adrenals Flashcards
ACTH independent Cushing’s
- Adrenal adenoma or carcinoma
- Macronodular hyperplasia
- Primary pigmented nodular adrenal disease
- McCune‐Albright syndrome
ACTH dependent Cushings
ACTH dependent
– Cushing disease – pituitary adenoma
– Ectopic corticotropin syndrome (ACTH)
ACTH‐Secreting Pituitary Adenoma
ACTH‐Secreting Pituitary Adenoma
~70% of cases of endogenous hypercortisolism
W>M
Most frequently seen in young adults
Majority are microadenomas
Macroadenoma also possible
Rarely corticotroph cell hyperplasia without a discrete adenoma
- Primary
- Secondary from excessive stimulation from a hypothalamic corticotrophin‐releasing hormone (CRH)‐producing tumor
Secretion of Ectopic ACTH by Nonpituitary Tumors
•
Secretion of Ectopic ACTH by Nonpituitary Tumors
- ~10% of ACTH‐dependent Cushing syndrome
- Most often seen with small‐cell carcinoma of the lung
- Other neoplasms
- Carcinoids
- Medullary thyroid carcinoma
- Islet cell tumors
- Sometimes neuroendocrine neoplasm produces ectopic corticotrophin releasing hormone (CRH)
- → ACTH secretion and hypercortisolism
Primary Adrenal Neoplasms and Primary Cortical hyperplasia
-
Primary Adrenal Neoplasms
- Most common cause of ACTH‐independent Cushing syndrome
- Adrenal adenoma (~10%)
- Adrenalcarcinoma(~5%)
- Produce most profound hypercortisolism
- See ↑ cortisol and ↓ ACTH
-
Primary cortical hyperplasia
- Uncommon
- Vast majority of hyperplastic adrenals are ACTH dependent
Cushing Syndrome: Morphology of the Adrenal Gland
Cushing Syndrome Morphology of the Adrenal Glands
- Cortical atrophy
- Seen when exogenous glucocor coids → suppression of ACTH → lack of stimulation of the zonae fasciculata and reticularis
- Diffuse hyperplasia (both glands enlarged)
- Endogenous hypercortisolism
- ACTH‐dependent Cushing syndrome
- Cortex can be variably nodular
Macronodular hyperplasia
Macronodular hyperplasia
- Endogenous hypercortisolism
- Adrenals almost entirely replaced by prominent nodules of varying sizes (≤3 cm)
- Areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity
Micronodular hyperplasia
Micronodular hyperplasia
- Endogenous hypercortisolism
- Composed of 1‐ to 3‐mm darkly pigmented (brown to black) micronodules, with atrophic intervening areas
- Pigment is thought to be lipofuscin
Primary Adrenocortical Neoplasms: classifications
Primary Adrenocortical Neoplasms
- Functional (Cushing syndrome) or non‐functional
- Morphologically indistinguishable
- Functional tumors: adjacent adrenal cortex and the contralateral adrenal gland are atrophic
- Yellow tumors surrounded by thin or well‐developed capsules
- Most weigh <30 gm
- Microscopically see cells that look like normal zona fasciculata
What tumor, and who is most likely to be seen with it?
Primary adrenal adenoma
- Most commonly seen in women aged 30‐50
- Adenomas (benign)
- Yellow tumors surrounded by thin or well‐developed capsules
- Most weigh<30 gm
- Microscopically see cells that look like normal zona fasciculata
primary adrenal neoplasms: adenoma vs carcinoma
functional/nonfunctional: Morphologically indistinguishable
Functional tumors: adjacent adrenal cortex and the contralateral adrenal gland are atrophic. Most commonly seen in women aged 30‐50
Adenomas (benign): Yellow tumor ssurrounded by thin or well‐developed capsules and most weigh<30 gm. Microscopically see cells that look like normal zona fasciculata
Carcinomas (malignant): Larger than the adenomas are usually > 200‐300 gm, Unencapsulated
Cushings clinical
- muscle: atrophy of what kind of muscle fibers?
- metabolism: what kind of profile?
