A RETROSPECTIVE STUDY OF HEPATIC HEMOSIDEROSIS AND IRON STORAGE DISEASE IN SEVERAL CAPTIVE AND FREE-RANGING AVIAN SPECIES.

Some wild species of mammals and birds are prone to excessive iron accumulation, especially when maintained in human care. Hemosiderosis is the process of intracellular accumulation of iron without evidence of toxicity, whereas hemochromatosis is characterized by severe iron accumulation with accompanying organ damage. Iron storage disease (ISD) occurs when organ damage is severe and causing clinical signs. This retrospective study investigated the occurrence of hemosiderosis and ISD across a variety of avian taxa, including captive and free-ranging birds. Archived paraffin-embedded hepatic samples from 103 birds from Belo Horizonte Zoo that died naturally in the period of 2008 to 2018 were re-evaluated with histologic and morphometric techniques, focusing on the identification and scoring of iron deposits in hepatocytes and the quantification of total affected hepatic area. The birds represented 13 orders, 22 families, and 52 genera, and 66 (64.0%) had some degree of iron accumulation in their liver. Importantly, no statistical difference was observed in the occurrence of iron accumulation between families, orders, or origin (free-ranging or captive). Direct and positive correlation was observed between the total area affected by the iron deposits and the histologic score. In this study, there were two cases with severe iron accumulation and clinical signs compatible with ISD: a barefaced curassow (Crax fasciolata) and a channel-billed toucan (Ramphastos vitellinus). This study indicates that iron accumulation may occur in a wide range of avian species, with frequencies and intensities that are similar between free-ranging birds and those in human care. It describes for the first time the occurrence of ISD in a Galliform species.

Prevalence of autoantibodies in pediatric patients with idiopathic pulmonary hemosiderosis: a scoping review of the literature in the period 1980-2021.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown etiology. Due to the frequent findings of autoimmune antibodies - autoantibodies, immunologic causation of the diffuse alveolar hemorrhage in IPH has been proposed, to assess the prevalence/frequency and type of autoantibodies in pediatric patients with IPH. In addition, the patient demographics, diagnostic modalities used to diagnose IPH, treatment, and outcomes were also evaluated. Scoping review: The PubMed, Medline, and Embase databases were searched with appropriate MeSH terms to identify relevant papers consistent with the defined inclusion criteria. Thirteen observational studies comprising a total of 352 pediatric patients were included in this review. The majority of subjects were girls 217 out of 352 (61.6%). The mean and median ages of patients ranged from 3.1-6.5 years to 2.3-7 years, respectively. In the 10 studies that specified the number of patients in their cohorts with either at least one positive autoantibody or no antibody, the overall prevalence of autoantibodies was 76 out of 288 patients (26.4%). The prevalence of specific antibodies was as follows: ANA, 20.3%; ANCA, 17%; anti-dsDNA, 9.1%; RF, 12%; anti-SMA, 23.2%; and celiac antibodies, 25.9%. Cow's milk protein allergy was present in 16.2% of the children. The significance of an association between IPH and the presence of autoantibodies has not been clarified. The autoantibodies could be suggestive of an overall immune dysregulation rather than causation. However, limited evidence based on a single study suggests that the presence of ANA may be associated with a higher risk of recurrence and worse outcomes. Further research, including prospective studies, will be crucial to explore a possible genetic linkage between vasculitides, systemic rheumatologic diseases, and IPH.

Clinical Penetrance of Hereditary Hemochromatosis-Related End-Organ Damage of C282Y Homozygosity, A Newfoundland Experience.

