Lecture 36 Flashcards
Working in to out, what are the layers of the adrenal gland?
- Medulla
- Zona reticularis
- Zona fasciculata
- Zona glomerulosa
- Capsule
What three zones make up the cortex of the adrenal gland?
- Zona reticularis
- Zona fasciculata
- Zona glomerulosa
What hormone is produced in the medulla?
Epinephrine
What hormones are synthesized in the zona reticularis and zona fasciculata?
- Glucocorticoids (ex. cortisol)
- Androgens (DHEA and androstenedione)
What hormone is made in the zona gomerulosa?
mineralocorticoid (aldosterone)
Which way does blood flow in the adrenal gland?
Capsulary artery -> capsule -> medula -> medullary vein
Where does the preganglionic sympathetic terminal of the adrenal gland synapse?
The medulla
What are the four basic systems that control stress and disease process?
- Central nervous system
- Peripheral nervous system (specifically autonomic nervous system)
- Endocrine system
- Immune system
What is the process of glucocorticoid synthesis?
- Stress received
- Hypothalamus secretes Corticotropin Releasing Hormone (CRH) which signals the anterior pituitary
- Anterior Pituitary secretes Corticotropin (ACTH, 39 aa) which signals the adrenal cortex (specifically zona fasciculata)
- Adrenal cortex creates 15-30 mg/day of corisol
What kinds of stress can trigger the hypothalamo-pituitary-adrenal cortex axis
- Physical via the Reticular Activating System
- Emotional via the Limbic System
How is corticotropin (ACTH) released in the anterior pituitary?
Through pituitary secretion with a diurnal variation (varied throughout the day
What is the half life of corticotropin (ACTH)?
15 minutes
What is the process of mineralocorticoid (aldosterone) synthesis?
- Renal hypoperfusion leads to increased renin production from juxtaglomerular cells (located in the afferent arterioles of the kidney).
- Renin combines with angiotensinogen to create Angiotensin I
- Angiotensin-Converting Enzyme (ACE) from pulmonary vasculature combines with Angiotensin I to create Angiotensin II
- Angiotensin II reaches the zona glomerulosa where it stimulates aldosterone secretion, which increases renal reabsorption of sodium and potassium excretion
What are the other uses of Angiotensin II?
- Kidneys: Decreased perfusion and filtration, increased sodium reabsorption and potassium excretion
- Hypothalamus: Increased thirst
- Vascular smooth muscle cells: Systemic vasoconstriction
What is the system called that creates aldosterone?
Renin-Angiotensin-Aldosterone system
Where is the aldosterone stimulating in the kidney?
Distal (convoluted) tubule
Where are the secondary sites of aldosterone stimulation?
- Proximal portion of kidney
- Intestinal mucosa
- Salivary glands
- Sweat glands
What is the order of flow for the nephron?
Brush border -> thin descending limb of loop of Henle -> Thick ascending limb of loop of Henle -> distal convoluted tubule -> intercalated cells -> principal cells -> Medullary collecting tubule
Increasing potassium excretion is the minor effect of ACTH
TRUE
How do glucocorticoid drugs and cortisol effect mineralocorticoid activity?
Increase in salt and water retention as it increases the mineralocorticoid activity
How does sodium flow through renal tubular cells when mineralocorticoid receptors are activated?
Flows in from the tubular fluid and is excreted through paired diffusion with potassium into the peritubular capillary
How does potassium flow through renal tubular cells when mineralocorticoid receptors are activated?
It enters the cell through the peritubular capillary via paired diffusion with sodium, where it then flows out of the cell to the tubular fluid, maintaining a voltage of -40mV in the tubular fluid
What is the process of synthesizing aldosterone-induced proteins?
- Mineralocorticoid receptor is activated
- mRNA is created due to receptor activation, which encode for AIPs
What are the effects of AIPS?
- Regulate the flow of sodium and potassium through the cell.
What can inhibit mineralocorticoid receptor binding?
