hyperthyroidism
symptoms
- b receptor stimulation –> hyperreflexia
- staring gaze with lid lag
- muscle weakness - CK elevated (will see muscle weakness in hypothyroid, but no elevated CK)
- hypocholesterolemia due to increased LDL receptor expression
Graves dz: HLA-DR3, HLA-B8
- goiter
- exophalmos - caused by lymphocytic infiltration –> cytokines that stimulate fibroblasts…., enlargement of extraocular muscles (myositis), fibroblast proliferation, and overproduction of mucopolysaccharides
- all in response to thyroid antibodies - fibroblasts have TSH receptors –> increased GAGs (GAGs are also increased in MVP, dermatan sulfate)
- also pretibial myxedema - scalloping of colloid
- treat with b-blockers, thioamide (blocks peroxidase), radioI ablation
- feared complication = thyroid storm (during stress) –> tachy, hyperthermia, vomiting and hypovolemic shock
- treat with PTU, b-blockers, KI, and steroids (4Ps, corticosteroids decrease 5-deiodinase activity) - if you surgically remove a thyroid gland - give postop calcitriol to prevent post hypocalcemia
toxic multinodular goiter = Plummer’s disease
- regions become TSH-indep
- hot nodules are rarely malignant - decreased TSH and rest of gland is suppressed
(v. s cold nodule - most cold nodules in women are benign, any cold nodule in a man/kid is cancer until proven otherwise)
multinodular goiter - due to I DEFICIENCY
- euthryoid - low thyroid results in increased TSH
- Jod-Basedow phenomenon - thyrotoxicosis if pt is made I replete
DKA
high anion gap! (+other findings)
metabolic acidosis = PaCO2 = 1.5*HCO3 + 8 +/- 2
- Kussmaul respirations
but in severe DKA - pts get pulm edema, respiratory fatigue, decreased MSE –> respiratory failure, hypoventilation
lose K - total body K deficit, so low intracellular stores
1) glycosuria-induced osmotic diuresis
2) hypovolemia-mediated increase in aldosterone secretion
- extracellular K+ concentrations are normal/increased
- hyposmolarity (due to volume depletion) –> hyperkalemia
- lack of insulin shift K extracellularly - insulin normally causes K+ to enter cells
* note - insulin and lack of insulin (as well b-agonists) will cause differences in intracellular K vs. extracellular K
- diuretics, mineralocorticoid excess, GI losses will change intracellular and extracellular K in the SAME direction
Klinefelter
progressive destruction and hyalinization of seminiferous tubules
- serum inhibin levels are low due to Sertoli cell damage
- Leydig cell dysfunction - low testosterone
- via feedback - LH and FSH are high
- gynecomastia - due to gonadotropin excess (stimulates aromatase)
- azoospermia
scenario: normal hormones but no sperm = obstruction (CF)
scenario 2: pt is on exogenous steroids - high blood testosterone but testosterone in testes is decreased –> low sperm count
scenario 3: cryptorchidism - Sertoli cells are damaged but Leydig cells are not –> high FSH, normal LH
hypothyroid
muscle weakness, brittle hair, diastolic HTN
T3 inhibits at hypothalamus and pituitary
- T3 is produced in peripheral tissues
hypothyroid - most common cause in US is Hashimoto (HLA-D5, also associated with pernicious anemia)
- autoimmune destruction due to inhibitory TSH receptor antibody- hyperthyroidism –> hypothyroidism
- moderately enlarged, non-tender thyroid
- can see antithryoglobulin and antimicrosomal antibodies - markers of damage, but dont mediate disease
- T3 has a short half-life and conversion in peripheral tissues can be variable = T3 levels fluctuate a lot and can remain normal until relatively-late stage hypothyroidism
- histology: focal formation of germinal centers (enlarging thyroid, be concerned for B cell lymphoma) and Hurthle cell change (follicular epithelium turns pink)
estrogen (preg, OCPs) increase TBG levels - will also increase total T4
cretinism
- 6 Ps: pot-bellied, pale, puffy-faced child, protruding umbilicus (hernia), protuberant tongue, poor brain development
- hoarse cry, prolonged jaundice
- causes - dysgenesis is most common in US
myxedema - hypothyrodism in older kids or adults
- myxedema esp in larynx (deeper voice) and enlarged tongue
subacute thryoiditis (de Quervian) - granulomatous thyroiditis that follows the flu, ESR is elevated, jaw pain - *tender* thyroid, self-limiting
silent thyroiditis - painless, associated with thyroid antibodies, can occur post-partum
Reidel fibrosing thyroiditis - hard as wood, nontender thyroid, fibrosis can extend to airway
- young females
- considered an IgG4-related systemic disease (reidel fibrosing thyroiditis, AI pancreatitis, retroperitoneal fibrosis, noninfectious aortitis
- mimic is anaplastic carinoma
myxedema coma = extreme hypothyroidism –> low CO, etc.
