The Prevalence of Adrenal, Parathyroid and Cardiac Dysfunction in Patients with Beta Thalassemia Major ()
1. Introduction
Adrenal gland dysfunction is an uncommon endocrine complication in patients with blood transfusion dependent Beta-Thalassemia Major (β-TM) [ 1 ]. In patient with β-TM, repeated blood transfusion and hemolysis of red blood cell, end up with iron overload [2]. Iron deposition affects adversely the function and the structure of myocardium, liver, parathyroid, thyroid and adrenal gland [3].
Iron chelating therapy at present is considered the standard care of this blood disorder with significant improvement of morbidity and increased rate of survival [4]. Patients with β-TM in the second decade of life and due to the lack of tolerance of chelating therapy and the repeated blood transfusion had delayed puberty, short stature and small weight compared with the normal people due to endocrine dysfunction namely hypogonadism, hypoadrenalism and hypothyroid dysfunction [5].
Left Ventricle (LV) systolic and diastolic function assessed by echocardiogram in patients with β-TM showed variable abnormalities depending on the patient’s disease severity and age [6,7].
LV diastolic function had been classified into three patterns of diastolic velocities, abnormal relaxation, pseudonormal and restrictive velocity pattern depending on ratio of LV early diastolic velocity (E wave) and the late filling (A wave) in addition to deceleration time of E wave [8].
The LV diastolic velocity pattern depends on the degree of predominance of the altered wall stiffness or the abnormal active relaxation. The restrictive pattern is characterized by high E wave velocity, diminished A wave, short DT and very high E/A ration >1.8 [9].
The Tissue Doppler echocardiography (TD) can detect regional myocardial diastolic dysfunction even in early phases of cardiac injury [10]. The TD velocity at the basal septum of mitral annulus, has been evaluated as a marker of myocardial stiffness and it was suggested that the ratio of early diastolic filling wave of PD to mitral annulus DT velocity (E/Em) does correlate positively with the LV end-diastolic pressure (LVEDP) [11]. Furthermore, it was shown that TD velocities of the early diastolic wave (Em) and systolic wave (Sm) were both reduced in stiff hypertensive myocardium [12].
Previous studies with multiple blood transfusions in β-TM patients showed variable prevalence of adrenal insufficiency in the range of 0% - 35% depending on the age of the study population, duration of blood transfusions, the level of serum Ferritin and the dose of iron chelating agent [13,14].
This study aims to 1) examine the incidence of adrenal insufficiency in patient with β-TM; 2) assess the correlation between the serum levels of cortisol hormone and serum Ferritin; and 3) evaluate the echocardiographic indices of LV systolic and diastolic functions using M mode and pulsed Doppler in transfusion dependent β-TM patients.
2. Material and Methods
The study subjects were 99 patients with transfusiondependent β-TM and 98 healthy individuals as a control group. The study was conducted over 12 month period from December 2011 to December 2012. Consecutive patients on regular follow-up in the Pediatric Hematology clinic at Salmaniya Medical Complex (SMC) in Bahrain were selected. The control group consisted of referred patients for assessment of Cardiac murmur in the pediatric clinic in the hospital. A constitutional ethical approval was obtained for the study.
2.1. Inclusion Criteria
In this cross sectional prospective study, each patient with β-TM after signing consent form gave a blood sample and booked for an echocardiogram in the same week. The blood test was done at the end of the week just prior to the blood transfusion. Patients were excluded if they had severe liver disease, an end-stage renal disease with creatinine clearance <30% of normal, advanced heart failure or hypertension cardiomyopathy.
2.2. Clinical and Biochemical Variables
Each patient in the study had a clinical and hematological data file including duration of disease, general examination for the pulse, blood pressure, presence or absence of pubic and axillary hair, cardiovascular assessment for apex beat displacement, jugular venous pressure wave, cardiac murmurs, lung field, hepatosplenomegaly and ankle edema.
