Lecture 2 Flashcards
Learning Outcomes
- [Similar structure to remaining endocrine lectures]
-Describe the location, gross function & morphology of the thyroid gland
-Thyroid hormones
Feedback loop
Synthesis & role of iodine
Secretion
Regulation by TSH
Activity
-Explain the pathophysiology underlying disorders of thyroid function
Relates to other modules (e.g. Pathology & Medicine)
Tests understanding of basic physiology (many symptoms are predictable if basic mechanisms are understood)
Anatomy/Function of the Thyroid Gland
-Adheres to the trachea, just below the larynx
-Tissue mass: 10-20g
-2 flat lobes connected by an isthmus
*Usually, right lobe > left
-Secretes thyroxine (T4), tri-iodothyronine (T3) and calcitonin
*T3, T4: iodine containing hormones
acting throughout the body
*Calcitonin: regulates plasma
calcium (see later lecture)
Morphology of the Thyroid Gland
*Functional unit = follicle
-Basement membrane anchors
follicle to connective tissue
-Epithelial outer layer (“follicular
cells”): secrete T3 and T4
-Central colloid-filled cavity
-Changes morphology between
active and inactive states (↑ activity
→ ↓ colloid storage)
*Colloid: mainly consists of glycoprotein (thyroglobulin)
*C-cells present in basement membrane and between follicles
-Secrete calcitonin
*Rich blood supply
-Approx twice kidney blood flow
-Regulated by ANS
Thyroid Feedback Pathways
Hypothalamus
↓Thyrotrophin Releasing Hormone (TRH
Anterior Pituitary
↓ thyroid stimulating Hormone (TSH)
Thyroid
↓(T3/T4)
→→ → → → → → → → → → → → ↑ (pathways feedback up to the anterior pituitary and hypothalamus)
Synthesis of Thyroid Hormones (T3/T4): Thyroglobulin & Iodination
*Two components are necessary: thyroglobulin and iodine
*Thyroglobulin = 670kDa glycoprotein- glycoprotein is a protein with a sugar molecule attached or has oligosaccarides attached to it
—-Comprises 2 peptides of 330kDa and carbohydrate moieties
—–Synthesised in follicular cell rough endoplasmic reticulum
——Packaged into vesicles and released into lumen by exocytosis
Stored as colloid
*Iodination
-T3 and T4 require dietary iodine (≈
75mg/day; 140µg/day recommended
in UK)
-“Iodide trapping”: Inorganic iodide
enters follicular cells via Na/I co-
transporter- this requires an active transport against the concentration gradient to maintain a low intercellular Na+ concentration inside the cell
-Iodine transported → follicle lumen
-Iodination of free tyrosine residues
of thyroglobulin
-Hydrolysis of iodinated
thyroglobulin → T3/T4
-Some T3 synthesised, but approx
20-fold more T4
-Thyroid stores several weeks supply
of T3/T4
Summary of Synthesis and Secretion
Synthesis and Secretion of Thyroid Hormones:
The thyroid gland produces two main hormones, thyroxine (T4) and triiodothyronine (T3), which are crucial for regulating metabolism, growth, and development. Here’s a summarized overview of their synthesis and secretion process:
- Iodide Uptake:
Iodine from the bloodstream is actively transported into the thyroid follicular cells via the sodium-iodide symporter (NIS) located on the basolateral membrane of the follicular cells. The iodide trap. - Iodide Oxidation and Organification:
Once inside the follicular cell, iodide is transported to the apical membrane of the cell, where it is oxidized to iodine by the enzyme thyroid peroxidase (TPO).
The oxidized iodine is then covalently attached to the tyrosine residues on thyroglobulin (a large glycoprotein produced by the thyroid) in a process called organification.
This leads to the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). - Coupling of Iodinated Tyrosines:
Two DIT molecules couple to form thyroxine (T4), or one MIT and one DIT molecule couple to form triiodothyronine (T3). This coupling is also catalyzed by TPO.