synthetic T3 is not recommended for treatment - it has a short half-life –> wide-fluctuations in T3 levels
progesterone
acts via type 1 nuclear receptor –> binds hormone and translocates to the nucleus
chronology of anterior pit deficiency
GH > FSH > LH > TSH, ACTH > PRL
- latter 3 are centrally located
FSH, LH, TSH, HCG - a and b subunits are paired in the ER and Golgi
POMC –> ACTH, b-endorphin, MSH
GH and prolactin are acidophils
GH
GHRH - binds to Gs–> activates adenylyl cyclase and phospholipase C
- GH contains disulfide bridges
pulsatile secretion - largest burst within 1 hour of falling asleep and during stages 3 and 4
secretion stimulated by: hypoglycemia and decreased FFA concentration, arginine, fasting/starvation
- stress, exercise
- estrogens/testosterones during puberty
- a-agonists and b-antagonists
- clonidine/arginine stim test to assess for deficiency
inhibited by: glucose, somatostatin, obesity/senescence, GH, pregnancy, b-agonists
GH release in low glucose state, a-agonists and b-antagonists
feedback loops:
1) GHRH inhibits its own secretion
2) somatomedin (ex IGFs) - inhibit anterior pit directly
3) somatomedins stimulate hypothalamus to secrete somatostatin –> inhibits anterior pit (Gi)
actions: direct tissue effects, growth mediated by IGF1 (produced in liver)
1) chondrocyte proliferation, increased protein synthesis and organ growth
2) diabetogenic - GH causes insulin resistance = decreased glucose uptake and increased lipolysis –> increased insulin levels
- GHRH analog tesamorelin is used to treat HIV-associated lipodystrophy
deficiency - any number of reasons, failure to generate somatomedins in liver
excess
- acromegaly - …increased risk of colorectal polyps and cancer, typical treatments and can also give cabergoline
Laron syndrome = dwarfism
- defective GH receptors - GH increased, IGF1 decreased
- ….small genitalia
drugs:
ocreotide - somatostatin analog
pegvisomant - GH receptor antagonist
tesamorelin - GHRH analog
prolactin
bromocriptine is a D agonist, cabergoline (more effective at D2, fewer side effects)
somatostatin
TRH and estrogens (OCPs, pregnancy) stimulate prolactin
actions:
1) breast development during puberty (duct proliferation), pregnancy (alveoli)
2) lactogenesis in response to suckling
- during pregnancy, high levels of estrogen and progE down regulate prolactin receptors in breast
3) inhibits ovulation - inhibits GnRH release
long-term complication = osteoporosis
hypopituitarism
pituitary adenoma - apoplexy
craniopharyngioma in kids
Sheehan syndrome - pituitary doubles in size during pregnancy, susceptible to infarct
empty sella syndrome
- idiopathic, more common in obese women
- trauma
- primary defect of sella - where arachnoid and CSF herniate into sella and destroy pituitary
posterior pit
secretory vesicles contain neurophysins - involved in posttranslational hormone processing
ADH = supraoptic nuclei
- blood osm, hypovolemia (decreases in volume by 10% –> baroreceptors –> vagus nerve –> hypothalamus)
- also stimulated by …hypoglycemia, nicotine, opiates, antineoplastic drugs
central DI - water deprivation fails to increase urine osm, greater than 50% increase seen in URINE osm after administration of ADH analog
- due to damage to hypothalamic nuclei! - if post pit is damaged, axonal regeneration and hypertrophy will still allow ADH release into circulation
- will see early SIADH
- treat with ddAVP (can also be used to treat nocturnal enuresis)nephrogenic DI - treat with thiazides!
