Adrenal insufficiency: An emerging challenge in thalassemia?
Authors: Marina Baldini, Marta Mancarella, Elena Cassinerio, Alessia Marcon, Alberto Giacinto Ambrogio, Irene Motta
Journal: American Journal of Hematology (2017)

Due to dramatic improvements in disease management, thalassemia major patients are now surviving into their fifties and sixties, and face new unexpected medical issues that may require urgent recognition and treatment. Iron overload, due to blood transfusion and to increased iron absorption from ineffective erythropoiesis, still remains the principal cause of morbidity in patients with transfusion-dependent thalassemia (TDT).1 Endocrine functions are markedly affected by iron overload, with the most frequent deficiency being hypogonadotropic hypogonadism, followed by diabetes mellitus, hypothyroidism, and hypoparathyroidism. The hypothalamic–pituitary–adrenal (HPA) axis is generally considered to be an infrequent target of chronic iron toxicity.2 Since adrenal insufficiency may have dramatic consequences in conditions of stress such as sepsis, acute diseases, trauma, and surgery, an early diagnosis is crucial. We report here three cases of adrenal insufficiency diagnosed in an acute setting, in TDT patients. Interestingly, none of them had previously shown symptoms and clinical signs of adrenal insufficiency and all had previously normal basal serum cortisol and ACTH values. Case 1: A 52-year-old male patient was admitted to the Intensive Care Unit in November 2015 for septic shock due to bacterial pneumonia, complicated by atrial fibrillation and heart failure. He was on oral iron chelation therapy with deferasirox (DFX), and the last T2* cardiovascular magnetic resonance (CMR) didn't show liver or cardiac iron overload (Table 1). He had hypogonadotropic hypogonadism, type 2 diabetes, and hypoparathyroidism, all treated with good compliance and results. With the septic shock being unresponsive to intravenous norepinephrine, an adrenal crisis was suspected, and subsequently confirmed by the prompt reversal of hypotension following IV administration of hydrocortisone. The diagnosis was later confirmed by low serum cortisol and ACTH values. Case 2: A 44-year-old male patient was admitted to the Intensive Care Unit in February 2015 for severe sepsis associated with hyponatremia, hypoglycemia, and altered mental state. He was on chelation therapy with DFX and had no liver or heart iron overload at the last T2* CMR (Table 1). The only known endocrine deficiency was hypogonadotropic hypogonadism. A severe hypoglycemia unresponsive to continuous IV glucose administration led to the clinical suspicion of adrenal insufficiency; after IV administration of hydrocortisone, blood glucose levels normalized. Once clinical conditions stabilized, an ACTH stimulation test confirmed the diagnosis of adrenal insufficiency. Case 3: In a 40-year-old male patient, a giant myelolipoma originating in the right adrenal gland was surgically removed.3 He was on iron chelation with DFX with no liver or heart iron overload detected at the last T2* CMR (Table 1). The only known endocrine deficiency was hypogonadotropic hypogonadism, on testosterone replacement. Basal adrenal function was normal; however an ACTH stimulation test prior to surgery was positive for adrenal insufficiency. Replacement with cortisone acetate was immediately started, and surgery was uneventful. Published data about adrenal insufficiency in adult thalassemic patients are scarce, since most studies include patients in their early decades of life.4, 5 The reported prevalence of this complication is extremely variable, depending on iron overload severity, available treatments, and diagnostic criteria. Iron toxicity can affect the HPA axis at different levels. The presence of high ACTH serum concentrations is consistent with direct damage to the adrenal glands, which can be confirmed by magnetic resonance imaging (MRI).6 Lower than normal ACTH levels suggest secondary (central) adrenal insufficiency due to pituitary iron deposition, although combined central and peripheral impairments cannot be ruled out. Adrenal insufficiency develops gradually, and symptoms, such as fatigue, may be aspecific and overlapping with those of chronic anemia. The main risk of undetected disease is that it may present with a life-threatening acute crisis. The hypothesis that subclinical adrenal impairment may be more common than expected in TDT patients, and sometimes revealed by conditions of stress, has been formulated by Scacchi et al.7 In 2010, they described a subnormal response to low-dose tetracosactide test in 32.1% of adult thalassemia patients with normal basal cortisol and ACTH values. At our Rare Disease Center, the annual endocrinological assessment of TDT patients always included basal adrenal function evaluation (ACTH and cortisol basal levels). Since a normal basal function cannot rule out a reduced functional reserve, we are now reconsidering new criteria for performing or repeating the stimulation test. Recently, De Sanctis et al., in a survey on hematologists and endocrinologists, showed poor knowledge in the diagnostic criteria for secondary adrenal insufficiency among hematologists, while higher awareness and knowledge of proper diagnostic criteria were found in centers with a dedicated endocrinologist and an established multidisciplinary approach.8 Further studies on larger thalassemic populations, including non-transfusion dependent thalassemia patients, are needed to establish criteria leading to the decision of performing dynamic tests of adrenal functions, as well as the appropriate use of these tests to inform clinical decisions. Nothing to report.