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M. Casale et al.
increase 0.5, 95% CI: 0.4–0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients’ risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.
Introduction
Transfusion-induced iron overload in thalassemia patients typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. However, those three phenomena have been studied to different extents.
In transfusion-dependent thalassemia (TDT) patients, mortality due to cardiovascular and hepatic complications has markedly declined during the last decades.1–3 The devel- opment of magnetic resonance imaging techniques (MRI), specifically designed to quantify myocardial and hepatic iron concentration, measuring heart T2* and liver iron con- centration (LIC), has enabled the design of clinical trials evaluating the efficacy of iron chelators in targeting specific iron overload.4 Moreover, new anti-hepatitis C drugs have remarkably reduced the complications linked to hepatitis C infection, which used to dramatically deteriorate liver iron overload.5
However, in spite of the outstanding advances in the care of cardiovascular and hepatic complications due to blood transfusions, the management of endocrine complications has been left behind and, nowadays, they are the most fre- quent and the most resource-draining complications in TDT patients.3 In addition, serological testing fails to iden- tify high-risk groups and, once occurred, these complica- tions are often irreversible. While MRI imaging of endocrine glands is promising in detecting preclinical dis- ease, it has not reached the level of validation required for routine clinical use.6
The once-daily oral iron chelator deferasirox (DFX) was shown to be effective in chelating iron from the heart and the liver, with preservation of the heart function,7–9 and with reversal of the hepatic fibrosis.10 While the effective control of heart and liver siderosis remains the primary goal in the management of TDT patients, observational data suggest that iron loading in endocrine organs may precede myocar- dial involvement and there is now substantial evidence on the role of iron overload in endocrine morbidity.11–14 While there have been small studies on endocrine disorders in TDT patients during chelation therapy with DFX,15,16 the data are still scarce, even though DFX is nowadays the most prescribed drug for iron chelation in TDT patients.17
The aim of this study was to assess the incidence of endocrine diseases including hypothyroidism, hypoparathyroidism, glucose metabolisms disorders, hypogonadism, and metabolic bone disease in patients suf- fering from TDT who are on treatment with the drug DFX.
Methods
In this multi-center study, TDT patients from 21 hospitals locat- ed in 21 cities and 19 regions of Italy were assessed for eligibility to be recruited in the cohort.
We considered the following endocrine conditions:
1. Hypothyroidism (overt: thyrotropin [TSH] >10 mU/mL and low free thyroxine [FT4]; subclinical: TSH 5–10 mU/mL and nor- mal FT4).
2. Hypoparathyroidism (low parathyroid hormone [PTH] and calcium and high phosphorus).
3. Hypogonadism (hypogonadotropic hypogonadism, in adult female: amenorrhea, low estradiol levels and low or normal luteinizing hormone and follicle stimulating hormone [LH/FSH] levels; in adult male: low testosterone levels, clinical signs or symptoms consistent with hypogonadism and low/normal LH/FSH. Testosterone reference ranges vary according to patients’ age at the time of biochemical assessment. In general, they were regarded as normal if >3.5 ng/mL and unequivocally pathological <2.3 ng/mL. Additional data [clinical features, free testosterone] were taken into account for values between 2.3 and 3.5 ng/mL. Hypergonadotropic hypogonadism, in adult female: amenorrhea and raised FSH [>30 U/L] with undetectable estradiol; in adult male: raised gonadotropins with low total testosterone and clinical signs consistent with hypogonadism).
4. Pubertal disturbances (delayed puberty: lack of breast bud- ding [Tanner stage 2] in girls by the age of 13 and testicular volume <4 mL in boys by the of 14; arrested puberty: lack of pubertal pro- gression over a year or more).
5. Disorders of glucose metabolism (diabetes: fasting plasma glucose ≥126 mg/dL or 2-hour plasma glucose [2-h PG] value dur- ing a 75-g oral glucose tolerance test [OGTT] >200 mg/dL; impaired fasting glucose [IFG]: fasting glucose between 100 and 125 mg/dL; impaired glucose tolerance: 2-h PG during 75-g OGTT levels between 140 and 199 mg/dL).
6. Bone metabolism disorder (BMD) (osteoporosis: bone miner- al density T score ≤-2.5 and Z score value ≤-2; osteopenia: T score value 1.01/-2.5 and Z score value 1.01/-2. In childhood, osteoporo- sis was defined by either the association of at least two patholog- ical fractures by the age of 10 years/ three by the age of 19 and Z score ≤-2 or by the finding of at least one vertebral crush, in the absence of high-energy trauma or local disease, irrespectively of the BMD recorded; low bone mineral density was defined as the finding of BMD Z score ≤-2, in the absence of the above-men- tioned additional criteria for osteoporosis).
According to standardized protocols,18 laboratory tests for detection of endocrine disorders were performed every year in patients with no endocrine complications and more frequently (every 3-6 months) in patients with endocrine disorders, as per consolidated clinical practice and according to the endocrinolo- gists’ prescription. Routine laboratory tests, such as glycemia and serum electrolytes, were assessed every 1-3 months in occasion of pre-transfusion cross-match testing. Weight, height and Tanner stage were assessed every 6 months in patients <18 years of age.
The study protocol was approved by Ethical Committees and Institutional Review Boards of all the participating centers and was conducted in accordance with the Declaration of Helsinki and ICH guidelines for good clinical practice. All patients provided written informed consent.
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