Association of heart failure in homozygous beta-thalassemia with the major histocompatibility complex.

BACKGROUND: In beta-thalassemia major, heart failure primarily affecting left ventricular systolic function is the most common complication and cause of death. Apart from iron deposition, it has been recently reported that myocarditis might be another contributing factor in the pathogenesis of acute or chronic heart failure, acting possibly through an autoimmune mechanism. In an attempt to assess the role of immunogenetic factors in the development of heart failure associated with beta-thalassemia major, we studied the frequency of major histocompatibility antigens/alleles A, B, DR, and DQ in homozygous beta-thalassemic patients with and without heart failure primarily affecting the left ventricle. METHODS AND RESULTS: Forty-five consecutive unrelated Greek patients with homozygous beta-thalassemia and left-sided chronic heart failure were studied. Fifty-eight unrelated Greek patients with homozygous beta-thalassemia without heart failure and 130 unrelated Greek healthy controls were also studied. In all subjects, class I HLA-A and -B typing was performed by the complement-mediated lymphocytotoxicity assay, whereas class II HLA-DR and -DQ typing was performed by polymerase chain reaction. HLA-DRB1*1401 allele frequency was significantly increased in patients with beta-thalassemia major without left-sided heart failure compared with those with heart failure (corrected P [P(c)]=0. 02, odds ratio 0.1) and healthy controls (P(c)=0.001). HLA-DQA1*0501 allele frequency was increased in patients with heart failure compared with patients without heart failure (P(c)=0.04, odds ratio 14) and healthy controls (P(c)=0.004). CONCLUSIONS: Differences exist in the immunogenetic profile between homozygous beta-thalassemic patients with and without left-sided heart failure, raising the possibility that genetically defined immune mechanisms may play an important role in the pathogenesis of heart failure in beta-thalassemia.

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.

Interferon-alpha 2b treatment of chronic hepatitis C in haemodialysis patients.

Nineteen haemodialysis (HD) patients with chronic hepatitis C were treated with interferon-alpha 2b (IFN-alpha) at a dose of 3 or 1 MU thrice weekly for 6 months and were followed-up for another 14 months without treatment. Six patients discontinued treatment because they either presented severe side-effects to IFN-alpha or had complications of their primary disease. Levels of AST and ALT were within normal limits on the 2nd month of treatment and remained so throughout the treatment and the follow-up period in all patients except one who showed an elevation of transaminase levels 2 months after the end of treatment. Serum HCVRNA became negative in 10/13 patients at the end of treatment and was negative in all patients on the 6th month and in 12/13 patients on the 14th month during the follow-up period. Levels of 2'5' oligosynthetase were increased significantly on the 2nd and 4th month of treatment and returned to pretreatment values the 2nd month after treatment. These findings demonstrate that haemodialysis patients with chronic hepatitis C respond well to interferon treatment and that a long-term response is achieved in a high proportion of patients.

Interferon treatment of chronic active hepatitis B: effect of a six month treatment regimen.

In this study of 17 patients with chronic active hepatitis B, the loss of hepatitis B virus DNA, the return to normal of alanine aminotransferase activities, and histological improvement after six months' treatment with 3 million units three times weekly with interferon alfa-2b, was achieved in 40% of hepatitis B e antigen (HBeAg) positive/anti HBe negative patients, and 41.66% of HBeAg negative/anti HBe positive patients. The reappearance of hepatitis B virus DNA was seen in most patients when treatment was stopped, although a higher percentage of HBeAg positive/anti HBe negative patients (20%) had a sustained loss of hepatitis B virus DNA, return to normal alanine aminotransferase activities, and histological improvement compared with HBeAg negative/anti HBe positive patients (8.3%).

Cognition in homozygous beta-thalassemia disease: a multichannel auditory event-related potential (P300) study.

Auditory Event-Related Potentials (AERP) were elicited in 25 beta-thalassemic patients, three days before and three days after a blood transfusion. The amplitude, latency and topographic distribution of P300 (P3) as well as N1, P2, N2 components were measured for the two assessment times. No significant differences in either amplitude, latency or topography were observed between the two situations, but thalassemic patients had significantly prolonged P3 latencies comparing to controls though none of them exceeded 3 standard deviations of the control mean values. Regarding P3 topography, 10 out of 25 patients showed a right centroparietal distribution area. It is concluded that information processing, as far as it is reflected in AERP components is impaired in thalassemic patients and blood transfusion have no significant influence in cognitive functions.

alpha-Interferon therapy in patients with chronic active hepatitis B: immunological profile.

