Guerin: Adrenal Gland Flashcards
Where is cortisol made?
Zona fasciculata
Where is aldosterone made?
zona glomerulosa
Where are the sex steroids made?
Zona reticularis
What does the adrenal medulla make?
-catechohlamines like epinephrine
What does the 3 zonas (GFR) make up?
The adrenal cortex
Cushing syndrome
-excess cortisol
most common cause of cushing syndrome
-exogenous glucocorticoids
What is it called when we have excess cortisol due to too much ACTH?
- Cushing DISEASE
- pituitary probs (adenoma)
When do we most often see secretion of ectopic ACTH by nonpituitary tumors?
-small-cell carcinoma of the lung
So, what causes the ACTH-independent Cushing syndrome then?
- primary adrenal neoplasms (most commonly)
- adrenal adenoma (10%)
- adrenal carcinoma (5%): produce most profound hypercortisolism
- high cortisol, low ACTH
- primary cortical hyperplasia ia uncommon… vast majority of hyperplastic adrenals are ACTH dependent
What will we see in the adrenal glands if there is exogenous glucocorticoids?
- cortical atrophy
- suppression of ACTH… lack of stimulation of the zonae fasciculata and reticularis
When do we see diffuse hyperplasia (both glands enlarged)?
- endogenous hypercortisolism
- ACTH-dependent Cushing syndrome
- Cortex can be variably nodular
Macronodular hyperplasia
- endogenous hypercortisolism
- adrenals almost entirely replaced by prominent nodules of varying sizes
- areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity
Micronodular hyperplasia
- endogenous hypercortisolism
- composed of 1-3 mm darkly pigmented (brown to black) micronudles, with atrophic intervening areas
- Pigment is through to be lipofuscin
What do adrenocortical adenomas look like?
- benign
- yellow tumors surrounded by thin or well-developed capsules
- most weigh <30 gm
- Microscopically see cells that look like normal zona fasciculata
What do adrenocortical carcinomas look like?
- LARGER than the adenomas (200-300 gm)… remember… size matters!
- Unencapsulated
Clinical course of adrenal neoplasms
- symptoms develop slowly over time
- early: htn and weight gain
- later more characteristic features: central pattern of fat deposition, moon facies, fat in the posterior neck and back
What happens to the fast twitch fibers in adrenal neoplasms?
- atrophy
- decreased muscle mass and proximal limb weakness
What happens because of the increased glucocorticoids from the adrenal neoplasm?
- hyperglycemia
- secondary diabetes
What are the catabolic effects of an adrenal neoplasm?
- loss of collagen and resorption of bones
- skin is thin, fragile, and easily bruised, poor wound healing, cutaneous striae are particularly common in abdominal area, osteoporosis
Why is there an increased risk of infection with adrenal neoplasms?
-you have immune suppression from all of the glucocorticoids probably
Diagnosis of Cushing syndrome
- increased 24 hour urine free-cortisol
- loss of normal diurnal pattern of cortisol secretion
how do we determine the cause of cushing syndrome?
- serum ACTH
- dexamethasone suppression test: urinary excretion of 17-hydroxycorticosteroids after administration of dexamethasone
out the options of pituitary cushing, ectopic ACTH, and Adrenal tumor, which of those is the only one that shows suppression from a high does of dexamethasone?
-Pituitary cushing
What is primary hyperaldosteronism?
- autonomous overproduction of aldosterone
- suppression of the renin-angiotensin system and decreased plasma renin activity
- elevated BP is the most common manifestation
Whatare the 3 mechanisms that cause primary hyperaldosteronism?
- adrenocortical neoplasm
- bilateral idiopathic hyperaldosteronism (IHA)
- Glucocorticoid-remediable hyperaldosteronism
What is an adrenal adenoma called?
Conn syndrome
- middle age most common
- rarely carcinoma
Which side do adenomas usually show up on?
-left
What is the characteristic microscopic feature of adenomas?
-spironolactone bodies
What are spironolactone bodies?
