Professional Documents
Culture Documents
Shamim I. Ahmad
Editors
Thyroid Disorders
Basic Science
and Clinical Practice
123
Thyroid Disorders
Syed Khalid Imam • Shamim I. Ahmad
Editors
Thyroid Disorders
Basic Science and Clinical Practice
Editors
Syed Khalid Imam Shamim I. Ahmad
Internal Medicine School of Science and Technology
Al-Mouwasat Hospital Nottingham Trent University
Jubail Nottingham
Saudi Arabia UK
The editor (SIA) wishes to dedicate this book to his wife, Riasat
Jan, for her patience, love, and persistent encouragement during
the production of this book and to his children, Alisha Ahmad
and Arsalan Mujtaba Ahmad, who have been giving him so much
pleasure with their innocent interceptions and resulting recovery
from the loss of energy. Also dedication goes to the caregivers,
nurses, and medics who painstakingly look after the patients
throughout their suffering period.
Preface
vii
viii Preface
The editors cordially acknowledge various authors of this book for their con-
tribution of the chapters with in-depth knowledge and highly skilled presen-
tation. Without their input, it would not have been possible to produce this
book on such an important subject and complicated disease. We would also
like to acknowledge the hard work, friendly approach, and patience of the
staff, especially of Ms Julia Megginson, of Springer Publications for efficient
and highly professional handling of this project.
ix
Editors
Shamim I Ahmad after obtaining his master’s degree in Botany from Patna
University, Bihar, India, and his Ph.D. in Molecular Genetics from Leicester
University, England, joined Nottingham Polytechnic as grade 1 lecturer and
subsequently promoted to Senior Lecturer. Nottingham Polytechnic subse-
quently became Nottingham Trent University where after serving for about
35 years, he took early retirement yet still serving as a part-time Senior
Lecturer. He is now spending much of his time producing/writing medical
books. For more than three decades, he researched on different areas of
molecular biology/genetics including thymineless death in bacteria, genetic
control of nucleotide catabolism, development of anti-AIDS drug, control of
microbial infection of burns, phages of thermophilic bacteria, and microbial
flora of Chernobyl after the accident at nuclear power station. But his main
interest, which started about 30 years ago, is DNA damage and repair specifi-
cally by near ultraviolet light specially through the photolysis of biological
compounds, production of reactive oxygen species, and their implications on
xi
xii Editors
6 Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Henrique Vara Luiz, Isabel Manita, and Jorge Portugal
7 Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Henrique Vara Luiz, Isabel Manita, and Jorge Portugal
8 Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Syed Khalid Imam
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von
Basedow Disease): An Overview of Treatment . . . . . . . . . . . . . 169
Hernando Vargas-Uricoechea, Anilza Bonelo-Perdomo,
Carlos Hernán Sierra-Torres, and Ivonne Meza-Cabrera
10 Subclinical Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Asim Hassan
xiii
xiv Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Contributors
Editors
Authors
xv
xvi Contributors
Abstract
Thyroid gland is one of the largest endocrine organs and releases triiodo-
thyronine and thyroxine. These hormones play a key role in fuel metabo-
lism and energy homeostasis and essential for normal growth and
development. Iodine is required for thyroid hormone synthesis and its
imbalance affect thyroid hormone function. Thyroid dysfunction is quite
common in the general population and contributes to significant health
issues. Therefore, it is prudent to early diagnose and treat so as to prevent
complications arising from its imbalance.
to initiate desired treatment. This chapter will Lalouette’s pyramid. It is of conical shape and
provide a concise overview of structure of thy- extends from the upper part of the isthmus, up
roid gland, disease burden in community, health across the thyroid cartilage to the hyoid bone.