The effect of interferon-alpha 2b (IFN) on viral markers, liver function and immunological parameters (CD3, CD4, CD8, B, NK, II-2 receptor and HLA-DR positive cells in blood and T cell proliferation) was studied in 9 patients with HBsAg(+), HBeAg(-) chronic active hepatitis (CAH). Three patients were HBV-DNA(+) and 6 also had complications of cirrhosis of the liver (LC). IFN was given at a dose of 2.5 mil IU x 3 weekly for 6 months. One patient with LC developed hepatic coma and died 2 months later. Severe leukopenia limited duration of treatment to 2 and 4 months in another 2 patients. By the end of treatment, the 8 patients were in good clinical status, SGOT, SGPT levels and prothrombin time were decreased, HBV-DNA became negative in 2 out of 3 patients and proportions of CD3, CD4, B, NK and activated cells were significantly decreased. When compared to controls, NK and activated cells were significantly increased in patients before and were gradually decreased by the end of treatment. In contrast, T transformed cells were significantly decreased before and ranged in normal levels by the end of treatment. These findings suggest that immunomodulatory activity possibly contributes to the beneficial effect of IFN therapy.

Neurophysiological and neuro-otological study of homozygous beta-thalassemia under long-term desferrioxamine (DFO) treatment.

This report presents data on visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs), as well as neurologic, ophthalmologic and otologic assessments performed on 120 patients with beta-thalassemia major undergoing long-term DFO treatment. A total of 32 patients showed abnormal VEPs and 14 abnormal BAEPs; seven had both VEP and BAEP abnormalities; 12 had sensorineural hearing loss (SNHL); 18 had conductive hearing loss, while 14 showed a combination of SNHL and conductive hearing loss. After DFO administration was modified (taking in consideration the serum ferritin levels) patients with abnormal findings were retested. The values of 15 patients of 23 who underwent VEP examinations had been normalized. Eleven of 15 who repeated the BAEP test had also gained normal values. The audiogram had not returned to normal in any patient with SNHL. In a second repetition of the examinations, no change was observed. It is concluded that in a great percentage of thalassemics at least one of the above examinations shows abnormal values. These abnormalities are mostly reversible, and probably reflect a dysfunction of the visual or auditory system, due either to DFO neurotoxicity or to iron overload or both.

Function of reticuloendothelial system in splenectomised thalassemics.

The activity of reticuloendothelial system (RES) was estimated in 19 patients with beta-thalassemia major, 20 +/- 4 years old, who had undergone successful splenectomy 6 +/- 5 years previously. The kinetics of 125I denatured human serum albumin in low and large doses was applied for this purpose and the parameters derived (effective RES blood flow-ERBF- and maximum phagocytic capacity-PCmax) were compared to those of nonsplenectomized thalassemics, detected in previous works, as well as to those of 13 healthy controls. In splenectomised thalassemics both parameters of RES activity were found significantly lower than those of nonsplenectomized patients (p less than 0.001). Compared to those of healthy controls, PCmax of splenectomised thalassemics was found not to be significantly different, while ERBF was significantly lower (p less than 0.001). No correlation was noted between the above parameters of RES function and the age of the patients, the age at which splenectomy was performed, the time lapsed since the operation, the amount of blood transfused to the patients after splenectomy or their serum ferritin levels. A pilot study performed in 6 out of the 19 splenectomised patients did not reveal any effect of blood transfusion on RES function parameters, by contrast to observations in nonsplenectomized thalassemics. The results of this study suggest that in splenectomised thalassemics the remaining RES reacts to the continuing hemolytic stimulus in a manner different than that of splenic RES of nonsplenectomized patients and account for, at least in part, the predisposition of the former group to infections.

Partial splenic embolisation for hypersplenism of thalassaemia major: five year follow up.

Six patients with thalassaemia major were treated by partial splenic embolisation as an alternative to splenectomy and followed up for five years. Results were compared with those in a matched control group of seven patients treated by splenectomy. All patients treated by partial splenic embolisation showed a reduction in blood transfusion requirements comparable with those in the controls and which remained unchanged over the five years. Serious infections that commonly occur in patients splenectomised for thalassaemia did not occur after embolisation, presumably owing to preservation of some immune function by the splenic remnant. By contrast with the change in platelet counts seen after splenectomy, platelet counts remained normal after partial splenic embolisation, so reducing the risk of thromboses. On the other hand, pre-existing leucopenia and thrombocytopenia were corrected after embolisation. It is concluded that partial splenic embolisation provides an alternative to splenectomy for thalassaemia major and is equally effective and much safer.

Assessment of iron stores in subjects heterozygous for beta-thalassaemia based on serum ferritin levels.

Serum ferritin concentration was assessed in male and female pregnant and non-pregnant thalassaemia carriers and in normal subjects of both sexes. Low ferritin levels were found in 61% of non-pregnant and in 32% of pregnant female beta-thalassaemia heterozygotes whereas male thalassaemia carriers had normal iron stores. Increased ferritin levels were not observed in any of the subjects examined. These findings show that iron deficiency is a common finding in female thalassaemia carriers of reproductive age who are not receiving iron supplementation.