Phenotypic expression of hemoglobin A2 in beta-thalassemia trait with iron deficiency

 Iron status was estimated in 463 heterozygous beta-thalassemics to delineate the effect of iron deficiency on the expression of hemoglobin A₂ (HbA₂) in these patients. One hundred and twenty-six (27.2%) patients with the trait were iron deficient. These iron-deficient patients had a significantly (p<0.0002) higher prevalence of anemia (90.5%) compared with iron-replete patients with the trait (71.5%). The mean hemoglobin (Hb) concentration, MCV, and MCH were significantly (p<0.0001) lower in patients with beta-thalassemia traits (BTT) who had iron deficiency than in those without iron deficiency. Mean RBC count and MCHC did not differ in the two groups. Mean HbA₂ was not significantly different in the two groups of patients with the trait and was elevated ( 1 3.5%) in all but one heterozygote investigated. Mean HbA₂/cell was significantly (p<0.05) lower in BTT patients with iron deficiency than in patients without iron deficiency. The presence of iron deficiency did not preclude the detection of BTT in this population. The effect of iron deficiency in BTT was apparent as a significant lowering of the Hb concentration and an increased prevalence of anemia. Iron therapy is warranted for BTT patients with iron-deficiency traits and would help to significantly raise their Hb concentration. The elevation ofHbA₂ was striking and could be used with reliability in making the diagnosis of BTT even in the presence of iron deficiency. Received: January 26, 1998 / Accepted: June 2, 1998     

Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns

Little is known about the outcome of pregnancy in women with beta-thalassemia intermedia (TI). Over 10 years, maternal and neonatal outcomes of women with TI followed at a single thalassemia center were reviewed. Nine spontaneous pregnancies in five women with TI were studied. Six pregnancies resulted in live newborns; two were complicated by first-trimester abortions and one by an unexplained intrauterine fetal death at 36 weeks' gestation. Two patients had splenectomy before pregnancy: one required cesarean delivery and splenectomy at 31(2/7) weeks' gestation for worsening hemolytic anemia and thrombocytopenia and another had splenectomy 8 weeks postpartum for symptomatic hypersplenism. Two patients had received transfusions before pregnancy, and two required them for the first time during pregnancy and developed antibodies, which contributed to worsening of their anemia and repeated transfusions. The mean number of transfusions received during pregnancy was 8.0 +/- 5.2 units. The mean lowest hemoglobin level in pregnancy was 5.2 +/- 2.0 g/dl. Cesarean delivery was performed in 42.9% of cases. Mean gestational age at delivery was 36.7+/- 3.1 weeks with intrauterine growth restriction (IUGR) complicating 57.1% of cases. In conclusion, IUGR complicates more than half of pregnancies with TI. Transfusions are needed in most cases, even in non-transfusion-dependent patients. Postpartum splenectomy might be necessary in some patients.     

Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies

Thalassaemia intermedia (TI) is a syndrome marked by its diverse underlying genetic basis although its pathophysiology remains unclear, particularly regarding the nature of iron loading and toxicity. It is, however, evident that there are key differences from the extensively studied thalassaemia major (TM) population and caution is required when assessing iron load based on serum ferritin values, as this approach is known to underestimate the true extent of iron loading in patients with TI. Although effective iron chelation therapy has been available for many years, studies in TI-specific populations are rare and evidence suggests that management of iron levels may be less rigorous than in patients with TM and other chronic anaemias. Better understanding of the need to assess and treat iron overload in both transfused and non-transfused TI patients is clearly required.     

Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia

Non-transferrin-bound iron (NTBI) was evaluated as an index of iron overload in a cross-sectional randomised study in 74 non-transfused patients with thalassaemia intermedia (TI). Mean NTBI (2·92 ± 3·43 μmol/l), serum ferritin (1023 ± 780 ng/ml) and liver iron concentration (LIC; 9·0 ± 7·4 mg Fe/g dry weight) were increased above reference-range levels. Significant positive correlations occurred between mean NTBI and LIC (Pearson correlation 0·36; P  = 0·002) and serum ferritin (Pearson correlation 0·421; P  < 0·0001); with higher levels observed in splenectomised patients. NTBI assessment has potential as a simple reliable approach to determining iron status in TI.     

Assessment of inpatients with idiopathic inflammatory myopathies: A 10-year single unit experience

Background

The burden of the patients with idiopathic inflammatory myopathies (IIM) including their admissions, diagnostic and therapeutic cares is similar to other severe diseases.

