[Treatment of thalassemia]. / Il trattamento della talassemia.

The management of Cooley's anemia today is based on: a careful transfusional therapy using international schedules with standardized parameters for evaluating its efficacy; prevention of iron overload improving the compliance for chelation therapy; blood transfusion with the optimal methods to prevent reactions mainly due to leukocytes; psychosocial and clinical approach of adolescent's problems.

[Audiologic evaluation of patients with thalassemic syndromes treated with desferrioxamine B]. / Valutazione audiologica in pazienti affetti da sindromi talassemiche trattati con desferossamina B.

Following various articles in literature which have appeared in the last 3 years regarding the neurotoxicity of desferrioxamine B we studied, from the auditory functionality point of view, 95 patients affected with transfusion-dependent thalassemic syndromes, under regular chelation treatment with desferrioxamine B. Our results lead us to conclude that at standard doses, between 40 and 60 mg/Kg/day, desferrioxamine B does not demonstrate a neurotoxicity enough to cause an organic deficit in the auditory sphere, while maintaining therapeutic efficacy.

[Critical evaluation of the causes of death in thalassemic subjects]. / Valutazione critica delle cause di morte nei soggetti talassemici.

We discuss 25 cases of death observed from 1971 to 1983 in a casistic of 155 patients with Thalassaemic Syndrome. Anemia as a cause of death is disappearing, new triggers are involved such as Yersinia Enterocolitica who can cause severe sepsis even in non-splenectomized patients. Iron overload appears to be the most severe complication in the second decade.

[New therapeutic trends in thalassemia: oral chelating agents]. / Nuove prospettive terapeutiche per la thalassemia: i chelanti orali.

The future therapeutic strategy for decreasing iron overload in poly-transfused patients will include oral chelation. The product currently undergoing the most intensive experimentation is Ll (1,2-dimethyl-3-hydroxypyrid-4-one). We report here a short-term efficacy study carried out in 10 thalassemic transfusion-dependent pediatric volunteer patients, already closely followed in our Day Hospital, after having provided their informed consent. In our study Ll, when compared to Desferrioxamine, was clearly efficacious and safe.

[Clinico-therapeutic findings on diabetic complications in thalassemia]. / Considerazioni clinico-terapeutiche sulla complicanza diabetica nella talassemia.

We describe 6 patients with thalassaemia major who developed diabetes. Etiopathogenesis, poor metabolic control, previous transfusion and chelation regimens are discussed. Antiaggregant therapy with A.S.A. and Dipiridamole may play a role in these patients for preventing thrombotic risk.

[Preliminary data on the endocrinologic evaluation of thalassemic adolescents]. / Dati preliminari sulla valutazione endocrinologica di adolescenti talassemici.

Endocrine disfunction are well known in young patients with thalassaemia major and are mainly due to iron overload. Gonadotrophin releasing hormone (GnRH) was administered to 13 boys aging more than 14 years and to 13 girls aging more than 13 years to assess pituitary function. Human Chorionic gonadotrophin (HCG) was also administered to 13 boys to evaluate their gonadal function. Most of the patients had evidence of pituitary hypofunction and in 4 boys there was evidence of gonadic failure. This study is mandatory for a correct therapeutic approach.

An unclassified case of congenital dyserythropoietic anaemia with a severe neonatal onset.

The case of a 13-year-old child with a congenital dyserythropoietic anaemia (CDA) is reported. A severe anaemia associated with a slight increase in reticulocytes, erythroblastosis, hyperbilirubinaemia, hepatosplenomegaly, generalized oedema and hypoproteinaemia was present at birth. Three exsanguino-transfusions were needed in the first 4 days of life. In the following years a continuous transfusional regimen was maintained in association with a chelating treatment. Bone marrow aspirates showed a striking hyperplasia of the erythroid lineage with ineffective erythropoiesis and changes of erythroblastic nuclei which were double but incompletely separated. Numerous histio-erythroblastic islands were also present. Electron microscopy studies did not show specific alterations of the erythropoietic cells. By a long-term evaluation of the clinical signs and of the haematological data, we came to the conclusion that the case does not fit into any of the three classical categories of CDA.

Congenital refractory anaemia with vacuolisation of bone marrow precursors, sideroblastosis and growth failure in a girl with normal endocrine pancreatic function.

