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67 Cards in this Set

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Lab test results of hypothyroidism?
Tyroid stimulating hormone (TSH) ↑

Total serum tyroxine (free+ bound) (TT4) ↓

Free thyroxine index (FT4I) ↓

Free T4 concentration ↓

Radioactive I123 uptade by the thyroid gland (RAIU) ↓
Lab test results of hyperthyroidism?
Tyroid stimulating hormone (TSH) ↓

Total serum tyroxine (free+ bound) (TT4) ↑

Free thyroxine index (FT4I) ↑

Free T4 concentration ↑

Radioactive I123 uptade by the thyroid gland (RAIU) ↑
What is the single most sensitive test of thyroid hormone status?
Signs and symptoms of hypothyroidism?
1. ↓HR, SV, CO, PP, BP; ↑TPR, low output HF
2. ↓ DTRs, stiffness and muscle fatigue
3. pale, cool, puffy skin, hypohydrosis
4. puffy face, large tongue, drooping eyelids, periorbital edema
5. ↓appetite, weight fain, constipation, lethargic
6. water retention, hyponatremia, pleural/peritoneal/pericardial effusions
7. ↓erythropoiesis, anemia
8. hyperprolactinemia, amenorrhea, galactorrhea, menorrhagia
9. ↓ metabolic rate, ↑ cholesterol/TGs
10. ↓ drug metabolism
Signs and symptoms of hyperthyroidism?
1. ↑HR, SV, CO, PP; ↓TPR, angina, high-outpt HF, atrial fibrillation
2. ↑DTRs, weakness and muscle fatigue
3. warm, moist skin, heat intolerance, pretibial dermopathy, hyperhydrosis
4. lid lag, diplopia, exopthalmos (proptosis)
5. ↑appetite, diarrhea, weight loss
6. nervous, emotionally labile
7. mild polyuria, pedal edema
8. ↑ erythropoiesis, anemia
9. amenorrhea
10. ↑ metabolic rate, ↓cholesterol/TG’s
11. ↑drug metabolism
Myxedema in hypothyroidism vs. hyperthyroidism
Myxedema: not fluid, actually mucopolysaccharides

-- puffy features in face
-- large tongue
-- drooping eyelids
-- periorbital edema

-- pretibial myxedema (skin below knees resembles orange peel)
CASE 1: What is the diagnosis?

35 y.o. man comes to clinic w/ non-specific complaints of
-- fatigue, constipation, and weight gain, cold, no matter what the temperature, and sweats little, even in hot weather

PE reveals
-- pale, slightly obese
-- cool, dry skin
-- slight puffiness of face
-- resting heart rate is 54bpm
-- blood pressure is 94/60
-- ↓ DTRs
-- cracks and chips in finger nails
-- large, firm, nontender thyroid

Labs reveal
-- plasma TSH is 10x normal
-- free T4 index is decreased to 20% of normal average
The patient has HYPOthyroidism (Hashimoto’s thyroiditis)

Plasma TSH is ↑ b/c there is not enough T4 circling, thus no negative feedback on the hypothalamus/pituitary
How do we treat hypothyroidism?
Why do we use L-thyroxine (T4) instead of a T3 (active ingredient) medication?
T4 has half life of 7 days
-- can be changed to active T3 in periphery
-- one drug delivers both hormones

T3 has half life of 1.5 days
L-thyroxine generics?
Synthetic, genetic preparations are as effective, stable, uniform, and cheaper than the proprietary products
Therapeutic endpoints of thyroxine?
1. Dose of thyroxine is increased every two weeks until the TSH is in the normal range.
-- measurement of the free thyroxine index may also be helpful in monitoring the efficacy of therapy

2. Some reversal of the signs/symptoms of hypothyroidism will occur w/in 2-3wks w/ full resolution in 4-6wks

3. Normal erythropoiesis and skin and nail growth may take longer

4. Change the dose slowly if TSH is not in the normal range
Who do we take special care with when treating w/ thyroxine?
Throxine can increase syth of B-receptors in heart