- eosinophilic, laminated cytoplasmic inclusions
- found after treatment with spironolactone (antihypertensive drug)
Will an adrenal adenoma suppress ACTH secretion?
no
-so adjacent adrenal cortex and contralateral gland are not atrophic
Bilateral idiopathic hyperaldosteronism
- most common cause of primary hyperaldosteronism
- pts older
- less severe hypertension
- pathogenesis is unclear
- bilateral nodular hyperplasia of the adrenal glands
Glucocorticoid-remediable hyperaldosteronism
- uncommon
- familial hyperaldosteronism
- rearrangement of chromosome 8 that places the gene for aldosterone synthase under the control of the ACTH responsive gene promoter
- ACTH stimulates the production of aldosterone
- suppressible by dexamethasone!
Secondary Hyperaldosteronism
-sldosterone released in response to activation of the renin-angiotensin system by increased plasma renin
When do we see secondary hyperaldosteronism?
- decreased renal perfusion
- arterial hypovolemia and edema
- pregnancy (estrogen increases renin…increased aldosterone)
What is the most important clinical thing with secondary hyperaldosteronism?
- Hypertension!!!
- aldosterone promotes sodium reabsorption… increased water reabsorption too
- K+ wasting
Diagnosing secondary hyperaldosteronism?
-elevated ratio of plasma aldosterone concentration to plasma renin activity
Confirmation test for secondary hyperaldosteronism
- aldosterone suppression test
- administer oral saline load, IV saline load, fludrocortisone
- If aldosterone is not suppressed: confirm primary hyperaldosteronism*
Tx of hyperaldosteronism
- varies depending on cause
- adenomas: surgical resection
- Bilateral hyperplasia: medication… aldosterone antagonist (Spironolactone)
- secondary hyperaldosteronism: tx underlying cause
CAH
- congenital adrenal hyperplasia
- auto recessive inherited metabolic errors
- enzyme probs
- if lots of androgens…. virilization
21 hydroxylase deficiency
- most common one by far
- Mutations of CYP21A2
What three distincitve syndromes come with 21 deficiency?
- Salt-wasting syndrome
- simple virilizing adrenogenital syndrome without salt wasting
- nonclassic or late-onset adrenal virilism
Salt wasting syndrome
- inability to convert progesterone into Deoxycorticosterone
- typically presents soon after birth
- salt wasting (hyponatremia and hyperkalemia)…. acidosis, htn, CV collapse, and possibly death
Simple virilizing adrenogenital syndrome without salt wasting
- presents as genital ambiguity
- 1/3 of 21 hydroxylase deficiency
- progressive virilization
Nonclassic or late-onset adrenal virilism
- most common
- only a partial deficiency in 21 hydroxylase function
- asymptomatic
- hirsutism, acne, and 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
What does 21 deficiency look like in females?
- clitoral hypertrophy and psuedohermaphroditism in infants
- oligomenorrhea, hirsutism, and acne in postpubertal
What does 21 deficiency look like in males?
- enlagement of the external genitalia and other evidence of precocious puberty in prepubertal patients
- oligospermia in older males
What should be suspected in any neonate witha mbiguous genitalia?
-CAH!
CAH effects on adrenal medulla
- high levels of intra-adrenal glucocorticoids are required to make catecholamine
- pts with severe salt-wasting 21 hydroxylase deficiency: low cortisol levels… adrenomedullary dysplasia…. hypotension and circulatory collapse
Tx of CAH
- exogenous glucocorticoids….. suppress ACTH levels
- mineralocorticoid supplementation is required in the salt-wasting variants of CAH
What did JFK have and what is it?
Addison disease
-primary Adrenocortical insufficiency
What is adrenal crisis?
Primary acute adrenocortical insufficiency
Primary acute adrenocortical insufficiency… what was bolded on that slide?
-Exogneous corticosteroids, in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
What is something involving blood that can cause primary acute adrenocortical insufficiency?
- Massive adrenal hemorrhage… damage to the adrenal cortex
- Newborns following a difficult delivery
- Pts on anticoagulant therapy
- Postsurgical pts who develop DIC
- Disseminated bacterial infection (Waterhouse-Friderichsen syndrome)
Waterhouse-Friderichsen Syndrome
- uncommon
- overwhelming bacterial infection…. classically Neisseria meningitidis septicemia
- rapidly progressive hypotension leading to shock
- disseminated intravascular coagulation associated with widespread purpura, particularly of the skin
- rapidy developing adrenocortical insufficiency associated with massive BILATERAL adrenal hemorrhage
- fatal, unless promptly recognized and treated
Primary chronic adrenocortical insufficiency
- ADDISON DISEASE!
