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Endocrine complications in iron overload
Table 1. Cross-tabulation of number of conditions at baseline and number of conditions occurred during the follow-up.
N. of endocrine diseases at baseline
0
1
2
3
4 Total
N. of new endocrine diseases occurred during follow-up
0123
75(63.6%) 32(27.1%) 10(8.5%) 1(0.9%) (23.3%) (36.4%) (66.7%) (100.0%)
87(71.9%) 30(24.8%) 4(3.3%) 0(0.0%) (27.0%) (34.1%) (26.7%) (0.0%)
86(80.4%) 21(19.6%) 0(0.0%) 0(0.0%)
118 121 107 65 15 426
Total
(100%) (27.7%)
(100%) (28.4%)
(100%) (25.1%)
(100%) (15.3%)
(100%)
(100%) (100%)
(26.7%)
59(90.8%) (18.3%)
(23.9%)
5 (7.7%) (5.7%)
(0.0%)
1(1.5%) (6.7%)
(0.0%) n/a
15(100.0%) 0 n/a n/a
(4.7%) (0.0%)
322(75.6%) 88(20.7%) (100%) (100%)
15(3.5%) (100%)
(3.5%)
1(0.2%) (100%)
Values represent the total number of patients in each category,with row and column percentages in parentheses.
A detailed description of all methods used is available in the
Online Supplementary Appendix.
Statistical analysis
Data were cleaned before the analysis: we checked all variables for missing, illogical or implausible values, also through cross- checks with related variables (e.g., chronologic orders). Continuous variables were checked for abnormal distributions and outliers. We used Cox-regression to fit survival analyses with follow-up days as the underlying time variable. Survival time was measured as the number of days passed from the beginning of the treatment regimen with the drug DFX to the first of either the diagnosis of the first new endocrine disease, side effect due to DFX leading to therapy suspension, death, or censoring. We cen- tered the covariates before interaction analyses. We adopted two strategies for the development of the multiple models: we either started with the covariates having higher biological plausibility of effect or with those with a lower P-value from at the bivariate stage. The two approaches reached the same final model. The assumption of proportional hazards was checked by using the Schoenfeld residuals test. We computed the proportion of varia- tion explained by the models (adjusted R2) using the Royston method with bootstrap confidence intervals (5,000 replications).19 We derived the predicted probabilities of developing a new endocrine disease within 5 years and 1 year by using the margins command in Stata v.14. Two patients were excluded from the analysis as they already had all possible five endocrine diseases at baseline.
Results
Out of 426 patients enrolled, accounting for 3,517 per- son per years, 104 participants developed at least one new endocrine disease after a mean and median follow- up time of 8 years (range, 1 month–18.5 years). The mean iron intake at baseline was 0.28+/-0.08 mg/kg/day (range, 0.14–0.49 mg/kg/day) and at the end of study was 0.26+/- 0.12 mg/kg/day (range, 0.16–0.50 mg/kg/day). The mean hemoglobin level was 9.8+/-0.68 g/dL (range, 9.4–10.6 g/dL) indicating the majority of patients had good control of their chronic anemia.
No deaths were recorded. Overall, 18 (4%) patients experienced adverse events (AE) that determined tempo-
rary or permanent DFX discontinuation. The most fre- quent AE were related to gastrointestinal intolerance (epi- gastralgia, heartburn, abdominal pain; n=8) and increased transaminases (n=8). Increased in serum creatinine (n=1) and Lichen planus (n=1) were reported as other AE which caused DFX interruption. In nine (2%) cases DFX was dis- continued because of treatment failure, reported as increase in serum ferritin (n=6), cardiac T2* (n=2), LIC (n=1). In one case treatment failure was reported along with gastrointestinal intolerance.
Table 1 shows a cross-tabulation between the number of endocrine diseases at baseline and the number of new endocrine diseases that occurred during the follow-up. The 75.6% of the total sample (322 of 426) did not devel- op any new endocrine disease during the follow-up (95% Confidence Interval [CI]: 71.2–79.6). Out of the 104 (24.4%) with newly diagnosed endocrinopathies, 84.6% developed only one endocrine disease (95% CI: 76.2– 90.9). Out of 118 patients with no endocrine diseases at baseline, 43 (36.4%) developed at least one endocrine dis- ease during the follow-up (95% CI: 27.8–45.8). Out of 121 patients having one endocrine disease at baseline already, 34 (28.1%) developed at least one additional endocrine disease during the follow-up (95% CI: 20.3– 37.0).
Among the 118 patients with no endocrine diseases at baseline, BMT disorders occurred the most (17.8% [95% CI:11.4–25.9]), followed by hypogonadism (12.7% [95% CI=7.3–20.1]). Those two conditions were also the most prevalent ones in patients with one disease at a baseline (80.2% [95% CI: 71.9–86.9] and 11.6% [95% CI: 6.5– 18.7] respectively) and were those that most likely occurred as additional diseases during the follow-up.
Figure 1 shows the overall crude risks for all 104 first incidents, by incident type and age group. It appears that most of the new incidents occurred after the age of 20 years, with a new spike between 35 and 45 years. As for pediatric patients, the increase seems to start after the age of 12 years. No cases of insulin-dependent diabetes were reported in patients with no endocrine disorders at base- line (Figure 2). Kaplan-Meier survival probability curves with age as the underlying time variable are reported in the Online Supplementary Appendix.
Tables 2A and 2B show a description of the sample by
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