Term
| What is the difference between T4 and T3? |
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Definition
T4 - 93% of what's secreted. Slower onset and longer acting -- like a prodrug for T3
T3 - 7% of what's secreted. 4x affinity for thyroid hormone receptor
Both establish the basal metabolic rate |
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Term
| What is the anatomy of the thyroid gland? |
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Definition
Wrapped around the trachea
Composed of follicles filled w/ secretory colloid.
Colloid composed of thyroglobulin - thyroid + iodine
Also secretes calcitonin
Highly vascularized |
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Term
| How is thyroid hormone secretion regulated? |
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Definition
HPT axis:
- Hypolathamus secretes Thyroid releasing hormone (TRH) --> Anterior pituitary releases thyroid stimulating hormone (TSH) from thyrotrophs --> Thyroid releases T4 and T3
- Negative feedback: high T4/T3 inhibits pituitary and hypothalamus. Doctor's measure TSH levels. |
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Term
| How is TRH dependent on body temperature? |
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Definition
- Cold --> increase in metabolism to generate heat. Stimulates HPT axis to release T4/T3
- Hot or anxiety - increase in body temperature does not require a high metabolism, TRH and thus T4/T3 falls. |
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Term
| What are the normal effects of T3/T4? |
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Definition
- Normal BMR and SNS transmission
- Glucose catabolism, fats for protein and cholesterol synthesis
- Normal CNS development
- Normal heart function
- Normal growth
- Normal GI motility
- Normal reproduction and skin |
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Term
| What are the effects of low T3/T4? |
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Definition
- Low BMR --> weight gain
- Decreased glucose metabolism
- Infants develop retardation, adults depression and memory loss
- Decreased HR and BP
- Stunted growth and joint pain
- Decr GI motility, constipation
- Sterility, decr lactation
- Pale, dry skin and thick hair |
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Term
| What are the effects of high T3/T4? |
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Definition
- High BMR --> weight loss
- catabolism of glucose and proteins
- irritability, personality changes
- Increase BP and SNS output
- Excess growth followed by a stunt in children. Bone demineralization in adults
- diarrhea and loss of appetite
- Male impotence
- Flushed, thin, moist skin, fine hair. |
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Term
| Where is iodine found for diet and how is it metabolized? |
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Definition
Table salt is iodinized. 1/5 is absorbed into the thyroid, the rest is excreted.
Iodide trapping: rate influenced by TSH, iodide actively pumped into the thyroid cell by Na/I symporter |
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Term
| How does Iodine enter the colloid? |
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Definition
| cAMP activates pKA --> phosphorylates Na/I symporter. Sodium and Iodide comes in. Iodide diffuses towards apical membrane to colloid. Iodide channel called pendrin --> colloid |
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Term
| What happens to iodine in the colloid? |
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Definition
Organification/Iodination - TPO and hydrogen peroxide oxidize to nascent iodine, then add to thyroglobulin molecules. Makes DITs (2 iodines) or MITs (1 iodine)
T4 - DIT + DIT
T3 - DIT + MIT |
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Term
| What happens to thyroxine after it's made in the colloid? |
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Definition
packaged into vesicles and endocytosis out
TSH-receptor stimulates release of these vesicles AND synthesis of T4/T3 |
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Term
| What is the MoA behind Grave's disease? |
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Definition
| An autoimmune disease, antibodies activate the TSH-receptor chronically. Too much T4/T3 made and released --> Hyperthyroidism. |
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Term
| What is the key to the T4/T3 salvage pathway? |
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Definition
Deiodinase
Without this enzyme, not enough thyroxine is made. |
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Term
| What are the hallmark hormone levels of Graves disease? |
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Definition
TSH drops due to negative feedback
Still have VERY high levels of T4/T3 due to antibody
anti-TSH antibody present
Goiter and bulging eyes |
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Term
| What happens the absence of iodide? |
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Definition
TSH bombards the colloid, causing it to grow.
