Thyroid Anatomy + Non-Neoplastic Pathology Flashcards
√Describe the embryology of the thyroid gland
SUMMARY (Cummings)
- Medial thyroid derives from the ventral diverticulum of the endoderm of the first and second pharyngeal pouches of the foramen cecum
- 4-7 GA: Diverticulum descends from the base of tongue to the pretracheal position. Proximal portion then retracts and degenerates into a fibrous stalk (persistence = TGDC)
- Lateral thyroid arise from fourth and fifth pharyngeal pouch and descend to join the medial portion
- Parafollicular C-cells arise from the neural crest of the fourth pharyngeal pouch as ultimobranchial bodies and infiltrate the upper portion of the thyroid lobes
DETAILS:
4 weeks GA:
- Endoderm on the floor of the pharynx between the 1st and 2nd arches invaginates and descends into the mesenchyme of the neck - this diverticulum is situated between the tuberculum impar (forms the oral tongue along with the lingual swellings) and the copula (forms the base of tongue)
4.5 weeks GA:
- Connection between the ventral thyroid diverticulum and the floor of the pharynx (foramen cecum) disappears
- Diverticulum develops into the median thyroid anlage
6-10 weeks GA:
- Thyroglossal duct has completed degenerated
- Cellular proliferation results in the right and left thyroid lobes, separated by an isthmus
- In up to 40-50% of individuals, the distal aspect of the duct persists as a pyramidal lobe
- The ultimobranchial body of the 4th arch fuses and is incorporated into the supero-lateral aspects of the thyroid lobes, and forms the parafollicular c-cells which secrete calcitonin
√What are the two types of capsules of the thyroid?
- True capsule: Peripheral condensation of the glandular tissue, gives rise to septa deep within thyroid parenchyma
- False capsule: Pre-tracheal layer of deep cervical fascia encapsulating thyroid
√What is the structural and functional unit of the thyroid?
FOLLICLES:
- A thyroid lobule is made up of aggregation of follicles
Histology:
- Follicles are lined by follicular cells, resting on a basement membrane, and have a cavity filled with colloid (homogenous gelatinous material)
- Colloid is composed of THYROGLOBULIN (protein made by thyroid gland, used to make T3/T4)
- Spaces between follicles = tissue stroma, capillaries, lymphatics
√Regarding follicular cells, discuss:
1. What are they?
2. What phases could follicular cells be in at any time?
3. What do follicular cells secrete?
4. What does the electron microscopy of a follicular cell look like?
FOLLICULAR CELLS:
- Lining cells of a thyroid follicle
- Follicular cells can have different levels of activity within the same thyroid tissue
PHASES:
1. Resting (inactive) phase: flat, squamous, abundant colloid within cavity
2. High active phase: columnar, scanty colloid
3. Moderately active phase: Cuboidal, reasonable colloid
FUNCTION (Secretes the following, influenced by TSH):
1. T3 (more active)
2. T4
ELECTRON MICROSCOPY:
1. Apical microvilli
2. Abundant granular endoplasmic reticulum
3. Supranuclear Golgi complex
4. Lysosomes
5. Microtubules
6. Microfilaments
√Regarding parafollicular C-cells, discuss:
1. What are alternative names?
2. Describe their structure and histology
3. Function
4. Electron microscopy
PARAFOLLICULAR C-CELLS:
- aka. Clear cells, light cells
- C stands for calcitonin (or clear)
STRUCTURE:
1. Polyhedral, pale-staining cells with oval and eccentric nuclei
2. Distributed BETWEEN follicular cells and their basement membrane; can also lie between adjoining follicular cells but do not reach the lumen; can also be seen between the follicles
FUNCTION:
- Secretes calcitonin (responsive to serum calcium levels)
- Other organs also secrete calcitonin: lungs, GI tract
ELECTRON MICROSCOPY:
1. Electron-dense secretory granules (100-200nm in diameter) of hormone calcitonin
√Regarding the anatomy of the thyroid, discuss:
