Evidence Of Iron Overload Research Articles

Genetically predicted biomarkers of iron homeostasis and risk of non-ischemic cardiomyopathy: A mendelian randomization study

Background and aimsBoth iron overload and iron deficiency have been associated with cardiovascular diseases in observational studies. Previous Mendelian Randomization (MR) studies discovered a protective effect of higher iron status on coronary atrial disease, while a neutral effect on all-cause heart failure. Using two-sample MR, we evaluated how genetically predicted systemic iron status affects the risk of non-ischemic cardiomyopathy and different phenotypes. Methods and resultsTwo-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR, 1.17; 95% CI, 1.13–1.38) when using nine separately selected genetic instruments. An increase in genetically determined serum iron (odds ratio [OR] per standard deviation [SD], 1.25; 95% confidence interval [CI], 1.13–1.38) and ferritin (OR, 1.49; 95% CI, 1.02–2.18) were associated with an increased risk of cardiomyopathy. Total iron binding capacity, a marker of reduced iron status, was inversely linked with cardiomyopathy (OR, 0.80; 95% CI, 0.65–0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. ConclusionsThese analyses support the causal effect of increased systemic iron status on a higher risk of non-ischemic cardiomyopathy. A screening test for cardiomyopathy should be considered in patients with evidence of iron overload. Future study is needed for exploring the mechanism of these causal variants on cardiomyopathy.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group

Background: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. Methods: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. Results: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1–2. Conclusions: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

P05 Osteoporosis in thalassemia; a case with multifactorial aetiology

Abstract Introduction Thalassemia patients are prone to osteoporosis due to multifactorial reasons, including anaemia, bone marrow expansion, iron overload and hypogonadism. Case description A 41-year-old British Asian male with beta thalassemia major was referred to rheumatology in 2018 for osteoporosis. In 2008, aged 27 years, whilst playing football, he developed a distal radial fracture and ulnar styloid process fracture and a DEXA scan had revealed low bone mineral density (BMD) for age. Subsequently, he was started on Ibandronic acid by his haematologist for a total of 10 years. After he was referred to rheumatology in 2018, bisphosphonates were discontinued as he had 5% improvement in BMD, a decade of bisphosphonates and no further fractures. Further assessment revealed multiple contributory factors for his osteoporosis. • Consistency low vitamin D – 9.6 nmol/L in 2009, average value of 20 • He was diagnosed with hypogonadism, poor compliance with IM testosterone injections • He had diabetes which was not optimally controlled • Evidence of iron overload with average serum ferritin of 2000 ug/L with deferasirox While these factors were optimised, it was decided to adopt a watch and wait policy with regards to specific osteoporosis treatment. Review in 2023 revealed serum testosterone level of 20.1 nmol/L (6.9-23.2) with better compliance with testosterone injections. Fructosamine levels were 310 (normal range 200-285) but it has reduced from a peak of 370. Serum ferritin levels have reduced to 776 down from a high of 5600. Normal vitamin D levels were maintained. The DEXA scan in 2023 revealed a spine T score of −2.4 which showed 10.2% increase in bone mineral density. DEXA scan in 2020 revealed T score of −3.1 in spine and −1.9 in hips. The P1NP level was 56 (19-69) which has reduced from 100 in 2021. Improvements in BMD and bone turnover markers were achieved through optimising contributory factors without any specific osteoporosis treatment. He will be monitored with periodic BMD and bone turnover markers. Discussion Anaemia and subsequent bone marrow expansion is a recognised cause for osteoporosis in thalassemia patients. While regular blood transfusions inhibit bone marrow expansion, ineffective erythropoiesis is not fully supressed. This patient received 3 units of blood every 4 weeks. Bone marrow expansion occurs mostly in trabecular bone resulting in low BMD is areas which generally have increased amount of trabecular bone such as the spine. Our patient had a lower BMD in the spine compared to the femoral neck. Iron overload directly disrupts bone formation and can result in endocrinopathies which contributes to osteoporosis. Hypogonadism is another well-recognised cause and is primarily results from iron deposition in pituitary and at times in the gonads. Hormonal replacement therapy reduces bone loss. Studies have shown that hypogonadic patients have more severe osteoporosis and predominant involvement of the femoral neck. Iron overload can cause diabetes mellitus and impaired growth hormone/ insulin growth factor-1 (IGF-1) axis which can contribute to osteoporosis. Our patient did have diabetes but had normal IGF-1 levels when checked previously. Deferoxamine which is one of iron chelating agents have been shown to reduce collagen synthesis and increases osteoblast apoptosis which might contribute to the development of osteoporosis. Vitamin D levels are well known to be low in patients with thalassemia compared to the general population. While there are no RCT’s to show that bisphosphonates reduce fracture risk, surrogate markers such as increased BMD and reduction in bone turnover markers are known to occur. Therefore, current guidance (Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK) recommends bisphosphonates to be considered in patients with a low BMD for age (Z-score &amp;lt; −2.0, T-score &amp;lt; −2.5 if post-menopausal or over 50), if there are fragility fractures or falling BMD despite adequate vitamin D levels, and hormone supplementation. Key learning points Learning point Important to assess for osteoporosis in thalassaemic patients. There are multiple factors contributing to the development of osteoporosis which needs to be addressed together with endocrinologist and haematologist. Bisphosphonates are recommended though further RCT evidence is required to support this