Goiter but no thyroxine secretion. Increased TSH levels. |
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Term
| How are T4 and T4 bound to plasma proteins? |
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Definition
HIGHLY bound to thyroxine-binding globulin and prealbumin/albumin.
Release occurs very slowly for T4, much more quickly for T3.
T3 has a lower affinity for plasma proteins than T4
T4 max at 10 days, T3 max at 2 days. |
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Term
| What are the conversions of T4? |
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Definition
- Outer ring deiodination of the 5' --> T3
- Inner ring deiodination of the 5' --> reverse T3 (rT3). Dominant in Wilson's syndrome where high levels of cortisol inhibit T3 conversion. rT3 has no proper thyroid hormone function
- T3 or rT3 deiodinated to T2 - inactive, no affinity |
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Term
| What does the thyroid receptor look like? |
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Definition
Receptor complexed with Retinoid X receptor
Binds to T3 --> Activates transcription to yield translation. |
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Term
Why is T4 used as the treatment for hypothyroidism?
What interferes with absorption? |
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Definition
consistent potency, longer duration
Absorption in the small intestine, very variable. Less variable on an empty stomach
Drugs that chelate acids: sucralfate, BAS, iron, calcium, aluminum, PPIs, and food.
3A4 inducers enhance excretion: Phenytoin, carbamazepine, rifampin, ritonavir.
Amiodarone has iodine in it, competes with T4 for deiodinase --> conversion to T3 |
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Term
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Definition
- By iodinase to T3 (1 5' iodine)
- Phase II Conjugation adds a Gluc or Sulf to hydroxy already present. No phase I. |
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Term
| Is levothyroxine or dextrothyroxine more active? |
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Definition
Levo-
Dextro- isomers are barely active.
- T3 is more active than T4
- ALSO - removal of 3 and 5 iodo groups abolishes activity
- Replacement with Bromine groups still has some activity, not as much as Iodine, not as electron withdrawing.
- Addition of bulk at 3' INCREASES activity! Why? Coplanarity, fits into receptor site. |
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Term
| What structure has the HIGHEST affinity for the thyroid receptor? |
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Definition
T3-like structure
Bulk at 3'
Iodine at 3 and 5 |
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Term
| What is contained in Armour Thyroid? |
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Definition
| Mixture of T4 and T3 as in thyroid glands and everything in a thyroid gland: thyroglobulin, DITs, MITs, enzymes, etc. |
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Term
| What is Liothyronine/Cytomel? |
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Definition
| L-T3. Rapid onset, short duration. Preparation for surgery. For Tx not used frequently due to cost and frequent dosing |
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Term
| What are the major classes of antithyroid agents? |
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Definition
- Antithyroid drugs - interfere directly with TH synthesis
- Iodide - Decrease TH release w/ no effect on synthesis
- Radioactive iodine - damages thyroid
- Ionic inhibitors - affect iodide transport: Perchlorate (a contaminate), thiocyanate (treats hyperthyroid), lithium (treats hyperthyroid) |
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Term
| What are Propylthiouracil/PTU and Methimazole/Tapazole used for? |
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Definition
Inhibit organification and coupling of MITs and DITs by inhibiting the enzyme TPO --> Tx of hyperthyroidism. Also decreases antibodies in Grave's disease.
- Takes time to work due to storage of hormone in the colloid.
- Unsafe in pregnancy, but benefit may outweigh risk.
- PTU inhibits T4 --> T3 by inhibiting deiodinase. |
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Term
| How is high concentration iodide used? |
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Definition
Only for acute 10-15 day inhibition of thyroid before surgery. No longer - escape phenomenon where patient gets worse.
- Used for surgery due to decrease in thyroid size and blood supply.
- Thyroid protective in case of exposure to I131 - saturates thyroid so radioactive iodide cannot be taken up. SSKI or Lugol's solution |
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Term
| What is radioactive iodide used for? |
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Definition
| I-123 and I-131 used for gamma particles to kill thyroid cancer |
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