Pathology Of the Thyroid Gland [601127]

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Pathology Of the Thyroid Gland
Ministry of Health of the Republic of Moldova

State University of Medicine and Pharmacy
"Nicolae Testemițanu"

Faculty of Medicine

Depar tment of :
Surgical Diseases

License Thesis
Student’s name and surname: AMUN TARIQ
year , group no. 1644
Scientific coordinator’s name and surname, title, scientific degree
Prof. Tudor Timis

Chișinău, year 2014/2015

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Table of Contents
Chapter I Introduction ………………………………………………… …….5
Chapter II Literature review ………………………………………………. 6
2.1 The Critical Role of the Thyroid Gland …………………………………… 6
2.2 Epidemiology ……………………………………………………………….6
2.3 Thyroid gland ………………………………………………………………7
2.3.1 Anatomy of the thyroid gland …………………………………………7
2.3.2 Physiology of thyroid gland …………………………… ……………..7
2.4 The thyroid hormones ………………………………………………………8
2.4.1 Thyroxine (T4) …………………………………………………………9
2.4.2 Triiodothyronine (T3) …………………………………………………9
2.4.3 Calcitonin 3…………………………………………………………….10
2.5 Synthesis of thyroid hormones ……………………………………………10
2.6 Mechanisms of thyroid hormone action ………………………………….12
2.6.1 Thyroid hormone receptors …………………………………………..13
2.6.2 Mechanisms of transcriptional regulation ……………………………14
2.7 Regulation of thyroid hormones …………………………………………. 15
2.7.1 Thyroid stimulating hormone (TSH) …………………………………16
2.9 Thyroid diseases …………………………………………………………..17
2.9.1 Hypothyroidism ………………………………………………………17
2.9.1.1 Symptoms of hypothyroidism …………………………………..17
2.9.1.2 Diagnosis of hypoth yroidism ……………………………………18
2.9.1.3 Differential Diagnosis of hypothyroidism ………………………18
2.9.2 Subclinical hypothyroidism ………………………………………….18
2.9.3 Hyperthyroidism ………………………………………………………19
2.9.3.1 Symptoms of hyperthyroidism ………………………………….19
2.9.3.2 Diagnosis of hyp erthyroidism …………………………………..20
2.9.3.3 Differential Diagnoses of hyperthyroidism ……………………..22
2.9.4 Subclinical hyperthyroidism …………………………………………23
2.10 treatment ………………………………………………………………….25
2.10.1 Management of hypothyroidism ……………………………….……25
2.10.2 Management of hyperthyroidism ……………………………………27
2.10.2.1 conservative treatment ………………………………….……….27
2.10.2.2 surgical treatment ………………………………………….……..27
2.10.2.2.1The indications for surgery ………………………………….28
2.10.2.2.2 Operation approaches ……………………………………….29
2.10.2.2.3 Postoperative complications ………………………………..38
Chapter III Case report ……………………………………………………… 40
Chapter IV Conclusion ………………………………………………………. 46
References……………………………………………………………………… 47

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List of Tables
Name Table page
Table 2.1: Ultrasonography of thyroid Cancer – Sabiston Textbook 21
Table 2.2: Main Genes involved in thyroid Cancer – Sabiston Textbook 23
Table 2.3: Indication for Interventional procedures – Sabiston Textbook 28
pregnancy

List of Figures
Name Page
Figure 2.1: Thyroid gland anatomy – Encyclopedia Britannica 7
Figure 2.2 – thyroid hormones production – Sabiston textbook 9
Figure 2.3: Structural formula of thyroid hormones and precursor 11
compounds [ 8].
Figure 2.4: Synthesis of thyroid hormones -pathwaymedicine.org/thyroid 11
-hormone -synthesis
Figure 2.5: TH action at the nuclear level – Wikipedia -Nuclear receptor 13
Figure 2.6: Molecular mechanisms of TH action – Wikipedia 14
Figure 2.7 -131I scan – Sabiston 21
Figure 2.8 -workup of a solitary thyroid nodule – Sabiston 24
Figure 2.9 -CT scan of thoracic inlet in goiter complication – Sabiston 25
Figure 2.10 – Cervical approach – sabiston textbook 30
Figure 2.11 – Thyroid lobe retraction medially 32
Figure 2.12 -thyroid resection – Sabiston Textbook 33
Figure 2.13 -Recurrent Laryngeal nerve location – Sabiston Textbook 34
Figure 3.1- Thyroid Goiter (Enlargement) 40
Figure 3.2-Coronal CT of clinical case NR.1 41
Figure 3.3- Axial CT of clinical case NR.1 41

List of abbreviations
AITD Autoimmune Thyroid Disease
DIT di -iodinated tyrosine
hCG Human Chorionic Gonadotropin,
LH Luteinizing Hormone
MEIA Microparticles Enzyme Immunoassay
MCT8 Monocarboxylate Transporter 8
MIT mono -iodinated tyrosine
OATP1C1 Organic Anion Transporter
PTH Parathyroid Hormone

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SRIH Somatostatin
TG Thyroglobulin
TBG Thyroid Binding Globulin
TH Thyroid Hormones
TSH Thyroid -Stimulating Hormone
TPO Thyroperoxidase
TRH Thyrotropin -Releasing Hormone
T4 T hyroxine
T3 Triiodothyronine

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CHAPTER (1)
INTRODUCTION

Thyroid disorder s is a general term representing several different diseases
involving thyroid hormones and the thyroid gland. Thyroid disorders are commonly
separated into two major categories, hyperthyroidism and hypothyroidism, depending on
whether serum thyroid hormone lev els (T4 and T3) are increased or decreased,
respectively. Thyroid disease generally may be sub -classified based on etiologic factors,
physiologic abnormalities, etc., as described in each section below.
About 200 million people in the world have some form of thyroid disease.
Thyroid disorders for the most part are treatable; however, untreated thyroid
disease can produce serious results in other parts of the body. Improved public
awareness and understa nding of thyroid disorders will enable patients and their families
to cope more effectively with the sometimes -disturbing course of thyroid illness. In this
way individuals will also be better equipped to play a role in alerting their physicians to
a suspected thyroid condition that may otherwise be difficult to diagnose in the
sometimes slowly developing initial phases.

Goal of the Study
– To study the clinical history and presentation of Thyroid pathologies.
– To study the various causes of thyroid pathologies
– To study and evaluate the effectiveness of different modalities of treatment of
thyroid pathologies
– To study about complications of surgical methods
– Improve public awareness and understanding of thyroid disorders

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CHAPTER (2)
LITERATURE REVIEW
2.1 The critical role of the thyroid gland
The thyroid gland plays a vital role in the overall body function during all stages
of life. Although relatively small, it produces hormones that regulate the body's overall
metabolism, the rate at which the body produces energy from nutrients.
Thyroid hormones influence growth and development, oxygen consumption and
heat production, nerve function, and metabolism of lipids, carbohydrates, proteins,
nucleic acids, vitamins, and inorganic ions. The y also have important effects on other
hormone actions [4]. If left untreated, thyroid disease can lead to an increased risk of
heart disease, osteoporosis and infertility. An estimated 13 million Americans have a
thyroid problem, but more than half remain undiagnosed. Thyroid hormones are
particularly important during pregnancy and play a key role in fetal development. Until
the fetal thyroid gland is developed at approximately 12 week's of gestation, the
maternal thyroid is solely responsible for deliveri ng thyroid hormone, which is essential
to fetal brain development. The placenta and amniotic fluid transfer small but crucial
amounts of thyroid hormone from the mother to the fetus. [5]

2.2 epidemiology
More than 13 million Americans are affected by thyro id disease, and more than
half of these remain undiagnosed. The American Association of Clinical
Endocrinologists (AACE) has initiated a campaign to increase public awareness of
thyroid disorders and educate Americans about key periods, from birth to advanced age,
when people are at increased risk for developing a thyroid disorder (see below). The
diagnosis of thyroid disease can be particularly challenging.
Patients often present with vague, general clinical manifestations; in particular, the
elderly may not associate the signs and symptoms with a disease process and thus may
not bring them to the attention of their primary care provider.
The prevalence and incidence of thyroid disorders is influenced primarily by sex and
age.
Thyroid disorders are mor e common in women than men, and in older adults
compared with younger age groups. The prevalence of unsuspected overt
hyperthyroidism and hypothyroidism are both estimated to be 0.6% or less in women,
based on several epidemiologic studies. Age is also a f actor; for overt hyperthyroidism,
the prevalence rate is 1.4% for women aged 60 or older and 0.45% for women aged 40
to 60. For men more than 60 years of age, the prevalence rate of hyperthyroidism is
estimated to be 0.13%. A similar pattern is observed fo r the prevalence rate of
hypothyroidism. The prevalence rate of overt hypothyroidism is 2% for women aged 70
to 80, 1.4% for all women 60 years and older, and 0.5% for women aged 40 to 60. In
comparison, the prevalence rate of overt hypothyroidism is 0.8% for men 60 years and

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older. The estimated annual incidence of hyperthyroidism for women ranges from 0.36
to 0.47 per 1,000 women, and for men ranges from 0.087 to 0.101 per 1,000 men. In
terms of hypothyroidism, the estimated incidence is 2.4 per 1,000 wom en each year.
Overt thyroid dysfunction is uncommon in women less than 40 years old and in men
<60 years of age.

