Lecture 35 Flashcards
Where is the medulla of the thyroid gland?
Between the follicles
What does the medulla contain?
Neural crest- derived parafollicular C-cells that produce and release calcitonin
What triggers calcitonin release by C-cells?
Increased serum calcium
What is calcitonin?
32 aa protein enoded by a gene located on chromosome 11 p, which is also expressedi n other tissues as calcitonin gene-related peptide (CGRP, 37aa)
What is the function of CGRP?
Acts as both a neurotransmitter and vasodilator properties and is involved in completion of the process of testicular descent.
What is the main function of calcitonin?
Antagonize the effects of parathyroid (decrese bone resorption and increase renal calcium excretion)
What is a nutritional disorder related to hypercalcitoninemia?
High Ca-diet leading to mineral imbalance
What kind of cancer can hypercalcitoninemia lead to?
Thyroid Neoplasia (ex. medullary thyrid carcinoma in humans and ultimobranchial tumors in bulls)
How are ultimobranchial bodies affected by ultimobranchial tumors?
Ultimobranchial bodies fuse with the thyroid gland and are thought to develop into the parafollicular cells.
How is T3/T4 formed?
- Iodide is cotransported with sodium via an ATP driven sodium-iodide symporter (iodide trap)
- Diffusion of iodide to the apical plasma membrane
(Thyroid peroxidase (TPO) reduces H2O2, elevating the oxidation state of iodide to an iodinating species, and attaches the iodine to tyrosyls in thyroglobin (TG) in a nonspecific manner) - Iodide is oxidized and attached to rings of tyrosines in thyroglobulin (DIT if 2 iodine, MIT if 1 iodine)
- The iodinated ring of one MIT or DIT is added to another DIT to form T3 or T4 respectively
- Endocytosis of thyroglubulin containing T3 and T4
- Lysosomal enzymes release T3 and T4 from TG
- T3 and T4 secretion (1:20)
How is thyroglobulin synthesized?
- Free amino acids re-used for TG synthesis
- TG is synthesized in follicle cell and secreted to colloid
T4 is much more potent than T3
FALSE - much less potent with a longer half life (5-7 days vs. 18 hours)
TH effects are chronic
TRUE - The biological effect of T3 is more rapid and requires 3 days for peak effect vs 11 days for T4
How is T3 activated?
T4 is converted to active T3 at target tissue by 5’-mono-deiodinase action.
How does T3 function?
After T4 goes through deiodination across the cell membrane, T3 binds to nuclear receptors and initiates transcription of a variety of proteins and enzymes
Overall effects of thyroid hormone
Increase metabolic rate and O2 consumption as well as many general effects in target audience
What causes deiodination?
Selenium-containing deiodinases are involved in T4 metabolism, thus dietary selenium is essential for active T3 production
What other proteins and hormones are created due to T3 binding to nuclear receptor and that bind to intracellular/nuclear receptors (aka transcription factors)?
- Steroid hormones
- Prostaglandins
- Vitamin D
- retinoic acid
- thyroid hormones
What permissive effects are caused via nuclear receptor transcription factors?
Normal growth and development of bones and central nervous system
What intracellular effects occur due to the nuclear receptor?
- Increased mitochondria activity
- Increased respiratory enzyme activity
- Increased sodium-potassium-ATPase activity
- Increased activity of other enzymes
Which leads to
- Increased O2 consumption
- Increased metabolic rate
What whole body effects occur due to increased O2 consumption and increased metabolic rate?
- Increased CO2 and ventilation in lungs
- Increased cardiac output
- Increased urea and renal function in kidneys
List symptoms of hyperthyroidism
- Nervousness
- Weight loss
- Diarrhea
- Tachycardia
- Insomnia
- Increased appetite
- Heat intolerance
- Oligomenorrhea (sparce and infrequent menstrual cycles)
- Muscle wasting
- Goiter
- Exophthalmos
List symptoms of hypothyroidism
- Lethargy, slow cerebration
- Weight gain
- Constipation
- Bradycardia
- Sleepiness
- Anorexia
- Cold intolerance
- Menorrhagia (heavy menstrual cycles)
- Weakness
- Dry, coarse skin, Goiter
- Facial edema
List causes of hypothyroidism
- Most often caused by Hashimoto’s disease (autoimmune lymphocytic thyroiditis)
- Iatrogenic interventions (surgery, radioactive iodine treatment, drugs such as lithium)
- Dietary (Iodine deficiency; ‘goitrogen’ vegetables)
Sequelae of hypothyroidism
- Deficiency of thyrod hormones slows down metabolism but clinical presentation depends on the duration and severity of hormone deficiency
- Cretinism
- Myxedema
What is Cretinism?
