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Treatment of Chronic Hepatitis C virus (HCV) infection in patients suffering from hereditary β-thalassemia major is a concern due to drug complications and liver malfunction. The aim of the present study was to evaluate treatment outcome of Direct-Acting Antiviral (DAA) therapy in thalassemia major patients infected with HCV in a three year follow-up.In a cohort study, long-term safety and efficacy of DAA therapy were evaluated in a group of thalassemia major patients suffering from chronic HCV infection. Hematologic and biochemical parameters as well as liver Fibroscan monitoring were assessed at the onset and three years after the treatment.From among 84 patients enrolled in the study, 53.6% were males, 36.9% had cirrhosis, 96.4% had a history of Desferal usage, and 78.6% had a history of splenectomy. Unfortunately, 7 participants (8.3%) died prior to the end of follow-up with nearly half of them having Iron overload and heart failure complications. Fibroscan score, ALT, AST, and ferritin were significantly lower compared with baseline evaluation, while Hb, creatinine, and direct bilirubin increased significantly in the third year after the treatment.Safety and efficacy of Sofosbuvir and Daclatasvir in thalassemia patients assessed previously but our three year follow-up showed their mild complications and death into a long-term period after DAAs treatment and 91.7% three year survival rate, which may affected by other confounding factors, such as liver malfunction and Iron overload.

Epidemiological studies on transfusional iron overload (TIO) in the general population of heavily transfused patients are scarce. The aim of this work was to provide a picture on the distribution and management of this complication within the context of unselected individuals attending a general hospital.We retrospectively assessed the characteristics of 611 patients from a single institution having received at least 20 red blood cell (RBC) units over a 10-year period.About two-thirds of these individuals were males and their median age at the 20th RBC was 72years (range: 10-98). Myelodysplastic syndromes (MDS) and acute myeloid leukemia represented the most frequent underlying conditions (53%) but lymphoid malignancies and solid malignancies accounted for 13.6 and 7.3% respectively. In the vast majority of cases various comorbidities (range: 1-6 per patient) were registered including especially cardiovascular disorders. The highest cumulative RBC numbers were observed in MDS patients. Serum ferritin was assessed in 451 patients (73.8%) and ≥1000μg/L in 250 cases, ≥2000μg/L in 100 cases and ≥2500μg/L in 71 cases. Only 97 patients (15.9%) received a treatment for TIO using either a chelator (n=93) or phlebotomy (n=4).TIO is not limited to MDS or hemoglobin disorders. Its assessment and management are suboptimal in clinical practice. The ratio of patients receiving iron chelation is markedly lower than theoretically expected mainly because of comorbidities or drug intolerance.

We evaluated frequency, pattern, and associations of renal iron accumulation in sickle/β-thalassemia. Thirty-three sickle/β-thalassemia patients (36.5 ± 14.7 years; 13 females), 14 homozygous sickle cell disease (SCD) patients, and 71 thalassemia major (TM) patients, enrolled in the E-MIOT Network, underwent magnetic resonance imaging. Iron overload (IO) was quantified by the T2* technique. Sickle/β-thalassemia patients had a significantly lower frequency of renal IO (T2* 31 ms) than homozygous SCD patients (9.1% vs. 57.1%; P = 0.001), besides having similar hepatic, cardiac and pancreatic IO. Kidney T2* values were comparable between regularly transfused sickle/β-thalassemia and TM patients but were significantly lower in regularly transfused homozygous SCD patients than in the other two groups. In sickle/β-thalassemia patients, global renal T2* values were not associated with age, gender, splenectomy, and presence of regular transfusions or chelation. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (R = - 0.709; P 0.0001) and indirect bilirubin (R = - 0.462; P = 0.012). Renal IO is not common in sickle/β-thalassemia patients, with a prevalence significantly lower compared to that of homozygous SCD patients, but with a similar underlying mechanism due to the chronic hemolysis.

