PHYSIOLOGY MSGD5

MSGD 4 - Hyperthyroidism
N/A

OUTLINE On physical examination, BP 130/80, HR 110, RR 20,

I. THE CASE! T 36.9. Patient was positive for exophthalmos. A
II. BIOCHEMISTRY – Introduction to Hormones palpable non-tender anterior neck mass was
Two Classes of Hormones noted. The mass appears to be diffusely enlarged as
Group I Hormones
Group II (Peptide) Hormones
seen after doing neck ultrasound. Thyroid function test
The Information Pathway showed the following results: TSH Decreased, FT3
Coordinated Response to Stimulus Increased, FT4 Increased.
III. ANATOMY – Thyroid Gland Anatomy
Brief Description and Boundaries Medical management with PTU was initiated and
Blood Supply and Innervation eventually, patient underwent total thyroidectomy as
Veins, Arteries and Nerves (VANs) definitive treatment.
IV. PHYSIOLOGY – HPO Axis
V. PHYSIOLOGY – Synthesis of Thyroid Hormone
FT3 – Free T3
Thyroid Hormone
Formation/Synthesis FT4 – Free T4
VI. PHYSIOLOGY – Thyroid Hormone Function
VII. CASE – Differentiate Signs and Symptoms Observed in II. BIOCHEMISTRY – Introduction to Hormones
Hypothyroidism and Hyperthyroidism
VIII. CASE – GRAVE’s DISEASE Two Classes of Hormones
IX. CASE – Results of the Thyroid Function Test
X. CASE – PTU • Hormones are usually classified based on the following:
XI. CASE – Thyroidectomy ▪ Chemical composition
XII. EXTRA - Management ▪ Soluble properties
▪ Location of receptors
REFERENCES ▪ Nature of the signal used to mediate
• Brunicardi FC, Andersen DK, Billar TR, Dunn DL, Hunter JG, hormone action
Matthews JB, Pollock RE. 2010. Schwartz’s Principles of
*Basis of Group I and II classification
Surgery, 10/e. McGraw-Hill Medical Education.
• Devlin TM. 2011. Textbook of Biochemistry with Clinical Table 1: Group I vs Group II hormones
Correlations, 7/e. John Wiley & Sons, Inc.
• Grossman H, Porth CM. 2014. Porth’s Pathophysiology – GROUP I GROUP II
Concepts of Altered Health States, 9/e. Lippincott’s Williams and
TYPES Steroids, Polypeptides,
Wilkins
• Hall JE. 2015. Guyton and Hall Physiology Review, 13/e. iodothyronines, proteins,
Saunders. calcitriol, retinoids glycoproteins,
• Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, catecholamines
Loscalzo JL (eds.). Harrison’s Principles of Internal Medicine, SOLUBILITY Lipophilic Hydrophilic
19/e. 2015. McGraw-Hill.
TRANSPORT Yes No
• Moore KL, Dalley AF, Agur AMR. 2014. Clinically Oriented
Anatomy, 14/e. Lippincott Williams and Wilkins PROTEINS (e.g., is
• Rodwell, VW, Bender DA, Botham KM, Kennelly PJ, Weil PA. it bound to albumin
2015. Harper’s Illustrated Biochemistry (30th ed.). The in circulation?)
McGraw-Hill Education PLASMA HALF- Long (hours to days) Short (minutes)
• Rubin R, Strayer DS. 2012. Rubin’s Pathophysiology
LIFE
Clinocopathological Foundations of Medicine, 6/e. Lippincott
Williams and Wiliins LOCATION OF Intracellular Plasma membrane
• Trevor AJ, Katzung BG, Hall MK, Masters SB. 2013. RECEPTOR
Pharmacology Examination and Board Review, 10/e. McGraw MEDIATOR Receptor-hormone cAMP, cGMP, Ca2+,
Hill. complex metabolites of
• MedScape
phosphoinositols,
• WebMD
kinase cascades
I. THE CASE! EFFECT Slow (because there faster
A 25 year old female presented with 5 months history is usually alteration
of intermittent palpitations. There were no precipitating of the gene
factors noted. transcription)

