Document Text Contents
Page 1
Thyroid Disorders
Syed Khalid Imam
Shamim I. Ahmad
Editors
Basic Science
and Clinical Practice
123
Page 2
Thyroid Disorders
Page 163
152
Currently 27 families with a total of 152 affected
individuals with non-autoimmune familial hyper-
thyroidism have been reported . The hyperthy-
roidism is caused by monoallelic gain-of-function
germline mutations in the TSH receptor [ 46 , 47 ].
Affected individuals have a suppressed TSH
and elevated peripheral hormones in the absence
of TSH receptor-stimulating antibodies and TPO
antibodies. The family history is key in order to
demonstrate familial clustering suggestive for an
autosomal dominant disorder. Ultimately, the
diagnosis requires sequence analysis of the TSH
receptor gene in order to evaluate it for the pres-
ence of a monalllelic mutation.
Clinical Features
Generally, a constellation of information, includ-
ing the extent and duration of symptoms, past
medical history, and social and family history, in
addition to the information derived from physical
examination, help to guide the clinician to the
appropriate diagnosis.
The family history should include careful eval-
uation of the autoimmune disease, thyroid disease
and emigration from iodine-defi cient parts of the
world. Health care provider should also review a
complete list of medications and dietary supple-
ments. A number of compounds—including
expectorants, amiodarone, iodinated contrast
agents, and health food supplements containing
seaweed or thyroid gland extracts—contain large
amounts of iodine that can induce hyperthyroid-
ism in a patient with thyroid autonomy. Rarely,
iodine exposure can cause hyperthyroidism
in a patient with an apparently healthy thyroid.
Hyperthyroidism presents with multiple
symptoms that vary according to the age of the
patient, duration of illness, magnitude of hormone
excess, and presence of comorbid conditions.
Symptoms are related to the thyroid hormone’s
stimulation of catabolic enzymopathic activity
and catabolism, and enhancement of sensitivity to
catecholamines. Older patients often present with
a paucity of classic signs and symptoms, which
can make the diagnosis more diffi cult [ 41 , 48 ].
Hyperthyroidism leads to an apparent increase
in sympathetic nervous system. Younger patients
tend to exhibit symptoms of sympathetic activa-
tion, such as anxiety, hyperactivity, and tremor,
while older patients have more cardiovascular
symptoms, including dyspnea and atrial fi brilla-
tion with unexplained weight loss [ 37 , 49 ].
The clinical manifestations of hyperthyroid-
ism do not always correlate with the extent of the
biochemical abnormality.
Common symptoms of hyperthyroidism
include the following:
• Nervousness
• Insomnia
• Anxiety
• Increased perspiration
• Heat intolerance
• Hyperactivity
• Palpitations
• Weight loss despite increased appetite.
• Hyperdefecation
• Reduction in menstrual fl ow or
oligomenorrhea
Common signs of hyperthyroidism include
the following:
• Diffuse goiter/toxic nodule/multinodular
goiter
• Exophthalmos
• Tachycardia or atrial arrhythmia
• Systolic hypertension
• Warm, moist, smooth skin
• Lid lag
• Stare
• Hand tremor
• Proximal myopathy
• Brisk deep tendon refl exes
Features pathognomonic of Graves’ disease
include the following:
• Orbitopathy
• Thyroid bruit
• Pretibial myxedema
• Acropachy
Features of Graves Ophthalmopathy
Approximately 50 % of patients with Graves thy-
S.K. Imam
Page 164
153
rotoxicosis have mild thyroid ophthalmopathy.
Often, this is manifested only by periorbital
edema, but it also can include conjunctival edema
(chemosis), injection, poor lid closure, extraocu-
lar muscle dysfunction (diplopia), and Proptosis .
Evidence of thyroid eye disease and high thyroid
hormone levels confi rms the diagnosis of autoim-
mune Grave disease.
Graves Dermopathy In rare instances, Graves
disease affects the skin through deposition of gly-
cosaminoglycans in the dermis of the lower leg.
This causes nonpitting edema, which is usually
associated with erythema and thickening of the
skin, without pain or pruritus.
Features Related to Other Causes
of Hyperthyroidism
Toxic adenomas present with signs and symp-
toms of hyperthyroidism and/or a thyroid nodule.
