1. Describe the gross anatomy of the hypothalamus and the pituitary gland.

Describe the
gross anatomy, blood supply, venous and lymphatic drainage of the thyroid gland.

a. Hypothalamus​ - controls pituitary gland, releasing hormones

i. Anatomy
- 3 main regions: Supraoptic region, Tuberal region and Mammillary region
b. Pituitary gland - the master gland of the endocrine system, dependent on the hypothalamus,
stimulating hormones
Anatomy
Anterior Lobe Pituitary Gland
- Linked to hypothalamus by hypothalamic-hypophyseal portal system
- Pars intermedia - connection to hypothalamus through posterior pituitary
- Hormones: GH, prolactin, TSH, LH, FSH and ACTH
Posterior Lobe Pituitary Gland
- Derived from neural tissues
- Neurohypophysis, composed mainly of glial cells: ​Pituicytes - do not secrete hormones,
act to support large number of terminal fibers and terminal nerve endings, and originate
in the supraoptic and paraventricular nuclei of hypothalamus
- hypophyseal stalk - physical connection to hypothalamus
- Hormones: ADH & oxytocin
c. Thyroid gland
i. Anatomy
- butterfly shaped endocrine gland consists of right and left pear-shaped lobe connected
by an isthmus surrounded by a sheath which attaches the gland to the larynx and trachea
- Pyramidal lobe is often present and it projects upwards from the isthmus, to the left of
the midline.
- location: anterior neck, between C5 and T1, behind sternohyoid and sternothyroid,
wrapping around cricoid cartilage and superior tracheal rings, inferior to thyroid cartilage
of the larynx, bound by pretracheal fascia
ii. Blood supply​: Superior thyroid artery (from external carotid), inferior thyroid artery (from
thyrocervical trunk) and thyroid ima artery
 iii. Venous Drainage​:Superior & Middle (both drain into internal jugular vein) and Inferior
thyroid veins (drain into brachiocephalic vein in thorax)

iv. Innervation​: ANS; para - superior laryngeal nerve and sympa - superior, middle and
inferior ganglia of sympathetic trunk

2. Describe the histology of the hypothalamus, the pituitary, and the thyroid gland.
a. Hypothalamus
i. Microscopically it is composed of small nerve cells that are arranged in groups or nuclei
b. Pituitary
Composed of two lobes

1. ​Anterior lobe​ (​adenohypophysis​) - glandular portion

2. ​Posterior lobe​ (​neurohypophysis​) – nervous portion

Anterior lobe​- composed of cells arranged in cords separated by fenestrated capillaries and reticular
connective tissue

Divided into three parts:

1. Pars distalis - contain two main cell types; accounts for 75% of the adenohypophysis and has a
thin fibrous capsule

a. Chromophobes – stain poorly

b. Chromophils – secretory cells in which hormone is stored in cytoplasmic granules

 1. Acidophils- pinkish stain with acidic dye of H&E; secrete either growth
hormone (somatotropin) or prolactin and are called somatotrophs and lactotrophs

2. Basophils – bluish stains with basic dye of H&E; corticotrophs,

gonadotrophs, and thyrotrophs with target cells in the adrenal cortex, gonads,
and thyroid gland respectively

With two exceptions, each type of anterior pituitary cell makes one kind of hormone. Gonadotrophs
secrete two different glycoproteins: follicle-stimulating hormone(FSH) and luteinizing hormone (LH; called
interstitial cell-stimulating hormone [ICSH] in men. The main protein synthesized in corticotrophs is
pro-opiomelanocortin (POMC) which is cleaved post translationally into the polypeptiode homones
adrenocortical trophic hormone (ACTH) and β-lipotropin (​-LPH​). Hormones produced by the pars distalis
have widespread functional activities. They regulate almost all other endocrine glands, ovarian function
and sperm production, milk production, and the metabolism of muscle, bone, and adipose tissue.

2. Pars Tuberalis- smallest part located around the infundibular stem; highly vascular. Most of the
cells of the pars tuberalis are gonadotrophs
3. Pars intermedia- lies between the pars distalis and the pars nervosa; contains small cystic
spaces (Rathke’s cysts) that are remnants of the lumen of Rathke’s pouch. Contains basophil
cells (corticotrophs), chromophobes, and small, colloid-filled cysts derived from the lumen of the
embryonic hypophyseal pouch. Best developed and active during fetal life, corticotrophs of the
pars intermedia express POMC but cleave it differently from cells in the pars distalis, producing
mainly smaller peptide hormones, including two forms of melanocyte-stimulating hormone (MSH),
y-LPH and β-endorphin. MSH inceases melanocyte activity but the overall functional significance
of the pars intermedia remains uncertain