2.3 Thyroid gland
2.3.1 Anatomy of the thyroid gland
The thyroid gland is one of the largest endocrine glands in the body, weighing 2-3
grams in neonates and 18 -60 grams in adults, and is increased in pregnancy. This gland
is found in the neck inferior to the thyroid cartilage (also known as the Adam's apple in
men) as shown in Figure (2.1). It is a butterfly -shaped organ and composed of two con e-
like lobes: right lobe and left lobe, connected with the isthmus. The organ is situated on
the anterior side of the neck, lying against and around the larynx and trachea, reaching
posteriorly the oesophagus and carotid sheath [6].
Figure 2.1: Thyroid gl and anatomy – Encyclopedia Britannica

2.3.2 Physiology of thyroid gland

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Thyroid gland produces the hormones T4, T3, and calcitonin . Up to 80% of the
T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is
about ten times more active than T4 [7].

2.4 The thyroid hormones
The thyroid gland secretes two hormones, L -T4 and L – T3. The thyroid hormones
are the only iodine -containing compounds with established physiologic significance in
vertebrates [8]. T4 is the predominant form of thyroid hormone. It’s called T4 because it
contains four iodine atoms for each hormone molecule. When one specific iodine atom
is removed from the T4 molecule, it becomes RT3 or T3 , the form necessary for doing
the thyroid’s job for the body’s cells. Nearly all cells have special enzymes inside of
them (deiodinases) that remove an iodine from T4 to make it into T3. The thyroid gland
usually releases around 80 percent of its hormones as T4 and 20 percent as T3 [9]. When
this T4 and T3 enter the blood, most of these hormones stick to blood proteins made by
the liver, called thyroid hormone transport proteins .
Thyroid hormones (TH) are transported in serum non covalently bound to three
proteins: T4 – (TBG), albumin, and transthyretin prev iously called pre – albumin [10].
The relative distribution of TH among the binding proteins is directly related to
both their affinities and concentrations. In steady state conditions, the bound hormone
fraction is in equilibrium with a free unbound fracti on, which represents a minute
amount of the total circulating TH: 0.03% for T4 and 0.3% for T3 [11]. The
production of thyroid hormones is based on the organization of thyroid epithelial cells in
functional units, the thyroid follicles, a single layer of polarized forms envelope of a
spherical structure with an internal compartment, the follicle lumen. Thyroid hormone
synthesis is dependent on the cell polarity that conditions the targeting of specific
membrane protein, either on the external side of the f ollicle (facing the blood capillaries)
or on the internal side and on the tightness of the follicle lumen that allows the gathering
of substrates and the storage of products of the reactions. Thyroid hormone secretion
relies on the existence of stores of p re-synthesized hormones in the follicle lumen and
cell polarity -dependent transport and handling processes leading to the deli very of
hormones into the blood stream [8]. After concentrating iodide, the thyroid rapidly
oxidizes it and binds it to tyrosyl re sidues in thyroglobulin (TG) followed by coupling of
iodotyrosines to form T4 and T3. The process requires the presence of iodide, a
peroxidase (TPO), a supply of H2O2, and an iodine acceptor protein (TG) [ 12].
Figure 2.2 – thyroid hormones production – Sabiston textbook

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2.4.1 Thyroxine
3,5,3',5' -tetraiodothyronine (T4), a form of thyroid hormones, is the major
hormone secreted by the follicular cells of the thyroid gland. Thyroxine is
synthesized via the iodination and covalent bonding of the phenyl portions of
tyrosine residues found in an initial peptide, TG which is secreted into thyroid
granules. These iodinated diphenyl compounds are cleaved from their peptide
backbone upon being stimulated b y thyroid stimulating hormone. T4 is
transported in blood, with globulin (TBG), 99.95% of the secreted T4 being
protein bound principally to thyroxine -binding globulin, to transthyretin and
serum albumin. T4 is involved in controlling the rate of metabolic processes in
the body and influencing physical development. Thyroxine is a prohormone and a
reservoir for the active thyroid hormone T3 which is about four times more potent.
T4 is converted in the tissues by deiodinases to T3. The "D" isomer is called
"Dextrothyroxine and is used as a lipid modifying agent. The half -life of thyroxine
once released into the blood circulatory system is about one week ( 13).

2.4.2 Triiodothyronine
TSH activates the production of T4 and T3. This process is under regulation.
In the thyroid, T4 is converted to T3. TSH is inhibited mainly by T3. The thyroid
gland releases greater amounts of T4 than T3, so plasma concentrations of T4 are 40 –
fold higher than those of T3. Most of the circulating T3 is formed peripherally by

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deiodi nation of T4 (85%), a process that involves the removal of iodine from carbon 5
on the outer ring of T4. Thus, T4 acts as prohormone for T3. In addition, T3 exhibits
greater activity and is produced in smaller quantity. It is the most powerful thyroid
horm one, and affects almost every process in the body, including body temperature,
growth, and heart rate. The biological half -life is 2.5 days [13].
2.4.3 Calcitonin
An additional hormone produced by the thyroid gland contributes to the
regulation of blood ca lcium levels. Parafollicular cells produce calcitonin in response to
hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to
the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential
than PTH, as ca lcium metabolism remains clinically normal after removal of the thyroid,
but not the parathyroids [14].

2.5 Synthesis of thyroid hormones
The first step in the formation of thyroid hormones (TH) involves the active
accumulation of iodide from the extracellular fluid across the basolateral membrane and
into the thyroid follicular cell. The protein responsible for this was previously described
as the iodide trap or iodide pump. Because the transport into the follicular cell of iod ide
against its concentration gradient is coupled with transport of sodium, the protein was
named the sodium/iodide symporter (NIS) ( 15). The iodide pump is linked to a Na+ -K+-
pump, which requires energy in the form of oxidative phosphorylation (ATP) and i s
inhibited by ouabain. The thyroid absorption of iodide is also inhibited by negative ions
(such as perchlorate, pertechnetate, thiocyanate and nitrate), because they compete with
the iodide at the trap. In the follicular cell, iodide passes down its elec trochemical
gradient through the apical membrane and into the follicular colloid. Iodide is instantly
oxidised – with hydrogen peroxide as oxidant by a thyroid peroxidase to atomic or
molecular iodine at the colloid surface of the apical membrane. Thiouracil and
sulfonamides block this peroxidase. The rough endoplasmic reticulum synthesises a
large storage molecule called thyroglobulin. This compound is build up by a long
peptide chain with tyrosine units and a carbohydrate unit completed by the Gol gi
apparatus. Iodide -free thyroglobulin is transported in vesicles to the apical membrane,
where they fuse with the membrane and finally release thyroglobulin at the apical
membrane. At the apical membrane the oxidised iodide is attached to the tyrosine un its
(Ltyrosine) in thyroglobulin at one or two positions, forming the hormone precursors
mono -iodotyrosine (MIT), and di -iodotyrosine (DIT), respectively (Figure 2.2). This and
the following reactions are dependent on thyroid peroxidase in the presence of hydrogen
peroxide -both located at the apical membrane. As MIT couples to DIT it produces tri –
iodothyronine (3,5,3` -T3), whereas two DIT molecules form tetraiodothyronine (T4), or
thyroxine. These two molecules are the two thyroid hormones.
Small amounts o f the inactive reverse T3 (3,3`,5` – T3) is also synthesised [16].

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Figure 2. 3: Structural formula of thyroid hormones and precursor
compounds [ 8].

