Learning Objectives:

Learning Objectives: Pathophysiology

1. Discuss the normal anatomy of the thyroid

•​ ​Size, weight, lobes, Blood supplies
•​ ​Histological findings of a normal gland

A.
The thyroid is a butterfly-shaped endocrine gland located a ​ nteriorly in the lower neck,
extending from the level of the fifth cervical vertebra down to the first thoracic. The shape
is formed by by 2 elongated lateral lobes, each measuring 50 to 60 mm in length, with
superior and inferior poles connected by a median isthmus, with an average height of
12-15 mm, overlying the second to fourth tracheal rings. A normal thyroid gland in an
adult weighs 25-30g, and may enlarge during menstruation and pregnancy.
A pyramidal lobe may be present, in which case it arises from the thyroid isthmus, usually on
the left side. This is a remnant of the thyroglossal duct.
Arterial blood is supplied to the thyroid by the superior thyroid artery, a branch of the
external carotid artery, and the inferior thyroid artery, a branch of the thyrocervical trunk.
The superior thyroid artery will split into the anterior and posterior branches supplying the
thyroid, and the inferior thyroid artery will split into the superior and inferior branches.
Some branches will anastomose with the branches of the contralateral artery.
An anatomical variant, the thyroid ima artery, branches directly from the subclavian artery to
supply the thyroid.
Venous blood is drained by the superior and middle thyroid veins, which drain into the
internal jugular vein, and the inferior thyroid veins, that drain into the brachiocephalic
veins.
The normal thyroid gland is divided into lobules that contain 20 to 40 follicles, which are
spherical and average 30 um in diameter. Each follicle is lined by follicular cells, cuboidal
epithelial cells that contain a central storage of colloid, which is secreted by the cuboidal
follicular cells under the influence of TSH. The other group of secretory cells in the
thyroid gland can be seen as either individual cells or clumped in small groups in the
interfollicular stroma, secrete calcitonin, and are called C cells or parafollicular cells.

2. Discuss how the thyroid hormones are produced.

3. Discuss the mechanisms/pathophysiology of NNTG

The pathogenesis of MNG encompasses processes of ​diffuse follicular

hyperplasia​, ​focal nodular proliferation and eventual ​acquisition of functional
automaticity​. The development of MNG is a result of long-term exposure of the
thyroid gland to proliferative stimuli, such as iodine deficiency, goitrogens and inborn
error of thyroid hormone synthesis. All of the above results in insufficient thyroid
hormone production and stimulate pituitary secretion of thyroid stimulating hormone
(TSH).

TSH is a glycoprotein with stimulatory effect on the trophic and iodine metabolism
pathway in the thyroid follicular cells. TSH binding to the cell membrane G
protein-coupled receptor activates the cAMP and phospholipase C signalling
pathways, which in turn upregulates the process of iodine uptake and organification,
thyroglobulin synthesis, iodotyrosine coupling and iodothyronine (T3, T4) secretion,
leading to a short-term response in thyroid hormone production. ​In the long-term,
TSH also stimulates proliferation of follicular cells to increase the functional mass of
thyroid gland. Clinically, ​TSH stimulation results in enlargement of thyroid gland,
increased radio-iodine uptake and increased T4 and T3 levels.

Nodule formation is postulated to be the result of both an inherent and acquired

heterogeneity in proliferative and functional upregulation of the follicular cells. The
thyroid follicular cells are inherently heterogeneous with regard to thyroid hormone
production and proliferation in response to TSH stimulation, such that under
intermediate level of stimulation, a subpopulation of follicular cells outgrows other
cells and expand into macroscopic nodules. On the other hand, ​follicular cells
acquiring activating somatic mutations in the cell proliferation pathways can
expand clonally to form a nodule​. About 60 – 70% of nodules form by the later
mechanism and are monoclonal in origin. Somatic mutations leading to constitutive
activation of TSH receptors are found in about 60% of autonomously functioning
nodules. The remaining 40% of functioning nodules are TSH receptor mutation
negative with poorly understood genetic mechanism behind.

