Recovery of Hypothalamic-Pituitary-Adrenal Axis in Paediatric Cushing Disease

Christina Tatsi; Megan Neely; Chelsi Flippo; Maria-Eleni Bompou; Meg Keil; Constantine A. Stratakis

Disclosures

Clin Endocrinol. 2021;94(1):40-47. 

In This Article

Results

Characteristics of the Patient Cohort

Of the 231 paediatric patients with CD evaluated under protocol 97-CH-0076 from 1997 until 2019, 130 patients fulfilled the inclusion criteria. Patients were excluded because of persistent disease (n = 32), insufficient follow-up time or data (n = 67) or lost to follow-up before a TSS was performed (n = 2) (Figure 1). Of patients with persistent disease, 10 patients underwent second TSS within one month after the first one, as per our institute's protocol, and achieved remission. However, these patients were excluded from the analysis as they had two interventions. The baseline clinical and biochemical data of the included patients at the time of their diagnosis are presented in Table 1.

Figure 1.

Flowchart of included and excluded patients of the study

Time to Recovery of the Complete Cohort

Overall, 102 patients showed evidence of recovery of the HPA axis during their follow-up. Using a survival analysis, there was a 50% probability of recovery by a median time of 12.7 months postoperatively (95% CI: 12.2–13.4) (Figure 2). For those patients who recovered, the duration of postoperative AI ranged from 3 to 35 months, with median value of 12.3 months. Only 3 patients recovered within less than 3 months after TSS, while 3 patients recovered more than 2 years after surgery. Twenty-eight patients did not have recovery of the HPA axis by a median follow-up time of 12.7 (18.3) months.

Figure 2.

Kaplan-Meier curve of time to recovery for the complete cohort. Dashed line corresponds to the median time to recovery (12.7 mo). Light blue area corresponds to 95% confidence interval (CI) of the probability of recovery. Risk table shows all patients at risk at each time point [Colour figure can be viewed at wileyonlinelibrary.com]

Factors Associated With Time to Recovery

Univariable analysis of the association of time to recovery with each variable of interest did not identify any factor significantly associated with the outcome (Table 2). On multivariable analysis, a negative correlation was identified with UFCxULN [beta coefficient= −0.06, hazard ratio (HR) = 0.94, 95% CI: 0.89–0.999], suggesting that for every increase in UFC by onefold the ULN, there was an increase in the time to recovery by 6%. Correlations with other variables such as duration of disease (HR = 0.87, 95% CI: 0.75–1.00) could be of interest, but did not reach statistical significance.

Recurrence Risk and Correlation With Recovery Time

To investigate whether recovery time correlates with the risk for recurrence, we computed the HR for the time to recurrence or persistent remission, based on the duration of postoperative AI for patients who recovered (n = 102). An increased risk for recurrence was noted with earlier recovery (P = .0342). Specifically, there was 14% decrease in the risk for recurrence (HR: 0.86, 95% CI: 0.75–0.99) with every additional month of duration of AI. On review of the data, all patients who recurred (n = 15) had experienced recovery within 15 months after TSS (Figure 3), whereas none of the patients who recovered after 15 months or had not yet recovered at their latest follow-up of more than 15 months postoperatively (n = 22) had recurred.

Figure 3.

Kaplan-Meier curve presentation of time to recovery for patients who later recurred (grey) versus those with persistent remission (blue). Risk table shows all patients at risk at each time point. Hazard ratio (HR) corresponds to the Cox model of time to recurrence or persistent remission (in months) based on recovery time [Colour figure can be viewed at wileyonlinelibrary.com]

Characteristics of Patients With and Without Recurrence

Overall, 15 patients (11.5%) recurred at a median of 44 months (range: 6.3–97 months) after TSS. We further investigated whether baseline characteristics of patients who later recurred differed from those of patients without recurrence during their follow-up. Patients were similar at various baseline characteristics, including age, gender, anthropometric measurements and biochemical data (Table 1). Patients with recurrence had larger tumours at baseline as measured at preoperative MRI (5.5 vs 4 mm, P = .039). As one would expect, patients with cavernous sinus invasion were more represented in the cohort of patients with recurrence but this did not reach statistical significance and may be associated with the larger tumour size.

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