Mitapivat Improves Iron Overload in Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. Iron overload is highly prevalent in patients (pts) with PK deficiency regardless of transfusion requirements, suggesting dyserythropoietic features. Iron overload can lead to serious complications including liver cirrhosis, cardiomyopathy, arrhythmia, sudden cardiac death, and endocrine dysfunction. In pts with PK deficiency, ineffective erythropoiesis combined with chronic hemolysis contributes to the manifestation of iron overload. Increased erythropoietic drive leading to erythroferrone-induced hepcidin suppression results in increased iron absorption and abnormal iron metabolism in PK deficiency. Furthermore, transfusions increase the existing burden of iron overload in PK deficiency. Mitapivat (AG-348) is a first-in-class, oral, allosteric activator of the red blood cell wildtype and mutant PK enzyme (PKR) that is approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, which has been shown to improve ineffective erythropoiesis and hemolysis. Previously reported data from ACTIVATE (NCT03548220) and its long-term extension (LTE) study (NCT03853798) also showed that treatment with mitapivat improved markers of iron homeostasis in adults with PK deficiency (up to 72 weeks [wks]). Here, we provide longer-term data from the LTE study on the impact of mitapivat on iron homeostasis and iron overload, and also assess liver iron concentration (LIC) changes in pts with iron overload at baseline (BL). Methods: In ACTIVATE (double-blind, placebo [PBO]-controlled study), pts with PK deficiency who were not regularly transfused were randomized 1:1 to receive mitapivat or PBO. Pts who had demonstrated clinical benefit from mitapivat on completion of the fixed-dose period for ACTIVATE (24 wks), or who were assigned to the PBO arm in ACTIVATE, were eligible to continue in the LTE. All pts enrolled in the LTE received mitapivat. Pts from ACTIVATE who continued in the LTE were categorized into the mitapivat-to-mitapivat arm (M/M) or PBO-to-mitapivat arm (P/M). The ACTIVATE/LTE analysis assessed changes from BL over time (up to 96 wks), for both study arms, in markers related to iron homeostasis and overload, including erythroferrone, soluble transferrin receptor (sTfR), hepcidin, and LIC by magnetic resonance imaging. LIC changes over time in pts with evidence of iron overload at BL, were also assessed; pts were considered to have iron overload at BL if they met at least 1 of 3 criteria: BL ferritin >1000 mg/L, BL average LIC >3 mg Fe/g dry weight (dw), or chelation therapy within the last year before study start. For this calculation, BL was defined as the last assessment before start of treatment with mitapivat, and LIC data from pts in the M/M arm were pooled together with data from pts in the P/M arm and summarized over the time they were treated with mitapivat. Results: 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40). Meaningful improvements in hepcidin, erythroferrone, sTfR, and LIC values were observed with mitapivat treatment previously; here, we confirm these meaningful improvements are continued up to 96 wks (Table). These measurements were improved early-on, within 24 wks of starting treatment in the M/M arm, but remained relatively unchanged in the P/M arm while on PBO. Similar improvements to the M/M arm were seen in the P/M arm after switching to mitapivat in the LTE. Among pts treated with mitapivat (N=78), 55.1% (n=43) met the criteria for iron overload at BL. These pts showed clinically meaningful and continued improvements in iron overload over time as measured by LIC (median [Q1, Q3] decrease from BL to Wk 96 of mitapivat treatment of -1.95 [-4.85, -0.70] mg Fe/g dw) (Figure). Conclusions: Activation of PKR with mitapivat was associated with meaningful long-term improvements in iron homeostasis and overload. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload in pts with PK deficiency. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S3260 A Case of Smoldering Multiple Myeloma in a Patient With Gaucher’s Disease Diagnosed on Liver Biopsy

Introduction: We describe a rare case of Gaucher Disease (GD) diagnosed on liver biopsy in a patient with thrombocytopenia and hepatic steatosis with subsequent findings of smoldering multiple myeloma (SMM). Case Description/Methods: 59-year-old male with history of chronic thrombocytopenia presented to the clinic for mild elevation in liver enzymes. At the time of evaluation, patient was asymptomatic and denied any history or risk factors for liver disease. Labs were notable for ALT 53, AST 43, Total bilirubin 0.5, alkaline phosphatase 111, INR 1, platelet 73, and ferritin 1157. Serology for hemochromatosis, autoimmune hepatitis, and viral hepatitis were negative. A CT scan of abdomen revealed hepatic steatosis and splenomegaly. Transient elastography was consistent with stage F3-F4 fibrosis. Subsequent liver biopsy showed features of steatohepatitis and sinusoidal cells with pale-gray striated cytoplasm characteristic of Gaucher’s cells. No evidence of iron overload and cirrhosis on trichome stain. The degree of thrombocytopenia and splenomegaly were out of proportion to the liver disease, prompting further hematological evaluation. Serum protein electrophoresis showed 1300 mg/dL IgA kappa monoclonal protein spike. Bone marrow biopsy revealed hypercellular marrow (50%), Gaucher cells, and plasma cell neoplasm ( >20%) consistent with Type I GD with smoldering multiple myeloma given absence of end organ damage. He was treated conservatively with close monitoring for disease progression. (Figure) Discussion: GD is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme glucocerebrosidase that leads to accumulation of glycophospholipids in the cells of the reticuloendothelial system. It is a multisystem progressive disorder with involvement of bone marrow, liver and spleen. Type 1 GD is the most common non-neuropathic variant in adults with prevalence of 1:1000. Predominant clinical features include thrombocytopenia, hepatosplenomegaly with variable patterns of liver involvement ranging from sub-clinical to decompensated cirrhosis. GD is often associated with laboratory abnormalities including hyperferritinemia or hypergammaglobulinemia that may lead to misdiagnosis with other chronic liver conditions. Additionally, there is an increased risk of multiple myeloma and other gammopathies in type 1 GD. Lack of awareness of early clinical course and its associated conditions can lead to delay in diagnosis and treatment.Figure 1.: (A) There is mild pericellular fibrosis, but no periportal or bridging fibrosis. Mild steatosis supportive of a component of NASH accompany the Gaucher's cells is seen (Trichrome, 100X). (B) Sinusoidal cells are enlarged and show pale-gray striated cytoplasm representing Gaucher's cells whereas the hepatocytes are ballooned. Inflammatory infiltrates are absent(hematoxylin and eosin, 200X). (C) The Gaucher's cell are positive for the histiocytic marker CD68 (Immunohistochemistry, 200X).

