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Endocrinology Flashcards

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1
Q

What is the function of endocrine glands?

A

Endocrine – glands secrete hormone into blood stream which acts at some distant tissue site. Pancreatic insulin (ß-cells) → muscle and fat

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2
Q

What is the function of exocrine glands?

A

Exocrine – glands secrete non-hormone into ductal system for delivery to distant or adjacent site. Pancreatic enzymes (acinar cells) → intestinal contents

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3
Q

Function of paracrine sys.?

A

Paracrine – cells secrete hormone that acts directly on other nearby cells Testosterone (Leydig cells) → seminiferous tubules

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4
Q

What are hormones?

A

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.

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5
Q

What types of substances can be hormones? Where are they secreted/ or derived from?

A

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)

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6
Q

What are the differences between proteins and steroids concerning solubility and function as hormones?

A

-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

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7
Q

What are examples of hormones that are Aromatic amino acid derivatives?

A

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

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8
Q

What concept does this diagram depict?

A

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)

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9
Q

Explain the concept of positive & negative feedback.

A

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

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10
Q

Defects in the hypothalamus, pituitary gland and target organs/tissues each represent what level of endocrine disease?

A

Hypothalamus- Tertiary (rare)

Pituitary- Secondary

Tissues/organs- Primary

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11
Q

Where is the pituitary gland located?

A

The midline base of the brain

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12
Q

What are the posterior and anterior pituitary?

How does the hypothalamus act upon them?

A

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

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13
Q

Where are nuerohypophysial hormones made? Examples and their actions?

A

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

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14
Q

What are the two categories of Adenohypophysial Hormones?

List the hormones in each group.

A

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)
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15
Q

What secretes Growth Hormone? What inhibits it?

A

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

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16
Q

HOW is Growth Hormone GH secreted?

A

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

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17
Q

What are the anabolic actions of GH?

A

Anabolic:

Increases protein synthesis, esp. in muscle

Soft tissue, bone and cartilage growth

Gluconeogenesis (glucogenic)

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18
Q

What is the catabolic function of GH?

A

Stimulating lipolyisis.

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19
Q

What does IGF stand for? Examples?

A

insulin-like growth factor

(IGFs, somatomedins, sulfation factor)

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20
Q

GH stimulates the formation of ______ in the liver acting as a _______hormone as well and the liver an endocrine organ.

A

IGFs

trophic

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21
Q

What is the most important IGF? Where is it made? What does it respond to? Howis it measured?

A

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)

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22
Q

What is the name of this disorder? What is it a result of?

A

Hypersecretion:

Gigantism – GH excess during growth phase

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23
Q

What is this disorder?

A

Acromegaly – GH excess after growth complete

commonly result from pituitary tumor

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24
Q

What disorders result from GH HYPOsecretion?

A

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

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25
Q

How are GH Hypo/Hyper secretion measured?

A

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

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26
Q

How is prolactin unique?

A

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, …)

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27
Q

How is prolactin similar to GH? How is it stimulated?

A

Pulsatile secretion, similar to GH

Stimulated by pregnancy and suckling

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28
Q

What is the purpose/fnxn/action of prolactin?

A

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

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29
Q

What is a prolactinoma?

A

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)

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30
Q

How is prolactin measured?

A

Immunoassay (sandwich typically)

Reference intervals are method dependent

Males 5-21 ng/mL, females 6-30 ng/mL

———–Increased in pregnancy

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31
Q

Why would you need a dilution protocol for measuring prolactin?

A

Hook effect

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32
Q

What is macroprolactin?

A

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?

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33
Q

What is pan hypopituitarism?

What causes it?

A

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

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34
Q

Describe Thyroid location and physiology.

A

Thyroid gland (18-60 g) straddles trachea (left and right lobes, connected by isthmus)

Four parathyroids on back of gland, 2 each lobe

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35
Q

How are Throid cells arranged?

A

Thyroid cells arranged as follicles: Colloid and parafollicular

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36
Q

What is Colloid primarily made of?

A

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)

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37
Q

What does the thyroid parafollicular cells secrete? Is it significant in the clinical lab?

A
  • Calcitonin
  • No
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38
Q

What is TPO?

What is it’s significance?

A

Thyroid peroxidase

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39
Q

What is TRH?

A

Thyrotropin releasing hormone (TRH)- Stimulates release of thyrotropin

3 amino acid peptide (can also stimulate release of prolactin)

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40
Q

What is TSH?

A

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

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41
Q

What is T4 and T3?

A

Thyroxine (T4) and Triiodothyronine (T3)

Physiologically active hormones (esp. T3)

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42
Q

Between T3 and T4, which is primarily secreted?

A

T4 is the primary secreted hormone

T3 secreted, but mostly peripheral deiodination of T4 by tissues, esp. liver and kidney

43
Q

How is T4 transported?

A

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)

44
Q

What is this image?

A

Peripheraal T4 metabolism

45
Q

Differences among T4, T3 and rT3?

