Endocrinology Flashcards
What is the function of endocrine glands?
Endocrine – glands secrete hormone into blood stream which acts at some distant tissue site. Pancreatic insulin (ß-cells) → muscle and fat
What is the function of exocrine glands?
Exocrine – glands secrete non-hormone into ductal system for delivery to distant or adjacent site. Pancreatic enzymes (acinar cells) → intestinal contents
Function of paracrine sys.?
Paracrine – cells secrete hormone that acts directly on other nearby cells Testosterone (Leydig cells) → seminiferous tubules
What are hormones?
Hormones are chemical messengers (signaling molecules) that are secreted directly into the blood, which carries them to organs and tissues of the body to exert their functions. There are many types of hormones that act on different aspects of bodily functions and processes.
What types of substances can be hormones? Where are they secreted/ or derived from?
Proteins or polypeptides: Hypothalamus, pituitary, pancreas, intestines, stomach, kidney, heart, parathyroids, liver.
Steroids: Cholesterol derived
Aromatic amino acid derivatives : Derived from tyrosine
Catchecolamines (soluble, neurological actions)
What are the differences between proteins and steroids concerning solubility and function as hormones?
-Proteins are water soluble and usually circulate without a carrier protein. -They interact with cell membrane receptors. EXAMPLE: -Inducing intracellular protein kinase action (G-coupled proteins) -Steroids are lipid soluble and transported bound to protein. -Internalized into cell, interact with nuclear receptors Modulate gene transcription
What are examples of hormones that are Aromatic amino acid derivatives?
T3 and T4 (Thyroid hormones) -Transported bound to protein -Internalized into cell, interact with nuclear receptors (modulate gene transcription) Catecholamines (epinephrine, norepinephrine, dopamine) —-Soluble —-Mostly neurological actions
What concept does this diagram depict?
The Endocrine “Axis” Concept
Hypothalamic releasing hormones stimulate pituitary secretion of trophic hormones
Trophic hormones stimulate endocrine gland synthesis or secretion of primary hormone
Endocrine hormone binds to specific receptors and effects action at target tissue(s)
Explain the concept of positive & negative feedback.
Negative feedback:
———-An endocrine hormone acts upon either pituitary or hypothalamus to decrease secretion of the releasing factor or trophic hormone responsible for its secretion
———-More common
Positive feedback:
———–An endocrine hormone acts upon either pituitary or hypothalamus to increase secretion of the releasing factor or trophic hormone responsible for its secretion
————Estradiol from developing follicle
Defects in the hypothalamus, pituitary gland and target organs/tissues each represent what level of endocrine disease?
Hypothalamus- Tertiary (rare)
Pituitary- Secondary
Tissues/organs- Primary
Where is the pituitary gland located?
The midline base of the brain
What are the posterior and anterior pituitary?
How does the hypothalamus act upon them?
Anterior pituitary (adeno-hypophysis) – gland nature
————Hypothalamic neurons secrete releasing factors into circulation which directly feeds pituitary
Posterior pituitary (neuro-hypophysis) – neural nature
———–Hypothalamic neurons extend into neurohypophysis and secrete their hormones there
Where are nuerohypophysial hormones made? Examples and their actions?
Synthesized in the hypothalamus and transported via axons for storage in posterior pituitary
Arginine vasopressin (AVP, antidiuretic hormone, ADH)
Cyclic nonapeptide
Acts on kidney tubules to increase water reabsorption
Vasoconstrictor
Hypothalamic osmoreceptors & cardiac/carotid baroreceptors
Oxytocin
Cyclic nonapeptide differs from AVP by two amino acids
Involved in lactation and parturition
Milk letdown
Uterine contraction
Pitocin® – synthetic oxytocin to induce labor
What are the two categories of Adenohypophysial Hormones?
List the hormones in each group.
Direct effector hormones
- Growth hormone (GH, hGH)
- Prolactin (Prl)
Trophic hormones:
- Adrenocorticotropic hormone (ACTH)
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Thyroid stimulating hormone (thyrotropin, TSH)
What secretes Growth Hormone? What inhibits it?
