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Histology Ch 21 755-762
Thyroid Gland – Diffuse Multinodal
Thyroid gland bilobed gland is in the anterior region of neck next to larynx and trachea
-composed of 2 lateral lobes connected by an isthmus with a pyramidal lobe going up from this
-thyroid follicles constitute functional units of the gland
-Thyroid gland develops during 4th week of gestation from endodermal lining of floor of pharynx
-primordium grows caudally and forms duct-like invagination called thyroglossal duct
-pyramidal lobe is a remnant of the thyroglossal duct
-9th week of gestation, endodermal cells differentiate into follicular cells becoming follicles that
contain colloid by the 14th week of gestation
-Week 7: epithelial cells lining invagination of 4th branchial pouches known as ultimobranchial
bodies migrate down thyroid gland and fuse inside to form parafollicular cells
-thyroid follicle is the structural and functional unit of the thyroid gland; follicular epithelium has
colloid and are simple cuboidal epithelium
-follicular epithelium has follicular and parafollicular cells
Follicular Cells (principal cells) – responsible for T3 and T4 hormone production; endocytic
vesicles called colloidal resorption droplets and lysosomes are present at apical cytoplasm
Parafollicular (C) cells – located at periphery of epithelium and within basal lamina but have no
exposure to follicle lumen. These cells secrete calcitonin to regulate Ca metabolism
Thyroid gland produces 3 hormones essential to metabolism and homeostasis:
1. Thyroxine (T4) and Triiodothyronine (T3) – secreted by follicular cells to regulate cell
and tissue basal metabolism and heat production and influence body
growth/development. Regulated by TSH from anterior pituitary
2. Calcitonin – synthesized by parafollicular cells and is antagonist to PTH. It regulates
serum calcium levels by inducing resorptive action of osteoclasts for Ca bone deposition
-secretion regulated by plasma Ca levels (high levels stimulate secretion)
-calcitonin secreted by several endocrine tumors, and is used as tumor marker
-principal component of colloid is a large, iodinated glycoprotein called thyroglobulin containing
120 tyrosine residues and is used to store thyroid hormones
-active thyroid hormones are liberated from thyroglobulin and released into capillaries
Synthesis of thyroid hormones involves several steps:
1. Synthesis of thyroglobulin – synthesized in rER of follicular cells and excreted into lumen
2. Resorption, diffusion, and oxidation of iodide – follicular epithelial cells actively transport
iodide from blood into cytoplasm using ATP-ase dependent Na/I symporters (NIS) from
basolateral membrane of follicular cells
a. NIS concentrates iodide on the inside, and iodide diffuses to apical side of
membrane and transported to lumen of follicle by iodide/chloride transporter
called PENDRIN on apical membrane
3. Iodide is immediately oxidized to iodine in colloid by thyroid peroxidase (TPO)
4. Iodination of Thyroglobulin – 1 or 2 iodine atoms are added to tyrosines of thyroglobulin in
colloid and is also catalyzed by thyroid peroxidase (TPO)
a. Addition of 1 iodine to tyrosine  monoiodotyrosine (MIT) and a second
transforms it to diiodotyrosine (DIT) residue
5. Formation of T3 and T4 – by oxidative coupling reactions of two iodinated tyrosine residues
in close proximity; DIT + MIT  T3, and DIT + DIT  T4
6. Resorption of Colloid – in response to TSH, follicular cells take up thyroglobulin from colloid
by endocytosis, after which it follows one of 2 intracellular pathways:
a. Lysosomal Pathway – internalized thyroglobulin transported to early endosomes
which mature or fuse to lysosomes; resorption can be confirmed by colloidal
resorption droplets in apical region
i. Thyroglobulin is then degraded by lysosomal proteases into T3 and T4, DIT,
and MIT; this is MAJOR pathway for colloid resorption
b. Transepithelial Pathway – thyroglobulin is transported intact from apical to
basolateral membrane through the help of apical membrane receptor megalin
which faces the colloid. Thyroglobulin internalized by megalin avoids lysosomal