Excess bodily iron content is commonly associated with obesity and metabolic associated medical conditions and is thought to lead to cardiovascular disease. The effect of Roux-en-Y gastric bypass (RYGB) on hepatic iron overload remains to be determined.To assess the evolution of histologically proven hepatic iron overload after RYGB.This is an exploratory historical cohort study in which 42 individuals who underwent RYGB, and then a second surgical procedure had paired liver biopsies collected. Hepatic iron overload and NAFLD features were assessed through histopathological examination. Biochemical iron metabolism parameters were also assessed.The mean age at RYGB was 47 ± 10.2 years and 92.9% were female. The average time elapsed between RYGB and the second surgical procedure was 20.6 ± 15.4 months. The mean percentage of total weight loss between the two procedures was 26.7 ± 9.4%. Significant reductions in ferritin (220.8 ± 202.9 vs. 101.6 ± 116.7 ng/mL; p = 0.006), hemoglobin (13.7 ± 1.8 vs. 12.1 ± 2.6 g/dL; p = 0.01), and red blood cell count (4.7 ± 0.7 vs. 4.3 ± 0.5 10RYGB led to a significant decrease in hepatic iron overload, emerging as a possible therapeutical tool for this condition in individuals with obesity and dysmetabolic iron overload syndrome.

Magnetic resonance imaging (MRI)-based liver iron quantification is the standard of care to guide chelation therapy in children at risk of hemochromatosis. T2* relaxometry is the most widely used technique but requires third-party software for post-processing. Vendor-provided three-dimensional (3-D) multi-echo Dixon techniques are now available that allow inline/automated post-processing.The purpose of our study was to evaluate the diagnostic accuracy of a volumetric multi-echo Dixon technique using conventional T2* relaxometry as the reference standard in a pediatric and young adult population.In this retrospective study, we queried the radiology information system to identify all MRIs performed for liver iron quantification from July 2015 to January 2020. All patients had undergone T2* relaxometry on a 1.5-tesla (T) scanner for liver iron concentration (LIC) estimation. In addition, a 3-D multi-echo Dixon was performed using Siemens Healthineers LiverLab (Erlangen, Germany). Two readers independently estimated liver R2* and T2* on the multi-echo Dixon by drawing free-hand regions of interest on the scanner-generated R2* and T2* maps. Conventional T2*-relaxometry-based LIC was the reference standard. We estimated interobserver agreement by concordance correlation coefficient (CCC). We used Bland-Altman analysis and Pearson correlation coefficient (r) to compare LIC by the two methods.Fifty-four MRIs on 38 patients (22 females) were available for analysis. Mean patient age was 11.8 years (standard deviation [SD] 5.3 years). Reference standard LIC ranged 1.1-21.1 (median 6.8) mg/g dry weight of liver. The concordance between readers for T2* estimation using 3-D multi-echo Dixon was substantial (CCC 0.99, confidence interval 0.99-1.00). Bland-Altman plot showed that all observations were clustered around the zero bias line if the LIC average was ≤8 mg/g, and r was very strong (reader 1 r=0.93, reader 2 r=0.92, both P-values0.001). With increasing LIC, there was a pattern of poor agreement on the Bland-Altman plot, with observations crossing the lower limits of agreement, and r was very weak (reader 1 r=0.05, P-value 0.84; reader 2 r=0.17, P-value 0.44).Vendor-based 3-D multi-echo Dixon allows for excellent interobserver correlation in liver T2* estimation. LIC estimated by this method has a very strong correlation with conventional T2* relaxometry if liver iron overload is mild-moderate (LIC ≤8 mg/g).

Background: Recent studies have found that there are significant associations between body iron status and the development of diabetes. In the present study, we aimed to analyze the association among iron overload (IO), insulin resistance (IR), and diabetes in Chinese adults, and to explore the sex difference.Methods: Men and women (age >19 years) who participated in the Chinese Health and Nutrition Survey and did not have diabetes at baseline were followed between 2009 and 2015 (n=5,779). Over a mean of 6 years, 75 participants were diagnosed with incident diabetes. Logistic regression was used to assess the risk factors associated with IO. Cox proportional hazard regression was used to estimate the risk of incident diabetes and to determine whether the risk differed among subgroups. Causal mediation analysis (CMA) was used to explore the mechanism linking IO and diabetes.Results: According to sex-stratified multivariable-adjusted Cox proportional hazards regression, IO increased the risk of incident diabetes. Women with IO had a higher risk of diabetes than men. Subgroup analysis with respect to age showed that the association between IO and diabetes was stronger in older women and younger men (P

Hepcidin (HEPC) hormone production is expected to be elevated in cases accompanying iron overload, but the opposite impact of ineffective erythropoiesis in β-thalassemia major (β-TM) patients overrides this effect. The role of the HEPC-to-ferritin (FER) ratio and its components in iron metabolism along with their diagnostic cutoff values, sensitivity, specificity, and accuracy in β-TM patients with iron overload, were examined in this study. This was a 1:1 case-control study with 120 participants, ages ranging from 2 to 30 years of both sexes, who were assigned into two groups: 60 β-TM patients with iron overload, and a control group, comprising 60 healthy individuals matched by gender and age. In the present study, we found slightly elevated serum HEPC concentration (21.9 ng/mL) compared to the controls (9.9 ng/mL), which was not statistically significant (