Upon consultation, patient had no subjective

complaints. She was non-hypertensive, non-diabetic, Group I Hormones
non-smoker, non-alcoholic beverage drinker and a
• lipophilic/ hydrophobic (water-insoluble)
non-coffee drinker. Review of systems revealed
• derived from cholesterol with the exception of T3
weight loss despite Increased appetite, excessive
sweating and tremors. (triiodothyronine) and T4 (tetraiodothyronine/ thyroxine)
Lecture Title: MSGD 5 – Hyperthyroidism / Graves Disease
Module: 5
Transcribed by: MOLINA GASE
 ▪ Which are derived from tyrosine
• easily diffuses across cell membrane
• binds to INTRACELLULAR RECEPTORS
• After secretion, these hormones associate with
transport proteins (improve solubility while prolonging
the plasma half-life)
• Hormone-Receptor Complex bind specific DNA region
known as HRE or hormone response element

Group II (Peptide) Hormones

• Water-soluble hormones
• Generally peptides
• Unable to cross the cell membrane (since the
hormone is hydrophilic while the membrane is
hydrophobic)
• Majority of hormones belong to this group
• Do not require transport proteins (thus have short
plasma half-life)
• Have membrane receptors and use intracellular
messengers Figure 1: The Information Pathway
• Initiate a response by binding to a receptor located in
the plasma membrane (and initiates the production of Coordinated Response to Stimulus
second messengers)
• Able to influence intracellular processes without
entering the cell

The Information Pathway

• Hormones can affect any of these steps although
steroids’ predominant effect is on gene transcription
• Refers to the general flow of information in gene
expression – from gene to the protein coded for by that
specific gene
• Hormones may affect any part of the pathway
• Primary/usual effect of steroid (Group I) hormones is on
gene transcription (mRNA synthesis from information
read on the gene in the DNA); thus the target of Group
I hormones is the nucleus, and they have a slower Figure 2: Hormones are coordinated in their responses.
effect
• Group II hormones target metabolic pathways, thus • Group I hormones are usually for alteration of gene
creating changes in cellular behavior faster transcription. They can also affect the synthesis of other
proteins, which play crucial roles in the various signaling
cascades. There is actually an overlap. There are also
group II hormones that can alter gene expression.

III. ANATOMY – Thyroid Gland Anatomy

Brief Description and Boundaries
• The thyroid gland consists right and left lobes
connected by a narrow isthmus. Each lobe is pear-
shaped and surrounded by a sheath which attaches the
gland to the larynx and trachea. A pyramidal lobe is
often present and it projects upwards from the isthmus,
to the left of the midline.
• The thyroid gland is located in the anterior neck,
spanning between the C5 and T1 vertebrae. It is an
endocrine gland. It is said to have a butterfly shape.
• It lies behind the sternohyoid and sternothyroid
muscles, wrapping around the cricoid cartilage and
superior tracheal rings. It is inferior to the thyroid
Lecture Title: Hyperthyroidism and Graves Disease 2
Module: MSGD 5
Transcribed by: MOLINA GASE
 cartilae of the larynx. The gland is in the visceral IV. PHYSIOLOGY – HPO Axis
comprtment of the neck, along with the trachea,
esophagus, and pharynx. The compartment is bound by
pretracheal fascia.

