The Adrenal

Vic Vernenkar, D.O. St. Barnabas Dept. Of Surgery

Adrenal Anatomy

Composed of a cortex and medulla, which have separate embryology.

Adrenal Anatomy

The adrenal cortex arises fro m the coelomic mesoderm between the fourth and sixth weeks of gestation.

Adrenal Anatomy

The adrenal medulla is derived from cells of the neural crest that also form the sympathetic nervous system and the sympathetic ganglia.Some of these neural crest cells migrate into the adrenal cortex to form the adrenal medulla, but chromaffin tissue may also develop in extraadrenal sites. The most common site of extraadrenal chromaffin tissue is the organ of Zuckerkandl, located adjacent to the aorta near IMA.

Adrenal Anatomy

The glands weigh about 4g each, located in the retroperitoneum along the superior-medial aspect of the kidneys. Yellow appearance because of their high lipid content. 3-5 cm in length, 4-6mm in thickness

Adrenal Glands (Normal)

Adrenal Anatomy

Left>right Receive arterial blood from branches of the inferior phrenic artery, aorta, and renal arteries. The right adrenal vein is short and exits the gland medially to enter the vena cava. The left adrenal vein exits anteriorly and usually drains into the left renal vein. As a result, adrenal venous catheterization is accomplished more easily on the left than the right.

Adrenal Anatomy

The adrenal cortex is composed of three zones histologically. Outer zona glomerulosa, site for aldosterone synthesis. Central zona fasciculata and inner zona reticularis produce both cortisol and androgens.

Adrenal Anatomy

Most of the blood supply to the medulla comes from venous blood draining through the cortex. This provides the adrenal chromaffin cells with high concentration of the enzyme phenyethanolamine Nmethyltransferase (PNMT) required for conversion of norepinephrine to epinephrine.

The Cortex

Three major hormones Cortisol Androgens Aldosterone

The Cortex

Zona glomerulosa is the exclusive site of production of aldosterone because it lacks the enzyme 17 alpha hydroxylase necessary for production of 17 a- progesterone and 17 apregnalone, which are the precursors to cortisol and androgens.

The Cortex

Zona fasciculata and reticularis function as a unit to produce cortisol, androgens, and small amounts of estrogen, but it lacks the enzymes necessary to convert 18hydroxycorticosterone to aldosterone.

Cortex

Cholesterol is the precursor from which all adrenal steroids are synthesized. Conversion of cholesterol to pregnenolone is the rate limiting step in adrenal steroidogenesis and is the major site of action of ACTH.

Steroidogenesis
Cholesterol
Cholesterol desmolase

17-hydroxylase

17,20 lyase

Pregnenolone

17-Hydroxypregnenolone
3 hydroxysteroid dehydrogenase

DHEA

Progesterone

17-Hydroxyprogesterone
21-hydroxylase

Androstenedione

11-Deoxycorticosterone

11-Deoxycortisol

Testosterone

11-hydroxylase

Corticosterone
Aldosterone synthase

Cortisol

Estradiol

Aldosterone

Glucocorticoids

Regulated by hypothalamus and pituitary via secretion of CRH and ACTH.

Glucocorticoids

Cortisol, like ACTH is secreted in a pulsitile manner, and plasma levels closely parallel those of ACTH. Superimposed on this is a circadian rhythm that results in peak cortisol levels in the early morning and a nadir in the late evening. Physical and emotional stress (trauma, surgery, and hypoglycemia) increase cortisol secretion by stimulating release of CRH and ACTH from hypothalamus and pituitary respectively.

Glucocorticoids

Normal daily production of cortisol is 10-30mg. The liver is the main site of metabolism. Two major metabolites are 17hydroxycorticosteroids and 17ketosteroids, excreted in the urine.

Glucocorticoids

Metabolic effects are stimulation of hepatic gluconeogenesis, inhibition of protein synthesis, increased protein catabolism, and lipolysis of adipose tissue.

Glucocorticoids

The increased release of AA from muscle protein and release of glycerol and free fatty acids from fat provide the substrate for hepatic gluconeogenesis. Also increase glycogen synthesis, peripheral uptake of glucose is inhibited, and may cause hyperglycemia and increased insulin secretion.

Glucocorticoids

Loss of collagen, impair wound healing by inhibition of fibroblasts. Inhibit bone formation, reduce calcium absorption by gut (steroid induced osteoporosis).

Glucocorticoids

Numerous antiinflammatory actions, which include inhibition of leukocyte mobilization and function, decreased migration of inflammatory cells to sites of injury, decreased production of inflammatory mediators (IL-1, leukotrienes, and bradykinins). Also essential for cardiovascular stability, as evidenced by the collapse that occurs in patients with adrenal insufficiency.

Androgens

Dehydro-3-epiandrosterone (DHEA) and DHEA sulfate. Minimal direct biologic activity. In periphery they undergo conversion to androgens, testosterone, and dihydrotestosterone.

Androgens

Increased in Cushing syndrome, adrenal carcinoma, congenital adrenal hyperplasia. In adult men accounts for only 5% of testosterone, in prepubertal boys, however, increased production may be manifested by the early development of secondary sexual characteristics and penile enlargement. In females, manifested by acne, hirsuitism, virilization, and amenorrhea.