pathway and vesicles are delivered to basolateral membrane of follicular cells
-under high TSH stimulation, megalin expression is increased and large amounts of thyroglobulin
follows transepithelial pathway, which reduces extent of T4 and T3 release
-patients with Grave’s disease have detectable thyroglobulin in the blood
7. Release of T4 and T3 – majority of T3/4 liberated by lysosomal pathway in a T4:3 ratio of
20:1, and they cross basal membrane and enter blood/lymph capillaries
-most hormones immediately bound to thyroxin-binding protein or nonspecific albumin
leaving small amounts of unbound circulating hormone
-only follicular cells are capable of producing T4, whereas the most T3 (5x more active than
T4), produced through conversion from T5 by organs like kidney, liver, and heart
-Thyroid hormones play an essential role in normal fetal development – T3 and T4 cross
placental barrier and critical in early brain development, and deficiency in thyroid hormone
during fetal development causes irreversible CNS damage
Clinical Correlation: Abnormal Thyroid Function – most common symptom of thyroid disease is
goiter, an enlargement of thyroid gland
Hypothyroidism – caused by insufficient dietary iodine (endemic/iodine deficiency goiter) or
autoimmune thyroiditis (Hashimoto’s thyroiditis)
-autoimmune thyroiditis characterized by presence of auto-antibodies against thyroglobulin,
thyroid peroxidase, and TSH receptor, resulting in thyroid cell apoptosis and follicular
-low thyroid hormone causes excessive TSH release to cause hypertrophy of thyroid
-adult hypothyroidism causes myxedema (sluggishness)
Hyperthyroidism (toxic goiter or Grave’s disease) – excessive thyroid hormones are released,
and people with Grave’s disease show autoantibodies, which bind TSH receptors and stimulate
cAMP on follicular cells leading to increased thyroid hormone secretion
-negative feedback causes levels of TSH to be normal, but thyroid gland undergoes hypertrophy
under these circumstances and thyroid hormone is secreted at high rates for increased
-increased metabolism, sympathetic nerve activities, tachycardia, protruding eyeballs
Parathyroid Glands – small endocrine glands associated with thyroid, come in superior and
inferior parathyroid glands located in connective tissue on posterior surface of lateral lobes of
thyroid gland
The INFERIOR parathyroid glands derived from the THIRD branchial pouch, the SUPERIOR
parathyroid glands from the 4th branchial pouch
Principal Cells – more numerous parenchymal cells of parathyroid are responsible for synthesis,
storage, and secretion of Parathyroid Hormone (PTH), can replicate when chronically stimulated
by changes in blood calcium
Oxyphil Cells – not known to have a secretory role and don’t have secretory vesicles
Parathyroids function in regulation of Ca and PO4 levels. Parathyroid hormone (PTH) is
essential for life, so care needs to be taken when removing thyroid gland during thyroidectomy
-PTH binds to PTH receptors on target cells to initiate G-protein cascade and causes level of Ca in
the blood to increase and REDUCES serum phosphate
-secretion of PTH is regulated by serum Ca through simple feedback system
PTH functions at several sites:
1. Action on bone tissue – PTH acts directly on osteoprogenitor cells, osteoblasts,
osteocytes, and bone lining cells; NOT osteoclasts (osteoclasts indirectly stimulated by
PTH through RANKL/RANK system)
a. Binding of PTH to osteoblasts increases RANK production and decreases
osteoprotegerin (OPG) secretion to stimulate osteoclast differentiation
b. PTH also has anabolic effect on bone in small amounts, and is used in treatment
for osteoporosis
2. Kidney Excretion of Ca – decreased by PTH stimulation of tubular reabsorption,
conserving Ca
3. Urinary PO4 excretion – increased by PTH secretion to lower PO4 plasma concentration
4. Kidney conversion of 25-OH vitamin D  1,25-OH vitamin D – regulated by PTH which
stimulates activity of 1a-hydroxylase and increases production of active hormone
5. Intestinal absorption of Calcium – increased under influence of PTH. Vitamin D3 has
greater effect than PTH on intestinal absorption
-PTH and calcitonin have reciprocal effects in regulation of blood calcium