Adrenals Glands path Flashcards
Adrenal cortex is divided into what layers?
What does each layer produce?
- Zona Glomerulosa: mineralocorticoids (aldosterone)
- Zona Fasciculata: Glucocorticoids (Cortisol)
- Zona Reticularis: Adrenal androgens and estrogens
What cells are in the adrenal medulla and what do they make and secrete
Chromaffin cells: catecholamines, mainly epinephrine
Excess of cortisol is called what
Cushing syndrome
What are the syndromes called that are caused from excessive androgens
-Adrenogenital or virilizing syndromes
What is the most common cause of Cushing syndrome
-Exogenous: Glucocorticoids (“steroids”)
What are the Endogenous causes of Cushing syndrome that are ACTH dependent?
- -Cushing disease: pituitary adenoma
- Ectopic coricotropin syndrome (ACTH)
What are the Endogenous causes of Cushing syndrome that are ACTH independent?
- Adrenal adenoma or carcinoma
- Macronodular hyperplasia
- Primary pigmented nodular adrenal disease
- McCune-Albright syndrome
What makes up 70% of endogenous hypercortisolism?
ACTH-secreting pituitary adenoma
What is the epidemiology of an ACTH secreting pituitary adenoma
- W>M (4x)
- most frequent in young adults
- Majority are Microadenomas
Ectopic ACTH secretion by a nonpituitary tumor is most often due to what
small cell carcinoma of the lung
Sometimes a neuroendocrine neoplasm produces ectopic corticotrophin releasing hormone (CRH) . . leading to what
-ACTH secretion and hypercortisolism
What is the most common causes of ACTH independent Cushing syndrome
Primary Adrenal neoplasms
- Adenoma (10%)
- Carcinoma (5%): produce the most profound hypercortisolism
in a primary adrenal neoplasm producing hypercortisolism, what happens to ACTH levels
go down
Explain the cortical atrophy associated with administration of exogenous glucocorticoids
-suppression of ACTH –> lack of stimulationg of Zona Fasciculata and reticularis
Describe Diffuse hyperplasia of adrenals in Cushing syndrome
- both glands enlarged
- Endogenous hypercortisolism
- ACTH-dependent
- Cortex can be variably nodular
What are the two types of adrenal gland hyperplasia?
- Macronodular
- micronodular
Describe macronodular hyperplasia of adrenal glands
- Endogenous hypercortisolsim
- Adrenals almost entirely replaced by prominent nodules of varying sizes (less than or equal to 3 cm)
- Areas b/t macroscopic nodules also demonstrate evidence of microscopic nodularity
Describe micronodular hyperplasia of adrenal glands
- endogenous hyperplasia
- Composed of 1 to 3 mm darkly pigmented (brown to black) micronodules, with atrophic intervening areas
- pigment is thought to be lipfuscin
Generalities for Primary adrenocortical neoplasms
- Can be functional (Cushing syndrome) or non-Functional
- Morphologically indistinct
- in functional tumors: adjacent adrenal cortex and the contralateral adrenal gland are atrophic
Age and gender for Primary adrenocorical neoplasms
women aged 30-50
Describe a primary adrenocortical adenoma
- benign
- Yellow tumors surrounded by thin or well developed capsules
- most weigh < 30gms
- microscopically see cells that look like normal fasciculata
Describe a primary adrenocortical carcinoma
- malignant
- Larger than the adenomas (usually > 200-300 gms)
- UNencapsulated
What are the early manifestations of a Cushing syndrome
- HTN
- weigh gain
Later more characteristic features of a primary Cushing syndrome
- Central pattern of fat deposition (truncal obesity)
- Moon facies
- Fat in the posterior neck and back (buffalo hump)
Clinical course of cushing syndrome
- develp slowly over time
- Atrophy of fast-twitch myofibers–> decreased muscle mass and proximal limb weakness
- Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells . . .Hyperglycemia, glucosuria, and polydispia (SECONDARY DIABETES)
- increased risk of infections (IMMUNE SUPPRESSION)
The catabolic effect of Cushing syndrome causes loss of collagen and resorption of bone. . .this leads to what symptoms
- Skin is thin, fragile, and easily bruised
- poor wound healing
- cutaneous striae are particularly common in the abdominal area
- Osteoporosis
How do you diagnose Cushing syndrome?
