Use of deferasirox (Exjade) for iron overload in peritoneal dialysis patients.

A 54 year old male with b-Thalassemia major developed ESRD and was managed with continuous ambulatory peritoneal dialysis. Although not able to be transfused due to high titre red cell antibodies he did require management of iron overload. Deferasirox (Exjade) was administered orally. There was concern that excretion of iron via the peritoneal dialysate may raise the risk of iron-dependent infections (Yersinia and Rhizopus).Whilst receiving Exjade 1000mg /day, a total collection of 12.7L of peritoneal dialysate was collected over a 24 hour period by the patient. The dialysate total iron levels were measured by ICP-MS at 0.46mmol/L which equates to 0.33mg of Fe in total. Over a 6 month period his serum ferritin fell from 3869µg/l to 1545µg/l. There were no episodes of peritonitis. Since only 7-8% of the deferasirox and iron complex is excreted through the urine, the amount of Fe seen in the patient's dialysate might be expected to be up to 1.5-1.6mg. Yet, the results of the Fe levels in the patient's PD fluid was a meagre 0.33mg, about five times lower than expected.Whilst only moderately effective at a dosage of 1000mg/day, deferasirox may be a safe agent for iron removal in iron overloaded peritoneal dialysis patients, as relatively low dialysate iron levels reduces the risk of Yersinia and Rhizopus infection.

Back to the basics.

The history and physical examination skills are being replaced by the tools of technology in establishing the actual cause of illness. We present a patient where the history and physical examination were essential in establishing the diagnosis. A 28-year-old female presented to the Emergency Department (ED) with an acute episode of epigastric pain radiating to the back associated with vomiting. Laboratory examinations revealed pancreatitis, imaging showed gallstones and the patient was admitted with the diagnosis of gallstone pancreatitis. A more detailed history and physical examination, however, was notable for a family history of "Mediterranean blood" and abdominal examination demonstrated splenomegaly and laboratory examination showed a microcytic anemia. The recognition of the family history, splenomegaly and microcytic anemia led to the diagnosis of thalassemia as the cause of the gallstone pancreatitis. Clearly, the history was essential in establishing the underlying cause of the problem.

Relationship between labile plasma iron, liver iron concentration and cardiac response in a deferasirox monotherapy trial.

The US04 trial was a multicenter, open-label, single arm trial of deferasirox monotherapy (30-40 mg/kg/day) for 18 months. Cardiac iron response was bimodal with improvements observed in patients with mild to moderate initial somatic iron stores; relationship of cardiac response to labile plasma iron is now presented. Labile plasma iron was measured at baseline, six months, and 12 months. In patients having a favorable cardiac response at 18 months, initial labile plasma iron was elevated in only 31% of patients at baseline and no patient at six or 12 months. Cardiac non-responders had elevated labile plasma iron in 50% of patients at baseline, 50% patients at six months, and 38% of patients at 12 months. Risk of abnormal labile plasma iron and cardiac response increased with initial liver iron concentration. Persistently increased labile plasma iron predicts cardiac non-response to deferasirox but labile plasma iron suppression does not guarantee favorable cardiac outcome. Study registered at www.clinicaltrials.gov (NCT00447694).

Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response.

Background: Deferasirox is the first line of treatment in iron overload. In spite of the many studies concerning the efficacy of deferasirox, some patients remain unresponsive to deferasirox.Methods: One hundred and sixty patients were enrolled in stratified-randomized controlled study. Patients were randomly divided into four regimens, group I (n = 40) received 30 mg/kg deferasirox, group II (n = 40) received 20 mg omeprazole and 30 mg/kg deferasirox, group III (n = 40) received 400 mg vitamin E and 30 mg/kg deferasirox and group IV (n = 40) received 420 mg silymarin and 30 mg/kg deferasirox. Blood specimens were collected from each patient for up to 24 h, and then plasma deferasirox concentrations were inspected.Results: Silymarin, Vitamin E, and omeprazole significantly increased the peak plasma concentration of deferasirox (P < 0.001) by 27.9, 14.9 and 2.4 fold, respectively, as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57, and 4.98-fold, respectively, following administration of omeprazole, vitamin E, and silymarin compared to deferasirox alone.Conclusion: Silymarin, vitamin E, and omeprazole represent promising adjuvant therapy to improve the chelation efficacy of deferasirox that might also be further applied to enhance the pharmacokinetics of deferasirox to overcome the lack of response.

Bone microarchitecture deteriorations and a fragility fracture in a patient with beta and alpha heterozygous thalassemia: a case report.