C282Y/H63D Compound Heterozygosity Is a Low Penetrance Genotype for Iron Overload-related Disease

BackgroundHereditary hemochromatosis (HH) occurs due to mutations in the HFE gene. While the C282Y mutation is the most common genotype reported in HH, other genotypes are found less frequently, indicating variable degrees of penetrance. We studied the penetrance of the C282Y/H63D compound heterozygote genotype in developing clinically significant iron overload.MethodsWe have completed a retrospective analysis on every individual within Newfoundland & Labrador who were diagnosed as C282Y/H63D compound heterozygote between 1996 and 2009 through a molecular genetics study. We collected data for up to 10 years following the initial genotyping using electronic health records, including laboratory values, phlebotomy status, radiologic reports and clinic records. Iron overload status was classified based on the HealthIron study.ResultsBetween 1996 and 2009, 247 individuals with available health records tested positive for C282Y/H63D compound heterozygosity. Over the 10 years of our study, 5.3% of patients exhibited iron overload-related disease on the background of documented iron overload. Including these individuals, 10.1% of patients had documented iron overload, 23.1% of patients had a provisional iron overload and the remaining 66.8% of patients had no evidence of iron overload. Only 44 patients had documented phlebotomies, likely based on their severe phenotype at baseline. Despite phlebotomy, the prevalence of iron overload was higher among these patients. The penetrance of compound heterozygosity was also significantly higher among men (P < 0.01).ConclusionC282Y/H63D compound heterozygosity is a low penetrance genotype in HH. This is the largest reported cohort of C282Y/H63D compound heterozygotes in North America with an extended follow-up.

Ferroptosis in inflammatory arthritis: A promising future.

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which is characterized by mitochondrial morphological changes and has a complex regulatory network. Ferroptosis has been gradually emphasized in the pathogenesis of inflammatory arthritis. In this review, we summarized the relevant research on ferroptosis in various inflammatory arthritis including rheumatoid arthritis (RA), osteoarthritis, gout arthritis, and ankylosing spondylitis, and focused on the relationship between RA and ferroptosis. In patients with RA and animal models of RA, there was evidence of iron overload and lipid peroxidation, as well as mitochondrial dysfunction that may be associated with ferroptosis. Ferroptosis inducers have shown good application prospects in tumor therapy, and some anti-rheumatic drugs such as methotrexate and sulfasalazine have been shown to have ferroptosis modulating effects. These phenomena suggest that the role of ferroptosis in the pathogenesis of inflammatory arthritis will be worth further study. The development of therapeutic strategies targeting ferroptosis for patients with inflammatory arthritis may be a promising future.

Bioinformatics and wet laboratory analysis of rs1800562 to predict genetic aetiology of iron overload in Nigeria

Abstract Introduction/Objective The most reported single nucleotide polymorphism (SNP) of the HFE gene is rs1800562, representing the substitution of Adenine for Guanine at position 847 of the HFE gene. This has been widely implicated in hereditary haemochromatosis and other conditions like altered cholesterol balance, Alzheimer’s disease and cutaneous photosensitivity. Abnormal HFE protein resulting from the mutant HFE gene leads to formation of excess iron which has been postulated as likely mechanism for these diseases. Although there is evidence of iron overload in Africans, only few studies have explored possible genetic causes, and prevalence of rs1800562 is not known in West African population. Hence the need to determine the prevalence of rs1800562 in Nigeria using computational and wet laboratory approach. Methods/Case Report Details of rs1800562 were retrieved from Ensembl Genome Browser version 99. Severity of the consequences of this SNP on protein product was determined using bioinformatics tools including SIFT, Polyphen, Mutation Assessor, HOPE, I-mutant and MutPred2. Genotyping of rs1800562 was done In silico using restriction fragment length polymorphism (RFLP). Primer3plus was used for primer design, NCBI BLAST and SMS were used for primer validation. We used Webcutter 2.0 to determine suitable restriction enzymes. The genotyping was simulated using USCS virtual PCR and RestrictionMapper. Whole blood samples were obtained from 200 participants selected randomly from a pool of blood donors. DNA was extracted and flanking region of rs1800562 was amplified. The amplified product was digested by RSA1and fragments examined on agarose gel electrophoresis. Results (if a Case Study enter NA) The MAF was found to be 0.01 globally and 0.02 in Africa. In the two Nigerian population examined (Yoruba and Esan population), MAF was 0.00. Mutation Assessor and SIFT Polyphen consistently predicted the mutation to be of severe consequences. Analysis on HOPE, I-mutant and Mutpred2 revealed loss of protein stability, change in net charges affecting the HFE protein localization and its interaction with other proteins. All the participants in the wet laboratory analysis were homozygous for the wild type allele of rs1800562 (MAF=0). Conclusion This study confirmed the In silico prediction of the absence of rs1800562 in Nigeria. Future studies should focus on other SNPs of the HFE gene as well as other gene involved in iron metabolism.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Hemochromatosis Arthropathy in Heterozygous HFE H63D Mutation Without Iron Overload- An Entity Less Commonly Touched