Special care should be taken in pts w/ CV risk factors
-- L-thyroxine should be given w/ care to pts w/ known or suspected CAD or myocardial dysfxn since excessive doses can precipitate MI or dysrhythmias (Afib)
-- begin w/ smaller doses in older pts
Toxicity of thyroxine?
-- tachycardia
-- wt loss
-- heat intolerance
-- nervousness

-- insomnia
-- accelerated bone growth
-- restlessness

MEASURE TSH: this value will indicate if these symptoms are due to overtreatment w/ T4
Case continued:

Two years after beginning successful thyroxine replacement therapy, pt is brought to the ER
-- obtunded, confused, hypothermic, and hypotensive
-- skin has yellow pallor, eyebrows are missing
-- face, especially the area around the eyes, is puffy
-- tongue and lips enlarged
-- speaks in hoarse whisper
-- slow respiration
-- hypercapnia, hypoglycemia, and hyponatremia
-- DTRs are almost completely absent

What is the diagnosis?

End-stage of prolonged hypothyroidism
-- medical emergency
-- early recognition and treatment is critical
How do we treat myxedematous coma?
1. Intubate and ventilate to reverse hypoxia and hypercapnia

2. Glucose for hypoglycemia

3. Use i.v. fluids w/ care b/c he is only hyponatremic

4. A LARGE “loading” dose of thyroxine is given i.v.
-- the TGB binding sites are empty and must be saturated before free T4 will circulate

All drugs myst be given i.v. due to poor GI absorption
Increased body temp and improved mental fxn indicate adequate therapy
Which drugs can cause hypothyroidism?


How do corticosteroids cause hypothyroidism?
1. inhibit release of TRH and TSH

2. prevent peripheral conversion of T4 to T3
How does lithium cause hypothyroidism?
1. inhibits secretion of T4 and T3 from thyroid gland

2. TT4 falls 25-35%

3. usually occurs in pts w/ previous decrease in thyroid fxn (Hashimoto’s)
How does amiodarone cause hypothyroidism?
1. may cause HYPOthyroidism by inhibiting the peripheral conversion of T4 to T3
-- can be managed by treating w/ thyroxine p.o.

2. may cause HYPERthyroidism b/c it contains 37% iodine by wt, which serves as substrate for thyroid peroxidase
-- synth of T4 and T3 is increased
CASE2 -- Diagnosis??

22 year old woman having trouble sleeping b/c her heart seems to be “racing,” even when she is lying still in bed. She is worried what she has cardiac abnormality
-- “funny-looking skin” just below her knees
-- lost weight and sweats profusely at times
-- Appears anxious and has fine tremor in her fingers
-- PE reveals a resting heart rate of 125bpm, BP of 140/70 and increased DTRs
-- skin below the knees resembles orange peel (raised, thickened, hyperpigmented
-- ask her to look down, and eyelids descend slowly
-- thyroid gland is diffusely enlarged

Plasma TSH is below limits of detection
Free T4 index is 4 times normal
Subsequent tests reveal increased RAIU
The patient has Grave’s disease, caused by an autoantibody which constantly stimulates thyroid TSH receptors
-- trophic effect of IgG causes thyroid to enlarge (goiter) and produce more T4 and T3
-- plasma T3 conc may be more than T4 concentration

**Lid lag is due to increased sympathetics; the muscles that control her lid are ½ skeletal and ½ smooth
-- the smooth muscle is controlled by the sympathetics and the reason for lid retraction

**Funny-looking skin below her knees is from pretibial dermopathy, a myxedema
What are the methods we use to treat hyperthyroidism (Grave’s disease)?
1. modify the tissue response to excessive thyroid hormone

2. prevent the synthesis/release of T4 and T3

3. Prevent conversion of T4 to T3

4. Destruction of the thyroid gland w/ radiation or surgery
What medication can we use to control the symptoms of hyperthyroidism?

Controls autonomic symptoms
-- tachycardia
-- palpitations
-- fatigue
-- weight loss
-- diaphoresis
-- heat intolerance
-- tremor and anxiety

DOES NOT alter the underlying excessive production of T4
What else is special about prolanolol?
It also blocks the peripheral conversion of T4 to T3 by blocking the 5-diodinase
****(no other beta blocker does this, thus this is the DOC)
Propanolol dosing?
Metabolism is very rapid in hyperthyroidism, so LARGE doses may be required initially
What if beta blockers are contraindicated?
DILTIAZEM can be used to control cardiac symptoms but will have no effect on the formation of T3
What are the MAIN drugs in treating hyperthyroidism?