Blood Supply and Innervation

Figure 4: HPT Axis

Honestly, hindi ko alam kung bakit HPO axis dahil

Hypothalamic-Pituitary-Ovary axis ‘yun…

• Very briefly the hypothalamic-pituitary-thyroid axis

describes the relationship between the hypothalamus,
Figure 3: The blood supply and venous drainage of the thyroid
pituitary gland and the thyroid.
glands.
• The hypothalamus releases thyroid releasing
Veins, Arteries and Nerves (VANs) hormone (TRH) in circulation to the anterior pituitary.
The anterior pituitary in turn releases thyroid
• The blood supply to the thyroid gland are the superior
stimulating hormone (TSH) in circulation to the
thyroid artery, the inferior thyroid artery, and
thyroid gland. The thyroid gland then releases
sometimes the thyroidea ima.
triiodothyronine (T3) and thyroxine (T4).
▪ The superior thyroid artery is a branch of
• TRH
the external carotid artery.
▪ Hypothalamus
▪ The inferior thyroid artery is a branch of
▪ Phospholipase Ca2+  IP3/DAG  TRH
the thyrocervical trunk.
release
• The veins from the thyroid gland are the superior
• TSH
thyroid, middle thyroid and the inferior thyroid
▪ Anterior pituitary
veins.
▪ ↑cAMP  TSH release
▪ The superior and middle thyroid veins
▪ Effects
drain into the internal jugular vein.
▪ Increase proteolysis of
▪ The inferior thyroid vein drains into the left
thyroglobulin
brachiocephalic vein in the thorax.
▪ Increase iodide puping
• Principal innervation of the thyroid gland derives from
▪ Increase tyrosine iodination
the autonomic nervous system.
▪ Increase size, number and
▪ Parasympathetic fibers come from the
secretion
vagus nerve (CN X).
▪ Factors affecting TSH release
▪ Sympathetic fibers are distributed from
▪ Cold temperature: ↑TSH
the superior, middle, and inferior ganglia
(Increase metabolism in order to
of the sympathetic trunk. These small
generate heat)
nerves enter the gland along with the
▪ Anxiety: ↓TSH
blood vessels.

Lecture Title: Hyperthyroidism and Graves Disease 3

Module: MSGD 5
Transcribed by: MOLINA GASE
 V. PHYSIOLOGY – Synthesis of Thyroid Hormone Process

Trapping of Iodine • Thyroid cells pump iodine actively into cells through NIS
(sodium iodide symporter)
• NIS transports iodide through secondary active transport via
Oxidation of Iodide Na+ concentration gradient formed by Na-K ATPase
Iodide Transport • Stimulated by TSH
(Trapping)
Iodination of Tyrosine Residues

Coupling of DIT to DIT (T4) or to MIT (T3)
Hydrolysis of Thyroglobin molecule from T4 and T3 Oxidation of
Iodide to Iodine
Figure 5: General pathway of T4 and T3 synthesis.
• Iodide cannot be incorporated to thyroglobulin; it must first be
oxidized (I- to I2)
• Enzyme: thyroid peroxidase located in the apical membrane.
Inhibition of this peroxidase system leads to zero production of
thyroid hormones.
• Iodine is transported to the colloid in exchange for chloride

Thyroid Hormone
• Iodothyronines
• Binding of iodine with thyroglobuline
▪ Secretory product of the thyroid gland • Tyrosine + I2 --> MIT
▪ Formed by coupling of two iodinated tyrosine • MIT + I- --> DIT
molecules Iodination (or • Catalyzed by iodinase
Organification)
▪ Three forms:
▪ T4 – thyroxine or tetraiodothyronine
• 90%, primarily a prehormone
• Synthesized by coupling of 2 DIT
(diiodotyrosine) • Binding of iodotyrosine residues with each other
▪ T3 – triiodothyronine (T3) • MIT + DIT --> T3
• DIT + DIT --> T4
• 10%, active form (more potent)
Coupling
• Synthesized by coupling of 1 MIT
(monoiodotyrosine) and 1 DIT
▪ Reverse T3 – Triiodothyronine
• <1%, inactive form
• Synthesized the same way as T3
• Most T4 is converted to T3 inside the peripheral cell • Hyrdolysis of thyroglobin molecule from T3 and T4
through the action of 5-deiodinase
Hydrolysis
Formation/Synthesis
Precursors

• Iodine
▪ Must be ingested (1 mg/week) to form
normal quality of thyroxine Figure 6: T3 and T4 synthesis (detailed)
▪ Absorbed in the GIT, most are excreted
Release and Transport
in the kidney, but some are delivered to
the thyroid
▪ Cannot be synthesized by the body
• Thyroglobulin
▪ Secreted from the apical membrane into
the lumen via exocytosis
▪ Contain about 70 tyrosine amino acids,
the major substrate that combine with
iodine to form the thyroid hormones
▪ Thyroid hormones within the
thyroglobulin molecule remain part of it
even as stored in the follicular colloid

