Comorbidities and complications in adult and paediatric patients with pyruvate kinase deficiency: Analysis from the Peak Registry.

Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.

Iron burden and endocrine complications in transfusion-dependent thalassemia patients In Sarawak, Malaysia: a retrospective study.

INTRODUCTION: Thalassaemia is one of the major health problems in Malaysia. With safe blood transfusion regime, the lifespan of patients with transfusion-dependent thalassaemia (TDT) has improved but at the cost of a higher risk of developing endocrine disorders. It is crucial for us to monitor the iron overload to prevent end organ damage. This study aims to evaluate the iron burden and prevalence of endocrinopathies in patients with TDT in Sarawak. MATERIALS AND METHODS: This retrospective cohort study was conducted between January 2020 to June 2020 in six government hospitals in Sarawak. A total of 89 patients with TDT, aged 10 years and above, were recruited. RESULTS: Out of the 89 patients, there were 54 males (60.7%) and 35 females (39.3%) with a median age of 21 years (range 10.0-65.0). Sixty-seven (75.3%) patients had betathalassaemia major and 15 (16.9%) patients had haemoglobin E beta-thalassaemia (HbE beta-thalassaemia), remaining seven patients had other genotypes. Thirty-one (34.8%) patients had mean serum ferritin 2500ng/ml and above, and 44 (66.6%) had liver iron concentration (LIC) ≥7mg/g. The prevalence of endocrine disorders in our cohort was 69.7%. The most common endocrinopathies were short stature (n=46, 51.7%), followed by hypogonadism (n=24, 26.9%), delayed puberty (n=23, 25.8%), hypothyroidism (n=10, 11.2%), diabetes mellitus (n=9, 10.1%), impaired glucose tolerance (n=6, 6.7%) and hypoparathyroidism (n=3, 3.3%). Endocrinopathies were significantly associated with age (p=0.01), age at initiating regular blood transfusion (p<0.01) and duration of regular blood transfusion (p<0.01). CONCLUSION: Our data shows that the development of endocrinopathies in TDT can be time dependent. Early detection of endocrine-related complications and prompt treatment with iron chelation therapy are important to improve morbidity and mortality. A multidisciplinary approach with good patient-doctor collaboration is the key to improving patient care in our settings.

Non-alcoholic fatty liver disease in hemochromatosis probands with iron overload and HFE p.C282Y/p.C282Y.

BACKGROUND: The aim of this study was to identify characteristics of non-alcoholic fatty liver disease (NAFLD) in adults with HFE p.C282Y/p.C282Y. METHODS: We retrospectively studied non-Hispanic white hemochromatosis probands with iron overload (serum ferritin (SF) > 300 µg/L (M), > 200 µg/L (F)) and p.C282Y/p.C282Y at non-screening diagnosis who did not report alcohol consumption > 14 g/d, have cirrhosis or other non-NAFLD liver disorders, use steatogenic medication, or have diagnoses of heritable disorders that increase NAFLD risk. We identified NAFLD-associated characteristics using univariate and multivariable analyses. RESULTS: There were 66 probands (31 men, 35 women), mean age 49 ± 14 (SD) y, of whom 16 (24.2%) had NAFLD. The following characteristics were higher in probands with NAFLD: median SF (1118 µg/L (range 259, 2663) vs. 567 µg/L (247, 2385); p = 0.0192); prevalence of elevated ALT/AST (alanine/aspartate aminotransferase) (43.8% vs. 10.0%; p = 0.0056); and prevalence of type 2 diabetes (T2DM) (31.3% vs. 10.0%; p = 0.0427). Mean age, sex, and prevalences of human leukocyte antigen-A*03 positivity, body mass index ≥ 30.0 kg/m2, hyperlipidemia, hypertension, and metabolic syndrome in probands with/without NAFLD did not differ significantly. Logistic regression on NAFLD using variables SF, elevated ALT/AST, and T2DM revealed: SF (p = 0.0318; odds ratio 1.0-1.0) and T2DM (p = 0.0342; 1.1-22.3). Median iron removed to achieve iron depletion (QFe) in probands with/without NAFLD did not differ significantly (3.6 g (1.4-7.2 g) vs. 2.8 g (0.7-11.0 g), respectively; p = 0.6862). CONCLUSIONS: NAFLD in hemochromatosis probands with p.C282Y/p.C282Y is associated with higher median SF and greater T2DM prevalence, after adjustment for other factors. NAFLD does not influence QFe significantly.