The signs and symptoms of thyrotoxicosis do not
differ from other etiologies. Features suggestive
for Graves’ disease such as endocrine ophthal-
mopathy, (pretibial) myxedema and acropachy
are missing. The onset of hyperthyroidism is
often insidious and more common in older
patients, who typically have larger adenomas.
Mechanical symptoms such as dysphagia or
hoarseness are uncommon. Autonomously func-
tioning nodules may remain stable in size, grow,
degenerate or become gradually toxic. In one
series, 10 % of patients followed for 6 years
became thyrotoxic [ 32 ]. Thyrotoxicosis may
develop independent of age, but is much more
common in nodules over 3 cm in diameter (up to
20 %).
Toxic Multinodular Goiter In addition to the
signs and symptoms associated with hyperthy-
roidism, patients with large toxic multinodular
goiters may also have dysphagia, shortness of
breath, stridor, or hoarseness.
Subacute thyroiditis often present with a his-
tory of a preceding respiratory tract infection
[ 50 ]. They may have fever, malaise, and soreness,
and the gland is exquisitely tender on palpation
and often displays a substantially increased
consistency.
Hydatiform Moles and Choriocarcinoma Most
women with hydatiform moles present with uter-
ine bleeding in the fi rst half of pregnancy. The
size of the uterus is large for the duration of ges-
tation [ 51 ].
Many women with molar pregnancies have
nausea and vomiting, some have pregnancy-
induced hypertension or pre-eclampsia. The
signs and symptoms of thyrotoxicosis are present
in some women, but they may be obscured
by toxemic signs. The characteristic features
belonging to Graves’ disease are missing.
Hyperthyroidism is usually not severe because of
a relatively short duration.
Women with choriocarcinomas present within
1 year after conception. The tumor may be con-
fi ned to the uterus, more frequently it is meta-
static to multiple organs such as the liver and
lungs. In men, choriocarcinomas of the testes is
often widely metastatic at initial presentation.
Gynecomastia is a common fi nding.
Struma Ovarii The clinical presentation may
include the fi nding of an abdominal mass, asci-
tes, pelvic pain, and, rarely, a pseudo-Meigs syn-
drome with pleural effusions. A subset of women
present with subclinical or overt thyrotoxicosis.
Goiter is only presented in patients with associ-
ated thyroid disease. For example, coexistence of
Graves’ disease and struma ovarii has been
reported [ 52 , 53 ].
Apathetic Hyperthyroidism
Hyperthyroidism in the elderly is a great mas-
querader, and even severe, life-threatening hyper-
thyroidism can easily be missed in patients older
than 60 years [ 54 ]. Not uncommonly, it appears in
an atypical manner, and the classic symptoms are
often absent. Graves disease and toxic multinodu-
lar goiter account for most cases in the elderly,
while as Solitary toxic adenomas are rare in elder
patients [ 55 – 58 ]. Again, like hypothyroidism, the
8 Hyperthyroidism
Page 326
319
lung maturation , 22
maturation , 21–22
myocardium , 19
neural development
brain development disruption , 52
metabolism , 51–52
on neural cell proliferation/differentiation , 52–54
non-genomic and mitochondrial effects , 54–55
synthesis and secretion , 50
transport , 51–52
uptake , 51–52
non-genomic pathways , 17
in pituitary , 21
replacement
benefi ts , 214
cardiovascular disease , 213–214
hypothyroid signs and symptoms , 213
serum lipid and apoprotein concentration , 214
serum TSH concentration , 214–215
structure of , 12
synthesis , 11–12
autonomic nervous system , 14–15
central regulation of , 13–14
deiodinases , 16
hypophysiotropic and non-hypophysiotropic
neurons , 14
hypophysiotropic TRH neurons , 15–16
iodine role in , 13
secreted TRH , 15
steps in , 12–13
transporters in secretion , 16
TRH production , 14
Wolff-Chiakoff effect , 13
Thyroiditis , 151, 187
amiodarone-associated , 96–97
classifi cation , 87–88, 108–109
