Thyroid gland

Pbl week2 endocrine block

 Objectives
• Histo
1- describe the histological structure of thyroid gland, including cell type structure
and functions
• Bio
2-describe the synthesis of thyroid hormone and discuss T3, T4 transport
• Physio
3-enumerate the effect of thyroid hormone on metabolism of the body
• Patho
4-define goiter, outline ideology, pathogenesis of different forms of goiter
5-classify and list different causes of thyrotoxicosis
• Pharma
6-list the main class of drugs used in treatment of hyperthyroidism
7-explain the mechanism of action, pharmacokinetic, side effect, toxicity and
contraindications of anti-thyroid drugs
 Thyroid gland
There are two types of cells found within the thyroid gland
1-follicular cells and 2-parafollicular cells
• Thyroid tissue is composed of 20–30 million microscopic spheres
• called thyroid follicles.
• The follicles are lined by a simple epithelium and their central cavity contains
a gelatinous glycoprotein called colloid (thyroglobulin).
• The thyroid is the only endocrine gland whose secretory product is stored in
great quantity.
• This accumulation is also unusual in that it occurs in the extracellular colloid.
• In humans, there is sufficient hormone within the follicles to supply the
organism for up to 3 months.
• In sections, follicular cells range from squamous to columnar
• and the follicles have variable diameter.
• The morphological appearance of thyroid follicles varies according to the
region of the gland and its functional activity.
• In the same gland, larger follicles that are full of colloid and have a cuboidal
or squamous epithelium are found alongside follicles that are lined by
columnar epithelium.
• Despite this variation, the gland is considered hypoactive when the average
composition of these follicles is squamous.
• The thyroid epithelium rests on a basal lamina.
• Its cells exhibit the characteristics of a cell that synthesizes, secretes,
absorbs, and digests proteins.
• The basal part of these cells is rich in RER.
• The nucleus is generally round and situated in the center of the cell.
• The apical pole has a discrete Golgi complex and small secretory granules
whose content is similar to that of the follicular colloid.
Abundant lysosomes, and some large phagosomes are found in this region.
The cell membrane of the apical pole has a moderate number of microvilli.
Mitochondria and cisternae of rough endoplasmic reticulum are dispersed
throughout the cytoplasm.
 Parafollicular cells

• • The other type of cell is the parafollicular, or C- cell, is found as part of the
follicular epithelium or as isolated clusters between thyroid follicles. •
Parafollicular cells are larger than thyroid follicular cells and with the light
microscope appear less stained. • They have a small amount of RER, long
mitochondria, and a large Golgi complex. • They have numerous small
granules containing calcitonin hormone.
Biochemistry
 Thyroid hormones:

• They are two hormones produced and released by the thyroid gland, namely
Tri-iodothyronine (T3 ) and
Tetra-Iodothyronine,T4 (Thyroxin)
• The main synthetized thyroid hormone is thyroxine, but tri-iodothyronine is
ten times more potent than T4.
•The major form of thyroid hormone in the blood is thyroxine (T4 ), which has
a longer half-life than T3 .
•In humans, the ratio of T4 to T3 released into the blood is approximately 14: 1.
T4 is converted to the active T3.
 Synthesis of Thyroid hormones:

•Thyroid hormones are synthesized by the iodination of tyrosine residues of a

large protein called “thyroglobulin TG” in thyroid gland.
•Therefor precursor molecule for thyroid hormones synthesis is tyrosine
(thyroid hormones are tyrosine based hormones).
•Thyroid hormone production is controlled by thyroid stimulating hormone
([TSH]) from the anterior pituitary. TSH secretion is itself controlled by
thyrotropin-releasing hormone (TRH) from the hypothalamustyrosine-based
 Steps in Synthesis of Thyroid hormones
include:

1. Thyroglobulin synthesis
2. Uptake and Oxidation of iodide (Dietary iodine is absorbed as iodide and
distributed in the extracellular fluid)
3. Iodination of tyrosine residue on thyroglobulin and Formation of MIT
(monoiodotyrosine) and DIT (diiodotyrosine)
4. Secretion
 1 Synthesis of thyroglobulin

• The follicular cells of the thyroid gland synthesize Thyroglobulin(TG)

• Thyroglobulin is a very large glycoprotein. It contains about 115 tyrosine
residues.
• Thyroglobulin is then secreted into the colloid by exocytosis
 2 Uptake and oxidation of iodide