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Indicators of glucose dysregulation and the relationship with iron overload in Chinese children with beta thalassemia major.

INTRODUCTION: Patients with beta thalassemia major (TM) have a higher risk of diabetes and an abnormal oral glucose tolerance test (OGTT), but there is no single agree monitoring parameter that reflects glycemic status. The possible mechanisms include iron overload and blood transfusion, but they require further investigation. PURPOSE: This study explored the role of glycated hemoglobin A1c (HbA1c), fructosamine, and glycated albumin (GA) in evaluating the glucose dysregulation and to determine the potential relationship between iron deposition and glucose metabolism disorder in beta TM. METHODS: A cross-sectional study was performed on 118 patients with beta TM and the control group consisted of 33 healthy children with no statistical differences in age, sex, and body mass index (BMI). Fast plasma glucose (FPG), fast insulin (FINS), insulin resistance index (HOMA-IRI), and insulin sensitivity index (HOMA-ISI) were compared between the patient and control groups. HbA1c, GA, fructosamine, and serum ferritin (SF) were measured in the patient group. OGTT, as well as heart and liver magnetic resonance imaging (MRI) T2*, was performed. For all statistical analyses, SPSS 21.0 was used and p < 0.05 was accepted as statistically significant. RESULTS: FPG, FINS, and HOMA-IRI were significantly increased while HOMA-ISI decreased in the beta TM patients when compared with those in the control group. In patients with beta TM, 17 (14.41%) of patients had been diagnosed with diabetes, while 48 (40.68%) had both impaired fasting glucose and impaired glucose tolerance. HbA1c, GA, and fructosamine were increased according to the degree of abnormal glucose metabolism. Statistically significant differences were found in age, SF, and cardiac T2* between the abnormal and normal OGTT groups. CONCLUSION: HbA1c may be used as a significant measure for monitoring glycemic levels in patients with beta TM. Furthermore, GA and fructosamine were alternative indicators of glucose status. Patients with heart iron deposition or an SF > 4000 µg/L were prone to abnormal glucose metabolism, so chelation therapy should be reinforced.

Thalassemia in the Philippines.

For an archipelago that has a rich history of trade with overseas merchants and colonial rule, the Philippine Islands are models of ethnic and cultural diversity, including hereditary blood disorders such as hemoglobinopathies. Pending a government-led comprehensive national screening program, available cluster data provides evidence of the prevalence of thalassemia in the country. The National Blood Services Act of 1994 was enacted to promote voluntary blood donation to address the supply of blood products but falls short in addressing the immense blood transfusion requirements of the thalassemic community. Iron overload monitoring and management is a considerable challenge due to high cost of laboratory tests and iron chelators on top of minimal health insurance coverage for the majority of Filipino patients with thalassemia. Continuous engagement with the thalassemia patient community and multi sectoral efforts are the means to ensure sustained improvement in the delivery of care.

The Prevalence of Hypothyroidism among Patients With ß-Thalassemia: A Systematic Review and Meta-Analysis of Cross-Sectional Studies.

As a cause of chronic blood transfusions, iron overload is an important issue in ß-thalassemia (ß-thal) patients that leads to multiple organ dysfunctions. This is an updated meta-analysis conducted to summarize the existing evidence of the prevalence of hypothyroidism (HT) among patients with transfusion-dependent (TDT) and non transfusion-dependent ß-thal (NTDT) and for the first time we meta-analyzed the relationship between ferritin level and HT. This systematic review and meta-analysis were done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We searched databases including Web of Science (ISI), Scopus, PubMed, Embase, and Scholar. The quality of the included studies was assessed based on the Newcastle-Ottawa scale (NOS) checklist. Meta-analysis was done using Stata statistical software. The pooled prevalence of total HT, subclinical HT, and overt HT among ß-thal patients was 13.25 [95% confidence interval (95% CI): 10.29-16.21; 11.84, 95% CI: 8.43-15.25 and 12.46, 95% CI: 1.05-23.87], respectively. The prevalence of total HT was 16.22% (95% CI: 12.36-20.08) in TDT and 7.22% (95% CI: 3.66-10.78) in NTDT patients. Serum ferritin (SF) levels were significantly lower in euthyroid compared to hypothyroid patients [standard mean difference (SMD) -2.15 (95% CI: -3.08, -1.21, p value <0.001]. The prevalence of HT was higher in TDT compared to NTDT patients. Moreover, our results showed a significant association of high serum ferritin (SF) levels with hypothyroidism in ß-thal patients. Both of these findings highlight the importance of prevention measures and timely diagnosis and management of iron overload in ß-thal patients.

