Central Adrenal Insufficiency

Definition, Etiology, PathogenesisTop

Central adrenal insufficiency (AI) is a clinical syndrome caused by a long-term deficit of adrenal cortex hormones due to adrenocorticotropic hormone (ACTH) deficiency. Acute and chronic causes: Table 1.

Most frequent causes: Inhibition of ACTH secretion by long-term exogenous glucocorticoid therapy, high-dose opioids, large tumors of the pituitary, craniopharyngiomas, neurosurgical treatment of the pituitary, and parasellar tumors/lesions.

Less frequent causes: Pituitary infarction/hemorrhage/apoplexy, postpartum pituitary hemorrhage (Sheehan syndrome: see Hypopituitarism), sellar neoplasms, sellar cystic lesions, immunotherapy, infiltrative (eg, hemochromatosis, sarcoidosis, histiocytosis X), infection/abscess, posttraumatic lesions/acquired brain injury, opioid use, hypophysitis, empty sella, congenital causes.

Clinical FeaturesTop

Symptoms are similar to those in Addison disease (primary AI) but usually develop more slowly and are less severe. A key difference is the lack of skin hyperpigmentation, due to ACTH and melanocyte-stimulating hormone (MSH) deficits. Hyperkalemia does not occur since secretion of mineralocorticoids is not impaired, as it depends to a greater degree on the renin-angiotensin system than on ACTH, and orthostatic hypotension is less common. Other features and biochemical findings of pituitary dysfunction (hypopituitarism and hormone excess in the case of a functioning adenoma) may also be present.

DiagnosisTop

Diagnostic Tests

1. Confirmatory hormone testing: see Primary Adrenal Insufficiency.

2. Imaging studies: Magnetic resonance imaging (MRI) or computed tomography (CT) may reveal a tumor, other lesion, hemorrhage of the hypothalamus-pituitary region, or an empty or partially empty sella.

TreatmentTop

Hormone replacement therapy: Ongoing replacement therapy should be augmented in periods of increased hormone requirements. Advise the patient on how to modify glucocorticoid dosage to adjust to stress (eg, infection, trauma, minor procedures such as tooth extraction; see below). The patient should receive and always carry a medical alert bracelet/card.

Comparison of relative potency, dose equivalence, and biological half-times of selected glucocorticoids: Table 2 in Primary Adrenal Insufficiency.

Glucocorticoid replacement: Hydrocortisone (15-20 mg/d orally), most frequently in 2 or 3 divided doses, with the highest dose in the morning and next dose in the afternoon ± evening (aim at reproducing the circadian cortisol secretion rhythm).Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness of some studies. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. doi: 10.1210/jc.2015-1710. Epub 2016 Jan 13. Review. PMID: 26760044; PMCID: PMC4880116. Prednisone (5-7.5 mg/d orally) in 1 or 2 divided doses. Dexamethasone and other long-acting synthetic analogues of cortisol are usually not recommended as the first option (they do not mimic the normal diurnal rhythm). Assess the effects of hormone replacement doses based on clinical symptoms and avoid overreplacement to prevent Cushing syndrome.

Guidance on glucocorticoid dosage and sick day management: see Primary Adrenal Insufficiency.

In patients with other pituitary hormonal deficiencies (such as central hypothyroidism and growth hormone deficiency) and existing AI, it is important to use glucocorticoid treatment prior to starting thyroid hormone or growth hormone to avoid precipitating an adrenal crisis.

Follow-UpTop

The key goals of treatment are reduction of symptoms, normalization of blood pressure and electrolyte levels, and general improvement of the patient’s condition while avoiding excessive doses to prevent Cushing syndrome. Use the lowest effective doses of hydrocortisone or prednisone.

Special ConsiderationsTop

Surgery

Hydrocortisone during major or moderate surgeryEvidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (observational studies) and indirectness of outcomes measured. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994 Apr;219(4):416-25. Review. PMID: 8161268; PMCID: PMC1243159.: While precise evidence is lacking, our pattern of practice is to administer hydrocortisone 50 to 100 mg as an IV infusion en route to surgery followed by 25 to 50 mg IM or IV every 6 to 8 hours or a continuous infusion of 200 mg over 24 hours. On day 1 after surgery, administer 25 to 50 mg IM or IV every 8 to 12 hours. On day 2 after surgery, administer 25 to 50 mg IM or IV in the morning. Starting from day 3 after surgery (or earlier if the patient tolerates fluids well and is clinically stable), switch to an oral hydrocortisone (less commonly prednisone) physiologic replacement dose.

In case of surgical complications, such as infection/sepsis, maintain a higher hydrocortisone dose (eg, 50 mg IV tid to qid) while reassessing the dose daily to avoid prolonged high-dose glucocorticoid exposure, and taper to physiologic dose when the patient is clinically improved and stable.

In minor surgeries the glucocorticoid dose can simply be doubled or tripled preoperatively and then tapered down quickly within 1 to 2 days.

PrognosisTop

AI caused by exogenous glucocorticoid use is reversible. Appropriately treated isolated central AI does not significantly affect life expectancy. However, the patients' quality of life may not be normal due to the currently used method of administering glucocorticoid therapy, which is not quite physiologic. Both undertreated and overtreated disease can cause significant morbidity.

In patients with hypopituitarism, the prognosis depends on the treatment and disturbances caused by deficiencies of other pituitary hormones (see Hypopituitarism).

TablesTop