PTU/methimazole MOA?
1. Prevents iodide organification by inhibiting the enzyme THYROID PEROXIDASE which converts iodide (I-) to iodine (Io)

2. Blocks coupling of MIT and DIT which are req’d for formation of T3 and T4

**Both cause decreases synthesis but NOT release of T4 and T3. Thus, their onset of action is slow

3. PTU also blocks the peripheral conversion of T4 to T3 (methimazole does not)
Therapeutic effects of PTU/methimazole?
1. depletion of T4 stores takes 3-4 wks, so rate of onset is slow

2. No “escape” phenomenon occurs

3. After the production of a euthyroid state w/ this drug, 20-40% of pts go into remission w/in 1 month – 2yrs. However, eventual relapse rate is 60-80%

4. If cessation of therapy results in reappearance of hyperthyroidism, patients are treated w/ reactive iodine (131I)
PTU/methimazole toxicity?
1. reversible agranulocytosis in <1% of pts

2. PTU has antivitamin K activity and potentiates the effects of warfarin

3. skin rash w/ itching – treat w/ histamine

4. Use PTU instead of methimazle in pregnant women
-- PTU highly bound to plasma proteins and less likely to cross the placenta as compared to methimazole
-- use minimally effective doses and shortest treatment periods possible
-- about 10% of neonates will have goiter if exposed to PTU in utero
What is the first-line treatment for hyperthyroidism?
Propanolol + PTU
How do we use radioactive iodine?
It is rapidly absorbed after p.o. dosing and concentrated in the thyroid
-- monitor uptake externally w/ a gamma radiation spectrometer
-- would like 40-60% uptake for good therapeutic effect

Beta rays painlessly kill thyroid parenchyma

Stop therapy w/ PTU or iodide about one wk prior to therapy so gland will exhibit good uptake

Patients requiring multiple treatments usually become HYPOthyroid and require life-long therapy w/ daily doses of thyroxine
What should we be cautious about when treating with radioactive iodine?
Thyroid storm – lysis of follicular cells may cause release of enough T4 to cause thyroid storm

Give pt iodide to take p.o. in case this happens
Iodide (Lugol’s solution)?
Use large doses of potassium iodide (KI) to:
1. immediately inhibit the release of T3 and T4 by preventing the proteolysis of thyroglobulin
2. cause a transient inhibition of the organification of iodide by preventing iodide trapping (Wolff-Chaikoff effect)

Iodinated radiocontrast compounds Iopanoic acid and ipodate also inhibit the release of T4 and inhibit the conversion of T4 to T3

Iodide decreases the size and vascularity of the thyroid gland over 2-7 days

Iodide is NOT used in the routine treatment of hyperthyroid and is rarely used as a single agent
Therapeutic uses of Iodide?
1. preparation of thyrotoxic patients for emergency surgery unrelated to the thyroid gland

2. preparationi of thyrotoxic patients for subtotal thyroidectomy

3. thyroid storm from hyperthyroidism

4. thyroid storm induced by treatment w/ 131I
Drawbacks of therapy with iodide?
1. large doses of iodide delay the action of PTU

2. large doses of iodide prevent the use of 131I for several weeks
CASE 2 continued:

The 22 y.o. woman is treated w/ PTU for 12 wks, but her hyperthyroidism proves refractory to medical therapy despite a doubling of the dose of PTU at 6wks. Two treatments w/ 131I reverses her hyperthyroidism, but she eventually became hypothyroid. Oral therapy w/ thyroxine is begun, and the daily dose is adjusted until the serum TSH conc is w/in normal range. Without your knowledge she begins to take an oral contraceptive (estrogen + progestin) prescribed by another physician. After a month she begins to develop signs and symptoms of hypothyroidism despite good drug compliance.

Lab teste reveal that the total T4 is at the high end of the normal range. FT4I is decreased below normal, and TSh is elevated.