Posterior lobe- ​composed of three parts

1. Pars nervosa- ​composed of small glial cells, the pituicytes with bracing processes and
unmyelinated nerve fibers

The hormones accumulate in axonal dilations are called neurosecretory bodies or Herring bodies

2. Infundibular Stalk
 3. Tuber cinereuum

C. Thyroid
Capsule​- dense irregular connective tissue; sends septa into parenchyma (thyroid follicles).
Composed of round epithelial thyroid follicles of variable diameter, each with simple epithelium and a
central lumen densely filled with gelatinous acidophilic colloid. The lumen is surrounded by simple
cuboidal epithelium (follicular cells/thyrocytes); follicles are closely packed with varying shapes and sizes.
Connective tissue and blood vessels between thyroid follicles

Parafollicular cells/ C cells – pale staining to clear cells amidst the follicular cells and in the perifollicular
connective tissue. Found in the basal lamina of the follicular epithelium or as isolated clusters between
follicles

3. Describe the structure and synthesis of the thyroid-releasing hormone (TRH),

thyroid-stimulating hormone (TSH), thyroxine (T4) and triiodothyronine (T3).

TRH
● The chemical structure of TRH is a peptide of 3 amino acid sequence of
pyroglutamyl,-histidyl-proline amide
1. In the nucleus, the gene for the hormone is transcribed into mRNA
2. mRNA is transferred to the cytoplasm and translated on the ribosomes to the first
product, a preprohormone
3. The signal peptide is removed in the endoplasmic reticulum, converting the
preprohormone to a prohormone
4. Prohormone is transferred to the Golgi apparatus where it is packaged in secretory
vesicles. IN the secretory vesicles, proteolytic enzymes cleave the peptide sequences
from the prohormone to produce the final hormone
5. The final hormone is stored in secretory vesicles until the endocrine cell is stimulated

(cytoplasm)preprohormone→(removal of signaling peptide in ER)prohormone→(golgi apparatus)

packaged in secretory vesicles-->cleavage of peptide sequences via proteolytic hormones-->TRH

TSH
● Glycoproteins with sugar moieties ​covalently ​linked to ​asparagine residues in their
polypeptide chains. Consist of two subunits, ​α and β​, which are ​not covalently linked;
none of the subunit alone is biologically active.
● During the biosynthetic process, pairing of the α and β subunits begins in the
endoplasmic reticulum​ and continues in the ​Golgi apparatus
T4 and T3
1. Thyroglobulin​, a glycoprotein containing large quantities of ​tyrosine​, is synthesized on
the RER and Golgi apparatus of the ​follicular cells​. They are incorporated into the
secretory vesicles and extruded across the apical membrane into the follicular lumen.
Later, the tyrosine residues of thyroglobulin are ​iodinated ​to form the precursors of
thyroid hormones
2. Na​+​-I​- ​, “I-trap”​. I​- is actively transported(secondary active transport) from blood into the
follicular epithelial cells against both chemical and electrical gradient.
3. Oxidation ​of I​- ​to I​2​. Once I​- is pumped into the cell, it traverses the cell to the apical
membrane where it is oxidized to I​2 ​by the enzyme thyroid ​peroxidase​.
4. Organification ​of I​2​. ​At the ​apical ​membrane, just inside the lumen of the follicle, I​2
combines with the tyrosine moieties of thyroglobulin, catalyzed by thyroid ​peroxidase​, to
form monoiodotyrosine(​MIT​) and diiodotyrosine (​DIT​)
5. Coupling ​reaction​. Catalyzed by thyroid ​peroxidase ​in two different reactions. One
reaction, two molecules of DIT combine to form T​4​. The other reaction one molecule of
MIT and one molecule of DIT combine to form T​3
6. Endocytosis of thyroglobulin. ​Iodinated thyroglobulin is endocytosed into the follicular
epithelial cell
7. Hydrolysis of T​4 and ​ T​3. ​Thyroglobulin droplets fuse with lysosomal membranes. The
lysosomal proteases​ then hydrolyze peptide bonds to release T​4 and ​ T​3

The two active thyroid hormones T​4​ and T​3​ differ only by a single atom of iodine

4. Outline the hypothalamic-pituitary-thyroid axis. Explain the role of each component of the
axis, and the mechanism by which this system regulates thyroid hormone release.

