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Endocrine complications in iron overload
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Side effect D Ferritin†
D LIC† D T2*† D TSH†
D TSH index†
D BMD femur (g/cm2)†
D BMD L1-L4 (g/cm2)†
2.8% (9/322) -405.3 (1263.5) -1.7 (6.6) 3.7 (12.1) 0.2 (4.0) 0.1 (0.8) 0.0 (0.2) 0.0 (0.2)
1.9% (2/104) 0.63 -413.4 (1481.1) 0.96 -1.7 (4.9) 0.97 3.4 (14.7) 0.85 0.3 (1.9) 0.89 0.2 (0.9) 0.29 -0.0 (0.2) 0.23
-0.1 (0.5) 0.009
For normally-distributed variables, data are presented as mean (standard deviation [SD]) with P-value from ANOVA. For log-normal variables, data are presented as geometric mean (×/geometric SD) with P-value from ANOVA on logged values. For continuous variables with other types of distributions, data are presented as median (interquartile range [IQR]) with P-value from Kruskal-Wallis test. For categorical variables, data are presented as % (n/total) with P-value from Pearson's chi-squared test. *Measured at baseline, unless otherwise specified. †Intra-individual difference between measures taken at the end and at the beginning of the follow-up. DFX: deferasirox ; BMD: bone metabolism dis- order; LIC: liver iron concentration; EF: ejection fractions; FT4: free thyroxine; TSH: thyrotropin; PTH: parathyroid hormone.
CI: 0.10–0.37). According to model 3A, each 50% increase in age was associated with an increase of about 18% in the hazard of an incident new disease (P=0.005) after having adjusted for TSH and number of previous endocrine conditions. Kaplan-Meier survival probability curves are reported in the Online Supplementary Appendix.
Table 4A shows the 5-year risk predictions according to levels of age, TSH, and number of endocrine diseases at baseline, based on estimates from model 3B. On average, the whole cohort of patients had a risk of 9.7% (95% CI: 6.3–13.1) of developing an additional endocrine disease within 5 years from the start of therapy with the drug DFX. However, there was considerable variation accord- ing the baseline conditions. For example, an average 14- year-old patient with a TSH of 3 mIU/L who already suf- fered from one endocrine disorder had a risk of develop- ing another disorder within 5 years of about a 10%, whereas a 35-year-old patient with a TSH of 5 mIU/L and no disease at baseline had a risk of 50%. Table 4B shows the 1-year risk predictions according to levels of age, TSH and number of endocrine diseases at baseline, based on estimates from model 3B. The overall 1-year risk was 1.1% (95% CI: 0.6–1.7).
Fifty-five patients were on therapy with levothyroxine at the beginning of the follow-up. We carried out a sensi- tivity analysis by running the same analysis on patients who were and were not on levothyroxine separately to see if levothyroxine modified the estimates from the final models. In patients who were (n=55) and were not (n=371) on levothyroxine, the adjusted hazard ratio [HR] for 1 mIU/L increase in TSH was 1.26 (95% CI: 1.02–1.55, P=0.032) and 1.29 (95% CI: 1.07–1.56, P=0.006) respec- tively. The estimates from the other predictors did not change either. Therefore, TSH was a predictor of addi- tional endocrine disease incidence regardless of levothy- roxine administration. In addition, we conducted strati- fied analyses after splitting the sample at the median fol- low-up time, or at the age of 16 years, or at 0/1+ preva- lent endocrine diseases at baseline. The results from those subgroup analyses were similar to the main one.
Given that chronic iron overload is supposed to be the main driver of endocrine complications due to blood transfusions, we have not only used the baseline markers of iron overload (ferritin, LIC, and T2*) in our predictive models, but we have also tested the latest available meas- ures and the difference between initial and final meas- ures. In no cases had those markers any effect on the inci- dence of endocrine complications. TSH was not correlat-
Table 3A. Risk factors for developing a new endocrine disease during the follow-up: results from the simplest multiple Cox regression model.
Variable at the beginning Mutually-adjusted
(95% CI)
P
<0.001 <0.001 0.005
of follow-up
Diseases at baseline (1 increase)
TSH (1 mIU/L increase)
Age (50% increase)
CI: Confidence Interval; TSH: thyrotropin.
hazard ratio
0.53 (0.43 0.66) 1.25 (1.13 1.38) 1.18 (1.05 1.33)
Table 3B. Risk factors for developing a new endocrine disease during the follow-up: results from the multiple Cox regression model showing the highest adjusted R2, which was used to draw the risk charts.
Variable at the beginning Mutually-adjusted
(95% CI)
P
<0.001 <0.001 0.053 0.022 0.041
of follow-up
Diseases at baseline (1 increase) TSH (1 mIU/L increase)
Age (5-year increase)
Child vs. Adult
Interaction Age*Child
CI: Confidence Interval; TSH: thyrotropin.
hazard ratio
0.54 (0.43 0.67) 1.26 (1.15 1.39) 1.12 (1.00 1.26) 6.70 (1.32 34.02) 1.59 (1.02 2.47)
ed with any marker of iron overload (Spearman's rhos <0.07, P>0.18).
Discussion
Endocrine complications remain the most common and resource-consuming disorders secondary to iron overload in TDT patients. In historical cohorts, disturbances of sexual axis affected 80% of patients, while BMD and short stature were reported in up to 60% and 50% of the overall study population, respectively. Prevalence of hypothyroidism and diabetes ranged from 6% to 14%, while hypoparathy- roidism was reported up to 25%.18
In our long-term cohort study of patient affected by TDT treated with the iron-chelating drug DFX, the risk of devel- oping an endocrine complication is generally lower than the previously reported risk, but there is considerable risk vari- ation, according to several parameters such as patient’s age, number of endocrine complications already present before the start of the therapy, and TSH serum concentration. We developed a simple risk chart enabling clinicians to derive an approximate estimate of their patients’ risk.
Ferritin, LIC and cardiac T2* are considered as markers of iron overload, but the correlation between those markers
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