What happened and what should you do about it?
Estrogens stimulate the hepatic synthesis of thyroxine binding globulin (TBG), transcortin, transferrin, renin substrate, fibrinogen, and sex hormone-binding globulin

Incresed TBG concentration causes:
1. total T4 to be at the high end of normal range b/c more binding sites for T4 are available since TBG concentration is increased
2. the FT4I to be decreased b/c previously free T4 has now become bound to TBG
3. decreased free thyroxine thus signs and symptoms of hypothyroidism
4. the TSH to be increased b/c less free T4 is avb to inhibit the hypothalamus and anterior pituitary
How else can the same situation occur?
1. pregnant woman who is on replacement therapy w/ thyroxine after being treated w/ 131I for Graves disease

2. a pregnant woman w/ Hashimoto’s disease who is on replacement therapy w/ thyroxine
Treatment w/ estrogen will not cause hypothyroidis in a patient w/ a normal thyroid gland because…?
-- decreased free T4 disinhibits hypothalamus and pituitary resulting in increased TSH

-- increased TSH stimulates thyroid to produce more T4 until free T4 concentration is restored to normal

-- Net effect would be increased TT4 and normal FT4I and TSH

A 69y.o. man is dx w/ hyperthyroidism (Graves’ disease), and treated w/ PTU is started. Pt lost to follow-up. Fourteen months later he appears in the ER b/c of
-- high fever
-- severe muscular weakness
-- SOB
-- thin, dyspneic, and fatigued after short walk to exam room
-- vomits frequently after eating and cannot sleep
-- snaps when you ask a question and complains
-- under severe stress

PE reveals fever, tremor, tachynea, hyperreflexia, and Afib

What is the diagnosis?
Thyroid storm
-- occurs in 2-6% of hyperthyroid pts
-- can be precipitated by infection, stress, subtherapeutic treatment w/ antithyroid drugs prior to thyroidectomy, treatment w/ I131 or iodine, surgery , abrupt cessation of therapy w/ PTU or methimazole, pregnancy and diabetic ketoacidosis

In most cases, does NOT appear to result from excessive circulating concentrations of T4 and T3 in many cases; rather, precipitated by stress

Thyroxine causes marked up-regulation of beta-adrenoceptors, and hyperthyroid patients exhibit exaggerated physiological responses to catecholamines
How do you treat thyroid storm?
1. PROPANOLOL is the single most important drug in the treatment of thyroid storm and usually causes the disappearance of symptoms w/in several hours

2. Supportive care
-- cooling
-- hydration/electrolytes
-- CV status
-- corticosteroids

3. Treatment w/ iodine
-- to block the release of T4 and T3
OR treatment w/ PTU
-- to block peripheral conversion of T4 to T3 and prevent organification of iodine

A 21y.o. man who is a farmer comes to see you b/c he has recently developed
-- extreme thirst, polydipsia, polyuria
-- excreting 10-12L of clear urine/day and has to get out of bed 3-4 times a night to urinate
-- heavy exercise in hot weather causes him to feel faint and produces even greater thirsl

PE reveals
-- healthy young male w/ normal neuro tests and BP
-- Serum Na concentration and osmolalaity are at a high end of the normal range
-- serum glucose conc is 108mg.dL (not hyperglycemic)
-- urinalysis is NEG for glucose and yields osmolality of 178mOsm
-- treatment w/ desmopressin by nasal spray increases urinary osmolality to 226mOsm after one hour.
-- Radio exam of pituitary is negative

What is the Dx?
Central (neurogenic) diabetes insipidus (DI)

Characterized by the lack of release of sufficient ADH from the posterior pituitary
-- may be idiopathic of caysed by trauma, malignancy, granulomas, sarcoidosis and infections

Dissection of the pituitary stalk by head trauma causes a transient DI
-- DI disappears b/c AVP is actually synthesized in the hypothalamus and eventually normal osmotic stimuli elicits the release of AVP from the hypothalamus

Normal physiological stimuli to ADH release (↑serum osmolality, volume depletion and hypotension) either do not cause the release of ADH or cause only a small increase in plasma ADH concentration
What are the subtypes of vasopressin receptors?
V1 receptors