issues related to its dysfunction and screening The pyramidal lobe is a remnant of the fetal thy-
strategy and recommendations. roid stalk, or thyroglossal duct [4]. The thyroid
is supplied with arterial blood from the superior
thyroid artery, a branch of the external carotid
Thyroid Gland: Basic Structure artery, and the inferior thyroid artery, a branch
of the thyrocervical trunk, and sometimes by the
The thyroid gland is a highly vascular butterfly- thyroid ima artery, branching directly from the
shaped brownish red organ and is composed of subclavian artery. The venous blood is drained
two cone-like right and left lobes connected via via superior thyroid veins, draining in the inter-
the isthmus. Each lobe is about 5 cm long, 3 cm nal jugular vein, and via inferior thyroid veins,
wide and 2 cm thick. The organ is situated on the draining via the plexus thyroideus impar in the
anterior side of the neck, lying against and around left brachiocephalic vein. Lymphatic drainage
the larynx and trachea, reaching posteriorly the passes frequently the lateral deep cervical lymph
esophagus and carotid sheath (See Fig. 1.1). It nodes and the pre- and paratracheal lymph
starts cranially at the oblique line on the thyroid nodes. The gland is supplied by parasympa-
cartilage (just below the laryngeal prominence, or thetic nerve input from the superior laryngeal
‘Adam’s Apple’), and extends inferiorly to approx- nerve and the recurrent laryngeal nerve [5].
imately the fifth or sixth tracheal ring [2, 3]. Gross examination of thyroid gland will reveal
The thyroid is one of the largest endocrine four light-colored small nodules placed on its
glands, weighing 2–3 g in neonates and 18–60 g surface. These are known as parathyroid glands.
in adults, and size is increased in pregnancy. The structure of a parathyroid gland is distinctly
Occasionally, in 28–55 % of population a third different from a thyroid gland. The cells that syn-
pyramidal lobe may be present, also known as thesize and secrete parathyroid hormone are
arranged in rather dense cords or nests around
abundant capillaries.
The microscopic structure of the thyroid is
quite distinctive. Thyroid epithelial cells are
Larynx
arranged in spheres called thyroid follicles.
Follicles are filled with colloid, a proteinaceous
depot of thyroid hormone precursor. In addition
to thyroid epithelial cells, the thyroid gland
Trachea
houses one other important endocrine cell, nes-
tled in spaces between thyroid follicles, called as
Right lobe of Left lobe of parafollicular or C cells which secrete the hor-
thyroid thyroid mone calcitonin.
Isthmus
subcontinent, it is reported to be the most com- 12]. In a population that has been screened previ-
mon among all endocrine diseases [6]. It is ously, the incidence of new cases of thyroid dys-
quite evident from western literature that function is the most important factor in
approximately 50 % of people in the commu- determining the yield of a second round of
nity have microscopic nodules, 15 % develops screening. In a 20-year follow-up of the
palpable goiters, 10 % shows an abnormal thy- Whickham population, the annual incidence of
roid-stimulating hormone level, and 5 % of overt thyroid dysfunction was 4.9 per 1000 in
women have overt hypothyroidism or hyperthy- women (4.1 hypothyroid and 0.8 hyperthyroid)
roidism and 3.5 % demonstrate occult papillary and 0.6 per 1000 in men (all hypothyroid) [14].
carcinoma [7]. In most other studies, the incidence of hyperthy-
As we know that iodine plays an important roidism is 0.3–0.4 per 1000 in women and 0.01–
role in thyroid hormone regulation and nearly 0.1 per 1000 in men [7]. Within a given geographic
one-third of the world’s population lives in region, older age, an elevated TSH level, antithy-
areas of iodine deficiency [8]. In areas where roid antibodies, and female sex are the strongest
the daily iodine intake is 50 mg, goiter is usu- risk factors for developing overt hypothyroidism.
ally endemic, and when the daily intake falls In the Whickham survey, for a 50-year-old
25 mg, congenital hypothyroidism is seen. The woman who has a serum TSH level of 6 mU/L
prevalence of goiter in areas of severe iodine and positive antithyroid antibodies, the risk for
deficiency can be as high as 80 %. Populations developing overt hypothyroidism over 20 years is
at particular risk tend to be remote and live in 57 %; for a serum TSH of 9 mU/L, the risk is
mountainous areas in South-East Asia, Latin 71 % [14].
