Title: Disorders of the Adrenal Glands FACULTY: Sara Lubitz, MD Notes prepared by Ryan Townsend SIGNIFICANCE: The adrenal

glands sit on top of the kidneys and are responsible for releasing hormones in response to stress. These glands receive signals from the hypothalamus/pituitary, kidney, and sympathetic nervous system which control the production of these hormones. Diseases of the adrenal glands cause symptoms and unique syndromes when they result in the over or underproduction of hormones. These diseases include hyperplasia and tumors which over-produce hormones, enzyme defects in steroid synthesis pathways, and adrenal insufficiency due to lack of hypothalamic/pituitary stimulation or due to direct destruction of the adrenal gland. If not treated, adrenal insufficiency may result in shock (adrenal crisis) and death. OBJECTIVES: 1.0 Review adrenal hormone synthesis in the cortex and medulla 1.1 The adrenal gland is organized into 2 areas of distinct function and origin. 1.1.1 Adrenal Medulla

Located at the core of the adrenal gland It contains hormone secreting chromaffin cells, which are derived from embryonic neural crest cells. Secretes catecholamines like epinephrine and norepinephrine in response to sympathetic stimulation. The adrenal medulla is the principal site for the conversion of the amino acid tyrosine into dopamine and then epinephrine or norepinephrine. Adrenal Cortex

1.1.2

Located outside the central medulla, and just under the capsular layer of the gland, is the adrenal cortex. It is broken up into three histologically and functionally distinct zones of cell types: From outside to in, it is helpful to remember the pneumonic GFR (adrenal sits on top of the kidney GFR), as well as The deeper you go, the sweeter it gets. 1.1.2.1 Zona Glomerulosa (salt) Mineralocorticoids Aldosterone production and secretion long-term regulation of blood pressure in response to

Increases sodium reabsorption in distal tubule and collecting duct. (Increased excretion of K+ and H+).

1.1.2.2

Aldosterone synthase turns corticosterone into aldosterone this enzyme is not present in any other areas of the adrenal gland. Zona Fasciculata (sugar) Glucocorticoids Corticosterone and Cortisol production/secretion stimulates gluconeogenesis, suppresses the immune system, aid in fat, protein and carbohydrate metabolism. Release triggered by ACTH from the anterior pituitary which is in turn triggered by CRH from the hypothalamus.

1.1.2.3

Produced by the enzyme 11-Beta-hydroxylase, which is found in both the zona fasiculata and reticularis. Zone Reticularis (sex) Androgens DHEAS, androstenedione are produced turned into estrogen and testosterone sex hormones.

2.0 Discuss Glucocorticoid Excess Cushings Syndrome any high cortisol state from any cause resulting in distinct clinical features. 2.1 Describe the signs and symptoms 2.2 Violacious striae deep and wide, purple stretch marks that do not change color differ from normal stretch marks. Most specific sign for Cushings. Central obesity, HTN, and Diabetes Mellitus Thin arms and legs from muscle atrophy and myopathy Round, full facial features Acne and Hirsutism (abnormal hair growth from excess male steroids) Menstrual irregularities and decreased libido Osteoporosis and infections

Differentiate Pseudo-Cushings Syndrome 2.2.1 Psuedo-Cushing syndrome is a high cortisol state that is caused by a supratentorial, higher brain cause. The high level neurons believe they are under stress and need more cortisol but they are not exposed to negative feedback mechanisms.

2.2.2 2.2.3

2.2.4

Due to exercise, pregnancy, uncontrolled diabetes, sleep apnea, alcoholism, chronic pain, psychiatric disorders, extreme obesity When a test question wants you to think pseudo-Cushings, they will tell you about one of these other conditions going on. Should be obvious on a test question (but not in real life!) Psueo-Cushings will NOT HAVE VIOLACIOUS STRIAE this is specific for Cushings Syndrome/Disease.

