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(Radiology. 2000;215:818-823.)
© RSNA, 2000

Neuroradiology

Transfusional Hemochromatosis: Quantitative Relation of MR Imaging Pituitary Signal Intensity Reduction to Hypogonadotropic Hypogonadism1

Gianvincenzo Sparacia, MD, Alberto Iaia, MD, Aurelia Banco, MD, Paolo D'Angelo, MD and Roberto Lagalla, MD

1 From the Institute of Radiology, Università di Palermo, Italy (G.S., A.B., R.L.); the Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (A.I.); and the Department of Pediatrics, Thalassemia Service, Ospedale "Villa Sofia," Palermo, Italy (P.D.). Received June 21, 1999; revision requested August 11; revision received September 29; accepted October 20. Address correspondence to G.S., Viale Strasburgo, 167, 90146 Palermo, Italy (e-mail: sparacia@unipa.it).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To assess the relationship between magnetic resonance (MR) imaging pituitary signal intensity reduction in patients with transfusional hemochromatosis and the clinical manifestation of hypogonadotropic hypogonadism.

MATERIALS AND METHODS: Pituitary MR imaging at 0.5 T was performed in 38 consecutive patients affected by secondary hemochromatosis and in 20 healthy volunteers. Serum ferritin levels were estimated in the affected population. Twenty (53%) of the 38 patients had hypogonadotropic hypogonadism diagnosed. Pituitary-to-fat signal intensity ratios were calculated from coronal gradient-echo (GRE) T2*-weighted MR images. The relationship between the quantitative reduction of the pituitary-to-fat signal intensity ratio and the clinical manifestation of pituitary dysfunction was assessed in the affected population. Signal intensity reduction in the anterior lobe of the pituitary gland was also correlated with the serum ferritin level.

RESULTS: The degree of reduction of the pituitary-to-fat signal intensity ratio correlated with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%. In addition, the reduction of pituitary signal intensity was greater in patients with higher ferritin levels (r = -0.55, r2 = -0.30, P < .001).

CONCLUSION: The degree of signal intensity reduction, measured as the pituitary-to-fat signal intensity ratio for GRE T2*-weighted images, in patients with secondary hemochromatosis correlates with the severity of pituitary dysfunction.

Index terms: Anemia, 145.652 • Hemochromatosis, 145.519 • Hormones • Pituitary, diseases, 145.519 • Pituitary, MR, 145.121412


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Hemochromatosis is a disorder caused by excess iron deposition in parenchymal cells that leads to cellular damage and organ dysfunction. The disorder has two categories: genetic (or primary) hemochromatosis and secondary (or acquired) hemochromatosis. In primary hemochromatosis, an inherited autosomal recessive defect results in elevated intestinal iron absorption, despite normal iron intake. Secondary hemochromatosis results from iron overload due to elevated intake, classically in the form of repeated blood transfusions (1,2); such a clinical scenario may be seen in the setting of ineffective erythropoiesis, for instance, in patients with thalassemia major.

The abnormal condition that ensues is similar in both primary and secondary hemochromatosis. When serum levels are elevated, iron is initially deposited in the reticuloendothelial cells; however, when their capacity is saturated (at about 10 g), the excess iron is deposited in parenchymal cells of the liver, spleen, and bone marrow in a crystalline form as ferritin and hemosiderin (3–5). Cirrhosis is a known clinical manifestation of hemochromatosis-induced hepatic failure. Eventually, as iron stores continue to increase, there is deposition in the skin, heart, gonads, and endocrine glands (2,6). Involvement of the pancreas, for instance, will cause parenchymal damage to the gland, which eventually will manifest itself as diabetes mellitus (7).

Iron deposition has also been described in other endocrine glands, including the anterior lobe of the pituitary gland. As a number of patients affected by hemochromatosis eventually develop hypogonadism, it has been postulated that this may in part be secondary to iron-induced cellular damage to the gonadotrophs (8,9). The presence of excess tissue iron can be demonstrated with magnetic resonance (MR) imaging, as the superparamagnetic effects of iron shorten T2 relaxation times (1,10,11).

Findings of a number of studies have shown that by exploiting such superparamagnetic effects pituitary iron deposition can be demonstrated with MR imaging in the form of a reduction of signal intensity in the anterior lobe (12–15). Gradient-echo (GRE) T2*-weighted imaging has been shown to be the most sensitive sequence for detecting excess pituitary iron deposition (16).

