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What are chemical messengers that are secreted from one organ in order to produce a response distant from its place of manufacture?
How are hormones secreted, and how do they exert their effects?
- They are secreted directly into the circulation.
- Exert their effects by binding to receptors in/on cells of target tissues or target organs.
How many receptors are in the cell membrane compared to what is needed for the maximum biologic response?
Usually more receptors in the cell membrane than are needed for the maximum biologic response.
How is maximum biologic response determined?
By hormone concentration.
How many nuclear receptors are within a cell as compared to other receptor types?
Low number of NUCLEAR receptors w/in a target.
How is the extent of the biologic response to a hormone determined?
Number of nuclear receptors.
What is the relative size, hydrophobicity, half-life (in minutes), receptor location, and mechanism of action for polypeptide/protein hormones?
- Size: large, >500 kDa
- Hydrophobicity: hydrophilic
- Serum half-life: minutes
- Receptor location: cell surface
- MOA: 2nd messengers
What is the relative size, hydrophobicity, half-life (in minutes), receptor location, and mechanism of action for steroid hormones and thyronines?
- Size: small, <500 kDa
- Hydrophobicity: hydrophobic
- Serum half-life: hours
- Receptor location: cytoplasm and nucleus
- MOA: direct nuclear actions
What mechanism is described as a method of hormone control in which high levels of hormone DECREASE hormone synthesis and secretion, while low levels STIMULATE synthesis and secretion?
- Negative feedback
- **decreased T3 stimulates pituitary to secrete TSH, when normal T3 levels are reached TSH release is inhibited**
What mechanism is described as a method of hormone control in which high levels of a hormone STIMULATE synthesis and release, while low levels INHIBIT synthesis and release?
- Positive feedback
- **increased LH stimulates ovaries to secrete estradiol during menstrual cycle**
When excess hormone is present, what happens to the cell receptors in order to maintain homeostasis? What happens when hormones are depleted?
- Receptors are down-regulated
- Receptors are up-regulated
Describe the alterations that can occur in endocrine tissue function that cause hyperfunction.
- Primary: alteration of hormone-secreting gland
- Secondary: alteration in pituitary or hypothalamus
- Ectopic: hormone secretion from tissue other than its usual source
Describe the alterations that can occur in endocrine tissue function that cause hypofunction.
- Resistance: inability of target tissue to recognize hormone
What is an adenoma?
- Benign enlargement of a cluster of cells.
- **Can become malignant (adenocarcinoma).**
What is a neoplasm?
Abnormal new growth of tissue; generally considered malignant.
What is hyperplasia?
Benign enlargement of entire gland.
How does ADH (vasopressin) maintain water balance?
- By inhibiting diuresis.
- Acts on renal tubules to increase water re-absorption and concentration of urine.
What is the release of ADH coordinated with in the brain?
Activation of the thirst center in the brain.
What regulates the secretion of ADH?
- Osmo-receptors in the hypothalamus (blood osmolality)
- Atrial and carotid baroreceptors (blood volume)
What stimulates the secretion the ADH?
- Hemo-concentration (incr temperature)
- Hypo-volemia/hypotension (nausea/vomiting)
- Hormones (angiotensin II, epinephrine, cortisol, estrogen, progesterone)
What are the drugs that stimulate ADH secretion?
What is an inhibitor of ADH secretion?
What is the plasma osmolality threshold for ADH release and stimulation of thirst?
- >285 osm/L
- **normal osmolality is 275-300 osm/L**
What are some ADH disorders?
- Diabetes Insipidus (DI)
- Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH)
What are some typical lab findings for diabetes insipidus?
- High urine output
- Low urine specific gravity
- Elevated BUN
What are some differential diagnosis for polyuria?
- Diabetes mellitus
- Cushing's syndrome
- Glucocorticoid therapy
- Psychogenic polydipsia
- Nocturnal polyuria of Parkinson's disease
- Lithium use
- Diabetes Insipidus
What is the typical clinical presentation for someone with diabetes insipidus?
- Excess urine volume (2-20 L/day) with a LOW specific gravity (decreased osmolality).
- Intense polydipsia.
- Fluid intake of 2-20 L/day.
- Possible hypernatremia, dehydration, hypotension, vascular collapse.
What differentiates the type of diabetes insidipus?
Name the 3 types of diabetes insipidus.
- Central (Neurogenic) DI: 1/3 of all cases
- Nephrogenic (kidney) DI
- Partial DI
What are the etiologies for deficiency of ADH secretion from the posterior pituitary (central (neurogenic) DI)?
- Hypothalamic/pituitary surgery.
- Trauma to pituitary stalk.
- Infection (encephalitis, syphilis, TB).
- Tumors of the pituitary, metastases to pituitary.
- Pituitary infarction (postpartum hemorrhage-Sheehan's syndrome)
- Pituitary inflammation.
What are the etiologies of renal insensitivity for ADH (nephrogenic (kidney) DI)?
- Chronic renal disease (any renal tubules defect)
- Chronic Hypercalcemia
- Sickle cell anemia
Name some medications that can cause nephrogenic (kidney) DI?
When would partial diabetes insipidus be suspected? How are the symptoms in comparison to the other types of DI?
- Suspect in pts w/ persistent urinary incontinence or bedwetting.
- Symptoms are LESS intense than other DI.
What is the initial evaluation of diabetes insipidus?
- No single test, instead....
- Use plasma and urine osmolality
- Water deprivation test
What are the diagnostic tests used to evaluate a pt for diabetes insipidus?
- 24 hour urine (volume, glucose, creatinine, osmolality). Urine volume <2 liters/24 hours rules out DI in adult.
- Serum (glucose, BUN, Ca, uric acid, Na, K, creatinine, osmolality).
- Pt hx and PE will guide choice of further diagnostic studies to determine central or nephrogenic DI.
What are the tests used to differentiate central DI from nephrogenic DI?
- Central DI: use Vasopressin Challenge Test, positive if you see decreased thirst and decreased urine output
- Nephrogenic DI: measure serum vasopressin (ADH) during modest fluid restriction, positive if ADH level is elevated
How is the Vasopressin Challenge Test performed?