America and Central Africa [9]. Iodization It is presumed that a 50-year-old woman who
programmes are of proven value in reducing has a normal TSH and negative antibody test car-
goiter size and in preventing goiter develop- ries a risk for only 4 % over 20 years. The risk for
ment and cretinism in children, but it should be progression is not evenly distributed throughout
remembered that iodization programmes can the follow-up period. Nearly all women who
also induce thyrotoxicosis, especially in those developed hypothyroidism within 5 years had an
aged more than 40 years with nodular goiters initial serum TSH greater than 10 mU/L.
[10]. In iodine-sufficient areas, most persons
with thyroid disorders have autoimmune dis-
ease, ranging from primary atrophic hypothy- Classification of Thyroid
roidism, Hashimoto’s thyroiditis to Dysfunction
hyperthyroidism caused by Graves’ disease
[10]. Data from screening large US population Thyroid dysfunction is a graded phenomenon,
Samples have revealed differences in the fre- and progresses from early to more advanced
quency of thyroid dysfunction and serum thy- forms. As better biochemical tests have come
roid antibody concentrations in different ethnic into use, classification of the grades of thyroid
groups [11, 12]. Whereas studies from Europe dysfunction has changed dramatically.
have revealed the influence of dietary iodine Historically, clinical, biochemical, and immuno-
intake on the epidemiology of thyroid dysfunc- logic criteria have been used to classify patients
tion [13]. See chapter ‘Iodine and thyroid’ for with milder degrees of thyroid dysfunction [15,
further detail. 16]. Today, the most common approach is to clas-
Hyperthyroidism and hypothyroidism are sify patients according to the results of thyroid
common conditions that have lifelong effects on function tests. In this classification, “overt hypo-
health. About 5 % of U.S. adults report having thyroidism” refers to patients who have an ele-
thyroid disease or taking thyroid medication [11, vated TSH and a low thyroxine (T4) level. “Overt
6 S.K. Imam
hyperthyroidism” refers to patients who have a [30–33]. TSH is positively associated with fast-
low TSH and an elevated T4 or triiodothyronine ing and postprandial insulin concentration and
(T3). negatively with insulin sensitivity Moreover, low
The terms “subclinical hypothyroidism” and normal FT4 levels are significantly associated
“mild thyroid failure” refer to patients who have with increased insulin resistance. Oxidative stress
an elevated TSH and a normal thyroxine level. is also affected by thyroid function with studies
The term “subclinical hyperthyroidism” is used however showing controversial outcomes [34].
to describe conditions characterized by a low Furthermore, endothelial and cardiac function as
TSH and normal levels of circulating thyroid hor- well as atherosclerosis have been positively asso-
mones (thyroxine and triiodothyronine). ciated with thyroid hormone dysfunction [35]. A
Subclinical hyperthyroidism has the same causes positive association between TSH and body mass
as overt hyperthyroidism [17]. index (BMI) or waist circumference has also
been described [36, 37].
Thyroid hormone excess causes left ventricu-
Thyroid Dysfunction and Health lar thickening, which is associated with an
Issues increased risk of heart failure and cardiac-related
death. Thyrotoxicosis has been associated with
Advocates of screening for subclinical hyperthy- dilated cardiomyopathy, right heart failure with
roidism argue that early treatment might prevent pulmonary hypertension, and diastolic dysfunc-
the later development of atrial fibrillation, osteo- tion and atrial fibrillation [38]. See chapter
porotic fractures, and complicated overt hyper- ‘arrhythmia and thyroid dysfunction’ for further
thyroidism. Other potential benefits of screening details. An increase in the rate of bone resorption
are earlier treatment of neuropsychiatric symp- occurs. Bone loss, measured by bone mineral
toms and prevention of the long-term conse- densitometry, can be seen in severe hyperthyroid-
quences of exposure of the heart muscle to ism at all ages and in both sexes. In mild subclini-
excessive stimulation from thyroid hormones cal disease, however, bone loss has been
[18–21]. convincingly shown only in postmenopausal
Thyroid function regulates a wide array of women.
metabolic parameters. Thyroid function signifi-
cantly affects lipoprotein metabolism as well as
some cardiovascular disease (CVD) risk factors, Screening for Thyroid Disorders
thus influencing overall CDV risk [11, 22, 23].
