In this study, we showed that at least one clinical endocrine complication was detected in two out of three TDT patients. The rate of iron deposition was 62.5% in liver, and 45% in pancreas tissue, and was 12.5% in heart tissue. The serum ferritin level of 841 ng/mL was shown as a threshold of iron deposition for liver, and for severe pancreatic iron burden. The pancreatic R2* value of 80 Hz was regarded as the threshold level for further cardiac and hepatic iron evaluation. Patients with short stature showed more iron load in the heart, and the more iron in heart resulted with the higher fasting blood glucose in serum. This result may suggest that patients with iron burden in the heart are at risk for diabetes.
As chelation therapy increased the life span of thalassemia patients, previously unminded complications foremost the endocrinal complications gained importance (16–20). The hypothetical reality of these complications is based on severe iron burden in endocrine organs, which disturbs their synthesis function. From the clinical practice point of view, the unfavorable effect of ferritin on pubertal development can be minimized by the use of appropriate chelation therapy in proper time [21, 22]. A very recent study showed the good effect of appropriate chelation therapy on endocrinologic complications in children with thalassemia [23].
We found that almost half of the patients had pancreatic iron overload. Noetzli et al. [6] and Au et al. [10] found the pancreatic iron load as 80%, Kolnagou et al. [24] found as 85%, de Assis et al. [13] found as 86%, and Meloni et al. [12] found a rate of 93% in patients with thalassemia. Our finding of a more favorable rate is debatable because half of the patients had a higher serum ferritin level over 1000 ng/mL. Even if we had chosen the cut-off value as T2* 26 ms, the iron overload rate in pancreas would be 50%. Furthermore, thalassemia major population and the T2* methodology might be the other possible explanations as it is dependent to the sequence, the software analysis, and the single scanner. On the other hand, our patients were closely followed up using proper chelation therapy.
One of the clinical benefits of MR imaging is that it is more accurate than serum analysis of ferritin in these patients. Previously, a serum ferritin level of over 2500 ng/mL was accepted as a risk factor for mortality in patients with thalassemia [7], currently, a serum ferritin level of 841 ng/mL was detected as the threshold level for liver iron burden and severe pancreatic iron burden using MR imaging. Moreover, a pancreatic R2* value of 80 Hz should alert us to cardiac and hepatic iron evaluation. Similar value of R2* (100 Hz) was shown by Noetzli et al. [6]. The relationship between MR results of organs can clearly show the systemic iron burden, and inform about the following complications that will occur.
Males were found to have a decreased T2* value in the pancreas in the present study. Moreover, we found a decreased level of insulin, and increased level of fructosamine in males compared with the levels in females (p = 0.06 and p = 0.05, respectively). We found no supporting data in the literature. No sex difference was detected between the diabetic patients. Disease duration, age and body mass index showed no difference between male and females. We found no helpful cause for this discrepancy. Pancreatic iron overload causes decreased insulin secretion and thus precipitating diabetes in patients with thalassemia. Insulin resistance, and insulin deficiency together revealed the complexity of diabetes in thalassemia [25, 26]. Thus, pancreatic and liver iron overload is shown to be associated with diabetes in patients with thalassemia [27]. Seventy percent of male patients had hepatic iron overload while 55% of female patients had hepatic iron burden. This finding illustrates that male patients with TDT should be closely followed up in terms of diabetes.
Using MR imaging, recent studies revealed the association between heart and liver with other organs in terms of iron overload [28–30]. We showed that the rate of hepatic (80%) and pancreatic (80%) iron overload were significantly higher among patients with cardiac iron overload. Moreover, the rate of hepatic (84%) and cardiac (22%) iron deposition were also increased among patients with pancreatic iron overload. This finding may be useful in the approach to patients with cardiac, and pancreatic iron burden. A very recent multicenter study with more than 1000 thalassemia major patients showed that patients with cardiac fibrosis and cardiac complications had significantly lower pancreas T2* level [37]. Researchers concluded that pancreatic iron overload is an indicator for cardiac iron burden. Cardiac iron overload can be managed through more aggressive treatment such as a combined chelator because chelation therapy acts on hepatic and extrahepatic tissue and extrahepatic organs release iron very slowly out of the body [31, 35], but also deferiprone in monotherapy [36].
The cardiac iron burden was found associated with diabetes in the recent literature [32]. We found consistent with the literature that the cardiac T2* value was negatively correlated with fasting blood glucose. Similarly, patients with diabetes and thalassemia can develop myocardial fibrosis. Therefore, disorders in carbonhydrate metabolism should be screened in patients with cardiac iron burden, or cardiac complications should be evaluated in patients with diabetes.
Patients with short stature were found prone to cardiac iron overload. In the literature, we found no exact correlation with short stature, and heart iron burden. Short stature can originate from deficiency of growth hormone, lack of growth factors due to liver dysfunction, degenerated bone metabolism, and disease chronicity [33, 34]. The chronic process of iron overload in hepatic and extrahepatic tissues can affect hormonal regulation, which in turn can cease the increase in height. The limitation of our study is its retrospective design, the restricted number of patients with significantly smaller and younger study cohorts, and lack of a control group.