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The Forgotten Consequences of the Opioid Epidemic: Adrenal Insufficiency Presenting with Hypercalcemia

Christina Ryu, MD – Resident, CPMC

Kwan Christina, MD – Fellow, California Pacific Medical Center

Kjersti Kirkeby, MD – ATTENDING, California Pacific Medical Center

Maggie So


Objective :

Chronic opioid use is often overlooked as a cause of secondary adrenal insufficiency, but physicians should be aware of this increasingly common cause, especially with the current opioid epidemic.

Methods : N/A

Results :

A 54-year-old woman with history of opioid abuse presented with generalized weakness, anorexia and depressed mood. Labs showed a corrected calcium of 13.7 mg/dL. Work-up revealed non-parathyroid hormone (PTH) mediated hypercalcemia with PTH 17 pg/ml in setting of non-elevated PTH related peptide (PTHrp), low 25-hydroxyvitamin D, low 1,25 dihydroxyvitamin D, normal free light chain ratio, low vitamin A and normal thyroid function. Calcium normalized and symptoms improved with IV fluids, calcitonin, furosemide and zoledronic acid. Etiology of hypercalcemia remained unclear at discharge.
She represented to the ED 1 day later with hypoglycemia (glucose 13 mg/dL) and hypotension. Work-up revealed undetectable morning cortisol and ACTH levels, suggestive of secondary adrenal insufficiency. Unfortunately, cosyntropin stimulation test was not performed to confirm diagnosis prior to starting glucocorticoids. Pituitary MRI revealed a microadenoma measuring 5x3x3 mm, but all other pituitary hormones were intact. Based on history and work-up, it was determined chronic opioid abuse was the most likely cause of her secondary adrenal insufficiency. The patient was started on steroids with immediate improvement.

Discussion : Studies have shown that chronic opioid use affects cortisol secretion likely due to interactions in the hypothalamus-pituitary-adrenal (HPA) axis. Opioids affect the HPA axis at multiple levels, but the primary site of action is thought to be the hypothalamus as seen in a study of morphine’s effect on rat hypothalamic fragments leading to the suppression of CRF-41. In studies of healthy volunteers, naloxone, an opioid antagonist, led to an increase in cortisol and CRH levels, suggesting that opioids exert tonic inhibition on the HPA axis. One study showed that acute administration of oral morphine led to suppression of serum basal cortisol and plasma ACTH. Further, though rare, adrenal insufficiency can cause hypercalcemia. The pathophysiology is unclear but appears to be related to increased bone resorption, volume contraction from adrenal insufficiency and increased proximal tubular calcium reabsorption in the setting of decreased kidney function.

Conclusion : This case highlights two points: adrenal insufficiency should be considered as a cause of unexplained non-PTH mediated hypercalcemia and the significant impact of chronic opioid use on the HPA axis. Given the current opioid epidemic, physicians need to recognize this commonly overlooked clinical entity.

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