1. Describe the lobes and size of the thyroid
2. What is Berry’s ligament?
THYROID GLAND:
- Two lateral lobes connected by a central isthmus
- 40% with a pyramidal lobe arising from either lobe, or midline isthmus and extends superiorly
- 15-25g in adults, ~4cm tall x 1.5cm width x 2cm depth
BERRY’S LIGAMENT:
- The middle layer of the deep cervical fascia posterior to the thyroid
- Condenses to form the posterior suspensory ligament (aka Berry’s), which connects the lobes of the thyroid to the cricoid cartilages and first 2 tracheal rings
√Describe the blood supply to the thyroid
TWO PAIRED ARTERIES PLUS IMA:
1. Inferior thyroid artery x 2
2. Superior thyroid artery x 2
3. Arteria Thyroidea Ima
Inferior thyroid artery:
- Arises from thyrocervical trunk (first branch of subclavian)
- Extends along anterior scalene and crosses beneath the long axis of the common carotid artery
- Lies anterior to RLN in 70% patients (landmark to find RLN at the tracheoesophageal groove - feel for the pulse)
- Main blood supply for parathyroid glands
Superior thyroid artery:
- First branch of the external carotid artery, courses along the inferior constrictor muscle and superior thyroid vein
- Courses posterolateral to the external SLN branch as it enters the cricothyroid muscle
Arteria Thyroidea Ima:
- May arise from the innominate, carotid, or aortic arch
- Supplies the thyroid gland near the midline
THREE PAIRS OF VEINS: All lead to internal jugular or innominate veins
1. Superior thyroid vein x 2
2. Middle thyroid vein x 2 (no arterial counterpart)
3. Inferior thyroid vein
√Regarding the recurrent laryngeal nerve, discuss:
1. Function
2. Embryology
3. What is a non-recurrent laryngeal nerve? When does this usually occur?
FUNCTION:
1. Motor supply to larynx
2. Some sensory supply to upper trachea and subglottis
EMBRYOLOGY:
- Inferior laryngeal nerves derive from sixth branchial arch
- Originate from the vagus under the sixth aortic arch
- RLN dragged caudally by the lowest persisting aortic arches
1. Right side - recurs around the 4th arch (subclavian)
2. Left side - recurs around the 6th arch (ligamentum arteriosum)
- Left RLN takes a more medial course (near the tracheoesophageal groove) compared to the right RLN (~2cm more lateral to trachea)
NON-RECURRENT LARYNGEAL NERVES:
- Usually occurs only on the right side, and enters a lateral course
- In almost all cases, an aberrant retroesophageal subclavian artery (Arteria lusoria) and other congenital malformation of vascular rings is present
See Laryngology notes for further details
√Regarding the superior laryngeal nerve, discuss:
1. What does the internal and external branches supply?
2. What does it typically travel with?
- Internal branch enters posterior thyrohyoid membrane to supply sensation to the supraglottis
- External branch extends medially along inferior constrictor muscle to enter the cricothyroid muscle
- Travels with the superior thyroid artery and vein
√What are the tubercles of Zuckerkandl?
Posterior extensions of each thyroid lobe
√Regarding the physiology of the thyroid gland, discuss:
1. What are the major hormones? What derivatives are they from?
2. What is the general pathway of thyroid hormone production?
3. Where is thyroid hormone storeed within the thyroid?
MAJOR HORMONES = Iodinated derivatives of tyrosine
1. T3: 3,5,3’-triiodothyronine
2. T4: Thyroxine; 3,5,3’,5’-tetraiodothyronine
PATHWAY:
Iodide + thyroglobulin = thyroid hormone
STORAGE: Within follicular lumen (storage of hormone and their derivatives)
√What are the 8 main steps in thyroid metabolism?