- Measure urine volume 12 hours prior to admin of Desmopressin (DDAVP)
- DDAVP given either by IV, subcutaneous injection or intranasally.
- Measure urine volume 12 hours after DDVAP admin.
- Patient has central DI if you see decreased thirst, decreased urine output (decreased urine osmolality). Serum Na MUST be measured immediately if there are any symptoms of hyponatremia.
- MRI pituitary and hypothalamus.
If the patient has central DI what will be seen in the patient at the end of a vasopressin challenge test?
- Decreased thirst.
- Decreased urine output (increased osmolality).
How would a nephrogenic DI be identified?
Measured serum vasopressin (ADH) during modest fluid restriction will show elevated vasopressin levels.
What are some complications of DI?
- Severe dehydration (central)-ensure adequate fluids are available.
- Hypernatremia (nephrogenic).
How is Central DI treated?
- Desmopressin acetate: via oral, IV, IM, subQ, intranasal/MDI (metered dose inhaler) routes.
- Treatment rarely causes hyponatremia (use lowest effective dose).
How is Nephrogenic DI treated?
- Acutely by fam/ER: Indomethacin (50 mg every 8 hrs)
- Long term by nephrologist: Indomethacin w/ hydrochlorothiazide (HCTZ), desmopressin, or amiloride (K-sparing diuretic); chlorpropamide (sulfonylurea) which is an antidiuretic potentiator
How is indomethacin in combination with hydrochlorothiazide (HCTZ), desmopressin, or amiloride effective in treating nephrogenic DI?
Decreases reabsorption or Na and Cl in the tubular fluid, and helps aid in Na excretion (stops compensatory loss of water when Na is retained).
What is the action of HCTZ and amiloride as diuretics?
They produce a hyperosmolar urine while decreasing urine output.
Why is it harder to treat nephrogenic DI?
Because kidney damage already occurred (most are secondary to chronic kidney disease).
What is a the treatment for chronic/mild DI?
Simply maintain adequate water intake.
What condition presents with normal vascular volume and hyponatremia?
- Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
- **inappropriate ADH secretion in the absence of any osmotic stimulus**
What are the two criteria that help determine syndrome of inappropriate anti-diuretic hormone (SIADH)?
- Decreased plasma osmolality.
- Inappropriate concentration of the urine.
- **if low blood volume and high serum osmolality don't exist there is no reason for ADH to be secreted hence the name**
How is ADH release normally regulated? What disorders can cause SIADH?
- Regulated by the central nervous system (osmoreceptors in the hypothalamus) and the chest (via baroreceptors).
- Disorders of the CNS and chest can cause SIADH.
What are the 3 main etiologies of SIADH?
- Tumors secreting ectopic ADH.
- Medication/Drug induced.
- Lesions in the pathway of receptors.
What are tumors (malignancies) associated with secreting ectopic ADH that cause SIADH?
- Small cell/oat cell cancer (80% of lung tumors assoc w/ SIADH)- chest CT/MRI should be performed on all pts with unexplained hyponatremia
- Prostate cancer
- Renal cell carcinoma
- Pancreatic cancer
What medications/drugs can induce SIADH?
- Antidepressants: SSRIs, tricyclics, MAOIs (incr ADH)
- Antineoplastic agents (incr ADH)
- MDMA, ecstacy (incr ADH)
- NSAIDs (potentiates ADH)
- Cytotoxic therapy (chemo/radiotherapy)
What are some disorders/diseases that can cause lesions in the pathway of osmo- and baroreceptors, causing SIADH?
- CNS disorders: stroke, subarachnoid hemorrhage, meningitis, encephalitis, trauma, brain tumor
- Pulmonary diseases: TB, bacterial pneumonia
- Pain, physical stress, postoperative states.
What is the clinical presentation of a pt with SIADH?
- Fatigue, headache, nausea and anorexia which can progress to nausea/vomiting and eventually neurologic impairment as Na decreases.
- Hyponatremia (if <120 mEq/L YOU MUST FIX IT NOW!)
- Low/decreased plasma osmolality (<280 mosml/kg)
- Inappropriately high urine osmolality for plasma osmolality.
- Urine sodium >20 mEq/L (elevated)
- Hypouricemia, low BUN (dilution + decreased clearance due to volume expanded state)
- Normal plasma volume (euvolemic). Pts do have excess total body water but 2/3 goes into the cells (ICF) and 1/3 goes to ECF which is minor and not usually noted on PE.
What are the symptoms of severe hyponatremia (<120 mEq/L)?
- Lethargy, confusion, stupor, coma
- Neuromuscular excitability, muscle twitching, seizures
- Vomiting, abdominal cramps
What conditions should you rule out as a cause of hyponatremia before thinking about/treating SIADH?
- Renal insufficiency
- Glucocorticoid deficiency
- Use of thiazide diuretics
How is treatment of SIADH determined?
- By severity and duration of hyponatremia.
- Hyponatremia occurs quickly and pt is symptomatic, treat quickly.
- Hyponatremia occurs over time and pt is asymptomatic, correctly slowly with water restriction over time.
How are euvolemic pts with SIADH treated?
- Water restriction (500-1000 ml/day) so Na intake does not become diluted.
- Adequate dietary Na intake.
- Demeclocyclin (tetracycline): useful for pts who can't adhere to water restriction (inhibits effect of ADH on distal renal tubule but there is danger of induced H2O intoxication).
How are hypovolemic pts with SIADH treated?
Isotonic fluids to suppress the hypovolemic stimulus for ADH release.
How is symptomatic hyponatremia treated?
- Refer to endocrinology and nephrology!
- If CNS symptoms are present, treat at ANY serum Na level with...
- IV saline + furosemide (Lasix)- hypertonic (3%) saline used when serum Na is <115 mEq/L
What is used as a medication to induce labor and can potentiate water retention?
What is the major function of the pituitary?
Supports lactation in the postpartum period (concentration of prolactin increase 10 fold during pregnancy and lactation).
