Anatomy, physiology and pathology of the thyroid gland

Dr Andrew Potter Registrar Department of Radiation Oncology Royal Adelaide Hospital

Anatomy

Thyroid gland
Single, bilobed gland in the neck Largest of all endocrine glands Produces hormones
thyroxine (T4) and tri-iodothyronine (T3) are dependent on iodine and regulate basal metabolic rate calcitonin which has a role in regulating blood calcium levels

Unique among human endocrine glands it stores large amount of inactive hormone within extracellular follicles

Structure - macro
Brownish-red and soft during life Usually weighs about 25-30g (larger in women) Surrounded by a thin, fibrous capsule of connective tissue
External to this is a false capsule formed by pretracheal fascia

Right and left lobes

United by a narrow isthmus, which extends across the trachea anterior to second and third tracheal cartilages

In some people a third pyramidal lobe exists, ascending from the isthmus towards hyoid bone

Position and relations

Clasps anterior and lateral surface of pharynx, larynx, oesophagus and trachea like a shield Lies deep to sternothyroid and sternohyoid muscles Parathyroid glands usually lie between posterior border of thyroid gland and its sheath (usually 2 on each side of the thyroid), often just lateral to anastomosis between vessel joining superior and inferior thyroid arteries Internal jugular vein and common carotid artery lie postero-lateral to thyroid

Position and relations

Recurrent laryngeal nerve is an important structure lying between trachea and thyroid
may be injured during thyroid surgery p ipsilateral VC paralysis, hoarse voice

Each lobe
pear-shaped and ~5cm long extends inferiorly on each side of trachea (and oesophagus), often to level of 6th tracheal cartilage

Attached to arch of cricoid cartilage and to oblique line of thyroid cartilage

moves up and down with swallowing and oscillates during speaking

CT appearance

Surface anatomy

Arterial supply
highly vascular main supply from superior and inferior thyroid arteries
lie between capsule and pretracheal fascia (false capsule)

all thyroid arteries anastomose with one another on and in the substance of the thyroid, but little anastomosis across the median plane (except for branches of superior thyroid artery)

Arterial supply
superior thyroid artery
first branch of ICA descends to superior pole of gland, pierces pretracheal fascia then divides into 2-3 branches

inferior thyroid artery

branch of thyro-cervical trunk runs superomedially posterior to carotid sheath reaches posterior aspect of gland divides into several branches which pierce pretracheal fascia to supply inferior pole of thyroid gland intimate relationship with recurrent laryngeal nerve in ~10% of people the thyroid ima artery arises from aorta, brachiocephalic trunk or ICA, ascends anterior to trachea to supply the isthmus

Venous drainage
usually 3 pairs of veins drain venous plexus on anterior surface of thyroid
superior thyroid veins drain superior poles middle thyroid veins drain lateral parts
superior and middle thyroid veins empty into internal jugular veins

inferior thyroid veins drain inferior poles

empty into brachio-cephalic veins often unite to form a single vein that drains into one or other brachio-cephalic vein

Lymphatic drainage
lymphatics run in the interlobular connective tissue, often around arteries communicate with a capsular network of lymph vessels pass to prelaryngeal LNs p pretracheal and paratracheal LNs lateral lymphatic vessels along superior thyroid veins pass to deep cervical LNs some drainage directly into brachio-cephalic LNs or directly into thoracic duct

Innervation
nerves derived from superior, middle and inferior cervical sympathetic ganglia
reach thyroid through cardiac and laryngeal branches of vagus nerve which accompany arterial supply

postganglionic fibres and vasomotor indirect action on thyroid by regulating blood vessels

Structure - micro
Functional units are follicles responsible for synthesis and secretion of T3 and T4
Irregular spheroidal structures consisting of a single layer of cuboidal epithelium + basement membrane Variable in size.