These iodinated thyroglobulin molecules are stored in the colloid of the thyroid follicles. - Endocytosis of Thyroglobulin:
When thyroid hormones are needed, thyroglobulin is taken back into the follicular cells by endocytosis from the colloid. - Proteolysis of Thyroglobulin:
Inside the follicular cells, thyroglobulin is broken down by lysosomal enzymes, releasing T3 and T4 into the cytoplasm. - Secretion of Thyroid Hormones:
The free T3 and T4 are then secreted into the bloodstream via diffusion.
The ratio of secreted T4 to T3 is about 90% T4 and 10% T3. However, T3 is the more active form, and T4 can be converted to T3 in peripheral tissues by deiodinase enzymes. - Transport in the Blood:
Once released into the bloodstream, thyroid hormones are mostly bound to transport proteins like thyroxine-binding globulin (TBG), transthyretin, and albumin, with a small fraction remaining free and biologically active.
Regulation:
The synthesis and secretion of thyroid hormones are regulated by the hypothalamic-pituitary-thyroid axis:
The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).
TSH stimulates the thyroid gland to produce and release T3 and T4.
Elevated levels of T3 and T4 exert negative feedback on both the pituitary and hypothalamus, reducing TRH and TSH release.
Summary:
Iodide uptake into thyroid follicular cells.
Iodine is oxidized and attached to thyroglobulin.
MIT and DIT couple to form T3 and T4.
Thyroglobulin is endocytosed and broken down, releasing T3 and T4.
T3 and T4 are secreted into the bloodstream, where they are mostly protein-bound.
Thyroid hormone secretion is regulated by the hypothalamic-pituitary-thyroid axis via TRH, TSH, and negative feedback from T3 and T4.
Roles of TSH in Thyroid Function
*TSH receptors on follicular cell surface by binding to its receptors results in:
-GPCR coupled to adenylate cyclase
*Stimulation of hormone synthesis
-↑ Iodide trapping via Na/I co-
transporter
-↑ Thyroglobulin synthesis
-↑ Iodination of thyroglobulin
*Stimulation of hormone secretion
-↑ Uptake of colloid by follicular cells
*Necessary for thyroid gland maintenance
-Gland rapidly atrophies in absence
of TSH!
Action of Thyroid Hormones
*T3 has far greater activity than T4
-Intracellular conversion of T4 to T3
by deiodinase 2
-Deiodinase 2 provides a mechanism
by which cells control sensitivity to
thyroid hormones
*Act as “growth factors” in multiple tissues
*Regulate gene transcription
-Cytoplasmic receptors → nucleus
-Effects take hours-days
*Induce specific tissue effects; also ↑ O2 consumption and heat production of whole body
-Altered protein metabolism
-↑ BMR (>100 enzyme systems
sensitive to T3)
-↑ activity of Na+/K+-ATPase
-↑ glucose uptake & lipolysis
Abnormal Thyroid Function
*Hyperthyroidism (thyrotoxicosis)
-e.g. Grave’s disease (autoimmune –
antibodies activate TSH receptor?)