Human homeostatic iron regulator protein gene (HFE gene) H63D mutations even when homozygous are rarely associated with iron overload. These mutations, independent of iron status, are associated with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) leading to arthropathy even for heterozygotes. The arthropathy does not respond to iron depletion. We report a case of a 62-year-old male with chronic generalized arthralgias with no evidence of iron overload or elevated inflammatory markers with characteristic radiographic hook-like osteophytes suggestive of hemochromatosis arthropathy. Further, he was found to be a carrier of HFE H63D mutation. Recognition of the association can help guide goal directed management.

Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium (PTCTC)

Introduction Congenital dyserythropoietic anemias (CDA) are a rare group of hereditary disorders characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. While some CDA patients respond to interferon α therapy (type I CDA) or splenectomy (type II CDA), others are dependent on chronic red cell transfusions lifelong. Hematopoietic cell transplant (HCT), remains the only curative option for this disease. In 39 patients reviewed by the European Society for Blood and Marrow Transplant (EBMT), graft rejection (GR) was 12% (1-23%), the 3-year overall survival (OS) and event free survival (EFS) were 71% (55-87%) and 45% (45-63%) respectively1. A trend towards higher incidence of GR and severe (Grade III-IV) acute graft versus host disease (GvHD) was observed in patients with iron overload and unrelated donor HCT but these risk factors were not statistically significant1. We report the outcomes in 17 children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) centers. Methods Clinical information on transplant and associated outcomes were collected retrospectively after IRB approval using a common questionnaire. Data were analyzed using descriptive statistics. Comparisons between groups were made using Fisher's exact tests. Survival estimates and corresponding 95% confidence intervals were performed using the Kaplan-Meier method. Results Seventeen patients (11 males) with CDA were eligible by diagnosis and underwent HCT from 2002-2019. The median age at diagnosis was 0.7 (range: 0.2 - 14) years. A majority (n=12) of patients had CDA type II while the remainder either had CDA type I (n=2) or were unknown (n=3). Twelve (71%) patients had evidence of iron overload by biopsy or imaging and 11 received pre-HCT chelation. Three of the 12 patients had liver fibrosis confirmed by biopsy. Thirteen patients had splenomegaly and four underwent splenectomy prior to HCT. Three patients received pre-HCT immunosuppressive therapy (PTIS). Median age at the time of HCT was 5.5 (range: 0.7 - 15) years. The median interval between diagnosis and HCT was 3.8 (range 0 - 12.3) years. Most patients received myeloablative busulfan-based conditioning (n=12); however, 5 patients received nonmyeloablative (n=1) or reduced intensity (n=4) fludarabine-based conditioning regimens. Donor sources included HLA matched sibling (n=3), matched unrelated (n=9), haploidentical (n=1) and mismatched unrelated (n=4) donors. Graft source was bone marrow in all but 2 patients who received umbilical cord blood. The median total nucleated cell (TNC) dose for bone marrow grafts was 6.0 (range: 3.4- 20.6) x 108/kg. Cord blood recipients received a TNC dose of 3.8 x 107 and 4.8 x 107/kg. Five (29%) patients developed acute GvHD grade II-IV, with one patient with grade III-IV acute GvHD (5.8%). Post-HCT complications included veno-occlusive disease (n=3), acute kidney injury (n=1), congestive cardiac failure (n=1), thrombotic microangiopathy (n=1), CMV viremia requiring therapy (n=2), mucormycosis (n=1), streptococcal pneumonia (n=1), recurrent clostridium difficle colitis (n=1), and parvovirus infection (n=1). Four patients developed chronic GvHD (23.5%; 2 limited and 2 extensive). Characteristics and outcomes of the four patients (23.5%) who developed GR are shown in Table 1. With a median follow-up of 3.4 (range: 0.08 - 14) years; fourteen patients are alive. Three patients died from respiratory failure due to adenovirus, congestive cardiac failure and extensive chronic GvHD post 2nd HCT. The 2-year OS, EFS and GvHD-free-rejection-free survival of the entire cohort (95% confidence interval) were 87% (72-100%), 64% (44 -92%), and 58% (39- 88%), respectively (Figure 1). Due to limited sample size, we did not find any patient or HCT-related factors that were associated with GR, OS or GvHD. Conclusion HCT can be curative for patients with CDA. The incidence of GR and GvHD in our CDA cohort was comparable to the recent EBMT report1. Strategies such as aggressive chelation, use of PTIS and perhaps early HCT in the presence of a suitable donor before co-morbidities occur are needed to improve engraftment without increasing risk for toxicities and mortality. Not unexpectedly we observed considerable morbidities in patients who had GR and required a 2nd HCT. Disclosures Pulsipher: Novartis: Honoraria; Bellicum: Honoraria; Jasper: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding.

