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Endocrine complications in iron overload
complications, there is not a LIC threshold below which cardiac and endocrine iron accumulation does not occur.27 The explanation of this paradox is that many chronically transfused patients have fully-saturated transferrin, regard- less of their LIC,28 and, as heart and endocrine glands exclu- sively accumulate NTBI, it is possible for them to be in pos- itive iron balance even if the total body iron balance (LIC) is neutral or negative.27 Patients who miss chelator doses expose their extrahepatic organs to unrestricted uptake of labile iron species.29
Previous studies reported a correlation between cardiac T2* and manifest endocrinopathies.21,22 However, those studies concerned patients with severe iron overload, with T2* <20 msec, while our sample had average ferritin <1,000 ng/mL, LIC <5 mg/dry weight (dw), and T2* >30 msec which are considered as the acceptable target levels to reach during iron-chelating therapy.18 It has been shown that the iron overload of endocrine glands preceded that of the heart, although both phenomena are mediated by NTBI.11 However, endocrine organs have superior reserve capacity and the clinical manifestations concerning them may appear years after silent iron accumulation.12 When iron overload continues, due to the lack of patient compliance or due to an inadequate dose of iron-binding therapy, the heart starts to show signs of overload, which can be identi- fied through MRI-T2*.20 Therefore, cardiac T2* is not an early indicator of iron overload. We have not found a corre- lation between T2* and endocrine complications in our cohort of patients, as the vast majority of our patients had an acceptable iron balance. Abnormal cardiac T2* is an excellent marker of NTBI control, but it is insensitive because exposure must be severe and quite prolonged. As a result, abnormal cardiac T2* has a very high positive predic- tive value for endocrine iron deposition. However, once the heart has been successfully de-ironed, endocrine glands typ- ically retain moderate iron deposition. Finally, even when the endocrine glands have been successfully de-ironed, their functional reserve has been destroyed.4,11,12,20-22
As there is considerable variation in the risk of endocrinopathies in patients without signs of heart and liver overload,17,21,22,30–32 and because those kinds of endocrinopathies, when manifest, are irreversible,17,21,22,30–32 further clinical and laboratory predictors in addition to MRI imaging of endocrine glands are needed to prevent endocrine complications.
We proposed our risk chart on the model 3B, in which the association between risk of complication and age was considered as being linear, while adding a binary marker of adulthood and an interaction parameter between age and adulthood. We preferred this model to the simpler model 3A (log-linear age alone) because it had a slightly better R2 and mostly because adults and children affected by TDT are usually treated in separate health care centers and as a matter of fact they define two separate categories. We have developed the largest analysis on endocrine compli- cations in TDT patients ever developed so far and this is the first study providing clear benchmarks for patients’ management. However, the predictive power of our risk chart must be improved and validated.
It is plausible that a diagnosis of an endocrinopathy pro- duces a warning effect that is similar to that observed after an abnormal cardiac T2*, which makes patients have bet- ter compliance and clinicians increase iron-chelating dose.33 That may explain why previous endocrinopathies were associated with lower incidence of new ones in our
sample. Another reason may be that the therapy for an endocrine disease ameliorates the function of other endocrine axes. This has been previously shown for BMD, metabolic syndrome, and glucose and lipid metabolism disorders after treatment for hypothyroidism and hypogo- nadism.34–36 Furthermore, endocrine glands are not equally vulnerable to the iron toxicity, and patients with more endocrinopathies have already wiped out the most endan- gered endocrine glands.
All our patients were on regular iron-chelation therapy and had acceptable levels of iron load. Therefore, the markers of iron overload were expected to be stable over time or to have minor fluctuations. However, iron over- load increased for same patients. If that phenomenon was due to scarce patient compliance and if compliance was associated with our explanatory variables, our estimates may be biased. However, also iron overload measures taken contemporaneously with disease incidence have shown no effect, as well as their deltas. A lack of compli- ance could have been assumed if at least the latest tests assessing iron overload were associated with higher risk.
Heightened TSH has been associated with endothelial dysfunction,37 defined as a diminished bioavailability of nitric oxide (NO) and/or an increase in vasoconstrictive factors such as endothelin (ET-1). That condition has been well documented in thalassemia patients and is associated with cardiac, hepatic and endocrine clinical complications.32,38 Endothelial dysfunction in TDT is a pro- gressive process, starting from childhood, and recent stud- ies found significantly higher plasma levels of asymmetric dimethylarginine (ADMA), a novel risk marker of cardio- vascular disease implicated in the pathogenesis of endothelial dysfunction, in very young TDT children.39 So, increased TSH may be an early expression of systemic endothelial dysfunction in TDT which is considered an independent risk factor of future complications.32 TSH appears the best marker of systemic endocrine gland dys- function, as its measurement is very accurate and widely used in clinical practice,40 differently from the several limits in the assessment of other pituitary hormones, as growth hormone (GH), adrenocorticotropic hormone (ACTH), LH/FSH.41 Furthermore, production of TSH is the last affected by the progressive damage of pituitary gland in TDT patients which impairs firstly GH secretion, followed by LH/FSH and ACTH.42 For all these reasons, TSH may be the sentinel for endocrine gland dysfunction. Along with TSH, age is also associated with endothelial dysfunction, which could be the main driver of endocrine and cardio- vascular risk.32 These observations pave the way for the early identification of clinical complications in other meta- bolic diseases, which have been reported greatly affected by iron overload.24
The variation in risk of complications that our best model could explain was insufficient (25%). Therefore, there must be factors other than those we considered that have some effect on the incidence on endocrine complica- tions. These may include NTBI, transferrin saturation, smoking, other markers of endothelial dysfunction, pan- creas and pituitary R2* which weren’t considered. Furthermore, the different chelation history among the study cohort (older patients treated for longer with subcu- taneous DFX compared to younger patients treated for longer with oral DFX) creates an inherent age effect to be taken into consideration.
The apparent increase in endocrine complications after
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