• Iodide ions (I-) transport from the plasma into the follicular cells of thyroid
gland by Active transport
• Active transport of iodide is mediated by iodide pump (sodium iodide
symporter (NIS)).
• Iodide ions (I-) is secreted via Pendrin channel to colloid.
•Iodide is oxidized into iodine (I+) . The oxidation need H2O2 and Thyroid
peroxidase (TPO )enzyme.
 3 Iodination of tyrosine residue on thyroglobulin
and Formation of MIT (monoiodotyrosine) and DIT
(diiodotyrosine):
• TPO uses iodine atom to iodinate selected tyrosine residues in thyroglobulin
(Tg), forming monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT)
• Organification is incorporation of iodine into tyrosine residues in
thyroglobulin for the production of thyroid hormone.
• Coupling of two DIT molecules produces T4
• T4 has four iodine atoms while T3 has three Coupling occurs within the
thyroglobulin molecule.
• The iodinated thyroglobulin in endocytosed and stored into the follicular
cell until needed
 4 Secretion of Thyroid Hormones:

• The cellular lysosome containing proteases, endopeptidases, glycoside

hydrolase, fuse with vesicles. In the fused vesicles, hydrolysis of thyroglobulin
occurs, releasing T4 , T3 , DIT, MIT, peptide fragments and amino acids
• T3 and T4 pass into blood across the basal cell membrane. DIT and MIT are de-
iodinated by NADPH dependent microsomal deiodinase and remove (I-) and this
reused again in T3 and T4 synthesis.
• Note : T4 can be metabolized in peripheral tissues to reverse T3 (rT3), which is
biologically inactive
 Transport of thyroid hormones

• Thyroid hormones are not very soluble in water (but are lipid soluble). Thus,
they are found in the circulation associated with binding proteins.
• Thyroxine binding globulin (TBG)( 70% of hormone).
• Pre-albumin (Transthyretin (TTR or TBPA) ( less than 15%of hormone) is a
transport protein in the serum and cerebrospinal fluid that carries the thyroid
hormone thyroxine (T4 ).
•Albumin (15% of hormone).
• Less than 1% of thyroid hormone is found free in the circulation.
Physiology
 MOA of thyroid hormone

• Thyroid hormone increases basal metabolic rate

• T3,T4 attach to specific nuclear receptors and increase the number of Na-K
ATPase pump
• Also increase the number and activity of mitochondria to produce more ATP
• The source of energy for the cells comes from lipolysis, gluconeogenesis,
and increased absorption in GIT
 3- enumerate the
effect of thyroid
hormone on
metabolism of
the body
• (ii) thyroid hormone increases FA
oxidation =more energy
• Lowers cholesterol level by excreting
it in bile and also by increasing the
number of LDL receptors on the liver
• Therefore, the liver will take up more
LDL and convert it to cholesterol
which will again be excreted in bile
• Patients who have hypothyroidism
often have hypercholesterolemia
because the thyroid hormone is not
able to decrease the levels of
cholesterol
Pathology
 What is goiter

• Enlargement of the thyroid, or goiter is caused by impaired synthesis of

thyroid hormone, which is most often the result of dietary iodine deficiency.
• Goiters can broadly be divided into two types:
• Diffuse nontoxic
• Multinodular.
 1- Diffuse Nontoxic (Simple) Goiter colloid
goiter

• Diffuse nontoxic (simple) goiter causes enlargement of the entire gland

without producing nodularity.
• It can be :
– Endemic goiter
– Sporadic goiter
 Pathogenesis of Endemic goiter

• Endemic goiter occurs in geographic areas where the soil, water, and food
supply contain low levels of iodine.
• The lack of iodine leads to decreased synthesis of thyroid hormone and a
compensatory increase in TSH, leading to follicular cell hypertrophy and
hyperplasia and goitrous enlargement.
 Pathogenesis of Sporadic goiter

• Sporadic goiter occurs less frequently than endemic goiter.

• Sporadic goiter can be caused by several conditions,
– Increase demand as in pregnancy and puberty.
– Ingestion of substances that interfere with thyroid hormone synthesis.
– Hereditary enzymatic defects that interfere with thyroid hormone synthesis.
 MORPHOLOGY of simple goiter
• Two phases can be identified in the evolution of diffuse nontoxic goiter:
• the hyperplastic phase
➢ The thyroid gland is diffusely and symmetrically enlarged the gland rarely
exceeds 100 to 150 gm.
➢ The follicles are lined by crowded columnar cells, which may pile up and
form projections similar to those seen in Graves disease.
• The phase of colloid involution.
• the stimulated follicular epithelium involutes to form an enlarged, colloid-
rich gland
 2- Multinodular goiters

