Endocrinology: HPT Axis & Adrenal Flashcards
Endocrine vs. Exocrine vs. Paracrine
Endocrine: glads secrete hormones into blood stream to act at a distant tissue site
Exocrine: glands secrete non-hormones (ie. enzyme) into ductal system for delivery to distant or adjacent site
Paracrine: cells secrete hormone that acts directly on other nearby cells (ie. testosterone)
Types of hormones
- Protein/polypeptide = water soluble, no carrier protein, mainly interact with membrane receptors (don’t enter cells)
- Steroid = cholesterol based, lipid soluble, bound to transport protein, interact w/ nuclear receptors inside of cell
- Aromatic AA Derivatives = derived from tyrosine, T3/T4 & Catecholamines
Endocrine (HPT) Axis concept
- Hypothalamus “releasing hormones” stimulate pituitary secretion of “trophic hormones”
–> trophic=stimulate production of another
hormone - Trophic hormone stimulates release of primary hormone, which then binds to specific receptor at target tissue
- Main control mechanism is negative feedback
Levels of Endocrine Disease
1’ = End Organ Hormone
- All hormones in axis (primary, secondary, tertiary) increased in hyperfunction or decreased in hypofunction
2’ = Pituitary Trophic Hormone
- Hypofx: Primary increases, Secondary & Tertiary decreased
- Hyperfx: Primary decreased, Secondary & Tertiary increased
3’ = Hypothalamic Releasing Factor
- Hypofx: Primary & Secondary increased, Tertiary decreased
- Hyperfx: Primary & Secondary decreased, Tertiary increased
Posterior Pituitary: Nature & Hormones
“Neurohypophysis” - Neural nature
- Hypothalamic neurons extend into gland and secrete hormones there
- AVP (ADH) and Oxytocin are produced in the hypothalamus and stored in the P.Pit.
Anterior Pituitary: Nature & Hormones
“Adenohypophysis” - Gland nature
- Hypothalamus secretes releasing factors into circulation which directly feeds A.Pit.
Hormones produced:
- hGH & Prolactin –> Direct effector
- ACTH, FSH, LH, TSH –> Trophic
Growth Hormone (hGH)
- Secreted by somatotrophic cells (1/3 wt of AP)
- Stimulated by GHRH, inhibited by Somatostatin
- Secreted in pulsatile fashion (avg interval 2-3 hrs) –> diurnal variation: highest during sleep, spikes after meals/exercise, can be undetectable between pulses
- Anabolic (protein/bone/glucose genesis) & Catabolic (lipolysis) functions
- Formation of IGFs –> synthesized in liver, IGF-1 measured by immunoassay rather than GH due to pulsatile secretion
Insulin-Like Growth Factor (IGF-1)
- Synthesized in liver in response to GH
- Unlike other protein hormones, IGF1 is bound to a carrier protein (IGF-BP3)
- Levels are directly related to GH concentration, and is more commonly measured to asses GH disorders due to higher stability
GH Hypersecretion
Gigantism = GH excess during growth phase
Acromegaly = GH excess after growth phase
—> Both commonly result from pituitary tumor
Tested for by Oral GTT (should suppress GH to
GH Hyposecretion
Pituitary Dwarfism = very small with proportional sizing, may result from tumors interfering GH secretion or genetic defect in GHRH/gene/receptor/IGF1
Adult Deficiency = vague symptoms (mental issues, osteoporosis, high chol)
Tested for w/ Insulin Tolerance or Arginine (should induce GH elevation, so looking for low levels)
Prolactin
- Primarily influence on lactation and suppressed release of GnRH (no LH/FSH after birth)
- Pulsatile secretion (similar to GH), not stimulated by a releasing hormone –> pregnancy/suckling (stimulated by TRH in pathological situations)
- Under constant inhibition by dopamine –>only non-peptide RH, loss of inhibition leads to uncontrolled secretion (drugs)
Prolactin Hypersecretion
- Prolactinoma (prl secreting pituitary tumor) –> levels >150-200 ng/ml, proportional to tumor size, HOOK EFFECT**, more obvious in female (effects noticeable)
- Pituitary stalk damage: dopamine decrease (also certain drugs)
- Hypothyroidism (1’ or 2’): high TRH
Prolactin testing
- Usually sandwich immunoassay (method dependent reference ranges)
- Subject to hook effect!! Need a dilution protocol
- Macroprolactin = IgG bound prolactin (inactive), most common cause of mild hyperprolactinemia
Panhypopituitarism
Ineffictiveness of all pituitary function
- pituitary, parapituitary, hypothalamic tumors
- trauma to pituitary stalk, radiation, surgery
- Sheehan’s Syndrome: postpartum infarction
- Loss of tropic hormones more critical/obvious than direct effector hormones, replacement is used to treat
Thyroid physiology
- Straddles trachea with 4 Parathyroids (2 on each lobe)
- Thyroid cells arranged as follicles, colloid primarily thyroglobulin