What is the percentage of hormone secreting pituitary tumors relative to the hormone they secrete?
- Prolactin: 60%
- Growth hormone (GH): 20%
- ACTH: 10%
- TSH, LH, RSH: rare
- Nonfunctional: 10%
What keeps prolactin "in check" in healthy, non-nursing individuals because it is secreted continuously unless otherwise inhibited?
What conditions cause increased prolactin secretion?
- Pregnancy (increased estrogen lvls in late pregnancy)
- Nipple piercing, augmentation mammoplasty, mastectomy
- Chronic chest wall stimulation
- Hypothyroidism (high TRH causes prolactin secretion)
- Pituitary stalk lesions
- Pituitary tumors that secrete prolactin
- Dopamine antagonists (Phenergan)
What causes decreased prolactin secretion?
- Dopamine agonists (cabergoline, bromocriptine, pergolide)
What is the clinical presentation of a prolactinoma in premenopausal women?
- Galactorrhea (lactation in absence of nursing)
- Amenorrhea (hyperprolactinemia suppresses pulsatile LH secretion)
- Visual field abnormalities (macroadenoma)
What is the clinical presentation of a prolactinoma in postmenopausal women and men?
- Space occupying effects more common (headaches, visual field disturbance)
- Erectile dysfuntion, diminished libido, occasionally gynecomastia (men).
What are possible space occupying effects of a prolactinoma/pituitary adenoma?
- CSF rhinorrhea (erosion of sella turcica floor/extension into sphenoid sinus)
- Unilateral defects in CN III (most common), CN IV, opthalmic and maxillary branches of CN V and VI
- Bi-temporal hemianopsia (loss of temporal vision if optic chiasm is compressed)
- Headaches, pituitary insufficiency
What is the first step in diagnosing a prolactinoma?
Check serum prolactin level.
If serum prolactin is elevated, what should you rule out as causes for the increase before performing imaging studies?
- Pregnancy (hcg)
- Hypothyroidism (TSH)
- Renal failure (BUN/creatinine)
- Cirrhosis (LFT)
- Hyperparathyroidism (Ca)
- Hypogonadism (FSH/LH/estradiol)
When should you perform a pituitary MRI? Which patients should always get an MRI?
- Serum prolactin >200 mg/dl
- Headaches/ visual field defects.
- Persistent increased prolactin without other cause.
- Pts with hyperprolactinemia when all other possible causes are ruled out should always get an MRI.
What is the treatment for a prolactinoma?
- Always treat underlying problems FIRST (if TSH is increased fix it first, then move on).
- Treatment of choice is medication (medical): cabergoline and bromocriptine (dopamine agonists)
- Surgical: transsphenoidal surgery
- Radiation therapy: last resort
Why is medication (medical) the treatment of choice for prolactinomas?
- 80% of pts have normal prolactin lvl w/ therapy (least invasive)
- Most tumors decrease in size early, max effect can take 1 year
- Encourage pt to take meds at bedtime to minimize SE of nausea, dizziness, orthostatic HOTN
- No evidence of teratogenicity
When is transsphenoidal surgery utilized?
- Tumors are unresponsive to medical therapy.
- Tumors affect visual fields.
- Tumors exhibit apoplexy (hemorrhage).
- Pt intolerant/refuses medical therapy.
- Pituitary function preserved in 95% of cases w/ microadenoma, increased risk with macroadenoma.
When is radiation used for treating a prolactinoma?
- Macroadenomas that enlarge despite medical therapy.
- **use as last resort due to high risk of panhypopituitarism (10-15%) of pts**
What are the things that increase secretion of growth hormone (GH)?
- GHRH (triggers pathway)
- Sleep (associated with growth hormone peaks)
- Trauma (stress to body)
- Acute Illness (stress to body)
What are the things that decrease secretion of growth hormone?
- Somatostatin (inhibitory peptide)
- Hyperglycemia/ingestion of food
- Increased lvls of IGF-1 (affects feedback loop)
What are the increasing effects of growth hormone?
- Linear growth in children (lengthens long bones BEFORE sex steroid production at puberty closes epiphyses)
- Overgrowth of bones in acral areas (hands, fingers, feet, face)
- Soft tissue growth (tracheal cartilage, synovium)
- Fatty acid release from adipose (antagonizes insulin stimulation of lipolysis)
- Insulin resistance at peripheral tissues (maintains glucose)
- Muscle growth (stimulates amino acid uptake, protein synthesis)
- Increased BMR and lean body mass
- Increased hepatic gluconeogenesis
- Induces Na and H2O retention (swollen hands and feet)
What are the decreasing effects of growth hormone (GH)?
- Decreases glucose uptake at muscle cells.
- Decreases peripheral glucose utilization.
What is the effect of a growth hormone (GH) producing pituitary adenoma on adults and children?
- Adults: acromegaly
- Children: gigantism and tall stature
A growth hormone producing pituitary adenoma is typically what size?
- Macroadenoma (>1 cm in diameter)
- **more space occupying effects**
What are the musculoskeletal signs/symptoms of acromegaly?
- Increased stature
- Protruding mandible (prognathia)
- Big tongue (macroglossia)
- Enlarged forehead (frontal bossing)
- Enlarged spade like hands with widened fingers
- Sweaty palms and large feet
- Osteoarthritis from abnormal joint loading
What are the cardiovascular signs and symptoms of acromegaly?
- Dilated cardiomypathy leading to cardiomegaly and eventually cardiac failure.
- Hypertension (50% of cases).
What are some general signs and symptoms of acromegaly?
- Excessive sweating
- Temporal hemianopsia
What is the "alphabet" for acromegaly symptoms?
- A: arthritis/arthralgias
- B: BP increased
- C: carpal tunnel
- D: diabetes
- E: enlarged organs
- F: field defects in vision
What is the first step in diagnosing acromegaly?
Obtain random IGF-1 level.
Why is measuring growth hormone (GH) not useful in diagnosing acromegaly?
Levels of GH fluctuate therefore its not an accurate picture of a disorder.
What levels of IGF-1 indicate the absence or presence of acromegaly?
