposomal iron; adherence to the iron supplementation was assessed by monthly pill counting. Changes of continuous variables during the study were analyzed by linear mixed models assuming an unstructured covariance matrix; this was done to take into account the correlation between repeated measures and missing points for patients not completing the study. Change of prevalence of corrected SF and TSAT values from baseline to month 1, 3 and 6 was analyzed by McNemar test. Results 38 patients (65.3 ± 15.2 years, 52.6% males, 35.1% diabetes, eGFR 38.5 ± 28.8 mL/min/1.73 m2) received at least one dose of liposomal iron (safety population). Efficacy population included 34 patients with at least one control visit after baseline. Clinical characteristics of patients enrolled in the two clinics did not differ. In efficacy population, baseline SF was 44 (IQR 19-82) ng/mL and TSAT 14.3 ± 5.9%, corresponding to a percentage of SF&amp;lt;100 ng/mL of 78.9%, and TSAT&amp;lt;20% in 89.5%; 64.7% had both parameters below the cut-offs. Anemia (defined as Hb&amp;lt;12 g/dL in women and &amp;lt;13 g/dL in men) was detected in 22/34 patients. Liposomal iron induced a progressive increase of TSAT from 14.3 ± 5.9%, at baseline to 20.0 ± 7.6% at month-6 (P = 0.009) whereas no difference was detected for SF (Fig. 1A and 1C). Accordingly, at the end of study, the prevalence of TSAT&amp;gt;20% significantly increased from 11.8% to 50.0% (P = 0.002) while correction of SF, mildly improved (from 23.5% to 30.0%, P = 0.214, Fig. 1B and 1D). When patients were stratified by anemia, a significant improvement of TSAT was observed in anemic patients (from 13.3 ± 5.8% to 20.2 ± 8.1%, P = 0.012), whereas no significant improvement was found in patients without anemia (P = 0.093). Adherence to iron supplementation was 100% in patients completing the study. Hb values did not significantly increase at month-6 in either anemic (+0.60 ± 1.39 g/dL, P = 0.258) or non-anemic (+0.08 ± 0.78 g/dL, P = 1.0) patients. In safety population (n = 38), 7 patients dropped out (18.4%). In particular, treatment was discontinued in 4 patients in the first month (2 for diarrhea, 1 for dyspepsia and constipation, and 1 for death), 1 patient after 3 months (switch to intravenous iron for symptomatic anemia), and 2 after five months (1 for dyspepsia and 1 for death). Conclusion The use of liposomal iron in patients with NDD-CKD is associated with a partial correction of functional ID (TSAT&amp;lt;20%), with no significant effect on iron storage. The small sample size prevents any causative conclusion, though it may provide some insights into using these compounds in patients with CKD.

#1650 Synergistic effects of mineral bone disorder (MBD) markers and iron metabolism markers on QT prolongation in maintenance haemodialysis patients

Abstract Background and Aims Prolonged QT interval is known to be common in maintenance haemodialysis (HD) patients, and QT prolongation is a risk for the development of fatal arrhythmias and cardiovascular complications. Previously, we showed that low Ca and low or high P before dialysis were associated with QT prolongation in HD patients. In this study, we aimed to investigate the effect of abnormalities in MBD markers such as Ca and P on QT time when added to abnormalities in markers of iron metabolism, a known cardiac prognostic factor due to abnormal energy metabolism in the myocardium. Method A cross-sectional study was conducted on adult maintenance HD patients enrolled in the 2020 Japanese Society for Dialysis Therapy Annual Survey. Patients with dialysis frequency less than 3 times per week and patients with absent serum Ca, serum P, transferrin saturation (TSAT), serum ferritin, and QTc were excluded. After describing patient characteristics, an analytical-epidemiological study was conducted with serum Ca, P, TSAT, and serum ferritin as exposure and QTc &amp;gt;500 msec as outcome. Exposure was defined as cut off values for Ca, P, TSAT, and serum ferritin of 8.4/10, 3.5/6, 20/40, and 100/300, respectively according to JSDT guideline. Adjusted variables in the multivariate analysis were age, gender, history of dialysis, BMI, and presence or absence of diabetes, previous cardiovascular disease, P adsorption medication, vitamin D analogue use, calcimimetics use. Missing values were addressed using Multiple Imputation by Chained Equations. All analyses were performed using STATA 18.0. The significance level was set at 5%. Results 169 705 patients were analysed. Among all subjects, 65.6% were male, mean age was 69.7 years (standard deviation (SD) 12.4), 50.6% had comorbid diabetes, 24.1% had previous cardiovascular disease, and mean serum Ca and P levels were 8.6 mg/dL (SD 0.7) and 5.2 mg/dL (SD 35.8), respectively. The mean QTc was 452 msec (SD 37.9). In multivariate analysis, the increased risk of QT prolongation in the low Ca, low P, and high P categories was further increased with low TSAT and cancelled with high TSAT (Table). In contrast, no such effect was appeared for ferritin. Conclusion The present study suggests that the association between lower serum Ca and lower and higher serum P levels and QTc prolongation in maintenance haemodialysis patients may be enhanced at low TSAT levels and weakened at normal and high TSAT levels.

