1 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
2 Departments of Pediatrics, University of Alexandria, Alexandria, Egypt.
3 Director of Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation, Antalya, Turkey.
4 National Center for Cancer Care and Research, Medical Oncology Hematology Section HMC, Doha, Qatar.
5 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman.
6 Department of Pediatrics, Ain Shams University, Cairo, Egypt.
7 Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon,” Naples, Italy.
8 Department of Paediatrics, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
9 Red Blood Cell and Haematopoietic Disorders Unit. Institute for Leukaemia Research Josep Carreras (IJC) and University of Barcelona, Catalonia, Spain.
10 First Department of Paediatrics, National Kapodistrian University of Athens, Athens, Greece.
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in thyroid function and thyroid function tests occur in patients with
β-thalassemia major (TM). The frequency of hypothyroidism in TM
patients ranges from 4% to 29% in different reports. The wide variation
has been attributed to several factors such as patients' genotype, age,
ethnic heterogeneity, treatment protocols of transfusions and
chelation, and varying compliance to treatment. Hypothyroidism is the
result of primary gland failure or insufficient thy¬roid gland
stimulation by the hypothalamus or pituitary gland. The main laboratory
parameters of thyroid function are the assessments of serum
thyroid-stimulating hor¬mone (TSH) and serum free thyroxine (FT4). It
is of primary importance to interpret these measure¬ments within the
context of the laboratory-specific normative range for each test. An
ele¬vated serum TSH level with a standard range of serum FT4 level is
consistent with subclinical hypothyroidism. A low serum FT4 level with
a low, or inappropriately normal, serum TSH level is consistent with
secondary hypothyroidism. Doctors caring for TM patients most commonly
encounter subjects with subclinical primary hypothy¬roidism in the
second decade of life. Several aspects remain to be elucidated as the
frequency of thyroid cancer and the possible existence of a
relationship between thyroid dysfunction, on one hand, cardiovascular
diseases, components of metabolic syndrome (insulin resistance) and
hypercoagulable state, on the other hand. Further studies are needed to
explain these emerging issues. Following a brief description of thyroid
hormone regulation, production and actions, this article is
conceptually divided into two parts; the first reports the spectrum of
thyroid disease occurring in patients with TM, and the second part
focuses on the emerging issues and the open problems in TM patients
with thyroid disorders.
Regulation of Thyroid Hormones Production and Physiologic Actions
Prevalence of Thyroid Disorders in Thalassemia Major1. Primary Hypothyroidism. The advent of more precise diagnostic techniques, which enable different aspects of thyroid function assessment, showed that hypothyroidism is a graded phenomenon. Therefore, several definitions have been used to define different aspects of impaired thyroid function including in TDT patients. The following grades have been identified: 1) Sub-biochemical hypothyroidism consists of an exaggerated TSH response to TRH test in the presence of normal TSH and FT4; 2) Sub-clinical hypothyroidism is a combination of high TSH (> 4.2 mIU/L and <10 mIU/L) with normal FT4 levels; 3) Overt (clinical) hypothyroidism is a combination of high TSH (TSH >10 mIU/L) with low FT4.
|Figure 1. Correlation between the age at diagnosis of primary and secondary hypothyroidism vs. the year of diagnosis (R2 =0.47). From: Delaporta P, Karantza M, Boiu S, Stokidis K, Petropoulou T, Papasotiriou I, Kattamis C, Kattamis A. Thyroid Function in Greek Patients with Thalassemia Major. Blood. 2012;120: Abs. 5176).|
|Table 1. Prevalence of thyroid dysfunctions and thyroid cancer in 364 Greek TM patients (mean age 33.0±9.9 years, 180 females and 184 males). From Delaporta P, Karantza M, Boiu S, Stokidis K, Petropoulou T, Papasotiriou I, Kattamis C, Kattamis A. Blood 2012;120: Abs. 5176, modified.|
Clinical Manifestations and other Diagnostic Parameters
The Long-Term Natural History of Thyroid Function in Thalassemia
Risk Factors for the Development of Thyroid Disorders in Addition to Iron Overload
Prevention of Endocrine Complications
|Figure 2. Prevalences of endocrine complications in 3 groups of 273 β-thalassemia major patients followed at the Thalassemia Centre of Ferrara. Cohorts 1 and 2 started late chelation therapy with desferrioxamine given s.c. (mean age: 16.7 ± 2.8 years and 9.1 ± 2.9 years, respectively) and Cohort 3 started early therapy (mean age: 2.8 ± 1.0 years) (From Ref. 21, modified).|
|Figure 3. Percentage of endocrine complications in patients with β-thalassemia major in relation to the compliance with long-term iron chelation therapy with desferrioxamine (De Sanctis V, personal observations).|
|Figure 4. When to consider treatment of hypothyroidism. Abbreviations: MRI: Magnetic Resonance Imaging; N: normal thyroid-stimulating hormone (TSH) level.|