Occasional scattered clear cells/parafollicular cells/C cells produce and secrete calcitonin Gland enveloped by outer capsule of loose supporting connective tissue and an inner fibro-elastic capsule Fine collagenous septa extend into the gland dividing into lobules and conveying blood supply, lymphatics and nerves Colloid is the secretory product of follicular cells
Extra-cellular proteinaceous substance composed of thyroid hormones linked together with protein (thyroglobulin)

Structure - micro

Embryology and development

first endocrine gland to appear in embryonic development begins to develop ~24 days after fertilisation from median endodermal thickening of pharynx forms a downgrowth called the thyroid diverticulum descends into the neck as the embryo and tongue grows passes anteriorly to developing hyoid and laryngeal cartilages for a time is connected to tongue by thyroglossal duct thyroid diverticulum is initially hollow but becomes solid and divides into L and R lobes connected by isthmus assumes definitive shape and final location by 7 weeks gestation, and the thyroglossal duct disappears initially consists of solid mass of endodermal cells, which are broken up into network of epithelial cords by invasion of surrounding vascular mesenchyme lumen forms colloid forms by 11th week and thyroid follicles are formed, and synthesis of hormones commences

Parathyroid glands
4 small ovoid glands Small but essential average total weight 130mg! Located on posterior of thyroid
Close to middle and inferior end of thyroid lobes Position variable, especially inferiorly

2 cell types
Chief cells
produce parathyroid hormone (PTH) Key role in regulating circulating calcium levels

Oxyphilic cells
Not clinically important

Function

Thyroid hormones structure

Derivatives of the amino acid tyrosine bound covalently to iodine 2 principal thyroid hormones
thyroxine (T4 or L-3,5,3',5'-tetraiodothyronine) triiodotyronine (T3 or L-3,5,3'-triiodothyronine)

Thyroid hormones structure

Thyroid hormones stored conjugated to thyroglobulin, but are cleaved by pinocytosis before being released into circulation Majority of the thyroid hormone secreted is T4 (90%), but T3 is the considerably more active hormone Although some T3 is also secreted, most is derived by deiodination of T4 in peripheral tissues, especially liver and kidney Deiodination of T4 also yields reverse T3 (no known metabolic activity) Both are poorly water soluble 99% of circulating thyroid hormone is bound to carrier protein (mostly thyroxine-binding globulin, but also transthyrein and albumin)
Provides a stable pool from which unbound/free hormone is released for uptake by target organs

Thyroid hormones function

Likely that all cells express thyroid hormone receptors Metabolism
Increases basal metabolic rate Increases carbohydrate and lipid metabolism

Normal growth Normal development

Especially CNS

Other systems
CVS increases heart rate, cardiac output CNS mental acuity Reproduction fertility requires normal thyroid function

Calcitonin function
Minor role in regulating (reducing) blood calcium concentration
Suppresses osteoclastic bone resorption Inhibits renal tubular reabsorption of calcium and phosphorus

Thyroid regulation

Effects of TSH on thyroid gland

Increased thyroglobulin proteolysis p increased circulating thyroid hormones Increased activity of iodide pump - increases cellular iodine uptake Increased iodination of tyrosine and coupling Increased size and secretory activity of thyroid cells Increased number of thyroid cells, plus change from cuboidal to columnar epithelial structure

Parathyroid hormone (PTH)

Overall effect is to increase plasma Ca++
Bone
Stimulation of osteoclastic bone resorption Efflux of Ca++ from bone fluid into plasma

Kidneys
Stimulates Ca++ retention and phosphate excretion

Intestine
Indirectly stimulates Ca++ absorption (by activating vitamin D)

PTH secretion increases with a decreasing concentration of Ca++

Pathology

Thyroid pathology
Normal thyroid function - euthyroidism Disease states may result in hyper- or hypothyroidism - relative excess or deficiency of thyroid hormones Any swelling of the thyroid may be termed a goitre
Toxic goitre: associated with increased thyroid hormone output Non-toxic goitre: normal hormone levels (Non-specific terms; dont relate to a particular pathology)

Thyroid pathology
Thyroid enlargement may be diffuse or nodular
Irregular multinodular enlargement (goitre) of the entire gland is common, especially in the elderly Focal nodular enlargement may be due to a tumour Symmetrical slightly nodular (bosselated) firm enlargement of the whole gland is characteristic of Hashimotos disease Symmetrical diffuse enlargement is usually associated with hyperthyroidism (eg. Graves disease)

Most thyroid enlargement (except Hashimotos) results from hyperplasia of thyroid follicles and their cells

Multinodular goitre
Common in the elderly Often undetected May present for cosmetic reasons (neck swelling) or compression symptoms (eg. trachea) Usually have normal thyroid function Cause uncertain
? Uneven response of thyroid tissue to fluctuating TSH levels over many years