#1122 Anaemia in CKD and cardiovascular risk; all cut from the same cloth?

Abstract Background and Aims Anaemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular morbidity and mortality, but most studies have not investigated its longitudinal association by sex and age. Our aim was to study the association between haemoglobin (Hb) current value and the hazard of major adverse cardiovascular event (MACE) in specific subgroups of CKD patients defined by age and sex. Because erythropoiesis-stimulating agents (ESA) are incriminated to modify the effect of Hb level on the hazard of event for high level of Hb, we have here only focused in non-ESA users CKD patients. Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. We included patients with at least one Hb, estimated glomerular filtration rate (eGFR), transferrin saturation (TSAT) or ferritin measurement. We studied all Hb measurements available until a first MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure; initiation of kidney replacement therapy; death from other causes; or initiation of ESA therapy, whichever came first. First, we estimated the individual trajectories of Hb, eGFR, TSAT, ferritin using multivariate share random effect joint model. Then, we estimated the association between Hb current value and MACE using a cause specific multivariate Cox model in 4 specific subgroups separately: women ≤ and &amp;gt;70 years, men ≤ and &amp;gt;70 years. All models were adjusted on current value of eGFR, TSAT, Ferritin, and baseline value of albumin-to-creatinine ratio, age, CKD aetiology, heart failure past history, alcohol consumption, iron treatment, antithrombotic and anticoagulant. When appropriate, spline functions were used for continuous variables to account for potential non-linear effects. Reference value of Hb for computing hazard ratio was 12 g/dL in women, and 13 in men according to current definition of anaemia. Results A total of 2742 patients were included in the analysis (median eGFR 33 ml/min/1.73 m2, median age at inclusion 69 years) together with 28423 Hb measurements (median of 13 per patient) collected during a median follow-up of 5.0 years. There were 551 women ≤70 (median Hb 12.4 g/dL, 34 (6.2%) MACE), 349 women &amp;gt; 70 (12.2 g/dL, 61 (17.5%) MACE), 1009 men ≤ 70 (13.4 g/dL, 104 (10.3%) MACE) and 833 men &amp;gt; 70 (13.0 g/dL, 163 (19.6%) MACE). No statistical significant association was found in males whatever their age (Hazard ratio of MACE for each 1 g/dL increase in Hb 1.0 (95% CI 0.9-1.1) in men &amp;lt; 70 and 0.9 (95% CI 0.8-1.1) in men &amp;gt; 70). For women, the hazard of MACE raised as the Hb values decreased, with a more pronounced increase in women &amp;gt; 70 (Fig. 1). For example, the hazard ratio for a Hb value of 10 g/dL compared to the reference was 2.0 (95% CI 0.9-4.7) in women &amp;lt; 70 and 3.3 (95% CI 1.5-7.2) in women &amp;gt; 70. Conclusion In non-ESA users CKD patients, anaemia is associated with the occurrence of MACE in females, especially those older than 70 years. These results raise question about a one-size-fits-all approach in the interpretation of low values of haemoglobin and anaemia management. It also suggests to evaluate the effect of anaemia therapies in men and women separately.