● The hypothalamic-pituitary-thyroid axis is composed of the ​hypothalamus​, ​anterior pituitary

gland​, and ​thyroid​.
○ The ​hypothalamus​ produces ​thyrotropin-releasing hormone​, ​TRH​.
○ The ​anterior pituitary gland​ produces t​ hyrotropin,​ ​TSH​.
○ The thyroid gland releases ​triiodothyronine​ and ​thyroxine,​ ​T3 and T4​, respectively.
● TRH
○ Secreted by nerve endings in the median eminence of the hypothalamus
 ■ Transported to the anterior pituitary gland through the hypothalamic-hypophyseal
portal blood
○ Binds to TRH receptors in the pituitary cell membrane
■ Activates ​phospholipase C​ →​ IP​3​/DAG​ → ​TSH release
● TSH
○ TSH binds to TSH receptors on the ​basal ​membrane surfaces of thyroid cell → adenylyl
cyclase → increase cAMP → activation of protein kinase → varied effects on the thyroid
cell
■ Increase proteolysis of thyroglobulin in follicular cells; thyroid hormones are
released to the bloodstream
■ Increased activity of the iodide pump​ → increased iodide trapping
■ Increased iodination of tyrosine​ to form thyroid hormones
■ Increased size​ and ​increased secretory activity​ of the thyroid cells
■ Increased number of thyroid cells
● Feedback mechanism
○ I​ncreased thyroid hormone​ levels in body fluids ​decreases TSH and TRH secretion
■ Thyroid hormone levels above 1.75 times normal → TSH secretion falls to zero
○ Decreased temperature → increased basal metabolic rate
○ Emotions such as excitement and anxiety decrease TSH secretion

5. How are T3 and T4 distributed throughout the body? How does this affect how their levels
are measured in serum tests? Explain the peripheral conversion that occurs between the two.

I. How are T3 and T4 distributed throughout the body?

- In the blood, thyroid hormone is predominantly transferred while bound to serum binding
proteins such as thyroid-binding globulin (TBG), transthyretin, or albumin. When it
reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells
either by diffusion or carrier-mediated transport. They then bind to nuclear alpha or beta
receptors in the respective tissue and cause activation of certain transcription factors.
This leads to the activation of certain genes in the cell type, leading to the cell-specific
response T3 and T4 exert.
- Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the
surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of
thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free
hormone into blood.
● Thyroid hormones are excised from their thyroglobulin scaffold by digestion in
lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis
proceeds in the following steps:
➔ Thyroid epithelial cells ingest colloid by endocytosis from their apical
borders - that colloid contains thyroglobulin decorated with thyroid
hormone.
➔ Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic
enzymes that digest thyroglobulin, thereby liberating free thyroid
hormones.
➔ Finally, free thyroid hormones apparently diffuse out of lysosomes,
through the basal plasma membrane of the cell, and into the blood where
they quickly bind to carrier proteins for transport to target cells.
 ➔
II. How does this affect how their levels are measured in serum tests? ​(mej di ko gets tanong dito)
- The thyroid gland constantly releases a certain amount of hormones into the blood. So a
blood test can be used to determine the amounts of hormones produced by the thyroid
gland. The blood test measures the levels of TSH and thyroid hormones triiodothyronine
(T3) and thyroxine (T4). A change in the TSH level can be an early sign of a thyroid
problem. If the TSH level in the blood is higher or lower than normal, the levels of thyroid
hormones T4 and T3 are also measured. Most thyroid hormones are bound to certain
proteins in the blood. Only unbound “free” thyroid hormones are active and have an
effect, though. So only the free thyroid hormones are measured
● Thyroid-stimulating hormone (TSH)​: ​High TSH levels → hypothyroidism
(underactive thyroid)​. The pituitary gland produces more TSH in order to
stimulate the thyroid gland to produce thyroid hormones. ​Very low TSH →
hyperthyroidism (overactive thyroid).​. The pituitary gland then produces less
TSH, in order to stop “telling” the thyroid gland to make more hormones.
● Free triiodothyronine (FT3) and free thyroxine (FT4)​: High levels of free
thyroid hormones in the blood may be a sign of an overactive thyroid, and low
levels could be a sign of an underactive thyroid.
● Thyroid antibodies​: The concentration of thyroid antibodies in the blood is
higher in certain disorders where the body’s immune system attacks the thyroid
gland. These include Hashimoto’s disease and Graves’ disease. Low levels of
thyroid antibodies may be a sign of various diseases, such as an inflammation of
the thyroid gland (thyroiditis), type 1 diabetes or rheumatoid arthritis.
● Calcitonin​: Calcitonin levels are usually higher in a certain type of thyroid
cancer. But high levels of calcitonin can also be a sign of other diseases, such as
kidney failure. Calcitonin levels play an important role in calcium and bone
metabolism too.

6. Describe the structure of thyroid receptors. Explain how these receptors mediate the
actions of the thyroid hormones T3 and T4.