Lipid profile in beta-thalassemia intermedia patients: correlation with erythroid bone marrow activity

Lipid abnormalities, including low levels of all fractions of serum lipids, have been repeatedly reported in all phenotypes of beta-thalassemia. Unexpectedly, in more recent studies, the concentration of total cholesterol (TC) and high- and/or low-density lipoprotein cholesterol (HDL-C and LDL-C) has been found in beta-thalassemia intermedia (TI) patients even lower than in thalassemia major, without a clear explanation of pathophysiology of these findings. This lack of information prompted us to evaluate the plasma lipids and lipoproteins pattern in the TI patients followed in our department; the data were compared with those found in hereditary spherocytosis patients. Furthermore, in both groups of patients, the erythroid bone marrow activity was evaluated, utilizing the level of soluble transferrin receptors (sTfR) in the plasma. Both groups of patients showed similar lipid abnormalities (low-TC, HDL-C and LDL-C) and the same increase of sTfR, with significantly lower hemoglobin levels in TI patients. Data analysis of our study shows that the lipid profile in TI patients is not influenced by age, sex, liver injury, hemoglobin or ferritin levels; the higher erythroid bone marrow activity with the enhanced cholesterol consumption could be the dominant mechanism implicated in the lipid abnormalities of TI patients.     

Revisiting beta thalassemia intermedia: past,present, and future prospects

Background: The spectrum of thalassemias is wide ranging from thalassemia minor, which consists of mild hypochromic microcytic anemia without obvious clinical manifestations, to thalassemia major (TM), which is characterized by severe anemia since the first years of life and is transfusion dependent. Thalassemia intermedia (TI) describes those patients with mild or moderate anemia.

Objective: To describe the genetic features and major clinical complications of TI, and the therapeutic approaches available in the management of this disease.

Methods: Publications from potentially relevant journals were searched on Medline.

Results and discussion: Over the past decade, the understanding of TI has increased with regard to pathophysiology and molecular studies. It is now clear that clinical presentation and specific complications make TI different from TM. It is associated with greater morbidity, a wider spectrum of organ dysfunction and more complications than previously thought.

Conclusion: TI is not a mild disease. The interplay of three hallmark pathophysiologic factors (ineffective erythropoiesis, chronic anemia, and iron overload) leads to the clinical presentations seen in TI. New treatment modalities are currently being investigated to broaden the options available for TI management.     

Diastolic function in young patients with beta-thalassemia major: an echocardiographic study

OBJECTIVE: We aimed to evaluate myocardial diastolic function in patients with beta-thalassemia major (beta-TM) using pulsed-tissue Doppler imaging (TDI) and flow propagation (VP), in relation to BNP levels. METHODS: We enrolled 192 consecutive patients with beta-TM (88 men (25 +/- 6 years) and 104 women (26 +/- 6 years), with normal left ventricular (LV) systolic function. By TDI, diastolic myocardial velocities were sampled at the lateral section of the mitral annulus (Smv, Emv, Amv). From the apical four-chamber view diastolic transmitral flow velocities, including measures of E- and A-waves were performed. The propagation velocity of early flow into the LV cavity was measured by color M-mode Doppler. Plasma BNP levels were measured in all patients. RESULTS: A nonlinear relationship was found between BNP levels and E/A ratio (beta coefficient for the second-order term = 1.4 +/- 0.4, P = 0.001). We also found a positive association of BNP levels with Amv (r = 0.28, P = 0.023), and a reverse with Smv (r =-0.59, P = 0.01) and Emv/Amv (r =-0.36, P = 0.019). Moreover, an inverse relationship was observed between BNP and Vp (r =-0.43, P = 0.012) levels. Finally, a strong positive linear relationship was found between E/Vp ratio and BNP levels (r = 0.76, P < 0.001). CONCLUSION: A U-curved association of E/A ratio of transmitral Doppler velocity was revealed with BNP levels, while the tissue Doppler of the Emv/Amv of the mitral annulus movement showed a negative linear association with BNP levels.     

Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia

Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade^®, 10–20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months (P = 0·005) and continued to decrease over the remainder of the study (P = 0·005). This small‐scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia.     

