Thyroid gland and parathyroid glands

The thyroid gland is a butterfly-shaped endocrine gland located inferior to the larynx and anterior to the trachea. The thyroid gland develops from the fusion of the median thyroid anlage with the two lateral thyroid anlages, which are derived from the pharyngeal pouches. The thyroid gland is contained by the pretracheal fascia and internal capsule. It receives its arterial supply from the superior and inferior thyroid arteries and drains into the superior, middle, and inferior thyroid veins. The lymphatics drain into the paratracheal and deep cervical lymph nodes. It receives sympathetic innervation via the cervical ganglion and parasympathetic innervation via the vagus nerve. The thyroid gland secretes thyroid hormones, which regulate body metabolism and growth, and calcitonin, which lowers serum calcium and phosphate through inhibition of osteoclasts. Hormone synthesis occurs in the epithelial lining of the thyroid follicles. The epithelial lining consists of follicular (thyroid epithelial) cells, which synthesize thyroid hormone, and parafollicular (C) cells, which synthesize calcitonin.

The parathyroid glands are four, oval-shaped endocrine glands located on the posterior surface of the thyroid gland. They are derived from the third and fourth pharyngeal pouches. The parathyroid glands receive their arterial supply from the inferior thyroid arteries and drain into the thyroid venous plexus. The lymphatics drain into the paratracheal and deep cervical lymph nodes. The parathyroid glands are innervated by the thyroid branch of the cervical ganglia. The parathyroid chief cells secrete parathyroid hormone, which maintains serum calcium and phosphate homeostasis and, furthermore, antagonizes the effect of calcitonin by increasing serum calcium and decreasing serum phosphate. The recurrent laryngeal nerves, parathyroid glands, sympathetic trunks, and the nerves of the carotid sheath are at risk of injury during thyroid surgery.

Overview

• Characteristics: butterfly-shaped, unpaired endocrine gland composed of two lobes
• Location
  • Located anteriorly in the lower part of the neck
  • Extends from C5–T1
  • Surrounded by pretracheal fascia (along with pharynx, trachea, esophagus)
  • Relations of the thyroid gland
    • Anteriorly: strap muscles (i.e., sternohyoid, sternothyroid, thyrohyoid, and omohyoid muscles)
    • Medially: the trachea, esophagus, recurrent laryngeal nerve (RLN), and the external branch of the superior laryngeal nerve
    • Posteriorly: the parathyroid glands cricoid cartilage, lower thyroid cartilage, and the carotid sheath with its contents (i.e., internal jugular vein, vagus nerve, and common carotid artery)
• Function
  • Production of thyroid hormones essential for regulating metabolism and growth
  • Parafollicular cells (C cells) produce calcitonin, which influences calcium homeostasis by lowering serum calcium (PTH antagonism).

Damage to the recurrent laryngeal nerves, parathyroid glands, sympathetic trunks, and even the nerves of the carotid sheath is possible during thyroidectomy because of the thyroid's location in the anterior neck.

Gross anatomy

• The thyroid gland is made up of a left lobe and a right lobe connected by an isthmus.
• An ascending pyramidal lobe is present in ∼ 50% of the population.
• The thyroid gland is encapsulated by:
  • Pretracheal fascia (false/surgical capsule)
  • Internal capsule (true capsule)
    • Inner connective tissue covering that cannot be separated from the gland
    • Forms septae, dividing the gland into lobes and lobules

Vasculature and innervation

• Lymphatics
  • Paratracheal nodes
  • Deep cervical nodes
• Innervation
  • Vagus nerve (parasympathetic)
  • Superior, middle, and inferior cervical ganglia of the sympathetic trunk

The inferior thyroid artery runs close to the recurrent laryngeal nerve and the superior thyroid artery close to the superior laryngeal nerve. Both nerves are at risk during thyroid surgery.

Lobules of thyroid gland

• Main component: thyroid follicles
  • Smallest functional units
  • Spherical, vesicular components of the thyroid gland lined with epithelium
  • Follicular lumen (central cavity) filled with colloid: storage of thyroglobulin, the thyroid hormone precursor
  • Epithelium contains two cell types
    • Thyroid epithelial cells
    • C cells
• Interfollicular spaces are filled by reticular connective tissue, fenestrated capillaries (facilitate the release of hormones into the blood), lymphatic vessels, adipocytes, and sympathetic nerves.

The thyroid gland produces thyroid hormones, which stimulate metabolism and growth, as well as calcitonin, which decreases bone resorption and is involved in plasma calcium homeostasis.

Calcitonin

• Function: lowers calcium in serum (see “Hypocalcemia”)
  • Bones: inhibits osteoclast activity
  • Kidneys: increases excretion of calcium and phosphate
  • Intestine: lowers calcium absorption
  • The physiological role of calcitonin is low as bone and calcium metabolism are mainly regulated by the parathyroid hormone and vitamin D
  • Released in response to increased serum calcium levels
• Clinical significance
  • Important as a tumor marker for medullary thyroid cancer
  • Acts as a synthetic analog for the treatment of osteoporosis (minimizes bone resorption)
  • The precursor procalcitonin plays an increasingly important role as a marker for bacterial infection (e.g., sepsis).