Lifted from GUYTON p.955-956

● Thyroid hormones activate Nuclear Receptors

● Thyroid hormone receptors are either
○ Attached to the DNA genetic strands
○ Located in proximity of the DNA genetic strand
 ● Thyroid hormone receptor forms a HETERODIMER with Retinoid X Receptor (RXR) at specific
thyroid hormone response elements ​on the DNA
● After binding, receptors will be activated and initiate the transcription process, thus large numbers
of different types of mRNA are formed.
● After few mins or hrs, there will be RNA translation on the Cytoplasmic Ribosome to form
hundreds of new intracellular proteins.
○ Not all proteins are increased by similar percentages

TAKE NOTE: Thyroid Hormone ​general effect is to activate nuclear transcription of large numbers of
genes wherein protein enzymes, structural proteins, transport proteins, and other substance are
synthesize. Thus, the net result is an increase in functional activity throughout the body. Its receptor
mediates to Thyroid hormone function through its binding to the RXR that causes a series of events
leading to the production of intracellular protein.

The effects of these proteins affects Cardiovascular system by increasing Cardiac output, tissue
blood flow, heart rate, heart strength, and Respiration.

Furthermore, it also affects Metabolism by ​increasing the activity of Mitochondria​, which in

turn increases the formation of ATP to energize cellular function; ​increases the activity of
Na-K-ATPase​, thus due to it’s consumption of energy, it increases the amount of heat produced leading
to the ​increase in body metabolic rate​. There alaso an increas in Oxygen consumption, glucose
absorption, Gluconeogenesis, and Lipolysis

7. Outline the direct and indirect physiologic effects of the thyroid hormones T3 and T4.

Berne & Levy, p. 731

CARDIOVASCULAR EFFECTS:

● T3 ​increases​ cardiac output - ensuring sufficient delivery of O2 to tissues

● resting heart rate and stroke volume are increased
● speed and force of myocardial contractions are ​enhanced while diastolic relaxation time is
shortened
○ systolic blood pressure is modestly augmented while diastolic blood pressure is
decreased
● thyroid hormone ​decreases systemic vascular resistance by dilating resistance arterioles in
the peripheral circulation
● Total blood volume is increased by activating the renin-angiotensin-aldosterone axis ​-
increasing renal tubular sodium reabsorption
● Cardiac inotropic effects of T3 are indirect​ - via responsiveness to ​catecholamines
● Myocardial ​calcium uptake is increased - ​enhances the contractile force!
○ Thyroid hormone inhibits expression of Na-Ca antiporter - increasing intramyocellular Ca!
● T3 also increases ​ryanodine Ca channels in the SR - promoting the ​release of Ca from the SR
during systole
● Sarcoplasmic reticulum Ca-ATPase (SERCA) is increased by T3 - ​sequestration of Ca during
diastole​ is facilitated and relaxation time is shortened

EFFECTS ON BASAL METABOLIC RATE

● Thyroid hormones ​increase basal rate of oxygen consumption and heat production
 ● Thyroid hormone increases the expression of ​mitochondrial uncoupling proteins -
demonstrated in all tissues except brain, gonads, and spleen
● Glucose and fatty acid uptake and oxidation are increased
● Thermogenesis naturally increases as well with O2 use
○ Changes in body temp parallels with fluctuations in levels of thyroid hormone
○ BUT!! Increase in body temp is compensated by a compensatory increase in heat loss
through ​appropriate thyroid hormone-mediated increases in blood flow, sweating,
and ventilation
● T3 augments ​glucose absorption from GI tract and increases glucose turnover ​(glucose
uptake, oxidation, and synthesis)
● In ​adipose tissue, ​thyroid hormone ​induces enzymes for synthesis of fatty acids, acetyl-CoA
carboxylase, and fatty acid synthase and enhances lipolysis!
● Lipid turnover ​(FFA release from adipose tissue and oxidation) is augmented
● Protein turnover (release of amino acids, protein degradation and protein synthesis and urea
formation) is also ​increased
○ T3 ​potentiates the respective stimulatory effects of ​epinephrine, norepinephrine,
glucagon, cortisol, and GH ON GLUCONEOGENESIS, LIPOLYSIS, KETOGENESIS,
AND PROTEOLYSIS
● Overall metabolic effect of thyroid hormone has been described as a ​ ccelerating t​ he response to
starvation!!
● Thyroid hormone stimulates ​synthesis of cholesterol - but more so its oxidation and biliary
secretion - ​net effect is a decrease in the plasma levels of total and low-density lipoprotein
cholesterol
● Clearance of ​adrenal and gonadal hormones, some B vitamins, certain administered drugs
are increases by thyroid hormone