- increased 24 hour urine free cortisol
- Loss of normal diurnal pattern of cortisol secretion
How do you determine the cause of Cushing syndrome?
- Serum ACTH
- Dexamethasone suppression test: Urinary excretion of 17-hydroxycorticosteroids after administration of dexamethasone
What cause of Cushing syndrome is the one that will suppress ACTH with HIGH dose dexamethoasone and therefore reduce urinary excretion of 17-hydroxycorticosteroids
Pituitary Cushing
Autonomous overproduction of aldosterone
Primary hyperaldosteronism
overproduction of aldosterone leads to suppression of the Renin-angiotensin system and decreased plasma renin activity leading to what?
Elevated blood pressure . . most common manifestation of Primary hyperaldosteronism
What are the 3 mechanisms that cause primary hyperaldosteronism?
- Adrenocortical neoplasm
- Bilateral idiopathic hyperaldosteronism
- Glucocorticoid-remediable hyperaldosteronism
What neoplasm most commonly causes primary hyperaldosteronism? . . what syndrome is this
- adenoma . . . Conn syndrome
- rarely carcinomas do this
age and gender for aldosterone secreting adenoma
middle ages most common
-W>M (2:1)
What side is preferentially affected by aldosterone secreting adenoma
Left
Morphology of aldosterone secreting adenoma
- usually solitary
- Small (<2 cm)
- well circumscribed
- brightly yellow grossly
- Characteristic microscopic feature: SPIRONOLACTONE BODIES
Explain the the spironolactone bodies in an aldosterone secreting adenoma are
- Eosinophilic, laminated cytoplasmic inclusions
- Found after treatment with spironolactone (antihypertensive drug)
Do aldosterone secreting adenomas usually suppress ACTH secretion?
NO, so adjacent adrenal cortex and contralateral gland are not atrophic
What is the most common cause of primary hyperaldosteronism
Bilateral idiopathic hyperaldosteronism
What are the features of bilateral idiopathic hyperaldosteronism
- older pts
- less sever HTN
- Pathogenesis unclear
- Bilateral nodular hyperplasia of the adrenal glands
Rearrangement of chromosome 8 that places the gene for aldosterone synthase under the control of the ACTH responsive gene promoter
- so ACTH stimulates the production of aldosterone
- suppressible by dexamethasone
- Glucocorticoid-remediable Hyperaldosteronism
- uncommon
- familial hyperaldosteronism
What is secondary hyperaldosteronism
Aldosterone is released in response to activation of the renin-angiotensin system by increase plasma renin
When do you see secondary hyperaldosteronism?
- Decreased renal perfusion: arteriolar nephrosclerosis, renal artery stenosis
- Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)
- Pregnancy: due to estrogen induced increases in plasma renin substrate
What are the long term effects of HTN on the CV system
- left ventricular hypertrophy and reduced diastolic volumes
- Stroke and myocardial infarction
Aldosterone also promotes sodium reabsorption which in turn increases reabsorption of water . . this does what?
- expands the extracellular fluid volume
- Elevated cardiac output
hyperaldosteronism lead to hypokalemia . .causing what?
- weakness
- paresthesias
- visual disturbances
- occasionally tetany
What is the screening test for hyperaldosteronism?
confirmation test?
- Elevated ratio of plasma aldosterone concentration to plasma renin
- Aldosterone suppression test: Administer oral saline load, IV saline load, or fludrocortisone. If aldosterone is not suppressed then it confirms primary hyperaldosteronism
Treatment of hyperaldosteronism
varies depending on cause
- Adenomas: surgical resection
- Bilateral hyperplasia: aldosterone antagonist (spironolactone)
- Secondary hyperaldosteronism . .treat underlying cause
What are the categories of adrenogenital syndromes?
- Disorders of sexual differentiation: virilization or feminization
- Primary gonadal disorders
- Primary adrenal disorders
ACTH regulates adrenal androgen formation. What does the adrenal cortex secrete that gets converted to testosterone in peripheral tissues?
