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Fig. 12.24 Diffuse goiter with no nodules (smooth surface) in a 27-year-old lady
Fig. 12.25 (a) A
31-year-old lady with
exophthalmos. (b) A
24-year-old lady with
“severe” exophthalmos
Note white sclera all
around
M. Sakr
glycosaminoglycan deposition, leukocyte inltration, and brosis of the orbit and extra-ocular
muscles.
Dermopathy, in the form of pretibial myxedema, occurs in 0.5–4% of patients. It consists of violaceous, plaque-like thickening, or
induration of the skin of the lower legs and feet
and may be associated with pain and pruritis.
Acropachy is rare (<1%) and is manifested by
thickening or clubbing of the ngers or toes,
nail changes, and periosteal new bone formation.
t.me/Dr_Mouayyad_AlbtousH
12.5.8.4 Diagnosis
Diagnosis of Graves’ disease is usually established by the presence of hyperthyroidism, diffuse symmetric goiter, low TSH levels, and
increased thyroidal RAI uptake (typically diffuse and symmetric). The measurement of thyroid receptor antibodies is not routinely
necessary. Documentation of high titers of
thyroid- stimulating immunoglobulins during
pregnancy in women with a history of Graves’
disease may be important in predicting the risk
of fetal and neonatal thyrotoxicosis [207].
12 Benign Thyroid Disease
317
Scintigraphy is used selectively to help differentiate thyrotoxicosis caused by Graves’ disease
from toxic MNG, a solitary toxic thyroid nodule, or Graves’ disease with a concomitant dominant thyroid nodule.
12.5.8.5 Management
Radioactive Iodine (RAI)
In the United States, the majority of patients with
Graves’ disease are treated with RAI, which
emits beta particles that locally destroy the follicular cells of the thyroid gland. Nordyke and
Gilbert reported that 90% of their patients treated
with a 10mCi of
131
I were cured. A higher dose
may be required in patients with large thyroid
glands (>50 g). However, they emphasized that
delayed hypothyroidism develops in most
patients with Graves’ disease treated with RAI
regardless of the dose of
131
I used. Accordingly,
denitive treatment of hyperthyroidism is the
most important consideration [210].
Symptomatic improvement usually occurs
6–8 weeks after receiving RAI treatment, and
complications are rare. Serum TSH levels are
monitored in all patients and thyroid replacement
with L-thyroxin is begun when TSH levels are
elevated. A pregnancy test should be obtained
prior to RAI administration in all women of the
child-bearing age as it is contraindicated during
pregnancy (and lactation).
Anti-thyroid Drugs (ATDs)
The thioamide drugs, Propylthiouracil (PTU) and
Methimazole, are used for treatment of Graves’
disease in children, pregnant, or breastfeeding
women, elderly patients with mild-to-moderate
symptoms without a goiter, and in preparation of
patients for RAI or surgery. Both drugs decrease
thyroid hormone synthesis by a dose-dependent
inhibition of the thyroid peroxidase enzyme. In
addition, PTU blocks the peripheral conversion
of T4–T3. When compared to Methimazole, PTU
has a greater protein binding that results in less
passage across the placenta and the mammary
epithelium, and that is why it is preferable in
women who are pregnant or breast feeding [205,
211]. The half-life of PTU is 2 h and is given
2–3times/day, whereas methimazole has a halflife of 6h and is given 1–2times/day.
A high thioamide dose is given initially (PTU
100–200mg, or Methimazole 10–30mg). Once
the free T4 and T3 levels have normalized, the
thioamide dose is tapered to the lowest dose that
will maintain a euthyroid state. Patients are kept
on a maintenance dose usually for 1–2 years.
Remissions are variable and most often last for
<6months. Hedley etal. reported that 40–80% of
patients develop recurrent thyrotoxicosis after
discontinuation of ATDs [212].
Minor side effects of thioamides may be doserelated or agent-related and include skin rash,
pruritis, urticaria, nausea, vomiting, myalgias or
arthralgias, fever and transient leukopenia. In
such cases, drug dosage is reduced or the other
thioamide drug substituted, though crosssensitivity may occur. Major side effects are idiopathic and include agranulocytosis, hepatitis,
aplastic anemia, and vasculitis.