RESPIRATORY EFFECTS

● Thyroid hormone ​stimulates O2 utilization and also enhances O2 supply

● T3 ​increases RESTING RESPIRATORY RATE, MINUTE VENTILATION AND VENTILATORY
RESPONSE ​to hypercapnia and hypoxia
○ These actions maintain normal arterial PO2 when O2 utilization is increased and normal
PCO2 when CO2 production is increased

SKELETAL MUSCLE EFFECTS

● Normal function of skeletal muscles also requires optimal amounts of thyroid hormone
○ This might be related to the regulation of energy production and storage
● Glycolysis and glycogenolysis are increased and glycogen and creatine phosphate are
reduced by an excess of T3 and T4

EFFECTS ON ANS AND CATECHOLAMINE ACTION

● There is ​synergism​ between catecholamines and thyroid hormones

○ Synergistic in the way of ​increasing metabolic rate, heat production, heart rate,
motor activity, and excitation of CNS
● T3 may ​enhance sympathetic nervous system activity by increasing the number of beta
adrenergic receptors in heart muscles and generation of ​intracellular second messengers
such as cAMP
EFFECTS ON GROWTH AND MATURATION

● A small but crucial amount of thyroid hormone ​crosses the placenta ​and the ​fetal thyroid axis
becomes functional midgestation
● Thyroid hormone is crucial for ​normal neurological development and proper bone formation
in the fetus
○ Deficiency can cause cretinism

EFFECTS ON BONE, HARD TISSUE, AND DERMIS

● Thyroid hormone ​increases endochondral ossification, linear growth of bones, and

maturation of epiphyseal bone centers
● T3 enhances ​maturation and activity of chondrocytes in the cartilage growth plate
● T3 also stimulates ​adult bone remodeling
● Normal degradative processes in these structural and integumentary tissues are also
stimulated by thyroid hormone
○ Too much or too little can lead to hair loss or abnormal nail formation

EFFECTS ON THE NERVOUS SYSTEM

● Thyroid hormone ​regulates the timing and pace of development of CNS

● Deficiency in utero and early infancy ​decreases growth of cerebral and cerebellar cortex,
proliferation of axons and branching dendrites, synaptogenesis, myelinization, and cell
migration
● Decreased thyroid hormone levels reduce cell size, RNA and protein content, tubulin- and
microtubule-associated protein, protein and lipid content of myelin, local production of critical
growth factors, and rates of protein synthesis
● Thyroid hormone also enhances wakefulness, alertness, responsiveness to various
stimuli, auditory sense, awareness of hunger, memory and learning capacity

EFFECTS ON REPRODUCTIVE ORGANS AND ENDOCRINE GLANDS

● Thyroid hormone plays an important, permissive role in the regulation of reproductive function
● The normal ovarian cycle of follicular development, maturation and ovulation, the
homologous testicular process of spermatogenesis, and maintenance of the healthy
pregnant state are all disrupted by significant fluctuations in thyroid hormone levels
● Ex. Thyroid hormone stimulates hepatic synthesis and release of sex steroid-binding globulin
● Kidney size, renal plasma flow, glomerular filtration rate, and transport rates are also
increased by thyroid hormone

8. ​What are the signs and symptoms of hyperthyroidism?

Cardiovascular ​–increase in cardiac output, caused by both increased peripheral oxygen needs and
increased cardiac contractility. Heart rate is increased, pulse pressure is widened, and peripheral vascular
resistance is decreased. Atrial fibrillation, which occurs in 10 to 20 percent of adults with hyperthyroidism,
is rare in children. Mitral valve prolapse

-tend to have low serum total and high-density lipoprotein (HDL) cholesterol concentrations and a low
total cholesterol/HDL cholesterol ratio.

●Gastrointestinal ​– Failure to gain weight or weight loss, despite an increase in appetite, is common.
Weight loss is caused primarily by increased calorigenesis, and secondarily by increased gut motility and
associated hyperdefecation and malabsorption, often with diarrhea and occasionally mild steatorrhea

However, with the increased prevalence of childhood obesity, some children may have normal weight at
the time of diagnosis; persistence of hyperphagia after treatment that restores euthyroidism may result in
excessive weight gain [​24​].

●Eyes ​– Stare and lid lag occur in many children with hyperthyroidism. "Stare" refers to the patient's
widely opened eyes, which give the appearance of staring. Lid lag is evaluated by having the patient
follow the examiner's finger as it is moved up and down. The patient has lid lag if the sclera can be seen
above the iris as the patient looks downward. These symptoms are caused by sympathetic overactivity,
possibly mediated by increased alpha-adrenergic receptors in some tissues, and so may be seen in any
form of hyperthyroidism

It is important to distinguish lid lag and stare from features of ophthalmopathy (proptosis and periorbital
edema), which are found in Graves disease, but almost never in other forms of hyperthyroidism.