The best-studied potential complications of Screening is defined as the application of a test to
hypothyroidism are hyperlipidemia, atheroscle- detect a potential disease or condition in a person
rosis, symptoms, and (for subclinical disease) who has no known signs or symptoms of that
progression to overt hypothyroidism [24–26]. In condition [39]. By this definition, screening with
pregnancy, subclinical hypothyroidism confers thyroid function tests may identify asymptomatic
additional risks to both mother and infant. individuals as well as patients who have mild and
Beyond their effect on lipid profile thyroid hor- nonspecific symptoms such as cold intolerance or
mones can equally affect a number of other meta- feeling a little tired.
bolic parameters related to CVD risk. Indeed,
thyroid function can influence adipocyte metabo-
lism and the production of adipokines [27–29]. Accuracy of Screening Tests
Hyperthyroidism has been associated with
increased levels of adiponectin, whereas hypo- Screening for thyroid dysfunction can be done
thyroidism is not associated with significant using a history and physical examination, antithy-
changes in adiponectin [27, 29]. Insulin resis- roid antibodies, or thyroid function tests, including
tance is also correlated with thyroid function various assays for TSH and T4. Today, the TSH
1 Thyroid: A General Overview 7
test is usually proposed as the initial test in screen- poor evidence that treatment improves clini-
ing because of its ability to detect abnormalities cally important outcomes in adults with screen-
before serum thyroxine and triiodothyronine lev- detected thyroid disease. Although the yield of
els are abnormal. When used to confirm suspected screening is greater in certain high-risk groups
thyroid disease in patients referred to an endocrine (e.g., postpartum women, persons with Down
specialty clinic, the sensitive TSH has a sensitivity syndrome, and the elderly), the USPSTF found
above 98 % and a specificity greater than 92 % for poor evidence that screening in these groups
the clinical and functional diagnosis [40]. leads to clinically important benefits. There is
In screening programs and in the primary care the potential for harm caused by false-positive
clinic, many patients found to have an abnormal screening tests; however, the magnitude of
TSH revert to normal over time. In one random- harm is not known. There is good evidence that
ized trial, for example, mildly elevated TSH lev- overtreatment with levothyroxine occurs in a
els reverted to normal in 8 of 19 patients given substantial proportion of patients, but the long-
placebo [41]. term harmful effects of overtreatment are not
In older subjects, only 59 % (range, 14–87 %) known. As a result, the USPSTF could not
of patients with an undetectable TSH on initial determine the balance of benefits and harms of
screening had an undetectable TSH level when screening asymptomatic adults for thyroid
the TSH was repeated [42, 43]. disease.
In the Framingham cohort, screening identi-
fied 41 people with an undetectable serum TSH
(≤0.1 mU/L) and a normal serum T4 level Recommendations of Other
(<129 nmol/L) [44]. After 4 years of follow-up, Authorities
when 33 of these people were retested, 29 had
higher serum TSH levels (>0.1 mU/L). The American Thyroid Association recommends
Nonthyroidal illness is an important cause of false measuring thyroid function in all adults begin-
positive TSH test results. In a recent systematic ning at age 35 years and every 5 years thereafter,
review of screening patients admitted to acute noting that more frequent screening may be
care and geriatric hospitals, the positive predictive appropriate in high-risk or symptomatic individ-
value of a low serum TSH (<0.1 mU/L) was 0.24, uals [46].
meaning that approximately 1 in 4 patients proved The Canadian Task Force on the Periodic
to have hyperthyroidism. For hypothyroidism, the Health Examination recommends maintaining a
predictive value of a serum TSH between 6.7 and high index of clinical suspicion for nonspecific
20 mU/L was 0.06. In 1996, the United States symptoms consistent with hypothyroidism when
Preventive Services task Force (USPSTF) recom- examining perimenopausal and postmenopausal
mended against routine screening for thyroid dis- women [47].
ease in asymptomatic adults but recommended The American College of Physicians recom-
screening based on the higher prevalence of dis- mends screening women older than 50 with one
ease and the increased likelihood that symptoms or more general symptoms that could be caused
of thyroid disease will be overlooked [45]. by thyroid disease [48].
