Christos Kattamis

Heart failure in beta thalassemia: a 5-year follow-up study

PURPOSE To evaluate the survival of patients with beta thalassemia and heart failure who were treated with iron chelation therapy. SUBJECTS AND METHODS Fifty-two consecutive patients with beta thalassemia and heart failure were followed in a prospective 5-year study. All patients underwent a full clinical examination with chest radiograph, electrocardiogram, and echocardiographic investigation performed at 6-month intervals or when a new symptom developed. RESULTS Of the 52 patients (mean [+/- SD] age, 24 +/- 5 years), 25 (48%) survived 5 years after the onset of heart failure. Forty-three patients had left-sided heart failure, and 9 had right-sided heart failure. Those with left-sided heart failure were younger at presentation with heart failure (22 +/- 4 years vs. 31 +/- 6 years; P <0.001), had lower ejection fractions (36% +/- 9% vs. 64% +/- 10%; P <0.001), and had a lower mean serum ferritin level (3355 +/- 1241 ng/mL vs. 6,397 +/- 1,613 ng/mL; P <0.001). CONCLUSION The 5-year survival rate in patients with beta thalassemia with heart failure was greater than previously reported. There are clinical characteristics that may make patients more likely to develop left- or right-sided heart failure.

Assessment of liver iron overload by T2-Quantitative magnetic resonance imaging: Correlation of T2-QMRI measurements with serum ferritin concentration and histologic grading of siderosis

PURPOSE To correlate hepatic 1/T2 values obtained by means of a T2-Quantitative MRI (T2-QMRI) technique with three widely applied methods for the evaluation of hemosiderosis, i.e., (a) liver iron concentrations (LFeC) (b) serum ferritin (SF), and (c) histologic grading of siderosis. The impact of coexisting hepatitis was also considered. T2-QMRI measurements were compared with signal intensity (SI) ratio measurements on conventional SE images. MATERIALS AND METHODS Liver T2 relaxation times were calculated in 40 thalassemic patients, on a 0.5 T magnetic resonance imaging system using a multiple spin-echo sequence with parameters: TR = 2500 ms, TE = 12 ms in 20 symmetrically repeatable echoes. RESULTS (a) 1/T2 values were well correlated (r = 0.97) with liver iron concentrations, which ranged from 2.32 to 18.0 mg/g dry weight (normal < 1.6 mg/g). (b) 1/T2 values were also correlated with serum ferritin levels (r = 0.84). At various 1/T2 values, serum ferritin levels were higher for the anti-HCV(+) patients than the anti-HCV(-) ones. (c) T2 values corresponding to successive grades of siderosis presented statistically significant differences. (d) SI ratio measurement assigned less statistically significant results, as compared to T2 values. CONCLUSION T2-QMRI measurement of T2 relaxation time is more accurate than SI ratios in evaluating liver iron overload. It is particularly useful for hemosiderotic patients with coexisting hepatitis since, in this case, serum ferritin is not considered a reliable index of hemosiderosis.

Phenotypic and molecular diversity of haemoglobin H disease: a Greek experience

Haemoglobin H (Hb H) disease is the severest form of α‐thalassaemia compatible with post‐natal life and occurs when α‐thalassaemia mutations interact to reduce α‐globin synthesis to levels approximately equivalent to the output of a single α‐globin gene. Hb H disease has variable clinical expression, mainly related to underlying genotypes. The spectrum of α‐thalassaemia determinants in Greece appears greater than in any other population studied and, in 75 Greek Hb H disease patients, we found 12 α‐thalassaemia mutations interacting to produce 15 Hb H disease genotypes. Evaluation of haematological, biochemical and clinical findings, and correlation with genotypes, defined genetic predictors of disease severity and factors involved in disease progression. In accordance with previous reports, patients with non‐deletion α‐thalassaemia mutations had more severe clinical expression. Additionally, we found that all patients with the most severe phenotypes had α‐thalassaemic globin variants. Phenotypic severity was not simply related to the degree of α‐globin deficiency: high Hb H levels were found to exacerbate anaemia by negatively influencing tissue oxygenation, and both Hb H and α‐thalassaemic haemoglobin variants appear to reduce red cell survival within the bone marrow and circulation. Together with the long‐term follow‐up in many patients, this report provides comprehensive information for management of Hb H disease and appropriate family counselling.

MUCOEPIDERMOID CARCINOMA OF THE BRONCHUS

Bronchoscopy in a 4.5-year-old girl with recurrent pneumonia showed an exophytic endobronchial mass. Biopsy disclosed microscopic and ultrastructural features of a low-grade mucoepidermoid carcinoma. Complete cure was accomplished by surgical removal of the tumor and right lower lobe.

Two novel polyadenylation mutations leading to β+‐thalassaemia

In an ongoing effort to identify point mutations causing β‐thalassaemia, we have found two previously unreported mutations which are located in the Poly A site of the β‐globin gene. The screening programme used amplified DNA and dot‐blot hybridization with several 32P‐labelled oligonucleotide probes. DNA samples which remained unidentified by this methodology were subjected to sequencing with 32P‐labelled primers and modified T7 DNA polymerase. The newly discovered mutations were confirmed by the dot‐blot hybridization technique. One type concerned an AATAAA→ÁTGAA mutation in the polyadenylation site and was found in one family from Yugoslavia (including one patient with the C→T mutation at codon 29 in trans), one from Bulgaria (the patient had the G→A mutation at IVS‐I‐110 in trans), and one from Greece (this patient had the C→G mutation at IVS‐II‐745 in trans). Haematological data for three simple heterozygotes suggested a rather mild β+‐thalassaemia. The second type involved an AATAAA→ÁTAGA mutation and was found in one family from Malaysia. The propositus had the βE mutation on the other chromosome, was originally diagnosed as mild Hb E‐β+‐thalassaemia, and had Hb A and Hb E percentages which were nearly the same.