●Neurologic ​– Graves disease can be associated with a variety of neurologic manifestations

•Movement disorders – Tremulousness and tremor are common in hyperthyroidism. The tremor is best
demonstrated from the outstretched hands or the tongue (fasciculations). Deep tendon reflexes are
hyperactive. Ataxia and chorea, which resolve with treatment of hyperthyroidism, have been reported [​28​].

•Co​gnitive dysfunction – Among very young children (<4 years), hyperthyroidism may cause
neurodevelopmental delay [​29​]. In particular, speech and language delay has been reported as an
unusual presentation of hyperthyroidism and improves with treatment for the hyperthyroidism [​30​].

•​Peripheral nervous system – Proximal muscle weakness may be present, with decreased muscle
mass and decreased efficiency of muscle contraction Rarely, patients may develop myasthenia gravis
and thymic enlargement.

•Periodic paralysis ​– Hypokalemic periodic paralysis (thyrotoxic periodic paralysis) is a rare disorder that
may be associated with hyperthyroidism, especially in Asian adolescent boys.

Rare neurologic manifestations that have been reported in Graves disease include benign intracranial
hypertension, which was reported in a child presenting with headache and papilledema; these findings
reversed with treatment Graves disease also has been reported in association with moyamoya disease, a
cerebrovascular disorder characterized by severe bilateral stenosis of the terminal portions of the carotid
arteries with prominent collateral circulation and cerebral ischemic events or epilepsy [​33​]. Although it is
rare, moyamoya disease should be considered in patients with Graves disease and focal neurologic
symptoms. A case report describes the initial co-presentation of new-onset Graves disease (with thyroid
storm) and type 1 diabetes mellitus, leading to cerebral infarctions and the additional diagnosis of
moyamoya disease in a 16-year-old girl

●​Behavioral and psychiatric – Children with hyperthyroidism tend to have greater mood swings and
disturbances of behavior, as compared with adults [​35​]. Their attention span decreases, they are usually
hyperactive, they sleep poorly, and their school performance deteriorates. Occasionally, children or adults
with hyperthyroidism may experience marked personality changes, agitation, depression, mania, or
psychosis [​36​]. (See ​"Neurologic manifestations of hyperthyroidism and Graves' disease"​.)

Many hyperthyroid children are referred to a developmental specialist or child psychiatrist to evaluate
emotional and behavioral symptoms before the presence of hyperthyroidism is suspected. Short attention
span and poor school performance are often incorrectly ascribed to attention deficit hyperactivity disorder.

●​Bone – Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and
reduced volume of trabecular bone [​37​]. Serum alkaline phosphatase and osteocalcin concentrations are
high, indicative of increased bone turnover. The increase in bone resorption may lead to an increase in
serum calcium concentrations, thereby inhibiting parathyroid hormone secretion and the conversion of
calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxyvitamin D). The net effect is osteoporosis and
an increased fracture risk in patients with chronic hyperthyroidism. (See ​"Bone disease with
hyperthyroidism and thyroid hormone therapy"​.)

●Skin ​– The skin is warm in hyperthyroidism because of increased blood flow; it is also smooth because
of a decrease in the keratin layer [​38​]. Sweating is increased because of increased calorigenesis.
Onycholysis (loosening of the nails from the nail bed, Plummer's nails) and softening of the nails and
thinning of the hair may occur. Vitiligo and alopecia areata can occur in association with autoimmune
disorders.

Dermopathy (pretibial myxedema), a component of the classic triad of Graves disease in adults, is rarely,
if ever, reported in children. (See ​"Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid
disease"​.)

Effects on growth and development

●Growth ​– Acceleration of growth is accompanied by advancement of epiphyseal maturation. The

acceleration in growth is usually subtle and depends upon the duration of hyperthyroidism before
diagnosis. As an example, in children who have had hyperthyroidism for one to two years, height may
increase from the 50​th to the 75​th percentile. The effect on growth may be more pronounced if
hyperthyroidism presents in early childhood. In a report of children aged 3.4 to 7.5 years, median height
was +1.25 standard deviations (SD), while body mass index was -0.48 SD [​39​]. With antithyroid drug
treatment, height velocity and bone age approach a more normal pattern. In a report of 101 children with
Graves disease from Italy, bone age was advanced at presentation [​40​]. Nonetheless, adult height was
normal after treatment with antithyroid drugs, and was even slightly increased in the boys who were
diagnosed during puberty.