Surgical Treatment
Surgery for treatment of patients with Graves’
disease results in immediate symptomatic
improvement and is indicated in pregnant patients
intolerant to ATDs, large goiters with compressive symptoms, concomitant solitary cold nodule, patients who fail to respond to multiple doses
of RAI, and those who prefer surgery.
The standard operation had been a bilateral
subtotal thyroidectomy (STT) in an attempt at
maintaining a euthyroid state postoperatively and
reducing the risk of RLN injury and hypoparathyroidism while minimizing the risk of recurrent
hyperthyroidism. However, it has been reported
that 10–15% of patients suffer from recurrent
hyperthyroidism after bilateral STT and the
majority of patients become hypothyroid within
10years. Consequently, TT has become the “procedure of choice” provided it is performed by
experienced hands. TT has also been recommended for patients with severe or progressive
ophthalmopathy and high TSH receptor antibody
titers [209]. Total removal of the thyroid gland is
advocated to decrease TSH receptor antibodies
and other antibodies directed against the extraocular muscles, orbit, and optic nerve [209].
t.me/Dr_Mouayyad_AlbtousH
318
M. Sakr
Prior to elective surgery, patients are rendered
biochemically euthyroid using ATDs. A
β-adrenergic-blocking agent (propranolol) is also
used for symptomatic treatment and maintaining
the resting heart rate between 60 and 80 beats/
min. Preparing the patient for surgery is important in order to eliminate the risk of peri- operative
thyroid storm.
12.5.9 Toxic Multinodular Goiter
(Plummer’s Disease)
Toxic MNG accounts for 5–15% of cases of thyrotoxicosis. It more commonly affects women
and typically occurs in elderly patients with a
long-standing MNG.It is thought to result from
progressive generation of autonomously functioning thyroid follicles overtime that have a
greater capacity to synthesize T4 and T3, eventually resulting in toxic MNG.
12.5.9.1 Diagnosis
Thyrotoxicosis is generally mild in comparison
to Graves’ disease and inltrative ophthalmopathy does not occur; however, patients often have
large goiters with compressive symptoms, and
cardiovascular manifestations occur more commonly because the patients are older. Laboratory
evaluation reveals a low serum TSH level with or
without elevated serum T4 and/or T3 levels.
Routine scintiscanning is not necessary.
12.5.9.2 Treatment
The goal in treatment is to eradicate all autonomously functioning thyroid follicles by surgical
resection or
131
I therapy. Because of the marked
thyroid enlargement and associated compressive
symptoms, TT is the usual treatment. Patients are
also pretreated with ATDs preoperatively to normalize their free T4 or T3 levels before proceeding with thyroidectomy.
Radioiodine may also be used for treatment.
However, toxic MNGs can be resistant to RAI
therapy, which is also usually not effective in
alleviating compressive symptoms related to thyroid enlargement. Treatment with
131
I is usually
reserved for elderly patients with multiple con-
current medical problems that place them at high
risk for surgery. Treatment with ATDs should be
considered prior to RAI administration especially
in patients with underlying heart disease. It must
be discontinued 3–5 days prior to treatment to
optimize RAI uptake and then resumed 1week
after treatment.
12.5.10 Solitary Toxic Nodule
A solitary toxic nodule is a discrete, autonomous,
hyperfunctioning nodule that occurs in an otherwise normal thyroid gland and causes hyperthyroidism. It accounts for 3–10% of spontaneous
thyrotoxicosis cases. The term “hyperfunctioning” nodule means that it takes up greater RAI
than the normal adjacent thyroid tissue. Only
25% of hyperfunctioning nodules are toxic. The
term “autonomous” means it functions independent of the hypothalamic–pituitary–thyroid feedback mechanism and secretes thyroid hormone
despite suppressed TSH levels.
12.5.10.1 Diagnosis
The clinical thyrotoxic manifestations of a solitary toxic nodule are generally milder than in
patients with Graves’ disease. It usually occurs
more commonly in women and in patients
<50years of age. Physical examination reveals a
single, discrete nodule in the thyroid gland conrmed by US.