1) thiazides inhibit NaCl reabsorption at the early DT
2) ECF and blood volume decreases - GFR decreases
3) and proximal reabsorption of solutes and water is increased = ultimately more water is reabsorbed
- can also use indomethacin, amiloride
SIADH - euvolemic hyponatremia with continued urinary Na excretion
- decreased aldosterone in response to water retention
- hyponatremia - swelling of nerves, seizures. Correct Na slowly to prevent central pontine demyelination.
- SCC lung/pulmonary infection, CNS trauma, drugs (antipsychotics, cyclophosphamide)
- increased urine osmolality during water deprivation indicates psychogenic polydipsia
......... oxytocin = paraventricular nuclei - milk ejection - by stimulating contraction of myoepithelial cells - smooth muscle contraction - inhibited by opioids
adrenal cortex and CORTISOL
mesoderm
CRH is released from PVN (same nucleus where oxytocin is made) –> Gs –> ACTH
1) stimulates transfer of stored cholesterol into mitochondria
2) stimulates binding of cholesterol to CYP450
3) activates cholesterol desmolase
- ACTH stimulated by low cortisol, sleep-wake transition (cortisol secretion is highest after waking), stress, ADH, a and b agonists
steroid hormone synthesis requires CYP450, O2, NADPH, FAD, Fe-containing enzymes
cortisol feedback loop - cortisol inhibits secretion by hypothalamus and ant pit
- also inhibits hippocampus –> hypothalamus
17-a-hydroxylase can be blocked and corticosterone will still be produced without deleterious effect
cortisol: catabolic and diabetogenic
1) mobilizes glucose - gluconeogenesis, protein catabolism, lipolysis (glycerol –> glucose), decreases glucose utilization and insulin sensitivity
2) anti-inflammatory
- induces synthesis of lipocortin - inhibits phospholipase A2
- inhibits histamine and serotonin release from mast cells
- inhibits IL2 production (can cause reactivation of Tb or candida)
- decreases eos, lymphocytes are redistributed to spleen/BM/LNs, monocytes and macrophages cant extravasate
- inhibits neutrophil adhesion
3) a1 receptors
4) inhibits bone formation and decreases fibroblast activity
5) increases GFR by causing vasodilation of afferent arterioles
6) decreases REM sleep
……………….
Cushings = hypercortisolism
- proximal muscle weakness, purple striae
- hyperglycemia –> excess insulin –> truncal obesity and fat deposition
- excess androgens, amenorrhea (due to HPA axis suppression)
- ACTH causes hyperPLASIA
- initially increased ACTH will increase cholesterol metabolism…
- with time - ACTH will induce protein synthesis (steroidogenic enzymes), cell proliferation - no ACTH causes atrophy
- tests: increased 24hr urine cortisol, increased midnight salivary cortisol, no suppression with overnight low-dose dexa
- Cushings disease - pituitary adenoma
- distinguish between pituitary adenoma and ectopic with high dose dexa or CRH stim test (ectopic secretion will not increase with CRH because pit ACTH is suppressed)
- ACTH levels: ectopic > pituitary > adrenal - treat with metyraprone (inhibits 11-hydroxylase - cortisol and aldosterone cant be produced) or ketoconazole
pt is on exogenous glucocorticoids –> widespread atrophy (of hypothalamic neurons, adrenals, etc.)