Figure 7: T3 and T4 release and transport

Lecture Title: Hyperthyroidism and Graves Disease 4

Module: MSGD 5
Transcribed by: MOLINA GASE
 Figure 8: Thyroid hormone synthesis
• DIT, MIT, T3 and T4 are located inside the
thyroglobulin molecule; the thyroglobulin stays stored
in the colloid and remains there until stimulated by TSH
• Thyroglobulin is not released into the circulating blood
in measurable amounts; T3 and T4 must first be cleaved
 PINOCYTOSIS
• Steps
▪ Apical surface of thyroid cells form finger-like
projections that close around small portions of
the colloid to form pinocytic vesicles
▪ Vesicles enter apex of thyroid cell
▪ Lysosomes in cell cytoplasm fuse with vesicle
and (proteases) digest thyroglobulin molecules
▪ Thyroxine and triiodothyronine are released, and
diffuse through basal membrane into the blood
• Only T3 and T4 are secreted; DIT and MIT are
deiodinated to recycle the I2 in reorganification for future
use
• Plasma transport proteins
▪ Thyroxine-binding globulin (TBG) –
main transport protein
▪ Prealbumin
▪ Albumin
• High-affinity to transport proteins
▪ Hormones are released to the tissue cells
slowly
▪ Long latent period before activity begins
▪ Longer duration of action
• T4 is more strongly bound to TBG than T3
▪ Free T4 < free T3
Lecture Title: Hyperthyroidism and Graves Disease
Module: MSGD 5
Transcribed by: MOLINA GASE
IMPORTANT!
It is more useful to measure free T3 and free T4 (than their bound
counterparts) because they are the only ones who are active
and are responsible for the clinical symptoms of a patient.
VI. PHYSIOLOGY – Thyroid Hormone Function
• Transcription of genes
▪ active nuclear transcription of genes
▪ Increased protein and enzyme synthesis
▪ Increase in functional activity throughout
the body
▪ most T4 is converted to T3
▪ intracellular TH receptors have
high affinity to T3
• Increased cellular metabolic activity
▪ Increased utilization of food as energy
▪ Increased rate of BOTH protein synthesis
and catabolism
▪ Increased growth rate of young people
▪ Excites mental processes
▪ Increased activity of other endocrine
organs (Increased rate of hormone
secretion)
• Increased number and activity of mitochondria
(Increased ATP)
• Increased active transport of ions through cell
membranes
• Growth
▪ Stimulation of carbohydrate metabolism
▪ Stimulation of fat metabolism
▪ Increased vitamin requirements
5
 ▪Increased BMR
▪Decreased body weight
▪ May not occur due to TH
increasing appetite
• On cardiovascular system
▪ Increased blood flow and cardiac
output
▪ Increased metabolism
Increased oxygen utilization 
Increased blood flow
Increased cardiac output
▪ Increased heart rate (chronotropic)
▪ Direct effect on excitability of the
heart
▪ Increased heart strength (inotropic)
▪ Due to Increased enzymatic
activity
▪ NORMAL mean arterial pressure
▪ Increased pulse pressure
▪ Increased systolic BP
• Increased heart
contractility
Increased cardiac
output  increast blood
volume  Increased
SBP
▪ Decreased diastolic BP
• Due to vasodilation
when heart is at rest
• On respiratory system
▪ Increased respiratory rate and depth of
respiration
▪ Increased metabolism
Increased oxygen utilization 
Increased CO2 production 
Increased respiratory
(hyperventilation) to expel CO2
• On digestive system
▪ Increased GI motility
▪ Increased secretion of digestive juices
• On central nervous system
▪ Excitatory effect on CNS
▪ Increased rapidity of cerebration
(working of the brain)
▪ Fine muscle tremor
• On sexual function
▪ Male:
▪ Increased TH – loss of libido
(also in women)
▪ Decreased TH – impotence
▪ Female:
▪ Increased TH – menorrhagia,
polymenorrhea, amenorrhea
▪ Decreased TH
oligomenorrhea, amenorrhea
Lecture Title: Hyperthyroidism and Graves Disease
Module: MSGD 5
Transcribed by: MOLINA GASE
VII. CASE – Differentiate Signs and Symptoms
Observed in Hypothyroidism and Hyperthyroidism
Hyperthyroidism Hypothyroidism
Inability to sleep Slowing of physical and mental
activities
• Neural synapses are
excited and more sensitive • Low T3 and T4 
 can’t sleep Decreased glucose
 metabolism  low ATP 
Decrease in energy for
 neuronal and muscular
functions
• Can also be from: low rate
of transcription 
Decreased proteins and
mitochondria  low basal
metabolic rate
Sensation of pounding chest Decreased ability to tolerate cold
• T3 and T4 has positive • Low levels of T3 and T4 
chronotropic and inotropic Decreased activity of
effects Na+/K+ ATPase  lower
• Act on SA node  rate of Na and K transport
Increased Na and K pumps  lower use of energy 
 hasten repolarization  lower heat generation 

