Ten/Eleven/Twelve Flashcards
(28 cards)
Describe the activity of the thyroid follicle cell including the various enzymes, receptors, substrates, etc. and what they do.
TSH binds to TSHR. This causes adenylate cyclase to form cAMP. cAMP first stimulates a sodium iodide symporter which results in iodide in the cell which is transported into the colloid by pendrin. cAMP also stimulates the production of thyroglobulin which is also released into the colloid. cAMP also stimulates TPO (thyroid peroxidase) which stimulates oxidation of iodide (I- to I2). TPO also stimulates the iodination of thyroglobulin which then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT) on the thyroglobulin. TPO also stimulates the coupling of MIT and DIT to form either T4 (levothyroxine or thyroxine) or T3 (Liothyroxine) which are bound to thyroglobulin. cAMP also stimulates the resorption of thyroglobulin, the lysosomal proteolysis of thyroglobulin (releasing T3 and T4) and the secretion of T3 or T4.
What are the regulators (including medications) of the activity of the thyroid follicle cell? What are their mechanisms?
Excess iodide inhibits TSH-stimulated T4/T3 release (?via inhibition of cAMP activity),
and this is the basis for iodide therapy in severe hyperthyroidism. The Thionamides
(Propylthiouracil, Methimazole) exert antithyroid effects by inhibiting the synthesis of thyroid
hormones. Mechanism: Inhibition of TPO activity, preventing oxidation of iodide and thereby
blocking coupling of iodine to thyroglobulin. Result: Depletion of performed hormone.
What percentage of T4 is bound to TBGs? Transthyretin? Albumin? Unbound? Which T4 is bioavailable? Same questions for T3? How do T4/T3 contrast in circulation?
Thyroid Hormone Transthyretin Albumen Free
Binding Globulin (TBG) Hormone
T4 Thyroid hormone binding globulin-70% Transthyretin-10% Albumin≈ 20% Free-0.03%*
T3 Thyroid hormone binding globulin-80% Transthyretin-10% Albumin≈ 10% Free-0.3%*
- T4 binds to serum proteins more tightly than T3, resulting in lower metabolic clearance rate, longer half-life (T4: 7 days, T3: 1 day). Like steroid hormones the bioavailable hormone levels more closely approximate free hormone + that bound to albumin.
How are T3, rT3, and T2 formed? What are the differences between the different thyroid hormones? What are 3 types of deiodinases? What do they do? Where? What is their substrate preference?
T4 is iodinated at the 3, 5, 5’, and 3’ positions. When the 5’ position is deiodinated, it becomes T3. If the 5 position is deiodinated, it becomes rT3. If both the 5 and the 5’ position are deiodinated, it becomes T2.
Type one can deiodinate at both the 5’ and 5 position. It provides T3 for the circulation and is found in the liver/kidney/thyroid/brain. It prefers rT3 then T4 then T3.
Type II can deiodinate at the 5’ position. It provides intracellular T3 for pituitary/brain (regulation of TSH and TRH) and brown adipose tissue, and T3 for the circulation. It is found in the pituitary/brain/brown adipose tissue/placenta/thyroid/skeletal and cardiace muscle. It prefers T4 over T3 a little bit.
Type Three can deodinate at the 5 position. It inactivates T4 and T3. It is located in the brain, placenta, and skin. It prefers T4 over T3.
What effect does illness have on Thyroid hormone metabolism? Explain the mechanism. Why might this be beneficial?
- Most nonthyroidal illness patients have low serum T3 levels.
- Free T4 levels are normal.
- TSH and TSH response to TRH normal.
- Serum rT3 levels elevated.
- Cause: decreased 5’-deiodinase activity of Type 1 deiodinase. (Less T3 formation in thyroid and more rT3 because loss of 5’-diodination of rT3 to 3,3’-diiodothyrine (T2).
- T3 and rT3 levels return to normal when illness resolves.
- This lowering of serum T3 levels may be beneficial, sparing protein catabolism.
Which two iodine containing drugs used in non-thyroidal illness have an effect on thyroid hormones? What is their mechanism? What are the results?
