Thyroid

An endocrine gland in the neck.

Embryology

• Originates from two separate precursor tissues, which then fuse to form the thyroid

Median thyroid precursor ('anlage')

• • • Forms from the primitive pharynx at G2
    • Appears as an epithelial proliferation in the floor of the pharynx between the tuberculum impar and copula, arising at the level of the second pharyngeal arch, between the first and second pharyngeal pouch
    • Descends towards the primitive heart, becoming a bilobed diverticulum with a median tubal structure called the thyroglossal duct, which keeps the structure connected to the tongue
    • Thyroglossal duct becomes a solid structure in the 5th week, after which it fragments and disappears, leaving the foramen caecum at the base of tongue superiorly, and the pyramidal lobe inferiorly (when present)
    • Thyroid continues to descend to its final position anterior to the trachea by the 7th week
    • Cells derived from median thyroid precursor arrange to form follicles and produce thyroid hormone by the 10th week of gestation

Lateral thyroid precursor

• • • Arises from the pharyngeal endoderm and fuses to the median precursor in the 5th week
    • Comprised of cells from the ultimobranchial body (ventral region of fourth pouch) which goes on to form the calcitonin-secreting parafollicular C cells
    • Comprises about one third of the eventual thyroid gland
    • According to Jamieson, also forms the tubercle of Zuckerkandl

Hyoid bone

• • • Formation of the hyoid bone is connected to the formation of the thyroid
    • Hyoids starts forming at 7th week and functionally divides the thyroglossal tract into superior and inferior aspects

Gross anatomy

• Reddish-brown in colour
• Rubbery in texture
• Two lobes connected by an isthmus 2-3mm thick
• Typical weight 20g, which is mostly made up from the right and left thyroid lobes. Each lobe has a narrow upper pole and a broader lower pole.
• 4-6cm in height, and 1.3-1.8cm in both transverse and A-P dimensions
• Resembles the silhouette of a butterfly in the A-P plane, with two lateral lobes connected by an isthmus draped over the upper trachea just caudal to the cricoid cartilage
• 50-65% of people have a pyramidal lobe - extending superiorly from the isthmus, representing the caudal remnant of the thyroglossal duct
• There is a small posterolateral pyramidal projection/bump called the tubercle of Zuckerkandl
  • A thickening from where the part from the lateral thyroid precursor (ultimobranchial body origin) fuses to the part from the median thyroid precursor (pharynx)
  • Intimately associated with RLN in many cases
• Surrounded by a fibrous capsule, which also forms separate 'pseudolobules' within the parenchyma itself
• The fibrous capsule also coalesces into a solid ligamentous structure at the posterolateral aspect of the upper trachea called the suspensory ligament of Berry (lateral ligaments of the thyroid gland), which is attached to the cricoid cartilage
• Avascular space of Reeves - medial to upper pole, between upper pole of thyroid, and cricothyroid muscle

Relations

• Deep to sternohyoid, sternothyroid, and superficial and middle layers of the deep cervical fascia
• Isthmus over second and third tracheal rings
• Each lobe's height extends from the level of the mid to upper aspect of the thyroid cartilage, down to the 5th or 6th tracheal ring
• Laterally extends to SCM and CCA
• Loosely attached to neighbouring structures - adheres only to the cricoid cartilage and the upper tracheal rings via the posterior suspensory, or 'Berry's', ligament

Arterial supply

Superior thyroid arteries

• • Originate from ECA - first branch, from anterior aspect
  • Divide as they enter the superior poles of the thyroid lobes
  • Can have a branch to parathyroid gland too

Inferior thyroid arteries

• • Branches from thyrocervical trunks of subclavian arteries, before running cephalad and posterior to the carotid sheath, before turning and entering from laterally at the level of mid-thyroid
  • Usually divides into two or three primary branches just before entering thyroid
  • Can have a branch to parathyroid gland too
  • Absent in 5%

Thyroid ima artery (2% of people only)

• • Arises directly from aorta or brachiocephalic artery
  • Follows a midline path and enters the thyroid isthmus or the inferior poles of the thyroid lobes