Blood utilization and characteristics of patients treated with chronic transfusion therapy in a large cohort of Brazilian patients with sickle cell disease.

BACKGROUND: Red blood cell (RBC) transfusions are used in sickle cell disease (SCD) to treat acute complications or as chronic transfusion therapy (CTT) to prevent severe manifestations. The objectives of this study were to describe blood utilization and adverse events (AEs) associated with RBCs in the Brazilian SCD population and compare characteristics of patients treated or not with CTT. STUDY DESIGN AND METHODS: A SCD cohort was established at six Brazilian centers. Medical and blood bank records were abstracted for clinical and transfusion history. Two controls not treated with CTT matched on center, SCD genotype, sex, and age were selected for each CTT case within the cohort to compare characteristics between the two groups. RESULTS: Most of the 2794-member cohort had received a transfusion (75.0% of children and 89.2% of adults) with 29.2% of patients receiving transfusion in the prior year. There were 170 (10.6%) children and 115 (9.2%) adults treated with CTT. Children not treated with CTT were more likely to have pain and acute chest hospitalizations in the prior year (25.3% vs. 11.9%, p = 0.0003; and 22.0% vs. 10.7%, p = 0.002, respectively). Both iron overload and alloimmunization were more common in CTT cases compared to controls (65.6% vs. 17.0% and 36.2% vs. 15.9%, respectively). A higher proportion of adults treated with CTT demonstrated oxygen saturation of greater than 95% compared to controls not treated (51.1% vs. 39.2%), while there was no difference in oxygenation between children treated or not. Of 4501 transfusion episodes, 28 (0.62%) AEs were reported. There was no difference in AEs associated with transfusions for acute indications versus CTT. CONCLUSION: Red blood cell transfusion was common in Brazilian SCD patients, with utilization driven by CTT. Transfusion reactions were not common; however, alloimmunization and iron overload were frequent among those on CTT, highlighting the need for novel clinical strategies to mitigate these risks.

Cardiac Iron Overload by MRI in Children With B-Thalassemia Major and its Correlation With Cardiac Function by Echocardiography.

BACKGROUND: Serial echocardiography is strongly recommended in asymptomatic B-thalassemia major (TM) patients for early detection of subtle cardiac dysfunction. T2*magnetic resonance imaging (MRI) is a noninvasive measurement of myocardial iron burden. Yet, it is not always available in many centers. Our study aimed to evaluate the myocardial function in TM patients using different echocardiographic modalities and to correlate these findings with cardiac T2*MRI. PATIENTS AND METHODS: This is a cross-sectional study that was carried out on 140 children with a mean age of 10.9±3.7 years. One hundred children with TM and 40 healthy children were matched for age and sex as a control group. Serum ferritin, serum iron, and iron-binding capacity were measured. Cardiac iron overload was assessed by T2*MRI and cardiac function was assessed by echocardiography. The local ethics committee approved the study. RESULTS: Among 100 children with TM, only 32% had cardiac iron overload of 8.525±5.45 detected by cardiac T2*MRI. Iron deposition correlated significantly with age. Markers of iron overload were significantly correlated with cardiac T2*MRI. There were significantly lower values of myocardial performance index, longitudinal strain, circumferential strain, area strain, and radial strain in TM patients compared with the controls (P<0.001). Only the myocardial performance index was correlated with T2*MRI. CONCLUSIONS: This study confirms that some parameters measured by tissue Doppler imaging such as the myocardial performance index could be useful for the early detection of cardiac impairment in asymptomatic TM patients when cardiac MRI is lacking. Further studies on a large scale to identify other parameters with high sensitivity are recommended.

Evaluation of Erythroferrone, Hepcidin, and Iron Overload Status in Iraqi Transfusion-Dependent ß-Thalassemia Major Patients.