Aldosterone

Maintains extracellular fluid volume and regulation of sodium and potassium. Renin-angiotensin system regulates it.

Aldosterone

Renin is secreted by juxtaglomerular cells of the kidney in response to decreased pressure in the renal afferent arterioles. Decreased sodium concentration sensed by the macula densa promote renin as well.

Aldosterone

Renin is also stimulated by hyperkalemia, and inhibited by potassium depletion. Angiotensin II is a potent vasoconstrictor, also stimulates zona glomerulosa to secrete aldosterone. Aldosterone then stimulates reabsorption of sodium in exchange for potassium and hydrogen ion secretion.

Renin-Angiotensin

Cushings Syndrome

Constellation of signs and symptoms that result from chronic glucocorticoid excess. Most common source is iatrogenic administration of glucocorticoids. ACTH-secreting tumors of pituitary are the most common cause of spontaneous Cushing syndrome.

Cushings Syndrome, Causes

Endogenous

Exogenous

Pituitary adenoma

(Cushings Disease) Ectopic ACTH production Ectopic CRH production Adrenal adenoma
Adrenal carcinoma Adrenal hyperplasia

Therapeutic steroids (pills, lotions, creams) Major depression Alcoholism

Cushings Syndrome

Pituitary Cushing, also termed Cushing disease, accounts for 70% of all cases of Cushing syndrome. Ectopic ACTH secreting tumors comprise 15% of all cases and associated with small cell cancers of the lung. Primary adrenal tumors (adenomas, carcinomas) account for 15-20% of cases.

Cushing Syndrome

These patients lose diurnal variation in cortisol levels. Elevated levels of urinary free cortisol present in 90% of patients. Normally only 1% of cortisol excreted in urine. Low dose dexamethasone suppression test will suppress pituitary secretion of ACTH and adrenal production of steroids. So, if am plasma cortisol is suppressed then Cushing is ruled out.

Cushing Syndrome

Plasma ACTH levels are used to differentiate ACTH-dependent (pituitary and ectopic ACTH secreting tumors) from adrenal causes of Cushing syndrome. With primary adrenal tumors, ACTH should be suppressed (<5pg/ml). With pituitary causes, it will be normal or slightly elevated (15-200pg/ml). With ectopic ACTH secreting tumors, it will be markedly elevated.

Cushing Syndrome

High Dose Dexamethasone Test may be used to distinguish pituitary from non-pituitary causes of ACTHdependent Cushing syndrome. Rationale is that the high dose will not suppress cortisol production from a primary adrenal neoplasm or ectopic ACTH secreting tumor.

Suspect Cushing Syndrome

24 hour urine free Cortisol X 3 days 100mg/24 hr.

Cushings Syndrome

Low dose Dexamethasone suppression test

Equivocal (possible pseudo-Cushings)

No suppression of plasma cortisol

Suppresses Plasma cortisol (<5 ng/ml) No cushings

Cushings Syndrome

Cushings Syndrome
Late-afternoon/midnight measurement of plasma cortisol + ACTH

Plasma cortisol >50ng/ml Plasma ACTH <5 pg/ml

Plasma cortisol >50 ng/ml, ACTH >50 pg/ml

No Cushings
ACTH-dependant Cushings Syndrome

ACTH-independent Cushings Adrenal tumor or hyperplasia

High dose dexamethasone suppression test ? Metyrapone stim. Test, ?inferior petrosal Sinus sampling

>50%reduction in cortisol Pituitary tumor (Cushings disease)

<50% reduction in cortisol

Adrenal CT/MRI

Pituitary CT/MRI Pituitary surgery

Ectopic ACTH

Thoracic/abdominal CT/MRI Treatment of primary lesion Bilateral adrenalectomy Necessary occasionally

Surgical removal
cure Failure Pituitary irradiation or Bilateral adrenalectomy

Adrenal Insufficiency, Addisons

Weight loss, anorexia Nausea, vomiting Weakness, tiredness, fatigue GI complaints abdominal pain Diarrhea Muscle pain Salt craving Hypotension, dizziness, syncope Lethargy, disorientation

90% 66% 94% 61% 28% 18% 16% 14% 14% 12%

Adrenal Insufficiency, Causes

Autoimmune Steroid withdrawal Adrenal atrophy (lymphocytic adenitis with fibrosis) Malignant infiltration Hemorrhage Sepsis Iatrogenic (post op) Sarcoidosis, Tuberculosis

Adrenal Insufficiency, Diagnosis

Hyponatremia Hyperkalemia Azotemia Hypercalcemia 10-30% associated with other endocrine disorders AM cortisol level, ACTH level Rapid ACTH test

0.25 mg IV cosyntropin Measure cortisol before and 60 min after Cortisol level should be >18mcg/dl at 60 min

Adrenal Insufficiency, Treatment

Acute stress dose dexamethasone Chronic hydrocortisone (200-300mg) plus fludrocortisone (.05-1.0mg/day) ACTH stim test to establish diagnosis

Hyperaldosteronism
1. 2. 3. 1. 2.