Serum iron dynamics and mortality in patients with heart failure: A population-based cohort study

Abstract Background Iron deficiency (ID) is common among patients with heart failure (HF). Little is known about the impact of serum iron dynamics on mortality in HF. Methods Using a previously validated territory-wide clinical information registry, all eligible patients with HF (N = 112, 938) from 1996 to 2020 were enrolled. The index date was defined as the date of which HF was first diagnosed. Iron, ferritin and transferrin saturation (TSAT) values were retrieved both at baseline (1 year before index date) and during follow-up period (1 year after the index date until study end). The association between iron levels and risk of mortality was evaluated both on a continuous scale using restricted cubic spline curves and by categories using Cox proportional hazards regression model with competing risk as appropriate. Cut-points of iron were determined by the optimal equal-HR method. Inverse probability of treatment weighting (IPTW) was used to balance the covariates among iron groups. Changes in iron from baseline to follow-up were expressed by Sankey curve. The outcome was all-cause mortality. Results The mean age of the cohort was 73.0±12.2 years and 51,340 (45.5%) were male. The association between iron levels and the risk of all-cause mortality was a U-shaped curve. The risk of all-cause mortality reached a nadir between iron levels of 8.2 umol/L and 25.8 umol/L and was lowest at 13.5 umol/L. Accordingly, iron levels were divided into 3 groups: low iron (≤8.2 umol/L), midrange (8.2-25.8 umol/L), high iron (&amp;gt;25.8 umol/L). Compared to those who remained at midrange iron level during follow-up, risk of mortality was higher in those with persistently low and persistently high iron levels (HR 1.32, 95%CI 1.27 to 1.38; HR 2.24, 95%CI 1.74 to 2.89, respectively). Further, changes in iron levels from low to high (HR 1.41, 95%CI 1.24 to 1.61); mid to low (HR 1.15, 95%CI 1.10 to 1.20), mid to high (HR 1.29, 95%CI 1.13 to 1.49); high to low (HR 1.36, 95%CI 1.15-1.60), or high to mid (HR 1.18, 95%CI 1.00-1.38) also demonstrated higher risks of mortality. (Table 1) Conclusion The prevalence of low iron status is high among patients with HF. Both low or high iron levels at baseline, and changes to the lower or higher ends of the iron level spectrum during follow-up were associated with higher risks of all-cause mortality.cubic spline curve

Iron Uptake from Ferric Maltol in Patients with Iron Deficiency with or without Anemia: Post Hoc analysis of a Multicenter, Open-Label, Randomized, Phase 1 Clinical Study

Introduction: Iron deficiency is the most common nutritional disorder in humans, accounting for more than half of the estimated 1.76 billion cases of anemia worldwide (https://www.healthdata.org/). Anemia is a serious health problem, but, even without anemia, people with iron deficiency may experience fatigue, headaches, restless legs, and other physical and cognitive impairments, severely limiting their daily activities and quality of life. Patients may require long-term iron replacement therapy to replenish iron stores. Traditional oral iron salts are often associated with intolerable gastrointestinal toxicity and poor absorption. Ferric maltol is a European Medicines Agency- and U.S. Food and Drug Administration-approved oral iron formulation that was uniquely designed to improve gastrointestinal absorption, resulting in increased iron uptake while minimizing the risk of intestinal damage or dysbiosis. In a Phase 1 study in adults with inflammatory bowel disease and iron deficiency, ferric maltol increased iron uptake and storage over time at twice-daily doses of 30-90 mg (Bokemeyer B et al. Eur J Drug Metab Pharmacokinet 2017;42:229-238). We assessed iron measures following ferric maltol treatment in patients with iron deficiency with or without anemia. Methods: In post hoc analyses of data from 17 of the Phase 1 study participants (4 men, 13 women), who received twice-daily ferric maltol 30 or 60 mg, we compared total iron and transferrin saturation (TSAT) maximum concentration ( Cmax) and area under the curve up to 6 hours (AUC 6h) on Days 1 and 8 in subgroups with and without anemia. Data are reported as arithmetic means (standard deviation). Results: Four of the 17 patients (all female) had iron deficiency with anemia. Median (range) baseline hemoglobin levels were 107.5 (100-114) g/L in the subgroup with anemia and 135 (127-159) g/L in the subgroup without anemia. Total serum iron and TSAT values on Days 1 and 8 were similar between the subgroups with and without anemia (Table). Conclusions: These data demonstrate similar iron uptake from ferric maltol in patients with iron deficiency with or without anemia. Given the adverse impact of iron deficiency, even without anemia, iron-replacement therapy should be considered in anyone with an indication of low iron availability (e.g., ferritin &amp;lt;30 ng/mL with any TSAT value or ferritin &amp;lt;100 ng/mL with TSAT &amp;lt;20%), regardless of hemoglobin level. At the approved dose of 30 mg twice daily, ferric maltol is an effective, well tolerated, and convenient to take long-term iron-replacement therapy.