Height and weight were obtained; the body surface area (BSA) and body mass index (BMI) were derived. The blood level of hemoglobin, serum ferritin, morning cortisol hormone, parathormone, calcium, phosphate, potassium, sodium and creatinine/estimated glomerular filtration rate (eGFR) were all recorded. The corrected calcium level was obtained by upward of calcium by 0.1 mmol/L for each 5 gm reduction of albumin below 40 gm/L.
Parathyroid hormone and cortisol were both analyzed using Chemiluminescence immune assay method with normal range of morning cortisol of (190 - 690 nmol/L) and parathormone of (1.0 - 6.5 nmol/L).
2.3. Echocardiography
Each patient in the study had the echo examination by 2.5 - 5 MHz transducer, using HP E33 echo machine. The echocardiography tests were performed by an echo technologist, who was blinded about the clinical condition of the patient. Data was reported as an average of at least five cardiac cycles. Another echo technician analyzed the data blindly and the data was taken as an average of the two readings. All measurements were conducted according to the recommendations of the American Society of Echocardiography (ASE) [15].
Each patient had echocardiographic measurements including M-mode, 2D echo, LV diastolic filling velocities. The M-mode echo parameters including the LV septal wall thickness, posterior LV wall thickness, mid LV cavity dimension in systole (LVESD) and diastole (LVEDD). Fractional shortening (FS%) and LV ejection fraction percentage (LVEF%) were measured using Teichholz formula: V = (7.0/(2.4 + D)*D3) [16]. Pulsed Doppler was acquired in the apical view, while patients in the partial left lateral decubitus position during the end of expiration.
The tissue Doppler velocity of the basal septal mitral annulus, early filling E wave velocity (Em), the calculated E/Em ratio and the systolic wave (Sm) were all recorded as a mean of five readings. The tricuspid valve velocity in systole (cm/s) was measured in apical view.
2.4. Statistical Analysis
The data was entered and analyzed using the Statistical Package of Social Sciences (SPSS) version 17.0 and presented as mean ± SD. Unpaired student t-test was used to analyze the differences between the variables in the control and the β-TM groups. The M-mode dimensions of the LV were adjusted and indexed for BSA of each patient. Correlation was tested between the serum level of cortisol as dependent variable and ferritin as independent variable. All other pulsed and tissue Doppler indices for systolic and diastolic functions were corrected for heart rate such as: E wave velocity, A wave velocity, DT, E/A ratio, E/Em ration, S wave and Em wave. The differences between groups was considered statistically significant at a probability value of <0.05.
3. Results
The demographic and biochemical data of all β-TM patients and the healthy controls are summarized in table 1. The β-TM patients are matching with the control group in age and gender with higher preponderance of male in both groups. β-TM patients had significantly lower body surface area and body mass index compared with control patients of (1.16 ± 0.11 vs 1.39 ± 0.14, p < 0.05) and (17.5 ∓ 1.9 vs 24.16 ∓ 2.7, p < 0.001) respectively. The mean difference between the serum potassium, sodium, corrected calcium and phosphate and eGFR in both groups is of no statistical significance. The serum ferritin level is significantly higher in the β-TM group compared with the control group (3337.87 ± 741.14 μg/L vs 220.56 ± 48.14 μg/L, p < 0.001).
The mean of serum cortisol and parathyroid hormones in β-TM patients are significantly lower than the control of (251.6 ∓ 63.7 vs 484.7 ∓ 84.3 nmol/L, p < 0.001) and (respectively 1.4 ∓ 1.2 vs 4.5 ∓ 2.7 nmol/L, p < 0.001). Pearson correlation test between ferritin and cortisol equals to −0.334 (p-value = 0.001). There is a weak negative relationship between ferritin and cortisol. This means that as the ferritin level increase the cortisol level decrease.
Table 2 shows the hemodynamic and echocardiographic variables in both groups. The blood pressure in systole and diastole and the heart rate were with no significant differences. In β-TM patients compared with