The initial diagnostic test is serum TSH, free
T4, and free T3 levels. Hyperfunctioning nodules
preferentially secrete T3 and so serum T3 levels
are more likely to be elevated in patients with an
autonomous nodule. A thyroid scan using
131
I
conrms the presence of a hyperfunctioning nodule. The pathology of a toxic solitary nodule is
almost uniformly either a follicular adenoma or
an adenomatous nodule. Carcinoma has been
reported in only about 1% of cases [213].
12.5.10.2 Treatment
Patients with an asymptomatic hyperfunctioning
thyroid nodule can be observed. Treatment is recommended in the presence of subclinical hyper-
thyroidism for patients who are at high risk of
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
319
cardiac side effects, for postmenopausal women
with decreased bone mineral density, and those
who have a hyperfunctioning nodule >3 cm in
diameter.
Surgical treatment has advantages over
131
I:
immediate symptomatic relief, avoidance of radiation exposure to the normal thyroid tissue, and
the low risk of complications. Both postoperative
hypothyroidism and recurrence of hyperthyroidism are uncommon. Radioiodine treatment usually requires higher doses of
131
I than are normally
used for treatment of Grave’s disease. It has the
disadvantages of delay in symptomatic relief,
exposure of normal thyroid tissue to radiation,
which may result in hypothyroidism in up to 35%
of patients, and concerns related to persistence of
the nodule [194].
Other less attractive therapeutic options
include ATDs and percutaneous ethanol injec-
tion. The ATDs are not curative and must be
given lifelong because to avoid recurrence of
hyperthyroidism. Their use is limited to preparing patients for surgical or RAI treatment
but may also be considered in elderly patients
with medical problems that preclude surgery
or RAI therapy. Ultrasound-guided ethanol
injection is effective in reversing hyperthyroidism, but it requires multiple painful injections, and can be complicated by transient
RLN paresis.
12.5.11 Thyrotoxicosis Secondary
toThyroiditis
Thyrotoxicosis secondary to thyroiditis is uncommon. It is typically transient and self-limited. It
may occur as a result of chronic lymphocytic or
Hashimoto’s thyroiditis (Hashtoxicosis), silent
(painless) thyroiditis, subacute (de Quervain’s)
thyroiditis, and RAI-induced thyroiditis. In contrast to Hashtoxicosis in which RAI uptake is
increased, silent, subacute, and RAI-induced thyroiditis are all characterized by the inability to
trap iodine, follicular cell destruction, and release
of preformed thyroid hormone resulting in thyrotoxicosis with a low RAI uptake.
12.5.11.1 Hashimoto’s Thyroiditis
Thyrotoxicosis in patients with Hashimoto’s thyroiditis typically occurs in the early course of the
disease and is transient in nature. It is thought to
be the result of lymphocyte production of stimulatory anti-TSH receptor antibodies, which are
present in 10–25% of all patients with chronic
lymphocytic thyroiditis. These patients have
marked elevation of anti-Tg and anti-TPO (antimicrosomal) antibody titers, and focal or diffuse
lymphocytic inltration of the thyroid gland.
Most patients are women between the ages of 30
and 50years. They may have a rm goiter and
rarely ophthalmopathy. As the disease progresses,
thyrotoxicosis resolves and hypothyroidism
develops instead. If symptoms of thyrotoxicosis
become problematic, a β-adrenergic-blocking
agent or ATD may be used. Patients are followed up clinically, and their serum TSH levels are
monitored for the inevitable development of
hypothyroidism, which will require hormone
replacement therapy.
12.5.11.2 Silent (Painless) Thyroiditis
Silent thyroiditis is the major cause of thyrotoxicosis in patients with low RAI uptake. It is an
autoimmune disorder that accounts for <5% of
all cases of thyrotoxicosis. It is a form of lymphocytic thyroiditis characterized by single or recurrent episodes of acute inammation of the thyroid
gland resulting in release of stored thyroid hormone. Patients are usually women between 30
and 40 years. Symptoms of thyrotoxicosis are
usually acute, mild, self-limited, and may be followed by transient hypothyroidism. Clinically,
patients may have a rm, non-tender goiter. AntiTPO and anti-Tg antibodies may be elevated, and
serum Tg level is markedly elevated. In general,
the condition requires no therapy, unless symptoms become problematic. In such cases, a
β-adrenergic antagonist and anti-inammatory
therapy with prednisone can be used. Because
increased thyroid hormone synthesis is not the
cause of thyrotoxicosis, ATDs are not effective.
