Term
Which of the following is FALSE regarding thyroid development?
1) Visualized at day 16/17
2) Derived from neuroectodermal tissue
3) Fetus is dependent upon maternal thyroid hormone particularly in the first trimester
4) Initial development is independent of TSH.
5) Functional hormone synthesis begins at 11 weeks gestation. |
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Definition
2- Thyroid is derived from endodermal epithelium in foregut (thyroid analage)
It is first visualized at day 16/17 as a median thickening that deepens to form a small pit (adjacent to myocardial cells), descending into the neck anterior to the trachea.
Thyroid development is initially independent of TSH (not even released until week 14) and begins producing functional hormone at week 11 |
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Term
| Describe the functional anatomy of the thyroid gland. |
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Definition
- Bilobed structure (right slightly bigger than left) joined by isthmus (3rd, pyramidal lobe sometimes present as the inferior portion of the thyroglossal duct cyst)
- Composed of endodermal follicles (globes of thyrocytes) that receive blood on the "outside" and secrete and store "colloid" on the "inside"
- Parafollicular cells or "C cells" are neural-crest derivatives that secrete calcitonin
Anatomical relationships
- 4 parathyroid glands (usually posterior to each lobe)
- Recurrent laryngeal nerves pass posterior to thyroid |
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Term
| What is the role of iodine metabolism in thyroid hormone synthesis? |
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Definition
Embryonic thyroid begins concentrating iodine and synthesizing T4 at week 11 (iodine can also concentrate in GI fluid and breast milk)
Iodine is required for active thyroid hormones and is added by peroxidases and removed by de-iodinases or halogenases
Patients with low iodine (<100) get 'endemic goiter' and hypothyroidism
**Can also get excess iodine-induced hypothyroidism (Wolff-Chaikoff effect) AND hyperthyroidism (Jod-Basedow effect) |
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Term
| Describe the basics of thyroid hormone synthesis |
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Definition
1) Thyroglobulin (TG) is produced synthesized and transported through brush border apical membrane
2) Sodium-Iodide symporter carries iodide in through basolateral membrane of thyrocyte ente
3) Enters colloid through apical membrane, via iodide-chloride transporter named "Pendrin" colloid, and is oxidized by Thyroid Peroxidase, leading to spontaneous attachment to tyrosines in TG (organification)
4) "Coupling" occurs as TG folds upon itself allowing iodo-tyrosines at N- and C-termini to interact and transfer iodo-phenyl group of one tyrosine to another
5) Mature TG is stored in colloid until T3 (active), T4 or iodide is needed |
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Term
| How is mature Thryoglobulin (containing T3, T4 and iodide) secreted from the thyroid gland? |
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Definition
1) Colloid is engulfed by apical membrane pseudopods and internalized (Pinocytosis)
2) Colloid fuses with lysosomes and is degradation by proteases, releasing T4 and T3, which are hydrophobic and free to exit the basolateral membrane of the thyrocyte.
3) Lysosomal degradation releases MIT and DIT, and "dehalogenase" cleaves iodine off of MIT and DIT and returns it to the thyroid pool for re-incorporation |
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Term
What is the role of each of the following in thyroid hormone synthesis/secretion?
1) Thyroglobulin
2) Sodium-iodide pump
3) Pendrin
4) Thyroid peroxidase
5) Dehalogenase |
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Definition
1) Thyroid-specific glycoprotein that serves as tyrosine-containing substrate for iodination and storage in the colloid.
2) Takes iodine up into from capillaries into thyrocytes via symport so that it can exit apically and enter the colloid
3) Apical membrane transporter (iodide-chloride) that allows iodide to enter the colloid
4) Oxidizes iodide to iodine so that it can spontaneously attach to tyrosine on TG (organification)
5) Once organified TG folds and is "coupled" into mature TG that is stored in colloid, it may be released. Once TG undergoes pinocytosis and enters the thyrocytes for lysosomal/protesomal degredation and T3/T4/iodine release, Dehalogenase recycles iodine that is bound by MT and DIT. |
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Term
| How is thyroid hormone synthesis regulated by the thyroid? |
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Definition
HPT axis and negative feedback (T3 and T4)
1) TRH released by hypothalamus into hypothalamic-hypophyseal portal system and delivered to adenohypophysis
2) Thyrotrophs in anterior pituitary release TSH, which enters systemic circulation and binds to extracellular TSH receptor on thyroid
3) TSH binding stimulates thyroid follicular cells to produce and secrete T4 and T3 (iodine uptake, organification, oxidation and pinocytosis/secretion)
**chronic stimulation leads to enlargement- goiter) |
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Term
Describe what occurs in each of the following steps of thyroid hormone synthesis.