Hashimoto’s (see Hashimoto’s thyroiditis (HT) )
interferon-induced , 98
interleukin-2 , 98–99
lithium , 97–98
lymphocytic and postpartum , 151
painless , 92–94
palpation , 107
postpartum , 94–96
radiation-induced , 106–107
Riedel’s , 99–101
subacute , 101–104, 151
suppurative , 104–106
with thyroid pain and tenderness , 101–107
trauma-induced , 107
without thyroid pain and tenderness , 88–101
Thyroid nodule
biochemical tests , 244–245
clinical problem , 240
computed tomography , 245, 246
diagnostic algorithm , 242
epidemiology , 240
18FDG-PET imaging , 242, 246
fi ne needle aspiration , 246–248
history , 240–241
investigations , 241–244
levothyroxine , 249–250
magnetic resonance imaging , 245, 246
percutaneous ethanol injection , 249
physical examination , 241
radio-iodine , 249
radionuclide scanning , 245–246
surgery , 248–249
treatment , 248
ultrasonography , 245–246
Thyroid peroxidase antibodies (TPOAb) , 35, 89
subclinical hypothyroidism , 216–217
Thyroid-stimulating hormone (TSH) , 7, 12, 44
Thyroid-stimulating hormone receptor
(TSHR) , 12, 67–68, 151–152
Thyroid-stimulating hormone receptor antibodies
(TRAb) , 304
Thyroid-Stimulating Immunoglobulin (TSI) level , 155
Thyroid storm
diagnosis , 226
do and don’ts/things not to be missed , 227
follow up of patients , 227
pathophysiology , 225
scoring system , 226
signs/symptoms , 225–226
treatment , 226–227
Thyroid volume , 43–44
Thyrotoxicosis , 6, 147
apathetic , 267
signs and symptoms of , 153
treatment of , 148
Thyrotoxic storm , 162–163
Thyrotrophin-releasing hormone (TRH) , 50
hypophysiotropic neurons , 15–16
production , 14
secretion , 12, 15, 126
stimulation , 12
Thyroxine (T4) , 12–13, 274
administration , 187
candidates replacement , 215–216
hypothyroidism treatment , 195
overdose , 233–234
replacement, pregnancy , 293
tionamide therapy , 171
Thyroxine-binding globulin (TBG) , 154, 290, 299
defi ciency , 131
non-pregnancy due to , 299
Topolanski’s sign , 73
Torsade de pointes (TdP) , 282
Total thyroidectomy (TT) , 161, 174
Toxic adenoma (TA)
clinical features , 153
etiology , 150–151
fi ne needle aspiration , 156
radioisotope fi ndings , 156
Toxic multinodular goiter (TMNG)
clinical features , 153
etiology , 150
radioactive iodine therapy , 156, 160
Transient hypothyroidism , 121
Index
Page 327
320
Transplacental transfer , 51
Trauma-induced thyroiditis , 107
Triiodothyronine (T3) , 12–13, 274
on atria , 275
on ventricles , 275–276
TSH . See Thyroid-stimulating hormone (TSH)
TSH-secreting adenomas (TSHomas) , 151
TT . See Total thyroidectomy (TT)
Tumor Necrosis Factor (TNF) , 178
Tumors induced hyperthyroidism , 151
Type II autoimmune polyendocrine syndrome , 149
Tyrosine kinase inhibitor (TKI) , 99
U
Ultrasound (US)
amiodarone-associated thyroiditis , 96
DTC , 256
Graves’ disease , 78, 156
Graves’ opthalmopathy , 179–180
Hashimoto’s thyroiditis , 89
hyperthyroidism , 155–156
painless thyroiditis , 93
postpartum thyroiditis , 95
Riedel’s thyroiditis , 100
subacute thyroiditis , 102
suppurative thyroiditis , 106
thyroid nodule , 245–246
Uncoupling protein (UCP) synthesis , 20
United States Preventive Services task Force (USPSTF) ,
7
U.S. Preventive Services Task Force , 195
V
Ventricular arrhythmia , 282
Ventricular fi brillation (VF)
pathogenesis , 277–278
triiodothyronine on , 275–276
Von Graefe’s sign , 73
W
Wechsler Intelligence Scale for Children-Revised
(WISC-R) , 268
White adipose tissue (WAT) , 19–20
Wide Range Achievement Test-Revised
(WRAT-R) , 268
Wilder’s sign , 73
Wolff-Chaikoff effect , 13, 40, 41, 120, 232
Index
Thyroid Disorders
Syed Khalid Imam
Shamim I. Ahmad
Editors
Basic Science
and Clinical Practice
123
Page 2
Thyroid Disorders
Page 163
152
Currently 27 families with a total of 152 affected
individuals with non-autoimmune familial hyper-
thyroidism have been reported . The hyperthy-
roidism is caused by monoallelic gain-of-function
germline mutations in the TSH receptor [ 46 , 47 ].