• produce the most extreme thyroid enlargements and are more frequently
mistaken for neoplasms than any other form of thyroid disease.
• they derive from simple goiter, they occur in both sporadic and endemic
forms, having the same female-to-male distribution
 MORPHOLOGY of multinodular goiter
• reach weights of more than 2000 gm.
• The pattern of enlargement
– may involve one lobe producing lateral pressure on midline structures, such
as the trachea and esophagus..
– Grows behind the sternum and clavicles to produce the so-called
intrathoracic or plunging goiter.
– A solitary nodule.
• Multinodular goiters are multilobulated, asymmetrically enlarged glands.
• On cut section, irregular nodules containing variable amounts of brown,
gelatinous colloid.
• Older lesions have areas of hemorrhage, fibrosis, calcification, and cystic
change.
• The microscopic appearance includes colloid-rich follicles lined by flattened,
inactive epithelium and areas of follicular hyperplasia, accompanied by
degenerative changes. There is no capsule, In contrast to follicular
neoplasm.
Objective 5
Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4.
But when this increase due to over-activation of thyroidal follicle called hyperthyroidism
Pharmacology
Classification of anti-thyroid drugs
 Thioamides

• carbimazole, which is converted to methimazole in vivo, is widely used.

• Methimazole is about ten times more potent than propylthiouracil and is
the drug of choice in adults and children.
• Due to a black box warning about severe hepatitis, propylthiouracil should
be reserved for use during the first trimester of pregnancy, in thyroid storm
• And in those experiencing adverse reactions to methimazole (other than
agranulocytosis or hepatitis.
 Thioamides
Pharmacokinetics:
• Methimazole is completely absorbed but at variable rates. It is readily accumulated by the
thyroid gland and has a volume of distribution similar to that of propylthiouracil
• Excretion is slower than with propylthiouracil;
• propylthiouracil is rapidly absorbed
• bioavailability of 50–80% may be due to incomplete absorption or a large first-pass effect
in the liver.
• short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for
methimazole) For propylthiouracil, giving the drug every 6–8 hours
• methimazole exerts an antithyroid effect for longer than 24 hours
• propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours
• Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA
pregnancy category D
• propylthiouracil is preferable during the first trimester of pregnancy because it is more
strongly protein-bound and, therefore, crosses the placenta less readily
 Thioamides

Pharmacodynamic:
MOA
• prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed
reactions and blocking iodine organification
• do not block uptake of iodide by the gland.
• Propylthiouracil but not methimazole also inhibits the peripheral deiodination of
T4 and T3
• Since the synthesis rather than the release of hormones is affected, the onset of
these agents is slow, often requiring 3–4 weeks before stores of T4 are
depleted.
 Thioamides

• S/E:
• most common adverse effect is a maculopapular pruritic rash (4–6%), An
increased risk of severe hepatitis, sometimes resulting in death, has been
reported with propylthiouracil (black box warning), .
• Cholestatic jaundice is more common with methimazole
• most dangerous complication is agranulocytosis
• Nausea, GIT distress.
• Inidication: • Hyper thyroidism,
 Anion inhibitors
Pharmacodynamics :
• Block uptake of iodide by the gland through competitive inhibition of iodide
transport.
• Since their effects can be overcome by large doses of iodides, their effectiveness is
unpredictable
• monovalent anions inhibit iodide trapping by NIS into the thyroid (Inhibitors of the
sodium iodide symporter (NIS).
• Thiocyanate(-SCN), Perchlorates(-CIO4), Nitrates(NO3)
• No longer used because of fatal side effects (very toxic)
Indication: The major clinical use for K-perchlorate is to block thyroidal reuptake of
Iodine in patients with iodide-induced hyperthyroidism.
S/E: associated with aplastic anemia
 Iodides

Used to be major antithyroid agents; today they are rarely used as sale
therapy
Pharmacodynamics:
• Inhibit organification and hormone release.
•reduce size and vascularity of the hyper plastic gland.
•Major function of pharmacological doses of iodides is to inhibit hormone
release, by inhibition of thyroglobulin proteolysis.
 Iodides
• indications:
---Preoperative preparation for surgery, because reduces vascularity, size, and
fragility of a hyperplastic gland.
• Disadvantages:
-Delays onset of thioamides. Why iodide not used before thioamide or radioactive iodine?
-prevent the use of radioactive iodine
• S\E: iodism
• acneiform rash (similar to that of bromism), swollen salivary glands, mucous
membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste,
bleeding disorders, and rarely, anaphylactoid reactions
• chronic use in pregnancy is avoided because cross placenta and cause fetal goiter
causes
 Radioactive iodine I 131
C/I: pregnant (teratogenic effects)
 Reference

• Robbins & Cotran Pathologic Basis of Disease

• _Mescher (2013) Junqueira's Basic Histology text & atlas (13th Ed.) Mc-Graw
Hill (1)
• Guyton-and-Hall-Textbook-of-Medical-Physiology-12th-Ed
• Basic and Clinical Pharmacology 14th Edition
• Lippincott Illustrated Reviews_ Biochemistry 7th Edition