1) Iodine uptake
2) Oxidation
3) Organification
4) Pinocytosis
5) Secretion |
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Definition
1) Iodine taken up from capillary through basolateral membrane of follicular cell via Na-iodide symporter.
2) Iodide is exported into colloid via Iodine-Chloride channel called Pendrin and is oxidized to Iodine by Thyroid peroxidase (TPO)
3) Iodine can spontaneously bind to TG in colloid
4) TG-iodine folds and undergoes "coupling," at which point it can be taken up into thyrocyte again.
5) TG-iodine is broken down by lysosomal enzymes and proteases to T4, T3 and iodine, which binds MIT and DIT and later recycled by dehalogenase. |
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Term
True or False:
T3 is the major secretory product of the thyroid gland |
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Definition
False:
T4 is major secretory product (10:1) and is peripherally converted to T3 (active form) by Deoidonase (selenoprotein)
**D1 is in liver and other peripheral tissues and makes majority of T3, while D2 in pituitary, brain and brown fat makes T3 intracellulary** |
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Term
| How is it that patients with hypothyroidism can be treated with T4 only, despite the fact that it is inactive? |
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Definition
T4 can be intracellularly converted to T3 by D2 Deiodinase in pituitary, brain and brown fat.
Majority of T4 is peripherally converted to T3 by D1 in liver and other tissues |
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Term
| How are thyroid hormones inactivated, degraded and excreted? |
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Definition
1) T4 converted by D3/D1 to reverse T3 (rT3), which is inactive
2) TH metabolized by sulfation and glucouronidation in liver and (to lesser extent) kidney
3) Oxidative deamination and decarboxylation of TH in liver creates locally metabolically active hormones (thyromimetics to treat lipid disorders). |
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Term
| How are T4 and T3 transported in the blood? |
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Definition
Hydrophobic, so require protein transport.
1) Thyroxine-binding globulin (TBG) is made by liver and has highest affinity
**Disorders that affect TBG can lower total T4/T3, but may not lower real free, active T3**
2) Albumin has low affinity by there is ALOT
3) Transthyretin- minor player |
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Term
| What are the major cellular actions of T4 and T3? |
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Definition
1) Enter membranes via MCT8 transporter (monocarboxylate)
**T4 may be converted to T3 intracellularly by D2**
2) T3 passes through nuclear envelope and binds TRs, that act as transcription factors
3) alpha-TR and beta-TR exert different effects and are required for fetal brain development. |
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Term
Which of the following is NOT a classic symptom/sign of hyperthyroidism?
1) Anxiety
2) Fever
3) Hyporeflexia
4) Tachycardia
5) Tremor
6) Heat intolerance |
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Definition
3- This is classic HYPOthyroidism
Hyperthyroid
1) Adrenergic (anxiety, tremor, nervous, perspiration, hyper-reflexive)
2) Metabolic (heat intolerance, weight loss, fever)
3) MISC (Myopathy, amenorrhea, psychosis) |
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Term
Which of the following is NOT a classic symptom/sign of hypothyroidism?
1) Dry skin
2) Fever
3) Cold intolerance
4) Weight gain
5) Bradycardia
6) Reduced myocardial contractility |
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Definition
2- This is a metabolic effect of HYPERthyroidism
Hypothyroidism
1) Adrenergic (tired, bradycardia, dry skin, constipation, hypo-reflexive, impaired heart contractility)
2) Metabolic (cold intolerance, weight gain, hypothermia)
3) MISC (myopathy, amenorrhea, psychosis ect.) |
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Term
| Why should you not given a pregnant women radioactive iodine (CT) after 10 weeks gestation? |
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Definition
Fetal derived T4 is detectible at this time, and radioactive transfer can cause fetal thyroid destruction.