- Colloid actively takes up iodine –> iodinates tyrosine residues in Tg (plus coupling of residues) –> release of T3 & T4
- Parafollicular cells release Calcitonin
Thyroid hormone synthesis
- In presence of inorganic iodide, TPO (thyroid peroxidase) facilitates iodination of tyrosine residues on Tg molecules
- Iodinated Tg couples with other iodinated Tg molecules
- Coupled Tg is then turned into T4 by Thyroglobulin Protease
Thyroid Hormones
- T4 is primary secreted hormone, T3 also secreted in smaller amounts but most is formed via T4 deiodination in peripheral tissues (liver)
- Transported bound to proteins (Thyroxine-binding globulin, albumin)
- Only free hormones are biologically active (free T4 measured, total T3 measured) with T3 accounting for most thyroid hormone activity in peripheral tissues
- Exert primarily intracellular actions by nuclear uptake and mRNA transcription –> increase metabolism, cardiac/CNS/GI activity, **fetal and neonate CNS development
Hyperthyroidism
- Increased appetite with weight loss, heat intolerance, upper CV/CNS effects
- Graves Disease: autoimmune stimulatory Ab to TSH receptor, may have bug eyes (exopthalmos), Ab can cross placenta so seen in neonates (POSITIVE TSI LEVELS)
- Thyroid nodules: single or multi, benign
- Thyroiditis: normal hormone production, but leakage from glands
- Increase in iodine ingestion (meds)
- Choriocarcinoma: hCG cross-rxn with TSH
10x more common in females
Hypothyroidism
- Cold intolerance, weight gain with lethargy, myxedema (puffiness), downer CV/CNS effects
- Hashimoto’s thyroiditis: Ab and cell-mediated, commonly anti-TPO/TG, most common in developed countries (POS ANTI-TPO)
- Iodine deficiency: most common worldwide
- Congenital
- Thyroid hormone resistance
- 2’/3’: Pituitary (TSH) or hypothalamic (TRH) failure, very rare
Stages of Primary Hypothyroidism
SUB-CLINICAL: lab evidence w/o symptoms
--> high TSH, normal T4, normal T3
EARLY:
--> high TSH, low T4, normal T3
MATURE:
--> high TSH, low T4, low T3Thyroid cancer
- Medullary carcinoma: parafollicular cells, use calcitonin as a tumor marker to monitor once dx is made
- Epithelial cancers: follicular or papillary, monitor using thyroglobulin assay once dx is made (sandwich assay but has anti-TG interference, LC-MS/MS available w/o interference)
–> Destroy thyroid gland (ablation) and monitor hormones to make sure no recurrence of tissue
Thyroid testing
- TSH: Primary test in thyroid evaluation, immunoassay, measures hypothalamic response –> increase w/ normal T4 suggests sub-clinical hypothyroidism
- T4/T3: Free T4 strongly recommended, done by competitive immunoassay (sm molecules), must displace bound fractions, T4 in mcg/dL T3 in ng/mL
- T3 uptake: obsolete, replaced by fT4
Free T4 testing
Direct dialysis - dialyze sample and measure T4 in dialysate w/ sensitive immunoassay
Equilibrium dialysis - reference method, I-125 T4 added to sample and dialyzed, “% radioactivity added x total T4 = fT4”
Two step fT4 estimate - best estimate, labeled T4 bind to unoccupied Ab sites, unbound is separated out and bound T4 is measured
One step fT4 estimate - T4 analog that binds to Ab, competitive immunoassay, works well in most cases (if >AMR, dilution isn’t an option)
Thyroid Autoantibodies
- Anti-TG: automated immunoassay
- Anti-TPO: automated immunoassay, elevated in Hashimoto’s dz, 10% asymptomatic patients
- Thyroid stimulating Ig (TSI): Ab to TSH receptor that stimulates when bound
- Thyrotropin binding inhibitory Ig (TBII): inhibits TSH receptor response
Non-thyroidal illness
- Thyroid hormone results may be abnormal in sick patients w/o thyroid disease –> “Euthyroid sick”
- Typically see decrease in total/free T3, low tT4 with normal fT4, mild TSH fluctuations (starts low and raises during recovery)
**Thyroid testing should not be done if patient has acute illness
Adrenal physiology and steroid types
- 90% of organ is cortex: yellowish tissue, three zones (glomerulosa, fasciculta, reticularis), produces steroid hormones
- 10% of organ is medulla: grayish tissue, produces catecholamines
- Three types of adrenal steroids hormones: Glucocorticoids, Mineralocorticoids, and Adrenal Androgens
Adrenal steroid biochemistry
- Glands have distinct pathways for hormone development, but are all derived from the transformation of Cholesterol to Pregnenolone (rate-limiting step for all paths)
- Aldosterone has its own pathway: stems from Pregnenolone -> Progesterone
- Cholesterol transformation stimulated by ACTH (trophic hormone produced by ant. pit.)