The pancreas in β-thalassemia major: MR imaging features and correlation with iron stores and glucose disturbunces

The study aims at describing the MR features of pancreas in beta-thalassemia major, investigating the relations between MR findings and glucose disturbances and between hepatic and pancreatic siderosis. Signal intensity ratios of the pancreas and liver to right paraspinous muscle (P/M, L/M) were retrospectively assessed on abdominal MR imaging studies of 31 transfusion-dependent patients with beta-thalassemia major undergoing quantification of hepatic siderosis and 10 healthy controls, using T1- (120/4/90), intermediate in and out of phase - (120/2.7, 4/20), and T2*-(120/15/20) weighted GRE sequences. Using the signal drop of the liver and pancreas on opposed phase images, we recorded serum ferritin and results of oral glucose tolerance test (OGTT). Decreased L/M and P/M on at least the T2* sequence were noticed in 31/31 and 30/31 patients, respectively, but no correlation between P/M and L/M was found. Patients with pathologic OGTT displayed a higher degree of hepatic siderosis (p < 0.04) and signal drop of pancreas on opposed phase imaging (p < 0.025), implying fatty replacement of pancreas. P/M was neither correlated with glucose disturbances nor serum ferritin. Iron deposition in the pancreas cannot be predicted by the degree of hepatic siderosis in beta-thalassemia major. Fatty replacement of the pancreas is common and may be associated with glucose disturbances.

Quantification of liver iron overload by T2 quantitative magnetic resonance imaging in thalassemia: impact of chronic hepatitis C on measurements.

PURPOSE Measurement of liver T2 values seems to be an accurate and sensitive magnetic resonance imaging (MRI) method for the quantification of liver hemosiderosis in multiple transfused patients with thalassemia. Because many of these patients have coexistent chronic hepatitis C virus (HCV) infection, the effect of inflammatory changes on liver T2 values was assessed. MATERIALS AND METHODS Liver MRI studies of 35 HCV+ and 17 HCV- patients with beta-thalassemia, 9 HCV+ patients without thalassemia, and 10 healthy controls of the same age range (13 to 32 years) were reviewed. Iron status was assessed by serum ferritin in all patients, and determination of liver iron concentration (LIC) was available in 16 HCV+ patients with thalassemia. Histologic activity index (HAI) and grades of siderosis were evaluated in all HCV+ patients with thalassemia. RESULTS Patients with thalassemia had significantly lower T2 values (P < 0.0001) than subjects without thalassemia, whereas no difference existed between HCV+ patients without thalassemia and healthy controls. In HCV+ patients, LIC correlated more nearly with T2 values (r = 0.93) than with serum ferritin (r = 0.73). T2 values were not influenced by HAI score or fibrosis. CONCLUSION Liver T2 values were found to be more accurate than serum ferritin in predicting liver iron overload and were not influenced by the presence of chronic hepatitis C. Therefore, MRI could serve as a noninvasive alternative to liver biopsy for the quantification of hemosiderosis in HCV+ patients with thalassemia.

Growth of Children with Thalassaemia Effect of Different Transfusion Regimens

Growth was studied in 74 children with homozygous β-thalassaemia aged 1 to 11 years, treated with three different transfusion regimens. In group I (38 cases) haemoglobin levels were maintained above 8 g./100 ml.; in group II (14 cases), pretransfusion haemoglobin levels ranged between 6 and 8 g./100 ml.; in group III (22 children), pretransfusion haemoglobin levels were below 6 g./100 ml. Children in group I grew normally, both in weight and height; those in groups II and III were retarded, particularly those in group III. Frequent transfusions, in spite of their disadvantages, at present constitute the treatment of choice.

Haplotype and mutation analysis in Greek patients with Wilson disease

In this study, we report the results of haplotype and mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Greek origin. We have analysed 25 WD families and two single patients and characterised 94% of the WD chromosomes investigated. We have found 12 different molecular defects (three frameshifts, two splice site, two nonsense, five missense mutations), four of which are novel. Five of the mutations are widely prevalent accounting for 74% of the WD chromosomes analysed. These results may enable preclinical diagnosis in the large majority of WD patients of Greek descent, thereby improving genetic counselling and disease management.

The triplicated α gene locus and β thalassaemia

Summary. In five families, the coinheritance of β thalassaemia and an additional α gene (ααα/αα) has been observed. Among the β thalassaemia heterozygotes, no phenotypic effect of the triplicated α gene was detected clinically or at the haematological level. Unexpectedly, however, four out of five β thalassaemia homozygotes with the ααα/αα gene complement had the milder clinical condition of thalassaemia intermedia and in at least one case there was evidence to suggest that this might be due to the ααα gene arrangement acting as an α thalassaemia allele.