Utility of red blood cell parameters and indices of iron homeostasis in evaluation of microcytosis without anemia or with mild anemia: a diagnostic accuracy study

Introduction: Asymptomatic microcytosis may be a prelude to microcytic hypochromic anemia of varied causes. Evaluation of red cell indices may help delineate cases needing further investigation like hemoglobin high-performance liquid chromatography (Hb-HPLC). In addition, markers of iron homeostasis will help confirm iron-deficient erythropoiesis (IDE)/iron deficiency anemia (IDA). Materials and Methods: This was a single institutional hospital-based study over a period of 18 months. The sample size was 60, which include all age groups, males and females, and values of mean corpuscular volume (MCV) &lt; 80 fL, Hb ≥ 10g/dL were taken as the inclusion criteria. Various derived red cell indices, Hb-HPLC, and iron parameters were assessed. HbHPLC and serum ferritin with transferrin saturation (TSAT) values were taken as the gold standard for diagnosis of hemoglobinopathies/thalassemia trait and IDA/IDE, respectively. Statistical Analysis: Mean with standard deviation was calculated for normally distributed data such as Hb, RBC count, RDW, MCV, MCH, MCHC, and hematocrit. Median with range was calculated for non-normally distributed data. Results: Out of 60 samples, 24 (40%) and 36 (60%) had abnormal and normal proportion of Hb variants, respectively. In total, seven indices were evaluated, which included Mentzer’s index, red cell distribution width index, Ehsani’s index, Sirdah’s formula, Matos–Carvalho index, Shine and Lal index, and Sehgal’s index. The Shine and Lal index showed better sensitivity (89%) and specificity (73%) for diagnosing pure thalassemia trait. The Sirdah index showed better sensitivity (78%) and specificity (42%) in diagnosing IDE/IDA. Ferritin showed better sensitivity (74%) and specificity (84%) in diagnosing pure IDA and TSAT showed better results in diagnosing IDA/IDE. Conclusion: The Shine and Lal index and Mentzer index can be used as screening tools and help detect subjects who require appropriate follow-up with confirmation by HbHPLC. Serum ferritin remains the gold standard for diagnosis of IDA.