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was −4.04 (0.48) mg/g dry weight for deferiprone vs −4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, −0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Background Standardized manual region of interest (ROI) sampling strategies for hepatic MRI steatosis and iron quantification are time consuming, with variable results. Purpose To evaluate the performance of automatic MRI whole-liver segmentation (WLS) for proton density fat fraction (PDFF) and iron estimation (transverse relaxometry [R2*]) versus manual ROI, with liver biopsy as the reference standard. Materials and Methods This prospective, cross-sectional, multicenter study recruited participants with chronic liver disease who underwent liver biopsy and chemical shift-encoded 3.0-T MRI between January 2017 and January 2021. Biopsy evaluation included histologic grading and digital pathology. MRI liver sampling strategies included manual ROI (two observers) and automatic whole-liver (deep learning algorithm) segmentation for PDFF- and R2*-derived measurements. Agreements between segmentation methods were measured using intraclass correlation coefficients (ICCs), and biases were evaluated using Bland-Altman analyses. Linear regression analyses were performed to determine the correlation between measurements and digital pathology. Results A total of 165 participants were included (mean age ± standard deviation, 55 years ± 12; 96 women; 101 of 165 participants [61%] with nonalcoholic fatty liver disease). Agreements between mean measurements were excellent, with ICCs of 0.98 for both PDFF and R2*. The median bias was 0.5% (interquartile range, -0.4% to 1.2%) for PDFF and 2.7 sec

Background: The improvement of beta thalassaemia treatments has led to an increase in life expectancy. This implies the emergence of new comorbidities. Amongst others, endocrine glands are extremely sensitive to iron overload. Objective: We aimed to understand the impact of the endocrine conditions on the patient’s quality of life (QOL). Results: Hypogonadism may present with lack or delay of pubertal development, sexual dysfunctions and impaired fertility, which impact QOL in both sexes. Early recognition and treatment, as well as choosing the most appropriate therapy, according to patient’s needs (fertility, pubertal development, psychological concerns, comorbidities), are advisable. Osteoporosis affects QOL irrespective of symptoms. Growth hormone deficiency may occur both in childhood and in adulthood, and it affects different aspects of QOL. In adults, it could be difficult to examine if the symptoms are due to GHD, and a trial of GH replacement could be useful to identify benefits and needs. Glucose metabolism impairment is common in thalassaemic patients and early recognition is mandatory because long-term complications can have a detrimental impact on QOL (as blindness or dialysis). Although the incidence of adrenal insufficiency seems to be rare in thalassaemic patients, when it occurs, it has a severe impact on QOL. Conclusion: Limited data is available on QOL in thalassaemic patients, and is even less related to endocrinopathies. We can speculate that endocrinopathies have an impact on everyday life. More studies are needed to allow our patients to achieve not just a longer life but also a better quality of life.

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Aims The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. Methods Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. Results In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). Conclusions In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.

Pregnant women frequently supplement their diets with iron to treat any cryptic anemia, on the assumption that if anemia is not present, there will be no negative consequences. However, in women who are already iron-replete, it has been suggested that this can lead to iron overload and an increased risk of certain pregnancy complications. One such complication is gestational diabetes. Fourteen clinical trials, case-control or cohort studies (found using Pubmed/Scopus/Web of Science) have investigated links between iron supplementation in pregnancy and risk of gestational diabetes, several of them finding significant associations with increased risk. Potential mechanisms include increased oxidative stress leading to insulin resistance and inadequate compensatory insulin secretion. Current evidence suggests that dietary supplementation with iron in pregnancy may increase a pregnant woman's chance of developing gestational diabetes, although available evidence is somewhat contradictory, and the magnitude of any increased risk appears relatively small. Meta-analyses have suggested the presence of significant heterogeneity in results between studies, urging a degree of caution in interpreting these results. It is currently suggested that advice to pregnant women about whether to supplement their diets with iron or not should consider both their current iron status and their other established risk factors for gestational diabetes., None