V2 receptors
What do V1 receptors do?
Increase TPR via contraction of vascular smooth muscle
What to V2 receptors do?
1. Increase renal water reabsorption in the late distal tubule and collecting duct
-- AVP stimulates AVP receptors on the basolateral mbrn
-- activation of adenyl cyclase activates CAMP-dependent protein kinase which increases the expression of water channels in the apical mbrn
-- hyperosmolar gradient in the interstitial fluid causes the tubular water to move into the interstitium
-- the reabsorption of water from the tubule concentrates the urine
-- lithium and PGE inhibit the vasopressin-dependent adenyl cyclase

2. Stimulation increases the release of coag factor VIII from hepatocytes and vonWillebrand’s factor from vascular endothelial cells

3. Decreased TPR via relaxation of vascular smooth muscle

Only small increments in plasma AVP concentration are required to increase urinary concentration whereas very large increments are required to increase blood pressure
How do we treat central diabetes insipidus?

A long-acting synthetic analog of AVP: duration of action is 6-20h

Ratio of V2:V1 receptor acivity is 4000:1, so less vasoconstrictor activity

Can be given s.c., i.v., or by nasal spray
-- s.c. dose is only 1/10 the nasal dose
-- allergic rhinitis or nasal congestion from URI slow absorption

Treatment causes marked reduction in daily urine volume

Limit water intake (just enough to satisfy thirst) to prevent water intoxication and hyponatremia
Other medical uses of Desmopressin?
1. treatment of nocturnal enuresis

2. Hemophilia A and type I (classic) VW disease
-- used to maintain hemostasis during and after surgery
-- used to stop trauma-induced and spontaneous bleeding
-- tolerance develops after several days due to depletion of preformed clotting factors
Desmopressin toxicity?
1. HTN (rare w/ nasal spray)

2. Hypotension w/ tachycardia (w/ i.v. or s.c. injection)

3. water intoxication and hyponatremia w/ excessive water intake
Reduces urinary volume by 25-50%

Reduction in urinary volume depends on natriuresis
1. natriuresis contracts ECF volume resulting in increased efficiency of solute/water reabsorption in the proximal tubule, thus sending less volume to the distal tubule where urine is diluted
2. inhibition of NaCl reabsorption by HCTZ in the distal tubule further impairs renal dilution
CASE 4 (continued)

Suppose that treatment w/ desmopressin did not cause urinary concentration in this patient.

What is the dx?
Nephrogenic diabetis insipidus (NDI)

1. Plasma ADH rises in response to an increase in plasma osmolality

2. Renal tubule is unresponsive to ADH (complete NDI) or a larger conc of ADH is req’d to produce antidiuresis (partial NDI)
How do we treat NDI?
1. adequate water intake

2. larger doses of desmopressin in pts w/ partial NDI

3. HCTZ (complete NDI)

53 y.o. woman treated w/ lithium for bipolar disease develops polyuria and polydipsia.

Daily urinary vol – 4.5L
Avg urinary osmolality – 236mOsm
Serum lithium conc is 0.88mEq/L (therapeutic window is 0.5-1.25mEq/L)

Why does she have polyuria/polydipsia?
Lithium-induced diabetes insipidus

1. about 80% of filtered lithium is reabsorbed in prox tubule

2. Lithium is not reabsorbed in the LofH or early distal tubule, but may be reabsorbed by the principal cells of the late distal tubule and collecting duct

3. conc of lithium in tubular urine increases dramatically as solute/water are reabsorbed in the distal tubule and collecting duct

4. Li enters the principal cells of the late distal tubule/CD via apical Na channel

5. Li causes nephrogenic DI by reducing activation of adenyl cyclase produced by AVP stimulation of basolateral V2 receptors
How do we treat Li-induced NDI?
AMILORIDE (best trtmt)
Amiloride MOA?
1. blocks Na channels in the principal cells and thus prevents entry of Li

2. Decreases urinary vol by 30-40% and increases urinary osmolality to >300mOsm

3. Does NOT appreciably decrease the renal clearance of lithium
-- no worry of dose toxicity
Another way to treat Li-induced NDI?
1. since Na depletion by HCTZ decreases urinary volume by increasing efficiency of solute/water reabsorption in the prox tubule, the reabsorption of lithium in the PT may reach 90% of the filtered load