- If random IGF level is normal it is NOT acromegaly.
- In the level is abnormal then order fasting IGF and prolactin.
- If IGF-1 level is elevated, give 75g glucose (glucose suppresses GH), if the GH level is elevated (>2 mU/L) after 60 mins, then acromegaly is confirmed.
What is the imaging study of choice for diagnoses of acromegaly? When would this not be performed?
- MRI with contrast (tumor seen in 90% of pts)
- Use CT of hypothalamus and pituitary if MRI is contraindicated
What are some differential diagnoses of elevated GH and IGF-1 levels?
- Recent exercise
- Eating immediately before IGF-1 assay is drawn
- Acute illness, agitation
- Diabetes mellitus
What are some complications that can happen with acromegaly?
- Impaired fasting glucose
- Diabetes Mellitus
- Cardiac enlargement
- Cardiac failure
- Carpal tunnel syndrome
What is the treatment of choice for acromegaly?
Pituitary microsurgery (endoscopic transnasal, transsphenoidal resection)- symptom remission in 70% of pts.
When would medical therapy be used in a pt with acromegaly? What medications are used?
- If pt has persistent acromegaly despite surgery.
- Dopamine agonists: cabergoline, bromocriptine (Parlodel)
- Somatostatin analogue: octreotide and lanreotide
- GH receptor antagonist: pegvisomant (blocks hepatic IGF-1 production, doesn't shrink tumor)
When would sterotactic radiosurgery be used in treatment for acromegaly?
Reserved for pts who fail surgical or medial therapy (last resort).
What condition is caused by ACTH hypersecretion from a benign pituitary adenoma?
Cushing's disease (3x more frequent in women)
What is the etiology of Cushing's disease?
- Excess ACTH from the pituitary gland results in increased cortisol release from the adrenal glands.
- 80-90% are benign micro adenomas <5mm in size.
What is the clinical presentation for a pt with hypercortisolism?
- Central obesity
- Facial plethora
- Thin skin, easy bruising/abdominal striae
- Glucose intolerance/diabetes
- Mentrual irregularity
- Muscle weakness
How is an ACTH producing pituitary tumor diagnosed?
- Night-time salivary cortisol
- 24 hour urinary free cortisol level + plasma ACTH level
What is the treatment for an ACTH producing pituitary tumor (Cushing's disease)?
- Transsphenoidal surgery
- Radiation therapy (esp children)
What hormones may show isolated hormone deficiencies during pituitary failure?
- **when ONE hormone is deficient levels of other pituitary hormones should be obtained**
What hormone deficiencies may be seen with disorders of pituitary failure?
- Isolated hormone deficiencies
- Multiple hormone deficiencies
- Panhypopituitarism (global failure, all hormones down)
What are the major causes of pituitary insufficiency?
- Invasion: pituitary adenoma, hypothalamic/CNS tumor
- Injury: head trauma
- Infarction: postpartum necrosis (Sheehans syndrome) is most common, pituitary apoplexy
- Infection: TB, encephalitis
- Iatrogenic: pituitary surgery or cranial radiation
- Immune: autoimmune hypophysitis
- Empty sella syndrome
What is the pathophysiology of postpartum necrosis (Sheehan's syndrome)?
- Vascularity & size of pituitary increases during pregnancy.
- Massive blood loss and/or hypovolemic shock during delivery.
- Pt presents w/ failure to lactate after delivery and amenorrhea.
- Pt may have s/s of hypothyroidism and/or glucocorticoid insufficiency.
- Symptoms can be acute or delayed.
- Panhypopituitarism may develop over 10-15 years.
What is the pathophysiology of pituitary apoplexy?
- Acute hemorrhage in a preexisting adenoma.
- Pt presents w/ severe headache and visual field deficits.
- Treat with glucocorticoids immediately (acute hypopituitarism).
- Pt requires immediate surgery for decompression of pituitary fossa.
What is the typical order of gradual loss of pituitary hormone secretion and function as a tumor grows?
- LH/FSH (gonadotropins)
What occurs with ACTH deficiency?
- Adrenal glands fail to secrete sufficient cortisol.
- Sudden deficiency: HOTN (may cause cardiovascular collapse)
- Chronic deficiency: weakness, fatigue, weight loss, HOTN
What occurs with TSH deficiency?
- Thyroid gland fails to secrete sufficient amounts of T4 and T3.
- Hypothyroidism: weakness, fatigue, weight change, etc
What occurs with a gonadotropin deficiency?
- Childhood: failure to enter normal puberty
- Girls- delayed breast development, scant pubic & axillary hair, primary amenorrhea
- Boys- phallus and testes remain small, body hair is sparse, failure of epiphyses to close if GH secretion continues
- Adult females: breast atrophy, loss of pubic and axillary hair, secondary amenorrhea, infertility
- Adult males: testicular atrophy, decreased libido, loss of body hair and decreased beard growth, erectile dysfunction, infertility
What occurs with GH deficiency or defect in GH receptors?
- Infants/children: growth retardation, short stature, fasting hypoglycemia
- Adults: increased abdominal adiposity, reduced strength and exercise capacity, decreased lean body mass and increased fat mass, impaired psychosocial well being, increased systolic blood pressure, increased LDL cholesterol, increased cardiac mortality
What occurs with prolactin deficiency?
- Asymptomatic in non-pregnant women/women not breastfeeding.
- Loss of lactation in postpartum period.
What type of results should be seen with hypopituitary labs?
Pituitary and target organ hormones should BOTH be low (i.e. free T4 is low and TSH is not elevated in response).
What is the treatment for hypopituitarism due to a pituitary tumor?
How is ACTH deficiency treated?
- 3.0-7.5 mg prednisone OR 15-30 mg hydrocortisone per day (2/3 in AM, 1/3 in PM)
- Increase dose during stress (acute illness, surgery, trauma).
How is TSH deficiency treated?
Synthroid (levothyroxine) 0.025-0.3 mg daily
How is gonadotropin deficiency treated?