David Marine first developed the concept, that in response to iodide deficiency, the
thyroid first goes through a period of hyperplasia as a consequence of the
resulting TSH stimulation, but eventually, possibly because of iodide repletion
or a decreased requirement for thyroid hormone, enters a resting phase
characterized by colloid storage and the histologic picture of a colloid goiter.
Marine believed that repetition of these two phases of the cycle would eventually
result in the formation of nontoxic multinodular goiter

By the time the goiter is well developed, serum TSH levels and TSH production rates
are usually normal or even suppressed. For example, Dige-Petersen and Hummer
evaluated basal and TRH-stimulated serum TSH levels in 15 patients with diffuse
goiter and 47 patients with nodular goiter. They found impairment of TRH-induced
TSH release in 27% of the patients with nodular goiter, suggesting thyroid autonomy,
but in only 1 of the 15 with diffuse goiter. Smeulers et al, studied clinically euthyroid
women with multinodular goiter and found that there was an inverse relationship
between the increment of TSH after administration of TRH, and size of the thyroid
 gland. It was also found that, while being still within the normal range, the mean
serum T3 concentration of the group with impaired TSH secretion was significantly
higher than the normal mean, whereas the mean value of serum T4 levels was not
elevated. These and other results are consistent with the hypothesis that ​a diffuse
goiter may precede the development of nodules​. They are also consistent with
the clinical observation that, ​with time, autonomy may occur, with suppression of
TSH release, even though such goiters were originally TSH dependent​.

4. Discuss the gross and histopathological findings of the thyroid gland in NNTG

Gross:
Multinodular goiters are ​multilobulated, asymmetrically enlarged glands that
can reach weights of more than 2000 gm. The pattern of enlargement is quite
unpredictable and may involve one lobe far more than the other, ​producing
lateral pressure on midline structures, such as the trachea and esophagus​.
In other instances the goiter grows behind the sternum and clavicles to produce
the so-called intrathoracic or plunging goiter. Occasionally, most of it is hidden
behind the trachea and esophagus; in other instances one nodule may stand out,
imparting the clinical appearance of a solitary nodule. ​On cut section, irregular
nodules containing variable amounts of brown, gelatinous colloid are
present​. Older lesions have areas of hemorrhage, fibrosis, calcification, and
cystic change.

Histology:
The microscopic appearance includes ​colloid-rich follicles lined by flattened,
inactive epithelium and areas of follicular hyperplasia​, accompanied by
degenerative changes related to physical stress. In contrast to follicular
neoplasms, a prominent capsule between the hyperplastic nodules and residual
compressed thyroid parenchyma​ is not present​.

5. Correlate and discuss the expected laboratory results with the pathophysiology

Learning Objectives ENT (Clinical)

1. What are the differential diagnosis for this case?

B. FOLLICULAR THYROID CARCINOMA
a. ​FTC originates in follicular cells and is the second most common cancer of the
thyroid, after papillary carcinoma. Follicular carcinoma present as slowly
enlarging painless nodules.
C. HASHIMOTOS’s THYROIDITIS
 a. ​ ashimoto’s Thyroiditis is an autoimmune disease that results in destruction of
H
the thyroid gland and gradual and progressive thyroid failure. It is the most
common cause of hypothyroidism in the world where iodine levels are sufficient.
This is caused by ​breakdown in self tolerance to thyroid autoantigens.
Induction of thyroid autoimmunity is accompanied by a progressive
depletion of thyroid epithelial cells by apoptosis and replacement of
thyroid parenchyma by mononuclear cell infiltration and fibrosis.

NNGT FOLLICULAR THYROID HASHIMOTO’s

CARCINOMA THYROIDITIS

EPIDEMIOLOGY - more common -> in females (3:1) -more common in females

in females -present more often in older (10:1 to 20:1)
-increase patients -most prevalent between
incidence with 45 to 65 y/o
age

SYMPTOMS - slowly growing -SLOWLY -Painless enlargement of

anterior neck ENLARGING,asymptomatic thyroid, with some degree
mass, thyroid mass or nodule that of hypothyroidism
asymmetrical can be felt in the neck - symmetric and diffuse
enlargement - pain is seldom an early enlargement
obstructive warning -slow onset of symptoms
symptoms - persisitent cough, Difficulty - fatigue, constipation, dry
-dry cough, of breathing, difficulty of skin, weight gain
dyspnea, swallowing -cold intolerance, voice
stridor, hoarseness, pressure
especially with symptoms
exertion
-solid food and
pill dysphagia
- hoarseness d/t
compression of
recurrent
laryngeal nerve