Affected individuals have a suppressed TSH
and elevated peripheral hormones in the absence
of TSH receptor-stimulating antibodies and TPO
antibodies. The family history is key in order to
demonstrate familial clustering suggestive for an
autosomal dominant disorder. Ultimately, the
diagnosis requires sequence analysis of the TSH
receptor gene in order to evaluate it for the pres-
ence of a monalllelic mutation.
Clinical Features
Generally, a constellation of information, includ-
ing the extent and duration of symptoms, past
medical history, and social and family history, in
addition to the information derived from physical
examination, help to guide the clinician to the
appropriate diagnosis.
The family history should include careful eval-
uation of the autoimmune disease, thyroid disease
and emigration from iodine-defi cient parts of the
world. Health care provider should also review a
complete list of medications and dietary supple-
ments. A number of compounds—including
expectorants, amiodarone, iodinated contrast
agents, and health food supplements containing
seaweed or thyroid gland extracts—contain large
amounts of iodine that can induce hyperthyroid-
ism in a patient with thyroid autonomy. Rarely,
iodine exposure can cause hyperthyroidism
in a patient with an apparently healthy thyroid.
Hyperthyroidism presents with multiple
symptoms that vary according to the age of the
patient, duration of illness, magnitude of hormone
excess, and presence of comorbid conditions.
Symptoms are related to the thyroid hormone’s
stimulation of catabolic enzymopathic activity
and catabolism, and enhancement of sensitivity to
catecholamines. Older patients often present with
a paucity of classic signs and symptoms, which
can make the diagnosis more diffi cult [ 41 , 48 ].
Hyperthyroidism leads to an apparent increase
in sympathetic nervous system. Younger patients
tend to exhibit symptoms of sympathetic activa-
tion, such as anxiety, hyperactivity, and tremor,
while older patients have more cardiovascular
symptoms, including dyspnea and atrial fi brilla-
tion with unexplained weight loss [ 37 , 49 ].
The clinical manifestations of hyperthyroid-
ism do not always correlate with the extent of the
biochemical abnormality.
Common symptoms of hyperthyroidism
include the following:
• Nervousness
• Insomnia
• Anxiety
• Increased perspiration
• Heat intolerance
• Hyperactivity
• Palpitations
• Weight loss despite increased appetite.
• Hyperdefecation
• Reduction in menstrual fl ow or
oligomenorrhea
Common signs of hyperthyroidism include
the following:
• Diffuse goiter/toxic nodule/multinodular
goiter
• Exophthalmos
• Tachycardia or atrial arrhythmia
• Systolic hypertension
• Warm, moist, smooth skin
• Lid lag
• Stare
• Hand tremor
• Proximal myopathy
• Brisk deep tendon refl exes
Features pathognomonic of Graves’ disease
include the following:
• Orbitopathy
• Thyroid bruit
• Pretibial myxedema
• Acropachy
Features of Graves Ophthalmopathy
Approximately 50 % of patients with Graves thy-
S.K. Imam
Page 164
153
rotoxicosis have mild thyroid ophthalmopathy.
Often, this is manifested only by periorbital
edema, but it also can include conjunctival edema
(chemosis), injection, poor lid closure, extraocu-
lar muscle dysfunction (diplopia), and Proptosis .
Evidence of thyroid eye disease and high thyroid
hormone levels confi rms the diagnosis of autoim-
mune Grave disease.
Graves Dermopathy In rare instances, Graves
disease affects the skin through deposition of gly-
cosaminoglycans in the dermis of the lower leg.
This causes nonpitting edema, which is usually
associated with erythema and thickening of the
skin, without pain or pruritus.
Features Related to Other Causes
of Hyperthyroidism
Toxic adenomas present with signs and symp-
toms of hyperthyroidism and/or a thyroid nodule.