Primary (suppressed renin) Adrenal adenoma Adrenal carcinoma Bilateral hyperplasia Secondary Renal artery stenosis Edematous states (cirrhosis, renal failure)

Hyperaldosteronism, Diagnosis

CT scan Adrenal vein sampling Urinary 18-hydroxycortisol elevated in adenoma. plasma hydroxycorticosterone (overnight recumbent)- > 100 in adenoma

Hyperaldosteronism, Diagnosis

Serum K < 3.6 mEq/L Plasma renin activity (PRA) < 1 ng/ml Plasma aldosterone >22 ng/dL Urine aldosterone > 14 mcg/24hrs Urine K > 40 mEq/24 hrs Plasma aldosterone:PRA ratio > 50:1

Hyperaldosteronism, Treatment

Bilateral hyperplasia-medical, spironolactone, amiloride. Unilateral adenoma- adrenalectomy.

Adrenal Medulla

L-Tyrosine converted to L-DOPA converted to Dopamine converted to L-Norepinephine converted to L-Epinephrine Degrades to VMA, metanephrine, normetanephrine

Catecholamines

Exert their effect by interaction will cellspecific receptors. The principle physiologic effect of alpha receptor stimulation is vasoconstriction.

Catecholamines

Two types of Beta receptors exist. Beta-1 receptors mediate inotropic and chronotropic stimulation of cardiac muscle, whereas Beta-2 receptors induce relaxation of smooth muscle in non-cardiac tissues, including blood vessels, the bronchi, uterus, and adipose tissue.

Pheochromocytoma

10% extraadrenal 10% bilateral 10%familial 10%children 10% malignant 10% assoc with MEN 10% present with a stroke

Pheochromocytoma

Pounding in chest (from B-1 receptor mediated increase in CO). Headaches Hands and feet become moist, cool, and pale (from A-receptor induced peripheral constriction). 10% present in pheocrisis 50% found as incidentaloma.

Pheochromocytoma

Elevated BP, fever, flushing, sweating, anxiety, feeling of doom. Most attacks are short-lived (15min). May be precipitated by position, stress, physical activity.

Pheochromocytoma, Diagnosis

24hr urinary catecholamines (NE, Epi, Dop) and metabolites (metanephrine, normetanephrine, VMA). Plasma catecholamine or metabolites during episode. Elevated serum epinephrine suggests pheo in medulla or Organ of Zukerkandl NO FNA! (can precipitate hypertensive crisis).

Pheochromocytoma, Diagnosis

Localizing studies: CT, MRI, MIBG scan

Thin cut CT detects most lesions: 97% intraabdominal. MRI: 90% pheos bright on T2 weighted scan MIBG: used for extraadrenal, recurrent, multifocal, malignant disease. Local invasion, disease outside of adrenal/paraganglionic tissue. No histological or clinical criteria can differentiate malignant disease.

Malignant disease

Pheochromocytoma, Treatment

Treatment is surgery Must medically optimize prior to surgery

Treat HTN Expand intravascular volume Control cardiac arrhythmias most commonly given 1-3 wks prior to OR. Other -adrenergic antagonists, CCB, ACEI used

Phenoxybenzamine (-adrenergic antagonist)

Pheochromocytoma, Treatment

PO salt and fluid repletion. May need -blocker as antiarrhythmic. Do not start until after pt -blocked. Metyrosine decreases catecholamine synthesis.

Incidentaloma

Found on work up for another cause, not on cancer workup

US 0.1% CT 0.4 to 4.4% MRI

70-94% are benign and nonfunctional >3cm more likely to be functional Up to 20% may be subclinically active Increase with age, no change in sex 5-25% will increase in size by at least 1cm

Incidentaloma

Increased risk of adrenocortical carcinoma with increasing size <4cm 2% 4.1-6cm 6% >6cm 25% No change with age or sex

Incidentaloma, Workup

Bioclinical examination

Dexamethasone suppression test Urinary/plasma catecholamine/metanephrines Serum potassium, plasma aldosterone concentration-plasma renin activity ratio (if hypertensive) Stool for occult blood CXR Mammogram

Rule out other malignancy

Incidentaloma, Who Gets Surgery?

Unilateral, functioning tumors. >6cm; 4-6 cm is a grey area. Rapid growth rate. Imaging not c/w benign adenoma. No surgery if workup reveals metastasis. ?Younger patients (increased lifetime cancer risk, longer f/u, lower incidence of adrenal masses).

Incidentaloma, Watchful Waiting

<4cm, nonfunctioning tumors. CT in 3 and 12 months. If no increase in size, no data to support further imaging. ? Periodic hormonal testing. If a tumor will start to hyperfunction, this will most likely happen in 3-4 yrs.

Functioning mass

Nonfunctioning mass

adrenalectomy

>4.5 cm Atypical CT appearance

<4.5 cm Benign appearance

History of Extraadrenal malignancy

Consider FNA

adrenalectomy

Repeat CT/MRI 3 and 12 months

+ FNA

- FNA

observe Adapted from Camerons, Current Surgical Therapy 7th ed. Pg 635 adrenalectomy