PHYSICAL - thyroid - firm and nontender nodule -puffy face, periorbital

EXAMINATION enlargement -painless mass edema
can be detected - signs of tracheal or -cold dry skin
when the patient esophageal compression Thickened and brittle nails
swallows -bradycardia
-macroglossia
-slow speech
 - displacement -peripheral neuropathy
of trachea can
be observed

NODULE/s -may vary in -usually solitary with a hard -*usually diffuse

size, in outline consistency
and architecture -average size: <5cm, ill
defined borders
-nodule is fixed in respect to
surrounding tissue
-moves with trachea at
swallowing

CAUSE/s -iodine - exposure to radiation - breakdown in self

deficiency tolerance to throid
- autoantigens
-genetic: polymorphisms

THYROID -normal or - -elevated TSH levels

FUNCTION TESTS indicate
subclinical or
overt
hyperthyroidism
(reduced TSH
levels)

Epidemiology Symptoms PE Cause

T​hyroid Nodule One in 12 to 15 Most thyroid a nodule in the Iodine deficiency.

young women has nodules don't thyroid gland will
Thyroid nodules a thyroid nodule. cause signs or usually move up Overgrowth of
are solid or symptoms. and down during normal thyroid
fluid-filled lumps One in 40 young Occasionally, swallowing tissue.
that form within men has a thyroid however, some
your thyroid, a nodule. nodules become Thyroid cyst
small gland so large that they
located at the can: Chronic
More than 95% of
base of your neck, inflammation of
all thyroid nodules
just above your Be felt the thyroid
are benign
breastbone. (thyroiditis)
(non-cancerous Be seen, often as
growths). a swelling at the Multinodular goiter
 Some are actually base of your neck
cysts, which are Thyroid cancer
filled with fluid Press on your
rather than thyroid windpipe or
tissue. esophagus,
causing shortness
of breath or
difficulty
swallowing

Some cases,
thyroid nodules
produce additional
thyroxine

2. Discuss about NNTG

​What is NNTG?
Nontoxic goiter is thyroid enlargement unrelated to hypothyroidism, hyperthyroidism,
inflammation or neoplasia.
It is usually asymptomatic.
Symptomatic patient may present with painless neck swelling, cosmetic complaints,
shortness of breath, sudden increase in goiter size with pain due to hemorrhage,
larger goiter causing obstructive signs eg dysphagia, choking sensation and
Pemberton's sign.
Pemberton maneuver is a physical examination tool used to demonstrate
the presence of latent pressure in the thoracic inlet. The maneuver is
achieved by having the patient elevate both arms until they touch the sides
of the face. A positive Pemberton's sign is marked by the presence of
facial congestion and cyanosis, as well as respiratory distress after
approximately one minute.​

​Epidemiology, risk factors, predilection

EPIDEMIOLOGY
MNG is the most common endocrine disorder affecting 500 to 600 million
people worldwide.

The national prevalence of thyroid dysfunction among adults in the

Philippines is 8.53%. Subclinical hyperthyroidism and subclinical
hypothyroidism are the most common thyroid dysfunctions with
prevalence rates of 5.33% and 2.18% respectively; while 0.6%
present with true hyperthyroidism and 0.4% present with true
hypothyroidism. Among the adult Filipino population, 8.9% have
goiters by physical examination. Half of the hyperthyroid patients have
goiter, while 1 out of 6 to 10 patients with other types of thyroid
dysfunction have goiter ​(The Philippine Thyroid Diseases Study (PhilTiDeS
1): Prevalence of Thyroid Disorders Among Adults in the Philippines, 2012).
 Of the 7,227 volunteers who responded to the survey and were
available for clinical examination, a total of 674 (or 8.9%) had
goiter. Of the 674 subjects with goiters, 379 (56%) had diffuse
enlargement while 295 (44%) had nodular goiter ​(The Philippine
Thyroid Diseases Study (PhilTiDeS 1): Prevalence of Thyroid Disorders
Among Adults in the Philippines, 2012)​.

PREDILECTION
Non endemic goiter is more common in women and elderly. An average figure
for sex distribution in both endemic and non endemic regions is 3:1
(Female: Male) ​Taken from:​ Khatawkar AV, Awati SM. Multi-nodular
goiter: Epidemiology, Etiology, Pathogenesis and Pathology. IAIM, 2015;

2(9): 152-156.