Venous drainage

Superior thyroid veins

• • Typically runs parallel to the superior thyroid arteries
  • Drains into IJV or facial vein (50/50)

Middle thyroid vein

• • Highly variable, but typically arises from the lateral aspect of the mid thyroid lobes
  • Drain into IJV

Inferior thyroid veins

• • Really more of a plexus that runs in a caudal direction from the inferior poles of the thyroid lobes
  • Drains into brachiocephalic veins

Lymphatics

• Lymphatic vessels course within the thyroid and drain into regional cervical lymph nodes
• Most lymphatic drainage from the thyroid goes to the peri-thyroidal lymph nodes in the central neck (VI), which includes the lymph nodes between the two carotid arteries and bounded by the hyoid bone superiorly and sternal notch inferiorly
  • 'Delphic node' just superior to isthmus
• Lateral neck jugular lymph nodes (Iia, III and IV) as well as those in posterior triangle (Vb) can also drain the thyroid
• Refer to 'neck' for description of levels

Related nerves

Autonomic

• • Directly supplied by a network of tiny autonomic nerves from the superior and middle cervical sympathetic ganglia, and parasympathetic fibres from the vagus

Recurrent laryngeal nerve

• • Embryology
    • Derived from the 6th pharyngeal arches, which form below the 6th aortic arches on each side
    • The nerves hook around 6th aortic arch structures and are pulled caudally during development
    • Parts of those arches then regress, leading to the final position of the nerve
    • Both nerves loop back, or 'recur', into the neck due to the heart and great vessels descending into the thorax, bringing the RLNs down with them
      • Left: The distal 6th arch persists as ductus arteriosum, and the 5th arch regresses. RLN loops under ligamentum arteriosum at the aortic arch and travels in the trache-oesophageal groove until it reaches the thyroid
      • Right: The distal 6th aortic arch and entire 5th arch regress, but the 4th arch persists as subclavian artery. RLN loops under the right carotid-subclavian artery junction  and migrates to the cricothyroid joint at the insertion into the larynx. It is therefore found in a slightly anterior plane and an oblique direction compared to the left RLN, which tends to stay deeper and straighter in the trache-oesophageal groove.

• Function
  • Most important nerve to the larynx
  • Innervates the motor function of all the intrinsic laryngeal muscles except for the cricothyroid
  • Sensory fibres from the lower larynx
  • Minor motor and sensory fibres from the trachea and oesophagus
• Path
  • Right:
    • From vagus nerve as it passes over right subclavian
    • Loops posteriorly under the artery, emerging medially to the right CCA in the central neck
    • Travels either within or in close proximity to the trach-oesophageal groove, along a slightly oblique course from lateral to medial (because it is pushed more laterally in the chest), and slightly more anterior to the left RLN
    • Can lie either in front of or behind the ITA
  • Left
    • Arises from left vagus as it crosses the aortic arch
    • Hooks posteriorly below the vessel, to the left and behind ligamentum arteriosum
    • Ascends on the right of the arch
    • Enters the trache-oesophageal groove, posterior to pre-tracheal fascia, and passes vertically
    • Most likely lies behind the ITA at the level of the thyroid
  • Both
    • Often makes a small 'knee' just prior to inserting to the larynx, which is the most common site for nerve injury
    • Dives into larynx beneath the inferior-most fibres of cricopharyngeus (inferior constrictor), behind the inferior cornu of the thyroid cartilage
• Landmarks
  • Characteristic glistening whitish colour compared to adjacent vessels; often has tiny blood vessels running along its surface (vasa nervorum).
  • Look first at mid-thyroid level, travelling within or in close proximity to the trache-oesophageal groove (60% of cases)
  • Tubercle of Zuckerkandl - the nerve is posterior to the tubercle in 90% of cases
  • Berry ligament/inferior thyroid artery are typically intimately associated with the nerve at the level of the cricoid cartilage. The nerve crosses the artery, usually posteriorly, and typically curves anteriorly toward the ligament before diving posteriorly again into the laryngeal insertion point at the cricothyroid joint (100% of nerves are posterior to ligament of Berry)
  • RLN always behind the ligament of Berry
  • Typically crosses the inferior thyroid artery perpendicularly as it travels into the larynx
  • RLN enters the larynx approximately 1cm below and just anterior to the readily palpable inferior cornu of the thyroid cartilage, just inferior to the lower edge of the inferior pharyngeal constrictor muscle (the most consistent RLN anatomical location in the neck)
• Variations
  • RLN may branch more proximally in 20-30% of cases - need to preserve all branches, especially the anterior branches, which predominantly provide motor function.
    • Typically occurs in the last 2cm of RLN
  • Non-recurrent laryngeal nerve -
    • Right (1%) - associated with aberrant right subclavian artery arising directly from the distal aortic arch instead of the innominate artery (the 'lusoria artery'). Right RLN then follows a straight path from vagus to larynx. If this condition is present, the right subclavian will pass posterior to oesophagus. Operative clue is that the carotid on that side is medial.
    • Left (extremely rare) - associated with situs inversus and a right-sided aortic arch
• Injury
  • Unilateral - paralysis of the ipsilateral vocal fold. Symptoms range from voice complaints such as hoarseness and vocal fatigue, to aspiration
    • I think if EBSLN is ok, the cord lies close to midline, and a lot of voice compensation from the other side can occur
    • If EBSLN is also damaged, the cord will be in mid-adduction, and hoarseness/inability to cough will be worse
  • Bilateral - bilateral vocal fold paralysis
    • Median position - prevent adequate air exchange - may require tracheostomy
    • Lateral position - high-risk for recurrent aspiration and pneumonia