Hormone levels reach mean adult levels at 36 weeks gestation |
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Term
| What happens to maternal thyroid physiology during pregnancy? |
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Definition
Increased demand for TH by 50%
1) TSH decreases during first trimester
2) TBG rises 2-3x because of estrogen increasing hepatic production and decreasing clearance
3) Increased GFR and renal clearance of iodides increases
4) Increased D2 and D3 levels result in increased degradation/utilization of TH |
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Term
| What is the "classic" demographic presentation of hypothyroidism? |
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Definition
Female:male ratio of 3:1 with 4-8% prevalence at around 50 years of age.
5-10% post-partum |
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Term
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Definition
Severe hypothyroidism during fetal development causing mental retardation and dwarfism.
Milder cases may reduce IQ |
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Term
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Definition
Hypothyroid emergency, usually in poor-controlled hypothyroidism in elderly with super-imposed event.
Admit to ICU, give stress-dose adrenal replacement with hydrocortisone and LT4 or LT3/LT4 combination
- Hypothermia, hypoventilation, bradycardia, effusions, cardiac failure, ileus and altered mental status
- DTRs are absent or delayed with skin and hair changes |
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Term
| What are the major adrenergic signs of hypothyroidism? |
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Definition
- Tired
- Bradycardia
- Diastolic hypertension
- Hyporeflexia
- Constipation/illeus |
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Term
| What are the major metabolic signs of hypothyroidism? |
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Definition
- Cold intolerance and hypothermia
- Weight gain
- Hypercholesterolemia
- Carpal tunnel
- Edema |
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Term
| Describe the diagnostic workup of suspected hypothyroidism. |
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Definition
1) Start with low levels of thyroid hormones (free T4 or free T3)
2) Look at TSH (not TRH) levels.
Primary- High TSH and Low free T4
Secondary- LOW/normal TSH and LOW T4 (High TRH)
Tertiary- LOW/normal TSH and LOW T4 (Low TRH)
**Primary-subclinical may have TSH increase with normal free T4** |
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Term
What diagnostic findings are associated with each of the following causes of hypothyroidism?
1) Hypothalamic irradiation
2) Hypophysitis/granulomatous disease
3) Chronic lymphocytic thyroiditis
4) Iodine thyroid damage |
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Definition
1) Tertiary (hypothalamic)
- Low TRH, Low TSH and Low free T4
2) Secondary (pituitary)
- High TRH, Low TSH, Low free T4
3) Primary (most common in US) Hashimotos
- High TRH, High TSH and low free T4
4) Primary (drug induced)
- High TRH, High TSH, low free T4 |
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Term
| Describe the pathophysiology underlying the most common cause of hypothyroidism in the US |
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Definition
Chronic lymphocytic Thyroiditis (Hashimotos) associated with elevated Anti-TSH, Anti-TG and anti-TPO antibodies
Iodine deficiency is most common worldwide
1) Lymphocytic invasion and germinal center establishment in thyroid
2) Intrathryoidal TSH-receptor inhibitory antibodies and destruction of gland by immune invasion.
3) Eventually, thyroid is replaced with scar tissue (Idiopathic hypothyroidism)
**can be "un-masked" with pregnancy consumption of T3/T4** |
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Term
| What is "Lingual thyroid" and how is it treated? |
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Definition
1) Thyroid failed to migrate from the base of the tongue to lie anterior to the trachea, but failed
2) Life-long thyroid hormone replacement |
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Term
| What is "thyroid agenesis" and how do you manage it? |
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Definition
Most common epidemiologic abnormality in neonates
1) Results in mental retardation if not caught early (mandatory heel-stick blood test for TSH at birth)
2) Preventible with thyroid hormone replacement |
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Term
| What is "Pendred's syndrome" and how is it treated? |
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Definition
1) Congenital defect in oxidation/organification step of thyroid hormone synthesis that produces Hypothyroidism and Deafness.
2) Treatment is thyroid replacement |
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Term
True or False:
Iodine deficiency and excess can both cause hypothyroidism |
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Definition
True!