Surgical or RAI treatment may be benecial in
the rare patient with recurrent disabling episodes
of silent thyroiditis with thyrotoxicosis.
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320
M. Sakr
12.5.11.3 Subacute Thyroiditis (de
Quervain’s, Granulomatous,
or Giant Cell Thyroiditis)
Subacute thyroiditis is a subacute, self-limited
inammatory condition of the thyroid gland characterized by neck pain, fever, myalgias, malaise,
mild-to-moderate thyroid enlargement, exquisite
neck tenderness, and symptoms of thyrotoxicosis,
which occur during the initial phase of inammation. Etiology is multi-factorial. A viral infection
may trigger an abnormal cell- mediated immune
response directed at the thyroid follicular cells
causing follicular cell destruction and release of
preformed thyroid hormone. A genetic predisposition may also be involved as suggested by the
association of HLA BW35 haplotype with subacute thyroiditis in certain patients [214].
Diagnosis is supported by the presence of a markedly elevated erythrocyte sedimentation rate
(ESR), an increased serum Tg level and a suppressed RAI uptake. Treatment is primarily supportive using nonsteroidal anti- inammatory
agents or prednisone. Thyrotoxicosis usually
requires no treatment and resolves within
3–6weeks. If symptoms become problematic, a
β-adrenergic blocking agent, but not ATDs, may
be given. If follicular cell destruction is extensive,
hypothyroidism may develop during the recovery
phase. Nevertheless, nearly 95% of patients
become euthyroid within 6months of onset.
12.5.12 Iodine-Induced
Thyrotoxicosis
Iodine-induced thyrotoxicosis usually occurs in
elderly patients with a preexisting MNG who are
given a large iodine (I2) load (e.g., oral expectorants, IV contrast material, etc). It is the only
cause of hyperthyroidism with a low RAI uptake
and accounts for <1% of all causes of thyrotoxicosis. Pathogenesis is not fully understood. In
normal individuals, large doses of I2 cause inhibition of I2 transport and a rapid decrease in thyroid
hormone synthesis and release (Wolff–Chaikoff
effect). It may also occur as a result of supplying
excess I2 to areas of autonomous function in the
thyroid gland (Jod Basedow effect) or due to an
increase in the I2 set point of the thyroid gland that
leads to increased thyroid hormone synthesis.
Diagnosis is suspected by a history of a recent
exogenous I2 load in a patient with a goiter and is
supported by a serum iodide concentration
>1.5mg/dL and a 24-h urinary iodide excretion
>1000mg. Treatment most often consists of discontinuation of the iodide source, although this
may be problematic in patients with refractory
arrhythmias on amiodarone [215]. Thioamide
drugs may also be used either alone or in combination with a beta-adrenergic antagonist and/or
potassium perchlorate, which competitively
inhibits I2 uptake by the thyroid gland. Radioiodine
therapy is not an option because the high I2 load
suppresses RAI uptake by the thyroid gland. Total
thyroidectomy may be indicated in patients with
amiodarone-induced thyrotoxicosis that is refractory to medical therapy or as an initial therapy for
patients who present with resurgence of lifethreatening cardiac arrhythmias [215].
12.5.13 Thyroditis
12.5.14 Introduction
Thyroiditis represents about 20% of all thyroid
diseases [216] and is caused by several factors,
most commonly autoimmune diseases
(Table12.18). Thyroid autoantibodies are mainly
directed against thyroid perioxidase (TPO) or
thyroglobulin (Tg) and have an association with
dened HLA haplotypes implying a genetic predisposition [217]. Iodine therapy, viral infections,
pregnancy, menopause, stress [218
modulating drugs such as interferon-α have also
been linked to autoimmune thyroiditis. Except
for Graves’ disease, most cases of autoimmune
thyroiditis present initially with hyperthyroidism
that returns to euthyroidism or falls to permanent
hypothyroidism (subclinical or overt).
