Athanasios Christoforidis

Correlative study of iron accumulation in liver, myocardium, and pituitary assessed with MRI in young thalassemic patients.

Clinical complications resulting from unevenly iron accumulation in individual organs of patients with β-thalassemia major can affect both expectancy and quality of life. Magnetic resonance imaging (MRI) offers a quantitative, noninvasive, accurate method for estimating iron levels in various tissues, not easily accessible with other techniques. The aim of this study was to evaluate and correlate the level of iron accumulation in different organs (anterior pituitary, myocardium, and liver) assessed with MRI, in children and young adults with β-thalassemia major. Thirty children and young adults (13 female and 17 male patients) with homozygous β-thalassemia, treated conventionally, were studied with hepatic, myocardial, and hypophyseal MRI. For liver and myocardium, we calculated the natural logarithm of the signal-to-air ratio in flash 2-dimensional sequences with electrocardiogram gating, whereas for anterior pituitary, the signal intensity was measured in sagittal T2 sequences. All scans were performed within 3 months. In 13 patients, data regarding liver iron concentrations (LIC) assessed by percutaneous liver biopsy were available. The mean of serum ferritin concentrations for 1 year before scans was calculated for each patient. MRI values in myocardium and liver showed a significant negative correlation to age (r=−0.73 and −0.69, respectively). For pituitary MRI, a linear regression with age was recorded in patients over 14 years of age (r=−0.67), whereas a relatively increased signal intensity reduction was recorded in pubertal subjects. Mean serum ferritin concentrations ranged from 252 to 5872 μg/L with an average of 1525±1047 μg/L. No statistical significant correlation was noted between mean ferritin levels versus liver, pituitary, and cardiac MRI values (r=−0.49, −0.28, and −0.1, respectively). Mean LIC values assessed by percutaneous biopsy were 13.76±11.6 mg/g of dry tissue. A statistically significant negative correlation was observed between liver MRI readings and LIC determined by biopsy (r=−0.89). None of the 3 organs studied with MRI were significantly correlated to each other. Pituitary to liver MRI values and liver to myocardial MRI values were moderately correlated (r=0.34 and 0.42, respectively). Pituitary MRI was not correlated at all to myocardial MRI (r=−0.001). In conclusion, iron accumulation in thalassemic patients is a procedure progressing with age, which seems to act independently in different organs. MRI represents a reliable, noninvasive method for assessing iron overload in various tissues, noneasily accessible with other techniques. Regular scanning, to recognize preclinically excessive iron deposits and intensified chelation therapy, can prevent serious and fatal complications.

MRI assessment of liver iron content in thalassamic patients with three different protocols: comparisons and correlations

Our aim was to assess liver iron content, in thalassaemic patients, by using three different MR protocols and compare their data. Ninety‐four thalassaemic patients (44 M and 50 F, mean age 25.82 ± 8.3 yrs), were enrolled in the study. In each patient, three measurements of the liver iron content were performed, with the use of a single imager, equipped with a 1.5 Tesla magnet. Liver R2* was measured on gradient‐echo sequence. Calculation of MR‐HIC values was based on an algorithm using liver to muscle (L/M) ratios in five axial gradient‐echo sequences. Finally, determination of liver R2 employed a 16‐echo, spin‐echo pulse sequence. Additionally, myocardial R2* value was determined for each patient. Results showed that all three magnetic resonance imaging (MRI) methods were highly correlated to each other and significantly correlated to serum ferritin concentrations. Liver R2 method showed an increased sensitivity in detecting liver iron contents in the upper range. No correlation occurred between each liver MRI parameter and myocardial R2* values. Finally, we managed to provide formulae for equating values obtaining with any of these three MRI methods.

Four-year evaluation of myocardial and liver iron assessed prospectively with serial MRI scans in young patients with β-thalassaemia major: comparison between different chelation regimens

This study was conducted in order to assess myocardial and liver iron concentrations (LICs) using serial magnetic resonance imaging (MRI) scans in patients with β‐thalassaemia major, over a 4‐yr period, and consequently to compare the effectiveness of different chelation regimens. Fifty children and young adults with β‐thalassaemia major (27 boys and 23 girls) were recruited (mean age: 14.74 ± 3.67 yr). All patients underwent detailed clinical examination, electrocardiography, echocardiography, myocardial and liver MRI at the beginning of the study, 2 and 4 yr after. Additionally, serum ferritin levels were regularly measured and data regarding LICs assessed by percutaneous liver biopsy were available in 26 patients. Both myocardial and liver MRI values showed a moderate inverse correlation with age (r = −0.379, P < 0.001 and r = −0.376, P < 0.001, respectively). Liver MRI was better correlated with serum ferritin concentrations (r = −0.342, P < 0.001) than myocardial MRI (r = −0.186, P = 0.011). Liver MRI values were highly correlated with LICs derived from percutaneous liver biopsy (r = −0.863, P < 0.001), whereas myocardial MRI values did not correlate at all with measurements derived from echocardiography. Regarding iron chelation treatment, patients receiving combined therapy with deferiprone and deferoxamine (DFO) significantly reduced myocardial iron overload during the 4‐yr study period, whilst patients in monotherapy with DFO showed a significant increase in LIC.

Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls

This study was conducted to assess the role of pelvic ultrasound variables in discriminating between normal girls and girls with different forms of sexual precocity, and to establish reliable cut‐off limits of pelvic ultrasound measurements for differentiating between these conditions.

Comparative study of dual energy X‐ray absorptiometry and quantitative ultrasonography with the use of biochemical markers of bone turnover in boys with haemophilia

Summary.  Our aim was to evaluate bone status in boys with haemophilia using dual energy X‐ray absorptiometry (DXA) and quantitative ultraSonography (QUS), and in addition, to compare these two methods with the use of biochemical markers of bone turnover. Twenty‐six boys with a mean decimal age of 12.08 ± 4.44 years were included in the study which included a DXA scan at lumbar spine and radial, as well as tibial QUS. Serum levels of soluble receptor activator of nuclear factor κB ligand (sRANK‐L), osteoprotegerin (OPG) and osteocalcin (OC) were measured and joint evaluation was performed using the Hemophilia Joint Health Score (HJHS). With regard to the study results, only 2 of 26 patients (7.7%) had bone mineral density (BMD) Z‐scores <−2, and 4 patients (15.4%) had BMD Z‐scores between −1 and −2. Only one patient had radial and other two had tibial QUS Z‐scores <−2. No agreement was recorded between QUS and DXA in identifying patients at risk for osteoporosis (k = 0.275, P = 0.063). Haemophiliacs had significantly higher serum levels of sRANK‐L (21.04 ± 4.78 vs. 18.58 ± 2.28 ng mL−1, P = 0.038) and of OC (5.35 ± 2.29 vs. 3.09 ± 0.61 ng mL−1, P = 0.002) and significantly decreased levels of OPG (15.78 ± 2.53 vs. 23.79 ± 4.39 pg mL−1, P < 0.001) compared with controls. QUS Z‐scores at tibia significantly correlated with HJH Scores (r = −0.450, P = 0.040), whereas lumbar BMD Z‐scores significantly correlated with body mass index Z‐scores (r = 0.500, P = 0.009). More studies are warranted to identify the most accurate densitometric method for assessing bone status in haemophiliacs.

Comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with β-thalassemia major

The aim of this study was to compare the effect of different long-term chelation regimens on heart and liver iron stores with the use of T2* magnetic resonance imaging (MRI) in patients with transfusion-dependent β-thalassemia major. Sixty-four patients (28 men, 36 women; mean age, 26.49 ± 5.8 years) were enrolled in the study. The 3 groups were based on the chelation therapy received. The first group (19 patients) received deferiprone (DFP) (75 mg/kg per day orally), the second group (23 patients) received deferoxamine (DFO) (30–50 mg/kg per day subcutaneously at least 5 times/week), and the third group (22 patients) received a combination of DFO (30–50 mg/kg per day, 2–3 days/week) and DFP (75 mg/kg per day, 7 days/week). MRI scans were acquired with an imager equipped with a 1.5 T magnet, and the data included myocardial and hepatic iron measurements obtained by means of T2*, and ventricular volumes and ejection fractions obtained with standard cardiovascular MRI techniques. The results revealed that the DFP and the combined groups had significantly less myocardial iron than the DFO group (mean myocardial T2*, 35.77 ± 18.3 milliseconds and 38.05 ± 15.3 milliseconds versus 23.77 ± 13 milliseconds [P =.02, andP =.001], respectively). On the contrary, the DFP group had a significantly higher hepatic iron content than the DFO and combined groups (mean hepatic T2*, 3.29 ± 2.5 milliseconds versus 8.16 ± 8.4 milliseconds and 11.3 ±10.9 milliseconds [P =.014, andP =.003], respectively). No correlation was observed between myocardial T2* and hepatic T2* values (r =-0.043;P =.37). Myocardial T2* values were inversely correlated with age (r =-0.249;P =.024) and positively correlated with both left and right ventricular ejection fractions (r = 0.33 [P =.004], andr = 0.279 [P =.014], respectively). Finally, liver T2* was strongly and inversely correlated with serum ferritin concentration (r =-0.465;P =.001). In conclusion, combined chelation therapy seems to sum the beneficial effects of DFO and DFP with respect to hepatic and myocardial iron. Because myocardial iron is not related to measurements of serum ferritin or hepatic T2*, important decisions on clinical management relating to cardiac risk should not rely on these conventional parameters. Thus, the use of MRI for assessing myocardial iron should be adopted in the routine clinical management of patients with β-thalassemia major.

