Adrenal Disorders

Anatomy of Adrenal Gland

Location	Function
Adrenal cortex	*Zona glomerulosa* Outer layer of adrenal gland Secretes mineralocorticoids (eg, aldosterone) to regulate sodium and potassium *Zona fasciculata* Middle layer of cortex Secretes glucocorticoids (eg, cortisol) Stimulated by ACTH, which is released by pituitary *Zona reticularis* Secretes sex steroids Androgens Estrogen precursors Progesterone
Adrenal medulla	Inner region of the adrenal gland *Secretes catecholamines* Epinephrine Norepinephrine

Classification of Adrenal Disorders

Region	Disorders due to deficient production	Disorders due to excess production
Zona Glomerulosa	Adrenal insufficiency	Hyperaldosteronism
Zona Fasciculata	Adrenal insufficiency	Cushing’s syndrome
Zona Reticularis	Adrenal insufficiency	Androgen secreting adenomas
Adrenal Medulla	Adrenal insufficiency	Pheochromocytoma

Classification of Adrenal Insufficiency

Type	Clinical Features
Primary adrenal insufficiency	Primary failure of bilateral adrenal glands Affects all layers of cortex and medulla
Secondary adrenal insufficiency	Pituitary failure with decreased ACTH secretion Mainly affects adrenal cortex in zona fasciculata Does not usually affect ACTH-independent areas Medulla Zona reticularis Zona glomerulosa
Tertiary adrenal insufficiency	Hypothalamic abnormalities leading to decreased corticotropin-releasing hormone (CRH) Affects ACTH dependent areas similar to secondary adrenal insufficiency

Clinical Presentation of Adrenal Insufficiency

Type	Clinical Features
Acute adrenal crisis	*Precipitating factors* Acute infection or other stressor in patients with chronic primary adrenal insufficiency Insufficient adrenal replacement therapy in underlying adrenal insufficiency Acute adrenal gland destruction *Clinical presentation* Hypotension with shock Nausea Vomiting Abdominal pain Weakness Fatigue Lethargy Anorexia Fever Possible confusion or coma
Chronic primary adrenal insufficiency	Deficiency of both mineralocorticoid and glucocorticoid function *Clinical presentation* Fatigue Nausea Vomiting Abdominal pain Weight loss Muscle and joint pain Skin hyperpigmentation due to increased melanocyte-stimulating hormone Postural hypotension Salt craving Depression Psychosis Mania Decreased libido Decreased axillary and pubic hair Amenorrhea in women Hyponatremia Hyperkalemia Normocytic anemia Hypoglycemia
Secondary/tertiary adrenal insufficiency	Weakness Fatigue Muscle and joint pain Depression Psychosis Mania Hypoglycemia due to ACTH deficiency

Diagnosis of Adrenal Insufficiency

Type	Recommendations
Measure AM cortisol and ACTH levels	*Low serum cortisol with high ACTH* Suggests primary adrenal insufficiency Measure plasma renin and aldosterone levels Low levels indicate primary adrenal insufficiency Levels unaffected in secondary/tertiary disease *Low serum cortisol with low ACTH* Suggests secondary or tertiary adrenal insufficiency *Normal serum cortisol and ACTH* Usually exclude adrenal insufficiency
ACTH stimulation test	Can be done as high dose (250 mcg IV bolus) or low dose (1 mcg IV bolus) *Normal response* Rise in serum cortisol concentration after either 30 or 60 minutes Excludes primary adrenal insufficiency
CRH stimulation test	*Exaggerated response* Suggests tertiary adrenal insufficiency *Absent or inappropriate response* Indicates secondary adrenal insufficiency
Primary adrenal insufficiency	*Abdominal CT* Evaluate adrenal gland size and/or calcifications *Testing to evaluate for etiology* Lab studies Chest x-ray Antibody tests for autoimmune adrenalitis in some cases
Secondary/tertiary adrenal insufficiency	Brain imaging to evaluate pituitary and hypothalamus Measure other pituitary hormone levels in cases of panhypopituitarism

Treatment of Adrenal Insufficiency

Type	Recommendations
Adrenal crisis	*Start treatment while awaiting investigation for diagnosis* IV hydration with saline solution IV dexamethasone preferred in cases without known diagnosis of adrenal insufficiency Hydrocortisone usually preferred in cases with known diagnosis of adrenal insufficiency
Chronic primary adrenal insufficiency	Hydrocortisone in 2-3 divided doses typically preferred in most patients Fludrocortisone may be required in some patients for mineralocorticoid replacement therapy
Secondary/tertiary adrenal insufficiency	Same treatment as chronic primary adrenal insufficiency Additional replacement therapy for other deficiency pituitary hormones (eg, thyroid, growth hormone)
Special situations	*Consider increasing therapy during following situations* Surgery Prolonged illness Trauma Critical illness Pregnancy Consider DHEA in women with clinical findings of androgen deficiency (eg, decreased libido, mood)

Overview of Cushing’s Syndrome

Type	Clinical Features
Etiologies	Iatrogenic (eg, glucocorticoids) Increased ACTH secretion from pituitary (Cushing’s disease) Ectopic ACTH production (eg, small cell lung cancer) Adrenal carcinoma and adenoma
Clinical presentation	Menstrual irregularities in women (eg, amenorrhea, oligomenorrhea) Androgen excess in women (eg, hirsutism, acne, virilization) Easy bruisability Purple striae on trunk and abdomen Skin hyperpigmentation Skin atrophy Hyperglycemia Central obesity Sleep apnea Hypertension Proximal muscle wasting and weakness Osteoporosis Mood changes Increased risk for infections
Diagnosis	*Initial tests* 24-hour urinary free cortisol measurement Overnight dexamethasone suppression test *Plasma ACTH if initial tests abnormal* Elevated ACTH indicates pituitary disease and requires brain imaging Low ACTH indicates primary adrenal disease and requires abdominal CT
Treatment	Trans-sphenoidal surgery for Cushing’s disease Surgical excision of tumor for ectopic ACTH production Adrenal enzyme inhibitors (eg, ketoconazole) for symptoms control in above cases Adrenalectomy in primary adrenal disease

Overview of Other Adrenocortical Tumors

Type	Clinical Features
Hyperaldosteronism	*Etiologies* Adrenal tumor Adrenal hyperplasia Increased renin production by kidney *Clinical presentation* Hypertension Spontaneous or low dose diuretic induced hypokalemia *Diagnosis* Elevated plasma aldosterone with undetectable or very low renin levels Elevated aldosterone/renin ratio > 30 suggests diagnosis Must stop mineralocorticoid receptor antagonists (eg, spironolactone), ACE inhibitors, ARBs, and direct renin inhibitors when testing hormone levels Adrenal CT in patients with abnormal values Adrenal vein sampling to differentiate between unilateral adenoma and bilateral hyperplasia *Treatment* Adrenalectomy in patients with unilateral disease Mineralocorticoid receptor antagonists in bilateral disease
Pheochromocytoma	*Clinical presentation* Episodic headache,sweating, and tachycardia Sustained or episodic hypertension, palpitations *Diagnosis* Elevated 24-hour urine fractionated metanephrines and catecholamines Elevated plasma fractionated metanephrines Abdominal CT or MRI for localizing tumor *Treatment* Adrenalectomy

References for Adrenal Disorders

Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. CurrOpin Endocrinol Diabetes Obes. 2010;17(3):217–223.
Link to article
Addison disease: early detection and treatment principles.Michels A,Michels N. Am Fam Physician. 2014 Apr 1;89(7):563-8.
Link to article

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