2. serum Li conc will increase due to decreased renal clearance
-- the dose may need to be reduced to prevent toxicity

Male pt w/ pulmonary small (oat) cell carcinoma has
-- serum [Na] of 132mEq/L (↓)
-- serum osmolality of 266 mOsm (↓)
-- urinary osmolality of 418 mOsm (↑)
-- serum uric acid is less than 2mg/dl (nl = 2-8)
-- BUN is less than 8mg/dl (nl = 8-20)
-- Hct is 33 (nl = 44-54)
-- No peripheral edema or evidence of abnormal adrenal or thyroid fxn is detected

What is the most likely cause of the hyponatremia and abnormalities of serum and urinary osmolality?
Syndrome of inappropriate ADH release (SIADH)

1. Secretion of ADH is autonomous and independent of serum osmolality

2. Excessive retention of water causes hypervolemia and dilutional hyponatremia which is usually asymptomatic as long as serum conc falls slowly or does not fall below 120mEq/L
-- NB: recall that furosemide and HCTZ can cause dilutional hyponatremia by a direct renal effect which is independent of AVP)
Symptoms of mild hyponatremia or slowly-developing hyponatremia?

During slowly developing hyponatremia, brain cells doe not become edematous b/c they extrude solute to equalize intracellular osmotic pressure w/ the extracellular osmotic pressure
Symptoms of rapidly-developing or severe hyponatremia?
Cerebral edema which results in
-- headache
-- restlessness
-- confusion
-- coma
-- convulsions

A rapid fall in serum Na conc does not allow sufficient time for brain cells to extrude solute, so extracellular hypotonicity favors the osmotic mvmt of water into cells causing edema
Why is peripheral edema absent in this patient?

What about serum uric acid, BUN, and Hct levels?
Extracellular hypotonicity leads to intracellular edema
-- 2/3 of excess water is located intracellularly
-- 1/3 is located in ECF volume

Expansion of ECF volume dilutes all three levels
What are the causes of SIADH?
1. nonendocrine neoplasms, esp small cell lung cancer

2. CNS disorders
-- trauma
-- CVA
-- TB
-- acute encephalitis

3. pulmonary infections
-- TB
-- abscess

4. adrenal insufficiency or hypothyroidism (hypotension induces AVP release through baroreflex)

5. Drugs
Drugs which can cause SIADH?



Chlorpropamide and SIADH?
An orally-active drug used to induce insulin release in pts w/ NIDDM

Increases release of AVP and potentiates the renal effects of AVP
Carbamazepine and SIADH?
Antiseizure drug

Increases release of AVP and potentiates the renal effects of AVP
Morphine and SIADH?
Opiates stim release of AVP

Can contribute to postop hyponatremia since pain, hypotension, hypoxia, and artificial ventilation w/ respirator can stimulate AVP release
Nicotine and SIADH?
Not a therapeutic agent

Pts w/ partial central DI may maintain adequate AVP release if they smoke cigarettes
How do we treat hyponatremia assoc w/ SIADH?
1. Restrict water intake to 800-1000ml/day
-- urine output will exceed this value and plasma Na conc will rise as water is lost

2. Infusion of 3% NaCl
-- used to raise serum Na conc in SEVERE symptomatic hyponatremia
-- do NOT increase serum Na conc faster than 2mEq/L/h to avoid pontine melinosis

3. Furosimide
-- action in the ascending L of H decreases the concentrating capacity of the kidney
-- usually give K supplements to prevent hypokalemia

4. Demeclocycline (a tetracycline antibiotic)***
-- inhibits antidiuretic action of AVP in the collecting duct
-- used to treat SIADH when serum Na < 120mEq/L and the pt has severe neuro symptoms
Overview of treatment of DI…
Complete Central DI
-- desmopressin

Partial Central DI
-- desmopressin

Partial Nephrogenic DI
-- HCTZ or large doses of desmopressin

Complete Nephrogenic DI
-- HCTZ or indomethacin

Li induced DI
-- amiloride (doesn’t alter Li clearance)

-- demeclocycline