#3256 LONGITUDINAL ASSOCIATION BETWEEN IRON STORES BIOMARKERS AND MAJOR ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Iron deficiency is a frequent condition in moderate to severe chronic kidney disease (CKD), often left under-screened, and infrequently supplemented. Iron deficiency is a major contributor to anemia, which is known to negatively impact outcomes and quality of life in CKD. However, evidence of an anemia-independent effect of iron deficiency on cardiovascular morbidity and all-cause mortality has emerged. Current challenges of studying the association between iron deficiency and the risk of events in CKD are the definition of critical thresholds for these biomarkers, the potential interaction between them, and their evolution over time. Previous observational cohort studies have only focused on baseline values of transferrin saturation and ferritin, the two traditional biomarkers of iron deficiency. Our aim was to study the longitudinal association between iron stores biomarkers and cardiovascular risk in CKD by evaluating the total effect of these biomarkers on major adverse cardiovascular events (MACE). Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. All patients with at least one measurement of TSAT and ferritin were included in the present study. Our primary endpoint was MACE, defined as the first event among cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Repeated measures of TSAT and ferritin were included as time-dependent variables in cause-specific Cox proportional hazard models for risk of MACE, with initiation of kidney replacement therapy (KRT) and death as competitive events. Models were adjusted for time-varying estimated glomerular filtration rate (eGFR), white cells and baseline age, sex, iron supplementation, and erythropoietin stimulating agents. Analyses were not adjusted for hemoglobin level because the aim of the study was to investigate the total effect of iron deficiency on MACE. Non-linear effects of TSAT and ferritin and their interaction were modeled using natural splines functions. Results A total of 2670 patients were included in the analysis: 65% were men, median age was 68 years (interquartile range IQR 60-76). Median baseline eGFR was 34 ml/min/1.73 m2 (IQR 25-44), TSAT was 24% (IQR 18-30) and ferritin was 127 ng/ml (IQR 72-230). Over a median follow-up period of 4.4 years, participants had a median of 5 (IQR 2-8) and 4 (IQR 2-6) measurements of ferritin and TSAT, respectively; 396 MACE before KRT were recorded. The negative nonlinear association of iron deficiency with MACE was essentially captured by TSAT, and the interaction terms between TSAT and ferritin were not statistically significant (p = 0.94). Compared with patients with TSAT of 20% and ferritin of 100 ng/ml, those with TSAT values &amp;lt; 20% had a higher adjusted hazard of MACE independently of ferritin values (See Figure 1); for example, for TSAT = 10% and ferritin = 100 ng/ml, the hazard ratio (HR) was 1.96, 95% CI (1.60-2.39). Conclusion In CKD patients under nephrology care, current value of TSAT below 20% was associated with higher risk of MACE regardless of ferritin current value. Before investigating strategies of treatment in clinical trials as PIVOTAL in dialysis patients, further studies clarifying critical thresholds of TSAT and ferritin in non-dialysis CKD patients, in presence or absence of anemia and among specific CKD subpopulations are highly desirable.

COMPARISON OF TRANSFERRIN SATURATION LEVELS IN ANEMIA OF CHRONIC DISEASE AND IRON DEFICIENCY ANEMIA: A CROSS-SECTIONAL STUDY

About 33 percent of the global population is anemic. Anemia of chronic disease (ACD) is caused by chronic inflammation. Iron deficiency anemia (IDA) is caused by a decrease in the body's iron reserves to form red blood cells. There are many clinical and laboratory similarities between ACD and IDA, but the treatment is very different. Transferrin saturation level can be used to differentiate between the two. This research is novel because it compares transferrin saturation levels in chronic and iron deficiency anemia. This study aims to determine the transferrin saturation level in patients with ACD and IDA. This research method uses a cross-sectional study. Data taken from medical records. The sample for this study were children with ACD and IDA aged 1 month to 18 years at Wahidin Sudirohusodo Hospital, Makassar. The results showed that the mean transferrin saturation value in DKA children (19.40%) was higher than that in ADB children (5.66%). The Mann-Whitney test showed that there was a significant difference between the two groups (p=0.001) with a transferrin saturation cut-off point between the DKA and IDA groups of 6.5% with a sensitivity of 73.6%, a specificity of 72.5%, positive predictive value (PPV) of 78%, negative predictive value (NPV) of 67%, and odds ratio (OR) of 19,476 (95% CI). In conclusion, transferrin saturation levels can differentiate IDA and ACD using a cut-off point of 6.5%.

Magnetic Resonance Liver Iron Concentration Can Guide Venesection Decision-Making in Hyperferritinemia.