Tilt-table Echocardiography Unmasks Early Diastolic Dysfunction in Patients With Hemoglobinopathies.

Individuals with hemoglobinopathy (sickle cell anemia and thalassemia major) are at risk for cardiac complications such as heart failure and cardiomyopathy. Diastolic dysfunction is known to precede systolic dysfunction in many cardiac diseases. This study sought to determine whether changes in left atrial (LA) function during manipulation of cardiac preload by tilt-table echocardiography can unmask subclinical diastolic dysfunction in pediatric patients with hemoglobinopathies. Eleven sickle cell anemia, 9 transfusion-dependent thalassemia major, and 10 control subjects underwent tilt-table echocardiogram in the supine (loading) and 30-degree upright (unloading) positions and cardiac magnetic resonance imaging (MRI). Echocardiography assessed LA and left ventricular (LV) strain, strain rate, mitral inflow, and annular velocities. MRI assessed LV function, myocardial T1 and T2* for iron deposition. Both thalassemia major and sickle cell anemia patients had normal LV function and no evidence of cardiac iron deposition on MRI T2* measurements. During cardiac loading, controls appropriately increased LA conduit (P=0.002) and reservoir strain (P=0.002), mitral e' velocity (P<0.0001) and medial e' velocity (P=0.002), while the hemoglobinopathy patients showed no change in these parameters. In pediatric sickle cell anemia and thalassemia, tilt-table echocardiography unmasked a failure to augment LA function in response to loading, suggesting altered myocardial relaxation is present, before evidence of iron overload or systolic dysfunction.

2424 Hepato to the Metal: The Irony of Wilson Disease

INTRODUCTION: Wilson Disease (WD) is a disorder of copper metabolism resulting in the accumulation of copper within the liver and other organs. It is caused by mutations in the ATP7B gene, which codes for a copper transport protein in the liver. The absent or compromised ATP7B protein not only causes copper accumulation in the liver but also reduces the amount of circulating ceruloplasmin. Hemochromatosis describes an iron overload syndrome that can be either primary or secondary, the latter carrying a broad differential. We describe a case of a patient with newly diagnosed WD with concomitant iron overload. CASE DESCRIPTION/METHODS: 30-year-old otherwise healthy male presents with eight-month history of persistently elevated LAEs (liver associated enzymes). Eight months ago his ALT was 127 U/L and his AST was 67 U/L with all other elements of his liver function being normal. He uses NSAIDs once a month for neck and low back pain. He denies supplement use and does not consume alcohol. No known family history of metabolic liver disease. Review of systems was otherwise normal including no neuropsychiatric symptoms Physical exam was normal. LAEs at current presentation were ALT of 155 U/L and AST of 75 U/L, with normal total bilirubin and ALP. He had new thrombocytopenia of 143,000/μL. INR was normal. Infectious, autoimmune, and metabolic serologic testing were all unremarkable except ceruloplasmin &lt;3.0 mg/dL and ferritin of 646 ng/mL. Iron (70 μg/dL) and iron saturation (24.1%) were normal. Concern for WD prompted a 24-hour urine copper collection. His 24 hour urine copper level was elevated (113 μg). Slit-lamp exam was normal. Liver ultrasound was unremarkable. Vibration controlled transient elastography score was elevated (11.8 kPa, IQR/med 8%). Liver biopsy revealed bridging fibrosis with negative copper staining, but iron stain showing moderate hepatocellular iron deposition. DISCUSSION: In addition to its copper carrying property, ceruloplasmin has ferroxidase activity. Hypoceruloplasminemia found in WD consequently leads to decreased amount of circulating iron and increased iron stores, leading to iron accumulation in the liver. Although primary hemochromatosis should be considered in the evaluation of patients with WD with evidence of iron overload, it is important to realize that iron overload can also be a second order effect of WD. Iron indices should be monitored in patients with WD, particularly during chelation therapy, as ceruloplasmin levels may further decrease and worsen iron accumulation.

Hazardous effect of the maintenance dose of iron sucrose versus iron dextran on oxidative burst activity of neutrophils in patients on regular hemodialysis; a pilot study

Introduction: Intravenous (IV) iron which is a potent pro-oxidant may decrease the phagocytic function of neutrophils and subsequently leads to repeated bacterial infections in patients on chronic regular hemodialysis (HD).Objectives: We aimed to evaluate the effect of IV iron dextran versus iron sucrose on oxidative burst activity of neutrophils in HD patients.Patients and Methods: A crossover study was included 20 prevalent HD patients were randomly divided into two groups; 10 patients each. Each group received a single dose of 100 mg iron sucrose or iron dextran then shifted to the other type after 4 weeks as a washout period. Patients with evidence of acute infections, diabetes mellitus, chronic liver disease, active collagen disease or any other acquired immune deficiency diseases were excluded. Patients on immunosuppressive drugs or with hypersensitivity to iron therapy or evidence of iron overload (TSAT &gt; 50% and/or ferritin &gt; 800 ng/mL) were also excluded. Erythropoietin maintenance dose was given to all patients. Urea reduction ratio (URR %), C-reactive protein (CRP) titer, complete blood picture and iron study were conducted. Neutrophil oxidative burst test was performed by flow-cytometry with an estimation of stimulation index before and after IV iron dosage. Results: Twenty patients (9 males, 11 females; mean age 49.40 ± 9.02 years) on chronic HD for a mean time of 10 ± 7.32 years. After 100 mg of IV iron infusion in HD patients, a highly significant difference in oxidative burst test of neutrophil cells before and after administration of iron regardless of its type was detected (P &lt; 0.01). This change over time is not significantly different between two types of iron (P &gt; 0.05). However, a significant increase in CRP titer after administration of iron dextran was seen (P = 0.016). Conclusion: Maintenance dosage of either IV iron sucrose or iron dextran (100 mg) had a hazardous effect on the neutrophilic phagocytosis demonstrated by the significant rise in the oxidative burst index in HD patients.

