1. Paul D Simmons, MD 4 January 2017
Adrenal Diseases
Paul D Simmons, MD
4 January 2017

2. The Road Ahead Review of adrenal anatomy and physiology
Addison’s disease
Secondary adrenal insufficiency
Cushing’s disease
Primary aldosteronism
Adrenal “incidentalomas”
Rarities not covered: congenital adrenal hyperplasia, pheochromocytoma, secondary aldosteronism

3. Review of Adrenal Anatomy and Physiology
Cortex
Glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Androgens (DHEA & androstenedione)
Medulla
Chromaffin cells: epi, norepi, histamine, serotonin, etc.

4. Functions of Major Cortical Hormones
HORMONE CLASS
EXEMPLAR
FUNCTIONS
Glucocorticoids
Cortisol
Anti-inflammatory and hepatic gluconeogenesis
Mineralocorticoids
Aldosterone
Regulates electrolyte exchange across membranes, esp Na/K
Adrenal androgens
DHEA and androstenedione
Converted to testosterone and dihydrotestosterone

5. HYPOFUNCTION DISORDERS
Failure produces TERTIARY hypofunction disorders
Failure produces SECONDARY hypofunction disorders
Failure produces PRIMARY hypofunction disorders
Ex: Addison’s (primary adrenal insufficiency)

6. Hyperfunction Disorders
HORMONE AFFECTED
SYNDROME
Adrenal androgens
Adrenal virilism
Glucocorticoids
Cushing syndrome
Aldosterone
Hyperaldosteronism
Catecholamines
Pheochromocytoma

7. Addison Disease

8. Addison Disease (Primary Adrenal Insufficiency)
Cause:
Usually idiopathic (70%), possibly autoimmune; can be due to TB, amyloidosis, hemorrhage, metastasis or drugs blocking metabolism (e.g., ketoconazole).
Pathophysiology
Deficient mineralocorticoids and glucocorticoids
Low aldo → increased Na excretion, decreased K excretion → hyponatremia, hyperkalemia
Urinary Na and H2O loss → hypovolemia, acidosis, hypotension, shock
Glucocorticoid deficiency → hypotension, increased insulin sensitivity, decreased gluconeogenesis and decreased glycogen stores, weakness, immunodeficiency
Low cortisol → increased ACTH production → hyperpigmentation

9. Addison Disease (Primary Adrenal Insufficiency)
Symptoms and Signs:
Early: Weakness, fatigue, orthostatic hypotension
Hyperpigmentation
Anorexia, nausea, vomiting, diarrhea, intolerance to cold
Late: Weight loss, dehydration, persistent hypotension

10. Addison Disease (Primary Adrenal Insufficiency)
Diagnosis:
Often “discovered” by incidental hyponatremia and hyperkalemia, low HCO3, high BUN and hypoglycemia
Confirmatory testing: low morning serum cortisol and high morning serum ACTH (cf. low ACTH + low cortisol in secondary adrenal insufficiency)
If borderline ACTH and cortisol, consider ACTH stim test - a dose of ACTH should increase the serum cortisol. If not, confirms Addison’s.
Other findings: high hct, low WBC, lymphocytosis and eosinophilia

11. Addison Disease (Primary Adrenal Insufficiency)
Treatment:
Hydrocortisone or prednisone
Hydrocortisone 20mg daily divided TID, usually 10mg AM, 5mg noon, 5mg evening.
Prednisone 5mg AM, 2.5mg PM.
Fludricortisone
Replaces aldosterone
mg daily, dose adjusted to keep renin levels normal
Watch for hypertension
Dose increase during acute illness
Double the usual doses of hydrocortisone or prednisone
Rx a preloaded syringe of hydrocortisone 100mg for the patient
Patient should wear a medical alert tag/bracelet

12. Secondary Adrenal Insufficiency

13. Secondary Adrenal Insufficiency
Pituitary-Level Lack of ACTH Stimulation
Causes: Panhypopituitarism, isolated failure of ACTH-secreting cells (corticotrophs), or sudden stop of exogenous steroids.
Diagnosis: Low ACTH and low serum cortisol. Confirmatory ACTH stim test will have normal or subnormal bump in cortisol. All cases should have CT/MRI imaging of pituitary to rule out mass or atrophy. No hyperpigmentation and normal Na/K.
Treatment: hydrocortisone or prednisone as in Addison’s disease; increase in acute illness. BUT...fludricortisone is not needed - the intact adrenals produce aldosterone.

14. Cushing Syndrome and Disease

15. Cushing Syndrome vs. Cushing Disease
Constellation of symptoms and signs from chronic high levels of cortisol and other corticosteroids.
Cushing DISEASE =
Cushing syndrome caused specifically by excess pituitary secretion of ACTH, usually due to a pituitary adenoma.

16. Etiology of Cushing Syndrome
ACTH Independent
ACTH Dependent
Hypersecretion by pituitary (Cushing disease)
Steroids Rx
Adrenal adenoma or carcinoma
Secretion by non-pituitary tumor (SCLC, carcinoid)
Exogenous ACTH

17. Cushings - Clinical Features
Moon facies with plethora
Truncal obesity (supraclavicular and dorsal cervical fatpads (“buffalo hump”))
Slender distal extremities, fingers
Muscle wasting, weakness
Skin thinning, easy bruising
Purple abdominal striae
HTN, renal calculi, glucose intolerance, immunosuppression