The American Association of Clinical
Endocrinologists recommends TSH measurement
The USPSTF: Summary in women of childbearing age before pregnancy
of Recommendation or during the first trimester [49].
The American College of Obstetricians and
The USPSTF found fair evidence that the Gynecologists recommends that physicians be
thyroid-stimulating hormone (TSH) test can aware of the symptoms and risk factors for post-
detect subclinical thyroid disease in persons partum thyroid dysfunction and evaluate patients
without symptoms of thyroid dysfunction, but when indicated [50].
8 S.K. Imam
The American Academy of Family Physicians and ectopic thyroid as assessed by computed tomog-
raphy: a multicenter study. Thyroid. 2013;23(1):
recommends against routine thyroid screening in
84–91.
asymptomatic patients younger than age 60 [51]. 5. Dorland. Dorland’s. Illustrated medical dictionary.
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Conclusion p. 999.
6. Kochupillai N. Clinical endocrinology in India. Curr
Thyroid gland is a highly vascular organ and
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performs various important metabolic func- 7. Wang C, Crapo LM. The epidemiology of thyroid dis-
tions and is necessary for normal growth and ease and implications for screening. Endocrinol
development, all these effects mediated by Metab Clin North Am. 1997;26(1):189–218.
8. Zimmerman MB. Iodine deficiency. Endocr Rev.
thyroid hormones. Thyroid gland dysfunction
2009;30:376–408.
is quite common in the community and con- 9. Vanderpump MP. The epidemiology of thyroid dis-
tributing a significant disease burden globally. ease. Br Med Bull. 2011;99:39–51.
Iodine plays an important role in thyroid hor- 10. Vanderpump MP. The epidemiology of thyroid dis-
eases. In: Braverman LE, Utiger RD, editors. Werner
mone synthesis and its nutrition should be
and Ingbar’s the thyroid: a fundamental and clinical
ensured to all individual at risk of deficiency. text. 9th ed. Philadelphia: JB Lippincott-Raven; 2005.
Although, Iodization programmes are of p. 398–496.
proven value in reducing goiter size and in 11. Canaris GJ, Manowitz NR, Mayor G, et al. The
Colorado thyroid disease prevalence study. Arch
preventing goiter development and cretinism
Intern Med. 2000;160:526–34.
in children, but it should be remembered that 12. Hollowell JG, Staehling NW, Flanders WD, et al.
iodization programmes can also induce hyper- Serum TSH, T4, and thyroid antibodies in the United
thyroidism, especially in those aged more than States population (1988 to 1994): National Health and
Nutrition Examination Survey (NHANES III). J Clin
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ing for thyroid dysfunction is generally not Environmental iodine intake affects the type of non-
recommended by many authorities, however, malignant thyroid disease. Thyroid. 2001;11:457–69.
14. Vanderpump MP, Tunbridge WMG, French JM, et al.
it should be considered for those at high risk
The incidence of thyroid disorders in the community:
of developing thyroid dysfunction. TSH is the a twenty-year follow-up of the Whickham survey.
best screening test to order with a sensitivity Clin Endocrinol (Oxf). 1995;43:55–68.
of over 98 % and has the ability to detect thy- 15. Helfand M, editor. Screening for thyroid dysfunction:
Rationale, strategies, and cost-effectiveness. St.
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Louis: Mosby-Year Book, Inc.; 1992.
Thyroid dysfunction carries significant degree 16. O’Reilly DS. Thyroid function tests-time for a reas-
of morbidity and mortality and early diagnosis sessment. BMJ. 2000;320:1332–4.
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18. Sawin C, Geller A, Wolf P. Low serum thyrotropin
concentrations as a risk factor for atrial fibrillation in
older persons. N Engl J Med. 1994;331:1249–52.