- cortisol levels that CANT rise in response to stress (surgery, infection) –> relative glucocorticoid deficiency even when pts baseline regimen is maintained
adrenal androgens
major source of androgens in women
adrenal androgens = DHEA and adnrostenedione, testosterone is minimally produced
side chain cleavage enzyme - converts cholesterol to pregnenolone
- first step in steroidogenic pathway
congenital adrenal hyperplasias - low cortisol, high ACTH
21-b-hydroxylase deficiency (AR) - only sex steroids (including 17-hydroxyprogesterone, which is specific to adrenals as opposed to the testes)
11-b-hydroxylase def - weak mineralocorticoids are being produced
17-hydroxylase def - excess of mineralocorticoids so aldosterone will be DECREASED (to due RAAS feedback)
- pseudohermaphroditism XY - ambiguous genitalia, undescended testes
- males and females dont undergo puberty
5a-reductase - inhibited by finasteride
aldosterone
ACTH controls cholesterol desmolase activity (only a tonic ACTH level is required), aldosterone synthase is stimulated by ang2
RAAS is activated by a decrease in ECF volume or increases (ang 2 binds to AT1 receptors on adrenals) in serum K+ (serum K+ acts directly –> triggers Ca2+ influx –> aldosterone secretion)
affinity for mineralocorticoid receptors for aldosterone = cortisol
- 11b-hydroxysteroid dehydrogenase
Conn syndrome - adrenal adenoma or bilateral adrenal hyperplasia
- high aldosterone, low renin = PA/PRA >20, treat with spironolactone and surgery
Secondary hyperaldosteronism - due to RAAS activation
no edema in hyperaldosteronism - because of volume/pressure-induced natriuresis (aldosterone escape mechanism)
adrenal insufficiency
Waterhouse-Friderichsen syndrome - classically young kid who gets an N. meningitidis infection –> DIC, endotoxic shock, petechial rash–> bilateral necrosis of adrenals –> exacerbated HYPOtension
Addison’s disease - autoimmune destruction of entire cortex (west) or Tb-associated destruction
- in general - in primary adrenal insufficiency, you will see cortisol AND aldosterone insufficiency
cosyntropin (ACTH analog) - tests adrenal reserve
metyrapone stim tets - blocks 11-deoxycortisol to cortisol
- normally - if you give metyrapone –> decrease cortisol –> increased ACTH
- in 2/3 adrenal insufficiency - both ACTH and 11-deoxycortisol remain decreased after test (gland has atrophied)
gluco/mineralocorticoids
fludrocortisone - synthetic aldosterone analog
- tox - same as glucocorticoids + edema, HF exacerbation, hyperpigmentation
tox for glucocorticoids - ….peptic ulcers, steroid diabetes, steroid psychosis (confusion, hallucinations)
dexamethasone will NOT cross-react with cortisol detecting assay
catecholamines
b: epi > NE
a: NE > epi
need vitamin C to make NE from DOPA
preG sympathetic fibers of greater splanchnic nerve release Ach –> chromaffin cells of adrenal
neuroblastoma - N-myc, Homer-Wright rosettes (also seen in medullloblastoma), opsoclonus-myoclonus syndrome
- smooth mass that can cross midline
- HVA (breakdown of dopamine) and VMA in urine
- Bombesin and NSE+
pheo - adrenal medulla is brown
- VHL, RET (tyrosine kinase), NF1, MEN2
- remember Hirschsprung’s disease is also associated with RET mutations - ….can get orthostatic hypotension due to low plasma volume
- surgical excision: but first give phenoxybenzamine (irreversible blocker of a receptors –> otherwise will get masssive HTN and death) and next give b-blockade (labetolol)
- rule of 10: 10% bilateral, 10% extra-adrenal (bladder wall), 10% malignant, 10% calcify, 10% kids
dopamine
somatostatin
decreases prolactin and TSH
- dopamine can be decreased - …chest wall injury (via ANS)
somatostatin - decreases GH and TSH
MEN
menin tumor suppressor gene, AD
MEN1: 3 Ps, c11
*primary hyperparathyroidism
pituitary tumors
pancreatic tumors (gastrinoma, insulinoma)
MEN2A: RET, 2Ps
*medullary thyroid cancer
pheochromocytoma
PTH adenoma