2.3

Summarize diagnostic testing 2.3.1 Screening tests there are high-sensitivity screening tests to pick up Cushings syndrome. From a clinical picture it is very hard to determine pseudo-Cushings from the syndrome. These will confirm: 2.3.1.1 Urine free cortisol levels should be 24 hour collection secretion rate is variable throughout the day so a one-time sample will not give accurate picture of average levels. 2.3.1.2 Midnight salivary cortisol - there should be close to non cortisol secretion at night. Higher levels would be abnormal from a midnight sample. Saliva is used because it is convienient. 2.3.1.3 Dexamethasone suppression test Low Dose 1mg of dex is given at 11 pm and plasma cortisol is checked at 8 am. o If Cushings syndrome (from any cause), then AM cortisol will be high, not suppressed. o Dex is like synthetic cortisol, normal person will sense high levels and lower ACTH accordingly. o Low dose is used for screening and can confirm Cushings syndrome. High dose 8mg of dex given at 11pm and plasma cortisol checked at 8am. o If patient has Cushings Disease (pituitary cause) then morning cortisol will suppress to 50% of baseline. A high dose still exerts some negative feedback on the pituitary production so ACTH/Cortisol will drop to about 50% baseline.

o Ectopic production will not be suppressed. If the cause is ectopic it will be outside the negative feedback control and cortisol wont drop. 2.4 Differentiate etiologies of Cushings syndrome: Pituitary (Cushings Disease), Adrenal, and Ectopic ACTH secretion 2.4.1 Regulation of Cortisol Hypothalamus releases CRH in response to low cortisol levels, or in response to sleep-wake cycle, catecholamines or endorphins. CRH tells pituitary (and adrenals) to make more ACTH. ACTH stimulates adrenals to make and release more cortisol. Highest levels of cortisol are in early AM upon waking after ACTH release. Helps you wake up, and raise glucose levels. (Jet-lag results from disruption of normal sleep/wake cycle.) Elevated cortisol levels can be a normal physiological state seen in pregnancy, stress, and strenuous exercise. (Psuedo-Cushing, as above).

2.4.2

ACTH Dependent causes (Pituitary adenoma or ectopic ACTH secreting tumor) measure a plasma ACTH level. If plasma ACTH is normal/high (>5) along with a high serum cortisol (>15), then it is ACTHDependent. 2.4.2.1 Cushings Disease (Pituitary tumor) Tumor makes ACTH causing the adrenal gland to make too much cortisol. The tumor does not respond to high cortisol level negative feedback. 2.4.2.1.1 Treatment transphenoidal hypophysectomy, radiation, bilateral adrenalectomy, or adrenal-blocking medication Ectopic ACTH secretion thymoma, small-cell lung carcinoma, pancreatic islet cell carcinoma, carcinoid tumors, thyroid medullary carcinoma, Pheochromocytoma. Outside pituitary axis, but still secrete ACTH. Will also not respond to high cortisol level negative feedback. 2.4.2.2.1 Treatment avoid pituitary surgery, surgery to remove ectopic tumor if possible, adrenal-blocking drugs

2.4.2.2

To determine between two ACTH-dependent causes: o CRH Stimulation test CRH dose to someone with pituitary tumor will slightly increase ACTH secretion. CRH dose in someone with ectopic ACTH tumor will make the same amount because healthy pituitary will respond to negative feedback. o High Dose dex suppression test see 2.3.1.3. Ectopic cause cortisol production will not be suppressed. Pituitary cause cortisol suppressed by 50% o Bilateral inferior petrosal sinus sampling catheterize the petrosal sinus, which drains the pituitary directly, and measure ACTH leaving the pituitary. Can be compared to a peripheral vein ACTH level.

2.4.3

ACTH Independent causes (Adrenal adenoma/carcinoma, nodular hyperplasia) - Low plasma ACTH (<5) with high serum cortisol (>15) is ACTH-Independent. 2.4.3.1 Primary adrenal disease - an adrenal tumor will produce too much cortisol. A healthy pituitary axis will sense high cortisol levels and appropriately be able to shut down ACTH secretion. 2.4.3.1.1 Treatment Adrenal surgery or adrenal-blocking drugs