The case is described of an 8-years-old girl with consanguineous parents. She was apparently well, apart, from growth retardation, until 18 months of age when she developed severe normocytic hypochromic anaemia. Bone marrow examination revealed vacuolisation of the erythroid and myeloid precursor, and electron microscopic studies showed striking sideroblastosis with ringed arrangement of the iron granules. Porphyrin metabolism was apparently normal, whereas blood levels of iron and ferritin were high. A careful study of the exocrine pancreas showed completely normal function. Vitamin B6 administration was unsuccessful. The patient is transfusion-dependent, and iron chelation treatment has produced good results. The case could be a new entity or a variant of congenital sideroblastic anaemia, since it has some features in common with the syndrome described by Pearson et al.

Hepatitis B or non-A, non-B virus infection in multitransfused thalassaemic patients.

We undertook a four year study of 128 thalassaemic patients who had undergone several transfusions, to determine the incidence of hepatitis B virus markers and the activities of transaminases in their sera each month. The results showed that the possibility of these patients contracting hepatitis B virus infection is still high, although on only one occasion was a transient antigenaemia found, indicating low viral replication. Furthermore, the probability of contact with hepatitis B virus increases with the number of transfusions and, therefore, with age. About 25% of these patients were positive for hepatitis B markers and 80% for other hepatitis markers including the case of cytomegalovirus hepatitis.

Sequential study of liver biopsy in thalassaemia.

Liver biopsies were performed in 47 thalassaemic children. 33 of them had laboratory findings that suggested chronic hepatitis; the other 14 patients, without such signs, underwent liver biopsies during splenectomy. Nine patients showed a more or less pronounced fibrosis, 26 showed chronic persistent hepatitis, and 12 had histological evidence of chronic aggressive hepatitis. The last 12 patients who had been treated with corticosteroids, and 9 other patients who showed a worsening of their liver function tests, underwent sequential biopsy. We suggest that chronic liver disease in thalassaemic children can produce inflammatory infiltration even without biochemical or clinical sign of chronic hepatitis, that it can progress towards cirrhosis even in patients with chronic persistent hepatitis, and that there appears to be no benefit in giving corticosteroids.

Evaluation of the supertransfusion regimen in homozygous beta-thalassaemia children.

The maintenance of physiological levels of haemoglobin is beneficial in the management of patients with thalassaemia major since it leads to better tissue oxygenation, reduction of blood volume, and reduced intestinal absorption of iron. We have studied 11 patients with thalassaemia major while treating them for 4-12 months with a standard transfusion regimen (mean pre-transfusion Hb 10.2 g/dl) and then for a second period of 7-18 months with a supertransfusion regimen (mean pre-transfusion Hb 12.3 g/dl). Blood consumption was 16.71 +/- 2.0 ml/kg/month in the first period; it rose to 20.30 +/- 3.5 ml/kg/month in the first 5 months of the second period, and then returned to the values of the first period (16.53 +/0 2.0 ml/kg/month). There were no significant differences in blood consumption between the two transfusion regimens, after the 5-month equilibration period.

Feasibility of prenatal diagnosis of beta thalassaemia by DNA polymorphisms in an Italian population.

A feasibility study of prenatal diagnosis of beta thalassaemia in a northern Italian population has been carried out. Twenty-five families have been studied, each consisting of two parents and a homozygous beta thalassaemia child, thus enabling linkage analysis of restriction fragment length polymorphisms (RFLPs) to the normal and the thalassaemic chromosomes. Using seven standard RFLPs, 19/25 families could be offered prenatal diagnosis; inclusion of the recently described Ava II psi beta polymorphism increased this figure to 23/25 (92%) of the families.

Meiotic recombination in the beta globin gene cluster causing an error in prenatal diagnosis of beta thalassaemia.

In the course of a prenatal diagnosis for beta thalassaemia by linkage analysis of restriction fragment length polymorphisms, a homozygous beta thalassaemia fetus was misdiagnosed as beta thalassaemia trait. Extensive studies of the polymorphic sites within the beta globin gene cluster in all the members of the family resulted in the conclusion that the paternal chromosome 11 of the newborn was different from that expected. Paternity was confirmed by HLA typing and blood group studies. The analysis of another polymorphic locus on chromosome 11 within the family was in agreement with the possibility of a crossing over between the two paternal chromosomes in a region 5' to the beta gene, previously indicated to contain a 'hot spot' area for recombination. This report underlines the risk of performing prenatal diagnosis using restriction polymorphisms 5' to the beta gene.

Survival and causes of death in thalassaemia major.

Survival and causes of death were studied in 1087 Italian patients with thalassaemia major who were born on or after Jan 1, 1960. At the age of 15 years, the Kaplan-Meier estimate of survival after the first decade of life was 80.6% for subjects born in 1960-64, 84.2% for those born in 1965-69, and 96.9% for those born in 1970-74. At the age of 20 years, survival from the age of 10 was 59.1% for patients born in 1960-64, and 70.2% for those born in 1965-69; at 25 years, survival from the age of 10 was 40.7% in the 1960-64 cohort. Overall survival from birth for patients born in 1970-74 was 97.4% at 10 years, and 94.4% at 15 years. The most common cause of death was heart disease, followed by infection, liver disease, and malignancy.