Spironolactone
How does cortisol’s anti-inflammatory effect work?
- Cortisol combines with phospholipase A2 to convert membrane phospholipids into arachidonic acid.
- However, cortisol inhibits cyclo-oxygenase meaning prostaglandins are not formed from the arachidonic acid
- Only leukotrines are created via reacting arachidonic acid with lipoxygenase
Cortisol exerts mainly catabolic actions
TRUE - with the exception of the liver, where it exerts anabolic actions
What are the effects of cortisol on the liver?
- Gluconeogenesis
- Potentiates actions of epinepherine and glucagon
- Glycogenesis
What are the effects of cortisol on skeletal muscle?
- Inhibits glucose uptake
- Glycogenesis
- Protein catabolism
What are the effects of cortisol on adipose tissue?
- Inhibits glucose uptake
- Lipolysis
How doe cortisol increase blood pressure?
- Facilitates activity of SNS by increasing expression of alpha and beta adrenergic receptors in multiple tissues
- At increased levels cortisol exerts mineralocorticoid actions on kidneys, which stimulates renal sodium reabsorption and increases plasma volume.
How does cortisol weaken bones?
At supraphysiologic levels cortisol reduces intestinal calcium absorption which precipitates an increase in PTH and causes osteoclastic activity.
What are the genomic actions of glucocorticoids?
Slows changes in gene expression that alter cellular function
How do genomic actions of glucocorticoids occur?
- Cytosolic glucocorticoid receptors (GR) change the gene express (increase/decrease)
- Transactivation through interaction of GC-GR with positive GC Response Element (pGRE)
- Transrepression through interaction of GC-GR with negative GC Response Element (nGRE)
What is the non-genomic action of glucocorticoids?
Rapid changes in cellular function that do not involve changes in gene expression
How do non-genomic actions of glucocorticoids occur?
- Multiple mechanisms mediated by cystolic GR, plasma membrane-bound Gr, and non-specific effects caused by GC interactions with cell membranes resulting in transmembrane currents, phosphorelation events, and calcium level changes
What is the pathway of steroidogenesis that creates C-21 Mineralocorticoids?
- Cholesterol degraded into pregnenolone
- Pregnenolone is synthesized into Progesterone using 3B-hydroxysteroid dehydrogenase/isomerase
- Progesterone is synthesized into 11-deoxycorticosterone using 21a-hydroxylase (CYP21)
- 11-deoxycorticosterone is synthesized into corticosterone using 11B-hydroxylase (CYP11B2)
- Corticosterone is synthesized into Aldosterone using 18-hydroxylase (CYP18B2/CYP11B2) and aldosterone synthase (which is activated via Angiotensin II)
What is the pathway of steroidogenesis that creates C-21 Glucocorticoids and Cortisone?
- Cholesterol degraded into pregnenolone
- Pregnenolone is synthesized into Progesterone using 3B-hydroxysteroid dehydrogenase/isomerase
- Pregnenolone is synthesized into 17-Hydroxypregnenolone using 17a-hydroxylase (CYP17)
- Progesterone is synthesized into 17-Hydroxyprogesterone using 17a-hydroxylase (CYP17)
- 17-Hydroxyprenenolone is also synthesized into 17- Hydroxyprogesterone using 3B-HSD
- 17-Hydroxyprogesterone is synthesized into 11-deoxycortisol using 21a-hydroxylase (CYP21)
- 11-Deoxycortisol is synthesized into cortisol using 11B-hydroxylase (CYP11B1)
- Cortisol is synthesized into inactive cortisone using 11B-HSD2
- Cortisone is synthesized into cortisol using 11B-HSD1
What is the pathway of steroidogenesis that creates C-19 Androgens?