- Two iodine containing drugs used in nonthyroidal illness inhibit 5’-deiodinase in all tissues. (iopanoic acid used for radiographic visualization of the gallbladder, and
amiodarone used to treat cardiac arrhythmias). - Result: elevated T4 (loss of 5’deiodination) and elevated TSH levels (no T3 production in pituitary so failure of T3 to suppress TSH-induced TSH release, see below).
What is TSH like? What is the TSHR like and where is it located? What is the TRHR like and where is it located? Describe the regulation of TRH/TSH release including the mechanism. What effects do hyper and hypo thyroidism have on TRH receptor expression? What other hormone might blunt TSH secretion?
- TSH: (Thyroid Stimulating Hormone = Thyrotropin) two
chain glycoprotein, α chain same as LH and FSH, β chain confers unique bioactivity. - TSH receptor in thyroid follicular cells is a G-protein coupled to adenylyl cyclase. All actions of TSH in these cells can be mimicked by cAMP.
- TRH (Thyrotropin Releasing Hormone) receptor on thyrotrophs signals via PLC hydrolysis of PIP2 forming IP3 and DAG, and exocytosis.
- Thyroid hormone negative feedback due to local T4 to T3 conversion (by Type 2 deiodinase) in brain and pituitary gland, resulting in decreased transcription of the pro-TRH, TSHα and TSHβ genes.
- Thyroid hormones also blunt the TSH-releasing activity of TRH (i.e. non-transcriptional effects too).
- Hypothyroidism increases and hyperthyroidism decreases TRH receptor expression on thyrotrophs.
- Glucocorticoid excess may also blunt TSH secretion.
Describe the mechanism of Thyroid hormones on their target cell.
- Primarily via interaction of T3 with nuclear receptors resulting increased transcription of several genes.
- Functionally thyroid hormones stimulate the cell surface Na+,K+-ATPase and therefore increase oxygen consumption.
- Increased ATPase activity is due to increased number of “pump units,” not an increase in the activity of pre-existing enzyme molecules.
- Increased number of myocardial β-adrenergic receptors.
- Increased activity of uncoupling proteins in mitochondria.
What effects do thyroid hormones have on calorigenesis? What does that mean? What are the mechanisms? What effect do thyroid hormones have on protein metabolism at different levels? Carbs? Lipids?
- Stimulate calorigenesis (i.e. increase basal metabolic rate).
- Increased Na+,K+ -ATPase activity is only part of the effect.
- Effects on mitochondrial oxidative phosphorylation are the major reason.
- Thyroid hormones stimulate Uncoupling Protein 3 (in skeletal muscle and heart) resulting in a bypass of ATP synthase and increased calorigenesis.
- Thyroid hormones stimulate protein synthesis (at normal levels) and degradation (when excess hormone present).
- Effects on carbohydrate metabolism include
a. Enhancement of actions of epinephrine to stimulate glycogenolysis (at high levels of hormone) and gluconeogenesis
b. Potentiate the action of insulin on glycogen synthesis (at low levels of hormone) and glucose utilization.
c. Enhance rate of intestinal glucose absorption and uptake into adipocytes and muscle. - Effects on lipid metabolism include:
a. When thyroid hormones low or absent, cholesterol synthesis and metabolism is decreased, but serum cholesterol levels actually increased because metabolism is inhibited more that synthesis.
b. In thyroid hormone excess, serum levels of cholesterol, phospholipids and triglycerides fall. (?Due to increased number of low-density lipoprotein receptors on the cell surface.)
Summarize the effects of T3/T4 at low levels and at high levels.
Summary of Thyroid Hormone Effects
Low levels T4/T3
Potentiate insulin’s action
Decrease cholesterol metabolism (raise serum cholesterol levels)
High levels T4/T3
Decrease serum cholesterol, phospolipids and tryglycerides
Increase protein degradation
Stimulate glycogenolysis and (glycogen synthesis, glucose utilization) gluconeogenesis
What is the thyroglossal duct cyst? What is its pathogenesis? How does it present?