●Puberty ​– The age of onset of puberty and attainment of pubertal stages does not appear to be altered
by hyperthyroidism]. Girls who have undergone menarche may develop oligomenorrhea or secondary
amenorrhea; anovulatory cycles are common Hyperthyroidism is associated with high levels of sex
hormone-binding globulin, which may result in high serum estradiol levels in girls and testosterone levels
in boys. However, unbound or free levels of these hormones are decreased, perhaps explaining why
luteinizing hormone levels are slightly elevated. Hyperthyroidism also is associated with increased
aromatization of androgens to estrogens. These hormonal changes have been associated with
gynecomastia in men; there have been no reports of gynecomastia in boys with Graves hyperthyroidism.

9. Explain the pathophysiology of hyperthyroidism. How is this distinguished from

thyrotoxicosis?

PATHOPHYSIOLOGY

Normally, the secretion of thyroid hormone is controlled by a complex feedback mechanism

involving the interaction of stimulatory and inhibitory factors (see the image below). Thyrotropin-releasing
hormone (TRH) from the hypothalamus stimulates the pituitary to release TSH.

Hypothalamic-pituitary-thyroid axis feedback. Schematic representation of negative feedback system that regulates
thyroid hormone levels. TRH = thyrotropin- releasing hormone; TSH = thyroid-stimulating hormone

Binding of TSH to receptors on the thyroid gland leads to the release of thyroid hormones—primarily T4
and to a lesser extent T3. In turn, elevated levels of these hormones act on the hypothalamus to decrease
TRH secretion and thus the synthesis of TSH.

Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is transported into the gland by an
iodide transporter, converted to iodine, and bound to thyroglobulin by the enzyme thyroid peroxidase
through a process called organification. This results in the formation of monoiodotyrosine (MIT) and
diiodotyrosine (DIT), which are coupled to form T3 and T4; these are then stored with thyroglobulin in the
thyroid’s follicular lumen. The thyroid contains a large supply of its preformed hormones.
Thyroid hormones diffuse into the peripheral circulation. More than 99.9% of T4 and T3 in the peripheral
circulation is bound to plasma proteins and is inactive. Free T3 is 20-100 times more biologically active
than free T4. Free T3 acts by binding to nuclear receptors (DNA-binding proteins in cell nuclei), regulating
the transcription of various cellular proteins.

Any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause
thyrotoxicosis. Disturbances of the normal homeostatic mechanism can occur at the level of the pituitary
gland, the thyroid gland, or in the periphery. Regardless of etiology, the result is an increase in
transcription in cellular proteins, causing an increase in the basal metabolic rate. In many ways, signs and
symptoms of hyperthyroidism resemble a state of catecholamine excess, and adrenergic blockade can
improve these symptoms.

10. Outline the different etiologies of hyperthyroidism.

Graves' disease (GD) is an autoimmune thyroid disease of unknown etiology. Recently, it is assumed that
the occurrence of GD co-existence with endogenous factors (genetic and interthyroid) and exogenous
(environmental).

11. Briefly explain the pathophysiology and complications of Graves disease. How is this
diagnosed? Relate this with your answers from nos. 4 and 5.

- Hyperthyroidism (Graves disease) is an autoimmune disorder characterized by increased

circulating levels of ​Thyroid-stimulating immunoglobulins​. These immunoglobulins are
antibodies to TSH receptors on thyroid follicular cells. These antibodies bind with the same
membrane receptors that bind TSH and induce continual activation of the cAMP system of the
cells with resultant development of hyperthyroidism. As a result increased secretion of thyroid
hormones and hypertrophy of the gland.
- This leads to an increase in metabolic rate because thyroid hormone increases O2 consumption
and BMR
- Complications:

Heart problems. Some of the most serious complications of hyperthyroidism involve the heart.
These include a rapid heart rate, a heart rhythm disorder called atrial fibrillation that increases
your risk of stroke, and congestive heart failure — a condition in which your heart can't circulate
enough blood to meet your body's needs.

Brittle bones. Untreated hyperthyroidism can also lead to weak, brittle bones (osteoporosis). The
strength of your bones depends, in part, on the amount of calcium and other minerals they
contain. Too much thyroid hormone interferes with your body's ability to incorporate calcium into
your bones.

Eye problems. People with Graves' ophthalmopathy develop eye problems, including bulging,
red or swollen eyes, sensitivity to light, and blurring or double vision. Untreated, severe eye
problems can lead to vision loss.

Red, swollen skin. In rare cases, people with Graves' disease develop Graves' dermopathy.
This affects the skin, causing redness and swelling, often on the shins and feet.