- uncommon
- progressive destruction of the adrenal cortex
- takes ~90% of cortex loss to get symptoms
Autoimmune Adrenalitis
- accounts for 60-70% of addison disease
- Autoimmune destruction of Steroidogenic cells
- Autoantibodies to 21 hydroxylase and 17 hydroxylase have been detected
What two clinical settings does Autoimmune Adrenalitis occur in?
- Autoimmune polyendocrine syndrome type 1 (APS1)
- APS2
APS1
- AKA Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED)
- chronic mucocutaneous candidiasis
- abnormalities of skin, dental enamel, and nails
- lots of AI disorders
- Mutatioins in the Autoimmune regulator (AIRE) gene on chromosome 21q22
What is AIRE used for?
- Central T-cell tolerance to peripheral tissue antigens is compromised…. autoimmunity
- Also develop autoantibodies against IL-17 and 22 (Crucial for defense against fungal infections)… that is for APS1
APS2
- usually starts in early adulthood
- presents as a combo of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
In regards to metastatic neoplasms, which of them contributes to Addison disease?
-lung and breast carniomas most commonly
What are some genetic causes of Addison disease?
- congenital adrenal hypoplasia… rare x-linked disease
- Adrenoleukodystrophyq
What infections can cause Addison disease?
- TB and fungal kinds
- AIDS at increased risk from several infeectious and noninfectious causes
Morphology of primary autoimmune adrenalitis
- irregularly shrunken glands, which may be difficut to identify grossly
- histologically: cortex contains scattered residual cortical cells in a collapsed netwrok of connective tissue, variable lymphoid infiltrate
Morphology of tuberculous and fungal disease (As a cause of Addison)
-adrenal architecture is effaced by a granulomatous inflammatory reaction
Morphology of metastatic carcinoma as a cause of addison disease?
-normal architecture obscured by the infiltrating neoplasm
Clinical course of addison disease
- begins insidiously
- early manifestations: progressive weakness and easy fatigability: often dismissed as nonspecific complaints
- GI disturbances: anorexia, nausea, vomiting, weight loss, and diarrhea
- Primary adrenal disease: get hyperpigmentation of the skin… results from elevated levels of POMC
Why do we have elevated levels of POMC?
-comes from ant pit and ais a precursor of both ACTH and MSH
In addison disease, will there by hyper or hypoglycemia?
- Hypoglycemia can occur
- from impaired gluconeogenesis
What else can precipitate an acute adrenal crisis?
- Stresses!
- infections, trauma, prodecures
- intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse
- death occurs rapidly unless corticosteroid therapy begins immediately
Secondary adrenocortical insufficiency
- any disorder of the hypothalamus and pituitary that reduces the output of ACTH
- Prolonged exogenous glucocorticoids… suppressed ACTH and adrenal function
- Dont see hyperpigmentation of primary addison
- Low cortisol and androgen output but normal or near-normal aldosterone… don’t see hyponatremia and hyperkalemia
- Exogenous ACTH….. prompt rise in plasma cortisol levels
Adrenocortical Neoplasms
- majority are sporadic
- Two familial cancer syndromes with increased risk of adrenocortical carcinomas
What are those two familial cancer syndromes with increased risk of adrenocortical carcinomas?
- -Li-Fraumeni syndrome: germline TP53 mutations
- Beckwith-Wiedemann Syndrome
If we have hyperaldosteronism and cushing syndrome, what is that most likely from?
-a functional adenoma
If we have a virilizing neoplasm, what is that most likely from?
-carcinoma
Adrenocortical adenomas
- most are clinically silent and discovered incidientally
- well-circumscribed nodular lesion
- usually yellow to yellow-brown because of the presence of lipid
- cortex adjacent to nonfunctional adenomas is normal
- if it is functional, the cortex is usually atrophic
Adrenocortical carcinomas
- Rare
- functional: virilism
- large, invasive
- invade adrenal vein, vena cava, and lymphatics
- Median pt survival is 2 years
What does adrenocortical carcinoma look like microscopically?
- looks like an adenoma (Pretty bland)
- Undiferentiated carcinoma
What is something that is much more common that we will need to separate from undifferentiated carcinomas of the adrenal cortex?
- metastases to the adrenal cortex
- much more common
Adrenal myelolipomas
-benign lesions composed fo mature fat andhematopoietic cells
Adrenal incidentaloma
- frequent abdominal imaging led to discovery many incidental adrenal masses
- asymptomatic
- small nonsecreting cortical adenomas
Adrenal Medulla, what’s it made of?