Clinically, thyroiditis is divided into acute, subacute, and chronic forms [219], and patients may
present either with severe thyroid pain (e.g., acute
suppurative thyroiditis, subacute de Quervain’s
], and immune-
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
321
Table 12.18
Autoimmune thyroiditis Nonimmune thyroiditis
• Hashimoto’s thyroiditis
• Fibrotic variant of
• Atrophic thyroiditis
• Variants of autoimmune
– Postpartum
– Silent or painless
– Subacute de
– Fibrotic Riedel’s
Etiology of thyroiditis
Hashimoto’s thyroiditis
(primary myxedema)
thyroiditis
thyroiditis
thyroiditis
Quervain’s
thyroiditis
thyroiditis
• Acute infectious
thyroiditis
• Radiation-induced
thyroiditis
• Palpation/trauma-
induced thyroiditis
• Sarcoidosis
• Vasculitis- associated
thyroiditis
• Postoperative
necrotizing
thyroiditis
• Drug-induced
thyroiditis
• Carcinoma-
associated thyroiditis
thyroiditis, radiation thyroiditis, traumatic thyroiditis) or without evident inammation but with goiter or thyroid dysfunction (e.g., silent thyroiditis,
Hashimoto’s, or Riedel’s thyroiditis).
12.5.15 Autoimmune Thyroiditis
12.5.15.1 Hashimoto’s Thyroiditis
(Chronic Lymphocytic
Thyroiditis, Struma
Lymphomatosa)
Epidemiology
Hashimoto’s thyroiditis (HT) is the most frequent
autoimmune thyroiditis and the most common
cause of hypothyroidism [216]. The annual inci-
dence of HT seen in practice Worldwide is
unknown but is roughly equal to that of Graves’
disease (approximately, 0.3–1.5 cases per 1000
population per year) [220–224]. Women are
10–20 times more affected than men, with a peak
incidence in the fth decade of life. The overall
incidence of hypothyroidism increases with age
in men and women. The prevalence of HT is
4.5% (4.2% subclinical and 0.3% clinical hypo-
thyroid) based on biochemical analysis but with
cytological diagnosis prevalence increases to
13.4% [225].
Etiology/Pathogenesis
The etiology of HT is multifactorial arising from
interaction between genetic and nongenetic factors (environmental, dietary, and demographic).
Genetic Factors
The genetic polymorphisms of the Human leukocyte antigens (HLA) mainly, HLA-DR3 and
HLA-DR5, T-cell immune response genes such
as cytotoxic T-lymphocyte-associated antigen-4
(CTLA-4) and protein tyrosine phosphate-22
(PTPN-22), vitamin D receptor (VDR) and
thyroid- specic genes play a major role in the
pathogenesis of HT [220].
HT is caused by a breakdown in self-tolerance
to thyroid auto-antigens. This is exemplied by the
presence of circulating autoantibodies against Tg
and TPO in most cases and to a lesser extent TSH
receptors (thyrotropin receptor-blocking antibodies). The inciting events have not been elucidated,
but possibilities include abnormalities of regulatory T-cells, or exposure of normally sequestered
thyroid antigen. Induction of thyroid autoimmunity is accompanied by a progressive depletion of
thyroid epithelial cells by apoptosis and replacement of thyroid parenchyma by mononuclear cell
inltration and brosis. Multiple immunologic
mechanisms may contribute to thyroid cell death,
including CD8+ cytotoxic T cell-mediated cell
death, cytokine-mediated cell death, and less
likely, binding of antithyroid antibodies followed
by antibody-dependent cell-mediated toxicity.
Having other autoimmune diseases is a risk
factor to develop HT, and the opposite is also
true. HT has a markedly higher clustering of
other autoimmune diseases, including Grave’s
disease, pernicious anemia, adrenal insufciency (Addison’s disease), celiac disease, and
type 1-diabetes mellitus (DM), rheumatoid
arthritis, Sjogren’s syndrome, systemic lupus
erythematosus, and vitiligo [225, 226]. HT is
associated with different non-thyroidal autoimmune diseases (NTADs) at different ages [201].
Compared with the general population, rstdegree relatives of persons with HT have a ninefold greater risk of developing the disease [227].
t.me/Dr_Mouayyad_AlbtousH
322
M. Sakr
Nongenetic Factors
In genetically susceptible individuals, preventable environmental factors, including high I2
intake [228], selenium (Se), and vitamin D de-
ciency [229], as well as infectious diseases (hep-
atitis C, Rubella, Herpes simplex virus (HSV),
Epstein–Bell virus (EBV), and Human T-cell
lympho-trophic viruses), and certain drugs (INFα, lithium, amiodarone), have been implicated in
the development of autoimmune thyroid disease
(may initiate the autoimmune process). These
factors may act through epigenetic modications,
like DNA methylation and histone modication
at the tissue level, which is evidenced by twin
studies.