External branch of superior laryngeal nerve

• • Anatomy
    • SLNs branch off vagus at the level of hyoid bone and run along the inferior pharyngeal constrictor, before running parallel to the upper aspect of the superior pole thyroid vessels and then terminating in the cricothyroid muscle
    • EBSLN typically runs fairly high above the thyroid lobe
    • Take care when ligating and dividing the superior pole vessels - can sometimes run quite close to the vessels and the upper thyroid lobe, and sometimes need to dissect it away
    • Cernea classification below
  • Function
    • Larynx - cricothyroid muscles, and contributes to vocal fold tone and tension
  • Injury
    • Paresis of ipsilateral cricothyroid, leading to inability to tighten ipsilateral cord
    • Difficulty achieving high pitch and vocal projection and volume

Internal branch of SLN

• • Supplies sensation to larynx above vocal cords

Histology

• Follicular cell
  • Predominant cell type
  • Responsible for production and secretion of thyroid hormone
• Parafollicular C cell
  • Secretes calcitonin
  • Located within the interfollicular stroma
  • Mainly found in the lateral aspect of the mid and upper thyroid lobes
• Histologic architecture
  • Arranged into spherical follicles containing colloid
  • Colloid is made up of thyroglobulin (Tg), which is the non-iodinated precursor to active thyroid hormone and acts as a reservoir

Variations

• Lingual thyroid - failure to migrate
• Thyroid rests - see above
• Hemi-agenesis
• Agenesis
• Thyroidea ima
• Pyramidal lobe
• Non-recurrent RLN