3.0 Discuss Primary Mineralocorticoid excess - Conns syndrome 3.1 Describe the signs and symptoms 3.1.1 Presentation - Clinical presentation consistent with excess aldosterone levels and activation of the RAAS Hypertension, hypokalemia, metabolic alkalosis. (There is no pituitary involvement in aldosterone production). Differentiate etiologies of mineralocorticoid excess adenoma vs. hyperplasia 3.2.1 Aldosterone producing adrenal adenoma if unilateral, can surgically resect the tumor. (Spironolactone if not a surgical candidate). 3.2.2 Bilateral Adrenal Hyperplasia Treated with spironolactone, which is an aldosterone antatgonist/potassium sparing diuretic. Also has anti-adrogen effects which may cause gynecomastia in men.

3.2

3.3

Summarize diagnostic testing 3.3.1 Screening Elevated serum aldosterone or elevated serum aldosterone-torenin ratio suggestive of primary hyperaldosteronism. 3.3.2 Confirmation Oral or IV salt loading should normally suppress aldosterone. Tumor or hyperplasia will not respond to negative feedback. 3.3.3 Localization CT scan of adrenals or adrenal vein sampling

4.0 Discuss Adrenal Insufficiency 4.1 Describe the signs and symptoms essentially opposite to Cushings. 4.1.1 Nearly all will have weight loss, weakness, hypoglycemia, fatigue, and anorexia, as well as some GI problems like nausea, vomiting or constipation results from cortisol deficiency. In primary: Salt craving, dehydration and postural hypotension/dizziness may also be present due to mineralocorticoid deficiency and the inability to conserve Na+ (hyponatremia) or excrete K+ (hyperkalemia). In Primary: Excess ACTH will lead to excess of MSH melanocyte stimulating hormone, and thus hyperpigmentation of mouth, flexor surface of hand, and nail beds, as well as vitiligo. (ACTH comes from a common precursor that is also used to form alpha-MSH.) Adrenal Crisis an endocrine emergency. At about 7 days without steroids, patient will present in shock with fever, hypotension, vomiting, renal failure, mental status change, hypoglycemia, anemia and death. Give IV Fluids and high-dose IV Glucocorticoids and mineralocorticoid replacement (for primary cause).

4.1.2

4.1.3

4.1.4

4.2

Differentiate the Etiologies: Primary vs. secondary adrenal insufficiency 4.2.1 Dignosis Cortrosyn/Cosyntropin (synthetic ACTH) is administered. If cortisol levels do not go up in response, this is adrenal insufficiency. [This does not tell us primary or secondary however if the adrenal gland is not exposed to ACTH because the pituitary does not make it, then over time it will atrophy and not respond to even synthetic ACTH.] 4.2.2 Primary Adrenal Insufficiency Addisons Disease The adrenal glands do not function. There is a loss of all cortex hormones mineralocorticoid, glucocorticoid, and androgens.

4.2.2.1

Causes Autoimmune disease is the most common cause in the US. TB is the most common cause worldwide. ! Other infectious causes: MAI, AIDS, CMV, Toxo. ! Adrenal hemorrhage - Waterhouse-Friedrichsen (sepsis), lupus anticoag, ITP, heparin ! Metastatic tumor/disease ! Drugs: ketoconazole, etomidate, metyrapone (decreased synthesis) and rifampin, dilatin, phenobarbital (increased catabolism) ! Familial familial glucocorticoid deficiency

4.2.3

Secondary Adrenal Insufficiency Pituitary problem will cause a loss of mainly glucocorticoids and some androgens. The mineralocorticoid/RAAS will remain intact. 4.2.3.1 Causes most common cause is iatrogenic exogenous steroid administration long-term use of steroids will cause the eventual shut down of any endogenous production of cortisol. Once steroids stopped, none will be produced. ! Pituitary/hypothalamic disease infiltrative tumor, granuloma, hemorrhage, autoimmune ! Surgery ! Congenital

5.0 Discuss Pheochromocytoma A rare catecholamine-secreting tumor of the adrenal medulla composed of benign or malignant chromaffin cells, from an isolated cause or a familial cause. Affects males = females in 3rd to 5th decade of life. If a pheo-like tumor forms outside the adrenal glands it is called a paraganglioma. 5.1 Describe the signs and symptoms 5.1.1 The 5 Ps Pressure (HTN), Pain (Headache), Perspiration, Palpitation, Pallor 5.1.2 Symptoms come in spells of 15-20 min duration, daily or monthly. 5.1.3 Can be cause spontaneously, or by diagnostic procedures like IA contrast; drugs like opiods, Beta-blockade, anesthesia induction, histamines, glucagons, ACTH; strenuous exercise that increases intra-abdominal pressure; or micturition if there is a bladder paraganglioma.