The clinical benefit of venesection in suspected iron overload can be unclear and serum ferritin may overestimate the degree of iron overload. To help inform practice, we examined magnetic resonance liver iron concentration (MRLIC) in a cohort investigated for haemochromatosis. One hundred and six subjects with suspected haemochromatosis underwent HFE genotyping and MRLIC with time-matched serum ferritin and transferrin saturation values. For those treated with venesection, volume of blood removed was calculated as a measure of iron overload. Forty-seven C282Y homozygotes had median ferritin 937µg/l and MRLIC 4.83mg/g; MRLIC was significantly higher vs non-homozygotes for any given ferritin concentration. No significant difference in MRLIC was observed between homozygotes with and without additional risk factors for hyperferritinemia. Thirty-three compound heterozygotes (C282Y/H63D) had median ferritin 767µg/l and MRLIC 2.58mg/g; ferritin < 750µg/l showed 100% specificity for lack of significant iron overload (< 3.2mg/g). 79% of C282Y/H63D had additional risk factors-mean MRLIC was significantly lower in this sub-group (2.4mg/g vs 3.23mg/g). 26 C282Y heterozygous or wild-type had median ferritin 1226µg/l and MRLIC 2.13mg/g; 69% with additional risk factors had significantly higher ferritin concentrations (with comparable MRLIC) and ferritin < 1000µg/l showed 100% specificity for lack of significant iron overload. In 31 patients (26 homozygotes, 5 C282Y/H63D) venesected to ferritin < 100µg/l, MRLIC and total venesection volume correlated strongly (r = 0.749), unlike MRLIC and serum ferritin. MRLIC is an accurate marker of iron overload in haemochromatosis. We propose serum ferritin thresholds in non-homozygotes which, if validated, could tailor cost-effective use of MRLIC in venesection decision-making.

Effects of Chronic Alcohol Consumption and Iron Deficiency on Maternal Folate Status and Reproductive Outcome in Mice

The influence of chronic alcohol consumption with or without iron deficiency on reproductive performance and folate status was studied. Female CBA/J mice were fed isocaloric liquid diets prior to and during pregnancy. A 2 × 2 factorial design was employed with ethanol-derived calories (EDC) and iron (Fe) as dietary variables. Groups received 0% EDC and 30 ppm Fe (CA); 0% EDC and 2 ppm Fe (CD); 20% EDC and 30 ppm Fe (EA); and 20% EDC and 2 ppm Fe (ED). Animals were killed on day 18 of gestation. Mean body weights were reduced in CD, EA and ED groups, while daily caloric intakes reduced only in CD and ED groups. Maternal values for hemoglobin, transferrin saturation and red cell folates decreased with iron deficiency and/or 20% EDC; hematocrit, serum iron and serum folates decreased only with iron deficiency. Blood ethanol levels were similar in EA and ED groups. Maternal liver total lipids and alcohol dehydrogenase activity increased only with 20% EDC, while dihydrofolate reductase activity decreased with iron deficiency and/or 20% EDC. Iron deficiency and/or 20% EDC adversely affected gestational performances in mice as indicated by increased resorptions and decreased percentages of live fetuses/litters and live fetal weights. Data indicate that iron deficiency and/or chronic ethanol consumption induce adverse effects on maternal reproductive performance of CBA/J mice possibly via alteration of folate metabolism.

Maintenance intravenous iron in hemodialysis patients to minimize erythropoietin doses: a double-blinded, randomized controlled trial (the MAINTAIN IRON trial)

In patients on chronic hemodialysis, there is no standard protocol for maintenance iron supplementation. This study aimed to compare two fixed-dose intravenous (IV) iron protocols to reduce erythropoiesis-stimulating agents (ESA). We conducted a double-blinded, randomized controlled study on hemodialysis patients having ferritin levels between 200 and 700 ng/dl and transferrin saturation values between 20 and 40%. Patients were assigned to receive either 100 or 200 mg of IV iron each month. ESA was adjusted every month to keep Hb between 10 and 12 g/dl. ESA dose at 12 months was the primary outcome. The secondary outcomes were all-cause mortality, cardiovascular events, absolute iron deficiency anemia (IDA), blood transfusion, adverse events, and iron withholding rate. Of the 79 eligible patients, 40 received 100 mg of IV iron, while 39 received 200 mg. At month 12, the mean monthly ESA dose in the 100-mg IV iron group was 35,706 ± 21,637 IU, compared to 26,382 ± 14,983 IU in the 200-mg group (P = 0.03). IDA was found in twelve patients (30%) in the 100-mg group and four patients (10.5%) in the 200-mg group (P = 0.05). In each group, three patients died (P = 0.9). Hospitalization, venous access thrombosis, and infection rates were similar in both groups. The withholding rate of IV iron was higher in 200-mg group (25% vs. 64.1%), but the protocol compliance was found more in 100-mg group (50% vs. 28.2%) (P = 0.001). In conclusion, monthly 200-mg IV iron infusions significantly reduce ESA doses but have a higher withholding rate. (Funded by the Kidney Foundation of Thailand and the Research Group in Nephrology and Renal Replacement Therapy from the Faculty of Medicine, Thammasat University).Thai Clinical Trials Registry number, TCTR20190707001.