Somatotrophs (secrete GH) comprise over 1/3 of pituitary wt
Stimulated by growth hormone releasing hormone (GHRH) – 44 aa peptide
Inhibited by somatostatin – 14 or 28 aa peptide
——–Hypothalamus and pancreatic δ-cells
HOW is Growth Hormone GH secreted?
Secreted in pulsatile fashion (avg interval 2-3 hrs)
—Greatest secretion during sleep
—Spikes occur after meals and exercise
—Blood GH may be undetectable between pulses
———Poor value of isolated GH blood samples
What are the anabolic actions of GH?
Anabolic:
Increases protein synthesis, esp. in muscle
Soft tissue, bone and cartilage growth
Gluconeogenesis (glucogenic)
What is the catabolic function of GH?
Stimulating lipolyisis.
What does IGF stand for? Examples?
insulin-like growth factor
(IGFs, somatomedins, sulfation factor)
GH stimulates the formation of ______ in the liver acting as a _______hormone as well and the liver an endocrine organ.
IGFs
trophic
What is the most important IGF? Where is it made? What does it respond to? Howis it measured?
IGF-1 – most important IGF
Previously known as somatomedin C
Synthesized by the liver in response to GH
Insulin structural homology
Bound to IGF-binding protein 3 (IGF-BP3)
Both IGF-1 and IGF-BP3 blood levels are positively correlated with GH secretion
Blood levels are more stable than GH
Preferred testing marker (± IGF-BP3)
Measure by immunoassay (limited platforms)
What is the name of this disorder? What is it a result of?
Hypersecretion:
Gigantism – GH excess during growth phase
What is this disorder?
Acromegaly – GH excess after growth complete
commonly result from pituitary tumor
What disorders result from GH HYPOsecretion?
Hyposecretion:
Pituitary dwarfism –
not the same as achondroplasia
Autosomal dominant FGFR3 mutation; homozygous fatal
May result from tumors that interfere with GH secretion
May also result from genetic defects in GHRH gene, GH gene, GH receptor, IGF-1 synthesis or receptor
Adult deficiency
Mental issues (vague) - social withdrawal, fatigue, …
Osteoporosis
Decreased lean body mass (muscle)
Inc. total and LDL cholesterol
How are GH Hypo/Hyper secretion measured?
Immunoassay – random GH sample not necessarily helpful (pulsatile secretion)——-IGF-1 preferred
Hypersecretion:
Oral GTT – should suppress elevated GH to <1 ng/mL
Hyposecretion:
Insulin tolerance test – hypoglycemia (<50 mg/dL)
—–induces GH secretion
——–Requires physician attendance and concurrent glucose testing
Arginine infusion – induces GH (safer that insulin tolerance test)
—-Failure of GH to rise confirms deficiency
How is prolactin unique?
No physiologic releasing hormone
—–TRH (thyrotropin releasing hormone) in pathological situations (e.g., hypothyroidism)
Under tonic (constant) inhibition by dopamine
Only non-peptide releasing hormone
Loss of inhibition leads to uncontrolled secretion
Drugs that affect dopamine affect Prl (anti-psychotics, e.g., phenothiazines, haloperidol, …)
How is prolactin similar to GH? How is it stimulated?
Pulsatile secretion, similar to GH
Stimulated by pregnancy and suckling
What is the purpose/fnxn/action of prolactin?
Primary action is influence on lactation
Requires actions of estrogens, steroids, thyroid
Induces growth of breast ducts and alveoli, milk proteins
Suppresses release of GnRH
Prevents secretion of FSH and LH, thus the downstream effects of those hormones
What is a prolactinoma?
Hypersecretion
Prolactinoma – prolactin secreting pituitary tumor
Prolactin level typically >150-200 ng/mL
Elevation proportional to tumor size
Be aware of potential hook effect
More obvious in females
Amenorrhea (GnRH suppression) and galactorrhea (breast milk)
Pituitary stalk damage – dec. dopamine delivery
Hypothyroidism (1° or 2°) – increased TRH
Venipuncture, breast exam (25-50 ng/mL)
Anti-dopaminergic drugs (esp. anti-psychotics)
How is prolactin measured?
Immunoassay (sandwich typically)
Reference intervals are method dependent
Males 5-21 ng/mL, females 6-30 ng/mL
———–Increased in pregnancy
Why would you need a dilution protocol for measuring prolactin?