5.2

Summarize diagnostic testing 5.2.1 5.2.2 Localization usually found incidentally on a CT or MRI of abdomen, and can be enhanced by Iodine 131 MIBG scan. Confirmation urine fractionated metanephrine and catecholamine levels (over 24 hours) or plasma metanephrine levels. Urine Vanillymandelic Acid (VMA) levels breakdown of catecholamines. Treatment once confirmed ALL should be treated with surgery due to potential for fatal hypertensive crisis. Should be pretreated with alpha and beta blockade prior to surgery, and managed BP closely during surgery.

5.2.3

5.3

Identify pheochromocytoma as part of the MEN2 syndromes 5.3.1 Multiple Endocrine Neoplasia 2 Pheochromocytoma makes up one of the three common findings in a patient with MEN-2a or MEN2b. 5.3.1.1 MEN-2A - Pheochromocytoma, medullary thyroid cancer, and hyperparathyroidism 5.3.1.2 MEN-2b - Pheochromocytoma, medullary thyroid cancer, and ganglioneuroma of tongue

6.0 Discuss Adrenal Masses 6.1 Describe the signs and symptoms 6.1.1 Is usually discovered incidentally and may just be an incidentiloma. Only 25% are functioning masses and may have subclinical symptoms. Symptoms would be like those of cortisol secreting or aldosterone secreting adenoma, or pheocromocytoma. 6.1.1.1 Also consider Adrenocortical Carcinoma abdominal pain from a mass affect, rapid onset of hypersecretion of androgens (hirsutism, acne, amenorrhea), cortisol (Cushings), Aldosterone (hypokalemia) and Estrogen (gynecomastia). Differentiate between benign and malignant disease check/image elsewhere in the body at the time of discovery malignant disease will often be metastasized, or the adrenal mass may be a metastasis of another primary tumor elsewhere.

6.2

6.3

Summarize diagnostic testing 6.3.1 Take a good history and physical 6.3.2 Hormonal testing screens for cushings syndrome, Pheochromocytoma or hyperaldosteronism. 6.3.3 Imaging phenotype examine size, borders, Hounsfield units, contrast 6.3.3.1 Adrenocortical carcinoma will be large mass >4cm, >10 hounsfield unit attenuation, irregular margins, rapid growth

7.0 Discuss Congenital Adrenal Hyperplasia Inherited autosomal recessive disorders of steroid biosynthesis pathway resulting in glucocorticoid and mineralocorticoid deficiencies. 7.1 Describe the signs and symptoms 7.1.1 Classic syndrome occurs at birth and is total lack of an enzyme. A female fetus exposed to high levels of DHEA/andro will develop male or ambiguous genitalia. Males will have large genitals and early puberty. Nonclassic syndrome is diagnosed later in life because it is from a partial loss of an enzyme. 21-Hydroxylase Deficiency most common manifestation (95%). Results in inability to make aldosterone and cortisol so children will present with hypotension and hyperkalemia with salt wasting, as well as have high levels of testosterone and androgens. A mild deficiency will not cause salt wasting, but may cause some hirsutism and oligomenorrhea/infertility.

7.1.2

7.2

Summarize diagnostic testing can be diagnosed by measuring precursor enzyme levels and high ACTH levels. (ACTH is increased because of deficient cortisol synthesis will cause adrenal hyperplasia cortisol precursors will also be upregulated, leading to overproduction of more sex steroids.) In 21-OHase deficiency the precursor enzyme we can measure is 17-hyrdoxyprogesterone which is specific for that deficiency since sex steroid levels can vary.