19. Parle JV, Maisonneuve P, Sheppard MC, Boyle P,
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Functions of Thyroid Hormones
2
Nishanth Dev, Jhuma Sankar, and M.V. Vinay
Abstract
Thyroid hormones (THs) play critical roles in growth, differentiation and
metabolism. They are important for optimal functioning of almost all tis-
sues with major effects on metabolic rate and oxygen consumption. The
thyroid gland secretes two biologically active thyroid hormones: thyroxine
(T4) and 3,5,3′-triiodothyronine (T3). TH synthesis and secretion is exqui-
sitely regulated by a negative-feedback system that involves the hypothal-
amus, pituitary, and thyroid gland (the HPT axis). Some of the important
functions of the thyroid hormones include- neural growth and differentia-
tion, myocardial contractility, regulation of bone formation and resorp-
tion, development and function of brown and white adipose tissue,
cholesterol metabolism and synthesis, and in-utero they are important for
fetal growth and differentiation. Thus, given their pleotropic effects, thy-
roid hormones are critical for survival and optimal functioning of the
human body.
N. Dev, MD (*)
Department of Medicine, ESIC Medical College Thyroid Hormone Synthesis
and Hospital, Faridabad, India
e-mail: devnishant@gmail.com
Thyroid gland is a chief endocrine gland in the
J. Sankar, MD • M.V. Vinay, MD
Department of Pediatrics, All India Institute of body situated in the anterior triangle of neck in
Medical Sciences, New Delhi, India front of thyroid cartilage. The thyroid gland
NH2 NH2
HO O CH2CH HO O CH2CH
COOH COOH
3,3´5-Triiodo-L-Thyronine Thyroxine
(T3) (T4)
secretes two biologically active thyroid hor- TH and described in detail in the section under
mones: thyroxine (T4) and 3,5,3′-triiodothyro- ‘central regulation of thyroid hormone func-
nine (T3) (Fig. 2.1). They are composed of a tion’ below. An important mechanism for the
phenyl ring attached via an ether linkage to a negative regulation of TSH is probably the
tyrosine molecule. Both have two iodine atoms intrapituitary conversion of circulating T4 to
on their inner tyrosine ring. The difference T3 by type II deiodinase.
between the two is that, T4 has two iodine atoms • TSH is the primary regulator of TH release and
on its phenyl (outer) ring, whereas T3 has only secretion. It also has a critical role in thyroid
one. The compound formed if an iodine atom is growth and development. TSH binds to the
removed from the inner ring of T4 is 3,3′,5′-triio- TSH receptor (TSHr), which also is a seven-
dothyronine (reverse T3, rT3), which has no bio- transmembrane spanning receptor coupled to
logical activity [1]. Gs. A number of thyroid genes, including Na+/
I− symporter (NIS), thyroglobulin (Tg), and
thyroid peroxidase (TPO), are stimulated by
Steps Involved in Synthesis TSH and promote the synthesis of TH [2].
of Thyroid Hormones • Iodide is actively transported and concen-
trated into the thyroid by NIS. The trapped
TH synthesis and secretion is exquisitely regu- iodide is oxidized by TPO in the presence of
lated by a negative-feedback system that involves hydrogen peroxide and incorporated into the
the hypothalamus, pituitary, and thyroid gland tyrosine residues of a 660-kDa glycoprotein,
[hypothalamic/pituitary/thyroid (HPT) axis] [2]. Tg. This iodination of specific tyrosines
located on Tg yields monoiodinated and diio-
• Thyrotropin releasing hormone (TRH) is a tri- dinated residues (MIT, monoiodo-tyrosines;
peptide (PyroGlu-His-Pro) synthesized in the DIT, diiodo-tyrosines) that are enzymatically
paraventricular nucleus of the hypothalamus. coupled to form T4 and T3 [5].