Sonographic assessment of uterine and ovarian development in normal girls aged 1 to 12 years

To provide normal references of sonographic uterine and ovarian size in girls aged 1–12 years.

Bone status of children with hemophilia A assessed with quantitative ultrasound sonography (QUS) and dual energy X-ray absorptiometry (DXA).

Recent studies report reduced bone mineral density (BMD) even among young adults and children with hemophilia. Our aim was to assess bone status in children and adolescents with hemophilia with 2 methods: Quantitative UltraSonography (QUS) and Dual energy x-ray Absorptiometry (DXA), and consequently to investigate the degree of correlation between them. Twenty-seven patients (17 with severe hemophilia; residual factor activity <1% and 10 with moderate hemophilia) participated in the study. Mean age was 12.28±4.48 y (range: 4.94 to 18.00 y). All patients were evaluated with QUS at radius and at tibia and had DXA scan at lumbar spine. Anthropometric parameters were measured using standard techniques and joint evaluation was carried out using the Hemophilia Joint Health Score (HJHS). Only 2 out of 27 patients (7.5%) had BMD Z-scores <−2, whereas another 4 patients (15%) had BMD Z-scores between −1 and −2. QUS values in both radius and tibia were generally within the normal limits as only 1 patient had radius and another 1 had tibia QUS Z-score <−2. HJH scores were significantly although negatively correlated to Z-scores of tibia QUS (r=−0.455, P=0.034). No correlations were observed between lumbar BMD and radius or tibia QUS and no agreement was recorded between QUS and DXA in identifying patients at risk for osteoporosis (k=0.262). In conclusion, our study showed that only a small number of children and young adults with hemophilia have impaired bone properties as assessed both by DXA and QUS; no correlation was observed between these 2 methods.

Combined chelation therapy improves glucose metabolism in patients with β-thalassaemia major

Douek, D.C., Vescio, R.A., Betts, M.R., Brenchley, J.M., Hill, B.J., Zhang, L., Berenson, J.R., Collins, R.H. & Koup, R.A. (2000) Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution. The Lancet, 355, 1875–1881. Hakim, F.T. & Gress, R. (2005) Reconstitution of the lymphocyte compartment after lymphocyte depletion: a key issue in clinical immunology. European Journal of Immunology, 35, 3099–3102. Hakim, F.T., Memon, S., Cepeda, R., Jones, E.C., Chow, C.K., KastenSportes, C., Odom, J., Vance, B.A., Christensen, B.L., Mackall, C.L. & Gress, R.E. (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. Journal of Clinical Investigation, 115, 930–939. Mansky, P., Arai, A., Stratton, P., Bernstein, D., Long, L.L., Reynolds, J., Chen, D., Steinberg, S.M., Lavende, N., Hoffman, K., Nathan, P.C., Parks, R., Augustine, E., Chaudhry, U., Derdak, J., Wiener, L., Gerber, L. & Mackall, C. (2006) Treatment late effects in long-term survivors of pediatric sarcomas. Pediatric Blood Cancer, (Epub ahead of print, 26 April 2006). Watanabe, N., De Rosa, S., Cmelak, A., Hoppe, R., Herzenberg, L.A. & Roederer, M. (1997) Long-term depletion of naı̈ve T cells in patients treated for Hodgkin’s disease. Blood, 90, 3662–3672. Weinberg, K., Blazar, B.R., Wagner, J.E., Agura, E., Hill, B.J., Smogorzewska, M., Koup, R.A., Betts, M.R., Collins, R.H. & Douek, D.C. (2001) Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood, 97, 1458–1466.

Poor correlations between measurements of bone quality by quantitative ultrasound sonography and dual energy X‐ray absorptiometry in patients with β‐thalassaemia major

Objectives:  Osteopenia/osteoporosis is a major component of morbidity even in young patients with β‐thalassaemia major. Dual energy X‐ray absorptiometry (DXA) is the reference method for determining bone mineral density (BMD). Quantitative ultrasound sonography (QUS) for bone measurement is a relatively new, inexpensive and radiation‐free method that could serve as an alternative to DXA. Our aim was to assess bone status in thalassaemic patients both with QUS and DXA and, consequently, to investigate the degree of correlation between the two methods.