The newly formed iodothyroglobulin forms one of the most important constituents
of the colloid material, present in the follicle of the thyroid unit. The other synthetic
reaction, that is closely linked to organification, is a coupling reaction, where
iodotyrosine molecules are coupled together. If two di -iodotyrosine molecules couple
together, the result is the formation of thyroxin (T4). If a di -iodotyrosine and a
monoiodotyrosine are coupled together, the result is the formation of tri -iodothyronine
(T3). (Figure 2.3).

Figure 2. 4: Synthesis of thyroid hormones -pathwaymedicine.org/thyroid -hormone –
synthesis

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Iodide is organified in the tyrosyl residues of Tg in a reaction catalyzed by TPO, in
the presence of H2O2, Tg contains MIT, DIT, T3, and T4 and is stored in colloid until
T3 and T4 need to be released into the blood [17].
From the perspective of the formation of thyroid hormone, the major coupling
reaction is the di -iodotyrosine coupling to produce T4. Although T3 is more biologically
active than T4, the major production of T3 actually occurs outside of the thyroid gland.
The majority of T3 is produce d by peripheral conversion from T4 in a deiodination
reaction involving a specific enzyme which removes one iodine from the outer ring of
T4. The T3 and T4 released from the thyroid by proteolysis reach the bloodstream where
they are bound to thyroid hormo ne binding proteins. The major thyroid hormone binding
protein is thyroxin binding globulin (TBG) which accounts for about 75% of the bound
hormone. In order to attain normal levels of thyroid hormone synthesis, an adequate
supply of iodine is essential. T he recommended minimum intake of iodine is 150
micrograms a day. Intake of less than 50 micrograms a day is associated with goiter.
High iodine levels inhibit iodide oxidation and organification. Additionally, iodine
excess inhibits thyroglobulin proteolys is [18].
Cells of the brain are a major target for the thyroid hormones T3 and T4. Thyroid
hormones play a particularly crucial role in brain maturation during fetal
development. A transport protein called organic anion transporter (OATP1C1) has
been ident ified that seems to be important for T4 transport across the blood brain
barrier. A second transport protein called monocarboxylate transporter 8 (MCT8) is
important for T3 transport across brain cell membranes [19].

2.6 Mechanisms of thyroid hormone action
As illustrated in Figure 2.4. circulating free TH enters the cell by either passive
diffusion or other. TH then enters the nucleus, where it binds to the nuclear
thyroidhormone receptor (TR). TR is a ligand -regulated transcription factor that is
intimately associated with chromatin, and also associates with other nuclear proteins to
form heterodimers. These in turn are bound to target DNAs known as TH -response
elements (TREs). The formation of a liganded TR/DNA complex leads to activation of
its associated gene, and to consequentchanges in messenger RNA (mRNA) and protein.
Thus, the central role of TR in the nuclear action of TH is evident.

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Figure 2. 5: TH action at the nuclear level – Wikipedia -Nuclear_receptor

Thyroid hormone (T4 and T3; TH) exerts numerous effects on the cell. Whereas
many of its actions involve regulation of gene expression, thyroid hormone may also act
at the plasma membrane, cytoplasm, mitochondrion, and other non -nuclear sites. T3 and
T4 ma y enter the cell by passive diffusion or other poorly defined pathways. In addition,
T4 may be deiodinated to more active T3 by iodothyronine 5′ -deiodinases. Furthermore,
T3 may be subjected to degradation within the cell. T3 then enters the nucleus to bin d to
the thyroid hormone receptor (TR). The TR, in collaboration with a number of other
nuclear proteins including the RXRs, form heterodimers that are bound to target DNA
sites known as thyroid hormone -response elements (TRE). The liganded TR/RXR/TRE
comp lex initiates alterations in gene expression among genes containing such TREs, and
these alterations in turn alter their corresponding mRNA and protein levels. [20,21].

2.6.1 THYROID HORMONE RECEPTORS
TRs are ligand -regulated transcription factors that are members of the steroid
hormone receptor superfamily. TRs are encoded by a protooncogene, c-erbA, and are
represented by two genomic loci (α and β), located on human chromosomes 17 and 3,

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respectively [22,38]. The T3 response element (TRE) is composed of r epeated DNA
sequences with different configurations. Although TRs can bind to TREs as monomers
or homodimers, the major form of TR bound to the TRE is the heterodimer with retinoid
X receptor (RXR) ( 23). Each TR contains a DNA -binding domain (DBD) with zin c
finger motifs, and a ligand binding domain (LBD). Ligand binding causes major
conformational changes in the LBD, that allow TRs to discriminate between coactivators
and corepressors [24]. The ability to bind specific sequences in target genes is crucial for
TR function. The consensus sequence recognized by nuclear receptors often contains a
hexamer AGGTCA known as the half site. Functional and efficient binding requires two
of the half -site sequences with different configurations [ 25,26]. TR predominantly bind
DNA response elements as heterodimers with RXRs Heterodimer formation is thought
to enhance DNA -binding affinity as well as p rovide target gene specificity, determined
by the spacing between two half sites [27].

2.6.2 MECHANISMS OF TRANSCRIPTIONAL REGULATION
As a transcriptional factor, a key function of the TR is to regulate the target gene
expression in response to multiple signaling pathways. TR constitutively bind to DNA
response elements in the absence and presence of the ligand. Unliganded TR represses
the basal transcription. Ligand binding causes derepression and enhances transcriptional
activation. Thus the biological significance of repression is to turn off target genes in the
absence of hormone and to increase the magnitude of transcripti onal activation by
hormone ligand. A group of cofactor proteins
(coactivators and corepressors) mediate repression and activation (Figure2.5).

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Figure 2. 6: Molecular mechanisms of TH action – Wikipedia

This diagram illustrates the factors involved in TH action on a TRE in the absence
(– T3 and presence (+T3) of TH. In the –T3 state, TR_RXR heterodimer is bound to a
TRE that is, in turn, associated with a corepressor. The presence of the corepressor in
this configuration results in silencing of the associa ted gene. The direct interaction of
unliganded TR with the basal transcription factor, TFIIB, may also participate in this
silencing function. The addition of T3 results in dissociation of the corepressor and
subsequent association with putative coactivato rs such as SRC -1 and CBP to result in
activation of the basal transcription machinery (TFIIB, TFIID, TFIIE and F, RNA
polymerase II, etc.) and stimulation of the associated gene by T3. Cofactors alone cannot
bind DNA but instead they directly interact with DNAbound nuclear receptors, as a
result of which they are recruited to the proximity of the target gene promoter region and
affect the rate of transcription. A higher levelA higher level of transcriptional regulation
is provided by a change of chromatin structure. Open chromatin is thought to facilitate
the assembly of basal transcriptional machinery and increase the transcription rate. In
contrast, a highly condensed chromatin blocks the entry of TATA -binding protein and
leads to transcriptional repressio n. Chromatin structure can be greatly affected by
acetylation of histones in the nucleosome octamer. Hyperacetylation of histones loosens
the interaction between DNA and nucleosome opposes the structural change of
nucleosomes brought by histone acetylation by reducing the net positive charge.
Conversely, histone deacetylation Both histone acetyltransferase and histone deacetylase
activities are functionally associated with coactivators and corepressors, respectively,
thus providing an enzymatic link to the activation and repression by nuclear
receptors. [28]

2.7 Regulation of thyroid hormones
The production of T4 and T3 is regulated by TSH, released by the anterior
pituitary that is in turn released as a result of thyrotropin -releasing hormone (TRH)
released by the hypothalamus. As shown in Figure 2.4, the thyroid and thyrotropes
form a negative feedback loop: TSH production is suppressed when the T4 levels are
high, and vice versa. The TSH production itself is modulated by TRH, which is
produced by the hypot halamus and secreted at an increased rate in situations such as
cold (in which an accelerated metabolism would generate more heat). TSH production is
blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones
(estrogen and testostero ne), and excessively high blood iodide concentration [29].
By a negative feedback mechanism, increased levels of free thyroid hormones (T4
and T3) inhibit TSH secretion from the pituitary, whereas decreased levels of T4 and T3
cause an increase in TSH release from the pituitary. TSH secretion is also influenced by
TRH synthesized in the hypothalamus. TRH causes release of TSH (Figure 2. 6).