It is transported via axons to the median emi- • The iodinated Tg containing MIT, DIT, T4,
nence and then to the anterior pituitary via the and T3, then is stored as an extracellular
portal capillary plexus. storage polypeptide in the colloid within the
• TRH binds to TRH receptors in pituitary thy- lumen of thyroid follicular cells.
rotropes, a subpopulation of pituitary cells • The secretion of THs requires endocytosis of
that secrete thyroid stimulating hormone the stored iodinated Tg from the apical surface
(TSH). TRH stimulation leads to release and of the thyroid follicular cell. The internalized
synthesis of new TSH in thyrotropes [3, 4]. Tg is incorporated in phagolysosomes and
• TSH is a 28-kDa glycoprotein composed of α- undergoes proteolytic digestion, recapture of
and β-subunits designated as glycoprotein MIT and DIT, and release of T4 and T3 into
hormone α- and TSH β-subunits. Both TRH the circulation via the basal surface. The
and TSH secretion are negatively regulated by majority of released TH is in the form of T4, as
2 Functions of Thyroid Hormones 13
total serum T4 is 40-fold higher than serum Iodine is absorbed from the GI tract in the form
T3. Only 0.03 % of the total serum T4 is free of iodide which circulates in the plasma with a
(unbound), with the remainder bound to car- half-life of 24 h. About 75–80 % of the total body
rier proteins such as thyroxine binding globu- iodine gets concentrated in the thyroid tissue
lin (TBG), albumin, and thyroid binding with the help of NIS (basolateral sodium iodide
prealbumin. Approximately 0.3 % of the total symporter) across a concentration gradient of
serum T3 is free, with the remainder bound to 20–50 times. Iodide is excreted mainly by the
TBG and albumin. It is the free TH that enters kidney within 24–48 h after consumption [1, 5,
target cells and generates a biological response. 6]. There are various methods of iodine estima-
• While T4 is solely produced by thyroid gland, tion namely calorimeter using spectrophotometry
T3 is a product of the thyroid as well as all tis- (most common), iodine specific electrode, neu-
sue in which it is produced by deiodination of tron activation analysis and mass spectrometry.
T4. Only 20 % of circulating T3 is synthesized
in the gland and rest is generated by peripheral Wolff- Chiakoff Effect
conversion of T4 by the deiodinase present in 3 In response to increasing doses of iodine above the
forms : type 1 deiodinase (D1), preferentially optimum level, the rate of thyroid hormone synthe-
expressed in the liver and also expressed in the sis and release decreases due to its inhibitory action
kidney, thyroid, and pituitary; D2, present in on the process of ‘organification’. This acute inhi-
the CNS, anterior pituitary, brown adipose tis- bition of organification secondary to high concen-
sue, and placenta; and D3 in the CNS, pla- tration of plasma iodode levels is termed as Wolff
centa, skin, and fetal tissue. D1 and D2 are Chiakoff effect (thyroid constipation). The under-
activating forms while D3 is the inactivating lying mechanism is probably due to inhibition of
form. These are seleno enzymes and selenium peroxidase enzyme and down regulation of NIS
deficiency is associated with decreased activ- transporter [8]. The methods to estimate burden of
ity. D2 is the primary activator enzyme causing iodine deficiency in field survey are :
rapid increase in intracellular T3 and thereby
regulate the effects in human tissues [6, 7]. 1. Palpatory method : In areas of moderate to
• In addition to the classical thyroid hormones, severe iodine deficiency, size of goiter will
thyroid gland also secretes non- classical thy- give an estimate of prevalence iodine
roid hormones namely thyronamines, tetrac, deficiency.
triac, di-iodothyronine and reverse T3. The 2. Spot UI (urinary iodine) concentration: More
functions and actions of these molecules are than 90 % of iodine is eliminated by kidney
still under research. and hence the median of UI in spot urine sam-
ple will give an estimate of recent intake of
iodine.