To date there are few studies that have investigated bone mineral density (BMD) and markers of bone metabolism in patients with thalassemia minor form. None of the previous trials presented bone structure analysis in the patient populations. We present the case of a 24-year-old Turkish woman with heterozygous beta and alpha thalassemia who sustained a low-trauma fracture of the inferior pubic ramus. Despite normal markers of bone metabolism, the dual X­ray absorptiometry (DXA) showed decreased areal bone mineral density. Furthermore, severely reduced bone structure parameters and reduced volumetric bone mineral density was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Due to these diagnostic findings at time of peak bone mass, an osteoanabolic therapy with teriparatide for 24 months was initiated. The findings concerning BMD and bone structure in this patient can be seen as caused by the beta and alpha thalassemia.

[Chronic pulmonary thromboembolism revealing beta-thalassemia intermedia after splenectomy]. / Coeur pulmonaire chronique postembolique révélant une bêtathalassémie intermédiaire après splénectomie.

INTRODUCTION: The clinical expression of beta-thalassemia intermedia is variable and complications are more frequent than in the minor form. Thromboembolism risk increase after splenectomy. Few cases of the type of complications are reported. CASE RECORD: A man was admitted for beta-thalassemia intermedia with moderate chronic hemolysis anemia, complicated by chronic pulmonary thromboembolism and liver iron overload. Post-traumatic splenectomy probably increase the risk of this two complications. The patient's respiratory status improved following bosentan therapy without worsening his hepatopathy. CONCLUSION: The present study also notes that thromboembolism complications can be an indicator of beta thalassemia and interrogate about the risk and the benefit of splenectomy in the treatment of beta-thalassemia intermedia.

Retinal abnormalities in ß-thalassemia major.

Patients with beta (ß)-thalassemia (ß-TM: ß-thalassemia major, ß-TI: ß-thalassemia intermedia) have a variety of complications that may affect all organs, including the eye. Ocular abnormalities include retinal pigment epithelial degeneration, angioid streaks, venous tortuosity, night blindness, visual field defects, decreased visual acuity, color vision abnormalities, and acute visual loss. Patients with ß-thalassemia major are transfusion dependent and require iron chelation therapy to survive. Retinal degeneration may result from either retinal iron accumulation from transfusion-induced iron overload or retinal toxicity induced by iron chelation therapy. Some who were never treated with iron chelation therapy exhibited retinopathy, and others receiving iron chelation therapy had chelator-induced retinopathy. We will focus on retinal abnormalities present in individuals with ß-thalassemia major viewed in light of new findings on the mechanisms and manifestations of retinal iron toxicity.

Episodic spastic paraparesis successfully treated with unaided blood transfusions: a case report.

BACKGROUND: Extramedullary haemopoiesis is a common compensatory phenomenon in most haemolytic anaemias. However, spinal cord compression due to extramedullary spinal epidural haemopoiesis is an extremely rare complication of thalassemia. In such situation patients present with paraplegia with a sensory level. Usual treatment options are surgery and/or radiotherapy. CASE PRESENTATION: Here we report a 27 year old Sri Lankan Muslim male with haemoglobin E-Beta thalassaemia presented with episodic spastic paraparesis when he was anaemic which was dramatically responded to blood transfusion therapy. CONCLUSION: Most of the reported cases with paraplegia have been treated with surgery with or without radiation therapy or radiation therapy alone. Our patient makes dramatic recovery after blood transfusion in each presentation.

Discriminant indexes to simplify the differential diagnosis between iron deficiency anemia and thalassemia minor in individuals with microcytic anemia

SUMMARY INTRODUCTION: Microcytic anemias are very common in clinical practice, with iron deficiency anemia (IDA) and thalassemia minor (TT) being the most prevalent. Diagnostic confirmation of these clinical entities requires tests involving iron metabolism profile, hemoglobin electrophoresis, and molecular analysis. In this context, several discriminant indices have been proposed to simplify the differential diagnosis between IDA and TM. OBJECTIVE: The aim of this paper was to demonstrate the clinical relevance of the use of discriminant indices in individuals with microcytic anemia to simplify the differential diagnosis between iron deficiency anemia and minor thalassemia. METHODS: A bibliographic and cross-sectional search was performed in the PubMed, SciELO and LILACS databases, using the following descriptors: iron deficiency anemia, thalassemia minor, and differential diagnosis. RESULTS: More than 40 mathematical indices based on erythrocyte parameters have been proposed in the hematological literature in individuals with microcytosis. Green & King indexes (IGK), Ehsani index, and erythrocyte count (RBC) had excellent performances, especially when their efficacy was observed in adults and children. CONCLUSIONS: Confirmatory tests for differential diagnosis between IDA and TM require time-consuming and costly methods. Despite the excellent performances of IGK, Ehsani index, and RBC, none of them presented sufficient sensitivity and specificity to establish a diagnosis. However, they can provide a powerful additional tool for diagnostic simplification between IDA and TM.