- Transported bound to protein (albumin, CBG) with free fraction biologically active –> lab measures total hormones not free
- Catabolism happens in the liver, renal excretion
Glucocorticoid function and regulation
- Cortisol main glucocorticoid
- Raises blood glucose and encourages breakdown of fat/protein, suppresses immune system response (anti-inflammatory), and controls blood pressure (increases GFR, effects similar to mineralocorticoids)
- CRH (hypothal) –> ACTH (a.pit.) –> stimulates cholesterol to pregnenolone transformation (in ZF/ZR)
- CRH release in response to stress and hypoglycemia, controlled by sleep-wake cycle (diurnal, circadian rhythm)
- Cortisol has negative feedback on CRH & ACTH release
Mineralocorticoid function and regulation
- Aldosterone main mineralocorticoid
- Increases sodium reabsorption by DCT and collecting duct (K-exchange) in order to maintain blood volume
- Controlled by Renin-Angiotensin-Aldosterone system (RAAS) –> angiotensin ll stimulates cholesterol to preg transfomation (ZG)
- Regulated largely by K levels –> stimulated by hyperkalemia, inhibited by hypokalemia
Adrenal Androgens
DHEA: similar to testosterone, but weaker. Produced in ZR.
Adrenal Function Tests
- Serum Cortisol
- Serum Aldosterone
- ACTH (stabilized by EDTA)
- all of above by competitive immunoassay or LC-MS/MS
- Anti-adrenal Antibody: done by ELISA or IFA, present in Addison’s Dz
- Urinary free cortisol: 24hr urine, requires solvent extraction/evaporation to remove polar cross-reacting metabolites –> preferred marker but pre-analytical issues (24hr urine)
- Salivary cortisol: collected by patient at home
Hypoadrenalism
- Hyperpigmentation, develops slowly, symptoms vague and non-specific, low Na and high K, hypoglycemia
- Primary Dz: low cortisol, high ACTH, w/ anti-adrenal antibodies (Addison’s dz)
- Secondary Dz: low cortisol, low ACTH due to pituitary dz or tumor, no primary symptoms or electrolyte disturbance (RAAS), panhypopituitarism
- Tertiary Dz: low CRH, very rare, commonly caused by exogenous steroids
Testing: ACTH stimulation –> draw baseline cortisol/ACTH and inject w/ synthetic sub, take cortisol at 30&60 min –> should increase, if subnormal suggests insufficiency
Treatment: Gluco/Mineralocorticoid replacement –> Prednisone, Florinef
Addison’s Disease
- Primary adrenal insufficiency –> not responding to ACTH stimulation
- 70% of cases are autoimmune
- Can also be a result of granulomatous dz (TB), infiltrative dz (neoplasia), infarction, adrenoleukodystrophy (degeneration of adrenals), congenital adrenal hyperplasia
- Addisonian Crisis: life threatening, develops with added stressors
Hyperadrenalism
- Hypertension, central obesity, carb intolerance, abdominal striae –> stemming from excess cortisol
- 68% Cushing’s disease: commonly due to pituitary hypersecretion of ACTH
- Adrenal adenoma or carcinoma, ectopic ACTH secretion (non-endocrine tumor), iatrogenic causes
- Pseudohyperadrenalism –> increase in serum cortisol due to high CBG (estrogens), urine cortisol will be normal
Hyperadrenalism testing
- Urinary free cortisol: 24 hr urine, 90% accuracy with proper collection, preferred test
- Salivary cortisol: elevation indicates loss of diurnal variation (serum cort has poor sensitivity)
- Dexamethasone Suppression: administer dexamethasone which should exhibit negative feedback, if cortisol still elevated = hypercortisolism
- ACTH test run to differentiate adrenal tumor –> low = primary adrenal tumor, high = pit or ectopic origin
also: RAAS testing in cases of hypertension, 17-hydroxyprogesteron or DHEA test in cases of virilization
Adrenal steroid biochemistry
- 21-Hydroxylase Deficiency : defect in CYP21 in aldosterone & cortisol pathways, accumulation of weak androgens (dehydroepi/andostrenedione)
- 11-B-Hydroxylase Deficiency : defect inCYP11 in aldosterone & cortisol pathways (one step farther than CYP21), accumulation of mid-products deoxy/corticosterone
Hyperaldrenalism:
Cushings Dz: high ACTH/Cortisol
Ectopic ACTH Syndrome: very high ACTH, high Cortisol
Adrenal Tumor: low ACTH, high Cortisol
Adrenal Medulla
- Synthesized and secretes catecholamines (epi, norepi, dopamine)
- Stimulate aderenergic receptors (alpha = vasoconstriction etc, beta = vasodilation etc)
- Catecholamines released in response to hypotension, hypoxia, exertion, cold, pain, fear –> epi & norepi converted to Vanillylmandelic Acid (VMA)
Adrenal medullary disorders & testing
- Pheochromocytoma: rare & benign tumor of medullary chromaffin cells
- May occur in multiple endocrine neoplasia (MEN): genetic mutations determine type 2a or 2b
- Hypertension in main symptom due to increase in catecholamines
Testing: Plasma metanephrines (midproduct between epi -> VMA), Urinary catecholamines or metanephrines (ratio to cr), Chromogranin A (tumor marker protein, not specific)