Decreased time between Decreased ability to
contractions tolerate cold
• Sensation is based on
inotropicity (strength)
rather than chronotropicity
(frequency) by afferent
vagal branches that enter
the heart and is sensitive to
pain and pressure
Easy fatigability Skin is puffy and dry
• Excess thyroid hormone • Low levels of T3 and T4 
promotes excess Increased activity of

catabolism  less proteins fibroblasts  Increased
for contraction  weaker GAGs (osmotic effect,
muscles require higher puffy skin), hyaluronic acid
rate excitation  Increased use and chondroitin sulfate
of neurotransmitters lead (Increased keratin
to depletion  fatigue formation, dry skin)
Normal BP but Increased HR Weak and always sleepy
(110/minute)
• Same explanation as slow
• HR is affected by mental and physical
chronotropic effect activities
• BP is normal but Increased • Decreased protein
systolic BP (inotropic synthesis  less
effect, Increase pump, contractile proteins 
Increase pressure) and muscle weakness
Decreased diastolic BP
• Mean arterial pressure
depends on both
Difficulty in swallowing food
• Thyroid gland is located at
levels of C5 to T1
• Enlargement of thyroid 
push thyroid cartilage
backwards  compresses
–
esophagus  sensation of
difficulty in swallowing
6
 Hyperthyroidism Hypothyroidism

Diarrhea Weight gain

• Excess thyroid hormone  Hair loss
stimulation of postsynaptic Depression
PNS neurons  Emotional liability
vasodilation  Increased Constipation
secretion  diarrhea Blurred vision
Parathesia and nerve
entrapment syndromes
Slowed speech and movements
Pallor
Jaundice

Tremors
• Excess TH  Increased
sensitivity of peripheral
nerves  Increased Figure 9: In type II hypersensitivity reactions, antibodies bind to cell
sensitivity of afferent nerve surface receptor and induce activation (e.g., TSH).
fibers of muscle spindles 
reflex oscillation  tremors
(i.e., finger tremors)
Intolerance to heat
• Excess TH  Increased
BMR  Increased internal
core temperature  body
compensates by
dissipating heat through
the skin (vasodilation) 
further heating of
extremities activate pain
receptors
Decreased sexual functioning
• Increased TH – loss of
libido in men and women
• Menorrhagia,
polymenorrhagia,
amenorrhea

VIII. CASE – GRAVE’s DISEASE

• A state of hyperthyroidism, goiter and
opthalmopathy
• Onset usually between ages of 20 and 40 years
Figure 10: Immune mechanisms of Graves Disease and Hashimoto
• An autoimmune disorder characterized by abnormal Thyroiditis.
stimulation of the thyroid gland stimulating antibodies
(TSH receptor antibodies) that act through normal TSH Irrelevant ang Hashimoto Thyroiditis… pero the point is
receptors “opposites” ang Graves disease at Hashimoto Thyroiditis.
▪ Modification of Type II cytotoxic Graves disease = autoimmune stimulation of thyroid to produce
antibodies TH and low TSH and TRH = hyperthyroidism
• May be associated with other diseases such as Hashimotothyroiditis = autoimmune destruction of TSH
Myesthenia Gravis receptors = low TH and high TSH and TRH = hypothyroidism
• Disease is associated with a major histocompatibility
complex class 1 chain-related gene A (MICA) IX. CASE – Results of the Thyroid Function Test
• Grave’s Disease
▪ Usually Grave’s diseases secondary to
mass of anterior pituitary gland or
hypothalamus and tertiary to excessive
ingestion of iodine (high precursor of T3
and T4)