- Uptake of iodine by thyroid (stimulated by TSH)
- Requires at least 100µg of iodine per day
- Pendrin: Apical membrane protein that release iodide into follicular lumen (Pendred Syndrome = mutation of pendrin causing mild hypothyroidism, goiter, hearing loss) - Coupling of iodine to Thyroglobulin Tg (organification) –> makes Monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- Thyroglobulin = glycoprotein that serves as matrix for hormone synthesis from iodine and vehicle for storage
- Occurs through: oxidation of iodide, then transfer of oxidized iodide to thyrosyl residues on thyroglobulin - Storage of MIT/DIT in colloid (fills the follicles)
- Re-absorption of MIT/DIT
- MIT/DIT link together to form T3 + T4
- Catalyzed by THYROPEROXIDASE (TPO)
- MIT + DIT = T3
- DIT + DIT = T4 - Release of T3 and T4 into serum (90% released as T4)
- THYROXINE-BINDING GLOBULIN (TBG): Binds 75% of circulating hormone (< 1% of circulating hormone is free); contains one hormone binding site and has a higher affinity for T4
- TRANSTHYRETIN: Binds ~10% of circulating hormone; contains two hormone binding sites; first site has lower affinity than TBG, second site even lower than the first
- ALBUMIN: Binds ~10-20% of circulating hormone; overall low affinity thyroid binding protein
- Unbound (0.2% T4, 0.3% T3) - Higher amount of T3 is unbound, given lower affinity to TBG - Liver, kidney, muscle, and anterior pituitary convert T4 to T3
- T4 must be converted to T3 to exert biologic actions; enzymes are:
- Type I Deiodinase: Primary source of circulating T3; found in kidney, liver, thyroid; INHIBITED by Prophylthiouracil (PTU)
- Type II Deiodinase: Found primarily in CNS, pituitary, placenta, and skin; mainly involved in local T3 production
- Type III Deiodinase: Inactivates T3/T4, role in protecting tissues from excess thyroid hormone; found in brain, skin, placenta, and high levels in fetal tissues - Breakdown of T3 and T4 release iodine
- Feedback to TRH/TSH (T3 causes negative feedback)
- T3 causes negative feedback
- TSH/TRH causes positive feedback
√What is the percentage of thyroid hormone that is T4? Which thyroid hormone is more active?
98% T4
T3 is four times more active than T4
√Regarding T3 and T4, discuss:
1. What are the half lives of each?
2. Where are they converted?
3. What are the synthetic compounds?
T3:
- Half life 1 day
- Converted peripherally
- Much more active than T4 (6 weeks)
- Liothyronine (Cytomel) is manufactured T3
T4:
- Half life 5-7 days
- 80% bound to TBG (Thryoxine binding globulin)
- Levothyroxine is manufactured T4 (2 weeks)
√How long prior to RAI treatment should you withdraw thyroxine and cytomel?
Levothyroxine = 6 weeks
Liothyronine = 2 weeks
Note: rhTSH (Recombinant TSH) is used to stimulate TSH for patients on thyroid hormone suppression therapy
- Useful for preparing for RAI ablation and monitoring for recurrence of thyroid cancer
- Does NOT need to be stopped prior to RAI
√What increases your levels of thyroxine binding globulin? 1
What decreases it? 2
INCREASES:
1. Estrogen
DECREASES:
1. Steroids
2. Liver failure
√Describe the Hypothalamus-pituitary axis with respect to control of thyroid function.
What are the effects of TSH on the thyroid? List 6.
HYPOTHALAMUS: Secretes TRH (Thyrotropin-releasing hormone)
ANTERIOR PITUITARY: Secretes TSH (aka. Thyrotropin; thyroid-stimulating hormone)
THYROID: Thyroid hormone (provides negative feedback to system above)
EFFECTS OF TSH ON THYROID:
1. Increase iodide uptake into cells
2. Increase organification (forming MIT/DIT)
3. Increase Tg synthesis and proteolysis
4. Alters distribution of iodoamino acids within Thyroglobulin (hydrolysis) to release MIT to DIT and T3 to T4, and release these into circulation
5. Increases intrathyroidal converstion of T4 to T3 by Type I/II deiodinases
6. Improves storage of T3 + T4 in the gland as colloid
Maintains structure of thyroid cells, and stimulates gland size and vascularity
Note: Prolonged iodine deficiency = goiter (increased cell stimulation)
√What are the effects of thyroid hormone on fetal and neonatal development? What can develop if there is a deficiency in thyroid hormone in the fetus? What about an excess?
- Maturation of CNS, muscle, bone and lung
Cretinism: Severe deficiency of thyroid hormone during fetal development, resulting in mental retardation, deafness, mutism, and stunted growth
Excess of thyroid hormone in fetal development can result in neurologic abnormalities
√What are the general actions of thyroid hormone on the body? List 9.
