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1
Department of Radiology, School of Medicine, University of Ioannina, 45110,
Ioannina, Greece.
2
Department of Physiology, School of Medicine, University of Ioannina, 45110,
Ioannina, Greece.
3
Department of Internal Medicine, Endocrine Unit, School of Medicine,
University of Ioannina, 45110, Ioannina, Greece.
Received April 11, 2000;
accepted after revision May 25, 2000.
Address correspondence to M. I. Argyropoulou.
Abstract
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SUBJECTS AND METHODS. In 29 patients with ß-thalassemia major and 40 controls, we assessed the 1/T2 of the pituitary gland in a 1.5-T MR unit, using a multiecho spin-echo sequence. In all patients, an extensive endocrine evaluation was performed, including measurements of spontaneous and stimulated levels of gonadotropins, thyroid hormones, growth hormone, insulinlike growth factor, and adrenal hormones.
RESULTS. A positive correlation was found between the 1/T2 and the serum ferritin level (r = 0.73, p < 0.001). The 1/T2 was higher in patients (mean, 0.020 msec-1; SD, 0.006) compared with that of controls (mean, 0.011 msec-1; SD, 0.001; p < 0.001). The 1/T2 was higher in patients with hypogonadotropic hypogonadism (mean, 0.024 msec-1; SD, 0.006) in comparison with that of patients without any pituitary dysfunction (mean, 0.017 msec-1; SD, 0.004; p < 0.05).
CONCLUSION. The T2 relaxation rate could be used as an index of pituitary iron overload, and it might be of value to monitor treatment with deferoxamine in patients with ß-thalassemia major.
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Patients with iron overload are treated with chelating agents such as deferoxamine. However, this type of treatment has complications and should be adapted to the needs of each patient [1]. The plasma level of ferritin, an iron storage protein, have been used as a marker of the degree of the body's iron burden. However, a direct assessment of iron deposition in different organs necessitates tissue biopsy, which is not always possible [6, 7].
In several studies MR imaging has been used for the evaluation of the degree of iron deposition in the tissues of patients with primary or secondary hemochromatosis [6,7,8,9,10,11,12,13]. A decrease in signal intensity has been observed in tissues with iron overload. This decrease is due to magnetic field inhomogeneities created by iron [14,15,16,17,18]. Therefore, on MR imaging, the adenohypophysis of patients with iron overload shows low signal intensity [9,10,11,12]. There are few previously published data, mainly case reports [11, 12], and only two MR studies of the pituitary gland with reference to a series of patients with ß-thalassemia major [10, 13]. The pituitary gland of these patients has been evaluated mainly by gradient-echo T2* sequences [9, 10, 13]. However, quantitative data of the T2 relaxation rate (1/T2) could be important for evaluating the degree of pituitary siderosis.
In this study we examined the pituitary gland of patients with ß-thalassemia major, using a 1.5-T unit. The purpose of the study was to evaluate the T2 relaxation rate as a marker of pituitary iron overload and to evaluate the relationship between the T2 relaxation rate and pituitary gland function.
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MR imaging of the hypothalamo-hypophyseal axis was performed in all patients and in 40 age- and sex-matched controls on a 1.5-T unit (Gyroscan ACS NT; Philips Medical Systems, Best, The Netherlands) with a head coil. The MR protocol consisted of the following parameters: sagittal and coronal T1-weighted images (TR/TE, 500/20; slice thickness, 3 mm with 0.3 intersection gap; field of view, 18 cm) and a single-slice spin-echo sequence (TR/TEs, 2000/20,40,60,80,100,120,140, and 160; slice thickness, 4 mm; matrix size, 256 x 256; field of view, 23 cm). The single-slice sequence was performed in a strictly midline sagittal plane and in a coronal plane passing from the middle of the anterior lobe. T2 values were calculated by the MR unit and displayed on the gray scale as an image. The T2 time was evaluated by the region of interest method. The region of interest covered the entire anterior lobe visualized in the section, and one measurement was taken in each plane. The two measurements were then averaged.
The serum ferritin levels of all patients were measured the day of the MR study. Routine baseline laboratory tests were performed in addition to extensive endocrine evaluation, including free thyroxine, triiodothyronine, thyrotropin, cortisol, dehydroepiandrosterone sulfate, adrenocorticotropic hormone, testosterone, estradiol, luteinizing hormone, folliclestimulating hormone, prolactin, insulinlike growth factor I, and growth hormone levels. The patients also underwent provocative testing with arginine (0.5 g/kg in a 10% solution), L-dopa (250-500 mg), insulin (0.1 U/kg), thyrotropin-releasing hormone (200 µg), and gonadotropin-releasing hormone (100 µg). Serum ferritin level measurements were determined by a standard method [19]. The hormone serum levels were assayed with radioimmunoassay kits described elsewhere [20, 21].