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Figure 2.6: Regulation of T3 and T4 secretion [30]

HPT: hypothalamus, PIT: pituitary, TRH: thyrotropin -releasing hormone, TSH:
Thyroid stimulating hormone, TBG: thyroid binding globulin, T4:thyroxine,
T3:triidothyronine.

2.7.1 Thyroid stimulating hormone (TSH)
TSH stimulates the thyroid gland to secrete the hormones T4 and T3. TSH is a
glycoprotein which consists of two subunits, the alpha and the beta subunit. The alpha
(α) subunit is identical to that of hCG, luteinizing hormone (LH), follicle -stimulating
hormone (FSH). The β (beta) subunit (TSHB) is unique to TSH, and therefore
determines its function. TSH production is controlled by a TRH, which is
manufactured in the hypothalamus and transported to the anterior pituitary gland via the
superior hypophyseal artery, where it increases TSH production and release.
Somatostatin is also produced by the hypothalam us, and has an opposite effect on
the pituitary production of TSH, decreasing or inhibiting its release. The level of thyroid
hormones (T3 and T4) in the blood have an effect on the pituitary release of TSH; When
the levels of T3 and T4 are low, the produc tion of TSH is increased and conversely,
when levels of T3 and T4 are high, then TSH production is decreased [31].
This effect creates a regulatory negative feedback loop. Determining TSH in the
serum is a basic search procedure in the diagnosis of the thy roid gland’s function. Its
regulation is based on feedback, howe ver, during pregnancy there are also other
mechanisms taking place (mainly suppression of TSH) presumably due to the
thyroidstimulating activity of hCG early in pregnancy when hCG levels are t he highest
[32].

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By using the classic reference interval for serum TSH, one might misdiagnose as
healthy women who already have a slight TSH elevation and, conversely, one might
suspect hyperthyroidism in normal women who have a lowered serum TSH value [33].

2.9 Thyroid diseases
2.9.1 Hypothyroidism
Hypothyroidism is almost due to disease within thyroid gland that causes a
decrease in the production of thyroid hormones. The most common causes of this
disorder are shown in Table 2.1.
Table 2.1. Etiology of hypothyroidism [34-36]
Hashimoto disease
Postthyroid ablation/removal
Iodine deficiency
Primary atrophic hypothyroidism
Infiltrative disease
TSH -dependent hypothyroidism
Women are more predisposed hyopthyroidism than men [37]. Hypothyroidism
during fetal development or early infancy results in cretinism (congenital
hypothyridism) which causes respiratory difficulties, persistent jaundice, and hoarse
crying, stunted growth (dwarfism), bone and muscle dystrophy, and mental deficiency in
older children, and the incidence is 3 times more in girls than in boys. Infants not treated
within the first 3 months or children within two years suffer irreversible mental
retardation [38].

2.9.1.1 Symptoms of hypothyroidism
The signs of hypothyroidism are depending on the organ which is affected. As
thyroid begins to fail, slight enlargement of thyroid gland (goiter), appearing as a lump
or swelling, then the patient may begin to feel tired. Some hair loss may be
noticed. Then ingernails become thickened, d ry, and brittle. Hypothyroidism becomes
more severe, changes may occur in the tissues beneath skin that lead to a
characteristic swollen appearance known as myxedema. This is often particularly
apparent around face and eyes [55]. Circulation is affected and heart rate slows.
Since intestinal activity slows down, patient may become constipated. A few pounds of
weight gain may occur. Muscles may become painful with leg cramps. Nervous system
may be affected in several ways. Some memory loss may be noticed, decreased ability to
think, and depression. Some patients suffer loss of balance and difficulty in walking. In
women, changes in reproductive system may cause longer, heavier, and more frequent
menstruation. Their ovaries may stop producing an egg each mon th, and, if so, it may be
difficult to get pregnant. So in hypothyroid, many of the affected bodily functions
simply slow down [39].

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2.9.1.2 Diagnosis of hypothyroidism
Appropriate laboratory evaluation is critical to establish the diagnosis and
cause of hypothyroidism in the most cost -effective way. The most valuable test is a
sensitive measurement of TSH level. A TSH assay should always be used as the
primary test to establish the diagnosis of primary hypothyroidism. Additional tests
may include the foll owing:
Free T4 estimate : determination of FT4 is by watching the amount of biologically
active hormone which is available to the a pregnant woman (as well as the fetus), and is
not affected by the concentration of binding proteins. Its concentration during pregnancy
is partly affected by both the inflow of iodine and the duration of the pregnancy. Some
consider it even more informative than TSH during pregnancy [14]. The fetus is
completely dependent upon thyroxin produced by the mother during the fir st trimester.
Even a small unnoticed malfunction of the mother’s thyroid gland, which doesn’t
necessarily endanger the course of the pregnancy, can affect the psychomotor
development of the child [40].
Thyroid autoantibodies —anti-thyroid peroxidase and a ntithyroglobulin
autoantibodies.
Thyroid scan, ultrasonography, or both (if necessary to evaluate suspicious
structural thyroid abnormalities [41].
2.9.1.3 Differential Diagnosis of hypothyroidism
Chronic kidney failure (nephrotic syndrome )
Chronic nephritis
Congestive heart failure (CHF)
Dementia from other causes
Depression
Euthyroid sick syndrome
Neurasthenia
Primary amyloidosis

2.9.2 Subclinical hypothyroidism
The term subclinical hypothyroidism is used for patients who have mildly
increased levels of serum TSH but normal thyroid hormone T4 and T3 levels [42]. An
increase in serum TSH concentration is an early and sensitive indicato r of decreased
thyroid reserve. However, the interpretation of thyroid function tests in the pediatric age
range is more difficult than in adults. Although normal ranges have been defined for all
age groups from birth to maturity, significant discrepancies still persist between different
laboratories. It is therefore important that each laboratory determines its own normal
values and the results must always be interpreted cautiously [43]. It is clear that

19
thyroxine therapy is indicated in overt hypothyroidi sm and uniform agreement exists
that it is also indicated for patients whose TSH levels are permanently increased above
10 mIU/L. For TSH levels between 5 – 10 mIU/L, therapy for these milder forms is
controversial. In clinical practice some doctors treat all such patients while others choose
to reassess the thyroid function in 3 -6 months to find out if the thyroid abnormality is
transient. Subclinical hypothyroidism is one spectrum of autoimmune thyroiditis, the
clinical course is variable and spontaneous remission may occur in adolescence [44].
Adults with subclinical hypothyroidism, especially with thyroid antibodies have been
shown to result in overt hypothyroidism with a rate of 5 -20 % per year. on the contrary,
a very low risk for overt hypothyroidism has been shown in children and adolescents
during a 5 year follow up [45].
Children and adolescents with type 1 diabetes, with juvenile arthritis and with
epilepsy who are treated with valproate or ca rbamazepine are in risk for subclinical
hypothyroidism and their thyroid function should be followed regularly [46]. Early
detection of subclinical hypothyroidism with treatment of thyroxine has shown to
improve growth and metabolic control in type 1 diabe tics [47]. Increased TSH -levels
with mildly increased thyroid hormone levels have also been found in up to 15 % of
obese children and adolescents [48]. There is, however, no need to treat these patients,
hyperthyrotropinemia is reversible after weight loss [49]. It has been suggested recently
that subclinical hypothyroidism is a cardiovascular risk factor in adults and
physiological thyroxine replacement has a beneficial effect on low density lipoprotein
cholesterol levels [50].

2.9.3 Hyperthyroidism
Hyperthyroidism is the consequence of excessive thyroid hormone action. The
causes of hyperthyroidism include the followings (Table 2.2):
Table 2.2: Etiology of hyperthyroidism [52,53]
Toxic diffuse goiter (Graves’ disease)
Toxic adenoma
Toxic multin odular goiter (Plummer’s disease)
Painful subacute thyroiditis
Silent thyroiditis, including lymphocytic and postpartum variations
Iodine -induced hyperthyroidism (for example, related to amiodarone therapy)
Excessive pituitary TSH or trophoblastic disease
Excessive ingestion of thyroid hormone
Globaly every year, 350.000 people develop some kind of hyperthyroidism, and it is
eight to ten times more common in women than in men [54].