- dehyroepiandrosterone
- and androstenedione
What adrenocortical neoplasms are more likely to produce adrenogenital syndromes
more likely carcinomas
What congenital disorder is a “pure” adrenogenital syndrome or as component of Cushing disease
Congenital adrenal Hyperplasia (CAH)
inheritance of CAH
autosomal recessive, inherited metabolic error
What enzyme is lacking or deficient in CAH?
there are several enzymes that can be affected involving the biosynthesis of cortical steroids, eps. cortisol
- increase in androgens –>virilization
- decrease in cortisol –> increase in ACTH and adrenal hyperplasia
If an enzyme in CAH impairs aldosterone secretion what happens
salt wasting along with virilizing syndrome
> 90% of CAH is deficiency in what enzyme
21-hydroxylase
what mutation involved in 21-hyroxylase deficiency
CYP21A2
What are the 3 distinctive syndrome found in 21-Hydroxylase deficiency?
- Salt-wasting syndrome
- Simple virilizing adrenogenital syndrome without salt wasting
- Nonclassic or late onset adrenal virilism
Salt wasting syndrome is the inability to covert _______ into ______
progesterone into deoxycoricosterone
how does salt wasting syndrome present
- Typically present soon after birth
- Virilization recognized in the female at birth or in utero
- Males come to clinical attention 5-15 days later because of some salt losing crisis
Describe what happens in salt wasting
- hyponatremia and hyperkalemia
- Acidosis
- hypotension
- cardiovascular collapse
- possibly death
Describe the features of simple virilizing adrenogenital syndrome without salt wasting
- presents as genital ambiguity
- about 1/3 of 21-hydroxylase deficiency
- progressive virilization
Describe the features of Nonclassic or late onset adrenal virilism
- most common form of 21-hydroxylase deficiency
- only a partial deficiency
- Asymptomatic
- Hirsutism, acne, menstrual irregularities
Morphology of CAH
- Adrenals are Bilaterally hyperplastic
- Cortex is thickened and nodular
- Cortex looks BROWN: due to total depletion of all lipid
Clinical course of CAH
- Androgen excess, with or without aldosterone and glucocorticoid deficiency
- onset of symptoms can be perinatal period, later childhood, or adulthood (least common)
- CAH should be suspected in any neonate with ambiguous genitalia
- severe enzyme deficiency in infancy can be life threatening with vomiting, dehydration, and salt wasting
describe in detail 21-hydroxylase deficiency in females
- Clitoral hypertrophy and pseudohermaphroditism in infants
- Oligomenorrhea, hirsutism, and acne in postpubertal
Describe in detail 21-hydroxylase deficiency in males
- enlargement of external genitalia and other evidence of precocious puberty in perpubertal pts
- Oligospermia in older males
CAH effects on the Adrenal medulla
- High levels of intra adrenal glucocorticoids are required to make catecholamines
- pts with severe salt wasting 21 hydroxylase deficiency have low cortisol –> adrenomedullary dysplasia (decreased catecholamine secretion) –> hypotension and circulatory collapse
What is the treatment of CAH?
- Exogenous glucocordicoids: replaces the glucocorticoids AND suppresses the ACTH levels which decreases synthesis of the steroid hormones
- Mineralocorticoid supplementation is required in the salt wasting variants of CAH
What is primary acute adrenocortical insufficiency called?
Adrenal crisis
What is primary chronic adrenocortical insufficiency called
Addison disease
Secondary adrenocortical insufficiency is from what?
decreased stimulation of the adrenal due to deficiency of ACTH
Primary acute adrenocortical insufficiency occurs in what settings?
- Crisis
- Exogenous corticosteroids in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
- Massive adrenal hemorrhage –> damage to adrenal cortex
What situations can cause massive adrenal hemorrhage leading to primary acute adrenocortical insufficiency?
- newborns following prolonged and difficult delivery with considerable trauma and hypoxia
- pts on anticoagulant therapy
- post surgical patients who develop DIC
- Disseminated bacterial infections (Waterhouse-Friderichsen syndrome)
Waterhouse Friderichsen syndrome is caused by an overwhelming bacterial infections, classically what?
