Sara Matin1, Masoud Ghanei Jahromi2, Zohreh Karemizadeh3, Sezaneh Haghpanah4,Vincenzo De Sanctis5, Ashraf Soliman6, Javad Dehbozorgian4, Zahra Majd1, Narges Rezaei4 and Mehran Karimi4*
1 Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Anesthesiology, Jahrom University of Medical Science, Jahrom, Iran
3 Metabolic and Endocrinology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
4 Hematology Research Center, Shiraz University of Medical Science, Shiraz, Iran.
5 Pediatric and Adolescent Outpatient Clinic, Quisisana Private Accredited Hospital, Ferrara (Italy)
6 Department of Pediatrics, Alexandria University Children’s Hospital, Alexandria, Egypt.
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Background. Endocrine dysfunction is not uncommon complication in patients with transfusion-dependent thalassemia and is thought to occur as a consequence of excessive iron overload. The primary objective of this study is to determine the frequency of adrenal insufficiency in patients with thalassemia major and thalassemia intermediate.
Methods. This cross-sectional study was done at the Shiraz University of Medical Sciences, Shiraz, Southern Iran, in 2013. One hundred and ninety patients were divided into two groups; thalassemia major(TM) and thalassemia intermediate (TI) groups. We measured 8 AM serum cortisol, ACTH and ferritin concentrations in all patients.
Results. The mean age of the TM and TI group were 22.5±5.7 and 23.8±6 years, respectively. 90 patients (47.4%) were splenectomized, 34 (36.2%) with TM and 56 (58.2%) with TI (p :<0.001). The median and interquartile range of serum ferritin levels were 2184±3700 ng/ml and 437±443ng/ml in TM and TI respectively (p< 0.001). Three patients with TM (1.6%) had low basal cortisol and ACTH levels. However, their cortisol response to ACTH stimulation was normal.
Conclusions. Low basal concentrations of cortisol and ACTH occurred in 1.6% of our adolescents young adult patients with TM suggesting a central defect in cortisol secretion at the basal state. However, cortisol response to standard – dose ACTH was normal in all patients with TM and TI.
β-thalassemias are a group of hereditary blood disorders
characterized by anomalies in the synthesis of the beta chains of
hemoglobin resulting in variable phenotypes, ranging from severe anemia
to clinically asymptomatic individuals. Three main forms have been
described: thalassemia major(TM) thalassemia intermedia (TI) and
thalassemia minor. Individuals with TM usually present within the first
two years of life with severe anemia, requiring regular red blood cell
The life expectancy of children and adolescents with TM and TI has markedly increased, due to improvement of the quality and techniques of blood transfusion and new development of effective oral iron chelators. However, TI patients still develop iron overload, despite the lack of need for blood transfusions, because of increased intestinal iron absorption.[2-5] Moreover, various endocrine abnormalities have been described in patients with TM and TI and most reports incriminate iron overload as an important factor in the development of target-organ dysfunction.[6,7]
Iron overload is toxic to parenchymal cells because it generates free radicals and induces oxidative stress causing damage to biomolecules, including lipids, proteins, and DNA.[1,3]
Therefore, regular surveillance of these patients is essential for early detection and management of possible complications, such as: heart failure and arrhythmias, chronic liver diseases, endocrine problems (hypogonadism, hypothyroidism, diabetes mellitus, hypoparathyroidism and adrenal insufficiency), growth failure, osteoporosis and thrombophilia.[1,6] In TM, the prevalence of adrenal insufficiency (AI) is variable because of the variable degree and duration of iron overload and not standardized cutoff cortisol values for diagnosing cortisol deficiency. In addition, the prevalence of AI has not been investigated well in adolescent patients with TI. Although, most studies have revealed intact pituitary adrenal axis in TM, several recent studies reported a significant prevalence of subclinical “biochemical” AI, ranging from 18-45% in these patients.[8-15] AI is either primary, due to deposition of excess iron in the adrenal gland or secondary due to the toxic effects of iron in the pituitary gland.[16-18] The combined measurement of early morning serum cortisol and plasma ACTH separates patients with primary adrenal insufficiency from healthy individuals and from those with secondary disease. While the diagnosis of overt adrenal failure is generally straightforward, the identification of asymptomatic patients with subtle dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is still a diagnostic challenge.
We assessed basal and stimulated cortisol secretion in relation to the degree of iron overload in 190 consecutive adolescent patients with TM and TI.
Subjects and Methods
Ninety-four TM and ninety-six TI patients were investigated. The
mean age of the TM and TI group were 22.5±5.7 and 23.8±6 years,
respectively. No significant age difference was found between the two
In the TM group, 55 subjects (58.5%) were females and 39 males (41.5%). In the TI group, 41 (42.7%) were women. All patients with TM have been on iron chelators with deferoxamine (DFO) (70%), combined DFO and deferiprone (DFP) (10%) or deferasirox (DFX) (20%).
The compliance to DFO and DFX iron chelators were fair and good, respectively. Among the study subjects, 90 (47.4%) had splenectomy, 34 (36.2%) with TM and 56 (58.2%) with TI, respectively (p:0.001). The median and interquartile range of serum ferritin levels in TM and TI groups were 2184±3700 ng/ml and 437±443 ng/ml respectively (p< 0.001). (Table 1)
In general, an early morning (8 am) plasma cortisol level lower than 6.2 µg/dL – (10th percentile) is suggestive for primary AI, whereas a value higher than 15 μg/dL makes the diagnosis highly unlikely. Therefore, we performed an ACTH stimulation test only in 3 patients (2 males and a female; 1.6%) with low basal levels of cortisol (Table 2).
Patient 1 was on treatment with DFO and had dilated cardiomyopathy with normal left ventricular ejection fraction (LVEF). Patient 2 has short stature and pubertal delay with mild systolic and diastolic cardiac dysfunction. He has been on iron chelation therapy with DFO plus DFP and L-thyroxine therapy for primary hypothyroidism. Patient 3, while on treatment with DFX, presented with diabetes mellitus, dilated cardiomyopathy and normal LVEF. None of the 3 TM patients were on sex hormone replacement therapy or had received corticosteroids treatment.
Patients 2 and 3 had poor compliance with iron chelation therapy.
The plasma cortisol response at 60 minutes post ACTH injection should reach ≥ 18 μg /dl in normal people. In our TM patients, the cortisol responses to ACTH stimulation test resulted in normal range (Table 2).
All patients with TI had normal basal serum ACTH and cortisol concentrations.
The median of ACTH concentrations did not differ significantly between patients with TM and TI (p: 0.072, Table 1). The median serum ferritin and basal serum cortisol levels were significantly higher in TM versus TI patients (p<0.001, Table 1).
|Table 1. Comparison of median and interquartile range of the serum ferritin (ng/ml), cortisol (µg/dL) and ACTH (pg/ml) between TM and TI groups.|
|Table 2. Age, sex, serum ferritin (ng/ml), basal ACTH (pg/ml), cortisol (ng/ml ) basal and after ACTH stimulating test (30 and 60 min).|
Our findings support the small prevalence of AI in adolescents and
young adults with TM. All patients with TI have normal basal cortisol
and ACTH secretion.
An early morning (8 am) plasma cortisol level lower the 10° percentile is suggestive for adrenal insufficiency, whereas a value higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol levels of intermediate range may be seen in patients with primary, secondary or tertiary adrenal insufficiency. In those cases and in patients with low basal cortisol and standard response to ACTH a strict collaboration with the endocrinologist is needed.