Hook effect
What is macroprolactin?
Macroprolactin – IgG bound prolactin (physiologically inactive)
Increased level due to reduced renal clearance
Precipitate with 12.5% PEG 6000 (1+1 with 25%)
14% of native prolactin may precipitate
Most common cause of (milder) hyperprolactinemia?
What is pan hypopituitarism?
What causes it?
Nothing is being secreted
Pituitary tumors
Parapituitary or hypothalamic tumors
Trauma, e.g., pituitary stalk section
Radiation therapy or cranial surgery
Infarction (postpartum: Sheehan’s syndrome)
Infection
Loss of direct effector hormones less apparent
Recombinant GH Rx in children, adults less common
Loss of tropic hormones more critical and obvious
Replace missing primary hormones as needed
Describe Thyroid location and physiology.
Thyroid gland (18-60 g) straddles trachea (left and right lobes, connected by isthmus)
Four parathyroids on back of gland, 2 each lobe
How are Throid cells arranged?
Thyroid cells arranged as follicles: Colloid and parafollicular
What is Colloid primarily made of?
Colloid primarily thyroglobulin (Tg):
Tg - tyrosine rich protein ~660 kD
Thyroid actively takes up iodine
Iodination of Tg tyrosine residues
Coupling of Tg tyrosine side chains
Release of thyroxine (T4)
-and triiodothyronine (T3)
What does the thyroid parafollicular cells secrete? Is it significant in the clinical lab?
- Calcitonin
- No
What is TPO?
What is it’s significance?
Thyroid peroxidase
What is TRH?
Thyrotropin releasing hormone (TRH)- Stimulates release of thyrotropin
3 amino acid peptide (can also stimulate release of prolactin)
What is TSH?
Thyrotropin (thyroid stimulating hormone, TSH)
28 kD peptide, α- and ß-subunits (identifiable via beta)
α-subunit identical with α-subunit of FSH, LH and hCG
Stimulates thyroid cell proliferation
Stimulates thyroid hormone production/secretion
What is T4 and T3?
Thyroxine (T4) and Triiodothyronine (T3)
Physiologically active hormones (esp. T3)
Between T3 and T4, which is primarily secreted?
T4 is the primary secreted hormone
T3 secreted, but mostly peripheral deiodination of T4 by tissues, esp. liver and kidney
How is T4 transported?
Transported bound to protein:
Thyroxine-binding globulin (TBG) - (60-75%)
Albumin - (15-30%)
Transthyretin (prealbumin, TBPA) - (~10%)
Only free hormones are biologically active
T4 – 99.98% bound (measure free fraction)
T3 – 99.7% bound (measure total, arguable free)
What is this image?
Peripheraal T4 metabolism
Differences among T4, T3 and rT3?
T4 production is exclusively thyroidal
70-90% of T3 is produced extrathyroidally
95-98% of rT3 is produced extrathyroidally
Most peripheral de-iodination occurs in liver
T3 accounts for most of the thyroid hormone activity in peripheral tissues
3-4 times more potent than T4
Some researchers have questioned whether T4 has any intrinsic biological activity
Reverse T3 (rT3) is biologically inactive
Thryroid Hormone actions?
T3 exerts primary intracellular actions by nuclear uptake and mRNA transcription
Increased metabolic activity (catabolic)
Increased cardiac activity (rate, output, contractility)
Increased CNS activity and sensitivity
Increased GI motility
Very important in fetal and neonatal CNS development
—–test in newborns. Deficiency CAN BE TREATED IF EARLY ENOUGH!
What are some conditions caused by Hyperthryoidism, or that cause hyperthyroidism?
Grave’s disease – autoimmune (60-80%)
Stimulatory Ab to TSH receptor (TSI, TSIg, TRAb)
May have exopthalmos
Ab can cross placenta→neonatal hyperthyroidism
Thyroid nodules – single or multinodular - benign
Thyroiditis – normal production, but leakage
Inc. iodine ingestion, e.g., amiodarone (cardiac med)
Factitious or iatrogenic – exogenous T4 excess
Pituitary tumor (rare)
Choriocarcinoma – hCG “cross-reaction” with TSH
10x more common in females
What are the signs and symptoms of hyperthyroidism?