Deficiency during fetal development that causes stunted growth and potential mental retardation
Usual cause of Cretinism?
Maternal hypothyroidism before fetal thyroid is developed.
Thyroid gland is active in fetal life
TRUE - alongside iodide from maternal circulation, fetal production of T4 reaches a clinically significant level at 18-20 weeks
Cretinism causes neurodevelopmental disorders
FALSE - fetal self-sufficiency of thyroid hormones protects the fetus, but preterm births combined with cretinism can suffer neurodevelopmental disorders because their own thyroid is insufficiently developed to meet their post natal needs
What is Myxedema?
Thyroid deficiency in adulthood, which presents as coarse puffy skin due to retention of fluid in the dermis of the skin
What are the lab results for hypothyroidism?
- Lowered T4
- Increased TSH
Hypothyroidism is 6x more common in women
TRUE - and affects 1:100 adults
Iodine deficiency is rare in the US
TRUE - 1:10000 molecules in salt is NaI instead of NaCl
What is a goiter?
Enlargement of the thyroid gland because of a lack of negative feedback on the anterior pituitary so TSH continues to be secreted uninhibited. Can be seen in both hypothyroidism and hyperthyroidism.
What is Hashitoxicosis/Hashimoto Thyroiditis?
A rare case where hypothyroidism doesn’t develop gradually because it is preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones.
How are lab levels affected by Hashitoxicosis?
Increased T4/T3 and decreased TSH and radioactive iodine uptake is decreased
Hashimoto thyroiditis is more common in women than men
TRUE - Somewhere between 10:1 to 20:1
What are the three proposed models for mechanism of thyrocyte destruction?
- T-cell-mediated cytotoxicity (CD8+ cytotoxic T-cell uses FasL to bind to Fas and kill the thyrocyte)
- Thyrocyte injury (CD4+ TH1 cell uses gamma-IFN to create an activated macrophage which injures the thyrocytes)
- Antibody-dependent cell mediated cytotoxicity (Plasma cell attaches to thyrocyte via anti-thyroid antibodies that attach to the Fc receptor on the plasma cells. The plasma cell then transforms into a NK cell.)
What is the common first step between the three proposed models for mechanism of thyrocyte destruction?
T-cell sensitization to thyroid antigens
Hyperthyroidism causes:
- In 75% of all cases, Graves’ disease
- Nodular goiter or solitary hyper-functioning adenoma in the thyroid or pituitary gland
What is Grave’s disease?
An autoimmune disease in which autoantibodies called thyroid-stimulating immunoglobulins or TSIs are produced against TSH receptors
Sequelae of Hyperthyroidism
- Characterized by an increased metabolic rate and acceleration of many physiologic functions
- Exophthalmos
- Tachycardia
- Goiter
- 1:50 women, 1:250 men
Lab results for hyperthyroidism
- Decreased TSH
- Increased T3, T4
- Increased antibodies to thyroid
Causes of Graves’ Disease
- Autoantibodies produced by plasma cells derived from sensitized T cells against TSH receptors present at the basal surface of thyroid follicular cells, bind to the receptor and mimic the effect of TSH. -> thyroid follicular cells become columnar and secrete large amounts of thyroid hormones into the blood circulation in an unregulated fashion
- Inflammatory cells in the stroma of the thyroid gland produce cytokines (IL-1, TNF-alpha, and interferon-gamma), that stimulate thyroid cells to produce cytokines, thus reinforcing the thyroidal autoimmune process
Symptoms of Graves’ Disease
- Goiter
- Exophthalmos
- Tachycardia
- Warm skin
- Fine finger tremors
Treatment of Graves’ Disease
Anti-thyroid drugs reduce the production of cytokines (immunosuppressive effect) leading to remission in some patients
How do cytokines cause hyperthyroidism by increased production?