Thyrotoxic crisis. Hyperthyroidism also places you at risk of thyrotoxic crisis — a sudden
intensification of your symptoms, leading to a fever, a rapid pulse and even delirium. If this
occurs, seek immediate medical care.
 -

12. What are the risk factors of Graves disease?

​Family history

- Because a family history of Graves' disease is a known risk factor, there is likely a gene or genes
that can make a person more susceptible to the disorder. However it is still unclear, genetics
contribute about 20-30% of the susceptibility for acquiring Graves’ disease

Several autoimmune thyroid disease susceptibility genes have been identified: ​CD40, CTLA-4,
thyroglobulin, TSH receptor, and PTPN22.
- Some of these susceptibility genes are specific to either Graves disease or
Hashimoto thyroiditis, while others confer susceptibility to both conditions.
HLA-DRB1​ and ​HLA-DQB1​ also appear to be associated with Graves’ disease susceptibility.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) - a major thyroid autoantibody susceptibility

gene, and it is a negative regulator of T-cell activation.

Gender

- Women are much more likely to develop Graves' disease than are men. 7-8x more

Age.

- Graves' disease usually develops in people younger than 40.

Other autoimmune disorders.

- People with other disorders of the immune system, such as type 1 diabetes or rheumatoid
arthritis, have an increased risk.

Emotional or physical stress.

- Stressful life events or illness may act as a trigger for the onset of Graves' disease among people
who are genetically susceptible.

Pregnancy.

- Pregnancy or recent childbirth may increase the risk of the disorder, particularly among women
who are genetically susceptible.

Smoking.

- Cigarette smoking, which can affect the immune system, increases the risk of Graves' disease.
Smokers who have Graves' disease are also at increased risk of developing Graves'
ophthalmopathy.

13. How is Graves disease managed? What classes of medications are given and why?
MANAGEMENT

- antithyroid drugs, radioactive iodine (RAI), or surgery (near-total thyroidectomy).

- The optimal approach depends on patient’s age, preference, geography, and clinical factors such
as, history of arrhythmia or ischemic heart disease, size of goiter, and severity of thyrotoxicosis.
Physicians should be familiar with the advantages and disadvantages of each therapy to best
counsel their patients.

Antithyroid drugs – inhibit synthesis of T3 (triiodothyronine) and T4 (thyroxine)

Methimazole

Propylthiouracil (PTU)

Potassium iodide

Sodium iodide 131I

A 12- to 18-month course of antithyroid drugs may lead to a remission in approximately 50% of patients
but can cause potentially significant (albeit rare) adverse reactions, including agranulocytosis and
hepatotoxicity. Adverse reactions typically occur within the first 90 days of therapy.

Radioactive iodine & Surgery

RAI - ​gradually shrinking your thyroid, ultimately destroying the gland. Thyroid gland is the main absorber
of iodine in the body so there is little chance that other parts of the body to be affected by radiation. Upon
administration, it is advised for the patient to intake lots of fluid to flush out RAI in urine. In 90% of cases,
only 1 dose is needed to treat hyperthyroidism, but in rare cases a second dose is needed.

RAI takes about 6 months to fully destroy thyroid gland, but symptoms get better after 1-2 month of RAI
intake.

Side effects: hypothyroidism, metallic taste in mouth that can last for weeks, nausea, swollen salivary
glands

Treating Graves disease with RAI and surgery result in gland destruction or removal, necessitating
life-long levothyroxine replacement. Use of RAI has also been associated with the development or
worsening of thyroid eye disease in approximately 15% to 20% of patients.

*levothyroxine - ​used to treat an underactive thyroid gland (hypothyroidism). It replaces or provides more
thyroid hormone, which is normally produced by the thyroid gland. Low thyroid hormone levels can occur
naturally or when the thyroid gland is injured by radiation/medications

Surgery is favored in patients with concomitant suspicious or malignant thyroid nodules, coexisting
hyperparathyroidism, and in patients with large goiters or moderate to severe thyroid eye disease who
cannot be treated using antithyroid drugs.

- However, surgery is associated with potential complications such as

hypoparathyroidism and vocal cord paralysis in a small proportion of patients.
Treatment during pregnancy

In pregnancy, antithyroid drugs are the primary therapy, but some women with Graves disease opt to
receive definitive therapy with RAI or surgery prior to becoming pregnant usually 6months to a year prior,
to avoid potential teratogenic* effects of antithyroid drugs during pregnancy.

*teratogenic – disturbance of fetus growth caused by radiation, drugs, chemicals, and infections

14. How do we advise patients with Graves disease in terms of the impact to their families and
their quality of life?
- Doctors usually give three options for treatment of grave’s disease: medicine, radioiodine therapy
or surgery. The goal of treating Grave’s disease is to inhibit the production of thyroid hormones,
lessen the severity of symptoms and prevent complications. The optimal approach still depends
on the patient and their preference based on their history of past diseases.