Ferric Carboxymaltose Versus Ferrous Glycine Sulfate For Treatment of Iron Deficiency Anemia and Their Effect On Vitamin B12 And Folic Acid: A Retrospective Study

Aim Anemia is a major public health problem, affecting about one-third of the world's population, and is most commonly caused by iron deficiency. Iron deficiency anemia requires oral or intravenous iron replacement therapy. The purpose of this study was to assess the change in several hematological parameters, vitamin B12, and folic acid from baseline to the first month of follow-up following therapy with oral ferrous glycine sulfate or intravenous ferric carboxymaltose. Methods: All patients who received oral ferrous glycine sulfate or intravenous ferric carboxymaltose for the treatment of iron deficiency anemia between January 1, 2016, and December 31, 2018, were included in the trial. Along with age and gender information, values of hemoglobin, ferritin, transferrin saturation, mean corpuscular volume, vitamin B12, and folic acid were derived from patients’ records at the beginning of treatment and first month follow-up. Results: Laboratory values obtained after treatment showed statistically significant improvement in both groups (intra group, p&amp;lt;0.001). When the percentage of change between groups was compared: Percentage-based increases in hemoglobin, mean corpuscular volume, transferrin saturation and ferritin values were significantly higher in the ferric carboxymaltose group (p&amp;lt;0.001). The percentage decrease in vitamin B12 and folic acid values was higher in the ferric carboxymaltose group (p=0.005 and p=0.01, respectively) when compared with oral ferrous glycine sulfate group. Conclusions: According to the findings of our study, iron deficiency anemia can be treated very successfully using ferric carboxymaltose; however, it should be remembered that concurrent supplementation of elements such vitamin B12 and folic acid is necessary for the appropriate progression of erythropoiesis.

Prognostic Value of Serum Transferrin Analysis in Patients with Ovarian Cancer and Cancer-Related Functional Iron Deficiency: A Retrospective Case-Control Study.

(1) Background: There are no reliable and widely available markers of functional iron deficiency (FID) in cancer. The aim of the study was to evaluate the role of transferrin (Tf) as a marker of cancer of the ovary (CrO) and related FID. (2) Methods: The study groups consisted of 118 patients with CrO and 69 control females. Blood serum iron status was determined on a Beckman Coulter AU (USA) analyzer. Tf quantification was performed by immunoturbidimetry. The relative contents of apo- and holo-Tf (iron-free and iron-saturated Tf, respectively) were determined in eight patients and a control female by immunochromatographic analysis based on the use of monoclonal single-domain antibodies (nanobodies). (3) Results: Four groups of patients with different iron statuses were selected according to ferritin and transferrin saturation values: absolute iron deficiency (AID) (n = 42), FID (n = 70), iron overload (n = 4), normal iron status (n = 2). The groups differed significantly in Tf values (p &lt; 0.0001). Lower values of Tf were associated with FID. Furthermore, FID is already found in the initial stages of CrO (26%). Immunosorbents based on nanobodies revealed the accumulation of apo-Tf and the decrease in holo-Tf in patients with CrO. (4) Conclusions: Tf may be a promising tool for diagnosing both CrO and associated FID.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Changes in obesity and iron deficiency between 4 and 9 years of age. Longitudinal study of childhood obesity (ELOIN).