1) Deficiency is most common worldwide cause of hypothyroidism and mental retardation
2) Excess (Wolff-Chaikoff") can also cause it. |
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Term
| What drugs are potential causes of hypothyroidism? |
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Definition
1) Lithium
2) Methimazole (Tapezole) which is anti-thyroid drug |
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Term
What is the appropriate treatment for each of the following
1) Complete thyroid hormone deficiency
2) Mild hypothyroidism
3) Sub-clinical hypothyroidism
4) Pregnancy |
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Definition
Give T4/synthroid/levothyroxine
1) 1.6 ug/kg per day (100-150 ug per day)
2) 25-75 ug per day
3) Debated, but will increase cardiac contractility and improve lipids
4) Vary by requirements |
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Term
Patient presents in a confused sate. They are tachycardic and hypotensive and are running a fever.
You suspect "thyroid storm," but want to confirm your diagnosis and treat.
What do you do? |
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Definition
1) Confusion + CV collapse + fever in the setting of hyperthyroidism= Thyroid storm
2) Huge doses of iodide as NaI or SSKI (Lugol's solution), preceded by anti-thyroid drugs (PTU) and high-dose steroids.
Call the endocrinologist! |
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Term
| What is the most common cause of hyperthyroidism in the US and what are the major complications? |
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Definition
Over-treatment with T4 (High T4 and low TSH)
Tachycardia and Osteoporosis |
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Term
| What is graves disease and who gets it? |
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Definition
Diffuse toxic goiter= Women 8X more likely than men.
- Autoimmune production of thyroid-stimulating immunoglobulins that binds and stimulate TSH receptor (opposite of Hashimoto's)
- Will look like any hyperthyroidism (fever, weight loss, tachycardia, ect), EXCEPT for
1) Ophthalmopathy (lymphocytic invasion)
2) Pretibial myxedema (raised, purplish, non-tender plaques) |
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Term
| How can you treat a women with signs of hyperthyroidism and raised, non-tender purpleish plaques on their shins? |
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Definition
Pre-tibial myxedema+ Hyperthyroid= Graves (opthalmic?)
1) Radioactive iodine for complete ablation of thyroid (requires long-term replacement)
2) Anti-thyroid drugs
- Methimazole (Tapazole)
- Propylthiouracil (PTU)
3) Thyroidectomy (rare)
Symptoms of hyperthyroidism can be handled with Beta Blockers (propanolol or atenolol) |
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Term
Which of the following is NOT a typical management strategy for Grave's disease?
1) Propylthiouracil
2) Methimazole
3) Propanalol
4) Prednisone
5) Radioactive iodine |
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Definition
4- Steroids cause more side effects than are worth it
1 and 2 are thiourea drugs that treat thyroid
5 will ablate thyroid
3 will treat hyperthyroidism symptoms. |
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Term
| What is Toxic Multinodular Goiter (TMNG) and why is of clinical concern? |
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Definition
Benign nodules in middle aged and older people (particularly women) that can mimic thyroid cancer, but tend not to release T4 or T3.
15% WILL produce T4/T3, and are termed "toxic".
Treated with iodine (higher doses than Graves), thiourea drugs or surgery. |
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Term
| What is the treatment for rare Toxic Solitary Nodules of the thyroid? |
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Definition
| Radioactive iodide, which will ONLY be taken up by "hot" nodule (as opposed to Graves, where whole thyroid is ablated) |
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Term
Which form of hyperthyroidism is described by each of the following and how do you treat?
1) Painful, granulomatous and self-limited Cocksackie infection of thyroid often presenting as throat/ear pain.
2) Diffuse lymphocytic infiltration of thyroid gland producing painless hyperthyroidism in post-partum women.
3) Iodine exposure
4) Benign or malignant tumors that produce hCG in pregnant and post-partum women
5) Ovarian tumors that contain teratomas which differentiate into thyroid tissue and overproduce thyroid hormones |
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Definition
1) Subacute thyroiditis (SAT)
- Treat with beta blockers and NSAIDs, NOT thiourea drugs since T4/T3 is released from damaged thyroid.
2) Lymphocytic thyroiditis
- Treat with beta blocker (beta adrenergic symptoms) and will go away in a few weeks (no thiourea)
3) Jod-Basedow phenomenon
- Withhold iodine and maybe add anti-thyroid drugs and beta blockers.
4) Choriosarcoma (hCG is weak stimulator of TSHR)
- Get hCG level and pelvic US
5) Struma ovarii
- treat with ovarectomy |
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Term
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Definition
Ovarian tumors that contain teratomas which differentiate into thyroid tissue and overproduce thyroid hormones!