Thyroid hormones

Thyroid hormone synthesis

• The thyroid hormones T₃ (triiodothyronine) and T₄ (thyroxine, tetraiodothyronine) are synthesized by thyrocytes in the thyroid follicles. ^[1]
  1. Thyroglobulin, an iodine-free hormone precursor, is stored in the follicular lumen.
  2. Iodide is actively taken up by thyrocytes and transported into the follicular lumen.
  3. Here, thyroid peroxidase catalyzes the iodination of tyrosine residues of thyroglobulin, creating precursors monoiodotyrosine (MIT) and diiodotyrosine (DIT) and eventually the thyroid hormones.
  4. To release T₃ and T₄, the iodinated thyroglobulin must be taken up again by thyrocytes, where it is broken down by lysosomes, thus releasing attached T₄ and T₃.
  5. T₄ and T₃ are then transported out of the thyrocyte into the blood.
• More T₄ is produced than T₃ but T₃ is more potent than T₄.
  • Peripheral 5'-deiodinase (or type II iodothyronine deiodinase) in the thyroid, pituitary gland, muscle, and brown fat converts T₄ into the biologically active T₃.
  • Half of the T₄ is processed into biologically inactive T₃ (reverse T3).
• The half-life of T₃ is about one day (∼ 20 hours) and the half-life of T₄ is about one week (∼ 190 hours) .

Thyroxine hormone is produced from tyrosine and iodine.

Transport and degradation

Thyroid hormones are lipophilic, but due to their charged amino acid derivatives, they cannot simply diffuse across the lipid bilayer. Instead, they cross the plasma membrane with the help of transporter proteins (facilitated diffusion). Also, most of the circulating thyroid hormones are inactive and bound to transport proteins. Only a very small fraction (∼ 0.3%) is unbound and biologically active.

• Transport proteins
  • Thyroxine-binding globulin (TBG)
    • TBG binds most of the serum T₃/T_4.
    • The bound fraction of T₃/T₄ is biologically inactive.
    • Hyperestrogenemia (e.g., pregnancy, OCP use) → ↑ TBG synthesis → ↓ free T₃/T₄ in serum → ↑ thyroid hormone synthesis
    • Hypoproteinemia (e.g., nephrotic syndrome, chronic liver disease) → ↓ TBG synthesis → ↑ free T₃/T₄ in serum → ↓ thyroid hormone synthesis
  • Transthyretin (prealbumin)
    • Transport protein synthesized by the liver that carries thyroxine and the retinol-RBP complex
    • Negative acute phase protein
    • Decrease in transthyretin leads to the preservation of amino acids for positive acute phase reactants.
    • Conditions that result in the accumulation of transthyretin include senile cardiac amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy.
  • Albumin
• Degradation (liver): after sulfation/glucuronidation (biotransformation), thyroid hormones are excreted via bile

Effect

In general, thyroid hormones increase the metabolic rate: oxygen and energy consumption as well as thermogenesis increase under their influence.

Regulation

• Hypothalamic-pituitary axis
  • Stimulant (e.g., stress, extreme cold) → release of thyrotropin-releasing hormone (TRH) → ↑ secretion of thyroid-stimulating hormone (TSH) by the pituitary gland → ↑ synthesis and release of T₃ and T₄ by the thyroid gland
  • Negative feedback by ↑ free T₃ or T₄ → ↓ release of TRH and ↓ pituitary sensitivity to TRH → ↓ thyroid hormones synthesis
  • TSH release can also be decreased by somatostatin, dopamine, and glucocorticoids (outside of the hypothalamic-pituitary axis).
  • TSH stimulating antibodies in Graves disease result in the direct stimulation of the pituitary gland and TSH release. (See “Graves disease” for more information.)
• TBG: See “Transport and degradation” section above.
• Wolff-Chaikoff effect: a transient decrease in the production of thyroid hormones following the ingestion of a large amount of iodine via thyroid peroxidase inhibition
• Drugs
  • Decreased T4 → T3 conversion: glucocorticoids, propylthiouracil (PTU), β-blockers
  • Increased T4 → rT conversion: growth hormone, glucocorticoids
  • Thyroid peroxidase inhibition: PTU, methimazole

TPO is stimulated by TSH and inhibited by PTU, methimazole, and excess iodine (Wolff-Chaikoff effect), resulting in, respectively, high and low thyroid hormone levels.

Thyroid-stimulating hormone (TSH) from the pituitary gland stimulates the basolateral uptake of iodine as well as the biosynthesis and release of thyroid hormones.

TSH levels are very sensitive to thyroid hormone dysfunction. If thyroid hormone levels are very high, TSH can fall below detection limits and if they are very low, TSH increases markedly. Therefore, serum TSH is an important parameter for assessing thyroid function and is usually the first step in thyroid diagnostics.

