Caterina Borgna-Pignatti

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.

Survival and Disease Complications in Thalassemia Major

Abstract: We studied survival and disease complications in 1,146 patients with thalassemia major, born from January 1, 1960 to December 31, 1987. At last follow‐up, in March 1997, probability of survival to age 20 years was 89% and to age 25 years was 82% for patients born in the years 1970‐1974. Patients who died had a serum ferritin level, measured the year before death, significantly higher than those who survived. Diabetes was present in 5.4% of the patients; heart failure in 6.4%; arrhythmias in 5.0%, thrombosis in 1.1%, hypothyroidism in 11.6%, HIV infection in 1.8%. Hypogonadism was diagnosed in 55% of 578 patients who had reached pubertal age: 83.5% of hypogonadic females and 78.6% of males were receiving substitutive hormonal therapy. In conclusion, the survival of patients with thalassemia major is good and improving, but the prevalence of severe complications is still high.

Hepatocellular carcinoma in the thalassaemia syndromes

Hepatocellular carcinoma (HCC) frequently complicates hepatic cirrhosis secondary to viral infection or iron overload. Therefore, patients affected by thalassaemia syndromes have a theoretically high risk of developing the tumour. We collected data on patients attending Italian centres for the treatment of thalassaemia. Twenty‐two cases of HCC were identified; 15 were male. At diagnosis, the mean age was 45 ± 11 years and the mean serum ferritin was 1764 ± 1448 μg/l. Eighty‐six percent had been infected by hepatitis C virus. Nineteen of 22 cases were diagnosed after 1993, suggesting that this problem is becoming more frequent with the aging population of thalassaemia patients.

Modern treatment of thalassaemia intermedia

The term thalassaemia intermedia includes a large spectrum of conditions of varying severity. Blood transfusion and chelation are necessary in some patients, especially during childhood, in order to promote growth and prevent bone deformities. Alloimunisation, however, is frequent and can be difficult to control. Splenectomy is usually needed at some time because of hypersplenism and mechanical encumbrance. Reactivation of HbF is possible only in a small proportion of patients: hydroxycarbamide (also known as hydroxyurea) appears to be the most effective drug for this purpose. Antioxidant agents, although theoretically useful, do not improve haemoglobin levels. Stem cell transplantation is an option limited to the severe forms. Gene therapy and other molecular approaches are subjects of intense study. Numerous complications, including pulmonary hypertension, thrombotic events, pseudoxanthoma elasticum and osteoporosis, have been described and all contribute to complicate the treatment of a disease that represents a significant burden for the patients and their families.

A moderate transfusion regimen may reduce iron loading in beta‐ thalassemia major without producing excessive expansion of erythropoiesis

BACKGROUND: Hypertransfusion with a baseline hemoglobin of 10 to 12 g per dL is still considered by many to be the mainstay of conservative therapy for beta‐thalassemia major. However, this regimen is frequently associated with manifestations of transfusion iron overload, despite regular chelation therapy with subcutaneous desferoxamine. STUDY DESIGN AND METHODS: To verify whether a transfusion regimen with a target pretransfusion hemoglobin level between 9 and 10 g per dL can allow a significant reduction in blood consumption, while still effectively suppressing erythropoiesis, the records were reviewed of 32 beta‐ thalassemia major patients, who were maintained at a pretransfusion hemoglobin of 11.3 +/− 0.5 g per dL between 1981 and 1986. These patients were switched at the beginning of 1987 to a transfusion regimen with pretransfusion hemoglobin of 9.4 +/− 0.4 g per dL. The degree of erythroid marrow activity was evaluated in these patients and in 32 subjects with beta‐thalassemia intermedia through the simple measurement of serum transferrin receptor. RESULTS: After the adoption of the moderate transfusion regimen, transfusion requirements decreased from 137 +/− 26 to 104 +/− 23 mL per kg per year of red cells (p < 0.0001), and mean serum ferritin decreased from 2448 +/− 1515 to 1187 +/− 816 micrograms per L (p < 0.0001), with one‐half of patients achieving serum ferritin levels lower than 1000 micrograms per L. The proportion of patients having spontaneous pubertal development increased significantly (p < 0.01), as a result of less iron‐related gonadotropin insufficiency. At the lower pretransfusion hemoglobin, erythroid marrow activity did not exceed two to three times normal levels in most subjects. CONCLUSION: As compared with hypertransfusion, moderate transfusion may allow more effective prevention of iron loading, with higher likelihood of spontaneous pubertal development and without producing excessive expansion of erythropoiesis.