It stimulates the production of iodothyroglobulin by increasing thyroglobulin production, which increases the use of iodine in the cell -> more diffusion of iodine.
What is Graves’ ophthalmopathy?
Inflammation of extraocular muscles and increase in orbital adipose and connective tissue due to Graves’ disease
What causes Graves’ ophthalmopathy?
- Circulating anti-TSHr ligands bind to TSH receptor expressed by the fibroblasts in the tretrobulbar tissue
- Cytokines produced by T cells stimulate adipogenesis from preadipocyte fibroblasts
- Fibroblasts produce proteoglycans and collagen fibers
- Retrobulbar edema and fibrosis of extraocular muscles occur
- Exophthalmos caused by the increased muscle pushing on the eye
How does hyperthyroidism cause tachycardia?
-T3 enters nucleus of a cardiocyte and binds to nuclear receptors and thyroid hormone response element in genes
- T3 stimulates phospholamban, a protein involved in the release and uptake of calcium into the sarcoplasmic reticulum (critical for systolic contraction and diastolic relaxation)
- Phospholamban is regulated by phosphorylation which increases diastolic function and is related to the thyroid hormone-mediated changes in contractility of cardiac muscle
In addition to phospholamban, what does T3 also regulate?
Gene expression for encoding Beta-adrenergic receptors, Calcium-ATPase and other proteins in cardiomyocytes
What is thyroid storm?
Complication of hyperthyroidism/thyrotoxicosis with infection or physical manipulation
How does thyroid storm present?
- Fever
- Agitation
- Confusion
- Irregular heartbeats leading to heart failure (especially in older patients)
Thyroid storm prevention
Suppress thyroid function with anti-thyroid drugs called thionamides such as propylthiouracil (PTU) in severe cases of Grave’s disease
Treatment for thyroid storm
- Beta blocker to inhibit beta-adrenoreceptors
- Drug such as PTU which inhibits iodination and conjugation steps of TH synthesis
- Sodium iodide which blocks the release of synthesized TH and causes a transient decrease in TH synthesis by preventing iodine organification in an autoregulatory mechanism known as the Wolff-Chaikoff effect
How does ANS increase of calcium uptake differ from hyperthyroid calcium uptake in cardiomyocytes?
- Catecholamines (fight or flight neurohormones) uptake into sarcoplasmic reticulum which increases the rate of myocardial relaxation called lusitropy
- Hyperthyroid uptakes in the cytosol which leads to incresed myocardial contractility called positive intropy while myocardial relaxation is decreased
How can thyroid disease be assessed in a clinical setting?
- Fine-Needle Aspiration (cytology)
- Hormonal Evaluation (primary vs. secondary vs. tertiary)
- Radioactive Iodine Uptake
Why is fine needle aspiration used in testing for thyroid disease?
Useful risk stratification to avoid unnecessary surgery as nodules are benign >95% of the time.
How is radioactive iodine uptake testing fo thyroid disease?
Hyperactive gland takes up increased amounts of the tracer whereas an underactive gland would take up subnormal amounts
When would a low dose of radioactve iodine be used?
- To test if a nodule is hot (functioning; likely benign) or cold (nonfunctioning; likely malignant)
- If hyperthyroidism is due to thyroiditis there will be minimal uptake vs. Graves’ disease (increased uptake).
When would a high dose of radioactive iodine be used?
To treat hyperthyroidism
What are the risks of using radioactive iodine to treat hyperthyroidism?
- May kill thyroid but easy to maintain as synthetics are inexpensive
- Other risks are minimal
Where does medullary thyroid carcinoma originate from?
Parafollicular C-cells
Where does papillary carcinoma orignate from?
Follicular cells that produce thyroglobulin
What histopathology feature is characteristic of papillary carcinoma?
Nuclear changes:
- Prominent clearing
- Nuclear grooves
- Membrane bound nucleoli
What histopathology feature is characteristic of Hashimoto’s Thyroiditis?
Bigger circular blue cells called Hurthle cells