Overview

The thyroid gland develops in the first trimester of pregnancy from the fusion of the median thyroid anlage with the two lateral thyroid anlages derived from the pharyngeal pouches. Both follicular cells and C cells arise from pharyngeal endoderm ^[3][4][5]

• Median thyroid anlage
  • An endodermal thickening in the floor of the primordial pharynx between the 1^st and 2^ndpharyngeal pouches
  • This thickening becomes the thyroid diverticulum.
  • Differentiates into the follicular cells of the thyroid gland (i.e., the major portion of the lobes and isthmus of the thyroid gland)
• Lateral thyroid anlagen (ultimobranchial bodies)
  • Paired endodermal cell thickenings derived from the 4^th branchial pouch
  • Fuse with the median thyroid anlage
  • Differentiate into the parafollicular C cells of the thyroid gland

Follicular cells arise mainly from the median thyroid anlage.
Parafollicular C cells arise mainly from the lateral thyroid anlage.

Thyroid diverticulum

• A thyroid gland precursor that originates from the floor of the primordial pharynx
• It is located initially at the middle of the floor of the pharynx, near the base of the tongue, i.e., foramen cecum (tongue).
• It descends the neck, forming the thyroglossal duct, to settle into its adult anatomical position.
• The thyroglossal duct usually obliterates after the thyroid gland has descended.
  • However, in about 50% of people, the distal portion of the duct remains as a clinically unremarkable pyramidal lobe of extra thyroid tissue
  • Thyroglossal cyst: caused by a persistent thyroglossal duct (See “Congenital neck masses” for more details)
  • Lingual thyroid: caused by failure in descent of the thyroid gland to its normal position during embryogenesis
• The foramen cecum of the tongue remains.

During embryological thyroid migration, remnants of thyroid tissue can remain in the tongue (lingual thyroid) or elsewhere along the migration path. Incidental removal of ectopic thyroid tissue may result in hypothyroidism if the ectopic tissue is the only functioning thyroid tissue in the body.

• Goiter
• Hypothyroidism
  • Iodine deficiency
  • Congenital hypothyroidism (cretinism)
  • Wolff-Chaikoff effect
  • Hashimoto thyroiditis
  • Riedel thyroiditis
  • Postpartum thyroiditis
  • Subacute thyroiditis (e.g., de Quervain)
• Hyperthyroidism
  • Graves disease
  • Thyroid adenoma
  • Toxic multinodular
    goiter
  • Thyrotoxicosis and thyroid storm
  • Drug-induced: amiodarone, lithium
  • Jod-Basedow phenomenon
  • Thyrotropic pituitary adenoma
  • Struma ovarii
  • Iodine excess
• Thyroid nodules (e.g., thyroid cysts)
• Thyroid cancer
  • Papillary thyroid cancer
  • Follicular thyroid cancer
  • Anaplastic thyroid cancer
  • Medullary thyroid cancer
    • MEN 2A
    • MEN 2B
• Antithyroid drugs
• Thyroid surgery

Overview

• Characteristics
  • There are four, oval-shaped endocrine glands embedded in the posterior surface of the thyroid gland
    • Two superior parathyroid glands: located near the superior pole of the thyroid gland at the junction of cricoid and thyroid cartilages.
    • Two inferior parathyroid glands: located in the area between the inferior poles of the thyroid lobes and the superior mediastinum.
• Function: secretion of parathyroid hormone (PTH) in response to low calcium serum levels
• Vasculature
  • Arterial supply: inferior thyroid arteries
  • Venous drainage: thyroid plexus of veins
  • Lymphatic drainage: deep cervical nodes, paratracheal nodes
• Innervation: thyroid branches of the cervical ganglia

Microscopic anatomy

• Cell types
  • Adipocytes (∼ 50%)
  • Parathyroid cells (parathyroid chief cells)
    • Polygonal, hormone-secreting cells with round nucleus
    • Produce and secrete PTH
    • Have calcium-sensing receptors (CaSR), which detect changes in calcium concentration and modulate PTH secretion
  • Oxyphil cells: red/pink cytoplasm; function not clear

Function of PTH

• PTH increases serum calcium and decreases serum phosphate (see “Calcium homeostasis”).
  • High extracellular calcium → activation of calcium-sensitive receptors → ↓ PTH excretion
  • Low extracellular calcium → inhibition of calcium-sensitive receptors → ↑ PTH excretion

Embryology

• Superior parathyroid glands: derived from the fourth pharyngeal pouch
• Inferior parathyroid gland: derived from the third pharyngeal pouch

DiGeorge syndrome is a congenital T-cell immunodeficiency that is caused by microdeletion at chromosome 22 (22q11.2). The deletion leads to defective development of the third and fourth pharyngeal pouches, resulting in aplastic parathyroids and hypocalcemia due to PTH deficiency.

Clinical significance

• Hyperparathyroidism
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Thyroidectomy
• Familial hypocalciuric hypercalcemia
• Nelson syndrome
• MEN 1
• MEN 2A
• Osteitis fibrosacystica
• Renal osteodystrophy

Surgery of the thyroid and parathyroid glands can result in destroyed or removed parathyroid glands due to their variable position. This may result in hypoparathyroidism and hypocalcemia.