20
2.9.3.1 Symptoms of hyperthyroidism
The spectrum of possible signs and symptoms associated with the various
causes of hyperthyroidism includes nervousness and irritability, Palpitations and
tachycardia, Heat intolerance or increased sweating, tremor, weight loss or gain,
alterations in appetite, diarrhea Sudden para lysis, Exertional intolerance and dyspnea,
menstrual disturbance (decreased flow), impaired fertility, mental disturbances, sleep
disturbances (including insomnia), Changes in vision, photophobia, eye irritation,
diplopia , Fatigue and muscle weakness, thyroid enlargement and Pretibial myxedema (in
patients with Graves’ disease). A patient with hyperthyroidism need not have all these
symptoms [52, 53]

2.9.3.2 Diagnosis of hyperthyroidism
 A comprehensive history should be elicited, and a thorough physical examination
should be performed, including the followings:
Weight and blood pressure
Pulse rate and cardiac rhythm
Thyroid palpation and auscultation (to determine thyroid size, nodularity,
and vascularity)
Neurom uscular examination
Eye examination (to detect evidence of exophthalmos or ophthalmopathy)
Dermatologic examination
Cardiovascular examination
Lymphatic examination (nodes and spleen)
 Laboratory Evaluation: The development of sensitive TSH assays has
considerably facilitated the diagnosis of hyperthyroidism. The sensitive TSH test
refers to a TSH assay with a functional sensitivity of 0.02 or less.
Hyperthyroidism of any cause results in a lower -than normal TSH level
(suppressed TSH). The sensitiv e TSH assay is the single best screening test for
hyperthyroidism. Other laboratory and isotope tests may include the
following [54]:

21

T4 or free T4
Triiodothyronine (T3) radioimmunoassay (RIA) or free T3
Thyroid autoantibodies, including TSH recept or antibodies
Thyroid -stimulating immunoglobulins (TSI)
Radioactive iodine uptake

Figure 2.7 -131I scan – Sabiston

22
2.9.3.3 Differential Diagnoses of hyperthyroidism
The manifestation of initial, vague and slightly expressed forms of thyrotoxicosis
can resemble neuroses, rheumatic disease, tuberculosis, chroniosepsis, postcastrate
syndrome, diencephalic lesions, and also malignant tumours. It particularly concerns
those cases, when the enlargement of thyroid gland is slight or it is failed to detect .
All the mentioned diseases are characterized by palpitation, heart pain excessive
sweating, subfebrile fever and loss of weight.
The acute development of thyrotoxicosis sometimes makes the necessity to rule out such
acute infectious diseases, as dysent ery, influenza or camp -fever.
The thyrotoxicosis with exophthalmos is necessary to differentiate with encephalitis,
ophthalmopathy. Encephalitic exophthalmos is characterized by combination of looking
upward paresis with diplopia, corneal ulceration, conj unctivitis, progressing, so -called
malignant exophthalmos, which rather frequently can result in loss of eye. By the way,
this type of exophthalmos is commonly unilateral.
Laboratory tests are important for differential diagnostics of thyrotoxicosis:
detecting of thyroid hormones, serum protein -bounded iodine, thyroid -iodine uptake,
biochemical, immunological investigations, sonography and scanning with the
radioiodine or technetium.
In particularly severe cases it is advisable to apply trial antithyroid therapy.

23
2.9.4 Sub clinical hyperthyroidism

Subclinical hyperthyroidism is an entity that is being increasingly recognized.
This may be both due to the aging of the population and the development of more
sensitive TSH. Subclinical hyperthyroidism is defined as the combination of a
supressed, usually undetectable serum TSH concentration, and normal serum free T3
and T4 concentrations. The TSH value is measured by an assay with a threshold of
detection that is 0.3 mU /L or less [55]. Patients with subclinical hyperthyroidism are
usually euthyroid, but symptoms or signs of thyrotoxicosis such as malaise, tachycardia,
nervousness and anxiety may be present. In elderly, atrial fibrillation may be the initial
manifestation . The sensitivity of the pituitary gland to respond to minor elevations in
serum or tissue T3 and T4 levels is the main pathophysiological mechanism of
subclinical hyperthyroidism. Abnormal TSH levels may remain for years without
clinical symptoms of overt hyperthyroidism. The rate of progression of subclinical
hyperthyroidism to overt disease is at least 1 to 3 percent per year [56]. A suppression of
TSH level may be due to nonthyroidal illness, steroid or dopamine administration, or
pituitary dysfunction; so, these conditions must be excluded.

24

Figure 2.8 -workup of a solitary thyroid nodule – Sabiston

According to its cause, subclinical hyperthyroidism can be classified as
endogenous and exogenous. The endogenous causes of subclinical hyperthyroidism
include multinodular goiter, Graves’ disease (early), solitary auto -nomous adenoma,
thyroiditis and other causes of hyperthyroidism e.g., trophoblastic tumors. The
exogenous causes of subclinical hyperthyroidism include treatment with evothyroxine,
exogeno us iodine exposure such as recent administration of radio contrast material. A
24-hour radioactive iodine uptake will generally be elevated in patients with Graves’
disease, multinodular goiter, and solitary autonomous nodule; but will be decreased in
patients in the hyperthyroid phase of subacute, silent, or postpartum thyroiditis and in
patients taking excess exogenous thyroid hormone. In clinical examination, thyroid
gland may be enlarged in some patients, but in most patients it is usually normal in siz e
[57].

25

Figure 2.9 -CT scan of thoracic inlet in goiter complication – Sabiston

2.10 Treatment
2.10.1 Hypothyroidism
The treatment goals for hypothyroidism are to reverse clinical progression and
correct metabolic derangements, as evidenced by normal blood levels of thyroid –
stimulating hormone (TSH) and free thyroxine (T4). Thyroid hormone is administered to
supplement o r replace endogenous production. In general, hypothyroidism can be
adequately treated with a constant daily dose of levothyroxine (LT4).
Thyroid hormone can be started at anticipated full replacement doses in
individuals who are young and otherwise healthy . In elderly patients and those with
known ischemic heart disease, treatment should begin with one fourth to one half the
expected dosage, and the dosage should be adjusted in small increments after no less

26
than 4 -6 weeks. For most cases of mild to moderat e hypothyroidism, a starting
levothyroxine dosage of 50 -75 µg/day will suffice.
Clinical benefits begin in 3 -5 days and level off after 4 -6 weeks. Achieving a TSH level
within the reference range may take several months because of delayed readaptation of
the hypothalamic -pituitary axis. In patients receiving treatment with LT4, dosing
changes should be made every 6 -8 weeks until the patient’s TSH is in target range.
In patients with central (ie, pituitary or hypothalamic) hypothyroidism, T4 levels rath er
than TSH levels are used to guide treatment. In most cases, the free T4 level should be
kept in the upper third of the reference range.
After dosage stabilization, patients can be monitored with annual or semiannual clinical
evaluations and TSH monitori ng. Patients should be monitored for symptoms and signs
of overtreatment, which include the following:
Tachycardia,Palpitations,Atrial fibrillation, Nervousness, Tiredness, Headache,
Increased excitability, Sleeplessness, Tremors and Possible angina
LT4 monotherapy remains the treatment of choice for hypothyroidism. A meta -analysis
of randomized, controlled trials of T4 -triiodothyronine (T3) combination therapy versus
T4 monotherapy for treatment of clinical hypothyroidism found no difference in
effective ness between combination therapy and monotherapy with respect to side effects
such as bodily pain, depression, fatigue, body weight, anxiety, quality of life, and total
low-density lipoprotein (LDL) and high -density lipoprotein (HDL) cholesterol and
trigly ceride levels. [19]
A study of athyrotic patients found a high heterogeneity in these patients’ ability
to produce T3 when treated with levothyroxine . Approximately 20% of these athyrotic
patient s did not maintain normal free T4 or free T3 values despite a normal
TSH. [20]However, it is unclear whether more physiologic treatments offer any benefit,
even in subgroups of hypothyroid patient s.
In patients who continue to have symptoms (eg, weight gain and fatigue) despite
normalization of the TSH level, one should consider causes other than hypothyroidism,
rather than simply increasing the thyroid hormone dose on the basis of symptoms alone
(see DDx). In some cases, however, symptom persistence is the result of a
polymorphism of the deiodinase 2 enzyme, which converts T4 to T3 in the brain; these
patients may benefit from combined LT4 -liothyronine (LT3) therapy, using a
physiologic LT4 -to-LT3 ratio in the range of 10 -14:1. [4]
Most patients with hypothyroidism can be treated in an ambulatory care setting.
Patients who require long -term continuous tube feeding routinely require intraven ous
(IV) LT4 replacement because the absorption of oral agents is impaired by the contents
of tube feeds. Alternatively, tube feeds can be withheld for 1 hour while the patient
receives an oral preparation of LT4. It should be noted that oral and IV prepar ations of

27
LT4 are not equivalent; consequently, great care must be taken in switching between
these formulations.
Patients with severe hypothyroidism requiring hospitalization (eg, myxedema)
may require aggressive management. Overreplacement or aggressive replacement with
any thyroid hormone may precipitate tachyarrhythmias or, very rarely, thyroid storm and
should be balanced against the need for urgent replacement. Risk is higher with T3
therapy.
Surgery is rarely needed in patients with hypothyroidism; i t is more commonly
required in the treatment of hyperthyroidism. However, surgery is indicated for large
goiters that compromise tracheoesophageal function [58].