All hormone assays were performed 1-8 days before the MR study. Moreover, none of the subjects in our study took any hormones or medication known to affect hypothalamic—pituitary function for at least 3 months before MR imaging. Informed consent was obtained from all subjects or from parents of the children included in the study. The study was performed with the approval of the institutional review board.
To assess the normality of distribution of the parameters, the Kolmogorov-Smirnov test was used. We studied the relationship between T2 relaxation rate and the serum ferritin level using the Pearson's correlation coefficient. Differences in T2 relaxation rates between patients and controls and between patients with pituitary gland dysfunction and those with normal pituitary gland function were studied with an unpaired two-tailed Student's t test. A p value less than 0.05 was considered statistically significant.
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In all patients the basal serum cortisol, free thyroxine, and triiodothyronine levels were within the normal range, as were the cortisol and growth hormone responses to provocative tests and the thyrotropin responses to the thyrotropin-releasing hormone test. Fifteen patients had subnormal serum luteinizing hormone and follicle-stimulating hormone responses to gonadotropin-releasing hormone, indicating hypogonadotropic hypogonadism (group 1), whereas in the remaining 14 patients responses were normal (group 2).
The T2 relaxation rate of the pituitary gland was greater in group 1 (mean, 0.024 msec-1; SD, 0.006) than that in group 2 (mean, 0.017 msec-1; SD, 0.004; p < 0.05). The T2 relaxation rate was greater in patients (mean, 0.020 msec-1; SD, 0.006) compared with that of the controls (mean, 0.011 msec-1; SD, 0.001; p < 0.001).
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The present study was performed with a 1.5-T unit, and the T2 relaxation rate was calculated with a multiecho spin-echo sequence. The T2 relaxation rate of the pituitary gland was significantly higher in patients with ß-thalassemia major than in those in the control group. This finding is not in agreement with the report of Sparacia et al. [9], who, using a 0.5-T unit to compare patients with ß-thalassemia major and healthy controls, did not find any significant differences in the T2 relaxation time of the pituitary gland. The apparent discordance between the two studies might be attributed to differences in strength of the magnetic field of the MR unit they used because T2 relaxation phenomena are more pronounced in magnetic fields of higher strength [14,15,16,17]. Moreover, the evaluation of the T2 relaxation rate is more precise at higher field strength because of an increase of the signal-to-noise ratio [18].
In patients with thalassemia the serum levels of ferritin are used as an index of total body iron load. However, ferritin and hemosiderin are intracellular iron storage proteins, and the degree of their concentration changes in different tissue [2, 3]. Therefore, an index of tissue iron deposition is necessary to evaluate the degree of local siderosis. Previous studies have shown that the T2 relaxation rate represents a good index of liver siderosis because it correlates well with serum ferritin levels and with iron content in hepatic biopsies [6, 7]. In the present study, a good correlation was found between the T2 relaxation rate of the pituitary and serum ferritin levels. This correlation allows a quantification of the pituitary T2 relaxation rate and therefore offers an index of pituitary siderosis.
In patients with ß-thalassemia major, hypogonadotropic hypogonadism is one of the most common endocrine abnormalities [1, 4, 5, 10, 13]. Histologic studies of the pituitary gland of patients with hemochromatosis showed nonheme iron in all five cell types of the adenohypophysis, but it was more pronounced in the gonadotrophs [2]. In patients with thalassemia, hypogonadotropic hypogonadism is considered the result of a decreased pituitary responsiveness to gonadotropin-releasing hormone because of damage of the adenohypophyseal gonadotrophs caused by iron cytotoxicity [4, 5]. The cytotoxic effect of iron appears to correlate with the quantity of iron in a specific organ [1,2,3]. Fifteen of 29 patients with thalassemia had hypogonadotropic hypogonadism. In these patients the pituitary T2 relaxation rate was higher compared with that in the patients with thalassemia without hypogonadotropic hypogonadism, indicating a higher degree of adenohypophyseal siderosis.
In conclusion, pituitary T2 relaxation rate correlates well with serum ferritin levels and represents a reliable marker of pituitary siderosis that might be of value to monitor treatment with defer-oxamine in patients with ß-thalassemia major.
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  Z Metafratzi, M I Argyropoulou, D N Kiortsis, C Tsampoulas, N Chaliassos, and S C Efremidis T2 relaxation rate of basal ganglia and cortex in patients with {beta}-thalassaemia major Br. J. Radiol., May 1, 2001; 74(881): 407 - 410. [Abstract] [Full Text] [PDF]
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