An unusual cause of adrenal insufficiency associated with valproic acid administration

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 142-166-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-143
Urvi Shah*1, Naweed Alzaman2 and Ronald M Lechan1
1Tufts Medical Center, Boston, MA, 2Tufts Med Ctr, Boston, MA
Background: In patients with seizures and low cortisol levels, it is essential to consider drugs as a secondary cause of adrenal insufficiency.

Clinical Case:  A 44 year old female with a past history significant for hypotonic cerebral palsy and petit mal seizure disorder presented with hypothermia (T 95.4 F) and hypotension (BP 70/50).  She was recently admitted for petit mal seizures and developed status epilepticus, for which she was started on valproate.  Biochemical studies were significant for a sodium of 141mEq/dL (N 135-145mEq/L), potassium 3.2mEq/dL (3.6-5.1 mEq/L), and BUN 2 mg/dL (6-24mg/dL).  The patient was volume resuscitated, monitored for seizure activity and warmed.  She was treated with antibiotics but continued hypotensive despite receiving intravenous fluids.  Pressors were begun, and after a random cortisol returned at 4mcg/dl, she was treated with hydrocortisone 100mg IV every 8h.  BP improved and pressors were rapidly discontinued.  Hydrocortisone was switched to dexamethasone and a Cortrosyn stimulation test revealed a basal cortisol of 3.5mcg/dL and maximally stimulated response of 20mcg/dL.  Valproate was discontinued and a subsequent AM cortisol was 12.2mcg/dL.  MRI of the brain revealed a normal sella turcica.

Conclusion:  Valproate is a GABA reuptake inhibitor and potentiates the action of GABA, an inhibitory neurotransmitter.  In experimental animals, long-term treatment with valproate decreased corticotropin-releasing hormone (CRH) concentrations in the hypothalamic median eminence and reduced CRH mRNA in the hypothalamic paraventricular nucleus (1). These regions comprise the origin and final locus of termination of hypophysiotropic CRH neurons that regulate anterior pituitary ACTH secretion.  Similarly, in human studies, valproate significantly diminished the cortisol response to hypoglycemic stress (2). The possibility that valproate led to transient adrenal insufficiency in the index case is suggested by her inappropriately low cortisol level when critically ill, rapid clinical improvement following iv steroids and a rise in cortisol level when valproate was discontinued.  The normal cortisol response to Cortrosyn was indicative of otherwise intact adrenal function.  We conclude that in patients treated with valproate, the possibility of drug-induced adrenal insufficiency due to suppression of the hypothalamic-pituitary-adrenal axis should be considered, particularly in the setting of acute illness.

1-Stout et al. Neuropsychopharmacology. 2001; 24(6):624-31. 2-Petraglia et al. Neuroendocrinology. 1986; 44(3):320-5.

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