- Estrogen/progesterone (females)
- Testosterone replacement (males)
- If fertility is desired: males receive hCG injections (similar to LH), clomiphene; females receive clomiphene to induce ovulation (increases chance for multiple birth)
How is growth hormone deficiency treated?
- Asymptomatic adults: no treatment
- Symptomatic adults: somatotropin (hGH) injections
- Children: hGH injections
What are the thyroid hormones?
- TSH (thyrotropin)
- Thyroxine (T4)
- Triiodothyronine (T3)
What is the major secretory product of the thyroid?
Which hormone is secreted in small amounts (10%) by the thyroid, and the remainder (90%) is produced in peripheral tissues from another circulating hormone?
- T3 (triiodothyronine)
- **T4 is the circulating hormone that produces it in peripheral tissues**
What thyroid hormone is the physiologically active hormone?
What is the influence of T3 on physiologic functions?
- Increases O2 consumption and metabolic rate.
- Increases heat production.
- Increases plasma levels of free fatty acids.
- Accelerates cellular oxidation of free fatty acids.
- Decreases plasma cholesterol, increases cholesterol excretion into the bile.
- Increases protein synthesis and degradation.
- Enhances gluconeogenesis, increases glucose absorption.
- Up regulates catecholamine receptors.
Less than 1% of total thyroid hormone is free and available to interact with target cells due to over 99% of circulating thyroid hormone being bound to carrier proteins. What are the carrier proteins that bind to thyroid hormones?
- Thyroid/ thyroxine-binding globulin (TBG)- major protein
- Thyroxine binding prealbumin
What are the tests used to evaluate thyroid function?
- Serum thyroid hormone levels
- Thyroid autoimmunity (antibody tests)
- Thyroid ultrasound
- Radioactive iodine uptake (RAIU) and scan
- Thyroid cytology (FNA, then biopsy)
What is the single most useful thyroid function test used?
- Serum thyroid stimulating hormone (TSH).
- Used to detect disorders and monitor treatment of hyper- and hypothyroidism.
What is the significance of low and elevated levels of serum TSH?
- Low: primary hyperthyroidism, exogenous thyroid hormone admin, other conditions/meds
- Elevated: primary hypothyroidism, secondary hyperthyroidism (excess TSH from pituitary), other conditions/meds
What test is an excellent screening test in addition to serum TSH? How and what does it measure?
- Serum free T4
- Its a DIRECT measurement of UNBOUND T4
Is the physiologically active fraction of total T4 (0.025%) affected by variations in protein binding?
What is serum free T4 used to monitor for?
T4 secretion in patients with hyperthyroidism.
What conditions cause increased thyroid protein binding?
- Pregnancy (inc TBG synthesis, dec TBG clearance)
- Estrogen treatment (inc TBG synthesis, dec TBG clearance)
- Acute hepatitis (damaged cells release TBG)
- Hereditary increase in TBG
- Hypothyroidism (dec catabolism of TBG)
What conditions cause decreased thyroid protein binding?
- Nonthyroid illness
- Testosterone treatment (dec TBG synthesis, inc TBG clearance)
- Hereditary decrease in TBG
- Hyperthyroidism (inc catabolism of TBG)
What are the tests used to detect thyroid autoimmunity?
- Anti-thyroid peroxidase antibodies: elevated early and persist indef in Hashimoto's thyroiditis
- Anti-thyroglobulin antibodies: elevated early then disappear in Hashimoto's thyroiditis, elevated in Grave's disease
- Serum thyroglobulin: elevated in autoimmune thyroid disease, inflammation or thyroid injury (mainly used as marker in pts with thyroid cancer, inc lvls may indicate cancer recurrence)
- Thyroid-stimulating immunoglobulin (Ig): activates TSH receptors (results in hyperthyroidism)
Overproduction of thyroid hormones by the thyroid gland.
Excess thyroid hormone from any cause acting on peripheral tissues.
What is radioactive iodine uptake (RAIU) and scan most helpful for?
Narrowing the differential diagnosis in patients with symptoms of hyperthyroidism.
What test is used to measure focal or diffuse changes in thyroid cell function/activity?
RAIU and scan
How is the RAIU and scan performed?
- Tracer dose of radioactive iodine is given to pt orally.
- Radioactive iodine is concentrated in the thyroid gland the same as plain iodine.
- Amount of tracer iodine is measure 6-24 hrs after admin.
- Normal is 10-30% per day, any more than that is hyperthyroidism.
What conditions does high radioactive iodine uptake during the RAIU and scan indicate?
- Graves disease (most common)
- Toxic multinodular goiter
- Toxic nodule
- Dietary iodine deficiency
What conditions does low radioactive iodine uptake during the RAIU and scan indicate?
- Subacute thyroiditis
- Thyroid gland damage (thyroiditis, RAI therapy, surgery)
- Anti-thyroid drugs
- Excess exogenous thyroid hormone
- Iodide containing medications
When should a RAIU and scan be performed?
- For pts with symptoms and signs of thyrotoxicosis.
- Determine quantity of radioiodine treatment for hyperthyroidism.
- Evaluation of suspicious thyroid nodule (not used as frequently).
- Localize/exclude metastatic thyroid cancer (whole body scan).
- Identify if a neck mass outside the normal thyroid location represents aberrantly located thyroid tissue.
What are the signs and symptoms of hyperthyroidism (thyrotoxicosis)?
- sweating, warm moist skin
- weight loss/gain
- heat intolerance
- resting tremor
- rapid relaxation of deep tendon reflexes
- menstrual irregularity
- atrial fibrillation
- lid lag and stare
- goiter (Grave's disease)
- ophthalmopathy (Graves & amiodarone induced)
- pretibial myxedema
- frequent bowel movements (inc BMR, greasy stools)
- osteoporosis (late)
What are clinical etiologies of excess amounts of T4 and T3 (thyrotoxicosis)?
- Graves disease
- Acute suppurative thyroiditis (infection/pus)
- Subacute thyroiditis (insidious)
- Hashimoto's thyroiditis
- Postpartum thyroiditis
- Pituitary tumor secreting excess TSH
What is the most common cause of thyrotoxicosis?
