Hypothyroidism Flashcards
What three main things does TSH stimulate in the follicular cell?
Stimulates IODIDE CHANNELS to transport iodide from the blood into the cell at the basolateral membrane (facing the blood)
Stimulates synthesis of THYROGLOBULIN
Stimulates THYROID PEROXIDASE
Describe the formation of T3 and T4 in the follicular cell.
In the presence of hydrogen peroxide, thyroid peroxidase can convert the iodide (which has been pumped into the colloid by the pendrin pumps) into a reactive iodine form.
TSH stimulates synthesis of a protein called thyroglobulin (moves to the apical surface - facing colloid) which is a long array of amino acids containing TYROSYL RESIDUES.
The tyrosyl residues can be iodinated by the reactive iodine in ONE or TWO positions forming MONOIODOTYROSINE (MIT) and DIIODOTYROSINE (DIT) respectively.
Continued stimulation of thyroid peroxidase will cause coupling reactions forming T3 and T4
At which positions are tyrosine iodinated?
3 and 5
Describe how iodothyronines are transported in the blood.
To prevent uptake by non-target tissues, T3 and T4 are mainly transported by PLASMA PROTEINS
The majority of T3 and T4 are transported by THYROXINE BINDING GLOBULIN (TBG)
Some T3 and T4 is transported by ALBUMIN (binds more loosely)
The BIOACTIVE component is the T3 and T4 that is UNBOUND
Describe the deiodination of T4.
T4 can be deiodinated to produce T3 which is MORE ACTIVE
T4 can be deiodinated in a different position to produce REVERSE T3 (which is INACTIVE)
Describe the mechanism of action of thyroxine.
Thyroxine enters the target cell and is converted to T3 by deiodinase
T3 then binds to a thyroid hormone receptor in the nucleus and then heterodimerises with a retinoid X receptor
This complex then binds to a thyroid response element (DNA segment, which alters gene expression
What are the two main drugs that are used in thyroxine and T3 replacement therapy?
T4 replacement – Levothyroxine Sodium
T3 replacement – Liothyronine Sodium
State the clinical use of thyroxine replacement, and how is it administered?
- Used to treat primary hypothyroidism, e.g. autoimmune, iatrogenic (post-thyroidectomy, post-radioactive iodine); oral administration; TSH used as guidance for thyroxine dose - aim to suppress TSH into the reference range
- Used to treat secondary hypothyroidism, e.g. pituitary tumour, post-pituitary surgery or radiotherapy; oral administration; can’t use TSH as a guide to dose - aim for fT4 middle of reference range
State some of the effects of hypothyroidism.
Reduced basal metabolic rate (everything slows down)
- Cold intolerance
- Deep voice
- Weight gain
- Loss of appetite
- Depression
- Lethargy
- Speech slows down
- Bradycardia
- Constipation
State the clinical use of Liothyronine
Used in Myxoedema coma (VERY RARE complication of hypothyroidism); iv initially, then oral when possible
Why would you give a patient combined thyroid hormone replacement (T3+T4)?
Some patients don’t feel better with T4 replacement alone though their TSH may be normal
What is the problem with giving T3 replacement?
T3 is very potent so it is difficult to get the dose right.
Too high a dose can lead to patients complaining of thyrotoxicosis type symptoms = palpitations, tremor, anxiety
What is the plasma half-life for Levothyroxine and Liothyronine?
6 days
2.5 days
What affects the bioavailability of T3 and T4 in the blood?
- Plasma binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines
- TBG falls with malnutrition and liver disease
- Certain co-administered drugs (e.g. phenytoin, salicylates) compete for protein binding sites
Iodothyronines are important in growth and development. What disease is caused by a lack of iodothyronines?
Cretinism