- chromaffin cells (specialized neural crest cells)
- Supporting (sustentacular) cells
What comes from the adrenal medulla?
-catecholamines (E and NE)
What is the paraganglion system composed of?
adrenal medulla and extra-adrenal paraganglia (made up of chromaffin cells)
What are the most important neoplasms of the adrenal medulla?
- Pheochromocytomas
- Neuroblastomas and other neuroblastic tumors
Pheochromocytomas
- neoplasms composed of chromaffin cells
- make and release catecholamines and sometimes peptide hormones
- rare cause of surgically correctable htn
What is the Rule of 10’s?
- for pheochromocytomas
- 10% are extra-adrenal (paragangliomas)
- 10% of sporadic pheochromocytomas are bilateral
- 10% are malignant (more common in extra-adrenal paragangliomas
- 10% don’t have htn
Paroxysmal episodes with Pheochromocytomas
- Abrupt, precipitous elevation in blood pressure
- caused by sudden release of catecholamines
- Tachycardia, palpitations, headache,.. etc…
Familial pheochromocytomas
- up to 25 % of pts with pheochromocytomas and paragangliomas
- typically younger
- more often bilateral… up to 50%
What gene is wrong with MEN2A and b
RET
- 2A: Pheo, Medullary thyroid carcinoma, pt hyperplasia
- 2B: Pheo, Medullary thyroid carcinoma, marfanoid habitus, mucocutaneous GNs
Morphology of Pheochromocytomas
- small to large…. wide range
- histology is variable
- very difficult to determine if pheochromocytomas are malignant
How is the malignancy of a pheochromocytoma defined?
-by the presence of metastases
Dx pheochromocytoma
- Increased urinary excretion of free catecholamines and metabolites
- VMA and metanephrines
Tx of Pheochromocytoma
- for isolated benign tumors: surgical excision
- OMG TX WITH ADRENERGIC-BLOCKING AGENTS PREOPERATIVELY AND INTRAOPERATIVELY TO PREVENT A HYPERTENSIVE CRISIS
- For multifocal lesions: medical treatment for htn
Multiple Endocrine Neoplasia (MEN) syndromes
- younger age than sporadic tumors
- multiple endocrine organs
- often multifocal in an effected organ
- usually preceded by an asymptomatic stage of hyperplasia involving the cell of origin
- tumors are usually preceded by an asymptomatic stage of hyperplasia involving the cell of origin
- tumors are usually more aggressive
MEN1
- Wermer’s syndrome
- 3 P’s: pituitary adenoma, parathyroid tumors, pancreatic tumors
MEN2A
- Sipple syndrome
- Hyperparathyroidism
- medullary thyroid cancer
- pheochromocytoma
MEN2B
- Marfanoid phenotype
- Mucosal neuromas
- Pheochromocytomas
- Ganglioneuromas
what kind of pituitary adenoma will we most likely see in MEN1?
-prolactinoma
What is the leading cause of morbidity and mortality in MEN1?
-Pancreas endocrine tumors
where is the most common site of gastrinomas (MEN1)
-duodenum
What is the MEN1 mutation
-germline mutations in the MEN1 tumor suppressor gene
MEN2A
- Sipple syndrome
- Pheochromocytoma
- Medullary thyroid carcinoma (100%*)
- Parathyroid hyperplasia
What mutation happens with MEN2A?
-germline mutations in RET proto-oncogene
MEN2B
- Medullary Carcinoma of the thyroid (100%)
- Pheochromocytomas
- Neuromas or ganglioneuromas of the skin, oral mucosa, eyes, resp tract, and GI tract
- Marfanoid habitus
- different RET mutation than MEN1
Which MEN is the aggressive diseases and has an adverse prognosis?
-MEN2B
What is recommended for family members of ppl with MEN2B?
- Genetic screening
- offered prophylactic thyroidectomy to prevent medullary thyroid carcinoma
- life-threatening
Familial medullary thyroid cancer
- Variant of MEN-2A
- only medullary thyroid cancer
- pts older
- more indolent course
Pineal gland
- minute, pinecone-shaped
- composed of pineocytes: photosensory and neuroendocrine functions
- secretes melatonin: control of circadian rhythms
- Tumors are rare