-Symptoms inc:
-goitre (enlarged thyroid)
-exophthalmos (protrusion of eyeballs)
-↑ Basal Metabolic Rate (BMR) & heart rate
-weight loss (due to ↑ BMR)
-Treatment: surgical removal or 131I ingestion
*Hypothyroidism
-Causes
-Iodine deficiency → ↓ T3 feedback
→ ↑ TSH → goitre
-Hashimoto’s thyroiditis
(autoimmune) → thyroid
destruction
*Myxedema: adults
-Iodine deficiency → ↓ T3 feedback → ↑ TSH → goitre
-Hashimoto’s thyroiditis (autoimmune) → thyroid destruction
*Myxedema: adults
Symptoms inc. -facial swelling
-↓ mental function
- lethargy
-↓ BMR & heart rate
*Cretinism: congenital, children
Symptoms inc. -mental retardation
-↓ body growth
*Treatment: hormone replacement (T4) or iodine supplements (in deficiency states)
*Diagnoses confirmed by assay of plasma T3 and T4
Summary
*Functional thyroid unit = follicles
*Follicular cells produce T3 and T4
-Dietary iodine necessary for synthesis (“iodide trap”)
-Iodination of thyroglobulin & hormone synthesis in lumen of follicle
-Thyroglobulin degradation in follicular cell, then hormone secretion
-Multi-step regulation by TSH
*Secreted hormone bound to plasma proteins (esp. TBP)
*Target tissues
-Convert most T4 to T3
-Multiple tissue responses
What would be the likely effect of 5 days without dietary iodine on,
TRH, TSH, T3, T4
If someone goes 5 days without dietary iodine, the following effects on TRH, TSH, T3, and T4 levels would likely occur:
- T3 and T4 Levels:
T3 and T4 levels would decrease. Iodine is a crucial component for the synthesis of thyroid hormones (T3 and T4). Without sufficient iodine, the thyroid gland would not be able to produce adequate amounts of these hormones.
However, after just 5 days without iodine, the decrease might be mild since the body has some stored iodine reserves. - TSH Levels:
TSH levels would increase. As T3 and T4 levels fall, the anterior pituitary detects this decrease and responds by secreting more thyroid-stimulating hormone (TSH). TSH stimulates the thyroid to increase hormone production. In the absence of sufficient iodine, the thyroid is unable to keep up with TSH stimulation, leading to elevated TSH levels. - TRH Levels:
TRH levels would increase. As T3 and T4 levels decrease, the hypothalamus would sense the drop and increase its production of thyrotropin-releasing hormone (TRH) to stimulate the pituitary to release more TSH. This increase in TRH is part of the negative feedback loop attempting to restore normal thyroid hormone levels.
Summary:
T3 and T4: Would decrease due to insufficient iodine for hormone synthesis.
TSH: Would increase to stimulate more thyroid hormone production.
TRH: Would increase in response to low T3 and T4 levels.
The overall result is an attempt by the body to compensate for low thyroid hormone levels by stimulating the thyroid gland to produce more, but this is limited by the lack of available iodine.
How might a loss of deiodinase 2 activity affect physiology?
A loss of deiodinase 2 (DIO2) activity would significantly impact thyroid hormone regulation, particularly the conversion of the inactive T4 (thyroxine) to the active T3 (triiodothyronine). Deiodinase 2 is responsible for converting T4 into T3 in peripheral tissues like the brain, pituitary, muscle, and brown fat.
Physiological Effects:
- Reduced Active T3:
Without DIO2, there would be less conversion of T4 to T3, leading to lower levels of T3, the more potent thyroid hormone responsible for most of the hormone’s biological effects (like regulating metabolism, growth, and development).- symptoms would be similar to someone that has hypothyroidism
2.Compensatory Increase in T4:
The body may respond by increasing T4 production due to feedback from the hypothalamus and pituitary, but this would still not compensate fully because T4 alone is less active than T3.
- Impaired Metabolic Function:
Lower T3 levels would impair the body’s metabolic processes. Symptoms could include weight gain, fatigue, cold intolerance, slowed heart rate, and cognitive issues.
- Hypothyroid-Like Symptoms:
Even though the thyroid gland may still produce normal amounts of T4, the lack of conversion to T3 can lead to symptoms similar to hypothyroidism.
- Impact on Specific Tissues:
Tissues that rely heavily on DIO2 for local T3 production, such as the brain and pituitary, may experience reduced T3 signaling, leading to cognitive dysfunction, mood changes, and impaired feedback on the hypothalamic-pituitary-thyroid axis.