Pathology
Gross Appearance
In HT, the enlarged thyroid gland is generally diffuse and symmetrical, often with a conspicuous
pyramidal lobe. Consistency is rm but not stony
hard as in Reidle’s thyroiditis. There is no extension of the process outside the gland. The capsular surface is gently lobulated and non-adherent
to surrounding tissues. The cut surface is distinctly nodular. The tissue involved by HT is
pinkish-tan to frankly yellowish (Fig.12.26) in
color.
Microscopical Picture
In HT, there is a diffuse process consisting of a
combination of epithelial cell destruction, lymphoid cellular inltration, and brosis. The thyroid cells tend to be slightly larger in size and
assume an acidophilic staining character; they
are then called Hurthle or Askanazy cells and are
packed with mitochondria. The follicular spaces
shrink and colloid is absent or sparse. In contrast
to subacute thyroiditis, foreign body giant cells
and granulomas are not features of HTs.
Clusters of macrophage-like cells may be seen
within the follicles. The lymphoid inltration in
the interstitial tissue is accompanied by actual
follicles and germinal centers (Fig.12.27) [230].
Hashimoto’s thyroiditis has been graded based
on lymphocytic inltration seen on cytology into
Grades 0–3, where “Grade 0” means no lymphoid cells, Grade I is mild, Grade II moderate,
and Grade III (Fig.12.28) severe lymphoid cell
inltration (Table12.19).
Clinical Presentation andCourse
Clinically, the patient with HT can be euthyroid,
hyperthyroid, or hypothyroid based on the degree
of thyroid destruction. Patients with HT may
present initially with features of hyperthyroidism
(hashi-toxicosis) due to the release of preformed
thyroxine from the destroyed thyroid follicles.
Fig. 12.26 Hashimoto’s thyroiditis (HT). Note the symmetrical enlargement of the gland and the yellowish
discoloration
t.me/Dr_Mouayyad_AlbtousH
Fig. 12.27 Microscopic picture of Hashimoto’s thyroiditis (HT). The dominant feature is a profuse mononuclear
lymphocytic inltrate accompanied by actual follicles and
germinal centers
12 Benign Thyroid Disease
Fig. 12.28 Grade III Haswhimoto’s thyroiditis (HT),
marked inammation, and germinal center formation as in
a reactive node. Note polymorphic population of lymphoid cells in contrast to a lymphoma (May Grünwald
Giemsa)
Table 12.19
material
Grade Morphological features %
Grade 0 No lymphoid cells. 0
Grade I
(mild)
Grade II
(moderate)
Grade III
(severe)
Grading of thyroiditis on cytological
Few lymphoid cells
inltrating the follicles/
increased number of
lymphocytes in the
background.
Moderate lymphocytic
inltration or mild
lymphocytic inltration with
Hurthle cell change/giant
cells/anisonucleosis
Florid lymphocytic
inammation with germinal
center formation, very few
follicular cells left
38.67%
44%
17.33%
The disease then progresses to subclinical and
overt hypothyroidism and ultimately thyroid failure. Thus, HT begins as a gradual, painless,
homogeneous enlargement of the thyroid gland
and gradual development of manifestations hypothyroidism. In some cases, the thyroid gland may
become rm, large, and lobulated; rarely causing
pressure symptoms such as dysphonia, dyspnea
or dysphagia, or mild pain and tenderness [222].
Hashimoto’s disease is about seven times
more common in women than in men. It can
occur in teens and young women but more commonly shows up in middle age, particularly for
323
men. Patients with HT often have family members who have thyroid or other autoimmune dis-
eases, and sometimes have other autoimmune
diseases themselves. HT is also characterized by
the invasion of thyroid tissue by leukocytes,
mainly T- lymphocytes. A rare, but serious complication is thyroid lymphoma, generally the
B-cell type, non- Hodgkin lymphoma (NHL).