2.10.2 Hyperthyroidism
2.10.2.1Conservative treatment
Initial treatment is to render the patient euthyroid by administration of antithyroid
medication in the form of propylthiouracil or carbimazole, both of which prevent
coupling of iodotyrosine. Patients with Graves’ disease are generally treated with
medica tion for 12 –18 months. Alternative treatments are ablation with radioactive
iodine, usually reserved for patients more than 40 years of age because of the theoretical
teratogenic risk, or total thyroidectomy. Graves’ disease is treated by surgery if there is
relapse following initial medical treatment (about 50% of the time) or non -compliance
with such treatment, or if ophthalmopathy is present, in which case radioiodine ablation
is contraindicated. Toxic multinodular goitre and toxic adenoma are best treat ed
surgically once the patient is rendered euthyroid by antithyroid medication.
2.10.2.2 Surgical procedures
The surgical method of treatment is considered to be radical and the most
effective. The operation almost always allows to liquidate the manifesta tions of
hyperthyroidism together with its morphological base. The efficiency of this method in
the specialized clinics reaches 95 -97 %.

28

2.10.2.2.1 The indications for surgery
include thyrotoxicosis of moderate gravity when the conservative treatment is
inefficient during 2 -3 months, severe forms of thyrotoxicosis, goiter of IV -V degree
despite the gravity of thyrotoxicosis, and also nodular transformation of toxic goiter.
The surgical method is not recommended for the patients with thyrotoxicosis with
severe concomitant diseases and dysfunction of vital systems.
The obligatory requirement of successful surgery of the patients with
thyrotoxicosis is the careful preoperative preparation, which goal is the liquidation or
decreasing of hyperthyroidism, that achievement of euthyroid state. Preoperative
preparation should be complex, pathogenically proved and individual.
The appropriate place in preoperative period should possess psychological
preparation. The patients stay in chambers together with patients recovering after
operation. In severe form of thyrotoxicosis a strict bed regime is ordered. The diet
should be high -caloric, rich with proteins, vitamins. The patient must take antithyroid
drugs under the control of general blood analysis. To prevent leukopenia and

29
agranulocytosis instituted leukopoetic agents. Besides antithyroid therapy, are advisable
reserpin that characterized by hypotensive, sedative and antithyroid activity, beta –
blockers and tran quilizers for decreasing stimulation of CNS.
In severe form of thyrotoxicosis, at presence of hypoproteinemia is advisable the
intravenous infusion of protein substitute solutions (albumin, protein, plasma). With the
purpose of detoxycation applied neohaem odes, neocompensan. For exhausted patients
beside high -caloric diet applied parenteral infusion of glucose, intralipid, amino acids
and vitamins, particularly of B -group. The patient with sings of heart failure
simultaneously should take cardiac glycosides and other cardiac agents. One of the
measures in preoperative preparation is the regulation of reduced function of suprarenal
glands. Glycocorticoids (hydrocortisone etc.) administered in daily dosage of 25 -50 mg
2-3 times per day during 3 -4 days before t he operation and 2 -3 days after it. Preoperative
preparation should also include regulation of hemostatic dysfunction (vicasol,
aethamsylat, dicynon, inhibitors of proteases).
The preoperative preparation is considered to be sufficient, if the state of th e
patient is regarded to euthyroid or approximate to it. It is testified by normalization of
pulse (90 -80 per minute), increase of weight on 3 -5 kg, liquidation of nervousness and
irritability, disappearance of tremor, regulation of function of cardiovascu lar system,
liver, suprarenal glands, CNS and basal metabolism.
Anesthesia . The method of choice is endotracheal narcosis.

2.10.2.2.2 Operation approaches :
Cervical Approach
Before any cervical exploration the patient must be appropriately positioned with
the neck extended. We favor full muscle relaxation, which allows optimal positioning.
After positioning, and before skin preparation, an excellent opportunity to perform neck
ultrasound is available. A transverse incision is made about two fingerbreadths above the
clavicular heads. The incision is placed in a way that provides a direct approach to the
thyroid gland and its adjacent structures while allowing optimal postoperati ve cosmetic
results. If possible, the incision incorporates normal skin lines to aid in optimal cosmetic
healing. The lateral borders of the incision can approach the medial borders of the
sternocleidomastoid muscle but can be lengthened if the lateral asp ect of the neck is to
be investigated. The skin incision is carried through subcutaneous fat and the platysmal
muscle, and superior and inferior flaps are dissected in a bloodless plane beneath the
platysmal layer. The anterior jugular veins are identified , and any that are crossing or
running along the midline can be divided

30

Figure 2.10 – Cervical approach – sabiston textbook
The midline raphe can be identified between the sternohyoid muscles, and this
raphe is divided in a bloodless plane from the thyroid cartilage superiorly to the sternal
notch inferiorly. As the plane immediately beneath the sternohyoid muscles is entered,
one encounters the isthmus of the thyroid in the midline and each of the lobes late rally.
Above and below the isthmus are the cartilaginous rings of the trachea. Blunt finger
dissection can separate the sternohyoid muscle from the thyroid capsule medially and
identify the sternothyroid muscles in a deep and lateral position. The sternoth yroid
muscles do not meet in the midline and must be separated off the thyroid capsule to gain
lateral exposure to the thyroid. In patients who have previously undergone FNA, it may
be that the planes under the sternothyroid muscle are obliterated by recen t hemorrhage
or scarring. If the patient has previously had thyroid surgery, these muscle groups will
be densely adherent to the trachea and perhaps the tracheoesophageal groove. Great care

31
must be used in this circumstance to identify the parathyroids and recurrent laryngeal
nerve. When the recurrent laryngeal nerve has been identified on either side, it is
mandatory to track it through any scar tissue or thyroid carcinoma. Every effort must be
made to avoid sacrificing the nerve. In rare situations, such as anaplastic thyroid
carcinoma, aggressive well -differentiated carcinoma, or obvious involvement with other
head and neck tumors, the nerve may be sacrificed. If a recurrent laryngeal nerve is
found to have been injured during the course of an otherwise u ncomplicated operation,
every attempt is made to repair it initially with microscope -aided visualization and
microvascular technique (8 -0 or 9 -0 monofilament sutures). Dissection between the
sternohyoid and the sternothyroid muscles gains exposure to the l ateral and deeper
structures. Exposure of these lateral structures is enhanced by placing medial traction on
the thyroid lobe on the side being dissected. Care must be taken to divide the middle
thyroid vein before it is placed under excessive traction by this maneuver. With lateral
retraction of the muscles and medial retraction of the thyroid lobe, the common carotid
is quickly defined. On the left side, the esophagus is more prominent because of its more
lateral position at this level in the neck. Defini tion of this area can be enhanced by
placement of an esophageal stethoscope, which allows easier palpation of the esophagus.
In the case of complicated lateral thyroid masses, lymphadenopathy, or previous
surgery, it may be necessary to gain exposure later ally by dividing the sternohyoid and
sternothyroid muscles. It is rarely necessary to divide these two muscles, however,
because lateral traction generally provides good exposure. If transection of the
sternohyoid or sternothyroid muscle is necessary, it i s done superiorly to minimize
denervation because both these muscle groups are innervated from a caudal direction
through the ansa hypoglossi nerves. By gaining access to the plane immediately above
the thyroid sheath and placing lateral traction on the st rap muscles of the neck, the
operating surgeon should be able to visualize the entirety of the anterior surface of the
thyroid, even in reoperative cases. Traction on the thyroid lobes in a medial direction
helps identify a dissection plane for gaining acc ess to the superior pole vessels. To
skeletonize the superior pole vessels, one needs to have good exposure laterally between
the common carotid artery and the superior aspect of the ipsilateral thyroid lobe. One
can then enter behind or posterior to the s uperior thyroid pole adjacent to the
cricothyroid muscle. Careful dissection in this area avoids injury to the external
laryngeal nerve.
Most patients (75% -80%) have external laryngeal nerves that run on the
cricothyroid muscle and are separate from the s uperior vessels; however, this leaves a
significant number of patients in whom the nerve runs in close proximity to the superior
pole vessels and could be divided if care is not exercised. After the superior pole vessels
are carefully dissected and identif ied, they can be double -ligated adjacent to their
entrance into the thyroid lobe. After the superior thyroid vessels and middle thyroid
veins have been divided, continued medial retraction of the thyroid lobe allows the