We performed this study to evaluate the MR imaging signal intensity reduction in the anterior lobe of the pituitary gland in patients with thalassemia and transfusional hemochromatosis and to investigate the relationship of the degree of signal intensity reduction to the clinical severity of pituitary dysfunction manifested as hypogonadotropic hypogonadism.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Subjects
The study was approved by the local ethics committee, and written informed consent was obtained from all patients before starting the clinical study. Thirty-eight consecutive patients with secondary hemochromatosis due to transfusion-dependent thalassemia major (12 female, 26 male patients; age range, 12–40 years; mean age, 23.3 years ± 6 [SD]) underwent MR imaging examination of the pituitary gland. They were being treated with transfusion regimens that maintained the hemoglobin level between 9.5 and 10.5 g/dL (95 and 105 g/L) and received iron chelation therapy with deferoxamine mesylate (Desferal; Ciba-Geigy, Basel, Switzerland), which consisted of an 8–10-hour subcutaneous infusion at the dosage of 40–50 mg/kg per day five to six times per week.

Serum ferritin levels were measured in all patients by using radioimmunoassay to assess the severity of iron overload. Plasma testosterone levels were measured in male patients, plasma estradiol levels were measured in female patients, and plasma luteinizing hormone and follicle-stimulating hormone levels were measured in all patients by using radioimmunoassay. A gonadotropin-releasing hormone challenge test was performed, with acquisition of luteinizing hormone and follicle-stimulating hormone levels at 0, 30, 45, 60, 90, and 120 minutes after intravenous administration of 2 mL of gonadorelin containing 0.1 mg of sermorelina (Relisorm SL 100; Serono, Aubonne, Switzerland). These laboratory data were collected to confirm the diagnosis of hypogonadotropic hypogonadism.

Twenty (53%) of the 38 patients had a diagnosis of hypogonadotropic hypogonadism established with laboratory data (see the previous paragraph) and on clinical grounds, with impotence or poor sexual activity, testicular atrophy, and rarefaction of pubic hair. Thus, the patients were divided into two groups: Group 1 (n = 20; five female, 15 male patients; age range, 15–40 years; mean age, 22.5 years ± 5.7 [SD]) comprised patients with hypogonadotropic hypogonadism; group 2 (n = 18; seven female, 11 male patients; age range, 12–34 years; mean age, 24.0 years ± 6.6) comprised patients without hypogonadotropic hypogonadism. Hormonal status is summarized in the Table.


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  		Hormonal Values
 
Twenty healthy volunteers (eight female, 12 male volunteers; age range, 12–38 years; mean age, 26.5 years ± 7.0) underwent imaging as a control group.

MR Imaging Examination
MR imaging examinations were performed with a 0.5-T superconducting unit (Vectra; GE Medical Systems, Milwaukee, Wis) by using a GRE T2*-weighted sequence (650/30 [repetition time msec/echo time msec]; flip angle, 20°). Four-millimeter coronal images parallel to the pituitary stalk and 4-mm sagittal images through the pituitary gland were obtained with an intersection gap of 1 mm and four signals acquired. The image matrix was 192 x 256. The field of view was 24 cm.

Image Analysis
Signal intensities were measured in consensus by two investigators (G.S., A.B.), with the use of operator-defined regions of interest of 3 mm2 on the coronal GRE T2*-weighted images.

The midline of the pituitary gland in the coronal plane was established as the midpoint between the medial borders of the intracavernous internal carotid arteries' flow voids. From this point, the mean signal intensity of the anterior lobe of the pituitary gland was determined as the mean of the signal intensities from three regions of interest placed in the midportion and the left and right sides of the anterior lobe. The signal intensity of fat was also measured with a single region of interest of 3 mm2 placed in the nasopharyngeal fat between the medial pterygoid muscle and the lateral pterygoid muscle on the left.

The ratio of the mean adenohypophyseal signal intensity to the nasopharyngeal fat signal intensity (pituitary-to-fat signal intensity ratio) was calculated. Data acquired from healthy control subjects were used as a reference.