We and others have previously shown that abnormal pelvic environment plays an important role in the unexplained infertility of endometriosis. However, whether iron overload caused by ectopic periodic bleeding found in patients with endometriosis participates in endometriosis-associated reproductive failure is unknown. This study aimed to investigate effects of iron at level relevant to pelvic iron overload on the development of preimplantation mouse embryo. Two-cell embryos were collected, and cultured to blastocysts in G1/G2 medium supplemented with iron alone or in combination with iron chelator. The development rates, ATP level, mitochondrial membrane potential (MMP), reactive oxygen species level (ROS), and apoptotic and ferroptotic indices were compared between control and iron treatments across each specific developmental stage. Prolonged exposure to iron remarkably impaired early embryo development in vitro by hampering blastocyst formation (P < 0.001), which could be partly restored by iron chelator (P < 0.001). The arrest of embryo development was linked with iron-initiated mitochondrial dysfunction with reduction of ATP generation and MMP (P < 0.05 and P < 0.001, respectively). Impaired mitochondria altered ROS accumulation post-iron exposure at morula stage and blastocyst stage (P < 0.05). Moreover, Iron-exposed blastocyst stage embryos showed higher apoptotic and ferroptotic rates (P < 0.001 and P < 0.05, respectively). Our results highlight that pathologically relevant level of iron compromises preimplantation mouse embryo development by disrupting mitochondrial function and triggering both apoptosis and ferroptosis, which implicates that excess iron found in peritoneal fluid of women with endometriosis likely participates in endometriosis-associated reproductive failure.

PURPOSE To evaluate the precision profile (repeatability and reproducibility) of quantitative STEAM-MRS and to determine the relationships between multiple MR biomarkers of chronic liver disease in subjects with iron overload at both 1.5 Tesla (T) and 3T. METHODS MRS data were acquired in patients with known or suspected liver iron overload. Two STEAM-MRS sequences (multi-TE and multi-TE-TR) were acquired at both 1.5T and 3T (same day), including test-retest acquisition. Each acquisition enabled estimation of R1, R2, and FWHM (each separately for water and fat); and proton density fat fraction. The test-retest repeatability and reproducibility across acquisition modes (multi-TE vs. multi-TE-TR) of the estimates were evaluated using intraclass correlation coefficients, linear regression, and Bland-Altman analyses. Multi-parametric relationships between parameters at each field strength, across field strengths, and with liver iron concentration were also evaluated using linear and nonlinear regression. RESULTS Fifty-six (n = 56) subjects (10 to 73 years, 37 males/19 females) were successfully recruited. Both STEAM-MRS sequences demonstrated good-to-excellent precision (intraclass correlation coefficient ≥ 0.81) for the quantification of R1water , R2water , FWHMwater , and proton density fat fraction at both 1.5T and 3T. Additionally, several moderate (R2 = 0.50 to 0.69) to high (R2 ≥ 0.70) correlations were observed between biomarkers, across field strengths, and with liver iron concentration. CONCLUSIONS Over a broad range of liver iron concentration, STEAM-MRS enables rapid and precise measurement of multiple biomarkers of chronic liver disease. By evaluating the multi-parametric relationships between biomarkers, this work may advance the comprehensive MRS-based assessment of chronic liver disease and may help establish biomarkers of chronic liver disease.

Background Hepatic iron content (HIC) is an important parameter for the management of iron overload. Non-invasive HIC assessment is often performed using biopsy-calibrated two-dimensional breath-hold Cartesian gradient echo (2D BH GRE) R2 * -MRI. However, breath-holding is not possible in most pediatric patients or those with respiratory problems, and three-dimensional free-breathing radial GRE (3D FB rGRE) has emerged as a viable alternative. Purpose To evaluate the performance of a 3D FB rGRE and validate its R2 * and fat fraction (FF) quantification with 3D breath-hold Cartesian GRE (3D BH cGRE) and biopsy-calibrated 2D BH GRE across a wide range of HICs. Study type Retrospective. Subjects Twenty-nine patients with hepatic iron overload (22 females, median age: 15 [5-25] years). Field strength/sequence Three-dimensional radial and 2D and 3D Cartesian multi-echo GRE at 1.5 T. Assessment R2 * and FF maps were computed for 3D GREs using a multi-spectral fat model and 2D GRE R2 * maps were calculated using a mono-exponential model. Mean R2 * and FF values were calculated via whole-liver contouring and T2 * -thresholding by three operators. Statistical tests Inter- and intra-observer reproducibility was assessed using Bland-Altman and intraclass correlation coefficient (ICC). Linear regression and Bland-Altman analysis were performed to compare R2 * and FF values among the three acquisitions. One-way repeated-measures ANOVA and Wilcoxon signed-rank tests, respectively, were used to test for significant differences between R2 * and FF values obtained with different acquisitions. Statistical significance was assumed at P Results The mean biases and ICC for inter- and intra-observer reproducibility were close to 0% and >0.99, respectively for both R2 * and FF. The 3D FB rGRE R2 * and FF values were not significantly different (P > 0.44) and highly correlated (R2 ≥ 0.98) with breath-hold Cartesian GREs, with mean biases ≤ ±2.5% and slopes 0.90-1.12. In non-breath-holding patients, Cartesian GREs showed motion artifacts, whereas 3D FB rGRE exhibited only minimal streaking artifacts. Data conclusion Free-breathing 3D radial GRE is a viable alternative in non-breath-hold patients for accurate HIC estimation. Level of evidence 3 TECHNICAL EFFICACY: Stage 2.