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

CARDIAC IRON AND CARDIAC DISEASE IN MALES AND FEMALES WITH TRANSFUSION-DEPENDENT THALASSEMIA MAJOR: A T2* MAGNETIC RESONANCE IMAGING STUDY

Background It has been repeatedly reported that female patients with thalassemia major survive longer than males and that the difference is due to a lower rate of cardiac disease in females. Design and Methods We compared the cardiac iron load as measured by T2* magnetic resonance imaging in 776 patients (370 males) examined at the National Research Council as part of an Italian cooperative study. We also established normal left ventricular ejection fraction values for our population. Results The prevalence of cardiac disease was higher in males than in females (105 males versus 69 females; P<0.0001). Cardiac T2* was significantly lower in patients with heart dysfunction (P<0.0001), but no difference was observed according to sex. Twenty males and five females had a history of cardiac arrhythmias. Their cardiac T2* was not significantly lower than that of patients without arrhythmias (24 ms versus 26 ms; P=0.381), nor was there a difference between sexes. Liver T2* was significantly lower in males and females with heart dysfunction compared to those without. Ferritin levels were higher in patients of both sexes with heart dysfunction without significant differences between males and females. Conclusions Males and females are at the same risk of accumulating iron in their hearts, but females tolerate iron toxicity better, possibly as an effect of reduced sensitivity to chronic oxidative stress.

A trial of high-dose dexamethasone therapy for chronic idiopathic thrombocytopenic purpura in childhood

OBJECTIVE To determine the efficacy of high-dose dexamethasone in chronic idiopathic thrombocytopenic purpura of childhood. METHODS Seventeen patients entered the protocol. Dexamethasone was to be given orally in two divided doses at a dosage of 20 mg/m2 for 4 consecutive days every 28 days for six courses. RESULTS One month after the end of the sixth course, six patients (35%) had platelet values within the normal range. One year later, five patients (29%) still have normal platelet values. Five patients discontinued treatment before completion because of lack of response and in one case for important side effects. Duration of the disease before treatment was inversely correlated with response to dexamethasone: 5 of 10 patients who had had thrombocytopenia for 30 months or less went into remission, as opposed to none of the seven who had been sick for a longer period (p = 0.04). Side effects included fatigue or irritability, anxiety, abdominal pain, striae, hirsutism, acne, and weight gain. CONCLUSIONS Contrary to what is observed in adults, in our patients pulsed dexamethasone therapy did not prove to be uniformly effective. However, in view of its effectiveness in a third of the patients, acceptable side effects, and low cost, we believe that this treatment could be considered in patients with chronic idiopathic thrombocytopenic purpura who do not tolerate the disease well, especially if no more than 3 years have elapsed since diagnosis. Larger studies will be necessary to define which patients will respond to this type of therapy.

Complications of thalassemia major and their treatment

The life of patients with thalassemia has improved both in duration and in quality in industrialized countries. Complications are still common and include heart disease (heart failure and arrhythmias), chronic liver hepatitis, which can evolve in cirrhosis and, rarely, in hepatocellular carcinoma, endocrine problems (hypogonadism, hypothyroidism, diabetes, hypoparathyroidism), stunted growth, osteoporosis, thrombophilia and pseudoxanthoma elasticum. The incidence of complications is decreasing in younger cohorts of patients who have been transfused with blood that has been screened for viruses and thanks to the introduction of new oral iron chelators and imaging methods. The accurate measurement of iron deposits allows better management of iron overload. In addition, therapy for several complications is available. Specialized competence in treating patients with thalassemia is of great importance.

Frequency of Factor V Leiden in Juvenile Migraine With Aura

Patients with migraine are known to be at risk for stroke. It has been reported that in a group of patients with cerebral ischemia and the Leiden mutation of factor V, 67% had classical migraine. We have studied the frequency of this mutation in a group of Italian children and adolescents affected by migraine with aura.