A

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

46
Q

Thryroid Hormone actions?

A

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!

47
Q

What are some conditions caused by Hyperthryoidism, or that cause hyperthyroidism?

A

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

48
Q

What are the signs and symptoms of hyperthyroidism?

A

Increased appetite, yet weight loss

Heat intolerance, diaphoresis (sweating)

Decreased HDL cholesterol

Palpitations, tachycardia, inc. systolic BP

Restlessness, fatigue, exaggerated reflexes, tremor

49
Q

Hypothyroid conditions?

A

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

50
Q

Causes of Sec. and Tertiary Hypothroidism?

A

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

51
Q

Signs and symptoms of hypothyroidism?

A

Cold intolerance

Weight gain and lethargy

Myxedema – subcutaneous swelling due to mucopolysacharride depostion

Bradycardia, hypotension, HF

Apathy, depressed reflexes

52
Q

What are some thyroid cancers?

A

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

53
Q

What is the primary test in evaluating Thyroid status?

A

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.

54
Q

How are T3 and T4 measured

A

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

55
Q

What happens when TBG increases?

A

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

56
Q

What is RT3U?

A

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

57
Q

How is free T4 or T3 measured?

A

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

58
Q

How are Free T4 estimates done?

A

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

59
Q

Describe the thyroid fxn algorithm and reflex testing.

A
60
Q

Describe four thyroid autoantibodies. How are they measured? What conditions are they common in?

A

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

61
Q

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?

A

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

62
Q

Why shouldn’t thyroid testing be done in acutely ill patients?

A

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

63
Q

Where are the adrenal glands located?

A

Top of kidneys

64
Q

Adrenal glands are yeloowish and mostly cortex. What are the three histological zones?

A

Zona glomerulosa

Zona fasciculta

Zona reticularis

65
Q

The adrenal glands are made up of three parts….????

A

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

66
Q

What are the adrenal steroids?

A

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)

67
Q

What is the rate limiting step in adrenal steroid creation?

A

conversion of choolesterol to pregnenolone

68
Q

How are steroids transported?

A

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

69
Q

How are steroids catabolized?

A

Catabolism

Hydroxylation and conjugation (hepatic)

Double bond reduction

Renal excretion

70
Q

How are glucocorticoids regulated?

A

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

71
Q

What controls Hypothalamic CRH relaease?

A

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

72
Q

How are mineralocorticoids regulated?

A

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

73
Q

?????

A

CORTISOL REGULATION

74
Q

???????

A

ALDOSTERONE REGULATION

75
Q

Glucocorticoid Functions?

A

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*
76
Q

Mineralcorticoid (aldost.) Effects???

A

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)

77
Q

What are adrenal fnc tests?

A

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

78
Q
A
79
Q

Signs and symptoms of Hypoadrenalism?

A

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

80
Q

Conditions associated with Hypoadrenalism?

A

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)

81
Q

What are causes of Secondary and Tertiary hypoadrenalism?

A

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

82
Q

In primary Hypoadrenalism what is tested?

A

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

83
Q

In secondary disease (hypoadrenalism) what is tested?

A

cortisol decreased

ACTH decreased

84
Q

What is the Cosyntropin (ACTH) stimulation test?

A

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

85
Q

What is CRH simulation test?

A

Hypoadrenalism test

CRH simulation test

Increase in ACTH suggests tertiary dz, no inc. 2°

86
Q

How is hypoadrenalism treated?

A

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

87
Q

This is a depiction of?

A

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

88
Q

What are conditions associated with hyperadrenalism?

A

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

89
Q

Primary hyperaldosteronism is also called?

A

Primary hyperaldosteronism (Conn’s syndrome)

Hypokalemia, possible hypernatremia

Metabolic alkalosis

Refractory hypertension (does not respond well to treatment)

Usually results from adrenal adenoma

90
Q

Secondary hyperaldosteronism results fom?

A

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

91
Q

What is Congenital Adrenal Hyperplasia (CAH)

A

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

92
Q

What tests are done for hyperadrenalism?

A

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)

93
Q
A
94
Q

Decscribe the HPA Axis in Hyperadrenalism

A

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

95
Q

Hyperadrenalism Testing - Hypertension

A

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

96
Q
A
97
Q

Hyperadrenalism Testing - Virilization

A

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

98
Q

What is made by the adrenal medulla?

A

Catecholamines:

Epinephrine, Norepinephrine and Dopamine

***stimulate adrenergic receptors

99
Q

Catecholamines are released in response to?

A

hypotension, hypoxia, exertion, cold, pain, fear

100
Q

Describe catecholamin metabolism.

A

MAO – monoamine oxidase

COMT – catechol-O-methyltransferase

Very rapid blood turnover (T1/2 of minutes)

101
Q

What is Pheochromocytoma?

A

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

102
Q

Adrenal Medullary Testing

A

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

103
Q
A

clinical chemistry (9 decks)

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