- skin, immune system, bone
- Atrophy of fast‐twitch myofibers → decreased muscle mass and proximal limb weakness
- Glucorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells
- Hyperglycemia, glucosuria and polydipsia (secondary diabetes)
- The catabolic effects → loss of collagen and resorp on of bones
- Skin is thin, fragile, and easily bruised
- Poor wound healing
- – Cutaneous striae are particularly common in the abdominal area
- – Osteoporosis
- Increased risk of infections (imm
Diagnosis of Cushing Syndrome (2)
- Diagnosis of Cushing Syndrome
- Increased 24‐hour urine free‐cortisol
- Loss of normal diurnal pattern of cortisol secretion
Determining the cause of Cushing Syndrome•
Determining the cause of Cushing Syndrome
- Serum ACTH
- Dexamethasone suppression test: Urinary excretion of 17‐hydroxycorticosteroids after administration of dexamethasone
identify the etiologies described in each column
- cushing’s disease (pituitary ACTH secreting microadenoma most common) (ACTH suppressed with high dose)
- Ectopic and adrenal tumor behave the same way to the dexamethasone test
Primary Hyperaldosteronism
Caused by
Mechanism
Primary Hyperaldosteronism
Caused by one of three mechanisms:
- Adrenocortical neoplasm
- Bilateral idiopathic hyperaldosteronism (IHA)
- Glucocorticoid‐remediable hyperaldosteronism
Autonomous overproduction of aldosterone
- Suppression of the renin‐angiotensin system and decreased plasma renin activity –> elevated BP is the most common manifestation
Adrenocrotical Adenoma: name, gender, age, lateral preferences
Adenoma: most common cause of hyperaldosteronism
- Called Conn Syndrome
- 30‐40 yrs most common
- W > M (2 : 1)
- Left > right
Usually solitary, Small (<2 cm in diameter), Well‐circumscribed lesions, Bright yellow grossly
Characteristic microscopic feature: spironolactone bodies
Adrenocortical adenoma: tumor in Conn’s syndrome
- Usually solitary
- Small (<2 cm in diameter)
- Well‐circumscribed lesions
- Bright yellow grossly
- Characteristic microscopic feature: spironolactone bodies
Bilateral Idiopathic Hyperaldosteronism
- 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
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
in addition to primary hyperaldosteronism, conn’s, and glucocorticoid remediable hyperaldosteronism, aldosterone released in response to activation of the renin‐angiotensin system by ↑ plasma renin is also seen in….
- Seen in:
- 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
spironalactone bodies found in aldosterone secreting adenomas (conn’s). eiosinophilic, laminated cytoplasmic inclusions
Clinical Course of hyperaldosteronism
- Hypertension (most important)
- – ~5‐10% all hypertensive patients
- Clinical Course
- – ~20% of treatment resistant hypertensives
- – Most common cause of secondary hypertension (i.e.,an identifiable cause)
- Long‐term effects of hypertension on the CV system:
- – Left ventricular hypertrophy and reduced diastolic volumes
- – Stroke and myocardial infarction
- Aldosterone also promotes sodium reabsorp on → increased reabsorption of water
- – Expands the extracellular fluid volume
- – Elevated cardiac output
-
Hypokalemia (↓K) typically seen
- Weakness, paresthesias, visual dist
Screening and confirmation test and diagnosis of hyperaldosteronism
- Screening test:
- Elevated ratio of plasma aldosterone concentration to plasma renin activity
- Confirmation test:
- Aldosterone suppression test
- Administer: oral saline load, IV saline load, fludrocortisone
- If aldosterone is not suppressed: confirm primary hyperaldosteronism
tx for bilateral remediable hyperaldo and adenomas, secondary hyperaldo
- Varies depending on the cause
- Adenomas: surgical resection
- Treatment
-
Bilateral hyperplasia:
- Aldosterone antagonist (e.g. spironolactone)
-
Secondary hyperaldosteronism:
- Treat underlying cause
-
Bilateral hyperplasia:
Adrenogenital Syndromes
- Adrenogenital Syndromes
- Disorders of sexual differentiation: Virilization or feminization
- Primary gonadal disorders
- Primary adrenal disoders
- Disorders of sexual differentiation: Virilization or feminization
- ACTH regulates adrenal androgen formation:
- Adrenal cortex secretes dehydroepiandrosterone and androstenedione
- Converted to testosterone in peripheral tissues
- Adrenal cortex secretes dehydroepiandrosterone and androstenedione
- “Pure” syndrome or as a component of Cushing disease
- Adrenocortical neoplasms (more likely carcinoma)
- Congenital adrenal hyperplasia (CAH)
Congenital Adrenal Hyperplasia (CAH)
Congenital Adrenal Hyperplasia (CAH)
- Several autosomal‐recessive, inherited metabolic errors
- Deficiency or total lack of an enzyme involved in the biosynthesis of cortical steroids, esp. cortisol
21‐Hydroxylase Deficiency
- >90% of CAH
- Mutations of CYP21A2
- Three distinctive syndromes:
- Salt‐wasting syndrome
- Simple virilizing adrenogenital syndrome without salt wasting
- Nonclassic or late‐onset adrenal virilism
Salt‐Wasting Syndrome
- main problem
- typcially presents for boys/girls
- what it can cause
- Salt‐Wasting Syndrome
- Inability to convert progesterone into deoxycorticosterone
-
Typically presents soon after birth
- Virilization recognized in the female at birth or in uter
-
Males come to clinical attention 5‐15 days later because of some salt‐losing crisis
- Salt wasting (hyponatremia and hyperkalemia) → acidosis, hypotension, cardiovascular collapse, and possibly death
girls vs boys: salt wasting syndrome
- Inability to convert progesterone into deoxycorticosterone
- Typically presents soon after birth
- Virilization recognized in the female at birth or in uter
- Males come to clinical attention 5‐15 days later because of some salt‐losing crisis
- Salt wasting (hyponatremia and hyperkalemia) → acidosis, hypotension, cardiovascular collapse, and possibly death
progressive virilzation
- Simple Virilizing Adrenogenital Syndrome Without Salt Wasting
- Presents as genital ambiguity
- ~1/3 of 21‐hydroxylase deficiency
- Progressive virilization
most common andrenogenital 21 hydroxylase deficiency syndrome
- Nonclassic or Late‐onset Adrenal Virilism
- Most common
- Only a partial deficiency in 21‐hydroxylase
- function
- Asymptomatic
- Hirsutism, acne, and menstrual irregularities
an xx baby is born with virilizing features, identified too late and die. autopsy is shown below. what is the condition?
- congenital adrenal hyperplasia
- Adrenals are bilaterally hyperplastic
- Cortex is thickened and nodular
- Cortex looks brown due to total depletion of all lipid
hould be suspected in any neonate with ambiguous genitalia
CAH
newborn with clitoral hypertrophy and pseudohermaphroditism in infants
CAH 21 oh deficiency
adolescent girl visits your clinic and you diagnose oligomenorrhea, hirsutism, and acne in postpubertal
CAH 21 Oh deficiency
in CAH, severe enzyme deficiency in infancy can be life‐threatening. describe some symptoms
Severe enzyme deficiency in infancy can be life‐threatening with vomiting, dehydration, and salt wasting
CAH and the adrenal medulla
High levels of intra‐adrenal glucocorticoids are required to make catecholamine, epinephrine and norepinephrine
Pts with severe salt‐wasting 21‐hydroxylase deficiency:
- Low cortisol levels → adrenomedullary dysplasia (↓ catecholamine secre on) → hypotension and circulatory collapse
Treatment of CAH
- Treatment of CAH
- Exogenous glucocorticoids
- Replaces glucocorticoids AND Suppress ACTH levels which decreases the excessive synthesis of the steroid hormones
- responsible for many of the clinical abnormalities
- Mineralocorticoid supplementation
addison’s diz: chronic adrenal insufficiency
Adrenocortical Insufficiency
Adrenocortical Insufficiency
Primary acute adrenocortical insufficiency (adrenal crisis)
Primary chronic adrenocortical insufficiency (Addison disease)
Secondary from decreased stimulation of the adrenals due to a deficiency of ACTH
what causes adreanal insufficiency
- Crisis:
- Pt with chronic adrenocortical insufficiency precipitated by any form of stress
- Adrenal glands can’t provide immediate increase in steroid output
- 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 the adrenal cortex
- New borns following prolonged and difficult delivery with considerable trauma and hypoxia
- Pts on anti coagulant therapy
- Postsurgical patients who develop disseminated intravascular coagulation