Cirrhosis associated with multiple transfusions in thalassaemia.

The study of surgical liver biopsy specimens obtained during splenectomy in 86 children with thalassaemia indicated that such patients may develop liver disease that evolves into cirrhosis. Histological characteristics suggest that it is post-necrotic cirrhosis. Onset of cirrhosis in some patients may occur as early as 7-8 years old, and at age about 15-16 years most children with thalassaemia show features of cirrhosis. In addition to fibrosis, hepatitis, or even aggressive hepatitis may develop as has also been observed in patients without thalassaemia who have undergone multiple transfusions. This study presents the current probable evolution of liver disease in patients with thalassaemia and may thus serve as a reference from which to evaluate any future progress in the treatment and care of patients with Cooley's disease.

Growth and sexual maturation in thalassemia major.

Growth and sexual development were evaluated in 250 adolescents with beta-thalassemia major. Before transfusion hemoglobin concentration had not been less than 9.5 gm/dl in the last 5 years; desferrioxamine had been administered for 7 to 10 years, including by the subcutaneous route for 3 years. Thirty-seven percent of patients were found to be 2 SD below the mean for normal height; after age 14 years the percentage was 62% for males and 35% for females. Eighty-three percent of males and 75% of females had delayed skeletal maturation. Complete lack of pubescent changes was present in 38% of females and 67% of males aged 12 to 18 years. Only 19% of females had experienced menarche; secondary amenorrhea intervened in a third of them. A multiple regression analysis of indicators of pubertal development with age, age at first transfusion, age at splenectomy, number of transfusions, serum transaminase and ferritin, and duration and intensity of chelation therapy failed to identify the factors responsible for the variation observed in sexual maturation among patients with thalassemia.

Haemoglobin levels and blood requirement in thalassaemia.

The relationship between blood requirement and the mean level of maintained haemoglobin was examined in 392 patients with homozygous beta-thalassaemia. Pre- and post-transfusional haemoglobin levels and the amounts of blood transfused were measured during a 1-year period. No significant differences were noted in the blood requirements of patients (splenectomised or not) irrespective of the haemoglobin level. It may be supposed that if the mean haemoglobin level is high the haematopoietic activity is inhibited, and hence the bone marrow mass and total blood volume are reduced. High haemoglobin levels may thus be obtained with no increase in blood intake.

Treatment with biosynthetic growth hormone of short thalassaemic patients with impaired growth hormone secretion.

OBJECTIVE: Impairment of linear growth is a common clinical feature in patients with beta-thalassaemia major. Although growth hormone secretion appears to be normal in many short thalassaemic patients, it proves to be deficient in some of them. In these cases, administration of biosynthetic growth hormone seems justified. The aim of this study was to evaluate the effect of such treatment in a group of patients with beta-thalassaemia major presenting with growth failure and impairment of growth hormone secretion. DESIGN: Recombinant human growth hormone, 0.6 U/kg body weight per week, given subcutaneously in three divided doses, was administered for 12 months. PATIENTS: Eight prepubertal patients with beta-thalassaemia major, presenting with severe growth retardation and impaired growth hormone secretion in response to provocative stimuli (insulin-induced hypoglycaemia, L-dopa and growth hormone-releasing hormone), were investigated. MEASUREMENTS: Height and pubertal stage of the patients, as well as plasma levels of insulin-like growth factor I, were determined before, during and after biosynthetic growth hormone treatment. RESULTS: During the first 6 months of therapy, a significant increase of growth velocity was observed, from a mean pretreatment value of 2.1 +/- 0.45 cm/year to a value of 4.8 +/- 0.66 cm/year (P less than 0.002). Mean growth rate at 12 months (4.1 +/- 0.50 cm/year), though slightly decreased in comparison to that recorded at 6 months, was still significantly higher than basal (P less than 0.001). A significant increase in plasma levels of insulin-like growth factor I was recorded during treatment (2.82 +/- 0.47 vs 0.96 +/- 0.22 U/ml, P less than 0.005). No side-effects, adverse reactions or alterations in routine laboratory examinations ensued during or after therapy. CONCLUSIONS: It appears from these data that biosynthetic growth hormone administration is worth serious consideration in patients with beta-thalassaemia major presenting growth retardation and impaired growth hormone secretion.