INTRODUCTION: Hereditary hemochromatosis is an autosomal recessive disorder of iron absorption, leading to organ dysfunction. C282Y gene homozygosity is implicated in 80%-95% of cases of hereditary hemochromatosis. The clinical penetrance of this genotype remains unclear. The purpose of the study was to better describe the clinical penetrance and disease progression of C282Y homozygotes. METHODS: This is a retrospective study of all individuals in Newfoundland and Labrador, Canada, homozygous for the C282Y mutation from 1999 to 2009. Using electronic health records, laboratory values, phlebotomy status, radiologic reports, and clinic records were recorded up to November 2017. Iron overload status was classified via the HealthIron study. SPSS Version 19.0 (IBM Corporation) was used for descriptive statistics. Predictors of disease penetrance were assessed with logistic regression; a Student t test was used for continuous variables, and χ tests were used for categorical variables. RESULTS: Between 1999 and 2009, 360 individuals tested positive for C282Y/C282Y. The mean age of diagnosis was 49.1 years. Three hundred six individuals had adequate follow-up for analysis (mean 11.6 years). End-organ damage was observed in 18.3%, with 5.8% developing liver disease. End-organ damage was more frequently observed in men 24.3% vs 10.5% (P < 0.05). Clinical penetrance in postmenopausal women approached that of men 18.3%. DISCUSSION: This is the largest reported cohort of C282Y homozygotes, followed for an extended duration of time in North America. The findings reflect outcomes in routine clinical practice and suggest that C282Y homozygosity uncommonly causes end-organ damage and liver disease.

Frequency, Extent, and Correlates of Superficial Siderosis and Ependymal Siderosis in Premature Infants with Germinal Matrix Hemorrhage: An SWI Study.

BACKGROUND AND PURPOSE: Germinal matrix intraventricular hemorrhage is a common complication of prematurity. An underrecognized complication of germinal matrix intraventricular hemorrhage is superficial siderosis, and the clinical consequences of superficial siderosis are not well-known. We aimed to investigate the prevalence, anatomic distribution, and severity of superficial siderosis and ependymal siderosis in premature infants with germinal matrix intraventricular hemorrhage using SWI. MATERIALS AND METHODS: In this retrospective study, we included 88 patients across all grades of germinal matrix intraventricular hemorrhage who underwent MR imaging at term-equivalent age. Images were evaluated for the presence, distribution, and severity of superficial siderosis and ependymal siderosis. Univariate and multivariate logistic regression analyses were performed to determine factors associated with superficial siderosis and ependymal siderosis. The agreement among T1, T2, and SWI sequences was examined. RESULTS: Seventy-two patients had brain stem superficial siderosis, and 79 patients had ependymal siderosis. The presence, extent, and severity of superficial siderosis and ependymal siderosis were closely related to the grade of germinal matrix intraventricular hemorrhage and intraventricular hematoma volume. Brain stem superficial siderosis had a stronger correlation with intraventricular hemorrhage than with cerebellar hemorrhage. Compared with SWI, T1 and T2 sequences detected only small proportions of patients with superficial siderosis (12.5% and 6.9%, respectively). CONCLUSIONS: The incidence of superficial siderosis and ependymal siderosis is very high in preterm infants with germinal matrix intraventricular hemorrhage when assessed by SWI at term-equivalent age. The presence and extent of superficial siderosis and ependymal siderosis are closely related to germinal matrix intraventricular hemorrhage grade and intraventricular hematoma volume. Additional prospective studies using SWI are needed to clearly determine the clinical consequences of germinal matrix intraventricular hemorrhage with superficial siderosis and ependymal siderosis.

Functional iron deficiency in patients on hemodialysis: prevalence, nutritional assessment, and biomarkers of oxidative stress and inflammation / Deficiência funcional de ferro em pacientes em hemodiálise: prevalência, avaliação nutricional e de biomarcadores de estresse oxidativo e de inflamação

Abstract Introduction: Anemic patients with chronic kidney disease (CKD) can be divided into anemic patients without or with functional iron deficiency (FID). The increase in the number of cases of hemosiderosis in patients on hemodialysis (HD) attributed to excessive intravenous iron replacement has called for the investigation of the factors involved in the genesis of FID. Objectives: This study aimed to describe the prevalence of FID in patients with CKD on HD, characterize the included individuals in terms of clinical and workup parameters, and assess their nutritional, oxidative stress, and inflammation statuses. This cross-sectional study assembled a convenience sample of 183 patients with CKD on HD treated in Southern Brazil. Patients meeting the inclusion and exclusion criteria were divided into two groups, one with anemic subjects with FID and one with anemic patients without FID. Participants answered a questionnaire probing into socio-epidemiological factors, underwent anthropometric measurements, and were tested for markers of anemia, oxidative stress, inflammation, and nutrition. Statistical analysis: The date sets were treated on software package GraphPad InStat version 3.1. Variables were tested with the Kolmogorov-Smirnov, chi-square, Student's t, and Mann-Whitney tests. Statistical significance was attributed to differences with a p < 0.05. Results: Markers of inflammation were not statistically different between the two groups. Markers of anemia and nutrition were significantly lower in patients with FID. Patients with FID were prescribed higher doses of parenteral iron (p < 0,05). Discussion: FID was associated with lower nutritional marker levels, but not to increased levels of markers of inflammation or oxidative stress, as reported in the literature. Additional studies on the subject are needed.

Resumo Introdução: A anemia na DRC pode ser dividida em anemia sem deficiência funcional de ferro e com deficiência funcional de ferro (ADFF). Diante do aumento dos casos de hemossiderose em pacientes em hemodiálise, atribuídos à reposição excessiva de ferro endovenoso, maiores conhecimentos sobre os fatores envolvidos na gênese da ADFF são importantes. Objetivos: documentar a prevalência de ADFF em renais crônicos em hemodiálise. Caracterizar clínica e laboratorialmente os portadores de ADFF em HD e avaliar o estado nutricional, estresse oxidativo e inflamatório. Estudo transversal, amostra de conveniência, envolvendo 183 renais crônicos em hemodiálise no sul do Brasil. Após aplicação dos critérios de exclusão, os pacientes foram separados em dois grupos: portadores de anemia com e sem deficiência funcional de ferro. Foram submetidos a questionário socioepidemiológico, à análise antropométrica e análise laboratorial dos marcadores de anemia, estresse oxidativo, inflamatórios e nutricionais. Análise estatística: programa GraphPad InStat versão 3.1. Foram aplicados os testes: Kolmogorov-Smirnov, qui-quadrado, t de Student e Mann-Whitney. Nível de significância adotado de 5%. Resultados: não houve diferença significativa nos marcadores inflamatórios entre os dois grupos. Houve diferença significativa nos marcadores de anemia e nutrição, significativamente menores nos pacientes com ADFF. Pacientes com ADFF receberam doses mais elevadas de ferro parenteral (p < 0,05). Discussão: ADFF esteve associada a menores valores de marcadores nutricionais, mas não esteve associada a marcadores inflamatórios ou de estresse oxidativo aumentados, como relatado na literatura. Estudos adicionais sobre o tema são necessários.

Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy: A meta-analysis.

OBJECTIVE: To assess the association of cortical superficial siderosis (cSS) presence and extent with future bleeding risk in cerebral amyloid angiopathy (CAA). METHODS: This was a meta-analysis of clinical cohorts of symptomatic patients with CAA who had T2*-MRI at baseline and clinical follow-up for future intracerebral hemorrhage (ICH). We pooled data in a 2-stage meta-analysis using random effects models. Covariate-adjusted hazard ratios (adjHR) from multivariable Cox proportional hazard models were used. RESULTS: We included data from 6 eligible studies (n = 1,239). cSS pooled prevalence was 34% (95% confidence interval [CI] 26%-41%; I 2 87.94%; p < 0.001): focal cSS prevalence was 14% (95% CI 12%-16%; I 2 6.75%; p = 0.37), and disseminated cSS prevalence was 20% (95% CI 13%-26%; I 2 90.39%; p < 0.001). During a mean follow-up of 3.1 years (range 1-4 years), 162/1,239 patients experienced a symptomatic ICH-pooled incidence rate 6.9% per year (95% CI 3.9%-9.8% per year; I 2 83%; p < 0.001). ICH incidence rates per year according to cSS status were 3.9% (95% CI 1.7%-6.1%; I 2 70%; p = 0.018) for patients without cSS, 11.1% (95% CI 7%-15.2%; I 2 56.8%; p = 0.074) for cSS presence, 9.1% (95% CI 5.5%-12.8%; I 2 0%; p = 0.994) for focal cSS, and 12.5% (95% CI 5.3%-19.7%; I 2 73.2%; p = 0.011) for disseminated cSS. In adjusted pooled analysis, any cSS presence was independently associated with increased future ICH risk (adjHR 2.14; 95% CI 1.19-3.85; p < 0.0001). Focal cSS was linked with ICH risk (adjHR 2.11; 95% CI 1.31-2.41; p = 0.002), while disseminated cSS conferred the strongest bleeding risk (adjHR 4.28; 95% CI 2.91-6.30; p < 0.0001). CONCLUSION: In patients with CAA, cSS presence and extent are the most important MRI prognostic risk factors for future ICH, likely useful in treatment planning. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in symptomatic CAA survivors with baseline T2*-MRI, cSS (particularly if disseminated, i.e., affecting >3 sulci) increases the risk of future ICH.

Functional iron deficiency in patients on hemodialysis: prevalence, nutritional assessment, and biomarkers of oxidative stress and inflammation.

INTRODUCTION: Anemic patients with chronic kidney disease (CKD) can be divided into anemic patients without or with functional iron deficiency (FID). The increase in the number of cases of hemosiderosis in patients on hemodialysis (HD) attributed to excessive intravenous iron replacement has called for the investigation of the factors involved in the genesis of FID. OBJECTIVES: This study aimed to describe the prevalence of FID in patients with CKD on HD, characterize the included individuals in terms of clinical and workup parameters, and assess their nutritional, oxidative stress, and inflammation statuses. This cross-sectional study assembled a convenience sample of 183 patients with CKD on HD treated in Southern Brazil. Patients meeting the inclusion and exclusion criteria were divided into two groups, one with anemic subjects with FID and one with anemic patients without FID. Participants answered a questionnaire probing into socio-epidemiological factors, underwent anthropometric measurements, and were tested for markers of anemia, oxidative stress, inflammation, and nutrition. STATISTICAL ANALYSIS: The date sets were treated on software package GraphPad InStat version 3.1. Variables were tested with the Kolmogorov-Smirnov, chi-square, Student's t, and Mann-Whitney tests. Statistical significance was attributed to differences with a p < 0.05. RESULTS: Markers of inflammation were not statistically different between the two groups. Markers of anemia and nutrition were significantly lower in patients with FID. Patients with FID were prescribed higher doses of parenteral iron (p < 0,05). DISCUSSION: FID was associated with lower nutritional marker levels, but not to increased levels of markers of inflammation or oxidative stress, as reported in the literature. Additional studies on the subject are needed.

Nationwide epidemiological survey of superficial hemosiderosis in Japan.

BACKGROUND: The Japanese guideline for diagnosis and classification of superficial hemosiderosis (SHS) has recently been published, for which patient medical expenses are supported by the Ministry of Health. We sought to clarify the clinical features, method of diagnosis, and treatment for SHS in Japan. METHODS: We sent a questionnaire survey to 792 medical institutes of the Japanese Society of Neurology, to collect information about SHS, including patients during 2017. RESULTS: We received replies from 287 institutes (36.2%). Estimated total number of patients with SHS in 2017 was 129 at 55 institutes. All patients were diagnosed by neurologists. Among 123 patients with available data, 81 patients (63%) had "classical" type (c-SHS), 29 (24%) had "localized" type (l-SHS), and 13 patients (10%) had "atypical" type (a-SHS). Five patients with l-SHS were excluded because of lacking detailed information. There were available data for the cause of SHS in 77 patients (63%): 55 (69%) with c-SHS, 16 (55%) with l-SHS, and 6 (48%) with a-SHS. Pharmacological or surgical treatment was given at 31 institutes. Medical expense subsidies were filed for 41% of patients. CONCLUSIONS: Using the Japanese guideline for diagnosis of SHS, over 100 patients were confirmed as having SHS with characteristic clinical features. SHS is not a rare clinical condition in Japan.

Anatomical hemispherectomy revisited-outcome, blood loss, hydrocephalus, and absence of chronic hemosiderosis.

PURPOSE: To evaluate microsurgical trans-sylvian trans-ventricular anatomical hemispherectomy with regard to seizure outcome, risk of hydrocephalus, blood loss, and risk of chronic hemosiderosis in patients with intractable seizures selected for surgery using current preoperative assessment techniques. METHODS: Out of 86 patients who underwent hemispherectomy between February 2000 and April 2019, by a single surgeon, at a tertiary care referral center, 77 patients (ages 0.2-20 years; 40 females) who had an anatomical hemispherectomy were analyzed. Five of these were 'palliative' surgeries. One-stage anatomical hemispherectomy was performed in 55 children, two-stage anatomical hemispherectomy after extraoperative intracranial monitoring in 16, and six hemispherectomies were done following failed previous resection. Mean follow-up duration was 5.7 years (range 1-16.84 years). Forty-six patients had postoperative MRI scans. RESULTS: Ninety percent of children with non-palliative hemispherectomy achieved ILAE Class-1 outcome. Twenty-seven patients were no longer taking anticonvulsant medications. Surgical failures (n = 4) included one patient with previous meningoencephalitis, one with anti-GAD antibody encephalitis, one with idiopathic neonatal thalamic hemorrhage, and one with extensive tuberous sclerosis. There were no failures among patients with malformations of cortical development. Estimated average blood loss during surgery was 387 ml. Ten (21%) children developed hydrocephalus and required a shunt following one-stage hemispherectomy, whereas 10 (50%) patients developed hydrocephalus among those who had extraoperative intracranial monitoring. Only 20% of the shunts malfunctioned in the first year. Early malfunctions were related to the valve and later to fracture disconnection of the shunt. One patent had a traumatic subdural hematoma. None of the patients developed clinical signs of chronic 'superficial cerebral hemosiderosis' nor was there evidence of radiologically persistent chronic hemosiderosis in patients who had postoperative MRI imaging. CONCLUSION: Surgical results of anatomical hemispherectomy are excellent in carefully selected cases. Post-operative complications of hydrocephalus and intraoperative blood loss are comparable to those reported for hemispheric disconnective surgery (hemispherotomy). The rate of shunt malfunction was less than that reported for patients with hydrocephalus of other etiologies Absence of chronic 'superficial hemosiderosis', even on long-term follow-up, suggests that anatomical hemispherectomy should be revisited as a viable option in patients with intractable seizures and altered anatomy such as in malformations of cortical development, a group that has a reported high rate of seizure recurrence related to incomplete disconnection following hemispheric disconnective surgery.

Increased cerebral microbleeds and cortical superficial siderosis in pediatric patients with Down syndrome.

BACKGROUND: Patients with Down syndrome carry a third copy of the amyloid precursor protein gene, which is localized on chromosome 21. Consequently, these patients are prone to develop early-onset Alzheimer disease and cerebral amyloid angiopathy. Post-mortem studies suggest increased amyloid deposition to be already detectable in children with Down syndrome. The aim of our study was to evaluate if amyloid-related changes in pediatric Down syndrome patients can be detected in vivo using MRI biomarkers of cerebral microbleeds and cortical superficial siderosis. MATERIALS AND METHODS: This retrospective study included 12 patients with Down syndrome (mean age = 5.0 years) and 12 age-matched control subjects (mean age = 4.8 years). Frequency and location of microbleeds and siderosis were assessed on blood-sensitive MRI sequences in a consensus reading by two radiologists applying a modified Microbleed Anatomical Rating Scale. RESULTS: Down syndrome patients showed a significantly higher mean microbleeds count and likelihood of siderosis than age-matched controls. Across groups, the highest microbleeds count was found in lobar regions (gray and white matter of frontal, parietal, temporal, and occipital lobes, and the insula), while fewer microbleeds were located in subcortical and infratentorial regions. The number of microbleeds increased over time in all three Down syndrome patients with a follow-up exam. CONCLUSION: In vivo MRI biomarkers can support the diagnosis of early-onset cerebral amyloid angiopathy, which might already be present in pediatric Down syndrome patients. This might contribute to clinical decision-making and potentially to the development of therapeutic and prophylactic approaches, as cerebral amyloid angiopathy increases the risk for intracranial hemorrhage and may be associated with increased risk of developing Alzheimer disease.

Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features. METHODS: Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space. RESULTS: cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients. CONCLUSIONS: cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA.

Screening for hemosiderosis in patients receiving multiple red blood cell transfusions.

BACKGROUND: The dramatic impact of hemosiderosis on survival in chronically transfused patients with hereditary anemia is well known. We evaluated whether patients receiving multiple red blood cell (RBC) transfusions are adequately screened for hemosiderosis. METHODS: We retrospectively assessed hemosiderosis screening and prevalence in adult patients that received over twenty RBC units in the University Medical Centre Utrecht from 2010 till 2015. Hemosiderosis was defined as ferritin ≥1000 µg/L. Adequate screening for chronically transfused patients was defined as any ferritin determined up to 3 months before or any moment after the last transfusion, while for patients that received all transfusions within 3 months (bulk transfusion), ferritin had to be determined after at least twenty transfusions. RESULTS: Of 471 patients, only 38.6% was adequately screened and hemosiderosis prevalence was 46.7%. Hemosiderosis prevalence was 47% in the chronic transfusion group and 12% in the bulk transfusion group. In patients transfused because of hematological malignancy or cardiothoracic surgery, respectively, 74% and 31% were adequately screened and hemosiderosis prevalence was 53% and 13%, respectively. CONCLUSION: Hemosiderosis screening in our routine practice is suboptimal. Hemosiderosis is not an exclusive complication of multiple transfusions in the hematology ward. We recommend screening for hemosiderosis in all patients receiving multiple transfusions.

Frequency and appearance of hemosiderin depositions after aneurysmal subarachnoid hemorrhage treated by endovascular therapy.

INTRODUCTION: It is still unclear how often subarachnoid hemorrhage (SAH) leads to chronic hemosiderin depositions. In this study, we aimed to determine the frequency of chronic hemosiderin depositions after aneurysmal SAH in patients who did not undergo surgery. Furthermore, we analyzed typical MRI patterns of chronic SAH and sought to obtain information on the temporal course of MRI signal changes. METHODS: We retrospectively analyzed 90 patients who had undergone endovascular treatment for acute aneurysmal SAH. In all patients, initial CT studies and at least one T2*-weighted MRI obtained 6 months or later after SAH were analyzed for the presence and anatomical distribution of SAH or chronic hemosiderin depositions. In total, 185 T2*-weighted MRI studies obtained between 2 days and 148 months after SAH were evaluated (mean follow-up 30.2 months). RESULTS: On MRI studies obtained later than 6 months after SAH, subpial hemosiderin depositions were found in 50 patients (55.5%). Most frequent localizations were the parenchyma adjacent to the frontal and parietal sulci and the insular cisterns. While the appearance of hemosiderin depositions was dynamic within the first 3 months, no changes were found during subsequent follow-up. MR signal changes were not only conclusive with subarachnoid hemosiderin depositions but in many cases also resembled those that have been associated with cortical hemosiderosis. CONCLUSIONS: T2*-weighted MRI is an effective means of diagnosing prior SAH. Our study suggests that chronic hemosiderin depositions can be found in a considerable number of patients after a single event of subarachnoid hemorrhage.

[Evaluation of transfusion hemochromatosis prevalence, SFVTT-01 study: preliminary results of the SFVTT working group]. / Évaluation de la prévalence de l'hémosidérose post-transfusionnelle, étude SFVTT-01: résultats préliminaires du groupe de travail de la SFVTT.

RATIONAL: Although notification of post-transfusion hemosiderosis is mandatory since 1994 among the French hemovigilance network, it is so far largely under reported. PATIENTS AND METHODS: We screened 42,443 patients hospitalized for blood diseases in France in 2009 and 2010 and determined which patients had received more than 20 PRC. Among them, we selected those having at least one measure of serum ferritin, and subsequently those which ferritin was greater than or equal to 1000 ng/mL. RESULTS: Three thousand eight hundred and twelve patients (9%) received more than 20 PRC, 1935 (4.5%) had a ferritin assay, which was increased in 1216 patients (2.9%). Eight hundred and eighty-one patients underwent an hemovigilance report form. Forty-nine percent had low-risk myelodysplasia or acute leukemia, 7% hemoglobinopathies. Hemosiderosis was asymptomatic for 680 patients (77%), serious 188 (88%) and life-threatening for 11 (1%). Two patients died of terminal heart failure. The most severe hemosiderosis (≥ grade 2) were low-risk myelodysplasia and idiopathic aplastic anemia. Ninety-two percent of thalassemia patients and 46% of sickle cell anemia patients received an iron chelator. For low-risk myelodysplastic syndromes and idiopathic aplastic anemia, 228 of the 317 patients whose treatment is known and who could benefit from iron chelation (72%) have not received it. CONCLUSION: These results encourage seeking optimal transmission of information (over 20 CGR) to the clinician, and prolonging hemovigilance action towards a more comprehensive statement of post-transfusion hemochromatosis.

Assessment of iron overload in very young children with limited thalassemia care resources in South China.

Southern China has one of the world's largest population of patients needing transfusions. Transfusion and chelation are not uniformly available and no magnetic resonance imaging (MRI) assessment data exists to date. A total of 153 young ß-thalassemia major (ß-TM) patients were assessed using a validated 1.5T scanner in Hong Kong, People's Republic of China (PRC). Their median age was 13 (range 7 to 30), and most patients were young (22.0% age <10, 73.0% age <15, 88.0% age <18). Erratic health care made estimation of total transfusion and chelation exposure impossible. Despite their early age, 24.0% had severe cardiac hemosiderosis [T2*<10 milliseconds (ms)], at ages as early as 8 years old. Median heart iron was 1.68 mg/g dry weight (range 0.19-7.66) and increased with age (p = 0.017), while liver iron was 22.2 mg/g dry weight (range 3.15 to 39.2). Serum ferritin levels were poor predictors of heart and liver, or pancreatic R* and pituitary R* values. Magnetic resonance imaging scans are needed to screen very young ß-TM patients with immediate risk of premature cardiac death in developing nations and triage them to more intensive treatment. This is particularly important in countries with a large number of patients and limited resources. Our data suggests that in developing countries, there is no lower limit for thalassemia MRI scanning programs.

Low prevalence of cardiac siderosis in heavily iron loaded Egyptian thalassemia major patients.

Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine ß-thalassemia patients receiving chelation therapy (mean age of 20.8 ± 6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean ± standard deviation (range) of cardiac T2* was 28.5 ± 11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7 ± 4.7 % (55 to 78 %), and the liver iron concentration (LIC) was 26.1 ± 13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510 ± 2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 %, the serum ferritin was >2,500 ng/ml. The prevalence of myocardial siderosis (T2* of <20 ms) was 24.7 % (mean age 20.9 ± 7.5 years), with mean T2* of 12.7 ± 4.4 ms, mean LVEF of 68.6 ±5.8 %, mean LIC of 30.9 ± 13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P = 0.65, P = 0.085, P = 0.99, and P = 0.63, respectively). Severe cardiac siderosis (T2* of <10 ms) was present in 7.9 %, with a mean age of 18.4 ± 4.4 years. Although these patients had a mean T2* of 7.8 ± 1.7 ms, the LVEF was 65.1 ± 6.2 %, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 %). LIC and serum ferritin results were 29.8 ± 17.0 mg/g and 7,200 ± 6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P = 0.5), LVEF (P = 0.14), LIC (P = 0.97), or serum ferritin (P = 0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.

Focal hemosiderin deposits and ß-amyloid load in the ADNI cohort.