RESUMO INTRODUÇÃO: Anemias microcíticas são muito comuns na prática clínica, sendo a anemia ferropriva (AF) e a talassemia menor (TM) as mais prevalentes. A confirmação diagnóstica dessas entidades clínicas requer testes que envolvem o perfil do metabolismo do ferro, eletroforese de hemoglobinas e análises moleculares. Nesse contexto, vários índices discriminantes têm sido propostos para simplificação do diagnóstico diferencial entre AF e TM. OBJETIVO: O objetivo deste artigo foi demonstrar a relevância clínica da utilização de índices discriminantes em indivíduos com anemia microcítica, para simplificação do diagnóstico diferencial entre anemia ferropriva e talassemia menor. MÉTODOS: Foi realizada uma pesquisa bibliográfica e transversal nas bases de dados PubMed, SciELO e Lilacs, utilizando-se os seguintes descritores: anemia ferropriva, talassemia menor e diagnóstico diferencial. RESULTADOS: Mais de 40 índices matemáticos baseados em parâmetros eritrocitários foram propostos na literatura hematológica em indivíduos com microcitose. Os índices de Green & King (IGK), o índice de Ehsani e a contagem de eritrócitos (RBC) obtiveram excelentes desempenhos, especialmente quando sua eficácia foi observada em adultos e crianças. CONCLUSÕES: Testes confirmatórios para o diagnóstico diferencial entre AF e TM demandam métodos que consomem bastante tempo e alto custo. Apesar dos excelentes desempenhos do IGK, do índice de Ehsani e do RBC, nenhum deles possui sensibilidade e especificidade suficientes para firmar diagnóstico. No entanto, podem fornecer uma poderosa ferramenta adicional para simplificação diagnóstica entre AF e TM.

Deferiprone or deferoxamine vs. combination therapy in patients with beta-thalassemia major: a case study in Taiwan.

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with beta-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years (p = 0.04), 22 patients receiving L1 for 1-2 years (p < 0.01) and 31 receiving the combined therapy (p = 0.01), yet significantly higher in those receiving DFO only (p < 0.01). One patient showed transient neutropenia; arthropathy in one patient and gastrointestinal upset in two were noted, with no significant change in alanine aminotransferase (ALT) level. Of 17 patients who were submitted to a liver biopsy, 15 showed no significant change in hepatic fibrosis scores after therapy with L1. None of the 88 patients, including 31 who received the combined therapy, have abandoned oral L1 treatment due to adverse effects. Results of this study proved that L1 or combined therapy with L1 and DFO is effective in reducing SP; incidence of adverse events was low in patients with TM.

Intensification of chelating-therapy in patients with thalassemia major.

With the introduction of "hypertransfusion" regimens the extent of disease- and therapy-related hemosiderosis has become the survival limiting factor for patients with beta-thalassemia major as iron transferred with transfusions cannot be excreted by physiological means. Subsequent introduction of deferoxamine therapy for iron elimination and prophylaxis of hemosiderosis has improved prognosis and life quality of these patients considerably. We report our experience with seven adolescent patients with beta-thalassemia and ineffective subcutaneous therapy and severe hemosiderosis-related organ complications. For that reason they received i. v. intensified chelate therapy. The patients were given 70 to 120 mg/kg DFO 7 days a week continuously via a Port-a-cath or Hickman central venous line. Under high-dose i. v. DFO therapy, serum ferritin levels significantly decreased in all patients. Target serum ferritin levels of 3 000 ng/ml were reached after 12 to 20 months of treatment. In 3 of the 5 patients that were treated for longer than 43 months serum ferritin levels even dropped below 2 000 ng/ml. Serum ferritin levels also correlated well with SQUID examinations. Therefore, monitoring of serum ferritin may be useful to monitor patient's compliance and control intensified DFO therapy. Continuous administration of the intensified DFO therapy induced normalization of liver function and left ventricular cardiac function in all patients who are still alive. Two patients died due to cardiac decompensation. In five patients 19 episodes of central catheter-related infections were observed (1.5 infections per 1 000 catheter days). No DFO-associated allergic reactions nor irreversible organ dysfunction were observed. Our results indicate that intensified i. v. DFO therapy is an effective and safe method for treatment of severe organ dysfunction in patients with thalassemia major. The most severe problems are catheter-related infections and inconsistent long-term compliance.

Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty.

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.