MEN 2B: RET, 1P *medullary thyroid cancer pheochromocytoma mucosal (lips, tongue) adenoma associated with marfanoid habitus
apetite
ghrelin - stimulates hunger and GH, produces by stomach
- sleep deprivation and PW increase ghrelin production
leptin
endocannabinoids - act at hypothalamus and NAcc
- increased appetite
signaling pathways
vasodilators work by cGMP - ANP/BNP, NO
insulin and GF - receptor tyrosine kinases –> MAPK
JAK/STAT - EPO/thrombopoietin/G-CSF, cytokines, prolactin and GH
IP3 - GnRH, TRH
- ADH (V1), Ang2, oxytocin
- gastrin, histamine (H1)
cAMP - all else
steroid hormones (including thyroid hormone) - OCPs, pregnancy increase SHBG
thyroid hormone production
1) thyroglobulin - contains large amounts of tyrosine
2) Na+/I- transport - thiocyanate and perchlorate block I- uptake
3) oxidation of I- to I2 by thyroid peroxidase - I2 travels to lumen
4) organification of I2 - thyroid peroxidase catalyzes I2 addition to tyrosine –> MIT, DIT
- Wolf-Chaikoff effect - high levels of I- inhibit thyroid hormone production
5) coupling reaction by thyroid peroxidase - T3 and T4
6) endocytosis of thryoglobulin - upon TSH binding
7) hydrolysis of T3 and T4 by lysosomal enzymes (and thyroid deiodinase)
- Li prevents thyroid hormone release
feedback: T3 inhibits TSH secretion by downregulating TRH receptors on ant pit
TBG decreases in - liver failure, steroids (T4 will be low)
- increases in pregnancy (estrogen inhibits TBG breakdown)
- salicylates decrease binding of T4 to TBG
- thyroid hormone increases SHBG production
- circulating levels of TBG can be assessed by: pts serum + radioactive T3 + T3 resin
5-deiodinase - liver and peripheral tissues
- starvation/illness/stress inhibits 5-deiodinase in muscle –> lower O2 consumption and BMR
- decreased conversion of T4 to T3 - pregnancy, neonatal period, hepatic and renal failure, b-blockers, glucocorticoids, and amiodarone
- obesity increases T4 to T3 conversion
PTU - blocks thyroid peroxidase and 5-deiodinase, safe during first trimester pregnancy
- agranulocytosis, aplastic anemia, hepatotox
methimazole - inhibits thyroid peroxidase
- can cause aplasia cutis
- used in second/third trimesters - risk of PTU-induced hepatotox
changes in thyroid hormones:
1) TSH
2) T4
3) T3
thyroid hormone actions
1) BMR - in all tissues except brain, gonads, spleen
2) metabolism - increase blood glucose
3) CV and respiratory - b1 receptors, etc. produced
4) growth: acts synergistically with GH and somatomedin –> bone formation and maturation
- in hypothyroidism - bone age < chronologic age
3) CNS effects are age dependent
thyroid hormones are synergistic with catecholamines - b-blockers can treat many symptoms of hyperthyroidism
thryoid embryology
foramen cecum
thyroglossal duct cyst v.s. persistent cervical sinus leading to branchial cleft cyst in lateral neck
lingual thryoid and ectopic thryoid glands - 1/3 of pts are hypothyroid
thyroid an C cells = endoderm
thyroid neoplasia
solitary nodule - more likely to benign than malignant
- will see variably sized follicles, colloid, and macrophages in benign nodules
- radioI uptake will be increase in Graves, nodular goiter, will be DECREASED in neoplasm
- FNA - otherwise thyroid will bleed
papillary carcinoma (80%)
- exposure to ionizing radiation in childhood is a major risk factor (classically older person who was radiated for acne)
- RET and BRAF mutations
- Orphan Annie eyed nuclei (aka clear nuclei with purple rim cell border), Psammoma bodies
- often spreads to cervical nodes - excellent prognosis
follicular adenoma - usually nonfunctional, surrounded by fibrous capsule
follicular carcinoma - invasion through capsule, RAS mutation
- mets hematogenously
medullary carcinoma - malignant proliferation of parafollicular C cells
- calcitonin deposits locally as amyloid - sheet of malignant cells in amyloid stroma
anaplastic carcinoma - invades local structures, poor prognosis