- Increase metabolism of protein, carbohydrates, and fats
- Modulation of several enzyme activities
- Increase Cardiac output and heart rate
- Increase heat production
- Increase RBC mass
- Increase O2 consumption
- Increase metabolic rate (calorigenesis)
- Epinephrine potentiation
- Decrease cholesterol
√What are the different types of thyroid function studies that can be performed? 5
- Thyroid hormone measurement
- Serum TSH measurement
- Serum thyroglobulin measurement
- Thyroid antibody status
- Radioactive iodine uptake test
√Regarding the measurement of thyroid hormone, discuss:
1. What is measured?
2. What are the indications to obtain T3 level? 3
MEASUREMENTS USING RADIOIMMUNOASSAY:
1. T4 (most commonly obtained)
2. T3
INDICATIONS FOR SERUM T3 LEVEL:
1. Determine severity of hyperthyroidism
2. Confirm diagnosis of suspected thyrotoxicosis in cases of normal Serum T4 levels
3. Evaluate patients with autonomously functioning thyroid adenomas (may have normal T4 and suppressed TSH)
√What are the indications to obtain TSH measurement? 5
- Diagnosis of primary hypothyroidism (elevated TSH; degree may be determined by obtaining T4)
- Diagnosis of hyperthyroidism / subclinical hyperthyroidism
- Guidance of thyroid hormone replacement therapy
- Determination of TSH suppression in treating thyroid cancer
- Determination of suppressive therapy for nodular goiter (not commonly used in US)
√What is the utility of serum thyroglobulin measurement? What is the main indication?
Elevated in almost all types of thyroid disorders, thus not that useful of a test
Main indication:
- Monitoring well-differentiated thyroid carcinoma (elevated or increasing level after initial surgical or ablation therapy suggests persistence or recurrence of tumor)
√What are thyroid antibodies that can be measured? What are their indications?
ANTIBODIES: Present in autoimmune thyroid disease
1. Antithyroid antibodies (ATAs)
2. Antimicrosomal antibodies (AMAs)
3. Thyroid stimulating antibodies
AMA = Anti-TPO
- ~100% Hashimoto thyroiditis
- ~80% Graves disease
- Also positive in many other autoimmune diseases (e.g. lupus, RA, Sjogrens, T1DM, Addison’s disease)
- ATA less sensitive, but more specific (not as useful in autoimmune thyroid disease detection)
Measurement of Thyroid-Stimulating Antibodies
- Thyroid-stimulating immunoglobulin detectable in 90-95% of hyperthyroid Graves’ disease patients
- No indicated for routine diagnostic evaluation of suspected Graves’, but useful if diagnosis if not evident
√Regarding the Radioactive Iodine uptake test, discuss:
1. How does the procedure work?
2. What are the indications?
3. What is normal uptake?
RAI UPTAKE:
- Oral administration of iodine-123, followed by measurement of % in thyroid gland after 24 hours
INDICATIONS:
1. Differentiating high vs. low-uptake hyperthyroidism
2. Not as useful now for differentiation hypo vs. hyperthyroidism
Normal Uptake ~15-20%
√What are the 3 broad classes of anti-thyroid agents?
- Inhibits TH synthesis
- Inhibit TH secretion
- Inhibit TH metabolism
√What are the symptoms of hypothyroid? List as many as you can think of
- General:
- Weakness and fatigue
- Cold intolerance
- Weight gain
- Hair loss
- Edema of hands and face
- Thick, dry skin and dry hair
- Decreased tendency to sweat - GI symptoms:
- Constipation
- Anorexia
- Intermittent nausea and vomiting
- Dysphagia (more common if external compression)
- Bloating - GU symptoms:
- Menstrual disorders
- Polyuria - CVS symptoms:
- Bradycardia
- Hypertension
- Intermittent angina
- Pericardial effusion
- Peripheral edema - CNS symptoms:
- Daytime somnolence, nighttime insomnia
- Mental and physical slowness
- Headaches and dizziness
- Delayed reflexes
- Psychologic symptoms - depression, anxiety - MSK symptoms:
- Arthritis
- Stiffness of joints
- Muscle cramps - OHNS symptoms:
- Hearing loss
- Dizziness
- Tinnitus
- Voice aberrations (vocal cords may be thickened and polypoid along edges, causing harsh raspy voice)
- Middle ear effusion
- Slurred speech with enlarged tongue