Increased appetite, yet weight loss
Heat intolerance, diaphoresis (sweating)
Decreased HDL cholesterol
Palpitations, tachycardia, inc. systolic BP
Restlessness, fatigue, exaggerated reflexes, tremor
Hypothyroid conditions?
Hashimoto’s thyroiditis– both antibody and cell mediated (lymphocytic)
>90% have antibodies to thyroid peroxidase (TPO) and/or thyroglobulin (TG)
Most common in developed countries
Iodine deficiency (most common worldwide)
Thyroidectomy or radioablation (131I)
Congenital – 1:~4000 births, newborn screens
Secondary or tertiary - <1% of cases
Thyroid hormone resistance – rare autosomal dominant
Subclinical – laboratory evidence (inc. TSH with normal T4) w/o symptoms
—————-10x more common in females
Causes of Sec. and Tertiary Hypothroidism?
Pituitary (TSH) or hypothalamic (TRH) failure
Very rare
Isolated TSH deficiency is uncommon; usually associated with panhypopituitarism.
Sheehan’s Syndrome
Endocrine-inactive adenomas
Other space-occupying lesions
Signs and symptoms of hypothyroidism?
Cold intolerance
Weight gain and lethargy
Myxedema – subcutaneous swelling due to mucopolysacharride depostion
Bradycardia, hypotension, HF
Apathy, depressed reflexes
What are some thyroid cancers?
Medullary carcinoma (parafollicular cells)
Use calcitonin as a tumor marker once diagnosis is made
Epithelial cancers (follicular, papillary)
Monitor using thyroglobulin assay once diagnosis is made
What is the primary test in evaluating Thyroid status?
TSH
Measures hypothalamic response to (free) T4 levels
Measure by immunoassay using test with sensitivity to ≤ 0.01 mcIU/mL (“3rd generation”)
Reference interval 0.27-4.20 mcIU/mL
Some suggest lower upper limit (~2.5 mcIU/mL)
Increases to 4.20-~10.00 with normal (free) T4 suggest subclinical hypothyroidism.
Common, esp. in older females. Follow w/o Rx.
How are T3 and T4 measured
Measure by competitive immunoassay
Must displace bound T4 or T3 from serum proteins
Reference interval:
Total T4: 4.8-10.4 mcg/dL Note units
Total T3: 90-200 ng/mL difference
T4 increased in pregnancy (inc. TBG(affect total not free) due to E2)–-estrogens do this
Total levels may be confusing due to protein binding alterations (T4 99.98%, T3 99.7%)
Free T4 strongly recommended now
Free T3 assays not as robust
What happens when TBG increases?
TBG increases in pregnancy, OCT, HRT
Free hormone falls temporarily
TSH stimulates synthesis of more T4
Free T4 normalizes
Total T4 now elevated, but free T4 normal
What is RT3U?
RT3U (T3 uptake) - Obsolete assay that estimated available TBG (and other proteins)
Add labeled T3 to sample (binds to proteins)
Precipitate non-bound T3 with binding resin
% uptake by resin inversely proportional to TBG
In combination with total T4 to yield T7 or FTI (free thyroxine index).
Replaced by direct free T4 measurement or estimate
How is free T4 or T3 measured?
Direct dialysis – dialyze sample and measure T4 in dialysate with sensitive immunoassay
Labor intensive and not as suitable to volume
Equilibrium dialysis – reference method
125I T4 added to sample and dialyzed
Free T4 = % radioactivity added in dialysate x total T4
Labor intensive and not as suitable to volume
Reference Intervals:
Free T4: 0.9-1.7 ng/mL
Free T3: 210-440 pg/dL
How are Free T4 estimates done?
Two-step
No displacing T4 from proteins, free T4 binds to Ab
Add labeled T4, binds to unoccupied Ab sites
Separate unbound label and measure bound
Better estimate than one-step in unusual cases
Also automatable, but less common
One-step (analog)
T4 analog that binds to Ab, but “not serum binding proteins”
Competitive immunoassay, automatable
Work well in most cases
Cannot dilute samples with results >ULN
Follow with total T4 until FT4 back on the curve
Describe the thyroid fxn algorithm and reflex testing.
