PALM Block 8: Endocrine 5 - Adrenal Cortex Pathology and Multiple Endocrine Neoplasms
What regulates androgen formation?
ACTH
It is more common for an ectopic tumor to secrete (ACTH/CRH)
ACTH Rarely a tumor that secretes CRH => ACTH secretion => hypercortisolism
What are the two main types of autoimmune adrenalitis and which is assoc. w/ candidiasis?
APS 1 (candida) APS 2
What three pathologies is Sipple syndrome characterized by?
ATP Adrenal Pheochromocytoma Medullary Thyroid Carcinoma Parathyroid Hyperplasia
What happens in salt-wasting?
Acidosis, hypotension May lead to CV collapse and death
Chronic adrenocortical insufficiency?
Addison Disease
What are cuases of ACTH-independent Cushing syndrome?
Adenomas Carcinomas
How does MEN-2B overlap w/ MEN-2A?
Adrenal pheochromocytoma Medullary thyroid carcinoma (but multifocal and more aggressive) Germ-line mutations of RET proto-oncogene on chromosome 10q11.2
What are adrenal causes of androgen excess?
Adrenocortical neoplasms Congenital adrenal hyperplasia
WF is more common in (children/adults)
Adults
State if the following will be low or high in Simple virilizing adrenogenital syndrome without salt-wasting: Aldosterone Glucocorticoid Testosterone
Aldosterone - low Glucocorticoid - low Testosterone - high
In general, MENs: Arise in (younger/older) pts. Arise in (a single/multiple) organ(s) Often (solitary/multifocal) Usually (indolent/agressive)
Arise in YOUNGER pts. Arise in MULTIPLE organs Often MULTIFOCAL Usually AGGRESSIVE
What is the most common cause of Addison Disease?
Autoimmune adrenalitis
What are some causes of Addison Disease?
Autoimmune adrenalitis Tb AIDS Metastatic carcinoma
Mode of inheritance of congenital adrenal hyperplasia?
Autosomal recessive
What is the most common cause of hyperaldosteronism?
Bilateral idiopathic hyperaldosteronism
What are 3 causes of primary hyperaldosteronism?
Bilateral idiopathic hyperaldosteronism Adrenal cortical neoplasm/Conn syndrome Glucocorticoid-suppressible
A virilizing neoplasm is more likely to be a(n) (adenoma/carcinoma)
Carcinoma
Carcinoma metastatic to the adrenal is much (less/more) common than primary carcinoma
Carcinoma metastatic to the adrenal is much MORE common than primary carcinoma
Adrenocortcal neoplasms associated w/ virilization are more likely to be androgen-secreting (adenoma/carcinomas)
Carcinomas
What are classic features of Cushing syndrome?
Central pattern of fat deposition Secondary diabetes Collagen loss and bone resorption Hirsutism Moon facies Osteoporosis Buffalo hump Obesity Thin, wrinkled skin Skin ulcers
What are two scenarios in which primary acute adrenocortical insufficiency arises?
Crisis in pt with chronic insufficiency brought on by any stress that requires h steroid output from glands that cannot respond Massive hemorrhage of the adrenals
What is secondary adrenocortical insufficiency due to?
Decrease in ACTH
When is secondary hyperaldosteronism encountered?
Decreased renal perfusion Arterial hypovolemia and edema: CHF, cirrhosis, nephrotic syndrome Pregnancy
What can cause secondary adrenocortical insufficiency?
Disorders of hypothalamus or pituitary Prolonged administration of exogenous glucocorticoids
Atrophy of adrenal gland is seen in (endogenous/exogenous) Cushing
Exogenous
What are two causes of acute adrenocortical insufficiency?
Exogenous steroid sudden withdrawal Waterhouse-Friderichsen Syndrome
T or F Carcinomas produce the same hypercortisolism when compared to adenomas
FALSE Caricinomas are worse
T or F To differentiate between an functional and non-functional adrenal neoplasm, you must look at the morphology
FALSE You need a clinical evaluation and observation of hormones and metabolites in the blood
Familial medullary thyroid cancer, a variant of MEN-2A typically develops at (younger/older) ages and is (less/more) indolent
Familial medullary thyroid cancer, a variant of MEN-2A typically develops at OLDER ages and is MORE indolent No other clinical manifestations
Pituitary hypersecretion of ACTH is usually seen in (females/males)
Females
When and how is virilization recognized in males and females?
Females: Usually recognized at birth due to mild to marked clitoral enlargement (looks phallic). Males: Generally unrecognized at birth. 5-15 days later have salt-wasting crisis.