18. Diagnosis of Cushing Syndrome
Urinary free cortisol
Almost all Cushing pts have UFC > 120, but many pts with UFC have obesity, PCOS or depression.
If clinical syndrome + very high UFC (4x ULN) = diagnosis
If clinical syndrome + mildly high or normal UFC → further testing
Dexamethasone suppression test
Give 1-2mg dexamethasone PO at , then check cortisol at
Normal: =< 1.8 ug/mL; if Cushing pts have higher levels
Another option (low-dose): 0.5 mg PO q 6h x 2 days
Midnight serum or salivary levels
Normal diurnal cycle nadir is 1.8 ug/mL at midnight; Cushing pts have higher levels
Serum ACTH levels; if detectable, provocative testing (dexameth or CRH)
Undetectable ACTH = adrenal cause; high ACTH = pituitary cause

19. Diagnostic Tests in Cushing Syndrome
Diagnosis
Serum Cortisol, 9 am
Salivary or Serum Cortisol, Midnight
Urinary Free Cortisol
Low-Dose or Overnight Dexamethasone
High-Dose Dexamethasone
Corticotropin-Releasing Hormone
ACTH Level
Normal N N* S
Cushing disease
N or ↑ ↑ NS
Ectopic ACTH
Flat ↑↑
Adrenal tumor ↓
*May be elevated in non-Cushing conditions.
Flat = no significant rise in ACTH or cortisol; N = normal; NS =nonsuppression; S = suppression; ↑↑= greatly increased; ↑=increased; ↓=decreased.

20. Treatment of Cushing Syndrome
High protein intake, potassium administration or potassium-sparing diuretics
Acute treatment to stabilize patient
Adrenal inhibitors
Metyrapone or ketoconazole → inhibit cortisol secretion by the adrenals
Surgery or radiation therapy for pituitary, adrenal or ectopic tumors
Complex, and may need specialty centers in pediatric patients
Somatostatin analogues, dopamine agonists (cabergoline) or mifeprestone (blocks cortisol receptors, but increases cortisol levels and can cause hypokalemia)
Specialty consultation is recommended, especially if surgical/radiotherapy not an option (e.g., widespread metastatic disease).

21. Primary Aldosteronism (Conn Syndrome)

22. Aldosterone
Most potent mineralocorticoid → Na retention in the renal distal tubule and K /H+ wasting → hypervolemic hypernatremia, hypokalemia, metabolic alkalosis.
Primary aldosteronism is caused by an adrenal adenoma, carcinoma or hyperplasia (e.g., congenital adrenal hyperplasia).

23. Clinical Features of Primary Aldosteronism
Hypervolemia
Hypernatremia
Hypokalemia
Metabolic alkalosis
Episodic weakness, paresthesias, transient paralysis, tetany
Diastolic hypertension
Hypokalemia nephropathy with polyuria, polydipsia
Often, mild-moderate hypertension can be the only manifestation!
Edema is UNCOMMON

24. Diagnosis of Primary Aldosteronism
Illness script: Hypertension and hypokalemia.
Plasma aldosterone level
Plasma renin activity (PRA)
Ideally, no renin-angiotensin-aldosterone drugs (thiazides, ACEI/ARB, beta-blockers) for 4-6 wks prior to testing
PRA measured in the morning with patient recumbent
Diagnosis: plasma aldosterone >15 ng/mL, low PRA, PAL:PRA > 20
Low PAL, low PRA = non-aldosterone mineralocorticoid excess (licorice, Cushing, Liddle synd.)
High PAL, high PRA = secondary hyperaldosteronism
Adrenal imaging and catheterization
CT or MRI to distinguish between adenoma vs hyperplasia
Adrenal vein catheterization to determine if unilateral (adenoma) or bilateral (hyperplasia)

25. Treatment of Primary Aldosteronism
Surgical removal of adenomas
Surgical adrenalectomy not effective in 70% of pts with hyperplasia, so not recommended
Medical therapy for hyperplasia
Spironolactone, eplerenone for hyperplasia
Eplerenone is more specific, does not antagonize the testosterone receptor, so recommended in men
Most hyperplasia patients need anti-HTN therapy

26. Adrenal Incidentalomas

27. Adrenal Masses Incidentally Found on Imaging
The number to remember: If > 4cm, biopsy.
Epidemiology: found on 3-4% of CTs and MRIs.
One study: 1.2% of lesions were malignant, all were >5cm in diameter
Metastases to the adrenals: bronchogenic carcinoma, renal cell cancer, melanoma.

28. Evaluation of Adrenal Incidentalomas
Size
Follow-up / Evaluation
< 1 cm with fatty or cystic features
No further follow-up needed
1-4 cm
Most benign - repeat imaging in 6-12 mos, 10 HU or less on contrast CT, CT washout or other specialized tests
> 4 cm (unless clearly benign, e.g. cyst or myelolipoma)
Further specialized imaging, biopsy in most cases

29. What About Testing for Functioning Masses?
If no symptoms or signs suggestive of functional mass (i.e., Cushingoid features, electrolyte abnormalities…) - no testing needed.
Mayo Clinic recommends yearly surveillance with:
24-hour urine cortisol
Plasma metanephrine/catecholamine levels
Plasma renin activity, plasma aldosterone level
Reference: ACR Appropriateness Criteria:

30. Key Learning Points
Primary = adrenal gland; secondary = pituitary; tertiary = hypothalamic
Addison disease diagnosis - hyponatremia, hyperkalemia, hypotension, hyperpigmentation; diagnosis via low morning cortisol, high morning ACTH
Addison disease treatment - hydrocortisone and fludricortisone; don’t forget increased stress doses in illness!
Secondary adrenal insufficiency - low cortisol AND low ACTH; treat with hydrocortisone but no fludricortisone needed
Cushing diagnosis - UFC, dexa suppression test, midnight cortisol levels
Cushing treatment - surgery for adenoma; medication for hyperplasia
Adrenal incidentaloma - <1cm benign; 1-4cm depends; > 4cm biopsy; check ACR Appropriateness for imaging