Physiology

Thyroid hormone

• • Synthesis
    • Occurs within the thyroid follicle unit, and is dependent on the presence of iodine
    • Follicular cells actively transport iodide anion across the cell membrane from the bloodstream into the cytoplasm via the Na/I symporter membrane protein, achieving a concentration within the follicular cells much higher than the systemic circulation
    • Iodide moves towards the follicular cell border with the colloid stores, and anions are oxidised to form the neutral I2 molecule, which can pass through the cell membrane into the colloid.
    • Colloid stores Tg, which contains a multitude of tyrosine residues. Colloid also contains the enzyme thyroid peroxidase (TPO), which catalyzes the next major step in thyroid hormone synthesis, which is the iodination of tyrosine residues on Tg, creating the molecule mono-iodotyrosine or di-iodotyrosine (DIT).
    • These two molecules form covalent bonds with one another to constitute the active forms of thyroid hormone tetra-iodothyronine or thyroxine (T4) (formed by two DITs and carrying four iodine molecules), or tri-iodothyronine (T3) (formed by a DIT and mono-iodotyrosine).
    • When stimulated by TSH, the follicular cells transport the activated thyroid hormones from the colloid centre into the bloodstream.
  • Function
    • >99% of circulating thyroid hormones are bound to transport proteins such as albumin and T4-binding globulins; <1% exists in free form
    • T3 is the more potent form, but there is normally a higher concentration of T4 compared to T3
    • Many target organs can convert T4 to T3 through the deiodinase system
    • T4 and T3 bind to mitochondrial receptors leading to increased ATP production and energy consumption to produce heat - primary driver of basal metabolic rate
    • Critical for normal development, especially neurological
    • Increases cardiac output and vasodilation
    • Influences normal reproductive function
  • Regulation
    • Low circulating T4 and T3 stimulate the hypothalamus to release thyrotropin-releasing hormone, which in turn stimulates the release of thyroid stimulating hormone from the anterior pituitary
    • TSH stimulates the formation of thyroid hormones by binding to its receptor on thyroid follicular cells - increased transport of iodine, as well as transport and release of T4 and T3 from the colloid into the bloodstream
    • Elevated T4 and T3 causes the reverse effect
  • Iodine
    • Average daily requirement 0.1mg, all through diet
    • Thyroid uses almost all of it

Calcitonin

• • Synthesis
    • Produces by parafollicular C cells
    • Not regulated by the same process as thyroid hormone
    • Release is stimulated by high serum calcium levels
  • Function
    • Poorly understood
    • Decreases serum concentration of calcium through its end effect actions on bone (increasing osteoblast and decreasing osteoclast activity), gut (decreasing calcium absorption), and kidney (increasing calcium excretion)
    • Absence of calcitonin does not lead to a noticeable change in calcium homeostasis

Thyroid physiology in pregnancy

• Maternal thyroid hormone production rises significantly in first trimester, and declines steadily afterward
• Thyroid dysfunction causes congenital defects up until the fetal thyroid can produce its own hormone, which occurs about the mid-second trimester

Thyroid biomarkers

• TSH
  • Secreted from anterior pituitary in pulsatile fashion, following circadian rhythm
  • Normal range 0.4-4.12mIU/L
  • Measurement can be affected by other illness (euthyroid sick syndrome) and medications such as glucocorticoids, frusemide, anticonvulsants and metformin
• T3 and T4
  • Because high proportions of both hormones are bound in systemic circulation, measurement of free T4/T3 is more useful than total levels, which can be affected by fluctuations in levels of transporter proteins
• Thyroid autoantibodies
  • TPOAb (anti-TPO)
    • Most accurate and most commonly used screening test for autoimmune thyroiditis (positive in >90% of patients, as well as 80% of patients with Graves disease; false positive rate 10-15%)
  • TgAb (anti-Tg)
    • 80% sensitivity for autoimmune thyroiditis and 30% sensitivity for Graves disease
    • 10-15% false positive rate
    • Presence of TgAb interferes with the use of Tg measurement for the surveillance of differentiated thyroid cancer
  • TRAb (anti-TSH receptor)
    • Reserved for diagnostic confirmation of Graves disease - positive in >90% of patients with the disease
    • Hypothesised to more closely correlate with severity of Graves
• Thyroglobulin (Tg)
  • Precursor protein for the active iodinated forms of thyroid hormone
  • Majority stored in colloid, but a small amount escapes into systemic circulation
  • Particularly elevated in patients with differentiated thyroid cancer, but it's not helpful prior to surgery. Post-operative serum Tg measurement after total thyroidectomy is among the most sensitive cancer biomarkers in existence (as long as TgAb is absent - check it at the same time).
  • Sensitivity can be augmented with TSH stimulation
• Calcitonin
  • Serum calcitonin is the most useful biomarker for detection and surveillance of medullary thyroid cancer
  • Can be performed in patients with or at risk of MTC (MEN2 syndrome)
  • Controversial whether it is a good test in the workup of a thyroid nodule