Heart failure in beta-thalassemia syndromes: a decade of progress

The thalassemias are common monogenic disorders of hemoglobin synthesis. beta-thalassemias are the most important among the thalassemia syndromes and have become a worldwide clinical problem due to an increasing immigrant population. In beta-thalassemia major, regular blood transfusions are necessary early in life. Beta-thalassemia intermedia refers to a less severe phenotype, whereas beta-thalassemia/hemoglobin E disease encompasses a broad phenotypic spectrum. Blood transfusions and increased gastrointestinal iron absorption result in iron overload and tissue damage. Among patients with beta-thalassemia major, biventricular, dilated cardiomyopathy remains the leading cause of mortality. In some patients, a restrictive type of left ventricular cardiomyopathy or pulmonary hypertension is noted. The clinical course, although variable and occasionally fulminant, is more benign in recent than in older series. Myocarditis has been described as a cause of left-sided heart failure in younger patients. Pulmonary arterial hypertension is the principal cause of heart failure in beta-thalassemia intermedia. Chelation therapy has improved prognosis in beta-thalassemia major both by reducing the incidence of heart failure and by reversing cardiomyopathy. Estimation of the patient's cardiac risk is mainly based on clinical criteria and serial echocardiography. A new cardiovascular magnetic resonance technique will probably fulfill the need for more precise risk stratification in beta-thalassemia syndromes. By increasing the proportion of patients on optimal chelation, survival in beta-thalassemia major may further improve. Recent advances in gene therapy are expected to result in the long-awaited cure of this disease.     

A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation

Elevated serum ferritin concentrations are common in clinical practice. In this review, we provide an approach to interpreting the serum ferritin elevation in relationship to other clinical parameters including the patient history, transferrin saturation, serum concentrations of alanine, and aspartate aminotransferases (ALT, AST), testing for HFE mutations, liver imaging, liver biopsy, and liver iron concentration. We used observations from a large series of patients with hepatic iron overload documented by liver iron concentration measurement from two referral practices as a gold standard to guide the interpretation of the predictive values of non-invasive iron tests. Three case studies illustrate common problems in interpreting iron blood tests.     

Hemoglobin Dhonburi alpha 2 beta 2 126 (H4) Val----Gly: a new unstable beta variant producing a beta-thalassemia intermedia phenotype in association with beta zero-thalassemia

While investigating the mechanism of a beta-thalassemia intermedia phenotype in a 34 year old Thai male, a new Hb variant beta 126 Val----Gly named Hb Dhonburi was discovered. Genetic and structural studies revealed the existence of a beta zero-thalassemia genotype in association with the beta variant. The new variant is unstable but exhibits normal oxygen binding properties. Hb Dhonburi was also discovered in the mother of the propositus in association with Hb E.     

Intermediate geriatric care in Geneva: A 10-year experience

The ageing of the population generates an increased demand for acute healthcare services in persons aged over 65, who can represent up to half of the patients treated in intensive care units (ICU). However, the number of available ICU beds is limited. Intermediate care units (IntCU), requires less human and technical resources, and has been proposed as an alternative to intensive care in the geriatric population. This article reports a 10-year, single centre experience from Geneva of continuous care and its impact on mortality in a geriatric population. Between 1998–1999 and 2000–2001, after the creation of the IntCU, we observed a significant reduction in in-hospital mortality. Thanks to increased medical and nursing care, IntCUs provide greater security for patients and their family, thereby improving their satisfaction with care.     

Pacemaker infections: a 10-year experience

BACKGROUND: Infection is a major complication of pacemaker and defibrillator (PPM/ICD) implantation. The experience in an Australian regional centre is reported. METHODS: Ten years' (1994-2004) cases of PPM/ICD infection retrospectively analysed and compared to overall insertion data; management and outcomes examined. RESULTS: A total 39 cases (79.5% male, median age 71.3 years) identified, 24 in the primary centre where 1481 procedures performed (infection rate 1.6%). Patients with infection had average 2.2 procedures performed (odds ratio for infection if >1 procedure=4.7); 14 (36%) first implantations, 35 (90%) pacemakers, 11 (28%) recurrent. No difference in operation duration or difficulty between infected and non-infected cases. Infection in 18 cases (46%) involved lead/s, 16 (41%) generator and 5 (13%) both. Median time to presentation was 7.9 months. Echocardiography demonstrated lead vegetations in 8 cases. Organisms identified in 25 (64%)-92% Staphylococci (65% S. aureus); blood cultures positive in 18. PPM/ICD removed in 26 (67%), including lead/s in 89%; average hospital stay 37 days. One death attributable to PPM/ICD infection (mortality 2.6%), median follow-up 29.3 months. CONCLUSIONS: A PPM/ICD infection rate of 1.6% (endocarditis 0.3%) demonstrated. Second and subsequent procedures carried almost 5 times greater infection risk.