Patients with ß-thalassemia major (ß-TM) show ineffective erythropoiesis and iron overload, which is the leading cause of mortality and organ injury. The present study aimed to investigate the relationships between two iron regulatory hormones, hepcidin and erythroferrone (ERFE) levels, and iron status parameters in Iraqi patients with ß-TM. Iron status parameters and hormones were measured in 60 patients and compared with 30 healthy controls. The results indicated significant changes in different iron status parameters, while ferritin with the ∼11-fold increase showed the most change. Significant reduction in hepcidin and an increase in ERFE levels were detected in patients when compared to the control group, while no direct correlation was identified with the other measured iron status parameters. The receiver operating characteristic (ROC) analysis showed that the z-score of the composite of ERFE + ferritin has a full diagnostic ability for ß-TM. In conclusion, our findings indicated the correlation between different iron status parameters and ferritin as the leading predictor of iron overload and two main iron regulatory hormones.

Cardiac complications and iron overload in beta thalassemia major patients-a systematic review and meta-analysis.

Despite the major improvement in therapeutic management of thalassemia major, iron overload is considered a challenging conundrum in these patients and heart disease still remains a major cause of morbidity and mortality in these patients. Therefore, this study aimed to investigate the prevalence of cardiac iron overload and cardiovascular complications in transfusion-dependent thalassemia patients in the worldwide. The following databases were searched: ISI/Web of Science, Embase, PubMed, Scopus, up to February 30, 2018. The quality of the studies was evaluated using the Joanna Briggs Institute Prevalence Critical Appraisal Tool. The random model based on Metaprop was used. One hundred forty-two studies were included. The total number of patients included was 26,893. The mean age of patients was 22.6 (SD = 1.7) years. Based on Metaprop, the overall prevalence of cardiac iron overload/myocardial sidoresis (T2* < 20 ms) and cardiac complications in thalassemia major patients in the worldwide was 25% (95% CI 22-28%) and 42% (95% CI 37-46%), respectively. The results of this study show that the prevalence of cardiac iron overload and cardiovascular complications in patients with thalassemia major is almost high. Therefore, iron chelation and careful monitoring of serum ferritin level will prevent the cardiac iron overload, and interval monitoring of patients with transfusion-dependent thalassemia (TDT) by echocardiography and electrocardiography will help with early detection of cardiovascular complications.

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality.

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.

Prevalence of extramedullary hematopoiesis, renal cysts, splenic and hepatic lesions, and vertebral hemangiomas among thalassemic patients: a retrospective study from the Myocardial Iron Overload in Thalassemia (MIOT) network.

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report.

Compliance with Deferoxamine Therapy and Thyroid Dysfunction of Patients with ß-Thalassemia Major in Syria.

Hypothyroidism is one of the common endocrine complications described in patients with ß-thalassemia major (ß-TM). Studies have reported its incidence and severity depending on the region, quality of management and treatment protocols. The reported thyroid dysfunction includes overt hypothyroidism, subclinical hypothyroidism and rarely, central hypothyroidism. The main aims of this study were to identify the incidence of hypothyroidism in 82 patients with ß-TM in Syria, and also to evaluate the effect of compliance with deferoxamine (DFO) therapy on the patients' thyroid function. Out of the 82 patients included in this study, 24 had subclinical hypothyroidism (29.27%) and one patient had overt hypothyroidism (1.22%). It was demonstrated by this study that noncompliance with DFO therapy increases the risk of thyroid dysfunction 6.38-times compared to compliance with DFO [risk ratio (RR) = 6.385; 95% confidence interval (95% CI) 2.40-16.95)]. These results emphasize the importance of compliance with chelation therapy to minimize the burden of thyropathy on patients' quality of life, and also augment the rationale for a routine follow-up and endocrine evaluation for early detection and management of these complications.

Serum ferritin levels and irregular use of iron chelators predict liver iron load in patients with major beta thalassemia: a cross-sectional study.

AIM: To determine whether serum ferritin, liver transaminases, and regularity and type of iron chelation protocol can be used to predict liver iron load as assessed by T2* magnetic resonance imaging (MRI) in patients with beta thalassemia major (TM). METHODS: This cross-sectional study, conducted from March 1, 2014 to March 1, 2015, involved 90 patients with beta TM on regular packed red blood cell transfusion. Liver and cardiac iron load were evaluated with T2* MRI. Compliance with iron-chelating agents, deferoxamine or deferasirox, and regularity of their use, as well as serum ferritin and liver transaminase levels were assessed. RESULTS: Patients with high serum ferritin were 2.068 times (95% confidence interval 1.26-3.37) more likely to have higher liver or cardiac iron load. High serum aspartate aminotransferases and irregular use of iron chelating agents, but not their type, predicted higher cardiac iron load. In a multiple regression model, serum ferritin level was the only significant predictor of liver and myocardial iron load. CONCLUSIONS: Higher serum ferritin strongly predicted the severity of cardiac and liver iron load. Irregular use of chelator drugs was associated with a higher risk of cardiac and liver iron load, regardless of the type of chelating agent.