What kind of a disorder is Grave's disease?
What is the pathophysiology of Graves disease?
- Autoantibodies bind to TSH receptors causing thyroid gland hyperfunction.
- Increased thyroid cell growth occurs.
- Diffuse overactivity of the thyroid gland (despite low TSH) results in increased release of thyroid hormones.
What are the findings on physical exam for a pt with Grave's disease?
- Smooth diffuse goiter (almost all pts)
- Possible bruit in goiter
- Thymus gland hyperplastic and enlarged
- Less common pretibial myxedema (infiltrative dermopathy)
- Grave's ophthalmopathy (exophthalmos)- unilater or bilateral (inflamed eye muscles from lymphocyte infiltration)
What are the lab findings for a pt with Graves disease?
- TSH suppressed
- FT4 and T3 elevated
- TSH receptor antibodies (80% of pts)
- Possible increased anti-thyroglobulin and anti-thyroperoxidase antibodies.
What is the RAIU and scan result in Graves disease?
Iodine is taken up diffusely throughout enlarged gland (increased uptake).
What are the treatments for hyperthyroidism (thyrotoxicosis)?
- Inderal (propanolol)/ nadolol: the only 2 beta blockers that inhibit peripheral conversion of T4 to T3, relieves tachycardia, sweating tremor, nervousness, no effect on thyroid hormone secretion, once pt at euthyroid state med dose is tapered
- Tapazole (methimazole), propylthiouracil (PTU): antithyroid drugs, inhibit hormone synthesis, treatment for several months, treatment of choice for pregnant females is PTU (tapazole is teratogenic)
- Oragrafin, Telepque: iodinated contrast agents provide temporary therapy for patients with severe symptoms, used before surgery to decrease vascularity of thyroid gland, inhibits conversion of T4 to T3 in peripheral tissues
- Radioactive iodine ablation of thyroid gland: treament of choice for Graves disease in adults unless pt is pregnant or plans to get pregnant, thyroid tissue takes up RAI and is destroyed (high risk of hypothyroidism), no risk of subsequent thyroid cancer, pt radioactive for days-should limit contact with others, no breastfeeding
- Surgery (subtotal thyroidectomy): not common since advent of RAI therapy, for pts w/ very large gland and obstructive symptoms, pregnant women not controlled w/ low doses of antithyroid drugs are candidates, performed if there is significant chance of malignancy
What are the side effects of anti-thyroid drugs (tapazole, propylthiouracil)?
- Rash (exfoliative dermatitis)
- Agranulocytosis (order CBC if fever, sore throat, oral ulcers, signs of infection present)
What are possible complications from a subtotal thyroidectomy (surgery)?
- Damage to recurrent laryngeal nerve
- Damage to parathyroid glands
- Hypothyroidism or continued hyperthyroidism
What diagnosis should be considered in elderly patients who develop a new mood disorder?
Apathetic hyperthyroidism (pts may present with angina pectoris).
What are the signs and symptoms of apathetic hyperthyroidism?
- Weight loss
A rare form of thyroiditis caused by bacteria. In immunocompromised patients it can be fungal, mycobacterial, or parasitic infection of the thyroid gland.
Acute suppurative thyroiditis (generally hyperthyroid)
What is the most common causative bacteria for acute suppurative thyroiditis?
Who are most at risk for developing acute suppurative thyroiditis?
- Immuncompromised individuals
- Those with preexisting thyroid disease
What are the signs and symptoms of acute suppurative thyroiditis?
- High fever and dysphagia
- Severe focal thyroid pain w/ fluctuation and overlying erythema
What lab tests are performed while treating acute suppurative thyroiditis? How is it treated?
- CBC: increased WBC count w/ left shift
- ESR: elevated
- Blood cultures and/or needle aspiration: determine causative organism via gram stain
- IV antibiotic therapy recommended
Is common, typically occurring in young and middle aged women, and is usually associated with a viral respiratory infection. 90% of cases resolve within 3-8 weeks.
Subacute thyroiditis (AKA de Quervain's thyroiditis, "viral" thyroiditis)
What condition is the most common cause of thyroid pain (exquisite pain)?
How does a pt with subacute thyroiditis present in physical exam?
With moderately enlarged, painful thyroid and hyperthyroidism, malaise, low-grade fever, and pharyngitis.
What are the typical lab findings for a pt with subacute thyroiditis?
- WBC count elevated w/ left shift
- ESR elevated
- C reactive protein may be elevated
How is subacute thyroiditis treated?
- NSAIDS or ASA for pain and inflammation (prednisone if NSAIDS ineffective)
- Beta blockers during hyperthyroid phase (Inderol-propanolol)
- Iodinated contrast agents (Oragrafin, Telepaque) for rapid improvement of thyrotoxic symptoms
- Synthroid (levothyroxine) during hypothyroid state which is usually transient
The most common autoimmune thyroid disorder in the U.S.
- Chronic lymphocytic thyroiditis (aka Hashimoto's thyroiditis)
- **more common in pts with other autoimmune disorders like diabetes, addison's, vitiligo**
What is the pathophysiology of chronic lymphocytic thyroiditis (Hashimoto's thyroiditis)?
- Transient hyperthyroidism may occur during initial destructive phase.
- Often hypothyroidism occurs (more common in smokers), few pts do recover thyroid function.
How does a pt with chronic lymphocytic thyroiditis (Hashimoto's) present in physical exam?
- Thyroid gland is non-tender
- Diffusely enlarged
- Finely nodular
- Can be only one lobe that is enlarged.
What is the hallmark laboratory finding in a patient with chronic lymphocytic thyroiditis (Hashimoto's thyroiditis)?
Circulating levels of thyroid antibodies (anti-thyroid peroxidase and anti-thyroglobulin), usually present in 90-95% of cases.
When is treatment for chronic lymphocytic thyroiditis indicated (Hashimoto's thyroiditis)? What medication is used?
- If there is goiter or clinical hypothyroidism.
- Synthroid (levothyroxine)
Also known as "silent" or "painless" thyroiditis, and is considered a subcategory of chronic lymphocytic thyroiditis.