-Neisseria meningitides septicemia
Also see Pseudomonas, Pneumococci, H. Flu or even staph
Describe the features of Waterhouse Friderichsen syndrome
- uncommon: any age but more common in kids
- rapidly progressive hypotension leading to shock
- DIC associated with widespread purpura, particularly of the skin
- Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
- Fatal unless promptly recognized and rteated
Uncommon
- progressive destruction of adrenal cortex
- take about 90% of cortex loss to get symtoms
Addison Disease
What accounts for 60-70% of Addison Disease
-Autoimmune Adrenalitis
Describe what autoimmune adrenalitis is? . . . . causes Addison disease
- autoimmune destruction of steroidogenic cells
- Autoantibodies to 21-Hydroxylase and 17-hydroxylase have been detected
Autoimmune adrenalitis occurs in what two clinical settings
-Autoimmune polyendocrine syndrome types 1 and 2 (APS1 and APS2)
What is the other name for APS1
-Autoimmune polyendocrinopathy, candidiasis, and ectoderma dystrophy (APECED)
Describe APS1 (APECED)
- Chronic mucocutaneous candidiasis
- Abnormalities of skin, dental enamel, and nails (ectodermal dystrophy)
- Autoimmune disorders: autoimmune adrenalitis, hypoparathyroidism, idiopathic hypogonadism, pernicious anemia
What is the mutation in APS1
- AIRE gene on chromosome 21q22
- central T cell tolerance to peripheral tissues antigens (in the thymus) is compromised –>autoimmunity
- Also develop autoantibodies against IL-17 and IL-22 (crucial for defense against fungal infections
Describe APS2
- usually starts in early childhood
- Presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
other miscellaneous causes of Addison Disease
-Infections: particarly Tb and fungals. AIDS at increased risk from several infections (CMV, MAI) and noninfectious (Kaposi sarcoma)
-Metastatic neoplasms: Lung and breast carcinomas most common. Others: GI carcinomas, melanoma, hematopoietic neoplasms
Genetic: congenital adrenal hypoplasia (rare X linked disease), and Adrenoleukodystrophy
Morphology of Primary autoimmune adrenalitis
- irregularly shrunken glands which may be difficult to identify grossly
- Histologically: cortex contains scattered residual cortical cells in a collapsed network of connective tissue. Variable lymphoid infiltrate
Morphology of Tb and fungal disease causing Addison
Adrenal architecture is effaced by a granulomatous inflammatory reaction
Morphology of a metastatic carcinoma causing Addison
normal architecture obscured by the infiltrating neoplasm
Early manifestations of Addison Disease
- Progressive weakness and easy fatigability
- often dismissed as nonspecific complaints
GI disturbances in Addison
- Anorexia
- Nausea
- vomiting
- Weight loss
- diarrhea
Skin manifestations in Primary Adrenal disease in Addison
- hyperpigmentation of the skin
- Especially on sun exposed areas and at pressure points (neck, elbows, knees, knuckles
- Results from elevated levels of POMC .. . precursor of both ACTH and MSH
Glucose and Addison Disease
- Hypoglycemia can occur
- from impaired gluconeogenesis
Stresses can precipitate an acute adrenal crisis in Addison Disease such as what?
- stresses: infections, trauma, or surgical procedures
- intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse
- Death occur rapidly unless corticosteroid therapy begins immediately
Secondary adrenocortical insufficiency is caused by what general process
any disorder of the hypothalamus and pituitary that reduces the output of ACTH
-Prolonged exogenous glucocorticoids –>suppressed ACTH and adrenal function
Contrast Primary from Secondary adrenocortical insufficiency
Secodary: don’t see hyperpigmentation
-also low cortisol and androgen output but notmal or near normal aldosterone so you don’t see hyponatremia and hyperkalemia
treatment of secondary adrenocortical insufficiency
-exogenous ACTH –> prompt rise in plasma cortisol levels
how do adrenocortical neoplasma arise
- Majority are sporadic
- Two familial cancer syndrome with increased risk of adrenocortical carcinomas: Li-Fraumeni sydndrome (germline TP53 mutations) and Beckwith-Wiedemann syndrome
Functional and non functional Adrenocortical neoplasm are indistinguishable morphologically so how do you differentiate them
clinically and by measuring hormone and hormone metabolites
Hyperaldosteronism and Cushing syndrome are more likely from what neoplasm?
Virilizing neoplasm?
- functional Adenoma
- carcinoma
Describe Adrenocortical Adenomas
- Most are clinically silent and discovered incidentally
- Well-circumscribed nodular lesion
- Up to 2.5 cm in diameter
- usually yellow to yellow brown from lipids
- Cortex adjacent to nonfunctional adenoma is normal vs. Functional adenoma where it’s usually atrophic