Match the following zonas to their lipids: Fasciculata Glomerulosa Reticularis Glucocorticoids Mineralocorticoid Sex steroids
Glomerulosa - Mineralocorticoids Fasciculata - Glucocorticoids Reticularis - Sex steroids Salty, sugar, sex
Disorders of sexual differentiation can be primary causes of which organs?
Gonadal Adrenal
What are Multiple Endocrine Neoplasia Syndromes (MENs)
Group of genetically inherited diseases that result in proliferative lesions (hyperplasia, adenomas, carcinomas) of multiple endocrine organs
Addison disease is assoc. w/: (Hypo/Hyper)kalemia (Hypo/Hyper)natremia (Hypo/Hyper)tension (Hypo/Hyper)glycemia
HYPERkalemia HYPOnatremia HYPOtension HYPOglycemia
In secondary hyperaldosteronism, plasma renin will be (low/high)
High
What are functional adrenal adenomas most commonly assoc. w/?
Hyperaldosteronism and Cushing
Adrenocortical neoplasms associated w/ virilization is often assoc. w/ hyper(aldosteronism/cortisolism)
Hypercortisolism
What can dexamethasone suppression test help discern?
Hypercortisolism/Cushing disease
What causes the hyperpigmentation in Addison Disease?
Hyperpigmentation due to h circulating levels of pro-opiomelanocortin (POMC), a precursor of ACTH and melanocyte stimulating hormone
Eponym for adrenocortical insufficiency?
Hypoadrenalism
In MEN-2A, Medullary Thyroid Carcinoma is typically (solitary/multifocal) and (indolent/aggressive)
In MEN-2A, Medullary Thyroid Carcinoma is typically MULTIFOCAL and AGGRESSIVE
In MEN-2A, adrenal pheochromocytoma is typically (UL/BL), (rarely/often) extra-adrenal, and can be (benign/malignant/either)
In MEN-2A, adrenal pheochromocytoma is typically BL, OFTEN extra-adrenal, and can be BENIGN OR MALIGNANT
In MEN-2A, parathyroid hyperplasia is (rarely/often) assoc. w/ kidney stones and (hyper/hypo)calcemia
In MEN-2A, parathyroid hyperplasia is OFTEN assoc. w/ kidney stones and HYPERcalcemia
How can one diagnose hypercortisolism/Cushing disease?
Increase in 24 hr urine free cortisol Loss of diurnal pattern of cortisol secretion (highest in AM)
How can you confirm primary aldosteronism?
Increase ratio of plasma aldosterone concentration to plasma renin activity. If positive, do confirmatory aldosterone suppression test: Captopril or salt-loading suppression tests
Which cancer syndromes is adrenal carcinoma syndrome assoc. w/?
Li-Fraumeni (germline p53 mutation) Beckwith-Wiedemann (imprinting disorder)
In primary hyperaldosteronism, plasma renin will be (low/high)
Low
In salt-wasting classic syndrome, mineralocorticoid production is (low/high)
Low Virtually none
Wermer Syndrome is: MEN-1 MEN-2A MEN-2B (MEN3)
MEN-1
Which of the following is assoc. w/ familial medullary thyroid cancer: MEN-1 MEN-2A MEN-2B (MEN3)
MEN-2A
Sipple Syndrome is: MEN-1 MEN-2A MEN-2B (MEN3)
MEN-2A/MEN-2
This pathology is assoc. w/ mucosal neuromas
MEN-2B
This pathology os assoc. w/ Marfanoid habitus
MEN-2B
Germ-line mutation seen in Wermer syndrome and what does this gene encode?
MEN1 gene at 11q13 Encodes menin
What is Waterhouse-Friderichsen syndrome (WF)?
Massive adrenal hemorrhage as a complication of bacteremic infection
100% of patients w/ MEN-2A will have: Adrenal Pheochromocytoma Medullary Thyroid Carcinoma Parathyroid Hyperplasia
Medullary Thyroid Carcinoma
This pathology has elaborate calcitonin (opposes action of PTH), sometimes other products
Medullary Thyroid Carcinoma in MEN-2A
This pathology is assoc. w/ parafollicular C-cell hyperplasia
Medullary Thyroid Carcinoma in MEN-2A
What is the only definitive evidence of adrenal carcinoma malignancy?
Metastasis
Gross of adrenal adenoma?
Most are clinically silent and incidental findings. Well-demarcated nodular lesion. In non-functional adenomas, adjacent cortex is normal (in theory)
Hyperaldosteronism is assoc. w/ (HTN/hypotension) and (hyperkalemia/hypokalemia)
NTN Hypokalemia
Organism most likely to cause WF?