What percentage of postpartum women develop hyperthyroidism and within what time frame? When does hypothyroidism tend to develop?
- Approximately 5-7%
- Hyperthyroidism within 6 months after delivery.
- Hypothyroidism 4-8 months after delivery.
How long do symptoms of postpartum thyroiditis last and how do they tend to resolve?
- Symptoms usually self-limited and mild, lasting up to one year.
- Most (80%) pts have normal thyroid function at 12 months, but 30-50% eventually develop permanent hypothyroidism several years later.
How does the thyroid in a pt with postpartum thyroiditis present?
- Goiter may be present
How is postpartum thyroiditis treated?
By symptoms as required.
A slowly enlarging stony hard mass within the thyroid gland, sometimes adherent to neck structures. Rarest form of thyroiditis, usually occurring in middle aged/elderly females.
What is the cause of Riedel's thyroiditis?
Fibrous infiltration of the thyroid gland (unknown etiology).
What causes hypothyroidism to occur with Riedel's thyroiditis?
Due to replacement of normal thyroid tissue with scar tissue.
What are the signs and symptoms of Riedel's thyroiditis?
How is a definitive diagnosis of Riedel's thyroiditis made?
Open biopsy (FNA doesn't usually yield sufficient tissue for dx).
What is the treatment for Riedel's thyroiditis?
- Surgery to relieve tracheal and esophageal compression.
- Nolvadex (tamoxifen)- may induce partial/complete remission in 3-6 months but med is taken for years
Enlargement of the thyroid gland caused by increased stimulation of the thyroid gland by TSH or by thyroid-stimulating immunoglobulins.
What are the two types of goiter?
- Diffuse simple (nontoxic) goiter
- Benign multinodular goiter
What kind of thyroid function can a patient with a goiter have?
What is the treatment for goiter with patients that have a normal or elevated TSH level?
- Suppression of thyroid gland with Synthroid (levothyroxine).
- **multiple nodule develop autonomous function and secrete excess T3 and T4**
In which patients do toxic multinodular goiter usually develop?
- Pts >50 yrs old
- Pts w/ hx of benign multinoldular goiter and have had normal thyroid function tests in the past
What are the diagnostic test findings for toxic multinodular goiter?
- Labs: FT4 and T3 elevated, TSH suppressed
- US: measure size, see if multi-nodular
- RAIU and scan: diffuse patchy uptake (multiple functioning nodules)
What is the treatment for toxic multinodular toxic goiter?
- Inderal (propanolol) for symptoms
- Anti-thyroid drugs (reverses hyperthyroidism, symptoms recur after meds discontinued)
- RAI ablation of thyroid (definitive tx, usually in lieu of surgery for elderly)
- Surgery (subtotal thyroidectomy) for pressure symptoms and cosmetic indications
What does a single thyroid nodule indicate?
- Benign adenoma (most common, 90-95%)
- Malignancy (primary/metastatic, 5-10% trick is to find these!)
What do multiple thyroid nodules indicate?
- Multinoldular goiter
- Iodine deficiency
- Graves disease
- Hashimotos thyroiditis
- Subacute thyroiditis
When are non-palpable nodules found?
Approx 50% of MRI, CT, or ultrasound scans of the neck performed for other reasons.
What are the signs and symptoms of a benign thyroid nodule?
Hypo/hyperthyroidism commonly occur.
What is the presentation of a benign thyroid nodule?
- No associated cervical lymphadenopathy
Who normally gets benign thyroid nodules?
Older females (may occur at any age either sex too).
Who normally gets malignant thyroid nodules?
- Young adults (esp males)
- Usually personal hx of another malignancy (thyroid or head/neck irradiation)
- Fam hx of medullary thyroid cancer increases risk
What are the signs and symptoms of a malignant thyroid nodule?
- Dysphagia, dysphonia, dyspnea
- Cervical lymphadenopathy common
- Usually single nodule present
What is the presentation of a malignant thyroid nodule?
- Firm or hard
- May be fixed or adherent to underlying muscles/trachea
- Tend to be larger than benign (>1 cm)
How are thyroid nodules evaluated?
- Assessing thyroid function (TSH, FT4)
- Thyroid ultrasound (cystic/solid, size, presence of non-palpable nodules, easy and low cost-preferred over MRI/CT, surveillance in pts w/ thyroid malignancy, guides FNA biopsy)
- FNA-fine needle aspiration (biopsy), is the preferred procedure for assessing a nodule (in conjunction w/ TSH and FT4 assays)
- Thyroid scan (RAI) 30% of "cold" nodules are malignant (hypo function), <10% of "hot" nodules are malignant (hyper function)
What is the treatment for benign thyroid nodules?
- Regular exams with ultrasound
- Request FNA biopsy if nodule increases in size
- Rx Synthroid if serum TSH is elevated or pt is hypothyroid
Which thyroid cancer is most frequent, the least aggressive, and absorbs iodine?
Which thyroid cancer is the 2nd most frequent, metastases to the neck nodes, bone, lung and absorbs iodine?
Which thyroid cancer is the 3rd most frequent, originates from parafollicular cells (increased calcitonin), and does NOT absorb iodine?
Which thyroid cancer is the 4th most frequent, most aggressive, presents in older pts as rapidly growing mass, has a poor prognosis (most pts survive <12 months), and does NOT absorb iodine?
What are the signs and symptoms of thyroid cancer?
- Palpable, firm, non-tender nodule
- Hyperthyroidism symptoms may be present
- Nodule is occasionally fixed to adjacent structures
- Recurrent laryngeal nerve palsy may be observed
What are the lab findings associated with thyroid cancer?
- Normal thyroid function tests (except in thyroiditis/hyperthyroidism)
- Serum thyroglobulin elevated (papillary, follicular)
- Serum calcitonin elevated (medullary)
- CEA may be elevated in any thyroid cancer
What is the treatment of choice for all thyroid cancers?
- Anaplastic (resection w/ radiation)
- Medullary (surgery only)
- Papillary, follicular (surgery followed by RAI)
How is post surgical RAI for papillary and follicular cancers helpful?