Lecture Title: Hyperthyroidism and Graves Disease 7

Module: MSGD 5
Transcribed by: MOLINA GASE
 ‘pag sinabing secondary to = because of/due to
So rephrased in another way, Grave’s disease DUE TO mass
of anterior pituitary gland, which is DUE TO excessive iodine
ingestion…
Pero hindi tayo sure sa secondary ng case… wala lang…para
masanay na tayo na secondary to… tertiary to, etc.
Sounds more cool, more professional!
• Grave’s Disease
▪ Primary hyperthyroidism
▪ Increased T3 and T4 due to
defect in the gland
▪ TSH and TRH levels will be low
(compensatory effect)
▪ Secondary hyperthyroidism
▪ Increased T3 and T4 due to
defect in hypothalamus or
anterior pituitary gland
▪ Increased TRH and TSH wil lead
to high T3 and T4
▪ Grave’s disease:
▪ Increased IgGs (specific for
cytotoxic T-lymphocyte gene 4
receptors)
FINAL DIAGNOSIS: Primary hyperthyroidism
X. CASE – PTU
Figure 11: Sites of actions of antithyroid drugs.
• Propylthiouracil (PTU) are small sulfur-containing
thioamides by blocking peroxidase-catalyzed
reactions, iondination of the tyrosine residues of
thyroglobulin, and coupling of DIT and MIT.
• Inhibits peripheral conversion of T4 to T3
• Do not inhibit the release of preformed TH
• Onset of activity requires 3 to 4 weeks for full effect
• Oral route
• Toxic effects include
▪ Skin rash
▪ Severe reactions
Lecture Title: Hyperthyroidism and Graves Disease
Module: MSGD 5
Transcribed by: MOLINA GASE
▪ Vasculitis
▪ Agranulocytosis
▪ Hypoprothrombinemia
▪ Liver dysfunction
XI. CASE – Thyroidectomy
• Nerves, parathyroids, and surrounding structures are all
at risk of injury during thyroidectomy.
• Nerves at risk of injury include:
▪ Recurrent laryngeal nerve
▪ Branch of the vagus nerve (CN X)
▪ Innervates all intrinsic muscles of the
larynx as well sensory and motor
functions of the esophagus and trachea
▪ Can cause airway obstruction if
accidentally severed
▪ External branches of the superior laryngeal
nerve
▪ Innervates the larynx
▪ Cervical sympathetic trunk is at risk of injury in
invasive thyroid cancers and retroesophageal
goiters and may result in Horner’s syndrome
▪ Horner’s syndrome – combination of
signs and symptoms resulting in
decreased pupil size, drooping eyelid and
decreased sweating ipsilateral to the
affected side
• Transient hypocalcemia (from surgical injury or
inadvertent removal of parathyroid tissue)
▪ Tested using Chvostek’s and Trosseau’s signs
• Permanent hypothyroidism
• Postoperative hematomas
• Bilateral vocal cord dysfunction with airway
compromises
• Surgical landmark = external carotid artery
▪ Not the inferior thyroid artery because it is
found behind the carotid sheath, which
contains the common carotid, CNX,
internal jugular, and deep cervical lymph
nodes
XII. EXTRA - Management
• Adrenergic effects of the heart is DIFFERENT for young
(sinus tachycardia) and elderly (atrial fibrillation)
• In hyperthyroidism there is Increased metabolic rate,
calorigenesis (generation of heat) and protein
breakdown = WEAKNESS
• Treatment (and this applies to ANY disease) should be
based on a physiological approach – CONTROL THE
SYMPTOMS FIRST then you plan out your treatment
• Beta blockers should be noncardiogenic NOT
cardiogenic; the effect is NOT confined to the heart
• If with fever, give Paracetamol and provide hydration
8