- Cholesterol degraded into pregnenolone
- Pregnenolone is synthesized into Progesterone using 3B-hydroxysteroid dehydrogenase/isomerase
- Pregnenolone is synthesized into 17-Hydroxypregnenolone using 17a-hydroxylase (CYP17)
- Progesterone is synthesized into 17-Hydroxyprogesterone using 17a-hydroxylase (CYP17)
- 17-Hydroxyprenenolone is also synthesized into 17- Hydroxyprogesterone using 3B-HSD
- 17-Hydroxypregnenolone is synthesized into Dehydroepiandrosterone using 17,20-lyase (CYP17)
- 17-Hydroxyprogesterone is synthesized into Androstenedione using 17,20-lyase (CYP17)
- Dehydroepiandrosterone is also synthesized into Androstenedione using 3B-HSD
What is the pathway of steroidogenesis that creates C-18 Estrogens?
- Cholesterol degraded into pregnenolone
- Pregnenolone is synthesized into Progesterone using 3B-hydroxysteroid dehydrogenase/isomerase
- Pregnenolone is synthesized into 17-Hydroxypregnenolone using 17a-hydroxylase (CYP17)
- Progesterone is synthesized into 17-Hydroxyprogesterone using 17a-hydroxylase (CYP17)
- 17-Hydroxyprenenolone is also synthesized into 17- Hydroxyprogesterone using 3B-HSD
- 17-Hydroxypregnenolone is synthesized into Dehydroepiandrosterone using 17,20-lyase (CYP17)
- 17-Hydroxyprogesterone is synthesized into Androstenedione using 17,20-lyase (CYP17)
- Dehydroepiandrosterone is also synthesized into Androstenedione using 3B-HSD
- Androstenedione is synthesized into Estrone using FSH and aromatase
- Androstenedione is synthesized into testosterone using 17B-hydroxysteroid dehydrogenase/Oxidoreductase
- Dehydroepiandrosterone is also synthesized into androstenediol using 17B-hydroxysteroid dehydrogenase/oxidoreductase type 1
- Androstenendiol is synthesized into testosterone using 3B-HSD
- Testosterone is synthesized into Estradiol using aromatase
- Estadiol and estrone spontaneously transform into each other
What is the pathway of steroidogenesis that creates Dihydrotestosterone?
- Cholesterol degraded into pregnenolone
- Pregnenolone is synthesized into Progesterone using 3B-hydroxysteroid dehydrogenase/isomerase
- Pregnenolone is synthesized into 17-Hydroxypregnenolone using 17a-hydroxylase (CYP17)
- Progesterone is synthesized into 17-Hydroxyprogesterone using 17a-hydroxylase (CYP17)
- 17-Hydroxyprenenolone is also synthesized into 17- Hydroxyprogesterone using 3B-HSD
- 17-Hydroxypregnenolone is synthesized into Dehydroepiandrosterone using 17,20-lyase (CYP17)
- 17-Hydroxyprogesterone is synthesized into Androstenedione using 17,20-lyase (CYP17)
- Dehydroepiandrosterone is also synthesized into Androstenedione using 3B-HSD
- Androstenedione is synthesized into testosterone using 17B-hydroxysteroid dehydrogenase/Oxidoreductase
- Dehydroepiandrosterone is also synthesized into androstenediol using 17B-hydroxysteroid dehydrogenase/oxidoreductase type 1
- Androstenendiol is synthesized into testosterone using 3B-HSD
- Testosterone is synthesized into dihydrotestosterone using 5a-reductase from peripheral tissues
What controls the rate-limiting step of cholesterol catalysis?
StAR (steroidogenic acute regulatory protein) which mediates transport of cholesterol from the outer to inner mitochondrial membrane where P450scc is located
What is the rate limiting step of cholesterol catalysis?
CYP11A (cholesterol desmolase/P450scc enzyme)
Where does the majority of the cholesterol for steroidogenesis come from?
About 80% of cholesterol comes from LDL-cholesterol. Alternatively, steroidogenic cells can synthesized cholesterol de novo from acetate
What major hormones are used during cholesterol catalysis?
ACTH (corticotropin) and LH (leutinizing hormone)
What are the C-21 Progestagens?