Statistical Analysis
Data are presented as means ± SDs. The significance of the differences in mean values between patients and control subjects was assessed by using the Student t test. A P value of less than .05 was considered to indicate a significant difference. To determine the correlation between MR imaging results and the severity of iron overload in the adenohypophysis, we performed a simple regression analysis by using serum ferritin levels and pituitary-to-fat signal intensity ratios. Statistical analysis was performed by using a statistical software program (ANALYSE-IT; Analyse-It Software, Leeds, United Kingdom).

The sensitivity and specificity of pituitary-to-fat signal intensity ratios in differentiating group I patients from group II patients were calculated and were charted as a receiver operating characteristic (ROC) curve by using the software program ROCKIT 0.9B (Metz CE, University of Chicago, Ill, 1998). It estimates a ROC curve with the assumption of bivariate normality. Thresholds for calculating sensitivity and specificity were defined by the upper limits of normal for biologic test results and were arbitrary for other results.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
All patients had elevated serum ferritin levels (mean, 3,302 µg/L ± 1,783; normal level, <300 µg/L), and their images showed reduction of signal intensity in the anterior lobe of the pituitary gland as compared with the signal intensity of the anterior lobe in control subjects (Fig 1). Specifically, the reduction in signal intensity was significantly different (P < .001) between the 38 (100%) patients and the control subjects, as well as between group 1 (20 [53%] of 38 patients) or group 2 (18 [47%] of 38 patients) and the control group (Fig 2).



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  		Figure 1a. Coronal GRE T2*-weighted images (650/30; flip angle, 20°) of the pituitary gland in a (a) 22-year-old male group 1 patient, (b) 18-year-old male group 2 patient, and (c) 23-year-old male healthy volunteer. The pituitary glands in a and b show markedly decreased signal intensity compared with that in c. Note that the pituitary gland in a shows almost no signal intensity comparable to that of air in the sphenoid sinus (s) and that it is lower in signal intensity than that in b.

 


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  		Figure 1b. Coronal GRE T2*-weighted images (650/30; flip angle, 20°) of the pituitary gland in a (a) 22-year-old male group 1 patient, (b) 18-year-old male group 2 patient, and (c) 23-year-old male healthy volunteer. The pituitary glands in a and b show markedly decreased signal intensity compared with that in c. Note that the pituitary gland in a shows almost no signal intensity comparable to that of air in the sphenoid sinus (s) and that it is lower in signal intensity than that in b.

 


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  		Figure 1c. Coronal GRE T2*-weighted images (650/30; flip angle, 20°) of the pituitary gland in a (a) 22-year-old male group 1 patient, (b) 18-year-old male group 2 patient, and (c) 23-year-old male healthy volunteer. The pituitary glands in a and b show markedly decreased signal intensity compared with that in c. Note that the pituitary gland in a shows almost no signal intensity comparable to that of air in the sphenoid sinus (s) and that it is lower in signal intensity than that in b.

 


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  		Figure 2. Chart shows pituitary-to-fat signal intensity ratios for the control group, all patients, group 1 patients, and group 2 patients. Values are expressed as means ± SDs. * indicates a P less than .001 in a comparison with values in control subjects. Note that all patients showed a reduction in the signal intensity of the anterior lobe of the pituitary gland as compared with that in the control subjects and that the reduction in signal intensity was more evident in patients with secondary hypogonadism (group 1 patients).

 
At ROC analysis, the area under the curve was 0.966 (Fig 3); therefore, the degree of signal intensity reduction in the anterior lobe of the pituitary gland was a reliable predictor in distinguishing group 1 patients from group 2 patients. With a pituitary-to-fat signal intensity ratio threshold of 1.1, we correctly identified 18 group 1 patients (true-positive results), with only two false-positive and two false-negative results (Fig 4). There were 16 true-negative results. The likelihood of hypogonadotropic pituitary dysfunction could thus be predicted by using the 1.1 pituitary-to-fat signal intensity ratio threshold, with a sensitivity and specificity of 90% and 89%, respectively, and an overall accuracy of 89%.



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  		Figure 3. Graph shows the ROC curve for using pituitary-to-fat signal intensity ratios in differentiating group 1 from group 2 patients. FPF = false-positive fraction, TPF = true-positive fraction. The area under the curve is 0.966; thus, the degree of signal intensity reduction in the anterior lobe of the pituitary gland is a reliable predictor of secondary hypogonadism.