The signs and symptoms of thyrotoxicosis do not
differ from other etiologies. Features suggestive
for Graves’ disease such as endocrine ophthal-
mopathy, (pretibial) myxedema and acropachy
are missing. The onset of hyperthyroidism is
often insidious and more common in older
patients, who typically have larger adenomas.
Mechanical symptoms such as dysphagia or
hoarseness are uncommon. Autonomously func-
tioning nodules may remain stable in size, grow,
degenerate or become gradually toxic. In one
series, 10 % of patients followed for 6 years
became thyrotoxic [ 32 ]. Thyrotoxicosis may
develop independent of age, but is much more
common in nodules over 3 cm in diameter (up to
20 %).
Toxic Multinodular Goiter In addition to the
signs and symptoms associated with hyperthy-
roidism, patients with large toxic multinodular
goiters may also have dysphagia, shortness of
breath, stridor, or hoarseness.
Subacute thyroiditis often present with a his-
tory of a preceding respiratory tract infection
[ 50 ]. They may have fever, malaise, and soreness,
and the gland is exquisitely tender on palpation
and often displays a substantially increased
consistency.
Hydatiform Moles and Choriocarcinoma Most
women with hydatiform moles present with uter-
ine bleeding in the fi rst half of pregnancy. The
size of the uterus is large for the duration of ges-
tation [ 51 ].
Many women with molar pregnancies have
nausea and vomiting, some have pregnancy-
induced hypertension or pre-eclampsia. The
signs and symptoms of thyrotoxicosis are present
in some women, but they may be obscured
by toxemic signs. The characteristic features
belonging to Graves’ disease are missing.
Hyperthyroidism is usually not severe because of
a relatively short duration.
Women with choriocarcinomas present within
1 year after conception. The tumor may be con-
fi ned to the uterus, more frequently it is meta-
static to multiple organs such as the liver and
lungs. In men, choriocarcinomas of the testes is
often widely metastatic at initial presentation.
Gynecomastia is a common fi nding.
Struma Ovarii The clinical presentation may
include the fi nding of an abdominal mass, asci-
tes, pelvic pain, and, rarely, a pseudo-Meigs syn-
drome with pleural effusions. A subset of women
present with subclinical or overt thyrotoxicosis.
Goiter is only presented in patients with associ-
ated thyroid disease. For example, coexistence of
Graves’ disease and struma ovarii has been
reported [ 52 , 53 ].
Apathetic Hyperthyroidism
Hyperthyroidism in the elderly is a great mas-
querader, and even severe, life-threatening hyper-
thyroidism can easily be missed in patients older
than 60 years [ 54 ]. Not uncommonly, it appears in
an atypical manner, and the classic symptoms are
often absent. Graves disease and toxic multinodu-
lar goiter account for most cases in the elderly,
while as Solitary toxic adenomas are rare in elder
patients [ 55 – 58 ]. Again, like hypothyroidism, the
8 Hyperthyroidism
Page 326
319
lung maturation , 22
maturation , 21–22
myocardium , 19
neural development
brain development disruption , 52
metabolism , 51–52
on neural cell proliferation/differentiation , 52–54
non-genomic and mitochondrial effects , 54–55
synthesis and secretion , 50
transport , 51–52
uptake , 51–52
non-genomic pathways , 17
in pituitary , 21
replacement
benefi ts , 214
cardiovascular disease , 213–214
hypothyroid signs and symptoms , 213
serum lipid and apoprotein concentration , 214
serum TSH concentration , 214–215
structure of , 12
synthesis , 11–12
autonomic nervous system , 14–15
central regulation of , 13–14
deiodinases , 16
hypophysiotropic and non-hypophysiotropic
neurons , 14
hypophysiotropic TRH neurons , 15–16
iodine role in , 13
secreted TRH , 15