Pregnenolone, progesterone, 11-deoxycorticosterone
How many carbons in cholesterol?
27
What are the C-21 mineralocorticoids?
Corticosterone, aldosterone
What are the C-21 Glucocorticoids?
17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol
What are the C-19 Androgens?
Dehydroepiandrosterone, Androstendione
What are the 17-keto steroids?
Dehydroepiandrosterone, androstenedione
What are the 17-hydroxy corticoids?
11-deoxycortisol, cortisol
What are the C-18 Estrogens?
Estrone, Estradiol
What molecules are synthesized in the zona glomerulosa?
C-21 mineralocorticoids
What molecules are synthesized in the zona fasciculata?
C-21 Glucocorticoids
What molecules are synthesized in the zona reticularis?
C-19 Androgens
Where is 11B-HSD1 expressed?
It is expressed in glucocorticoid target tissues where it is reversible.
Where is 11B-HSD2 expressed?
It is expressed in the kidney where it irreversibly catalyzes cortisol into inactive cortisone, which allows aldosterone to regulate non-specific mineralocorticoid recetors without interference from cortisol
C-19 Androgens are considered weak androgens
TRUE - they are used to produce strong androgens
What is a disorder of the zona glomerulosa?
Hyperaldosteronism - usually due to enzyme mutation/hypefunction or tumors
What is a disorder of the zona fasciculata?
Hypercortisolism (Cushing’s syndrome) - usually due to enzyme mutation/hypefunction or tumors
What is a disorder of the zona reticularis?
Adrenogenital syndrome
What is a disorder of the medulla of the adrenal gland?
Pheochromocytoma
What results in Addison’s disease?
Hypofunction/insufficiencey of zona fasciculata and zona glomerulosa
When is the human fetal hypothalamic-pituitary-adrenal axis fully functional?
When genitalia differentiate
What is required for normal sexual differentiation?
Timing and balance of fetal cortisol and androgen secretion
What does enzymatic mutations in adrenal steroidogenic pathways result in?
Secondary effects on sex steroid production and have lasting effects on sexual differentation
What is congenital adrenal hyperplasia?
21- and/or 11-hydroxylase deficiency, which impairs the synthesis of cortisol and aldosterone
What does the decrease in feedback inhibition due to 21- and/or 11- hydroxylase deficiency effect?
Increases secretion of ACTH, leading to incrased testosterone -> virilization and adrenogenital syndrome.
What does a deficiency in 3B-Hydroxysteroid dehydronase affect?
- No glucocorticoids, mineralocorticoids, androgens, and estrogens
- Salt excretion in urine
- Early death
What does a deficiency in 21a-Hydroxylase affect?
- Most common form of CAH
- Usually a partial deficiency
- ACTH elevated, causing an incresed shift to sex hormones and masculinization
What does a deficiency in 11B-Hydroxylase affect?
- Decresased cortisol, aldosterone, corticosterone
- Increased deoxycorticosterone leading to fluid retention and hypertension
- Masculinization
Mutations affecting enzymes primarily responsible for the production of cortisol and mineralocorticoids can have secondary effects on sex steroid prodution.
TRUE - the steroids that can no longer create the cortisol/mineralocorticoids can still be used for the creation of sex steroids, which is now its primary pathway.
Sequelae of 21-hydroxylse deficiency CAH
- Salt waster (75%) (salt loss leading to vomiting, weight loss, adrenal crisis and failure to thrive -> hyponatremic encephalopathy)
- Virilizers (25%) (Adrenogenital syndrome + dependent on sex)
- Non-classics (<1%)
What is hyponatremic encephalopathy?
Sodium levels in blood become very low -> water to enter brain cells and cause them to swell -> increased pressure and potential herniation
Symptoms of hyponatremic encephalopathy
- Headache
- Nausea
- Vomiting
- Confusion
- Seizures
- Brain stem compression and respiratory arrest
- Non-cardiogenic accumulation of fluid in lungs
- Fatal if not immediately treated
What is Adrenogenital Syndrome?