Describe four thyroid autoantibodies. How are they measured? What conditions are they common in?
Anti-thyroglobulin (anti-TG) – automated immunoassay
Anti-thyroid peroxidase (anti-TPO) – auto. immunoassay
Previously measured as anti-microsomal antibody by indirect immunofluorescence
Elevated (esp. anti-TPO) in Hashimoto’s thyroiditis
Present in about 10% of asymptomatic patients
Poorly standardized among manufacturers
Thyroid stimulating immunoglobulin (TSI, TSIg, TRAb)
Antibody to TSH receptor that stimulates when bound
Thyrotropin binding inhibitory immunoglobulin (TBII)
Inhibits TSH receptor response
What is thyroglobulin usd fo rconcerning cancers/tumors? How is it measured? What are some assay interferences? What new assay isnt affected by previous interferences?
Tumor marker for papillary or follicular thyroid cancer
Treated by thyroid ablation (I-131)
Undetectable TG means no functioning tissue remains
May take pts off replacement or stimulate with TSH
Measured by immunoassay (usually sandwich)
Interference by anti-TG antibodies
Assay must always include anti-TG
If anti-TG present, competitive assays may be less subject to interference, but not necessarily unaffected
Report should include cautionary statement if Abs present
New assay by LC-MS/MS not affected by Abs
Trypsin digestion, affinity concentration of specific peptide
Why shouldn’t thyroid testing be done in acutely ill patients?
Thyroid hormone results may be abnormal in sick patients w/o thyroid disease
“Euthyroid sick”:
Decrease in total and free T3
Increase in reverse T3 (no value in measuring)
Total T4 may decrease, but free T4 typically normal
Mild TSH depression during acute phase
Mild TSH increase during recovery
Thyroid assessment should not occur during acute illness
Where are the adrenal glands located?
Top of kidneys
Adrenal glands are yeloowish and mostly cortex. What are the three histological zones?
Zona glomerulosa
Zona fasciculta
Zona reticularis
The adrenal glands are made up of three parts….????
Suprarenal glands, approx. 4 gm
Cortex – 90% of organ weight
Yellowish tissue appearance
Three distinct histological zones
Zona glomerulosa
Zona fasciculta
Zona reticularis
Produces steroid hormones
Medulla – central 10%
Grayish tissue appearance
Produces catecholamine hormones
What are the adrenal steroids?
Steroid hormones
Derived from cholesterol
Up to 21 carbons
Glucocorticoids:
Cortisol
Zona fasciculata (ZF)
Mineralocorticoids:
Aldosterone
Zona glomerulosa (ZG)
Adrenal androgens (weaker than Testosterone):
Dehydroepiandrosterone, DHEA-SO4, androstenedione
Zona reticularis (ZR)
What is the rate limiting step in adrenal steroid creation?
conversion of choolesterol to pregnenolone
How are steroids transported?
Steroids are transported bound to protein
Albumin – low affinity, high capacity
Corticosteroid-binding globulin (CBG)
- High affinity, low capacity
- Cortisol – 96% bound (CBG saturated), 4% free (renal filtered)
- Aldosterone – 60% bound
Increased by estrogens
FREE STEROID FRACTION BIO ACTIVE
How are steroids catabolized?
Catabolism
Hydroxylation and conjugation (hepatic)
Double bond reduction
Renal excretion
How are glucocorticoids regulated?
Hypothalamic-pituitary-adrenal axis (HPA)
Corticotropin releasing hormone (CRH)
41 aa hypothalamic peptide
Adrenocorticotropic hormone (ACTH)
39 aa pituitary peptide
From pro-opiomelanocortin (POMC) precursor peptide
ß-melanocyte stimulating hormone (ß-MSH)
Responsible for pigmentation symptoms of Cushing’s
Stimulates cholesterol → pregnenolone (rate-limiting) in zona fasciculata and zona reticularis
Adrenocorticosteroids
Cortisol has negative feedback on ACTH & CRH release
What controls Hypothalamic CRH relaease?