I. THYROGLOSSAL DUCT CYST
A. Cystic dilation of thyroglossal duct remnant
1 . Thyroid develops at the base of tongue and then travels along the thyroglossal duct to the anterior neck.
2. Thyroglossal duct normally involutes; a persistent duct, however, may undergo cystic dilation,
B. Presents as an anterior neck mass
What is a lingual thyroid? How does it present?
U. LINGUAL T H Y R O I D
A. Persistence of thyroid tissue at the base of tongue
B. Presents as a base of tongue mass
What is the basic pathogenesis of hypothyroidism? What are 12 clinical features?
A. Increased level of circulating thyroid hormone
1 , Increases basal metabolic rate (due to increased synthesis of Na’-K” 1 ATPase)
2. Increases sympathetic nervous system activity (due to increased expression of beta-adrenergic receptors!
B. Clinical features include
1 . Weight loss despite increased appetite
2. Heat intolerance and sweating
3 . Tachycardia with increased cardiac output
4. Arrhythmia (e.g., atrial fibrillation), especially in the elderly
5 . Tremor, anxiety, insomnia, and heightened emotions
6. Staring gaze with lid lag
7. Diarrhea with malabsorption
8 . Oligomenorrhea
9. Bone resorption with hypercalcemia (risk for osteoporosis)
10. Decreased muscle mass with weakness
11. Hypocholesterolemia
12. Hyperglycemia (due to gluconeogenesis and glycogenosis)
What is the pathogenesis of graves disease? Who does it classically appear in? What are the clinical features and their mechanisms?
II. GRAVES DISEAS E
A. Autoantibody (IgG) that stimulates TSH receptor (type II hypersensitivity)
B. Leads to increased synthesis and release of thyroid hormone
1 . Most commo n cause of hyperthyroidis m
2. Classically occurs in women of childbearing age (20-40 years)
C. Clinical features include
1 . Hyperthyroidism
2. Diffuse goiter—Constant TSH stimulation leads to thyroid hyperplasia and hypertrophy (Pig. 15.1 A).
3 . Exophthalmos and pretibial myxedema
i. Fibroblasts behind the orbit and overlying the shin express the TSH receptor.
ii. TSH activation results in glycosaminoglycan (chondroitin sulfate and hyaluronic acid) buildup, inflammation, fibrosis, and edema leading to exophthalmos and pretibial myxedema.
What is the pathology of graves disease?
D. Irregular follicles with scalloped colloid and chronic inflammation are seen on histology (Fig. 15.IB).
E. Laboratory findings include
1 . Increased total and free T4 (free T4, down regulates TRH receptors in the anterior pituitary to decrease TSH release)
2. Hypocholesterolemia
3 . Increased serum glucose
F. Treatment involves (5-blockers, thioamide, and radioiodine ablation.
What is thyroid storm? What is the cause? How does it present? What is the treatment? What is the mechanism of the treatment?
G. Thyroid storm is a potentially fatal complication,
1 . Due to elevated catecholamines and massive hormone excess, usually in response to stress (e.g., surgery or childbirth)
2. Presents as arrhythmia, hyperthermia, and vomiting with hypovolemic shock
3 . Treatment is propylthiouracil (PTU), (beta-blockers, and steroids).
i. PTU inhibits peroxidase-mediated oxidation, organification, and coupling steps of thyroid hormone synthesis, as well as peripheral conversion of T4 to
T3
What is a multinodular goiter? What causes it? What is the usual result? What is another possible result?
III. MULTINODULAR GOITE R
A. Enlarged thyroid gland with multiple nodules (Fig. 15.2)
B. Due to relative iodine deficiency
C. Usually nontoxic (euthyroid)
D. Rarely, regions become TSH-independent leading to T release and hyperthyroidism (‘toxic goiter’).
What is cretinism? How is it characterized? What is the pathogenesis of this presentation? What are some causes? Mechanism of dyshormonogenetic goiter?