Thyroiditis
Viral
De Quervains thyroiditis
Affects younger/middle-aged women Slight diffuse, tender swollen gland Transient febrile illness, often viral origin (eg. mums with kids who have mumps/measles etc) Inflammatory destruction of follicular cells

Autoimmune
Graves disease Hashimotos disease

Graves disease
Most important cause of hyperthyroidism Autoimmune thyroiditis Diffuse thyroid enlargement and exophthalmos Follicular cells stimulated by IgG antibody (LATS) that causes constant thyroid hormone production, independent of TSH Large, fleshy thyroid gland with large follicles lined by active cells

Hashimotos disease
Destructive autoimmune thyroiditis Common in middle age, women > men Most common auto-antibodies are antimicrosomal Ab and anti-thyroglobulin Ab Diffusely enlarged thyroid, symmetrical and firm

Hypothyroidism
Cause Primary failure of thyroid gland Secondary to hypothalamic or pituitary failure Dietary iodine deficiency Hormone concentrations qT3 and T4, o TSH Goitre Yes

qT3 and T4, q TSH and/or q TRH

No

qT3 and T4, o TSH

Yes

Hyperthyroidism
Cause Abnormal thyroidstimulating immunoglobulin (eg. Graves disease) Secondary to excess hypothalamic or pituitary secretion Hypersecreting thyroid tumour Hormone concentrations Goitre

o T3 and T4, q TSH

Yes

o T3 and T4, o TSH and/or o TRH

Yes

o T3 and T4, q TSH

No

Thyroid malignancies
Follicular cell origin
Papillary carcinoma - 70% Follicular carcinoma - 25% Anaplastic carcinoma - rare

Parafollicular C cell origin

Medullary carcinoma - 5%

Papillary carcinoma
Follicular cell origin Well-differentiated Arises mostly in young adults Often multifocal Metastasises via lymphatics to neck nodes Slow-growing Excellent prognosis Treatment
Surgery - lobectomy/thyroidectomy Iodine-131 EBRT

Follicular carcinoma
Follicular cell origin Most common in middle age Metastasises via blood stream
Characteristically spreads to bone, lung

Good prognosis Treatment

Surgery Iodine-131 EBRT

Anaplastic carcinoma
Follicular cell origin Occurs exclusively in the elderly Poorly differentiated Rapidly progressive with direct invasion of adjacent structures Very poor prognosis Treatment - poor response
Surgery? EBRT? (Iodine-131?)

Medullary carcinoma
Arises in parafollicular C cells Sporadic or part of MEN syndrome Small cells containing neuro-endocrine granules Occurs in middle-aged and elderly Slow-growing Metastasises to lymph nodes Secretes calcitonin (blood test) Treatment
Surgery EBRT (but relatively radio-resistant) Low uptake of iodine-131 - limited role

Diagnostic tools
History and examination Thyroid function tests
T3, T4, TSH

Tumour markers
Thyroglobulin Anti-TG antibodies

Iodine-123 or 131 scan Ultrasound Biopsy

Role of radiotherapy
Iodine-131
Post-thyroidectomy for well differentiated tumours Typically 2600-3700MBq (70-100mCi) as ablative dose subsequent doses Small-volume metastatic disease Occasional use in benign hyperthyroidism

External beam RT
Post-thyroidectomy Metastatic disease Thyroid eye disease

Hyperparathyroidism
Increased PTH secretion is usually due to a (benign) parathyroid adenoma Solitary tumour, usually affecting a single PT gland Small, rarely palpable Presents with hypercalcaemia and elevated PTH Definitive treatment is parathyroidectomy

Hypoparathyroidism
Most commonly the result of surgical removal of parathyroids
Inadvertent or deliberate

Hypocalcaemia

Summary - thyroid
Major endocrine gland Located in the neck Closely related to parathyroid glands, thyroid cartilage, trachea, important nerves (recurrent laryngeal) and vessels Important role in metabolic regulation via thyroid hormones
T3 and T4 Stored extracellularly in inactive form

Summary
Regulated by feedback loop involving hypothalamus (TRH), pituitary (TSH) and thyroid hormones themselves Hypo- and hyperthyroidism are common conditions Benign and malignant pathology
Graves disease Hashimotos disease Papillary/follicular/anaplastic carcinoma Medullary carcinoma

Dont forget the parathyroids