Hypothalamic CRH release controlled by sleep-wake cycle (circadian rhythm, diurnal variation)
Cortisol levels highest in a.m. (6:00-10:00), lowest during sleep
Stress – direct effect on CRH
Neurogenic amines
Cytokines
Hypoglycemia
How are mineralocorticoids regulated?
Renin-angiotensin aldosterone system (RAAS)
Angiotensin II – stimulates cholesterol to pregnenolone in zona glomerulosa (vs ACTH in other two zones)
Potassium – hyperkalemia stimulates, hypokalemia inhibits aldosterone synthesis directly
ACTH – minor effect on mineralocorticoid regulation
Natriuretic peptides
ANP and BNP inhibit aldosterone secretion
?????
CORTISOL REGULATION
???????
ALDOSTERONE REGULATION
Glucocorticoid Functions?
Metabolic effects:
- Increases gluconeogenesis, glycogenesis, lipolysis*
- Increases protein catabolism, decreases protein synthesis*
Blood pressure control:
- Increases GFR, synthesis of angiotensinogen (liver)*
- In larger amounts, has mineralocorticoid actions*
- Limited by renal metabolism to cortisone, saturable enzyme*
Anti-inflammatory
- Decreases antibody, interleukin, interferon synthesis*
- Decreases circulating lymphocytes, eosinophils, monocytes*
- Stabilizes lysosomes*
- Inhibits leukocyte migration, phagocytosis*
Mineralcorticoid (aldost.) Effects???
Increases sodium reabsorption by distal convoluted tubule and collecting duct in exchange for potassium (or proton)
Reabsorbed sodium brings water to maintain blood volume/pressure
Other mineralocorticoids:
Cortisol – in very high amounts
11-deoxycorticosterone (DOC)
What are adrenal fnc tests?
Serum cortisol
Competitive immunoassay or LC-MS/MS
Reference interval: 6-25 mcg/dL (8:00 am), 3-16 (6:00 pm)
Serum aldosterone
Competitive immunoassay or LC-MS/MS
Reference interval: time, posture and Na diet dependent
ACTH
Immunoassay – EDTA stabilizes sample
Reference interval: 7-50 (m) or 5-27 (f) pg/mL (7:00-10:00 am)
Anti-adrenal antibody (21-hydroxylase)
Present in autoimmune Addison’s disease
ELISA or IFA
Urinary free cortisol
24 hr urine collection
Immunoassay (same as serum assay)
—–Requires solvent extraction and evaporation ——–to remove polar cross-reacting metabolites
LC-MS/MS
Reference ranges variable with age
Preferred marker, but subject to pre-analytical variability
Salivary cortisol (thought to rep free cortisol)
Usually collected (by patient at home) at 11:00 pm to demonstrate loss of diurnal variation in pts with Cushing’s syndrome
Signs and symptoms of Hypoadrenalism?
Develop slowly, often vague and non-specific
Weakness, fatigue, weight loss, hypotension
Hyperpigmentation with primary disease
Hyponatremia, hyperkalemia, hemoconcentration
Hypoglycemia
Addisonian crisis – life-threatening
Usually develops only with added stressors
Conditions associated with Hypoadrenalism?
Addison’s Dz - primary adrenal insufficiency
Autoimmune – 70% of cases
Anti-adrenal Abs, esp. 21-hydroxylase
Often associated with other autoimmune disorders
Granulomatous Dz – TB, sarcoid, Histo, fungi
Infiltrative Dz – neoplasia, amyloid, hemochrom.
Infarction
Adrenoleukodystrophy – VLCFA defect
Congenital adrenal hyperplasia (CAH)
What are causes of Secondary and Tertiary hypoadrenalism?
Secondary – decreased ACTH
Pituitary disease/tumor
- No hyperpigmentation
- No electrolyte disturbance (RAAS intact)
- May have hypogonadism and/or hypothyroidism
———-Panhypopituitarism
Tertiary – decreased CRH
- Extremely rare (hypothalamic)
- Most commonly caused by exogenous steroids
—–Must taper doses gradually to prevent Addisonian crisis
In primary Hypoadrenalism what is tested?
