Endocrine Abstracts

Background: Generalized glucocorticoid-resistance (GCR) is a broad spectrum and heterogeneous syndrome that may be familial or sporadic caused by mutations in glucocorticoid receptor function and signalling. These patients present with hypercortisolism with enlarged adrenals but no Cushing features. Identification of GCR requires extensive investigations.

Case report: An 81-year-old thin-built man of South-East Asian origin, presented with a 1-year history of reduced appetite, weight loss, postural symptoms and extreme fatigue. His family reported darkening skin creases, earlobes and scar tissues. His past medical history included Type 2 diabetes mellitus and hypertension. His CT-CAP excluded malignancy but found bilateral adrenal nodules suggestive of infiltrative process. This was confirmed by subsequent PET and biopsy which demonstrate adrenal histoplasmosis. Biochemistry revealed persistent hyponatremia at 125mmol/l, random cortisol 383 and 359 nmol/l (NR: 133-537) with ACTH 765 ng/l (NR:7.2-63.3), low renin and aldosterone, normal plasma metanephrines and adrenal androgens. His overnight-Dexamethasone-Suppression Test suppressed cortisol adequately to 41 nmol/l. His urine and serum free cortisol (using LCMS) was normal. Given non-concordance between clinical and biochemical findings, patient was commenced on hydrocortisone 10/5/5 mg daily. Within a month, he reported significant symptoms improvement. He regained weight with skin hyperpigmentation gradually resolved and normalisation of his serum sodium. His adrenal histoplasmosis was managed with Posaconazole 300 mg OD. This antifungal treatment is a cytochrome P450 inhibitor which should decrease steroid metabolites, but patient’s clinical status declined, and ACTH day curve showed high ACTH levels at 164, 381 and 221 ng/l and so hydrocortisone dose was increased instead.

Conclusion: Cortisol receptor resistance is a rare cause of normal/high cortisol levels with no Cushing’s features. This case is an unusual presentation of GCR. Cortisol replacement here improved patients’ symptoms, hyperpigmentation and helped maintain weight. The underlying molecular basis of GCR needs further research.