Background: Sickle cell disease is the commonest genetic disorder of haemoglobin due to inheritance of mutant haemo- globin genes from both parents. The disorder is characterized by chronic haemolysis which results in increased availability of iron from red blood cell destructions. Objective: To determine the prevalence of iron overload among non-chronically blood transfused preschool children with sickle cell anaemia. Methods: Serum ferritin was assayed and transferrin saturation derived in 97 steady state sickle cell anaemia children. Ele- vated iron stores were defined as serum ferritin level >300ng/ml, and transferrin saturation >45%. . Results: Serum ferritin level was greater than 300 mg/ml in 14 (14.4%) subjects and transferrin saturation >45% in six (6.2%) subjects with sickle cell anaemia. The prevalence of iron overload was 20.6%. The prevalence of iron overload was higher among subjects in older age group, female, with history of blood transfusion, and with single blood transfusion ses- sion. Conclusion: Iron overload is prevalent in older children; the number of blood transfusion sessions notwithstanding. Regu- lar assessment of serum ferritin is recommended. Keywords: Sickle cell anemia; iron overload; serum ferritin; transferrin saturation; elevated iron.

Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT45% and ferritin200 μg/L in females and TSAT50% and ferritin300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin50 μg/L during the induction phase and100 μg/L during the maintenance phase.血色病以转铁蛋白饱和度（TSAT）升高，进行性铁超载并主要影响肝脏为特征。早期诊断和放血治疗可预防肝硬化、肝细胞癌、糖尿病、关节病及其他并发症。对于遗传性血色病基因（HFE）p.Cys282Tyr纯合子变异的患者，女性TSAT45%和铁蛋白200 μg/L，男性和绝经后女性TSAT50%和铁蛋白300 μg/L可以疑似诊断血色病；对于其他HFE基因型的患者，除有TSAT升高和铁蛋白升高证据外，还需要在磁共振成像或肝活检中明确肝脏铁超载才可以诊断。诊断时应仔细评估肝脏纤维化状态和其他器官损害的程度，这决定了疾病的治疗及管理策略。晚期肝纤维化患者应定期进行肝癌筛查。放血治疗的追求目标是诱导期铁蛋白50 μg/L，维持期铁蛋白100 μg/L。.

Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment. We aim to quantitatively measure cerebral tissue R2* to investigate the brain iron deposition in children and young adults with SCD in comparison to beta thalassemia major (BTM) and healthy controls and evaluate its impact on neurocognitive functions in patients with SCD. Thirty-two SCD, fifteen BTM, and eleven controls were recruited. Multi-echo fast-gradient echo sequence brain MRI was performed, and brain R2* values of both caudate and thalamic regions were calculated. SCD patients were examined for the neurocognitive functions. SCD had high iron overload 0.30 ± 0.12 mg/kg/day. 68.9% of SCD had under-threshold IQ, 12.5% had moderate to severe anxiety, and 60.8% had depression. There were no differences between SCD, BTM, and controls in brain MRI except that left thalamus R2* higher in BTM than both SCD and controls (p = 0.032). Mean right caudate R2* was higher in female than male (p = 0.044). No significant association between brain R2* and LIC or heart R2* values in SCD. Left caudate R2* directly correlate with age and HbS%, and negatively correlate with HbA% while right thalamus R2* negatively correlate with transfusion index and among SCD patients.Conclusion: Neurocognitive dysfunction in SCD could not be explained solely by brain iron overload. What is Known: • Children with sickle cell disease are at great risk of brain damage due to their irregularly shaped red blood cells that can interrupt blood flow to the brain. • There are a number of factors that have negative brain effects that result in learning difficulties, and this not only due to increase brain iron content. What is New: • Assessment of quantitative brain iron content using MRI R2* in children and young adults with SCD in comparison to beta thalassemia major and healthy controls. • Impact of brain iron content on neurocognitive functions of children and young adults with SCD.