- Disseminated bacterial infection (Waterhouse‐Friderichsen syndrome)
WHFS
- Uncommon
- Any age, but more common in kids
- Overwhelming bacterial infection, classically Neisseria meningitidis septicemia
- Also see with Pseudomonas species, pneumococci, Haemophilus influenzae, or even staphylococci
- Rapidly progressive hypotension leading to shock
- Disseminated intravascular coagulation associated
- with widespread purpura, particularly of the skin
- Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
- Fatal, unless promptly recognition and treated
Progressive destruction of the adrenal cortex
Primary Chronic Adrenocortical Insufficiency (Addison Disease)
- Uncommon
- Progressive destruction of the adrenal cortex, requires up to 90% before symptoms show
a group of autosomal recessive disorders characterized by defects in the biosynthesis of steroids
CAH
Accounts for 60‐70% of Addison Disease
autoimmune adrenalitis
Accounts for 60‐70% of Addison Disease
Accounts for 60‐70% of Addison Disease
- Autoi-mmune destruction of steroidogenic cells
- Autoantibodies
- 21‐hydroxylase
- 17‐ hydroxylase have been detected
- Occurs in one of two clinical settings:
- Autoimmune polyendocrine syndrome type 1 (APS1)
- Autoimmune polyendocrine syndrome type 2 (APS2)
APS2
APS2
- Usually starts in early adulthood
- Presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
causes of Addison’s Dz
- Infections
- Particularly tuberculosis and fungal
- AIDS at increased risk from several infectious (CMV, MAI) and noninfectious (Kaposi sarcoma) causes
- Metastatic neoplasms
- Lung and breast carcinomas most commonly
- Others: GI carcinomas, melanoma, and hematopoietic neoplasms
- Genetic causes
- Congenital adrenal hypoplasia
- Rare X‐linked disease
- Adrenoleukodystrophy
Morphology: addisons–> primary, TB/fungal infection, metastatic causes
- Morphology
-
Primary autoimmune adrenalitis
- Irregularly shrunken glands, which may be difficult to
- Histology
- Cortex contains scattered residual cortical cells in a collapsed network of connective tissue
- Variable lymphoid infiltrate
-
Tuberculous and fungal disease
- Adrenal architecture is effaced by a granulomatous inflammatory reaction
-
Metastatic carcinoma
- Normal architecture obscured by the infiltrating neoplasm
-
Primary autoimmune adrenalitis
- Clinical symptoms of Addisons’s:
2.
- 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
- Especially on sun‐exposed areas and at pressure points (e.g. neck, elbows, knees, and knuckles)
- Results from elevated levels of pro‐opiomelanocortin (POMC)
- Comes from anterior pituitary and is a precursor of both ACTH and melanocyte stimulating hormone (MSH)
addisson’s
Addison’s, clinical
Hypoglycemia can occur
– From impaired gluconeogenesis
Stresses can precipitate an acute adrenal crisis
– E.g. infections, trauma, or surgical procedures
– Intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse
– Death occurs rapidly unless corticosteroid therapy begins immediately
hyperkalemia, hyponatremia, volume depletion, hyptotension: what other symptoms is this individual prone to develop?
adrenal insufficiency: lack of mineralcorticoids –> sodium loss without potassium excretion. other symptoms include intractable vomiting, abdominal pain, hypotension, coma, vascular collapse.
hypokalemia, weakness, parathesis, visual disturbances, frank tetany
primay hyperaldosteronism
- Mostareclinicallysilentanddiscovered incidentally
- Well‐circumscribed nodular lesion
- Up to 2.5 cm in diameter
- Usually yellow to yellow‐brown because of the presence of lipid
- Cortex adjacent to nonfunctional adenomas is normal
Adrenocortical Adenomas
neoplasms that can occur at any age, including childhood, and more likely to be functional. Often present with virilisation. These are large, invasive lesions, often > 20 cm in diameter. When smaller, and more‐circumscribed may be difficult to distinguish from an adenoma. Often invade nearby veins and lymphatics. Metastases to regional and periaortic nodes, lungs and other viscera common.
what is the median age of survival with these cancers? what do they look like microscopically?