RISK FACTORS
Etiology is usually unknown. Some known causes include iodine deficiency, iodine excess,
goitrogen ingestion, autoimmune disorders, thyroid hormone production defects and certain
medications.

Mild iodine deficiency associated or not with smoking, presence of natural goitrogenic,
drugs, familial goiter, genetic markers and gender (women) will decrease the
inhibition of serum T4 on the pituitary thyrotrophs. Increased TSH production will
cause diffuse goiter followed by nodule formation. Finally, after decades of life, a
large multinodular goiter is present with cystic areas, hemorrhage, fibrosis and
calcium deposits.
3. Relate the symptomatology and physical findings of the patient with the NNTG and difference
if this were a case of Toxic Goiter
Most patients with nontoxic MNG are asymptomatic and, by definition, euthyroid.
MNG typically develops over many years and is detected on routine physical
examination or when an individual notices an enlargement in the neck. If the goiter is
large enough, it can ultimately lead to compressive symptoms including difficulty
swallowing, respiratory distress (tracheal compression), or plethora (venous congestion),
but these symptoms are uncommon. Symptomatic MNGs are usually extraordinarily
large and/or develop fibrotic areas that cause compression. Sudden pain in a MNG is
usually caused by hemorrhage into a nodule but should raise the possibility of invasive
malignancy. Hoarseness, reflecting laryngeal nerve involvement, also suggests
malignancy.
The pathogenesis of toxic MNG appears to be similar to that of nontoxic MNG;
the major difference is the presence of functional autonomy in toxic MNG.The molecular
basis for autonomy in toxic MNG remains unknown.As in nontoxic goiters, many nodules
are polyclonal, while others are monoclonal and vary in their clonal origins. Genetic
abnormalities known to confer functional autonomy, such as activating TSH-R or Gsα
 mutations, are not usually found in the autonomous regions of toxic MNG goiter. In
addition to features of goiter, the clinical presentation of toxic MNG includes subclinical
hyperthyroidism or mild thyrotoxicosis. The patient is usually elderly and
may present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or
weight loss. Recent exposure to iodine, from contrast dyes or other sources, may
precipitate or exacerbate thyrotoxicosis.The TSH level is low. The T4 level may be
normal or minimally increased; T3 is often elevated to a greater degree than T4.Thyroid
scan shows heterogeneous uptake with multiple regions of increased and decreased
uptake; 24-h uptake of radioiodine may not be increased.

4. Discuss the medical and surgical management of NNTG

Medical Management
A. ​Radioactive iodine therapy​ - ​medical ba ito? Hindi ata :D
- Radioactive iodine (RAI) has been extensively and successfully used for the treatment of
toxic MNG but is not a widely considered treatment option for patients with nontoxic MNG
- a reasonable therapeutic option, particularly in patients who are older or have a
contraindication to surgery
- single orally administered dose will lead to the destruction of the toxic nodules and
restoration of euthyroidism over a 2- to 4-month period
- Obstructive symptoms improved in most patients who received radioactive iodine
- significant goiter size reduction when compared with levothyroxine suppressive therapy
- Adverse effects: thyroiditis, transient hyperthyroidism, hypothyroidism

B. ​Recombinant human TSH (rhTSH)​ - may have a role in radioactive iodine treatment for nontoxic
goiter
- pretreatment → single dose of 0.1 mg of recombinant human TSH (rhTSH)
- improves the efficacy of RAI by enhancing uptake in nontoxic thyroid tissue and allowing
the use of lower doses of RAI, while still resulting in greater reduction of goiter size

C. ​Thyroid hormone suppressive therapy​ - levothyroxine

- T4 therapy for nontoxic goiter was shown to reduce thyroid volume
- Goiter growth typically resumes after cessation of T4 therapy
- Because TSH has been regarded as a growth factor for thyroid epithelial cells, treatment
with levothyroxine in doses sufficient to suppress TSH has long been used to prevent or
reduce growth of thyroid nodules
- effectiveness remains controversial
- This treatment modality is not usually recommended: Levothyroxine suppressive therapy →
subclinical hyperthyroidism → With deleterious effects on the skeleton and increased risk of
atrial fibrillation and other cardiovascular complications
- should be particularly avoided in postmenopausal women with evidence of low bone mass,
in the elderly, and in those with cardiac disease, in whom the risk of this therapy generally
outweighs its uncertain benefits