Poor Access to Care Is a Risk Factor for Iron Overload in Adults with Sickle Cell Disease in Southern California

The lack of access to quality comprehensive care is a major problem for adults with sickle cell disease (SCD) and contributes to increased morbidity and mortality. This problem is especially acute in Los Angeles where the average lifespan is 10 years shorter than the national average. Without access to disease modifying therapies, patients utilize Emergency Department services and are repeatedly hospitalized. During inpatient stays many may be inappropriately transfused. The result can be severe iron overload, a significant cause of morbidity and mortality. Inattention to iron chelation in patients who are not cared for by knowledgeable SCD providers perpetuates this issue. In 2016 we cared for a new patient at our clinic in South Los Angeles who previously had a liver transplant due iron overload. This patient received multiple transfusions during her lifetime and was never seen in a comprehensive SCD clinic. This experience prompted us to evaluate our population of clinic patients to assess how lack of access to care might be a risk factor for iron overload.Methods: We performed a chart review of all patients with SCD who presented to either of two adult sickle cell clinics in Southern California: MLK Jr. Outpatient Center in Los Angeles and Center for Inherited Blood Disorders (CIBD) in Orange. We examined records from 2013-2018 from CIBD and from 2016-2018 from MLK. Patients were considered evaluable if they had a least one visit to clinic with labs that included iron studies and /or MRI. Iron saturations greater than 50% and /or a ferritin greater than 1000 was deemed indicative of iron overload when combined with a history of prior transfusions. Lack of access was defined as the absence of appropriate care for SCD for at least 12 months prior to the initial visit in our clinics. Patients were deemed in good SCD care if they had been transitioned from a pediatric SCD program or another adult SCD program where they received team based comprehensive services.Results: 74 patients were able to be evaluated. (Table 1). 53 patients were Hgb SS. Of those, 27 (50.9%) were not receiving appropriate SCD care for the prior 12 months when they first presented, 20 (74.1%) of those patients were iron overloaded. There were 9 patients with Hgb S/beta thalassemia 0 or +. Five (55.6%) of those patients were not receiving appropriate SCD care for the prior 12 months; one (35.6%) was iron overloaded. 12 patients had Hgb SC. Although 5 (41.7%) were not receiving appropriate SCD care at the time of presentation, none had evidence of iron overload. Using these data, the odds ratio of having iron overload if a patient was out of appropriate SCD care for the 12 months prior to evaluation was 6.8 (95% confidence interval 2,23.13), indicating that being out of good care is a risk factor for iron overload.Discussion: Although guidelines exist to prevent unnecessary transfusions in adult patients with SCD; lack of access to knowledgeable providers both in the inpatient and outpatient setting places them at a nearly 7 times higher risk for iron overload, a serious and preventable comorbidity. Our study indicates that many adults with SCD are not appropriately monitored or treated for transfusion related iron overload using guideline-based care, placing avoidable burdens on individual health and adding to healthcare costs. Further education of providers to address this issue is warranted. [Display omitted] DisclosuresBaker:Genentech: Research Funding.

Decreased Iron Overload and Oxidative Stress in Transfusion Dependent Patients with Myelodysplastic Syndromes (MDS) with the Oral Iron Chelator Deferiprone

Background: The majority of the patients with low risk myelodysplastic syndrome (MDS) become RBC-transfusion-dependent and thus symptoms resulting from iron overload and oxidative stress may develop. Yet, iron-chelation has not been part of the standard treatment for these patients. The purpose of this study was to assess the effect of deferiprone (L1), an iron chelator, on oxidative stress parameters in iron overloaded and blood dependent patients with low risk MDS.Methods: This work was supported by a grant from Apopharma.Nineteen low risk MDS patients were enrolled. Patients were classified as very low-, low- and intermediate-risk disease, according to the Revised International Prognostic Scoring System (IPSS-R). Inclusion criteria were a cumulative transfusion burden of >20 red blood cells (RBC) units and evidence of iron overload (serum ferritin >1,000 ng/mL). Deferiprone at a dose of up to a maximum dose of 100 mg/kg was administrated for 4 months. Blood samples were taken at baseline, at each monthly visit, and at the end of the study. The samples were tested for oxidative stress parameters: reactive oxygen species (ROS), phosphatidylserine (PS), glutathione (GSH) and membrane lipid peroxidation (LP); iron parameters: serum ferritin and cellular labile iron pool (LIP), and CBC. The primary efficacy variable as a measurement of oxidative stress was ROS. Student's t-test was applied for statistical analyses.Results: Patients (n=19) were treated with deferiprone in a daily dose of 25-100 mg/kg, median of 50 mg/kg/day. Eight patients received treatment for 120 days and completed the study. One of them had mild neutropenia that resolved after short discontinuation of the study drug and finished the study with no more complications. Eleven patients did not finish the study: eight patients due to gastrointestinal (GI) adverse effects, two patients withdrew their consent (one of them after mild neutropenia that resolved) and one patient was killed in a car accident. We thus had measurements of at least two time points for 16 of the patients. The median number of RBC transfusions during study period was 11 (2-20). The primary efficacy variable ROS, as a measurement of oxidative stress, was significantly decreased, in all three lineages: platelet, RBC and neutrophils (decrease of 32%, 33% and 32% respectively, each at P=0.001). Deferiprone administration was also associated with a reduction in other cellular markers of oxidative stress in RBC: PS, GSH, LP and LIP (decrease of 54%, 98%, 300%, and 42% respectively, each at P=0.001). No significant changes were observed in serum ferritin levels, likely due to the short treatment period in patients on repeated transfusion requirements.Conclusions: This is the first prospective study on chelation with Deferiprone in MDS patients. Our data provide preliminary evidence that administration of Deferiprone in a median daily dose of at 50 mg/kg can decrease iron-induced oxidative stress in iron-overloaded MDS patients. Of note, no events of agranulocytosis were observed. The future remains challenge is to prove that reduction in iron toxicity will eventually translate into a clinically meaningful improvement.Prof. Rachmilewitz who unfortunately passed away last year, had a significant contribution to the conception and design of this study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ferritin level changes and erythroid improvement in a group of adult politransfused patients treated with Deferasirox