Treat with ovarectomy. |
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Term
| Why might a post-menapausal woman on estrogen therapy appear with "factitious hyperthyroidism"? |
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Definition
| Estrogen increase TBG production by liver, which requires more T4/T3 production to occupy vacant sites (raises total but not free T3/T4) |
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Term
| Explain the basis for the Thyroid Stimulating Hormone test. When is it insufficient on its own? |
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Definition
Most accurate test of thyroid funciotn in ambulatory setting,
1) TSH is measured by non-competitive assay (sandwich ELISA)
- very sensitive
2) Need Total T4 and T3 confirmation when:
- acute changes in thyroid
- hypothalamic or pituitary disease
- thyroid hormone resistance
- interfering substances
Total T3/T4 is measured by Competitive immunoassay
3) Free T4/T3 levels are not affected by TBG (unlike total)
- Equilibrium dialysis (gold standard)
- Immunoassay
- Analog method
- Free thyroid hormone index (FTI) |
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Term
| What is the "Free thyroid hormone index" (FTI) and how is it used diagnostically? |
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Definition
Estimates Free T4 and T3
FTI= Total T4 X TH binding ratio (T3 resin uptake)
T3RU estimates number of unoccupied TH binding sites and correct for differences in binding protein concentrations and binding affinity of TH.
- If T3RU is high, patient's serum has DECREASED number of unoccupied TH binding sites (hyperthyroid) |
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Term
What is the T3 resin uptake measure and why is it useful?
What would it look like in Pregnancy and Nephrotic syndrome, respectively? |
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Definition
FTI= Total T4 X T3RU
1) T3RU estimates number of unoccupied TH binding sites and correct for differences in binding protein concentrations and binding affinity of TH.
Used in assessing possibility of increased and/or decreased binding proteins.
2) Pregnancy= increased binding proteins
- Low T3RU and high T4
3) Nephrotic= decreased binding proteins
- High T3RU and low T4 |
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Term
What would you see in terms of TSH, Total T4 and free T4 in each of the following conditions?
1) Primary hypothyroidism
2) Secondary hypothyroidism
3) Primary hyperthyroidism
4) Secondary hyperthyroidism
5) Subclinical hypothyroidism
6) Subclinical hyperthyroidism
7) Euthyroid sick syndrome |
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Definition
1) High TSH, Low free T4
2) Low TSH, Low free T4
3) Low TSH, High free T4 and total T4
4) High TSH and High free T4 and total T4
5) High TSH and normal free T4 (positive antibodies)
6) Low TSH and normal free T4
7) Elevated or decreased TSH, decreased/normal total T4 and elevated/normal free T4 |
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Term
| What are the medial and lateral anlages of the embryonic thyroid gland? |
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Definition
1) Medial
- originates from midline of anterior pharyngeal floor (endoderm)
- Migrates caudally from tongue base into neck (5th-7th w)
- Remains connected to tongue base by thyroglossal duct which atrophies after birth.
- Becomes FOLLICLES
2) Lateral
- Caudal projections of 4th or 5th branchial pouch
- Attach to lateral aspects of medial anlage
- Become parafollicular (C) cells |
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Term
Which thyroid conditions are described by each of the following histological depictions?
1) Dark red, glistening gland with hyperplastic follicles, papillary in-foldings and scant colloid with scalloping edges
2) Fleshy, tan colored gland with atrophic follicles, lymphocytes infiltrating and in germinal centers and Hurthle cell change (oncocytic cells)
3) Enlarged thyroid gland with multiple nodules, follicles of different sizes
- Cytology: macrophages, hemosiderin deposition and cystic fluid. |
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Definition
1) Grave's disease (Diffuse papillary hyperplasia)
2) Hashimotos thyroiditis (Chronic lymphocytic thyroiditis)
3) Nodular Goiter |
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Term
| What are the most common thyroid tumors? |
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Definition
95% of Follicle-derived and 80% are papillary carcinoma.
Other causes:
1) Follicle derived
- Papillary carcinoma (80%)
- Follicular adenoma or carcinoma (Follicular or Oncocytic)
2) C-cell derived
- Medullary carcinoma
3) Poorly differentiated
- Insular carcinoma
- Anaplastic carcinoma |
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