Endogenous endophthalmitis and necrotising pneumonia caused by Klebsiella pneumoniae in a child with beta-thalassaemia major.

A case beta-thalassaemia major complicated with Klebsiella pneumoniae endogenous endophthalmitis is presented to increase physician awareness of the association of the two clinical conditions. Severe morbidity including subretinal abscess and retinal detachment may develop despite aggressive intravenous and intravitreal ceftriaxone therapy, along with vitrectomy and external drainage.

Talassemia: características clínicas e radiográficas de interesse odontológico / Thalassemia: essential radiographic and clinical features of interest to dentistry

A talassemia é um tipo de anemia hereditária que afeta predominantemente indivíduos nascidos ou descendentes de países banhados pelo Mar Mediterrâneo, como Itália e Grécia. Também conhecida como anemia de Cooley e anemia mediterrânea, a doença provoca alterações na formação da hemoglobina e malformações do crânio, ossos longos, maxila e mandíbula. Apresenta dois quadros clínicos distintos: um grave, chamado de talassemia "maior", e outro leve, denominado talassemia "menor". O exame hematológico diagnostica as duas formas da doença. Suas manifestações clínicas e radiográficas incluem hepatoesplenomegalia, linfadenopatia, aumento da mandíbula, aumento dos espaços medulares, trabéculas ósseas espessas e em menor quantidade, lembrando "teia de aranha", deslocamento do canal mandibular com perda de detalhe de suas corticais superior e inferior e aspecto radiográfico de "cabelos em pé" na superfície do crânio. Algumas dessas manifestações são tão características e passíveis de serem observadas em radiografias que fazem parte da rotina do cirurgião-dentista. Neste relato de caso, são discutidas as alterações observadas na radiografia panorâmica de uma paciente com talassemia diagnosticada por meio de exame hematológico.

Thalassemia is a type of hereditary anemia that predominantly affects individuals born in or descendents of countries bathed by the Mediterranean Sea, such as Italy and Greece. Also known as Cooley's anemia and Mediterranean anemia, the disease causes alterations in hemoglobin formation and malformations of the cranium, long bones, maxilla and mandible. It presents two distinct clinical conditions: one severe, called "major" thalassemia, and the other mild, denominated "minor" thassalemia. Hematologic exam diagnoses the two forms of the disease. Its clinical and radiographic manifestations include hepatosplenomegalia, lymphadenopathy, augmented mandible, increase in medullary spaces, thick bone trabeculae and in lower quantity, resembling a "spider web", displacement of the mandibular canal, with loss of detail of its superior and inferior corticals and a radiographic aspect of "hair standing on end" at the surface of the cranium. Some of these manifestations are so characteristic and capable of being observed in radiographs that they form part of the dentist's routine. This case report discusses the alterations observed in the panoramic radiograph of a patient with thalassemia diagnosed by means of hematologic exam.

Resultados de un programa de pesquisa prenatal de la talasemia grave / Results of an antenatal screening programme for beta-thalessemia

Objetivos: Detectar el rasgo beta-talasémico durante el control prenatal de mujeres en la primera etapa del embarazo; reducir el nacimiento de niños homocigotos con beta-talasemia. Métodos: Se incluyeron embarazadas de hasta 18 semanas de gestación con antecedentes de no más de 3 embarazos, que asistían a una clínica de control prenatal. Se realizó una pesquisa mediante la estimación del volumen corpuscular medio, la hemoglobina corpuscular media y la prueba NESTROF. Se controló también a los esposos de las mujeres con pruebas positivas. Si ambos padres eran positivos, se confirmó el diagnóstico por medio de cromatografía líquida de alto rendimiento. Para la detección fetal de las parejas positivas se efectuó biopsia de vellosidades coriónicas o amniocentesis. Se ofreció la interrupción del embarazo a las mujeres con fetos con talasemia grave. Resultados: Se efectuó la pesquisa a 17339 madres en el período comprendido entre octubre de 1999 y marzo de 2010. Las pruebas de cribado fueron positivas para el volumen corpuscular medio, la hemoglobina corpuscular media y la pruebas de NESTROF en el 11.02%, 18.76% y 12.62% de las embarazadas, respectivamente. El 1.98% de las mujeres eran portadoras confirmadas. Un total de 54 parejas requirieron pruebas diagnósticas prenatales fetales. Se detectó talasemia grave en 19 fetos; todos esos embarazos fueron interrumpidos. Se encontró rasgo talasémico en 16 fetos. Conclusión: La pesquisa prenatal de la beta-talasemia es un abordaje rentable para evitar el nacimiento de niños afectados, en especial en países de alta prevalencia.