I CRETINIS M
A. Hypothyroidism in neonates and infants
B. Characterized by mental retardation, short stature with skeletal abnormalities, coarse facial features, enlarged tongue, and umbilical hernia
1 . Thyroid hormone is required for normal brain and skeletal development.
C. Causes include maternal hypothyroidism during early pregnancy, thyroid agenesis, dyshormonogenetic goiter, and iodine deficiency.
1 . Dyshormonogenetic goiter is due to a congenital detect in thyroid hormone production; most commonly involves thyroid peroxidase.
What is myxedema? What are the clinical features? What are the most common causes?
II. MYXEDEM A
A. Hypothyroidism In older children or adults
B. Clinical features are based on decreased basal metabolic rate and decreased sympathetic nervous system activity.
1 . Myxedema—accumulation of glycosaminoglycans in the skin and soft tissue; results in a deepening of voice (larynx) and large tongue
2. Weight gain despite normal appetite
3. Slowing of mental activity
4. Muscle weakness
5. Cold intolerance with decreased sweating
6. Bradycardia with decreased cardiac output, leading to shortness of breath and fatigue
7. Oligomenorrhea
8. Hypercholesterolemia
9. Constipation
C. Most commo n causes are iodine deficiency and Hashimoto thyroiditis; other causes include drugs (e.g., lithium) and surgical removal or radioablation of the thyroid.
What is Hashimoto thyroiditis? Pathogenesis? 3 clinical features? What is the pathology? What are they at increased risk for? How does that present?
I . H A S H I M O T O T H Y R O I D I T I S
A. Autoimmun e destruction of the thyroid gland; associated with HLA-DR5
1 . Most common cause of hypothyroidis m in regions where iodine levels are adequate
B. Clinical features
1 . Initially may present as hyperthyroidism (due to follicle damage)
2. Progresses to hypothyroidism; Decr. T4 and incr. TSH
3 . Antithyroglobulin and anti microsomal antibodies are often present (sign of thyroid damage).
C. Chronic inflammation with germinal centers and Hurthle cells (eosinophilic metaplasia of cells that line follicles) is seen on histology (Fig. 15.3).
D. Increased risk for B-cell (marginal zone) lymphoma; presents as an enlarging thyroid gland late in disease cours e
What is subacute granulamatous thyroiditis? How does it present? What is the prognosis?
II. SUBACUT E G R A N U L O M A T O U S (DE QUERVAIN ) T H Y R O I D I T I S
A. Granulomatous thyroiditis that follows a viral infection
B. Presents as a tender thyroid with transient hyperthyroidism
C. Self-limited; does not progress to hypothyroidism
What is Reidel fibrosing thyroiditis? What is the pathology? How does it present? In which patients?
III. REIDE L FIBROSING T H Y R O I D I T I S
A. Chronic inflammatio n with extensive fibrosis of the thyroid gland
B. Presents as hypothyroidis m with a ‘hard as wood, ‘ nontender thyroid gland
C. Fibrosis may extend to involve local structures (e.g., airway).
1 . Clinically mimic s anaplastic carcinoma, but patients are younger (40s), and malignant cells are absent
How does a thyroid neoplasia usually present? How test is used to further characterize it? What do the results mean? How is it biopsied? What are the 4 types of thyroid carcinoma? Which is most common?
BASIC PRINCIPLE S
A. Usually presents as a distinct, solitary nodule
1 . Thyroid nodules are more likely to be benign than malignant,
B . radioactive iodine uptake studies are useful to further characterize nodules.
1 . Increased uptake (‘hot’ nodule) is seen in Graves disease or nodular goiter.
2. Decreased uptake (‘cold’ nodule) is seen in adenoma and carcinoma; often warrants biopsy
C. Biopsy is performed by line needle aspiration (FNA).
Papillary-Most common
Follicular
Medullary
Anaplastic
What is a follicular adenoma? What is it like?
n . FOLLICULAR A D E N O M A
A. Benign proliferation of follicles surrounde d by a fibrous capsule (Fig. 15,4)
B, Usually nonfunctional; less commonly, may secrete thyroid hormone