Virilization continues after birth, resulting in rapid bone growth and maturation
How does Adrenogenital Syndrome affect females?
- Pseudohermaphrodites
- Progressive masculinization, hirsutism (growth of hair in place men usually get hair but women don’t), epiphyseal closure
- Secondary amenorrhea/oligomenorrhea
How does Adrenogenital Syndrom affect males?
- Appear normal at birth
- Somatic and sexual precocity <2-3 years
- “Little Hercules”
What do laboratory studies show comes with a 21-hydroxylase deficiency?
- Hyponatremia (low sodium) (due to hypoaldosteronism)
- Hyperkalemia (high potassium (due to hypoaldosteronism)
- Hypoglycemia (due to hypocortisolism)
- Elevated 17a-OH P (17a-hydroxyprogesterone) > 240 nmol/L (may not occur in mild cases, but will rise during a corticotropin (ACTH) stimulation test)
What is a normal value for an infant for 17a-OH P?
<3 nmol/L. Many neonatal screening programs have specific ranges because high levels may be seen in premies without CAH
21-hydroxylase deficiency is the most common cause of CAH
TRUE - 90-95% cases are caused by 21-hydroxylase deficiency
What is 17a-hydroxylase deficiency-induced hyperaldosteronism?
Deficiency shunts precursors into the aldosterone pathway only, as it is a bifunctional enzyme, and can lead to hypertension.
What are the causes of primary adrenocortical insufficiency?
- Hyposecretion of adrenal cortex
- Autoimmune (ex. antibodies to several steroidogenic enzymes with destruction of steroidogenic cells)
- Genetic (ex. adrenal insufficiency without neurologic disease in adrenoleukodystrophy)
- Infections (ex. tuberculosis)
- Injury (Addison Disease)
What is adrenoleukodystrophy?
A rare genetic disorder that affects the nervous system and adrenal glands, causing adrenocortical insufficiency
What are symptoms of Addison Disease?
- Lethargy
- Easy fatigability
- Depression
- Nausea, vomiing
- Hyperpigmentation
- Weight loss
- Arrhythmia
- Postural hypotension
- Syncope
- Amenorrhea
- Abdominal pain
- Diarrhea/constipation
- Anorexia
- Muscle weakness/atrophy
What are the lab results of Addison Disease?
- Decreased corticosteroids
- Increased ACTH and potassium
- Decreased sodium, chlorine, bicarbonate, and glucose
Why do Addison Disease Symptoms occur?
Results from the deficiency of glucocorticoids and mineralocorticoids. Adrenal androgens also missing, but is less obvious clinically
What are the causes of secondary adrenocortical insufficiency?
- Inadequate secretion of ACTH (anterior pituitary)
- Iatrogenic: prolonged exogenous corticosteroid therapy
What are the causes of tertiary adrenocortical insufficiency?
Lack of CRH secretion (hypothalamus), injury, and disease
Cause of generalized hyperpigmentation with vitiligo in Addison Disease?
When ACTH is cleaved from POMC (pro-opiomelanocortin), melanocyte-stimulatin hormone (MSH) is concurrently released. Both MSH and ACTH bind to Melanocortin 1 receptor on melanocytes and cause hyper-pigmentation of the skin.
What is the cause of primary hypercortisolism?
Hyperfunction of adrenal cortex
What is the causes of secondary hypercortisolism?
- Hyperfunction of ACTH-secreting cells (corticotrophs in the anterior pituitary)
- Cushing Disease aka Itsenko-Cushing Disease
What is the cause of tertiary (hypothalamus) hypercortisolism?
- CRH hypersecretion
What is a mnemonic to remember important features of Cushing Syndrome?
ADIPOSE:
- Adiposity
- Diabetes
- Infertility
- Pychologic problems
- Osteoporosis and muscle wasting
- Skin changes
- Elevated blood pressure
What is the process of Pituitary Cushing Syndrome?