 


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  		Figure 4. Scattergram of pituitary-to-fat signal intensity ratios versus patient population distribution. With the 1.1 pituitary-to-fat signal intensity ratio threshold (crossbar), a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89% in differentiating group 1 from group 2 patients was reached.

 
For all the patients, a negative correlation was found between the pituitary-to-fat signal intensity ratios and serum ferritin levels (r = -0.55, r2 = -0.30, P < .001). While the degree of signal intensity reduction was more pronounced in patients with higher serum ferritin levels, the results of regression analysis did not demonstrate a linear relationship between plasma ferritin concentration and MR imaging signal intensity reduction.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Secondary hemochromatosis is a condition encountered in patients undergoing repeated blood transfusions, which create a state of iron overload. The excess iron, as it is distributed in numerous organs, impairs the normal physiology of these organs. For instance, iron deposition in the liver, the pancreas, and the anterior lobe of the pituitary gland can create clinical dysfunction in the form of cirrhosis, diabetes mellitus, and secondary hypogonadism, respectively (2,4,7–9).

Imaging findings in organs with excess iron have been extensively described (4,6). Iron deposition in the liver, for instance, creates abnormally high attenuation at computed tomography (17). At MR imaging, there is marked signal intensity reduction due to decreased T2 relaxation time and magnetic field inhomogeneities created by the excess intracellular iron (1,10). Furthermore, it has been shown that, within certain ranges, the degree of signal intensity reduction on T2*-weighted images correlates linearly with the quantity of hepatic intracellular iron (11).

The presence of cerebral iron has also been investigated with MR imaging. Vymazal et al (18) found a linear correlation between the cerebral iron levels and the signal intensity reduction on MR images. It has been shown that MR imaging can be useful in determining pituitary iron overload in patients with hemochromatosis, whether they presented with clinical evidence of secondary hypogonadism (12,15) or with other nonpituitary manifestations of hemochromatosis (13,16).

The GRE T2*-weighted sequence has usually been regarded as the most sensitive technique for the detection of parenchymal iron deposition; this is likely due to the lack of a 180° refocusing pulse that partially recovers signal loss from the field inhomogeneity in spin-echo imaging (19,20). In fact, among the various imaging techniques that have been investigated, the best predictor of adenohypophyseal iron overload has been the signal intensity reduction in the anterior lobe of the pituitary gland on GRE T2*-weighted images (16).

Specifically, reduction of the pituitary-to-fat signal intensity ratios for GRE T2*-weighted images has been shown to be more sensitive for the determination of adenohypophysial iron deposition than other techniques, which include the pituitary-to-muscle signal intensity ratio for GRE T2*-weighted images. An explanation of this finding may be that fat behaves as inert tissue in relation to iron deposition, while the same is not true for muscle, as its signal intensity may be heterogeneous because of the presence of fat in fascial planes (20). Moreover, in a study on iron overload in the African population, the nonheme iron concentration in muscle was shown to increase with increasing body iron stores (21). Although GRE imaging is most sensitive to signal intensity reduction due to iron deposition, it can create substantial technical limitations at the skull base because of the susceptibility artifacts at the inferior aspect of the sella turcica and the adjacent pneumatized sphenoid sinus (22).

In this study, we demonstrated a highly significant (P < .001) reduction in the pituitary-to-fat signal intensity ratios on GRE T2*-weighted images in patients with transfusional hemochromatosis. Furthermore, we demonstrated a significant correlation between the degree of MR imaging signal intensity reduction in the anterior lobe of the pituitary gland and the presence of severe physiologic dysfunction of the gland.

Specifically, we found that by establishing a cutoff of 1.1 for the pituitary-to-fat signal intensity ratio for GRE T2*-weighted imaging, one can predict the presence of secondary hypogonadism with an accuracy of 89%. Our study findings demonstrated that 90% of patients with hemochromatosis and secondary hypogonadism (group 1 patients) had a pituitary-to-fat signal intensity ratio for GRE T2*-weighted imaging below 1.1, but only 11% of patients with hemochromatosis without secondary hypogonadism (group 2 patients) had a ratio below this cutoff. Patients with the lowest signal intensities (presumably representing higher hypophyseal iron levels) were much more likely to demonstrate clinical evidence of pituitary failure in the form of hypogonadotropic hypogonadism and tended to have higher serum ferritin levels than patients without hypogonadotropic hemochromatosis.

