Arterial elastorrhexis in beta-thalassaemia intermedia, sickle cell thalassaemia and hereditary spherocytosis.

Arterial and stromal elastorrhexis, an elastic tissue disorder, was recently described in beta-thalassaemia major. Histopathological material from 10 patients with thalassaemia intermedia, 14 with sickle cell thalassaemia and 18 with hereditary spherocytosis was examined in order to investigate the specificity of the arteriopathy. Histological re-examination was made in a total of 42 spleens with parasplenic lymph nodes in 14 cases, 26 surgical liver biopsies and 16 gallbladders with associated regional lymph nodes. Arteriopathy, qualitatively similar to that seen in beta-thalassaemia major, was found in up to 90% of extrasplenic muscular arteries. Elastorrhexis lesions were also found in intrasplenic arteries and in stromal elastic tissue of spleens and parasplenic lymph nodes, in the absence of tissue iron overload. The arteriopathy appears in the first decade of life even in spleens of normal weight, and seems unrelated to the severity of permanent anaemia. It is suggested that patients suffering from hereditary chronic haemolytic diseases are subject to an elastic tissue disorder which is similar to hereditary pseudoxanthoma elasticum, the earliest and most frequent manifestation of which is arterial elastorrhexis of muscular extrasplenic arteries.

Neutrophil elastase in patients with homozygous beta-thalassemia and pseudoxanthoma elasticum-like syndrome.

In this study we investigated the possible role of neutrophil (PMN) elastase and its natural inhibitor, alpha1-proteinase inhibitor (alpha1-PI) in the pathogenesis of the pseudoxanthoma elasticum (PXE)-like syndrome which is found in patients with homozygous beta-thalassemia. We studied 30 beta-thalassemia homozygotes with the PXE-like syndrome [PXE(+) group], 20 beta-thalassemia homozygotes without this syndrome [PXE(-) group] and 15 healthy controls. Plasma PMN elastase concentration in the PXE(+) and in the PXE(-) group was 136.4 +/- 89 and 163.8 +/- 126 microg/L, respectively (P > 0.05). In the control group, the concentration was 42.9 +/- 16.8 microg/L (P < 0.01 for the comparison with both patients' groups). The plasma alpha1-PI concentration in the PXE(+) and in the PXE(-) group was 2.28 +/- 0.75 and 2.6 +/- 0.96 g/L, respectively (P > 0.05). Using logistic regression, we studied the prognostic value for PXE of the following independent variables: number of transfusions, chelation therapy, mean hemoglobin concentration, PMN elastase concentration, alpha1-PI concentration, chronic transaminase elevation, and positivity for anti-HCV. None of the above variables was found to have significant prognostic value for the PXE. Plasma PMN elastase concentration is elevated in all beta-thalassemia homozygotes; its role in the pathogenesis of the PXE-like syndrome in beta-thalassemia can not be established, but our findings suggest that neutrophils of beta-thalassemia patients are activated, since PMN elastase is a marker of neutrophil activation.

Arterial elastorrhexis: manifestation of a generalized elastic tissue disorder in beta-thalassaemia major.

Pseudoxanthoma elasticum-like lesions of the eye and skin are frequently observed in beta-thalassaemia, and there has been speculation about associated vascular lesions. This led to our study of histopathological material from thalassaemic patients. Histological re-examination was made of a series of 45 spleens and 45 surgical liver biopsies from 45 patients with beta-thalassaemia major, aged 6-25 yr and treated over the 20-yr period 1975-95. Correlations between clinical, laboratory and histological findings were demonstrated by statistical analysis. Arteriopathy characterized by fragmentation and multiple defects of the internal elastic lamina ('arterial elastorrhexis'), with deposits of iron and calcium salts, was found in the hilar arteries of the spleen with a frequency of 96%. Similar lesions were observed in the parenchymal arteries and the stromal elastic tissue ('stromal elastorrhexis') of the spleen, liver and lymph nodes. Arterial and elastic tissue alterations appear in the first decade of life and become generalized over the course of the disease, independent of the time of onset of transfusion and iron chelation therapy. Arterial elastorrhexis is the earliest and most frequent manifestation of a systemic elastic tissue disorder in beta-thalassaemia major. It appears to be an acquired pseudoxanthoma elasticum-like syndrome, related primarily to tissue hypoxia and disturbance of elastin metabolism.

Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia.

In homozygous beta-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in beta-thalassemia homozygotes. A total of 251 Greek beta-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P > .05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous beta-thalassemia.

Iron overload and urinary lysosomal enzyme levels in beta-thalassaemia major.

UNLABELLED: The urinary levels of the lysosomal enzymes N-acetyl-beta-D-glucosaminidase (NAG) (EC 3.2.1.52) and alpha-mannosidase (EC 3.2.1.24) were evaluated in patients with beta-thalassaemia major and normal control subjects. Two groups of patients with different degrees of iron overload, as judged by their serum ferritin levels, were investigated. Renal disease was not present in any of the patients. A statistically significant increase in the levels of NAG was observed in the high ferritin (> 3,000 mg/dl) group compared to the low ferritin (< 3,000 mg/dl) and the control groups. No difference was observed in the urinary alpha-mannosidase levels between the groups examined. The finding of increased NAG levels in the patients with the increased iron load suggests that kidney lysosomes are a target of iron toxicity. The different behaviour of the two lysosomal enzymes may reflect the intra- and inter-lysosomal heterogeneity in kidney. CONCLUSION: Iron overload resulted in increased urinary levels of the lysosomal enzyme NAG which has been proposed as an early marker of kidney damage. Reduction of iron load, achieved by regular desferrioxamine infusion, resulted in normalisation of the urinary enzyme levels. Thus kidney lysosomes appear to be a target and possibly a mediator of iron toxicity in this tissue.