- Disruption of Negative Feedback:
Lower T3 levels can impair feedback regulation, leading to an increase in TSH levels. This elevated TSH might cause thyroid gland overstimulation in an attempt to increase T3 levels.
Summary:
Loss of deiodinase 2 activity would reduce the production of active T3 from T4, leading to symptoms associated with hypothyroidism and metabolic dysfunction, despite potentially normal levels of circulating T4.
What would be the effect of iodine supplementation in Hashimoto’s disease?
Hashimoto’s disease, also known as Hashimoto’s thyroiditis, is an autoimmune condition in which the immune system attacks the thyroid gland, leading to chronic inflammation and eventual hypothyroidism (underactive thyroid). The thyroid gland becomes less capable of producing sufficient thyroid hormones (T3 and T4), and treatment typically involves thyroid hormone replacement.
The effect of iodine supplementation in someone with Hashimoto’s disease can vary and is a subject of careful medical consideration due to the complex relationship between iodine and thyroid function.
Potential Effects of Iodine Supplementation in Hashimoto’s Disease:
- likelihood is no impact as they lack a functioning thyroid to make use of the iodine
1.Worsening of Autoimmunity:
Excess iodine can exacerbate the autoimmune response. High levels of iodine may stimulate further autoantibody production (such as thyroid peroxidase antibodies, or TPO antibodies) in patients with Hashimoto’s, worsening the attack on the thyroid gland. This can accelerate thyroid tissue destruction and worsen hypothyroidism.
- Increased Risk of Hypothyroidism:
In individuals with Hashimoto’s disease, high iodine intake may overwhelm the thyroid gland, leading to impaired hormone synthesis. The thyroid may respond to excess iodine with a Wolff-Chaikoff effect, a phenomenon where iodine overload inhibits thyroid hormone synthesis, potentially leading to more severe hypothyroidism.
- Thyroid Hormone Dysregulation:
Hashimoto’s disease already impairs the thyroid’s ability to regulate hormone production, and additional iodine can lead to further dysregulation of hormone levels. Instead of helping, iodine supplementation can disrupt the delicate balance the thyroid is trying to maintain.
- Thyroid Nodules or Goiter:
Excess iodine can promote the development of thyroid nodules or goiter (an enlarged thyroid), especially in individuals with underlying thyroid dysfunction. This can occur as the thyroid tries to compensate for hormone imbalances.
When Might Iodine Supplementation Be Appropriate?
In cases where someone with Hashimoto’s disease has been found to have an iodine deficiency, careful iodine supplementation might be necessary. However, iodine deficiency is relatively rare in areas where iodized salt is commonly used. Any supplementation should be done under the guidance of a healthcare provider to avoid exacerbating the autoimmune response.
General Considerations:
Iodine-rich diets (such as those with high seaweed consumption) can worsen Hashimoto’s symptoms.
Selenium supplementation is often considered alongside iodine because selenium supports thyroid hormone metabolism and may help reduce antibody levels in some Hashimoto’s patients.
Conclusion:
In most cases, iodine supplementation in Hashimoto’s disease is not recommended unless there is a clear iodine deficiency. Excess iodine can worsen the autoimmune response, leading to increased inflammation, more severe hypothyroidism, and further damage to the thyroid gland. It is critical that iodine levels be carefully monitored in individuals with autoimmune thyroid diseases, and any supplementation should be managed by a healthcare provider.
Endocrinology:2
. The Thyroid Gland
Secretion of Thyroid Hormones
Secretion of Thyroid Hormones*Colloid droplets taken up by follicle cells by endocytosis
*Lysosomes fuse with colloid droplets–Thyroglobulin degrades–Degradation products recycled
*Released T3 and T4 hormones diffuse into fenestrated capillaries surrounding the follicles
*In blood, hormones bind to plasma proteins–Mostly thyronine-binding protein (TBP)–Some prealbumin (TBPA) & albumin–T4 binds with ↑ affinity → ↑ half life (t½)