Cortisol (8:00 am) low (usually <6 mcg/dL)
<2.0 diagnostic, >20.0 rules out
ACTH (8:00 am) high (often >150 pg/mL)
Anti-adrenal antibodies (or anti-21-hydroxylase)
Establishes autoimmune etiology
In secondary disease (hypoadrenalism) what is tested?
cortisol decreased
ACTH decreased
What is the Cosyntropin (ACTH) stimulation test?
Hypoadrenalism test
Draw baseline cortisol level (± ACTH level)
Inject Cosyntropin® (synthetic ACTH 1-24)
Cortisol levels at 30 and 60 minutes post injection
Increase of >10 mcg/dL and to >20 mcg/dL normal
Subnormal response suggests 1° adrenal insufficiency, esp. with elevated baseline ACTH
Decreased baseline ACTH with low response may indicate secondary insufficiency or chronic steroid Rx
What is CRH simulation test?
Hypoadrenalism test
CRH simulation test
Increase in ACTH suggests tertiary dz, no inc. 2°
How is hypoadrenalism treated?
Glucocorticoid replacement
Prednisone – synthetic steroid
Metabolized to prednisolone
possible cortisol immunoassay cross-reactivity
Roche Elecsys: 148%
Methylprednisolone - Roche Elecsys: 249%
Triamcinalone
Beclomethasone
Mineralocorticoid replacement
Florinef - fludrocortisone
This is a depiction of?
Cushings Syndrome
Signs and symptoms resulting
from excess cortisol
Hypertension 85-90%
Central obesity 90%
Carbohydrate intolerance 80%
Facial signs 80%
Abdominal striae 65%
Hirsutism 65%
Buffalo hump
Hypokalemic metabolic alkalosis – why? less sodium uptake so more K and proton loss
What are conditions associated with hyperadrenalism?
Cushing’s disease (~68%):
When Cushing’s syndrome is caused by pituitary hypersecretion of ACTH (usually microadenoma)
Rarely due to CRH excess (may be ectopic)
Adrenal adenoma or carcinoma (~17%)
Ectopic ACTH secretion (~15%)
Non-endocrine tumor (esp. lung) secretes ACTH
Iatrogenic – glucocorticoid treatment (excess) (<1%)
Pseudohyperadrenalism – inc. serum cortisol due to inc. CBG (pregnancy, estrogen Rx)
—-Urine free cortisol will be normal
Primary hyperaldosteronism is also called?
Primary hyperaldosteronism (Conn’s syndrome)
Hypokalemia, possible hypernatremia
Metabolic alkalosis
Refractory hypertension (does not respond well to treatment)
Usually results from adrenal adenoma
Secondary hyperaldosteronism results fom?
Secondary hyperaldosteronism
Often results from renovascular disease, e.g., renal artery stenosis (narrowing)
Kidney (JGA) perceives decreased blood volume due to dec. perfusion
RAAS activation
What is Congenital Adrenal Hyperplasia (CAH)
21-hydroxylase deficiency (95% of cases)
Blocks formation of cortisol and aldosterone
Loss of negative feedback → ↑ ACTH
17-OH-P increase shunts to excess androgens
Virilization in females, possible ambiguous genitalia
Precocious puberty in males
Severe deficiency leads to salt-wasting
Newborn screening with 17-OH-progesterone
Late-onset form develops in adulthood, less severe
11-ß-hydroxylase deficiency (<5%)
Accumulation of 11-deoxycorticosterone (DOC)
DOC mineralocorticoid activity leads to hypertension, hypokalemia
What tests are done for hyperadrenalism?