Destroys remaining thyroid tissue once hypothyroidism is achieved.
How is use of thyroid hormone replacement (Synthroid) used as treatment for thyroid cancer?
- Dose may be calculated to suppress TSH on purpose.
- Part of post surgical treatment course.
- Synthroid is used to inhibit tumor growth by providing negative feedback on pituitary TSH secretion.
What is the hallmark of myxedema from hypothyroidism?
What is the most common cause of primary hypothyroidism? What can cause it?
- Hashimoto's thyroiditis
- Can be cause by Amiodarone because of high iodine content which can cause clinically significant hypothyroidism.
What are the lab findings for primary hypothyroidism?
- TSH elevated
- FT4 low or normal
- Elevated serum cholesterol and/or elevated prolacting level may be seen
- RAIU usually low
What are the signs and symptoms of hypothyroidism?
- dry skin and hair
- weight gain
- cold intolerance
- excessive sleep
- menstrual disturbances
- anemia (25-50% of pts)
- pericardial effusion
- delayed DTRs
- carpal tunnel syndrome
- goiter (hashimotos thyroiditis, finely nodular)
- hair thinning
- absence of sweating
- thin, brittle nails
- myalgias, arthralgias
What are the lab findings in a pt with subclinical hypothyroidism?
- Slightly elevated serum TSH (5-10 microU/ml)
- Normal FT4 level
How is subclinical hypothyroidism treated?
- Synthroid (levothyroxine) at very low doses.
- Or no treatment initially + periodic evaluations of serum TSH, treat if pt becomes symptomatic.
What are some complications that can occur with subclinical hypothyroidism?
- Mostly cardiac
- Increased risk of infection
- Organic psychoses w/ paranoid delusions
- Myxedema coma
What is the treatment of choice for hypothyroidism?
synthroid (levothyroxine)- T4 replacement
How does Synthroid treat hypothyroidism? What is the average starting dose?
- Its partially converted to T3 in the body
- Near normal T4 lvls seen 3-4 wks after initiating therapy
- Average starting dose is 25-75 mcg/day
How is synthroid dose monitored? When should it be checked after starting or changing dosage?
- With TSH level
- 6-8 weeks after starting/changing dose to check TSH (TSH should be between 0.4-2.0 mU/L)
- **don't over treat, too much thyroid hormone may cause atrial fibrillation & osteoporosis**
Which patients should you use caution with when treating with synthroid for hypothyroidism?
- Pts over 60 yrs
- Pts with ischemic heart disease
- Start dose a 25 mcg daily, increase every 1-3 weeks until pt is euthyroid
What does congenital hypothyroidism cause?
What is the etiology of cretinism?
- Aplasia/hypoplasia of the thyroid gland or failure of thyroid gland to migrate to its normal anatomical location.
- Newborns may appear normal at birth and develop normally for first 2-4 months.
What will happen if a baby is not treated for congenital hypothyroidism?
Mental retardation and growth failure.
What are the signs and symptoms of congenital hypothyroidism (cretinism)?
- Puffy ands and face
- Thickened tongue, poor muscle tone
- Deaf-mutism may occur
Why is early detection of congenital hypothyroidism (cretinism) so important that the FDA mandates newborn screening TSH levels?
Because deficits in intellectual development are not reversible.
What is the usual etiology for childhood (acquired) hypothyroidism?
What are the signs and symptoms of childhood (acquired) hypothyroidism?
- Slowed mentation
- Retarded bone development, decreased longitudinal growth
- Tick, dry, scaly skin with yellowish tinge, myxedema of the face
- Delayed sexual maturation
How is childhood (acquired) hypothyroidism treated?
Synthroid therapy reverses many of the clinical abnormalities, however full adult height may not be obtained due to delayed skeletal development.
What is secondary hypothyroidism?
TSH insufficiency (pituitary problem)
What are the causes for secondary hypothyroidism?
- pituitary tumor
- pituitary hemorrhage
- pituitary infarction
What serum levels will be seen with secondary hypothyroidism?
- Serum TSH is low/low normal
- T4 at lower limite of normal
- TRH elevated (increases prolactin as well)
What is a rare but severe and life threatening condition more common in older women who have had stroke or stopped taking medication, and it pts with history of hypothyroidism (poorly controlled)?
- Myxedema coma (crisis)
- 50% of pts experience this after being hospitalized for another illness.
What are precipitating factors for myxedema coma?
- Exposure to cold
- CNS depression
What is the clinical presentation for a pt with myxedema coma?
- Deep stupor/extreme weakness with altered mental status
- Severe hypothermia
- Hypoventilation w/ associated hypoxia and hypercapnia
How is myxedema coma (crisis) diagnosed? What labs would you run?
- Clinical diagnosis, urgent treatment required as there is a high mortality rate.
- Lab evaluation includes free T4, TSH, electrolytes, glucose, CBC, ABG and cortisol lvl to r/o concurrent adrenal insufficiency.
How is myxedema coma managed?
- Intubation, mechanical ventilation for hypercapnia/hypoxia
- Treat hypothermia (blankets only)
- Volume expansion via IV fluids (hypertonic saline for hyponatremia)
- Synthroid in large doses IV (400 mcg then 50-100 IV mcg/day)
- If adrenal insufficiency suspected, give corticosteroid IV until serum cortisol assay result is available
What is an extreme form of hyperthyroidism/thyrotoxicosis, is rare but when seen is most often in pts with Graves disease, and has a high mortality rate?
What are precipitating factors for thyroid storm?
- stressful illness
- thyroid surgery
- radioactive iodine administration
- discontinuing anti-thyroid drugs
What are the signs and symptoms of thyroid storm?
- marked delirium
- severe tachycardia or atrial fibrillation
- very high fever (hyperpyrexia out of proportion to other clinical findings is the hallmark, >103)
- sweating, tremors, restlessness
How is thyroid storm treated?
- Admit to ICU!
- Anti-thyroid drugs, potassium iodide, Inderal (propanolol), hydrocortisone
- Definitive treatment is I ablation or surgery