Tumor in anterior pituitary -> hypersecretion of ACTH -> adrenal hyperplasia -> cortisol hypersecretion
What is the process of Adrenal Cushing Syndrome?
Both nodular hyperplasia and tumors of the adrenal gland will cause hypersecretion of cortisol
What is the process of Paraneoplastic Cushing Syndrome?
Lung or nonendocrine cancer -> hypersecretion of ACTH -> adrenal hyperplasia -> hypersecretion of cortisol
What is the process of Iatrogenic Cushing Syndrome?
Patient takes steroids which leads to Cushing Syndrome and adrenal atrophy
Are ACTH-secretin pituitary adenomas responsive to its feedback mechanism?
It is only partially responsive to the feedback suppression of CRH.
Does paraneoplastic tumors respond to its feedback mechanism?
No, since they don’t have the corresponding receptors and ACTH is produced out side the hypothalamic-pituitary axis
Why is it important ectopic tumors don’t respond to cortisol?
Because the high levels of cortisol that is created to control the ACTH secretion will completely shut off ACTH from pituitary glands
Why does adrenal atrophy happen?
Because of low ACTH secretion (such as with chronic corticoid therapy)
How to diagnose Cushing Syndrome?
- Increased urinary free cortisol must be present
-Failure of serum cortisol to be suppressed to <5 micrograms/dL in response to low-dose dexamethasone
What laboratory tests are used in diagnosing Cushing syndrome?
- Free cortisol in urine collected over 24 hours (best and first screening for Cushing from simple obesity)
- Low dose (1-2 mg) dexamethasone suppression test (injected IV in a low dose at bed time and tested to see if suppresses normal morning rise of cortisol)
- High-dose (8mg) dexamethasone suppression test (injected to test pituitary adenoma vs. ectopic tumor ACTH suppression)
What are the laboratory value increases due to Cushing Syndrome?
Increased cortisol, insulin (leads to acanthosis nigricans), Glucose, Sodium and red blood cells
What are the symptoms of Cushing syndrome?
- Pituitary adenoma (70%)
- Depression
- Mood changes
- Thinning of hair
- Moon facies (round and puffy face due to swelling of fat deposits on sides of face)
- Androgen based hirsutism
- Buffalo hump (buildup of fat between shoulder blades)
- Acanthosis nigricans (dark velvety patches due to insulin spill over)
- Hypertension
- Adrenal lesion (hyperplasia or tumor)
- Cetral obesity
- Abdominal striae and stretch marks
- Amenorrhea
- Muscle weakness and atrophy
- Ecchymoses and thin skin (Large bruising that changes colors (red-> blue-green-> gold-brown))
- Poor wound healing
How does the body react after adrenal or pituitary tumor removal or treatment?
Body returns to physiological state
What is Conn syndrome?
Primary hypo-reninemic hyperaldosteronism, often caused by a tumor.
What is the pathway for secondary hyper-reninemic hyperaldosteronism?
Renin increased, which increases angiotensin II and increases aldosterone
What is the result of hyperaldosteronism?
Sodium and water retention, potassium excretion
What is the effect of aldosterone on kidneys?
Acts on distal renal tubule to promote sodium exchange for the potassium lost in urine
What does higher sodium and water retention do?
- Increased sodium in plasma
- Increased extracellular fluid volume (hypervolemia) -> increased cardiac output
- In Conn Syndrome, decreased Renin
- Hypertension
What does higher potassium excretion levels do?
- Lowered potassium in plasma
- Vasoconstriction -> increased cardiac output
- Hypertension
What is a pheochromocytoma?
In most instances, a functionally active tumor that secretes epinepthrine and norepinephrine, resulting in hypertention and related paroxysmal sympathetic effects
What is a paroxysmal sympathetic effect?
A spasm of muscles that are innervated by the sympathetic nervous system.
What pheochromocytomas are familial?