Recent studies revealed that children who are overweight have a higher risk of iron deficiency, although the etiology of this relationship remains unclear. The aim of the study was to evaluate the association between changes in obesity status between 4 and 9 years of age and iron deficiency. This population-based cohort study included 1347 children from the ELOIN study, conducted in Madrid, Spain. Follow-up with physical examinations and a computer-assisted telephone interview were carried out at 4, 6 and 9 years of age, and a blood test was performed at 9 years. Changes in obesity were estimated based on body mass index and waist circumference, according to the persistence or variation in obesity rates at 4, 6 and 9 years and were classified as follows: (1) Stable without obesity; (2) Remitting obesity at 9 years; (3) Incident obesity or relapse at 9 years; and (4) Stable with obesity. Iron deficiency was defined as transferrin saturation value below 16%. Odds ratios (ORs) for iron deficiency were estimated according to obesity status using logistic regression and adjusted for confounding variables, including C-reactive protein (CRP). The prevalence of iron deficiency in the stable general obesity (GO) and abdominal obesity (AO) groups was 38.2% and 41.2%, versus 23.6% and 23.4% in the stable without obesity groups, respectively. The ORs for iron deficiency were 1.85 (95% CI: 1.03-3.32) in the stable GO group and 2.34 (95% CI: 1.29-4.24) in the stable AO group. This association disappeared when CRP was included in the analysis. An extended state of obesity during the first stages of life is associated with iron deficiency, and this association may be mediated by CRP. Prevention and early detection of obesity in children should be a priority to avoid a double burden of malnutrition.

Comparison of daily oral iron replacement therapy with every other day treatment in female reproductive age patients with iron-deficiency anemia

Iron-deficiency anemia (IDA) is accepted as the most common cause of anemia in the world. The main goals of iron replacement therapy are to normalize the hemoglobin level and to replace iron stores. Current guidelines for treating iron deficiency recommend daily divided doses of iron to increase absorption. Hepcidin is a key regulator of systemic iron balance and acts in harmony with intracellular iron metabolism. Daily dosing and divided doses may increase serum hepcidin and decrease iron absorption. In this study, it was aimed to compare the effectiveness of daily and every other day oral iron replacement therapy in women of reproductive age with iron-deficiency anemia. We included premenopausal female patients aged between 18 and 50years with iron-deficiency anemia. Forty patients were given oral iron therapy at a daily dose of 2*80mg (iron sulfate). Forty-three patients were given iron treatment at a dose of 2*80mg (iron sulfate) every other day. After 2months of oral iron therapy, there was a significant improvement in hemoglobin, mean corpuscular volume, serum iron, total iron-binding capacity, and transferrin saturation in both groups. The values of hemoglobin, serum iron, transferrin saturation, and ferritin significantly increased at the end of the treatment for both groups. Although the median hepcidin level on the 15th-day measurement in the every other day treatment group was higher than that in the daily treatment group, there was no significant difference. As a result, the patients' compliance with the treatment can be increased by offering treatment every other day instead of daily, since it provides similar treatment effectiveness.

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress.

Evaluation of macular and optic disc radial peripapillary vessel density with optical coherence tomography angiography in iron deficiency anemia

PurposeTo investigate effect of iron deficiency anemia (IDA) on macular and radial peripapillary capillary (RPC) vascular changes by optical coherence tomography angiography (OCTA). MethodsThirty-three patients with IDA and 33 healthy controls were enrolled in the study. Foveal avascular zone (FAZ) area, macular superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density and RPC vessel density were evaluated by the AngioVue Imaging System. Hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), serum iron, total iron-binding capacity (TIBC), serum ferritin and transferrin saturation values were also recorded. ResultsThere were no statistically significant differences between the two groups in terms of FAZ area and FAZ perimeter while foveal density (FD) was significantly decreased in the IDA group. Compared to control group, IDA group revealed significantly decreased macular vessel density in all macular regions except fovea in both SCP and DCP. RPC vessel density was significantly decreased in whole image, peripapillary and superior-hemifield area wihout RNFL thinning. Hemoglobin level was positively correlated with SCP whole and RPC whole vessel density and serum iron level was also positively correlated with SCP whole vessel density. ConclusionMacular and optic disc vessel density were reduced in IDA patients. OCTA may be useful in detecting retinal ischemia before clinically visible signs of retinopathy associated with IDA appear.