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135–8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235–1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196–0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up., This work was funded by aGerencia Regional de Salud de Castilla y León grant(GRS1203/A/15) and a Rıo Hortega contract (CM19/00055),supported by the Instituto de Salud Carlos III in Spain (co-funded by the European Social Fund ‘Investing in yourfuture’).

Background We compared cardiovascular magnetic resonance segmental native T1 against T2* values for the detection of myocardial iron overload (MIO) in thalassaemia major and we evaluated the clinical correlates of native T1 measurements. Methods We considered 146 patients (87 females, 38.7 ± 11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network. T1 and T2* values were obtained in the 16 left ventricular (LV) segments. LV function parameters were quantified by cine images. Post-contrast late gadolinium enhancement (LGE) and T1 images were acquired. Results 64.1% of segments had normal T2* and T1 values while 10.1% had pathologic T2* and T1 values. In 526 (23.0%) segments, there was a pathologic T1 and a normal T2* value while 65 (2.8%) segments had a pathologic T2* value but a normal T1 and an extracellular volume (ECV) ≥ 25% was detected in 16 of 19 segments where ECV was quantified. Global native T1 was independent from gender or LV function but decreased with increasing age. Patients with replacement myocardial fibrosis had significantly lower native global T1. Patients with cardiac complications had significantly lower native global T1. Conclusions The combined use of both segmental native T1 and T2* values could improve the sensitivity for detecting MIO. Native T1 is associated with cardiac complications in thalassaemia major.

Transfusion-dependent thalassemia (TDT) patients require regular blood transfusions. The unavoidable consequence is iron overload. Iron chelation therapy is the mainstay of treatment, of which the favorable outcome depends mainly on adherence level. The aim of this study was to assess adherence to iron chelation therapy of TDT patients. A cross-sectional cohort of TDT patients were evaluated on their adherence to chelation therapy using the Thai version of Morisky Medication Adherence Scales (MMAS-8). A total of 70 patients (38 males, 32 females), with a median age of 10 years, were enrolled in the study. Sixteen patients (22.9%) and 54 patients (77.1%) were classified as high and medium-low adherence level groups. The raised serum ferritin value for 6 months previous to enrollment in the high adherence level group is lower than the medium-low adherence level group (276.4 vs. 413.0 ng/mL, p = 0.034, respectively). Factors impacted high adherence to iron chelation including younger age (p = 0.015) and deferasirox (DFX) administration (p = 0.025). The body weight and height in both groups were not statistically different. The most common obstacle to adherence was forgetfulness. The Thai version of MMAS-8 is a practical tool for evaluating adherence to chelation therapy in TDT patients. High adherence level of patients correlates with more controlled serum ferritin level. The younger age and once-daily dose chelation therapy are associated with better adherence.

Summary Beta‐thalassaemia is an inherited blood disorder characterised by ineffective erythropoiesis and anaemia. Consequently, hepcidin expression is reduced resulting in increased iron absorption and primary iron overload. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6) via cleavage of haemojuvelin (HJV), a co‐receptor for the bone morphogenetic protein (BMP)‐mothers against decapentaplegic homologue (SMAD) signalling pathway. Considering the central role of the TMPRSS6/HJV/hepcidin axis in iron homeostasis, the inhibition of TMPRSS6 expression represents a promising therapeutic strategy to increase hepcidin production and ameliorate anaemia and iron overload in β‐thalassaemia. In the present study, we investigated a small interfering RNA (siRNA) conjugate optimised for hepatic targeting of Tmprss6 (SLN124) in β‐thalassaemia mice (Hbbth3/+). Two subcutaneous injections of SLN124 (3 mg/kg) were sufficient to normalise hepcidin expression and reduce anaemia. We also observed a significant improvement in erythroid maturation, which was associated with a significant reduction in splenomegaly. Treatment with the iron chelator, deferiprone (DFP), did not impact any of the erythroid parameters. However, the combination of SLN124 with DFP was more effective in reducing hepatic iron overload than either treatment alone. Collectively, we show that the combination therapy can ameliorate several disease symptoms associated with chronic anaemia and iron overload, and therefore represents a promising pharmacological modality for the treatment of β‐thalassaemia and related disorders.

