The postoperative period after TSS for CD is complicated by an expected phase of AI, which is of variable duration. Our data suggest that the period of AI is not dependent on several clinical and biochemical markers of CD in children, including the age of the patient at diagnosis, and several markers of hypercortisolaemia, except UFC, which may predict a small increase in the duration of suppression of HPA axis. However, we identified a significant association of earlier recovery with increased risk for recurrence in the paediatric population, which provides a proof of concept for what was previously reported in adults.
The lack of association of postoperative AI with baseline markers of CD is not unexpected. Previous studies in adults have described several potentially interesting factors; however, the results have not been consistent. Specifically, Serban et al described that the duration of AI was positively correlated with the duration of disease, but not with any other baseline factors, including cortisol levels (urine or serum). Klose et al showed a potential correlation of age at diagnosis and duration of disease with the duration of AI, but not with other biochemical factors. In contrast, Hurtado et al described significant association of post-TSS AI with age and BMI at diagnosis, and duration of disease, as well as with post–dexamethasone suppression test cortisol levels; however, their study included only patients with ACTH-independent CS, which represents a fundamentally different process. The observation that duration of AI depends on the type of CS is further supported by other studies that showed that patients with ectopic CS or CD recover HPA function earlier than patients with ACTH-independent CS.[7,13] Furthermore, a study from our group in a cohort of paediatric patients (n = 57) failed to identify any significant correlation with clinical and biochemical factors preoperatively. We confirmed these results in a larger cohort of patients (n = 130) and in more extensive set of variables included in this analysis.
Recovery of the HPA axis following TSS in CD is thought to depend on the function of the CRH-secreting cells in the paraventricular nuclei of the hypothalamus.[4,14] The fact that we did not identify factors that contribute to this process with a more significant effect may imply that other factors that were not included in this study play an important role in the recovery process. For example, neuropeptides (such as GABA and opioids) are affected by hypercortisolaemia and have been shown to play a significant role in CRH secretion.[15,16] Those peptides need to be measured in the cerebrospinal fluid (CSF) which was not available from our patients. Another potential factor could be genetic background: genetic variations of the genes implicated in the HPA axis have been extensively studied for correlation with disease susceptibility and treatment response.[17–19] Preliminary results from a pilot study from our group showed variants in potential genes of interest that may be associated with the recovery time, including TBX19, MC5R, CABLES1 and HSD11B1. Further studies are underway to confirm functionally the effect of genetic factors in the recovery and overall function of the HPA axis.
The significance of this study lies initially on the counselling and guidance we provide to our patients. Based on this and previous studies, it seems that follow-up to document the recovery of the axis is required within the first 1–2 years after TSS as most patients recover within the first 12–18 months. In our institute, we often perform the first postoperative ACTH stimulation test 6 months after TSS, as most patients do not recover adrenal function earlier. Based on the peak cortisol level, we continue or wean the hydrocortisone dose (starting from the afternoon dose) until the 12-month ACTH stimulation test. Any further adjustments of the hydrocortisone dose and the follow-up intervals (ranging from 3 to 6 months until recovery) are guided by the peak cortisol value. This will allow patients to avoid exposure to unnecessary glucocorticoid therapy. All patients should be counselled on the signs and symptoms of AI, as adrenal crisis may be a life-threatening situation and can occur during the period of AI and potentially the months following recovery. All patients should be educated on management of illnesses and carry hydrocortisone injection and a medical alert for the duration of AI and, as we recommend in our institute, for at least six more months after documented recovery. Other than the possibility of adrenal crisis, patients should be aware that AI is associated with reduced quality of life and the transition from hypercortisolaemia to hypocortisolaemia (although under replacement therapy) may have an impact on their function, school performance and activity level.[22–24]
Another significant implication of this study is the report of the prognostic importance of earlier recovery for future risk of recurrence. Previous studies have shown increased risk for recurrence with earlier recovery in adult patients, but this has not been reported previously in the paediatric population.[5,25] In adults with recurrence, recovery of the axis was reported by 22–36 months. We here describe that all children with recurrence had recovery of the HPA axis function by 15 months and a significantly increased risk for recurrence with every month of earlier recovery is noted. Closer surveillance and appropriate counselling of patients who recover early should be performed as appropriately.
Certain limitations exist for the current study. First, this was a retrospective study, and thus, data collection was not as complete as it could be. To overcome this limitation, we applied multiple imputation analysis to impute the missing data. Patients were followed up at certain intervals after surgery. As per protocol, most of the patients are seen around 6 months and 12 months after TSS and then, as needed, every 3–6 months if they have not recovered adrenal function. Thus, we did not have assessment of the HPA axis at shorter time intervals. Furthermore, our data come from a centre of referral for other institutes in the United States and internationally, and thus, our patient population may not represent the typical cases of paediatric CD. However, this constitutes the largest paediatric cohort to our knowledge of a rare disease. Regarding the evaluation of recovery of HPA axis, we used the standard-dose cosyntropin stimulation test. The gold standard test for diagnosis of AI is considered the insulin tolerance test. There are several studies, including three meta-analyses, comparing the diagnostic accuracy between low (1 mcg) and standard (250 mcg) dose cosyntropin stimulation tests in patients with AI.[26–28] The most recent meta-analysis included 30 studies of patients with secondary AI and showed no statistical difference in the diagnostic accuracy of the two tests, although both test showed low sensitivity. Given the technical difficulties in performance of a low-dose test, in our institute, we have been performing only standard-dose testing for our patients.[29,30] Additionally, all patients have been at least 3 months postoperatively and had been exposed to low ACTH secretion for sufficient time to induce adrenal atrophy.
In summary, we report that in paediatric patients with CD, postoperative duration of AI does not depend on age at diagnosis or several other clinical and biochemical factors (except for UFC). This implies that the process of recovery depends on other factors, not measured in the current study. However, earlier recovery is associated with higher risk for recurrence, which has implications for the patients' follow-up and counselling.
The work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH).
This project was part of the research project of the Clinical Research Training Program at Duke University. We would like to thank Dr Matthew Crowley who served as a mentoring member of the advisor committee and provided helpful comments when designing the study. We would also like to thank all patients and families who have been part of our research protocols over the years.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Clin Endocrinol. 2021;94(1):40-47. © 2021 Blackwell Publishing