Neisseria meningitidis
Does hypokalemia have to be present to Dx primary hyperaldosteronism?
No
Will marked hyponatremia and hyperkalemia be seen in secondary adrenocortical insufficiency?
No
How does MEN-2B differ from MEN-2A?
No hyperparathyroidism. Instead... Mucosal neuromas/ ganglioneuromas of skin, GI, respiratory tract Marfanoid habitus
This disease is a partial deficiency in 21-hydroxylase function
Non-classic adrenal virilism
Sxs. of Non-classic adrenal virilism?
None => mild, such as hirsutism
How to Dx. Non-classic adrenal virilism?
Not seen on routine newborn screening Demonstration of biosynthetic defects in steroidogenesis Genetic studies
Which of the following organ locations is the most aggressive in MEN-1: Parathyroid Pituitary Pancreas
Pancreas Endocrine tumors: leading cause of morbidity and mortality Often present w/ metastasis
What are the 3 Ps of Wermer Syndrome (MEN-1)?
Parathyroid Pituitary Pancreas Also involves: duodenal gastrinomas, thyroid adenomas, etc/
What kind of tumors are associated w/ the following organs in MEN-1: Parathyroid Pituitary Pancreas
Parathyroid: Primary Hyperparathyroidism (most common) Adenomas or hyperplasia Pituitary: Prolactinoma Pancreas Gastrinoma associated with Zollinger-Ellison Insulinomas associated with hypoglycemia
Dexamethasone will suppress negative feedback on the (adrenal/ectopic/pituitary)
Pituitary
What are the 4 general causes of Cushing syndrome?
Pituitary Adrenal Paraneoplastic Iatrogenic
What is the most common cause of endogenous hypercortisolism?
Pituitary hypersecretion of ACTH
(Primary/Secondary/Both) Adrenocortical insufficiency is assoc. w/ hyperpigmentation
Primary
What is the most common cause of secondary HTN?
Primary hyperaldosteronism
How to trt. the following causes of hyperaldosteronism: Primary hyperplasia Adenoma Secondary
Primary hyperplasia: spironolactone (aldosterone antagonist) Adenoma: surgery Secondary: correct underlying cause
Action of 21-hydroxylase?
Progesterone => Deoxycortisone
What are people that have RET mutations advised to do?
Prophylactic thyroidectomy to prevent medullary carcinoma, which will otherwise occur
Germ-line mutation seen in Sipple syndrome (MEN-2A)?
RET proto-oncogene on chromosome 10q11.2
Clinical characteristics of WF?
Rapidly developing hypotension à shock DIC, extensive purpura Rapidly developing adrenocortical insufficiency, massive adrenal hemorrhage More in children Exact etiology of hemorrhage unknown. Fatal without prompt antibiotic Rx
This pathology has a total lack of 21-hydroxylase
Salt-wasting (classic) syndrome
What are the 3 distinctive syndromes that reflect total to mild 21-hydroxylase deficiency?
Salt-wasting (classic) syndrome Simple virilizing adrenogenital syndrome without salt-wasting Non-classic adrenal virilism
If someone has MTC in MEN-2 syndrome, what must their families do?
Screened for RET mutations
Administration of ACTH will increase plasma cortisol in (primary/secondary) adrenocortical insufficiency
Secondary
What is the cause of Ectopic ACTH secretion?
Secretion of ACTH by non-pituitary tumors
This disease is a less than a total lack of 21-hydroxylase
Simple virilizing adrenogenital syndrome without salt-wasting
Most common tumor of ectopic ACTH secretion
Small cell carcinoma of the lung
Most adrenal carcinomas are (familial/sporadic)
Sporadic
Adrenal steroid synthesis diagram
Steroid hormone synthesis begins with cholesterol Cortical enzymes catalyze sequential transformations Functional enzyme deficiency may block synthesis of a steroid while causing overproduction of another
What cells are targeted in Autoimmune adrenalitis and what are the AutoAbs directed against?
Steroidogenic cells Steroidogenic enzymes (21-hydroxylase, 17-hydroxylase)
T or F In Ectopic ACTH secretion, patients usually succumb to cancer before the hypercortisolism becomes an issue
TRUE
Neoplasms of endogenous Cushing are usually (UL/BL)
UL Adjacent gland may be atrophic
What are settings that can cause massive hemorrhage of the adrenals?
WF Anti-coags DIC
What percent of cortical cells are destroyed before clinical manifestations are seen in Addison Disease?
>90%