These findings lend support to the theory that excess iron deposition directly affects pituitary gonadotrophs. As findings of a histopathologic study by Bergeron and Kovacs (8) have shown, excess iron deposition causes pathologic changes in the gland that manifest as degranulation of the adenohypophysiocytes and decreased hormone storage within such cells. Furthermore, it has been shown that the excess iron deposition in the anterior lobe of the pituitary gland is preferentially distributed in the gonadotrophs and that the hypogonadism that ensues is due to pituitary hyporesponsiveness to gonadotropin-releasing hormone (23). Our observations suggest that the iron-induced cytotoxic effects on the gonadotrophs may occur when a threshold of iron overload is reached.

Findings of studies on liver iron overload have shown that serum ferritin levels do not have a linear correlation with the quantity of tissue iron deposition (1,20). It has been shown that only about half of the variation in serum ferritin levels accounts for similar variations in hepatic iron levels (24,25). Our results in transfusional hemochromatosis also indicate the limit of the serum ferritin level as a quantitative marker of adenohypophyseal iron concentration.

We found that patients with higher serum ferritin levels had more dramatic reductions of signal intensity in the anterior lobe of the pituitary gland. However, while we demonstrated that the inverse relationship between the serum ferritin level and the MR imaging signal intensity reduction is statistically significant (r = -0.55, r2 = -0.30, P < .001), results of the regression analysis did not demonstrate such a relationship to be linear. Therefore, the lack of a linear relationship impairs one's ability to exactly quantify adenohypophyseal iron deposition simply on the basis of varying serum ferritin levels.

In part, the challenge of estimating pituitary iron levels by using MR imaging is due to the indirect effects that are being measured, namely, the effect of ferritin and hemosiderin iron on the proton resonance behavior of tissue water (1). This is a complex interaction that involves several factors, including the number and size of iron cores in ferritin and hemosiderin, the hydration status, the applied field strength, and the MR imaging parameters used in the imaging sequences (16,20,25).

A number of points should be made with regard to the potential clinical applications of these data. First, as MR imaging does not yield absolute values, and in view of the differences in GRE sequences and in field strength among different MR imagers, our results obtained with a 0.5-T unit should be carefully interpreted and reproduced with MR units of different strengths prior to clinical application; it is reasonable to assume that, as the T2* shortening effect increases at least linearly with increasing magnet strength, the degree of signal intensity reduction in the adenohypophysis would be more dramatic at a higher field strength. On the other hand, higher field strength systems exacerbate skull base artifacts, as their stronger magnetic gradients increase the phase shift discrepancies (22).

Second, controversies exist with regard to the potential for reversibility of hypogonadotropic hypogonadism in patients with pituitary hemochromatosis by using iron-depletion therapy (23,26). Nonetheless, findings of some studies have indicated that gonadal dysfunction may be reversible at least in the early stage of both primary and secondary hemochromatosis (27–30). MR imaging could thus prove clinically useful; it could provide for earlier diagnosis of iron overload in the adenohypophysis, so that effective therapy might be initiated in a timely fashion to prevent or delay the clinical manifestations of secondary hypogonadism.

In summary, excess iron deposition in the anterior lobe of the pituitary gland leads to secondary hypogonadism in advanced cases of transfusion-induced hemochromatosis. We have shown that MR imaging with use of a GRE T2*-weighted pituitary-to-fat signal intensity ratio is a useful noninvasive tool for detecting adenohypophyseal iron overload in patients with transfusional hemochromatosis and for predicting the likelihood of pituitary dysfunction.


   Footnotes
 
Abbreviations: GRE = gradient echo, ROC = receiver operating characteristic

Author contributions: Guarantor of integrity of entire study, G.S.; study concepts and design, G.S.; definition of intellectual content, all authors; literature research, G.S., A.I.; clinical studies, G.S., A.B.; data acquisition, G.S., A.B.; data analysis, G.S., A.I.; statistical analysis, G.S.; manuscript preparation, G.S., A.I.; manuscript editing, G.S.; manuscript review, G.S., A.I., R.L.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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