Background and aimsChelating agents therapy is recommended for polytransfused patients that have evidence of iron overload (an elevated serum ferritin or received over 20 units of red blood cell transfusions). Deferasirox showed efficacy and safety in maintaining or reducing body iron. Iron chelation therapy was associated with hematopoiesis improvement in transfusion-dependent patients.Our objectives were to analyze differences in ferritin level in adult polytransfused patients treated with Deferasirox, to estimate the erythroid improvement and variation of the number of red blood cell transfusion after introducing Deferasirox, to evaluate the side effects of the treatment.MethodsRetrospective study including all the adult polytransfused patients treated with Deferasirox in Hematology Departments of three county hospitals in the North-West of Romania.ResultsWe included 40 polytransfused patients treated with Deferasirox in standard doses. There was a significant reduction in serum ferritine from baseline for all the patients (Friedman test, χ2(2)=26.82, p<0.001). Safety profile of Deferasirox was good (three digestive side effects). RBCT were administered before (mean 2.43±1.09 units/month) and after starting Deferasirox (mean 1.40±0.97 units/month), the difference is statistically significant (Student Test, t(39)=6.98, p<0.001).ConclusionsDeferasirox proves to be an effective iron chelator, the serum level of ferritine decreased for all the patients during the treatment and 22.5 % of the patients developed an erythroid improvement. Safety and compliance were good.

Iron supplementation in pregnant sicklers: an opinion

Morbidity associated with iron deficiency anaemia in pregnancy is increased in the presence of sickle cell anaemia. Iron supplementation in pregnant sicklers in a bid to resolve iron deficiency anaemia is recommended only after laboratory confirmation of iron deficiency. However, the greatest burden of sickle cell disease is seen in low and middle income countries where equipment for measuring body iron indices are unavailable.Sickle cell anaemia is an inherited disorder of haemoglobin synthesis characterized by life-long severe haemolytic anaemia. People with sickle cell anaemia are at increased risk of iron overload from haemolysis and recurrent multiple transfusions. Iron overload a complication of sickle cell disease, which is more often in thalassemias, is typically given undue fear in sickle cell anaemia especially in patients with no recent transfusion history. About a third of the haemolysis in sickle cell anaemia is intravascular, and the resulting excess iron is lost in urine. This may lead to a negative iron balance and iron deficiency. There is little evidence of iron overload in pregnant sicklers, and iron deficiency may be more common than suspected. Even when iron overload does occur in a condition called siderosis, the deposited iron is irreversible and thus cannot be reused by the body in case of susceptibility to iron deficiency. More so, in pregnancy there is an increase in the body’s iron requirement by about 1000–1200 mg which is usually not met by dietary intake. Iron supplements could be given to pregnant sicklers, caution should however be taken in patients with history of recurrent transfusion.Anaemia is a common and feared complication in pregnancy. The co-existence of iron deficiency anaemia and sickle cell anaemia worsens prognosis of pregnancy. Iron overload a possible complication of sickle cell anaemia is related to multiple transfusions. The urinary losses from intravascular haemolysis and increased dietary requirement in pregnancy predispose even pregnant sicklers to iron deficiency anaemia. Iron supplements should thus conveniently be given to pregnant sicklers with no history of recurrent transfusions.