Being an autoimmune disease, the clinical
course of HT is one of the relapsing episodes,
with up to 25% of the patients showing a
spontaneous recovery. The binding of autoantibodies to the thyrocytes accounts for complement and T-lymphocyte-mediated lysis of the
thyrocytes and non-regulated release of T3 and
T4, resulting in the transient hyperthyroidism
occasionally noted. Later on, destruction of the
thyroid parenchyma may lead to permanent
hypothyroidism.
Associated “Unusual” Syndromes
In the past few years, several unusual syndromes
believed to be associated with or part of the clinical spectrum of HT have been described; occasional patients develop “amyloid deposits” in the
thyroid [231]. In 1991, Shaw etal. [232] described
ve patients with a relapsing steroid-responsive
“encephalopathy” including episodes of stroke
and seizures, high CSF protein, abnormal EEG,
and normal CT scans. In the same year, Khardon
etal. [233] reported a steroid-responsive lymphocytic “interstitial pneumonitis” in four patients. It
remains uncertain how these illnesses relate to
lymphocytic thyroiditis, which has until now been
largely identied as an organ-specic disease.
When euthyroid and hypothyroid patients
with orbitopathy are TRAb-negative, but associated with HT, “Hashimoto’s ophthalmopathy”
may be considered [234, 235]. Because patients
with HT test negative for TRAb, other autoantibodies against an eye muscle antigen, such as
calsequestrin, avoprotein, or G2s, were postulated [236].
“Musculoskeletal” symptoms, including chest
pain, brositis, and rheumatoid arthritis, occur in
nearly 25% of patients [237], and any of the musculoskeletal symptoms of hypothyroidism may
occur. It has also been suggested that thyroiditis
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324
M. Sakr
predisposes to “vascular disease” and “coronary
occlusion” [238]. However, others have failed to
nd increased Tg-Ab in patients with coronary
artery disease or increased coronary disease in
association with thyroiditis [239].
Neoplastic Transformation
The link between HT and thyroid cancer remains
controversial [240, 241]. In 2007, Larson etal.
[242] reported that patients with HT were three
times more likely to have thyroid cancer, suggesting a strong link between chronic inammation
and cancer development.
The association between HT and PTC has
been a subject of long and ongoing debate; HT
has shown a wide range of occurrence from 5 to
85% in thyroid specimens resected for PTC
[243]. In addition, the clinico-pathological characteristics of PTC with concomitant HT have not
been denitely proposed [244, 245].
PI3K/Akt expression was increased in both
HT and well-differentiated thyroid cancer
(WDTC), suggesting a possible molecular mechanism for thyroid carcinogenesis. Several authors
reported that thyroid cancer may be associated
with less aggressive disease and better outcome
in patients with coexisting HT [241, 246, 247].
Variants
Fibrotic Hashimoto’s Thyroiditis
Fibrotic HT is a brotic variant of HT that
accounts for up to 10% of cases, mainly in elderly
patients with a preexisting goiter. It is characterized by a rapid increase in goiter size, which may
lead to the suspicion of malignancy or Riedel’s
brosing thyroiditis. However, the extensive
brotic changes and metaplasia noted on biopsies
are always limited to the gland in this variant.
Atrophic Hashimoto’s (Autoimmune)
Thyroiditis (Primary or Idiopathic Myxedema)
The atrophic autoimmune thyroiditis is the cause
of primary myxedema and should not be confused
with end-stage brotic HT.Most of the patients do
not show signs or symptoms of hypothyroidism till
the fourth to sixth decade of life, and women are
ve times more affected than men [248].
Investigations
Laboratory Studies
Low levels of thyroid hormones (T4 and T3)
with high TSH and circulating thyroid autoantibodies against TPO (in 70–90% of cases)
and Tg (in 40–70% of cases) confirm the
diagnosis of HT [216]. Occasionally, the
patient presents initially with hyperthyroidism associated with the presence of anti-TSH
receptor antibodies [243]. Gamma-globulin
levels may be elevated, although usually they
are normal. This alteration evidently reflects
the presence of high concentrations of circulating antibodies to Tg, for an antibody concentration as high as 5.2 mg/mL has been
reported [249].
Histology/Cytology
HT is a “histological” diagnosis. Fine-needle
aspiration (FNA) can be a useful diagnostic procedure but is infrequently required, except in
patients who have a discrete “nodule” in the
gland. The FNAC may frequently show Hürthle
cells and it may be difcult to distinguish HT at
times from a follicular neoplasm, PTC, or lowgrade MALT lymphoma. Immunohistochemistry studies may help to reach the
diagnosis.