BackgroundHuman leukocyte antigen (HLA)-A*03, hemochromatosis ancestral haplotype marker, was associated with greater iron overload in hemochromatosis cohorts reported before discovery of theHFEgene. We sought to learn whether an A*03-linked locus influences phenotypes in referredHFEp.C282Y homozygotes.MethodsWe tabulated these phenotypes in probands with p.C282Y homozygosity: age, transferrin saturation (TS), serum ferritin (SF), conditions related to iron overload, fibrosis-four variables (FIB-4) index and aspartate aminotransferase-to-platelet ratio index (APRI) predictors of severe hepatic fibrosis, and iron removed to achieve depletion (QFe/age). We analyzed phenotypes of men and women separately across three A*03 subgroups.ResultsThere were 104 men (57.8%) and 76 women (42.2%). Mean age (SD) was 49 ± 13 y. Mean TS was 79 ± 17%. Median SF (range) was 715 µg/L (28, 6103). Related conditions included: hemochromatosis arthropathy (21.7%); type 2 diabetes (18.9%); hypogonadotropic hypogonadism (5.8% of men); cardiomyopathy (0%); and cirrhosis (10.0%). Median QFe/age was 61 mg/y (0, 714). A*03 homozygosity, heterozygosity, and no A*03 occurred in 37 (20.6%), 104 (57.8%), and 39 probands (21.7%), respectively. In men, mean TS and median SF were significantly higher in A*03 homozygotes than heterozygotes but not A*03-negative probands. In men, median APRI was significantly lower in A*03 heterozygotes than homozygotes and A*03-negative probands. No other phenotypes, including QFe/age, differed significantly across A*03 subgroups in either men or women.ConclusionsOur results suggest that an A*03-linked locus does not influence phenotypes in referredHFEp.C282Y homozygotes. It is unlikely that heritable factors that modify phenotypes of p.C282Y homozygotes are linked to the hemochromatosis ancestral haplotype.

In the western world, 10-15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or hereditary hemochromatosis is much rarer.This review is based on pertinent publications retrieved by a selective search on the pathophysiology, clinical features, and diagnostic evaluation of iron deficiency and iron overload.The main causes of iron deficiency are malnutrition and blood loss. Its differential diagnosis includes iron-refractory iron deficiency anemia (IRIDA), a rare congenital disease in which the hepcidin level is pathologically elevated, as well as the more common anemia of chronic disease (anemia of chronic inflammation), in which increased amounts of hepcidin are formed under the influence of interleukin-6 and enteric iron uptake is blocked as a result. Iron overload comes about through long-term transfusion treatment or a congenital disturbance of iron metabolism (hemochromatosis). Its diagnostic evaluation is based on clinical and laboratory findings, imaging studies, and specific mutation analyses.Our improving understanding of the molecular pathophysiology of iron metabolism aids in the evaluation of iron deficiency and iron overload and may in future enable treatment not just with iron supplementation or iron chelation, but also with targeted pharmacological modulation of the hepcidin regulatory system.

The enzyme heme oxygenase-1 (HO-1) has cytoprotective effects by catalyzing the degradation of heme to produce carbon monoxide, iron and biliverdin. Furthermore, HO-1 activity has been associated with successful pregnancy. On the other hand, in the context of certain inflammatory conditions, HO-1 can induce iron overload and cell death. To investigate the role of HO-1 in gestational malaria, pregnant BALB/c mice were infected with Plasmodium berghei ANKA in early, mid and late gestation. We found that malaria affected the pregnancy outcome in the three periods evaluated. However, only poor pregnancy outcomes in early pregnancy were related to HO-1 upregulation, iron overload, lipid peroxidation and necrosis of the decidua, which were prevented by HO-1 inhibition. In conclusion, HO-1 expression must be finely tuned in gestational malaria to avoid the deleterious effect of increased enzyme activity.