A Phase II, Multicenter, Single-Arm Study to Evaluate the Safety and Efficacy of Deferasirox after Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

We conducted a prospective, phase II, multicenter, single-arm study to evaluate the efficacy and safety of deferasirox in patients age >2 to <18 years with β-thalassemia major (TM) who underwent hematopoietic stem cell transplantation (HSCT) and had evidence of iron overload (serum ferritin >1000 µg/L; cardiac MRI T2* <20 ms, or liver iron concentration [LIC; by MRI R2] ≥5 mg/g). Patients received deferasirox at an initial dose of 10 mg/kg/day, with up-titration to a maximum of 20 mg/kg/day. The study continued for 52 weeks and included a total of 27 patients (mean age, 9.1 ± 3.8 years; 70.4% male). One patient (3.7%) was lost to follow-up. The majority of patients (n = 20; 74.1%) were able to achieve the intended dose of 20 mg/kg/day. No deaths occurred. A total of 134 adverse events (AEs) were reported in 25 patients (92.6%) during the study. The majority of patients had grade 1 or 2 AEs, with only 8 patients (29.6%) experiencing grade 3 AEs. Only 10 AEs occurring in 4 patients (14.8%) were suspected to be related to deferasirox (ALT/AST increase, n = 4; urinary tract infection, n = 1). The deferasirox dose had to be adjusted or interrupted for 6 AEs occurring in 4 patients (14.8%). A total of 6 serious AEs occurred in 3 patients (11.1%), none of which were suspected to be related to deferasirox. From baseline to week 52, there were decreases in median concentrations of alanine aminotransferase (ALT), from 30.0 to 17.0 IU/L, and aspartate aminotransferase (AST), from 35.5 to 26.0 IU/L. Median serum creatinine and cystatin C concentrations were similar at baseline and week 52. There was a continuous and significant decrease in median serum ferritin level from 1718.0 µg/L at baseline to 845.3 µg/L following 52 weeks of therapy (P < .001); 9 patients (33.3%) achieved a level of <500 µg/L. There was also a significant decrease in median LIC (from 8.6 to 4.1 mg/g; P < .001) and an increase in median cardiac T2* (from 26.0 to 28.0 ms; P = .520) from baseline to week 52. Our findings indicate that deferasirox treatment at doses up to 20 mg/kg/day reduces the iron burden in children with TM post-HSCT, with a manageable safety profile.

The Phenotypic Spectrum of Pyruvate Kinase Deficiency (PKD) from the PKD Natural History Study (NHS): Description of Four Severity Groups By Anemia Status

▪Background: An international, multicenter registry was established to collect clinical data on patients with PKD, the most common glycolytic defect causing congenital non-spherocytic hemolytic anemia.Aim: To describe and categorize the phenotypic spectrum of PKD, including the range of lab parameters, management, and complications.Methods: 144 patients enrolled on the PKD NHS at 23 sites from 3/2014 to 6/2015. For this report, baseline and retrospective data were included. PKD patients were categorized into 4 severity groups (Gp1-Gp4), with increasing severity of the disease: Gp1. Never regularly transfused +/- prior acute transfusions; Gp2. Regular transfusions prior to splenectomy, post-splenectomy baseline hemoglobin (hb) >8.7 g/dl; Gp3. Regular transfusions prior to splenectomy, post-splenectomy baseline hb ≤8.7 g/dl; and Gp4. Post-splenectomy and currently regularly transfused. To reduce the risk of chance associations when dividing the cohort by phenotype, the cohort was divided into a test set (n=73) to define the categories and a subsequent validation set (n=71).Results: Median age at enrollment was 19.9 years (0.1-70.7) with 47% males. This cohort was 95% Caucasian and 38% Amish. Perinatal complications were frequently reported including preterm birth (33%), perinatal transfusions (35%), and hydrops (10%). Newborn jaundice was common, requiring phototherapy (91%) and/or exchange transfusion (46%). 68% (98/144) had undergone splenectomy at a median age of 3.1 years (0.6-28.1). Common indications for splenectomy included reducing transfusion burden, improving anemia, and enhancing quality of life. The median pre-splenectomy hb was 7.0 g/dl (4.5-12.5). Splenectomy reduced the transfusion burden in 91%. Triggers for hemolysis included: pregnancy (59%), infections (61%), stress (35%), and medications (6%). In the 37% (53/144) who required a cholecystectomy, the median age was 14 years (2.6-60.4) and 35 (66%) occurred post-splenectomy.In both the test and validation cohorts, increased severity was associated with a younger age at diagnosis (p<0.01) and higher ferritin (p<0.01, Table). More severe patients were more likely to receive iron chelation (p<0.01). Reticulocyte counts and MCV were incrementally higher with increasing severity in the non-regularly transfused Gps (p=0.02).Gp4 pts required regular transfusions even after splenectomy (11/98). In this group, the median age of splenectomy was 5.0 y (2.1-11.8).Ferritin was higher in those who had a splenectomy, even after adjusting for transfusion status (p<0.0001). In the Gp1 pts with available iron studies, even in the absence of regular transfusions, the majority had evidence of iron overload; 7/10 (70%) had a liver iron concentration (LIC) >4 mg/g dry weight and 9/11 (82%) had ferritin >500 ng/ml. Chelation was used in 35 patients at a median age of 11.8 years (1-53.7) with a median ferritin 815 ng/ml (182-5630) and median LIC 5.7 mg/g dry weight (1.7-46.0).Conclusions: This NHS cohort is the largest assembly of PKD patients to date. We defined 4 severity Groups, based on transfusion history, anemia, and splenectomy status. Complications (e.g. iron overload) correlate with disease severity but also occur in milder phenotypes. Based on these findings, regular monitoring of iron status and screening for gallstones should be considered. Transfusion dependence persisted despite splenectomy in 11% of patients. Prospective data from the NHS will provide guidance for monitoring and treatment in this rare anemia. [Display omitted] DisclosuresGrace:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morton:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Eber:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees. Nottage:Janssen Pharmaceuticals: Employment. Kuo:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Neufeld:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees.