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Abstract Introduction Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. Methods We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. Results We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. Conclusions Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
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Humanos , Criança , Talassemia , Sobrecarga de Ferro , Terapia por QuelaçãoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. METHODS: We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. RESULTS: We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. CONCLUSIONS: Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
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The iron ion is an essential element for most forms of life, however, it can damage biological systems when found in free form. Chelation therapy is very important, but it is precarious. Caffeic and ferulic acid are antioxidant compounds with many properties described in research such as anti-inflammatory, antiobesogenic, antithrombotic, vasodilator, and anti-tumor. The aim of the study was to evaluate presenting an in silico approach on the toxicity and bioavailability of caffeic and ferulic acid, subsequently, evaluating them in an iron overload model in vivo and providing a pharmacophoric model through molecular docking. The predictive in silico test did not show relevant toxicity of the compounds, therefore, the in vivo test was performed. The rats received dextran iron and the test groups received caffeic and ferulic acid orally for six weeks. Biochemical, hematological parameters, and tissue oxidative stress marker were analyzed. The experimental model showed increased serum iron levels and changes in several serum parameters such as glucose (215.8 ± 20.3 mg/dL), ALT (512.2 ± 128.7 U/L), creatine kinase (186.8 ± 30.1 U/L), and creatine kinase isoform MB (373.3 ± 69.7 U/L). Caffeic acid and, to a lessed degree, ferullic acid, attenuated the effects of iron overload on the rat serum biochemical parameters. Docking showed a pharmacophoric model where carbonic anhydrase interacted with the test molecules and caffeic acid showed less energy expenditure in this interaction. The results illustrate a new therapeutic action of phenolic compounds on iron overload. The possible interference of carbonic anhydrase in iron metabolism needs to be elucidated.
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Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-ß (Aß) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-ß protein precursor (AßPP) and Aß42 peptide, affecting Aß aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.
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Doença de Alzheimer/tratamento farmacológico , Quelantes/química , Quelantes/uso terapêutico , Polifenóis/química , Polifenóis/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Quelantes/metabolismo , Quelantes/farmacologia , Cobre/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Polifenóis/metabolismo , Polifenóis/farmacologia , Zinco/metabolismoRESUMO
OBJECTIVES: Deferasirox is an oral iron chelator with established dose-dependent efficacy for the treatment of iron overload secondary to transfusion. However, there is few data reporting the use of Desferasirox in adult patients with sickle cell disease (SCD) and transfusional iron overload. METHODS: We conducted a prospective, single center, nonrandomized study from January 2014 to March 2015 in Campinas, Brazil. Seven patients (five women, median age 50 y.o.) who were followed up on regular transfusion program were treated with a single daily dose of deferasirox (median dose 20â mg/kg). They were monitored for clinical symptoms, renal function and hepatotoxicity. RESULTS: One patient discontinued the study due to lack of compliance. Two patients reported mild to moderate adverse events (gastrointestinal disturbances). Five patients had the drug discontinued due to worsening of renal function. One patient had the drug discontinued due to severe hepatotoxicity that evolved to death; no patient finished the study. Discussion and conclusions: Deferasirox does not appear to be well tolerated in SCD patients older than 40 years, in which complications of the underlying disease are already fully installed. The choice of the ideal iron chelator for this population should include an evaluation of comorbidities and organic dysfunctions, as well as the need to find pharmacogenetic safety markers in this group of patients.
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Anemia Falciforme/tratamento farmacológico , Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Adulto , Idoso , Anemia Falciforme/patologia , Deferasirox/farmacologia , Feminino , Humanos , Quelantes de Ferro/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
INTRODUCTION AND AIM: Wilson's disease (WD) is an uncommon cause of acute liver failure (ALF). Our aim was to describe clinical features, diagnostic findings, treatments, and outcomes of patients with ALF due to WD. MATERIAL AND METHODS: Retrospective medical record reviews of all patients with ALF due to WD in eight years in Uruguay. RESULTS: WD was the cause of six (15%) of thirty-nine ALF cases. All patients were females, with a mean age of 18 years. Four patients presented with hyperacute liver failure and two with acute failure. Jaundice was the main complaint of all patients. Mean total bilirubin (TB), alkaline phosphatase (AP), AST, and ALT were 27.5 mg/dL, 45.5 lU/l, 156 IU/L, and 51 IU/L, respectively. Ceruloplasmin levels were low in four patients, urinary cooper was high in four, and two had Kayser-Fleischer rings. All patients had Coombs-negative hemolytic anemia, acute kidney injury, histochemical identifiable copper, and advanced fibrosis on liver histology. The average MELD score was 36. All patients were treated with d-penicillamine and listed for urgent liver transplantation (LT). Prometheus® was performed in one patient. Three patients died: two without LT and one after LT. Three patients survived: one without LT (New Wilson Index<11) and two with LT. The referral time to the program and the total time (referral plus waiting list time) were longer for non-survivors than for survivors (14 vs. 3 days and 23 vs. 8 respectively). CONCLUSION: All cases had typical clinical, analytical and histopathology characteristics. Early referral was determinant of prognosis.
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Degeneração Hepatolenticular/induzido quimicamente , Falência Hepática Aguda/etiologia , Transplante de Fígado , Listas de Espera/mortalidade , Adolescente , Criança , Feminino , Seguimentos , Degeneração Hepatolenticular/mortalidade , Humanos , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/cirurgia , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Uruguai/epidemiologia , Adulto JovemRESUMO
A sobrecarga de ferro é uma condição prejudicial para os pacientes, que apresentam uma diminuição significativa na qualidade de vida. Os fármacos quelantes são moléculas que têm capacidade de uso clínico para atuar como atenuadores da sobrecarga de metais. Neste trabalho apresentamos uma análise de sideróforos do tipo hidroxamato e quinona, com o objetivo de ampliar a gama de terapia de sobrecarga de ferro. Para cada composto foi realizado um ensaio competitivo com a sonda calce- ína para verificar a capacidade de ligação do ferro, e um ensaio antioxidante baseado na supressão da oxidação dependente de ferro da dihidrorrodamina (DHR) sob ascorbato. Foi observado que o hidroxamato cíclico piridoxatina apresentou capacidade de sequestrar ferro de substratos de alta afinidade, tanto em meio tamponado quanto em meio intracelular. Em ambas as situações também se mostrou um antioxidante eficiente. Entretanto, parece ser o mais tóxico do grupo dos hidroxamatos (que ainda continha o hidroxamato linear desferricoprogênio e o aromático desferriastercromo). Outros compostos naturais também foram estudados como possíveis candidatos a fármacos para sobrecarga de ferro. Complexos de ferro foram caracterizados por espectrofotometria para avaliar a estequiometria possível, considerando os sítios de ligação para cada composto. Ensaios de fluorescência revelaram que entre os quatro compostos em estudo (ácido clorogênico, lapachol, hemateína e hematoxilina), o complexo entre ferro e hemateína apresenta maior estabilidade relativa do que outros
Iron overload is a harmful condition for patients, who have a significant decrease in life quality. Chelating drugs are molecules that have the capacity for clinical use to act as attenuators of metal overload. In this work we present an analysis of hydroxamate and quinone-type siderophores, intending to broaden the range of iron overload therapy. For each compound it was conducted a competitive assay with the fluorescent probe calcein to verify the iron binding ability, and an antioxidant assay based on suppression of the iron-dependent oxidation of dihydrorhodamine (DHR) under ascorbate. It was observed that cyclic hydroxamate pyridoxatin displayed good ability to scavenge iron from high affinity substrates both in buffer and in intracellular medium. It was also an efficient antioxidant in both setups. However, pyridoxatin seems to be the most toxic from the hydroxamate group (composed also by the linear desferricoprogen and the aromatic desferriasterchrome). Other natural compounds have also been studied as possible candidates for iron-overload drug therapy. Iron complexes were characterized by spectrophotometry to assess the possible stoichiometry considering the binding sites for each compound. Fluorescence assays revealed that among the four compounds in study (chlorogenic acid, lapachol, hematein and hematoxylin), the complex between iron and hematein has higher relative stability than others
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Sideróforos/análise , Sobrecarga de Ferro/terapia , Fluorescência , Espectrofotometria/instrumentação , Terapia por Quelação , Desferroxamina/classificação , Ferro/efeitos adversos , AntioxidantesRESUMO
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the bloodâ»brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer's disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.
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Leishmaniasis is an infection caused by protozoa of the genus Leishmania and transmitted by sandflies. Current treatments are expensive and time-consuming, involving Sb(V)-based compounds, lipossomal amphotericin B and miltefosine. Recent studies suggest that inhibition of trypanothione reductase (TR) could be a specific target in the development of new drugs because it is essential and exclusive to trypanosomatids. This work presents the synthesis and characterization of new iminodibenzyl derivatives (dado) with ethylenediamine (ea), ethanolamine (en) and diethylenetriamine (dien) and their copper(II) complexes. Computational methods indicated that the complexes were highly lipophilic. Pro-oxidant activity assays by oxidation of the dihydrorhodamine (DHR) fluorimetric probe showed that [Cu(dado-ea)]2+ has the highest rate of oxidation, independent of H2O2 concentration. The toxicity to L. amazonensis promastigotes and RAW 264,7 macrophages was assessed, showing that dado-en was the most active new compound. Complexation to copper did not have an appreciable effect on the toxicity of the compounds.
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Benzilaminas/química , Leishmania/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/farmacologia , Antiprotozoários/toxicidade , Benzilaminas/farmacologia , Benzilaminas/toxicidade , Simulação por Computador , Cobre/química , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania/enzimologia , Ligantes , Macrófagos/efeitos dos fármacos , NADH NADPH Oxirredutases/antagonistas & inibidores , OxirreduçãoRESUMO
This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.
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Benzoatos/uso terapêutico , Hemocromatose/complicações , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Triazóis/uso terapêutico , Adulto , Idoso , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Biomarcadores , Deferasirox , Índices de Eritrócitos , Feminino , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/diagnóstico , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Fatores de Tempo , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversosRESUMO
Las manifestaciones clínicas de la intoxicación por plomo son variadas e inespecíficas y continúan siendo un reto diagnóstico, en especial cuando son producto de presentaciones tan infrecuentes como las secundarias a fragmentos por proyectiles de arma de fuego intraarticulares. En suamplio espectro de manifestaciones se han descrito cambios que van desde el déficit de atenciónhasta estados más avanzados como las polineuropatías. El diagnóstico se basa principalmente enla medición del metal en distintos elementos del paciente y el tratamiento en medidas generales desoporte y terapia de quelación. Describimos el caso de un hombre con el antecedente de una herida por arma de fuego en caderaderecha, con un cuadro clínico progresivo de dolor abdominal, anemia acompañada de punteadobasófilo y manifestaciones neurológicas. Con un estudio por electromiografía que reporto unapolineuropatía axonal desmielinizante motora y sensitiva. Sus niveles séricos de plomo fueron 113µg/dL (Rango normal hasta 10 µg/dL) y después de un esquema de tratamiento con edetato calciodisódico (EDTA) más D penicilamina los síntomas neurológicos mejoraron asociado a un controlsérico de plomo de 49.1 µg/dL. Conclusión: la intoxicación por plomo es causa de polineuropatía motora subaguda especialmente en pacientes con exposición prolongada y niveles séricos altos de plomo. (Acta Med Colomb2014; 39: 185-190).
The clinical manifestations of lead poisoning are varied and nonspecific and remain a diagnostic challenge, especially when they are product of infrequent presentations such as the secondary to intraarticular gun fire fragments. In its broad spectrum of manifestations, changes ranging from attention deficit disorder to more advanced states like polyneuropathies have been described. The diagnosis is based mainly on the measurement of metal in various elements of the patient, and treatment in general supportive measures and chelation therapy. The case of a man with a history of gunshot wound in right hip with a progressive clinical picture of abdominal pain, anemia accompanied by basophilic stippling and neurological manifestations is described. The electromyography reported a motor and sensory axonal demyelinating polyneuropathy. Serum levels of lead were 113 µg/dL (normal range up 10 µg/dL) and after a treatment regimen with calcium disodium edetate (EDTA ) plus D penicillamine, the neurological symptoms improved, associated with a serum lead control of 49.1 µg/dL. Conclusion: lead poisoning causes subacute motor polyneuropathy especially in patients with prolonged exposure and high serum lead levels. (Acta Med Colomb 2014; 39: 185-190).
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Humanos , Masculino , Adulto , Polineuropatias , Transtorno do Deficit de Atenção com Hiperatividade , Terapia por Quelação , Intoxicação por ChumboRESUMO
A intoxicação por chumbo, também conhecida como saturnismo, que ocorre em razão do projétil retido em ferimento por arma de fogo, é uma complicação já conhecida e descrita na literatura. O risco dessa intoxicação endógena por chumbo está associado ao contato do projétil com o líquido sinovial ou líquido cefalorraquidiano. O tratamento é feito com terapia de quelação, sendo definitivo com a retirada cirúrgica do projétil. Relatamos aqui um caso clínico de um paciente que desenvolveu intoxicação por chumbo em razão de projétil retido em contato com líquido sinovial. Paciente do gênero masculino, 24 anos, internado para investigação de quadro de dor abdominal associada a náuseas, vômitos e febre há 7 dias. Diagnosticado saturnismo, que foi confirmado por meio de exames laboratoriais e de imagem. Procedeu-se, então, à retirada dos fragmentos, além do segmento clínico de suporte. Apresentou evolução favorável após tratamento
Lead poisoning, also known as saturnism, caused by a retained bullet, is a well-known complication, and has also been described in literature. This endogenous intoxication is associated with the contact of the projectile with synovial liquid or cerebrospinalfluid. Chelation therapy is advised as a course of treatment in addition to the surgical removal of the projectile, both all- together sums up to a definitive optimum outcome. We discuss here a clinical case of a patient who developed lead poisoning due to a retained projectile within synovial liquid. Male patient,24 years old, admitted with the symptoms of abdominal pain, nausea, vomiting and fever for 7 days for investigation. He was diagnosed with saturnism, that was confirmed by laboratorial and imaging exams. The following procedure was the removal of fragments in addition to the continuous clinical follow-up. The patient presented with positive response to treatment.
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Humanos , Masculino , Adulto , Terapia por Quelação , Intoxicação por Chumbo/diagnóstico , Ferimentos por Arma de FogoRESUMO
Relatar um caso de sobrecarga de ferro secundária à xerocitose, uma doença rara, em uma adolescente, diagnosticada por meio de ressonância magnética em T2*. Relatamos o caso de uma paciente sintomática com xerocitose, nível de ferritina de 350ng/mL e sobrecarga de ferro cardíaca significativa. Ela foi diagnosticada por ressonância magnética em T2* e recebeu terapia de quelação. Análise por ectacitometria confirmou o diagnóstico de xerocitose hereditária. Na sequência, a ressonância magnética em T2* demonstrou resolução completa da sobrecarga de ferro em vários órgãos e novo ecocardiograma revelou resolução completa das alterações cardíacas anteriores. A paciente permanece em terapia de quelação. Xerocitose é uma desordem genética autossômica dominante rara, caracterizada por estomatocitose desidratada. O paciente pode apresentar fadiga intensa e sobrecarga de ferro. Sugerimos o uso regular de ressonância magnética em T2* para o diagnóstico e controle da resposta à quelação de ferro em xerocitose e acreditamos que o exame pode ser útil também em outras anemias hemolíticas que necessitam de transfusões.
To report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions.
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Adolescente , Feminino , Humanos , Anemia Hemolítica Congênita/diagnóstico , Hidropisia Fetal/diagnóstico , Sobrecarga de Ferro/diagnóstico , Anemia Hemolítica Congênita/complicações , Anemia Hemolítica Congênita/tratamento farmacológico , Terapia por Quelação , Desferroxamina/uso terapêutico , Hidropisia Fetal/tratamento farmacológico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Imageamento por Ressonância Magnética , Sideróforos/uso terapêuticoRESUMO
In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.
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In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions.
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Humanos , Talassemia beta , Transfusão de Sangue , Terapia por Quelação , Protocolos Clínicos , Quelantes de Ferro , Distúrbios do Metabolismo do Ferro , Imageamento por Ressonância MagnéticaRESUMO
En pediatría, las anemias crónicas hereditarias, como la anemia drepanocítica y los síndromes talasémicos, y en menor grado la anemia aplásica, la aplasia pura de serie roja y los síndromes mielodisplásicos y diseritropoyéticos, cursan con requerimientos transfusionales elevados y consecuentemente, con el peligro potencial de desarrollar sobrecarga de hierro. El hierro de la sangre transfundida es procesado inicialmente por los macrófagos, que digieren los eritrocitos senescentes y retornan el hierro a la transferrina del plasma. Esta carga de hierro transfusional puede saturar la transferrina y llevar a la formación de "hierro no unido a transferrina" en el plasma; éste es tomado por las células del parénquima hepático y depositado como ferritina y hemosiderina. El hierro puede ser reducido de férrico (Fe+3) a ferroso (Fe2+), y en esta forma catalizar la formación de radicales hidroxilo (altamente reactivos), que pueden causar daño oxidativo y afectar lípidos, proteínas y moléculas de ADN y llevar a la muerte celular o fibrosis. Diagnóstico. La medición del índice de saturación de la transferrina y las mediciones seriadas de ferritina sérica son métodos confiables y sencillos para evaluar la tendencia de la sobrecarga de hierro y la eficacia de la terapia de quelación. Un método no invasivo para esta evaluación es el Dispositivo de Interferencia Cuántica de Superconducción (SQUID). Este dispositivo no está disponible en nuestro país, y sólo cuentan con él cinco centros de todo el mundo. La resonancia magnética puede usarse para valorar la carga de hierro en el hígado, corazón y páncreas, y puede sustituir procedimientos invasivos como la biopsia cardiaca y hepática. Tratamiento. En la actualidad, la terapia de quelación de hierro se realiza con deferoxamina, deferiprona o deferasirox. Cuando la deferoxamina se administra por vía subcutánea se recomiendan 20-40 mg/kg/día en infusión continua de 10-12 horas, de preferencia nocturna, con bomba de infusión, durante 5 días a la semana, hasta lograr niveles de ferritina sérica ≤500 µg/L. Igualmente, para la vía intravenosa se utilizan de 20-40 mg/ kg/día, administrados durante 12-14 horas en infusión continua. No se recomienda la administración intramuscular por su baja acción quelante. La dosis usual de deferiprona es de 75 mg/kg/día. El deferasirox en dosis de 20-40 mg/kg puede producir una tasa de excreción de hierro de 0.3 mg/kg/día, que permite mantener el equilibrio férrico en pacientes con transfusiones; posee una potencia comparable a la deferoxamina. Aunque no existe evidencia categórica de que todos los pacientes anémicos politransfundidos desarrollarán sobrecarga de hierro, se recomienda realizar programas integrales de vigilancia para establecer un tratamiento temprano cuando se estime necesario.
In pediatrics, chronic genetic anemias such as sickle cell disease, thalassemic syndromes and, to a lesser degree, aplastic anemia, pure red cell aplasia, myelodysplastic syndromes and dyserythropoietic syndromes, are characterized by high transfusional requirements and, consequently, a potential risk to develop iron overload. Iron transfusional loading is initially processed by macrophages after the breakdown of senescent erythrocytes and the iron released to plasma transferrin. This transfusional iron load can saturate the transferrin and result in the emergency of toxic "plasma nontransferrin bound iron" that is taken up by the parenchymal hepatic cells and stored as ferritin and hemosiderin. The iron can be reduced from ferric (Fe3+) to ferrous (Fe2+) ions and catalyze the formation of free hydroxyl radicals (highly reactive) that may produce oxidative damage that may also affect lipids, proteins and DNA molecules and finally result in cellular death and/or fibrosis. Transferrin saturation index and serum ferritin serial measurements have shown to be simple and reliable techniques for efficiently evaluating iron overload and chelation therapy. The SQUID (Superconducting Quantum Interference Device) constitutes a noninvasive method for evaluating iron overload; however, this device is not available in México and only five medical centers worldwide have this equipment. Magnetic resonance imaging can be used to evaluate iron load in liver, heart, and pancreas and may replace invasive procedures such as heart or hepatic biopsies. Deferoxamine, deferiprone and deferasirox are currently used in the treatment of transfusional iron overload. Deferoxamine is infused SC (20-40 mg/kg/day) in a continuous infusion connected to a portable pump for 10-12 h, 5x/week, mainly at night, and IV 20-40 mg/kg/day in a continuous infusion for 1214 h. Intramuscular administration is not recommended due to the low chelation action. A daily dose of 75 mg/ kg of deferiprone is recommended. Deferasirox is safe, orally administered and is as effective as deferoxamine. The effective oral dose is 20-40 mg/kg. Iron balance is obtained with 0.3 mg/kg/day urinary iron excretion in transfusion-dependent patients. Even though there is no conclusive evidence that all anemic polytransfused patients will develop iron overload, it is recommended to carry out integral surveillance programs to establish early iron chelation therapies.
RESUMO
CONTEXT: Lead poisoning due to retained gunshot bullets is a well-known clinical problem that is fairly frequently described in the literature. The risk factors for this occurrence relate mainly to whether the lead bullet is in contact with the joint fluid or cerebrospinal fluid (CSF). The treatment for these cases entails chelation therapy while symptoms are shown and definitive surgical removal of the bullet as a potential source of lead. The aim of this paper is to describe a clinical case of lead poisoning due to a retained gunshot bullet in contact with CSF. CASE REPORT: A 42-year-old male was hit by gunshot bullets during a holdup, and one of them was retained in the spinal cord. Six years later, he developed intense low back pain and underwent laminectomy. Nine years later, he then underwent arthrodesis on L5-S1, but he developed intense abdominal pain after the surgical procedure. For five years, he was treated with calcium versenate in five-day cycles, with a good response. The chelation therapy cycles showed great efficacy during symptomatic periods, thus reducing the symptoms and signs of poisoning and promoting great amounts of lead excretion, thereby reducing the total lead burden responsible for the symptoms. Fortunately, over the last four years, the symptoms have improved and the urine levels of aminolevulinic acid (ALA) have declined, to reach complete normalization. This shows that a healing process is probably taking place on the spinal wound, thereby isolating the bullet fragments from CSF contact.
CONTEXTO: A intoxicação por chumbo devida a projétil retido em ferimento por arma de fogo é uma complicação já conhecida e descrita na literatura. O risco de intoxicação endógena por chumbo está associado ao contato do projétil com o líquido sinovial ou líquido o cefalorraquidiano. O tratamento requer terapia de quelação e retirada cirúrgica do projétil como tratamento definitivo. Este artigo descreve caso clínico de paciente que desenvolveu intoxicação por chumbo devida a projétil retido em contato com líquido cefalorraquidiano. RELATO DE CASO: Paciente masculino, 42 anos, foi baleado durante assalto e teve projéteis que se alojaram no abdômen, perna direita e coluna lombo-sacra. Seis anos depois, desenvolveu intensa lombociatalgia e foi submetido a laminectomia. Nove anos após o acidente, foi submetido a artrodese de L5-S1, quando foi tentada a retirada do projétil, sem sucesso, desenvolvendo no pós-operatório intensa dor abdominal. Foi então feito diagnóstico de intoxicação por chumbo, que foi tratada com gluconato de cálcio, com boa resposta. Durante os cinco anos seguintes, fez ciclos de quelação com ácido etilenodiaminotetracético (EDTA) cálcico, com boa evolução. Os ciclos de quelação mostraram grande eficácia na redução dos sinais e sintomas da intoxicação, promovendo um grande aumento da excreção de chumbo e reduzindo a carga corpórea total de chumbo responsável pelos sintomas. Nos últimos quatro anos, apresentou melhora dos sintomas de intoxicação, com diminuição dos níveis de ALA urinário até a normalização, mostrando que provavelmente houve um processo de cicatrização da lesão, isolando os fragmentos de chumbo do contato com o líquor.