32
posterior aspect of the thyroid lobe to be visualized. It is in this area that the superior
parathyroids are usually found lying in small deposits of fat within the thyroid sheath

Figure 2.11 – Thyroid lobe retraction medially

33

34
Figure 2.12 -thyroid resection

35
Figure 2.12 -thyroid resection – Sabiston Textbook

Figure 2.13 -Recurrent Laryngeal nerve location – Sabiston Textbook

Modified Radical Neck Dissection
Although there is some controversy about when to perform a modified radical
neck dissection for thyroid carcinoma, it is safe to say that this operation is most widely
performed in patients with documented disease in whom obvious and palpable
lymphadenopat hy lateral to the carotid sheath exists at the time of the original diagnosis
or occurs after preceding thyroid surgery. There appear to be limited data on the use of

36
prophylactic neck dissection in patients with well -differentiated thyroid carcinoma who
do not have palpable lymph nodes. In the case of papillary carcinoma, concern about
multicentricity and microscopic lymph node involvement appears to fuel this
controversy. For larger tumors and palpable nodes in this area, most authors advocate
total thyro idectomy and, at a minimum, central lymph node dissection. In the case of
microscopic lymph node involvement in the absence of palpable lateral lymph nodes, the
use of radioactive iodine before proceeding with prophylactic lateral lymph node
dissection has been advocated but not overwhelmingly accepted. Radioactive iodine
appears to be beneficial in this circumstance but is much less effective in ablating
palpable regional metastatic lymph node involvement. The use of selected removal of
palpable nodes in t he lateral compartment (so -called cherry picking) has largely been
abandoned. Therefore, modified radical neck dissection is primarily reserved for patients
with thyroid carcinoma and clinically palpable cervical lymph node metastases. This can
be accompli shed with an en bloc dissection that removes all the lymphatic and adipose
tissue in the lateral neck compartment while avoiding the cosmetic or functional
abnormality associated with removal of muscle groups that is used in the classic radical
neck dissec tion. The sternocleidomastoid muscle and spinal accessory nerve are spared.
A cervical skin incision is used for the operation, which is standard for most thyroid
operations. It is extended laterally and superiorly along the border of the
sternocleidomasto id muscle. Occasionally, it is necessary to make a higher incision
parallel to the previous surgical incision if higher lymph nodes are palpable. In initiating
the neck dissection, the surgeon must gain access deep to the sternocleidomastoid
muscle and rem ain anterior to the carotid sheath above the clavicle. Laterally, the
phrenic nerve is identified and preserved in the prevertebral fascia on the anterior
scalene muscle. On the left side, the phrenic nerve is immediately adjacent to the
thoracic duct at t he level of the junction of the internal jugular and subclavian veins. The
dissection begins just above the clavicle in this area. The goal of dissection is removal of
all tissue between the superficial and prevertebral fascia, except for the carotid arter y,
jugular vein, vagus, and phrenic and spinal accessory nerves. Additionally, the
sympathetic chain and the sternocleidomastoid muscle must be preserved. Dissection
continues in the cephalad direction, where the spinal accessory nerve is identified at the
deep and lateral surface of the sternocleidomastoid muscle. The nerve runs inferiorly in
the lateral aspect of the posterior triangle of the neck. The nerve can be traced as it gives
a branch to the sternocleidomastoid muscle at this level and then passes adjacent and
posterior to the digastric muscle. As the dissection proceeds in a more cephalad
direction, the hypoglossal nerve is encountered; it crosses anteriorly to the internal
carotid artery and internal jugular vein yet deep to the anterior facial v ein. It follows the
stylohyoid muscle into the submandibular triangle and innervates the muscles of the
tongue. If one chooses to ligate the internal jugular vein, care must be taken to not injure
the hypoglossal nerve as it crosses in this area. Medially, the surgeon must take care to

37
not injure the cervical sympathetic chain, which lies deep to the carotid sheath and just
anterior to the prevertebral fascia. The retropharyngeal lymphatics connect with the
cervical and jugular lymphatics across the chain i n this area and may have metastatic
deposits of thyroid cancer. Injury to the sympathetic chain in this area results in Horner's
syndrome, which includes ptosis, miosis, anhidrosis, and increased skin temperature on
the involved side. On completion of a mo dified radical dissection, a triangle of fibrofatty
tissue, which may or may not include the internal jugular vein, is dissected free and
oriented for pathology. It is not usually necessary to extend dissection into the
suprahyoid area unless there is exte nsive lymph node involvement, which occurs in only
a few patients with well -differentiated thyroid carcinoma ( ∼1%). Great care is taken
when dissecting structures in the lateral aspect of the neck, including the sympathetic
chain and recurrent laryngeal an d spinal accessory nerves, unless they are obviously and
grossly involved with tumor.
Median Sternotomy
Exploration of the anterior mediastinal space is within the armamentarium of an
experienced thyroid surgeon. Nearly every benign and malignant thyroid tumor can be
removed through cervical exploration. Occasionally, a median sternotomy may be
necessary in patients who need a reoperation, have large invasive tumors, have low –
lying thyroid glands and a large tumor, or have previously undergone radioiodine
ablation or external beam irradiation. Initial exploration usually involves a cervical
incision. If a median sternotomy is then required, a midline incision is made from the
middle of the cervical wound and extended inferiorly and onto the manubrium. Befo re
dividing the sternum, access is gained on the superior border of the manubrium and all
tissues deep to the sternum swept away bluntly with cotton sponges or finger dissection.
The midline sternal incision is made with a saw or splitting device and carri ed to the
level of the second, third, or fourth intercostal space as needed. We prefer a sternal split
of the cephalad half of the sternum, which usually provides excellent exposure and
avoids the possible instability associated with full sternotomy. Subst ernal thyroid
masses, including goiters or extension of malignancies, as well as ectopic parathyroid
adenomatous tissue, can be approached through this incision. The anteromedial fat pad
and thymus can be dissected to gain visualization of the pericardium superiorly. As one
proceeds laterally in this dissection, care must be taken to avoid injuring the pleura and
the phrenic nerves. The innominate vein is deep to the thymus. Virtually all low -lying
thyroid masses can be approached through this incision.

Postoperative period .
The clinical course of early postoperative period in the patients undergone the
operation mainly depends both on quality of preoperative preparation, and on technique
of the surgical intervention. In some patients, particularly with severe form of

38
thyrotox icosis, during first days after the operation it is possible to observe exacerbation
of thyrotoxicosis – postoperative thyrotoxic response.
There are three degrees of postoperative thyrotoxic response: mild, moderate
gravity and severe.
Characteristic sing s of mild degree is the tachycardia up to 120 per minute, fever
as high as 38°С, satisfactory state of the patient, tachypnea.
The moderate gravity of thyrotoxic response manifests by mild psychomotor
excitement. They complain of general weakness, headache , fever sensation, rapid pulse
to 120 -140 per minute (rhythmic, tense), sometimes extrasystole. Temperature raises as
high as 38,5 -39°С. Characteristic the considerable sweating, tachypnea, superficial
sleep.
Severe degree of thyrotoxic response is charact erized by expressed psychomotor
excitement. The patients are restless, frequently change positions in the bed, they
complain of considerable sweating, permanent fever sensation and expressed tremor.
Hyperemia of the face, pulsate vessels of the neck and cy anosis of leaps are evident. The
pulse rate usually exceeds 140 per minute, irregular and soft. The breathing is
superficial. Body temperature is 39 -40°С. The sleeplessness in such patients is almost
impossible to liquidate by hypnotic and narcotics agents .