We evaluated the feasibility and reproducibility of bone marrow T2* values and established the lower limit of normal in a cohort of healthy subjects. We investigated the clinical correlates of bone marrow T2* values in patients with thalassemia major (TM).Thirty healthy subjects and 274 consecutive TM patients (38.96 ± 8.49 years, 151 females) underwent MRI at 1.5T. An axial slice in the upper abdomen was acquired by a T2* gradient-echo multiecho sequence and the T2* value was calculated in a circular region of interest defined in the visible body of the first or second lumbar vertebra. In patients, also liver and heart T2* values were assessed.In healthy subjects bone marrow T2* values were independent of age and gender. The lower limit of normal for bone marrow T2* was 13 ms. In both healthy subjects and 30 randomly selected patients, the coefficient of variation for inter-operator-reproducibility was 10%. TM patients exhibited significantly lower bone marrow T2* values than healthy subjects (7.47 ± 5.18 ms vs. 17.08 ± 1.89 ms; p 0.0001). A pathological bone marrow T2* was detected in 82.8% of TM patients. In TM, the female sex was associated with reduced bone marrow T2* values. Bone marrow T2* values were inversely correlated with mean serum ferritin levels (R = -0.431; P 0.0001) and hepatic iron load (R = - 0.215; P 0.0001). A serum ferritin level 536 ng/ml predicted the presence of a pathological bone marrow T2*. A positive correlation was found between bone marrow and heart T2* values (R = 0.143; P = 0.018). A normal bone marrow T2* showed a negative predictive value of 100% for cardiac iron.Bone marrow T2* measurements can be easily obtained using the same sequences acquired for liver iron quantification and may bring new insights into the pathophysiology of iron deposition; hence, they should be incorporated into clinical practice.

Red blood cell (RBC) transfusion is an effective therapy for anemia, but repeated transfusions may cause iron overload-related damage to various organs. Iron chelation therapy, now widely available for patients who have received transfusions, is expected to reduce organ damage even in patients who received many transfusions. Therefore, determining when to start iron chelation therapy is important. In guidelines for iron chelation therapy, the serum ferritin level has been widely accepted as a practical marker for estimating iron overload. However, guidelines recommend multiple measurements of serum ferritin, because levels often fluctuate. Here, we investigated the usefulness of glycosylated ferritin as a marker of iron overload using a cohort consisted of 103 patients who had a total ferritin value over 1000 ng/mL. We found that the volume of RBCs transfused was clearly associated with the glycosylated ferritin level. We also found that acute inflammation, as represented by C-reactive protein values, was associated with increased non-glycosylated ferritin and that patients with hematopoietic diseases had higher glycosylated ferritin levels, possibly because of repeated RBC transfusions. We thus conclude that glycosylated ferritin may be an improved marker for predicting iron overload status.

This study proposed to investigate the effect of Ilex paraguariensis infusion on the absorption of non-heme iron in hereditary hemochromatosis (HH) patients with the HFE genotype. A two-way randomized, controlled, crossover trial was conducted on patients, aged 29-69 years, undergoing maintenance therapy. Fourteen HFE-HH patients ingested a meal containing 11.4 mg iron and 200 mL either of water (control) or of Ilex paraguariensis leaf infusion. The beverages were offered in random order, at intervals separated by a washout period of 7 days. Active surveillance showed no adverse effects. Blood samples were drawn shortly before and 1, 2, 3, and 4 h after the meal for serum iron measurement. A significant reduction in the postprandial serum iron was observed for HH patients after intake of the Ilex paraguariensis infusion (area under the curve (AUC) expressed as mean ± SEM: 173.3 ± 44.7 μmol h-1 L-1) compared to water (1449.4 ± 241.5 μmol h-1 L-1) (p < 0.001). In summary, intake of Ilex paraguariensis leaf infusion significantly inhibited the absorption of iron in patients with HH and, therefore, should be considered as a potential adjuvant for iron overload control.

Objectives: Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Me...

Individuals with Rett syndrome (RTT) commonly demonstrate Parkinsonian features and dystonia at teen age; however, the pathological reason remains unclear. Abnormal iron accumulation in deep gray matter were reported in some Parkinsonian-related disorders. In this study, we investigated the iron accumulation in deep gray matter of RTT and its correlation with dystonia severity. We recruited 18 RTT-diagnosed participants with MECP2 mutations, from age 4 to 28, and 28 age-gender matched controls and investigated the iron accumulation by susceptibility weighted image (SWI) in substantia nigra (SN), globus pallidus (GP), putamen, caudate nucleus, and thalamus. Pearson’s correlation was applied for the relation between iron accumulation and dystonia severity. In RTT, the severity of dystonia scales showed significant increase in subjects older than 10 years, and the contrast ratios of SWI also showed significant differences in putamen, caudate nucleus and the average values of SN, putamen, and GP between RTT and controls. The age demonstrated moderate to high negative correlations with contrast ratios. The dystonia scales were correlated with the average contrast ratio of SN, putamen and GP, indicating iron accumulation in dopaminergic system and related grey matter. As the first SWI study for RTT individuals, we found increased iron deposition in dopaminergic system and related grey matter, which may partly explain the gradually increased dystonia.