Histologically, the thyroid gland typically
shows diffuse lymphocytic and plasma cell
infiltration with the formation of lymphoid
follicles from follicular hyperplasia and damage to the follicular basement membrane.
Atrophy of the thyroid parenchyma is usually
evident. It also reveals scant colloid, and a
few epithelial cells, which may show Hurthle
cell change. In this context, Hurthle cells do
not represent a discrete adenoma. However, if
only abundant Hurthle cells dominate the
specimen, and there are few or no lymphocytes or macrophages, the biopsy must be
interpreted as a possible Hurthle cell tumor.
The correlation of FNA findings with the
presence of anti-TPO and anti-Tg antibodies
is helpful in confirming the diagnosis of
HT. Biopsy results are less frequently diagnostic in children [250].
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
325
Ultrasound Imaging
Ultrasound (US) may display an enlarged
gland with “normal” texture, focal, or diffuse
glandular enlargement with coarse, heterogenous, and hypo-echoic pattern, or a suggestion
of multiple ill-dened nodules (Fig. 12.29)
[251]. The presence of discrete hypo-echoic
micro-nodules (1–6mm) is strongly suggestive
of chronic thyroiditis. Fine echogenic brous
septa may produce pseudo-lobulated appearance. Color Doppler shows extensive
hypervascularity.
Ultrasonographic study aids in conrming
the presence of a thyroid nodule, in dening a
nodule as solid or cystic, and in dening features suggestive of malignancy, such as irregular margins, a poorly dened halo,
micro-calcication, and increased vascularity
on Doppler examination. Ultrasonography is
also useful in facilitating FNA of nodules in
general and, in particular, small or poorly
dened nodules when indicated and in patients
with distorted neck anatomy. A denite diagnosis of benign versus malignant thyroid lesion
can be conrmed only by cytological or histological examination of thyroid tissue.
Additional Studies
Other studies that are usually not routinely necessary for diagnosis or evaluation of hypothyroid
patients but may be performed for evaluation of
complications of primary hypothyroidism (when
indicated) include:
– Chest radiograph: It may show small pleural
effusions
– Electrocardiogram (ECG): It may show low-
voltage QRS tracing, nonspecic ST-wave
changes, and premature ventricular
contractions, prolongation of the QT interval,
and ventricular tachycardia may be noted
– Echocardiogram: It may show some pericar-
dial effusion in severe cases of hypothyroidism.
Dierential Diagnosis
Diseases that should be considered in the differential diagnosis of HT include subacute thyroiditis and reidle’s thyroiditis, Graves’ disease,
hypopituitarism, lithium- induced goiter, nontoxic goiter, thyroid neoplasm (PTC) [252–254],
and lymphoma [255–257], toxic nodular goiter,
Type-I and Type-II poly- glandular autoimmune
syndrome.
Management
No Treatment: Observation andMonitoring
Many patients with HT require no treatment, for
frequently the disease is asymptomatic and the
goiter is small. This approach is justied by the
old study of Vickery and Hamlin [258] who
found, on both clinical and pathological grounds,
that the disease may remain static and the clinical
condition unchanged over many years. Some
cases of spontaneous recovery of HT have been
reported [259].
Fig. 12.29 Ultrasound imaging of the thyroid gland
(right lobe longitudinal) in a patient with Hashimoto’s
thyroiditis (HT)
t.me/Dr_Mouayyad_AlbtousH
Medical Treatment/Balanced Diet
Treatment of HT is mainly medical; supplementing L-thyroxine (L-T4) for overt hypothyroidism,
usually for life. L-thyroxine has proved to reduce
the volume of the thyroid gland in both hypothyroidism and even euthyroid state [260]. The dos-
age of thyroxine should normally be that required
to bring the serum TSH level to the low normal
range, such as 0.3–1 μU/mL. This is typically
achieved with 1 μg L-T4/lb body weight/day,
ranging from 75 to 125 μg/day in women, and
125–200μg/day in men. The level of TSH is frequently monitored for dose adjustment till euthyroid state is attained thereafter every 6–12months.
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