ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019; 104(7): 2985–2993. PMID: 30844071.

Endogenous Cushing syndrome (CS) is a severe condition characterized by excessive glucocorticoid production (1). In 20% of cases, cortisol is secreted autonomously by the adrenal cortex (2). Adrenal CS is mostly caused by unilateral cortisol-producing adrenal adenomas (CPAs) and less frequently by cortisol-secreting carcinomas. Very rare causes of adrenal CS include primary bilateral macronodular adrenocortical hyperplasia (PBMAH), bilateral CPAs, and primary pigmented micronodular adrenal disease (3, 4). PBMAH presents on imaging with characteristic multiple bilateral macronodules (>10 mm) with hyperplasia and/or internodular atrophy (5). In most cases, PBMAH is a sporadic disorder, although familial cases have been described (6). The treatment of choice to control hypercortisolism in patients with PBMAH is bilateral adrenalectomy, which inevitably results in lifelong glucocorticoid dependence and risk of adrenal crisis (6). To avoid the induction of adrenal insufficiency, resection of only one adrenal gland has been advocated. Several recent studies have reported clinical and biochemical improvement after unilateral adrenalectomy (7, 8). However, the number of documented patients and associated follow-up time is limited.

Here, Andrea Osswald and colleagues report the largest series of 25 patients with PBMAH after unilateral adrenalectomy (unilat-ADX-PBMAH) with analysis of long-term results regarding biochemical and clinical outcomes, as well as morbidity and mortality. They compare outcomes their to 9 patients with PBMAH treated with bilateral adrenalectomy (bilat-ADX-PBMAH) and also 39 patients with CPA treated with unilateral adrenalectomy (unilat-ADX-CPA). The baseline clinical and biochemical parameters were comparable in patients with unilat-ADX-PBMAH, bilat-ADX-PBMAH, and unilat-ADX-CPA. Immediately after surgery, 84% of the patients with unilat-ADX-PBMAH experienced initial remission of Cushing syndrome, however at last follow-up (median, 50 months), only 32% of these patients remained biochemically controlled, which was lower than patients in the other two groups (P <0.001). Adrenalectomy of the contralateral side had to be performed in 12% of patients with initial unilat-ADX-PBMAH. Three of 20 patients with unilat-ADX-PBMAH (15%) died during follow-up; no deaths occurred in the other two groups (P <0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX and were presumed to be of CS-related causes.

These findings suggest that unilateral adrenalectomy of patients with PBMAH leads to initial clinical remission and a lower incidence of adrenal crisis, but subsequently leads to less sufficient biochemical control of hypercortisolism, potentially leading to higher mortality.

This is the first study to provide data on the long-term outcome and mortality of patients with PBMAH after adrenalectomy in comparison with a reference patient group. The decision to accept mild persistent hypercortisolism against lifelong glucocorticoid dependence is justifiable as long as it does not lead to enhanced mortality. In view of the presented data, unilateral adrenalectomy should be reserved for patients with PBMAH with asymmetric hyperplasia or mild cortisol secretion. Although these findings do not allow to define a safe 24-hour urinary free cortisol (UFC) cut-off, persistently elevated levels of more than two times the normal upper limit should lead to additional measures to control hypercortisolism, such as adrenostatic treatment or (subtotal) contralateral adrenal surgery.

References:

1. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2014; 4(2): 739–769.

2. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009; 23(5): 607–623.

3. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006; 367(9522): 1605–1617.

4. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009; 23(2):245–259.

5. De Venanzi A, Alencar GA, Bourdeau I, Fragoso MC, Lacroix A. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2014; 21(3): 177–184.

6. StratakisCA,KirschnerLS.Clinicalandgeneticanalysisofprimary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res. 1998; 30(6-7): 456–463.

7. Debillon E, Velayoudom-Cephise FL, Salenave S, Caron P, Chaffanjon P, Wagner T, Massoutier M, Lambert B, Benoit M, Young J, Tabarin A, Chabre O. Unilateral adrenalectomy as a first- line treatment of Cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 2015; 100(12): 4417–4424.

8. Lamas C, Alfaro JJ, Lucas T, Lecumberri B, Barcelo ? B, Estrada J. Is unilateral adrenalectomy an alternative treatment for ACTH- independent macronodular adrenal hyperplasia?: Long-term follow-up of four cases. Eur J Endocrinol. 2002; 146(2): 237–240.