Isolated serum cortisol has poor sensitivity
May be elevated or normal
Urinary free cortisol (UFC) – 24 hr collection
90% accurate with proper collection
Immunoassay (after extraction) or LC-MS/MS
Reference interval: <100 mcg/day
Preferred test with good collection
Salivary cortisol
Typically collected at 11:00 -12:00 pm (nadir) at home
Elevated levels (>100 ng/dL) indicate loss of diurnal variation
Dexamethasone Suppression (overnight or low-dose)
Pt takes 1 mg dexamethasone at 11:00 pm
Synthetic glucocorticoid 100x potency of cortisol
Should exhibit negative feedback on pituitary ACTH secretion
Draw serum cortisol at 8:00 am next morning
<5 (?<3) mcg/dL – normal suppression
(3)5-10 mcg/dL – equivocal
>10 mcg/dL – hypercortisolism
High dose DST – rarely used; no longer recommended
2 mg dex q6h for 48 hours
ACTH – differentiate adrenal tumor:
Low (<5 pg/mL) = ? primary adrenal tumor – follow with imaging
High = ? pituitary (5-199 pg/mL) or ectopic origin (≥200 pg/mL)
Decscribe the HPA Axis in Hyperadrenalism
First pic—Normal
Second pic: High ACTH High Cortisol in Cushings disease
Third pic: Really high ACTH High Cortisol in ectopic ACTh syndrome
Fourth pic Low ACTH High Cortisol eith an adrenal tumor
Differentiate pituitary vs ectopic source by imaging or inferior petrosal sinus sampling for ACTH vs peripheral ACTH ± post CRH
IPSS > 2x peripheral (>3x post CRH) = pituitary source (Cushing’s)
IPSS ≈ peripheral = ectopic source
Hyperadrenalism Testing - Hypertension
Serum (preferred) or 24 hr urine aldosterone
Immunoassay vs LC-MS/MS (preferred)
Plasma renin activity (PRA)
Sample
incubated to generate angiotensin I
Immuno- or LC-MS/MS assay for AT I
Reported in units of ng/mL/hr (AT I generated)
Collect in EDTA, chill and separate plasma w/in 2 hrs and freeze
Longer chilling cryoactivates prorenin to renin
Direct renin immunoassay – theoretically preferred
Few assays available
Decent correlation (~7-8x PRA)
Aldosterone:renin (PRA) ratio (ARR)
Ratio >20-25 (assay dependent) plus elevated aldosterone suggests primary aldosteronism
Or aldo:direct renin >3.0-3.7
Secondary (high renin) has lower ratio
Renovascular etiology
Metabolic alkalosis
Hypernatremia possible
Hypokalemia
Urine K >30 mmol/day OR
Spot urine K > urine Na
Hyperadrenalism Testing - Virilization
17-hydroxyprogesterone – LC-MS/MS
Used for Dx of 21-hydroxylase deficient CAH
Part of newborn screen
Monitor glucocorticoid replacement in CAH
Low 17HP indicates adequate replacement
Dehydroepiandrosterone sulfate (DHEAS) or DHEA
Adrenal androgens (<10% from gonads)
Elevated in virilization from adrenal hyperfunction
Measure by immunoassay or LC-MS/MS
Reference ranges for all highly sex and age variable
What is made by the adrenal medulla?
Catecholamines:
Epinephrine, Norepinephrine and Dopamine
***stimulate adrenergic receptors
Catecholamines are released in response to?
hypotension, hypoxia, exertion, cold, pain, fear
Describe catecholamin metabolism.
MAO – monoamine oxidase
COMT – catechol-O-methyltransferase
Very rapid blood turnover (T1/2 of minutes)
What is Pheochromocytoma?
Adrenal Medullary Diorder
Pheochromocytoma – rare, benign (80%) tumor of medullary chromaffin cells
May occur in extra-medullary sites (10%, paragangliomas)
Represents 0.1-0.6% of persistent hypertension
May occur in multiple endocrine neoplasia (MEN)
2A – hyperparathyroidism, medullary thyroid carcinoma
2B – mucosal neuromas, medullary thyroid carcinoma
Main symptom is hypertension
Sustained
Episodic
Adrenal Medullary Testing
VMA is obsolete!
Plasma catecholamines not recommended:
Requires patient be supine 20 minutes
Indwelling venous catheter
Draw in chilled green top, separate cold & freeze plasma within 30 minutes.
Plasma metanephrines preferred:
No requirements as above
Minimal (<10%) increase due to position or stress of venipuncture
Urinary catecholamines or metanephrines
Measure on random or timed samples
Random – ratio to creatinine
Collect during or immediately after hypertensive episode
Timed (24 hr)
May better cover episodic secretion, if complete
Assay by LC-MS/MS (preferred) or HPLC with electrochemical detector
Chromogranin A – tumor marker protein
Measure by immunoassay
Not specific for pheochromocytoma