2.10.2.2.3 Postoperative complications
The advantage of complete removal of disease -bearing tissue and efficient
subsequent application of postprocedure radioiodine ablation after total thyroidectomy
must be weighed against lesser procedures such as lob ectomy in terms of surgical
complications. The most important complications are postprocedure hypocalcemia
secondary to devascularization of the parathyroid and significant hoarseness caused by
recurrent laryngeal nerve injury induced by either traction or division.
Hypocalcemia
Rates of postprocedure hypocalcemia are about 5%, and it resolves in 80% of
cases in about 12 months. Therefore, every effort is made to evaluate the parathyroid
tissue intraoperatively. For glands that appear to be devascularized , the use of immediate
parathyroid autotransplantation of 1 -mm fragments of saline -chilled tissue into pockets
made in the sternocleidomastoid muscle or, more commonly, the brachioradialis muscle
is extremely effective in avoiding hypocalcemia.
Nerve Injur y
Superior Laryngeal Nerve
The superior laryngeal nerve has two branches —an internal one that supplies
sensory fibers to the larynx and an external one that supplies motor fibers to the
cricothyroid muscles and tenses the vocal cords. The external branch can run closely
adherent to the superior thyroid artery, and care must be exercised during dissection in

39
this area. Injury to the branch causes voice changes, huskiness, poor volume voice
fatigue, an d inability to sing at higher ranges.
Recurrent Laryngeal Nerve
As mentioned previously, the recurrent laryngeal nerve arises from the vagus and
is a mixed motor, sensory, and autonomous nerve that innervates both th e adductor and
abductor muscles. Unila teral injury is classically described as a paralyzed vocal cord
with loss of movement from the midline. A wide spectrum of injuries to the voice or
swallowing mechanisms, or to both, can occur because of the mixed fibers contained
within the nerve.[1] Temp orary or permanent voice change can result and is extremely
distressing to the patient.
Bleeding
Other complications such as bleeding and wound hematomas may require
immediate re -exploration, which is done in the operating room unless airway
compromise di ctates otherwise. These complications can be avoided by meticulous
hemostasis at closing, which results in less than a 1% rate of occurrence.[55]
Complication rates appear to be affected by surgeon experience. A study in
Maryland of 5860 patients reported the lowest complication rates in patients of surgeons
who performed more than 100 neck explorations annually

40
Chapter 3 case reports
1)Case report Nr.1: Multinodular Goiter and Airway Compression
in a Preeclamptic Patient

A 31 -year-old female presented at 33 weeks gestation complaining of severe
headache. After assessment by obstetrics, she was diagnosed with preeclampsia. She
also reported difficulty breathing when lying down for 3 weeks. She had a 3 -year history
of a thyr oid nodule, and previous fine -needle aspiration showed atypical cells suspicious
for papillary carcinoma. She had no other significant medical or family history.
On examination , she was hypertensive and in no apparent distress, but she
became short of brea th and had biphasic stridor when supine. She had a large, midline
neck mass obscuring
the thyroid cartilage and sternal notch .The mass was firm, non -mobile, non -tender, and
measured 5 cm. Bedside flexible fiberoptic laryngoscopy was normal.

Figure 2.14 – Thyroid Goiter ( Enlargement )

Laboratory tests showed normal thyroid function, electrolytes, and complete
blood count.
A CT with intravenous contrast of the neck and chest showed a markedly
enlarged heterogeneous thyroid gland with substernal extension and mass effect on the
trachea. Areas of calcification of the thyroid were noted.
Figure 2.15 -Coronal CT of clinical case NR.1

41

Figure 2.16 – Axial CT of clinical case NR.1

The findings were consistent with a multinodular goiter.

The patient was brought to the operating room, and anesthesia placed a
spinal and kept the head of the bed elevated. The obstetrical team delivered a

42
healthy infant via cesarean section. Anesthesiologist then intubated the patient
and otolaryngology perf ormed a total thyroidectomy (kocher) . The specimen
was removed in two segments .

A: thyroid mass B: Substernal part

Post-operative diagnosis :
Pathology was consistent with multinodular goiter with a solitary papillary micro –
carcinoma.
The patient remained intubated post -operatively and was transferred to the ICU.
She was extubated on postoperative day 2.

43
2) Case report Nr.2: Benign cervical goiters with acute airway obstruction.

A 64 -year-old hypertensive woman presented to our emergency room with a two –
day history of worsening shortness of breath and stridor. She had been aware of a
recurrent goiter for over 15 years, having had a partial thyroidectomy 35 years ago for
benign multi -nodular disease. Over the past year, she had been experiencing shortness of
breath on exertion, generally relieved by rest. However, the period of rest needed to
relieve her dyspnea had been increasing in duration. She did no t have any hyperthyroid
or hypothyroid symptoms and there was no history of fever, dysphagia, pain or
hoarseness .
On presentation to our emergency department she ha d marked stridor, tachypnea
(32 breaths/minute), tachycardia (120 beats/minute) and blood pressure of 160/95
mmHg. Her pulse oximeter oxygen saturation (spO 2) was 78% on room air.
A large multi -nodular goiter was obvious: right lobe 14×11 cm, left lobe 11×8 cm
.
All other examinations w ere normal. She was rushed to the operating room for
intubation under general anesthesia. A central line was also placed via the right
subclavian vein. On intubation, the larynx appeared normal and a endotracheal tube (ET)
was passed easily.

44
After intubation, she stabilized and was able to breathe comfortably with the ET in situ.
She was admitted to the intensive care unit and given propanolol 20 mg orally, three
times daily.
Her laboratory test results were within normal ranges, with a thyroid -stimulating
hormone (TSH) level of 1.4 mIU/L and free T4 level of 1.5 μg/dL.
A computed tomography (CT) scan of the neck and thorax showed gross
enlargement of both lobes of the thyroid with multiple nodules of varying sizes. There
was marked narrowing of th e cervical trachea with only the ET maintaining the patency
of the airway. There was mild retrosternal extension on the left side down to the level of
the origin of the great vessels but the retrosternal trachea was not compressed .

C7 level:

T2 level:

45

The results of an electrocardiogram (ECG) were normal, while the results of an
echocardiogram were consistent with hypertensive heart disease with an ejection
fraction of 65%.

A total thyroidectomy was performed on the fourth day after admission. The
gland was dissected easily with preservation of the recurrent laryngeal nerves and
parathyroids. A tracheostomy was placed prophylactically. The trachea was normal with
no features of tracheomalacia.
She returned to the intensive care unit and recovered with no complications. Her
calcium levels did not decline post -operatively. The tracheostomy was removed on day
10 post -operatively.
Postoperative diagnosis :
Histology tests confirmed a benign multi -nodular goiter.

.

46
Chapter 4

Conclusion

• The prevalence of goitre in areas of severe iodine deficiency can be as high as
80%
• In iodine -replete areas, most persons with thyroid disorders have
autoimmune disease, ranging from primary atrophic hypothyroidism,
Hashimoto's thyroiditis to thyrotoxicosis caused by Graves' disease.
• Up to 60 percent of those with thyroid disease are una ware of their condition.
• Women are five to eight times more likely than men to have thyroid
problems.
• Undiagnosed thyroid disease may put patients at risk for certain serious
conditions, such as cardiovascular diseases, osteoporosis and infertility.
• Perman ent Hypoparathyroidism following surgery on the thyroid gland
occurred in 8.5% of the patients.
• In an estimated 1 out of every 250 thyroid surgeries, damage is done to
the laryngeal nerve, the nerves that control the voice.
• postoperative bleeding (1.4%) an d wound infection (0.7%)
• 2-3 thyroidectomy per day are performed in the republic hospital in Chisinau
moldova

47

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[59] Sabiston Textbook of surgery Ed.18 -SECTION VIII – Endocrine -CHAPTER 36 –
Thyroid -SURGICAL APPROACHES TO THE THYROID GLAND AND
ADJACENT STRUCTURES

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Statement

I hereby declare that the license thesis titled “Pathology of the Thyroid Gland ” is
written by me and has never been submitted to another university or institution of
higher education in the country or abroad . Also , that all sources used , including those
on the Internet , are given in the paper with the rules for avoiding plagiarism :
– all the fragments of text reproduced exactly , even in his own translation from another
language are written between quotation marks and have a detailed reference source ;
– reformulation of the texts in own words written by other authors have detailed
reference ;
– summarizing the ideas of other authors have detailed reference to the original text .

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