The Adrenal

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The Adrenal

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

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Adrenal Anatomy

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

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Adrenal Anatomy

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

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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.

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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

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Adrenal Glands (Normal)
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Adrenal Anatomy

• Leftgtright
• 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.

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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.

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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 N- methyltransferase (PNMT)
  required for conversion of norepinephrine to
  epinephrine.

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The Cortex

• Three major hormones
• Cortisol
• Androgens
• Aldosterone

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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
  a-pregnalone, which are the precursors to
  cortisol and androgens.

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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 18-hydroxycorticosterone to
  aldosterone.

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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.

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Steroidogenesis
Cholesterol
Cholesterol desmolase
17a-hydroxylase
17,20 lyase
Pregnenolone Progesterone 11-Deoxycorticostero
ne Corticosterone Aldosterone
17-Hydroxypregnenolone 17-Hydroxyprogesterone
11-Deoxycortisol Cortisol
DHEA Androstenedione Testosterone Estradiol
3ß hydroxysteroid dehydrogenase 21ß-hydroxylase
11ß-hydroxylase Aldosterone synthase
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Glucocorticoids

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

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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.

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Glucocorticoids

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

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Glucocorticoids

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

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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.

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Glucocorticoids

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

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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.

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Androgens

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

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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.

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Aldosterone

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

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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.

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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.

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Renin-Angiotensin
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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.

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Cushings Syndrome, Causes

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

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

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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.

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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.

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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 (lt5pg/ml).
• With pituitary causes, it will be normal or
  slightly elevated (15-200pg/ml).
• With ectopic ACTH secreting tumors, it will be
  markedly elevated.

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Cushing Syndrome

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

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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 (lt5 ng/ml)
Cushings Syndrome
No cushings
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Cushings Syndrome
Late-afternoon/midnight measurement of plasma
cortisol ACTH
Plasma cortisol gt50 ng/ml, ACTH gt50 pg/ml
Plasma cortisol gt50ng/ml Plasma ACTH lt5 pg/ml
No Cushings
ACTH-dependant Cushings Syndrome
ACTH-independent Cushings
High dose dexamethasone suppression test ?
Metyrapone stim. Test, ?inferior petrosal Sinus
sampling
Adrenal tumor or hyperplasia
gt50reduction in cortisol
lt50 reduction in cortisol
Pituitary tumor (Cushings disease)
Ectopic ACTH
Adrenal CT/MRI
Pituitary CT/MRI
Pituitary surgery
Thoracic/abdominal CT/MRI
Surgical removal
Treatment of primary lesion Bilateral
adrenalectomy Necessary occasionally
cure
Failure Pituitary irradiation or Bilateral
adrenalectomy
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Adrenal Insufficiency, Addisons

• Weight loss, anorexia 90
• Nausea, vomiting 66
• Weakness, tiredness, fatigue 94
• GI complaints 61
• abdominal pain 28
• Diarrhea 18
• Muscle pain 16
• Salt craving 14
• Hypotension, dizziness, syncope 14
• Lethargy, disorientation 12

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Adrenal Insufficiency, Causes

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

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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 gt18mcg/dl at 60 min

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Adrenal Insufficiency, Treatment

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

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Hyperaldosteronism

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

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Hyperaldosteronism, Diagnosis

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

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Hyperaldosteronism, Diagnosis

• Serum K lt 3.6 mEq/L
• Plasma renin activity (PRA) lt 1 ng/ml
• Plasma aldosterone gt22 ng/dL
• Urine aldosterone gt 14 mcg/24hrs
• Urine K gt 40 mEq/24 hrs
• Plasma aldosteronePRA ratio gt 501

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Hyperaldosteronism, Treatment

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

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Adrenal Medulla

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

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Catecholamines

• Exert their effect by interaction will
  cell-specific receptors.
• The principle physiologic effect of alpha
  receptor stimulation is vasoconstriction.

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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.

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Pheochromocytoma

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

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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.

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Pheochromocytoma

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

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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).

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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.
• Malignant disease
• Local invasion, disease outside of
  adrenal/paraganglionic tissue.
• No histological or clinical criteria can
  differentiate malignant disease.

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Pheochromocytoma, Treatment

• Treatment is surgery
• Must medically optimize prior to surgery
• Treat HTN
• Expand intravascular volume
• Control cardiac arrhythmias
• Phenoxybenzamine (a-adrenergic antagonist)
• most commonly given 1-3 wks prior to OR.
• Other a-adrenergic antagonists, CCB, ACEI used

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Pheochromocytoma, Treatment

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

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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
• gt3cm 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

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Incidentaloma

• Increased risk of adrenocortical carcinoma with
  increasing size
• lt4cm 2
• 4.1-6cm 6
• gt6cm 25
• No change with age or sex

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Incidentaloma, Workup

• Bioclinical examination
• Dexamethasone suppression test
• Urinary/plasma catecholamine/metanephrines
• Serum potassium, plasma aldosterone
  concentration-plasma renin activity ratio (if
  hypertensive)
• Rule out other malignancy
• Stool for occult blood
• CXR
• Mammogram

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Incidentaloma, Who Gets Surgery?

• Unilateral, functioning tumors.
• gt6cm 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).

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Incidentaloma, Watchful Waiting

• lt4cm, 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.

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Functioning mass
Nonfunctioning mass
adrenalectomy
gt4.5 cm Atypical CT appearance
lt4.5 cm Benign appearance
History of Extraadrenal malignancy
Consider FNA
adrenalectomy
Repeat CT/MRI 3 and 12 months
FNA
- FNA
observe
adrenalectomy
Adapted from Camerons, Current Surgical Therapy
7th ed. Pg 635