- Mutations in VHL, RET, NF1 (Gene 17 Neurofibromatosis type 1),SDHB and SDHD
- If it is a tumor of multiple endocrine neoplasia syndrome type IIA or Type IIB
- Up to 25% of pheochromocytomas are familial
When is a pheochromocytoma suspected?
Hypertension is diagnosed in a young person that does not respond to standard antihypertensive treatment and is episodic
Can paroxysms of hypertension be triggered?
Yes, by exercise, anesthesia or even palpation of the abdomen
How are pheochromocytomas treated?
Surgically with excellent prognosis (90% benign)
What is the term for characteristic nests of cells with abundant cytoplasm?
Zellballen
What are Autoimmune Polyendocrine Syndromes (APS)?
Forms of autoimmune adrenalitis, which is the most common cause of primary adrenal insufficiency in developed countries
What are other names for APS1?
- Autoimmune polyendocrinopathy
- Canidiasis
- Ectodermal dystrophy
- Whitaker Syndrome
What are the symptoms of APS 1?
- Chronic mucocutaneous candidiasis
- Abnormalities of skin
- Abnormal dental enamel
- Absnormal nails (ectodermal dystrophy)
- Organ-specific autoimmune disorders
What is chronic mucocutaneous candidiasis?
A rare, hereditary immune disorder that causes chronic infections with the Candida fungus (skin, nails, mucous membranes)
What disorders is Whitaker Syndrome a combination of?
- Autoimmune adrenalitis
- Autoimmune hypoparathyroidim
- Idiopathic hypogonadism
- Pernicious anemia
All result in immune destruction of target organs
What is the cause of APS1?
Mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22
When does APS 2 start?
Early adulthood
What does APS2 present as?
- Adrenal insufficiency
- Autoimmune thyroiditis or type 1 diabetes
What is the cause of APS2?
It is more heterogeneous, but has not been linked to one gene.
APS 2 is the most common form of the polyglandular failure syndromes
TRUE
What all is left after the destruction of the adrenal gland due to autoimmune adrenalitis?
Subcapsular rim of cortical cells and extensive mononuclear cell infiltrate.
What is another name for APS2?
Schmidt Syndrome
What are Multiple Endocrine Neoplasia syndromes?
A group of genetically inherited diseases resulting in proliferative lesions (hyperplasia, adenomas and carcinomas) of multiple endocrine organs
What is MEN1?
Germline point mutations of the MEN1 tumor suppressor gene that normally enhances signalling through TGF-Beta to decrease cell proliferation and enhance p53 function
What is involved in MEN1?
- Parathyroid (in all cases)
- Pancreas
- Pituitary involved 3Ps
What is MEN2?
Activating germ line mutations of RET protooncogene encoding tyrosine kinase receptor
What is affected in MEN2A?
- Thyroid (all cases)
- Parathyroid
- Adrenal medulla
What is affected in MEN2B?
- Thyroid (all cases)
- Adrenal medulla
- GI ganglia
What are the distinct features of MEN syndrome tumors compared to sporadic tumors?
- Occur at a younger age
- Arise in multiple endocrine organs either synchronously or metachronously (different times)
- Even in one organ the tumor is often multifocal
- Tumors are usually preceded by an asymptomatic stage of endocrine hyperplasia
- Tumors are usually more aggressive and recur in a higher proportion of cases
How are MEN2 patients managed?
Prophylactic thyroidectomy because of near certainty of their developing medullary thyroid carcinoma, a potentialy deadly cancer of C-cells
How does the spectrum of MEN1 extend beyond the 3Ps (parathyroid, pancreas, pituitary)?
- Duodenum is the most common site of gastrinomas (far in excess of frequency of pancreatic gastrinomas)
- Carcinoid tumors
- Thyroid adenomas
- Adrenocortical adenomas
What happens in MEN1 with loss-of-function mutations of RET?
- Intestinal anganglionosis
- Hirschsprung disease
What is Hirschsprung disease?
Nerve cells of the large intestine don’t develop properly before birth, leading to limited or absence of peristalsis.