Median patient survival is about 2 years
Microscopically:
- Look like an adenoma (pretty bland)
- Undifferentiated carcinoma
- Need to differentiate from metastases to the adrenal cortex (much more common)
~2/3 have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations (can be fatal)
pheochromocytomas, neoplasm of the chromaffin cells
rule of 10s
“Rule of 10s”
- 10% are extra‐adrenal (called paragangliomas)
- 10% of sporadic pheochromocytomas are bilateral
- 10% are malignant
- Defined by the presence of metastatic disease
- Malignancy is more common in extra‐adrenal paragangliomas and in some germline mutations
- 10% don’t have hypertension
Tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension
Can also get abdominal pain, chest pain, nausea, and vomiting
Can be precipitated by…..
Pheocrhomocytomas
Can be precipitated by:
- Emotional stress
- Palpation in the region of the tumor
- Patients with urinary bladder paragangliomas occasionally precipitate a paroxysm during micturition
the 5 Ps of hyperadrenergic symptoms
- Pressure: BP increases
- Pain: headaches
- Perspiration
- Palpitations (tachycardia)
- Pallor
tumors/pheocrhomocytomas secrete epinephrine, norepinephrine, and dopamine, can cause episodic spells
pheochromocytomas acutely precipitate:
Acutely precipitate: Congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular accidents
Up to 25% of pts with pheochromocytomas and paragangliomas
Up to 25% of pts with pheochromocytomas and paragangliomas
- Typically younger
- More often bilateral – Up to 50%
renal cell carcinoma, hemangioblastoma, pancreatic endocrine neoplasm, pheocrhomocytoma, paraganglioma
VHL gene mutation
optic nerve glioma, pheochromocytoma
NF1, cafe au lat spots as well
SDHB, SDHC, SDHD
B- pheochromocytoma and paraganglioma, C just para, D- pheo and para
familial paraganlgioma 1, 3, 4
1- SDHD
3- SDHC
4- SDHB
how is malignancy determined in pheochromocytoma
malignancy is defined by metastasis
Tumors are usually preceded by an asymptomatic stage of hyperplasia involving the cell of origin
MEN tumors
- Tumors occur at a younger age than sporadic tumors
- Tumors arise in multiple endocrine organs
- Synchronously (at the same time)
- Metachronously (at different times)
- Tumors often multifocal in an affected organ
- Tumors are usually preceded by an asymptomatic
- stage of hyperplasia involving the cell of origin – E.g. C‐cell hyperplasia in thyroid of MEN‐2
- Tumors are usually more aggressive
MEN 1
MEN2 A
MEN 2 B
wermer syndrome, sipple syndrome
- MEN-1- wermer
- M2 A- sipple
Primary hyperparathyroidism seen in 80‐95% , initial manifestation in most, hyperplasia and adenomas. The leading cause of death in these patients is X and the other common tumor associated with this condition is what?
- MEN1
- Pancreas endocrine tumors; prolactinomas
-
Leading cause of morbidity and mortality: Pancreatic neuroendocrine neoplasms
- Usually aggressive and often present with metastatic disease
- Can find multiple “microadenomas” scattered throughout the pancreas along with one or two dominant lesions
- Often functional
- Pancreatic polypeptide is the most common (asymptomatic)
- Also see insulinomas and gastrinomas (Zollinger‐Ellisonsyndrome)
- Pituitary
- Most often prolactinoma
- Some somatotrophin‐secreting tumors
Other neoplasms of MEN1
MEN-1
- Duodenum: the most common site of gastrinomas
- Neuroendocrine (carcinoid) tumors
- Thyroid adenomas
- Adrenocortical adenomas
- Lipomas
Medullary carcinoma of the thyroid (~100%). Cause of this syndromic item?
MEN2A: mutation in the RET protooncogene
salt and pepper cytoplasm
clusters of polygonal spindle shaped chromaffin cells or chief cells surrounded by supporting sustentacular cells—> creating small nests or alveoli
neuroendocrine (chromaffin) tumor cells have a salt and pepper appearance in pheochromocytomas
zellballen are the nests of chromaffin cells surrounded by sustenatcular cells in pheochromocytomas
s-100 antibodies
pheochromocytomas: antibodies against sustentacular cells