BACKGROUND: Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid-modifying trials for treatment and prevention of Alzheimer's disease (AD). METHODS: Subjects were cognitively normal (n = 171), early-mild cognitive impairment (MCI) (n = 240), late-MCI (n = 111), and AD (n = 40) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6, and 12 months. ß-amyloid load was assessed with (18)F-florbetapir positron emission tomography. RESULTS: Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (P < .001) and ß-amyloid load (P < .001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation = 0.49; P < .001). CONCLUSIONS: Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with ß-amyloid load.

[GRACILE syndrome--a severe neonatal mitochondrial disorder]. / SGRACILE-oireyhtymä--vastasyntyneen vakava mitokondriotauti.

GRACILE syndrome belongs to the Finnish disease heritage, and is caused by a point mutation in the BCS1L-gene encoding a mitochondrial protein. This leads to dysfunction of the complex III in the respiratory chain. Significant fetal growth disturbance is the primary manifestation. Within the first day the newborn infant develops severe lactic acidosis. Hypoglycemia, elevated serum ferritin and conjugated bilirubin values and aminoaciduria imply mitochondrial liver disease and renal tubulopathy. In Finland, the diagnosis is based on the 232A>G mutation in the BCS1L-gene. No specific treatment is available. GRACILE syndrome leads to early death.

Retrospective epidemiological study of Latin American patients with transfusional hemosiderosis: the first Latin American epidemiological study in iron overload--the RELATH study.

The retrospective epidemiological study of Latin Americans with transfusional hemosiderosis is the first regional patient registry to gather data regarding the burden of transfusional hemosiderosis and patterns of care in these patients. Retrospective and cross-sectional data were collected on patients ≥2 years with selected chronic anemias and minimum 20 transfusions. In the 960 patients analyzed, sickle-cell disease (48·3%) and thalassemias (24·0%) were the most frequent underlying diagnoses. The registry enrolled 355 pediatric patients (187 with sickle-cell disease/94 with thalassemia). Serum ferritin was the most frequent method used to detect iron overload. Complications from transfusional hemosiderosis were reported in ~80% of patients; hepatic (65·3%), endocrine (27·5%), and cardiac (18·2%) being the most frequent. These data indicate that hemoglobinopathies and complications due to transfusional hemosiderosis are a significant clinical problem in the Latin American population with iron overload. Chelation therapy is used insufficiently and has a high rate of discontinuation.

Predicted costs of iron-chelators in myelodysplastic syndromes: a 10-year analysis based on actual prevalence and red cell transfusion rates.

Consideration of iron-chelation (IC) in transfusion-dependent patients is recommended in most clinical-practice guidelines on myelodysplastic syndromes (MDS). The financial impact of IC on health-care systems is predicted through economic modeling, but an analysis based on actual prevalence is lacking. Here, we have investigated the potential drug-costs and need for IC in a cohort of 189 United Kingdom-based MDS patients diagnosed from 2000 to 2010. Patients with low or intermediate-1 IPSS scores were identified as eligible for IC if ≥24 red cell units (RCU) had been transfused over 12 consecutive months or the transfusion-intensity averaged ≥2 RCU per month. Drug-costs were calculated from the time patients qualified for IC until death or last follow-up. In 159 patients with low/intermediate-1 MDS, survival was superior with a low IPSS score (P = 0.014), age <70 years (P = 0.043), transfusion-independence at diagnosis (P = 0.0056) and transfusion-intensity of <2 RCU per month (P = 0.009). Reflecting the time elapsed since diagnosis, longer survival was observed with a cumulative red cell load of ≥75 U (P = 0.046). By logistic-regression analysis, transfusion-intensity independently predicted survival (P = 0.0035) in low and intermediate-1 risk MDS patients. Forty-one patients fulfilled criteria for consideration of IC. Of these, 6 patients died within 1 month; 35 patients survived for a median of 16 months (range 1-61). Had patients commenced IC, the anticipated drug-costs alone would have been ~$526,880-$2,064,800 over 10 years. The lack of association between cumulative transfusion-load and survival calls for a prospective evaluation of the cost-utility of IC in patients surviving long-term, to enable evidence-based recommendations in MDS management.