Co-existing iron deficiency/overload in beta-thalassemia trait.

OBJECTIVE: To identify the co-existence of iron deficiency and iron overload in individuals with beta thalassaemia trait. METHODS: The cross-sectional study was conducted at Rehman Medical Institute and Khyber Medical University, Peshawar, Pakistan, September 1, 2015, to December 31, 2017, and comprised individuals with hypochromic microcytic blood picture. Haemoglobin electrophoresis was performed on their blood samples. Serum ferritin levels of subjects with Haemoglobin Subunit Alpha 2 levels between 3.5% and 7% were checked. Data were analysed using analysed using GraphPad Prism v6. RESULTS: Of the 292 subjects, 159(54.5%) were males and 133(45.5%) were females. Of these, 240 (82.2%) were anaemic and 52 (17.8%) had haemoglobin within the normal range. Serum ferritin level of 55(18.8%) subjects was low and 207(70.9%) were iron-replete. Notably, 30(10.3%) subjects had serum ferritin levels higher than the reference range, and this was more common among adults (p<0.001). CONCLUSIONS: Ferritin levels in beta thalassaemia trait can be low, normal or higher than the normal values..

Iron overload in patients with myelodysplastic syndromes: An updated overview.

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication.

Labile plasma iron as an indicator of patient adherence to iron chelation treatment.

Poor adherence of transfusion-dependent patients to chelation treatment is often the cause of persistent iron overload and ensuing morbidity. However, a tool to assess patient compliance with therapy is lacking in clinical practice. Labile plasma iron (LPI, the redox-active component of non-transferrin bound iron) has been studied as an indicator of systemic iron overload and of chelation efficacy, and may particularly reflect recent iron equilibrium. We considered the use of LPI as a potential indicator for recent chelation treatment in 18 transfusion-dependent pediatric patients. Samples were collected under chelation treatment or after a short interruption of the treatment, and LPI was measured by the FeROS assay (Aferrix, Tel Aviv, Israel). LPI was significantly higher after a short-term interruption of the chelation (median of 0.4 µM off-therapy [range:0-4] vs 0 µM on-therapy [range:0-2.8] (p < .001)). Conversely, serum iron, serum ferritin and calculated transferrin saturation were not significantly higher in the "off-therapy" samples compared to "on-therapy". In addition, in multivariate logistic regression analysis LPI was the variable most significantly associated with recent chelation treatment (p = .001). We conclude that LPI could serve as a useful indicator of compliance to chelation therapy.

Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1.

BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. RESULTS: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-α was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-α concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1ß, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-α level however, normalized in all treated patients, reaching the lowest values after 2years of therapy and continued to be stable during the remaining 2years of follow-up. CONCLUSIONS: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-α concentration in GD1.

Polyneuropathy and myopathy in beta-thalassemia major patients.

The thalassemias are the most common single gene disorder in the world. Nowadays, the average life expectancy of patients in developed countries has increased significantly, while, there was an increase of complications. We aimed to investigate peripheral neuropathy and myopathy in this patient group using a neurophysiological study. We performed nerve conduction studies and electromyography of upper and lower extremities on 36 beta-thalassemia major (ß-thal) patients. The electrophysiological findings were correlated with demographic data and laboratory parameters of the disease. Patients with ß-thal present polyneuropathy or myopathy at (50%). Polyneuropathy was detected in (38.9%) and myopathy in (27.8%), while polyneuropathy and myopathy were present at (16.7%) with an overlap of the diseases in 1/3 of the patients. There was not a statistically significant correlation of polyneuropathy and myopathy with age, sex, splenectomy, nor with respect to laboratory parameters, hemoglobin, and ferritin. However, there was a statistically significant correlation of polyneuropathy and myopathy with iron overload, as recorded by the magnetic resonance imaging (MRI) of the heart and the liver. Our findings suggest that iron overload plays a key role in the pathogenesis of polyneuropathy and myopathy in ß-thal patients, and performing heart and liver MRI for the prediction of such lesions in an annual basis is warranted.