steps in , 12–13
transporters in secretion , 16
TRH production , 14
Wolff-Chiakoff effect , 13
Thyroiditis , 151, 187
amiodarone-associated , 96–97
classifi cation , 87–88, 108–109
Hashimoto’s (see Hashimoto’s thyroiditis (HT) )
interferon-induced , 98
interleukin-2 , 98–99
lithium , 97–98
lymphocytic and postpartum , 151
painless , 92–94
palpation , 107
postpartum , 94–96
radiation-induced , 106–107
Riedel’s , 99–101
subacute , 101–104, 151
suppurative , 104–106
with thyroid pain and tenderness , 101–107
trauma-induced , 107
without thyroid pain and tenderness , 88–101
Thyroid nodule
biochemical tests , 244–245
clinical problem , 240
computed tomography , 245, 246
diagnostic algorithm , 242
epidemiology , 240
18FDG-PET imaging , 242, 246
fi ne needle aspiration , 246–248
history , 240–241
investigations , 241–244
levothyroxine , 249–250
magnetic resonance imaging , 245, 246
percutaneous ethanol injection , 249
physical examination , 241
radio-iodine , 249
radionuclide scanning , 245–246
surgery , 248–249
treatment , 248
ultrasonography , 245–246
Thyroid peroxidase antibodies (TPOAb) , 35, 89
subclinical hypothyroidism , 216–217
Thyroid-stimulating hormone (TSH) , 7, 12, 44
Thyroid-stimulating hormone receptor
(TSHR) , 12, 67–68, 151–152
Thyroid-stimulating hormone receptor antibodies
(TRAb) , 304
Thyroid-Stimulating Immunoglobulin (TSI) level , 155
Thyroid storm
diagnosis , 226
do and don’ts/things not to be missed , 227
follow up of patients , 227
pathophysiology , 225
scoring system , 226
signs/symptoms , 225–226
treatment , 226–227
Thyroid volume , 43–44
Thyrotoxicosis , 6, 147
apathetic , 267
signs and symptoms of , 153
treatment of , 148
Thyrotoxic storm , 162–163
Thyrotrophin-releasing hormone (TRH) , 50
hypophysiotropic neurons , 15–16
production , 14
secretion , 12, 15, 126
stimulation , 12
Thyroxine (T4) , 12–13, 274
administration , 187
candidates replacement , 215–216
hypothyroidism treatment , 195
overdose , 233–234
replacement, pregnancy , 293
tionamide therapy , 171
Thyroxine-binding globulin (TBG) , 154, 290, 299
defi ciency , 131
non-pregnancy due to , 299
Topolanski’s sign , 73
Torsade de pointes (TdP) , 282
Total thyroidectomy (TT) , 161, 174
Toxic adenoma (TA)
clinical features , 153
etiology , 150–151
fi ne needle aspiration , 156
radioisotope fi ndings , 156
Toxic multinodular goiter (TMNG)
clinical features , 153
etiology , 150
radioactive iodine therapy , 156, 160
Transient hypothyroidism , 121
Index
Page 327
320
Transplacental transfer , 51
Trauma-induced thyroiditis , 107
Triiodothyronine (T3) , 12–13, 274
on atria , 275
on ventricles , 275–276
TSH . See Thyroid-stimulating hormone (TSH)
TSH-secreting adenomas (TSHomas) , 151
TT . See Total thyroidectomy (TT)
Tumor Necrosis Factor (TNF) , 178
Tumors induced hyperthyroidism , 151
Type II autoimmune polyendocrine syndrome , 149
Tyrosine kinase inhibitor (TKI) , 99
U
Ultrasound (US)
amiodarone-associated thyroiditis , 96
DTC , 256
Graves’ disease , 78, 156
Graves’ opthalmopathy , 179–180
Hashimoto’s thyroiditis , 89
hyperthyroidism , 155–156
painless thyroiditis , 93
postpartum thyroiditis , 95
Riedel’s thyroiditis , 100
subacute thyroiditis , 102
suppurative thyroiditis , 106
thyroid nodule , 245–246
Uncoupling protein (UCP) synthesis , 20
United States Preventive Services task Force (USPSTF) ,
7
U.S. Preventive Services Task Force , 195
V
Ventricular arrhythmia , 282
Ventricular fi brillation (VF)
pathogenesis , 277–278
triiodothyronine on , 275–276
Von Graefe’s sign , 73
W
Wechsler Intelligence Scale for Children-Revised
(WISC-R) , 268
White adipose tissue (WAT) , 19–20
Wide Range Achievement Test-Revised
(WRAT-R) , 268
Wilder’s sign , 73
Wolff-Chaikoff effect , 13, 40, 41, 120, 232
Index