3. Thyroglobulin levels: In iodine deficiency,
Only 0.03 % and 0.3 % of total serum T4
thyroglobulin levels increase due to greater
and T3 respectively is free (unbound). It is
TSH stimulation and thyroid mass.
the free TH that enters target cells and gen-
erates a biological response
Central Regulation of Thyroid
Hormone Synthesis:
Role of Iodine in Thyroid Hormone The ‘Hypothalamic –Pituitary-
Synthesis and Function Thyroid Axis’
Iodine is the chief elemental composition of thy- The hypothalamic-pituitary-thyroid (HPT) axis
roid hormones and its deficiency is a major cause primarily functions to maintain normal, circulat-
of hypothyroidism in the developing world. ing levels of thyroid hormone that is essential for
14 N. Dev et al.
the biological function of all tissues. Important secretion, but it has no effect on TRH induced
among these functions are regulation of food release of TSH. Hypophysiotropic TRH neurons
intake and energy expenditure among others [1, also express the vesicular glutamate transporter
2, 6]. 2, establishing the glutamatergic phenotype of
these cells but its physiological significance is
Production of TRH unknown [9, 10].
This regulatory system contains a group of neu- In contrast to the hypophysiotropic TRH neu-
rons that reside in the hypothalamic paraventricu- rons, non-hypophysiotropic TRH synthesizing
lar nucleus (PVN), produce TRH, and integrate a neurons are widely distributed in the central ner-
wide variety of humoral and neuronal signals to vous system. However, there is little information
regulate the HPT axis. The TRH synthesizing available on the anatomy and physiologic effects
neurons are present in several brain regions, but of these neurons.
only hypophysiotropic TRH neurons located in
the PVN are involved in the central regulation of Role of Autonomic Nervous System
the HPT axis. This nucleus is a critical vegetative in Regulation of Thyroid Function
center of the hypothalamus and is located sym- In addition to the stimulation of TSH secretion of
metrically at the upper third of the third ventricle. the anterior pituitary by TRH, the central nervous
The PVN contains a magnocellular and a parvo- system can also regulate thyroid function via the
cellular division. The magnocellular division autonomic nervous system [11, 12]. The thyroid
houses oxytocin and vasopressin neurons that gland is innervated by both adrenergic nerve
project to the posterior pituitary. The parvocellu- fibers of the sympathetic nervous system and the
lar division is further divided into anterior, peri- cholinergic axons originating from the vagus
ventricular, medial, ventral, dorsal, and lateral nerve. Both sympathetic and parasympathetic
parvocellular subdivisions. In humans, the PVN nerves densely innervate the blood vessels of the
also contains a large population of TRH neurons, thyroid gland, but axon terminals of these auto-
especially in its medial part, but the location of nomic systems can also be found around the thy-
hypophysiotropic TRH neurons is not yet known roid follicles, indicating that not only the blood
[9, 10]. flow, but also the activity of thyroid follicles
could be under direct control of autonomic
Hypophysiotropic and Non- inputs. Unfortunately, relatively little data are
hypophysiotropic Neurons available about how these to the thyroid gland
Hypophysiotropic TRH neurons are functionally regulate thyroid function. However, the sympa-
different from the nonhypophysiotropic TRH thetic input seems to have an inhibitory action
neurons in the PVN. Only hypophysiotropic because electrical stimulation of the cervical
TRH neurons project to the external zone of the sympathetic trunk decreases thyroid blood flow.
median eminence, where their axon terminals Noradrenaline also inhibits the stimulatory effect
release TRH into the extracellular space of this of TSH on the thyroid cells in vitro and decreases
blood brain- barrier -free circumventricular thyroid hormone secretion in vivo. In contrast,
organ. TRH is then conveyed to the anterior pitu- electric stimulation of the thyroid nerve, which
itary via the hypophysial portal circulation where carries parasympathetic inputs to the thyroid
TRH regulates the secretion of TSH from thyro- gland, results in increased thyroid blood flow that
trophs and prolactin from lactotrophs. In addi- can be prevented by atropine pretreatment. In
tion to TRH, hypophysiotropic neurons also addition to the classical transmitters, the neuro-
express a second neuropeptide, cocaine and peptides, NPY and vasoactive intestinal peptide
amphetamine regulated transcript (CART) [2]. are also present in axons innervating the thyroid
CART is simultaneously released into the gland. NPY is present in the sympathetic inner-
hypophysial portal circulation and has been vation of the thyroid gland and inhibits thyroidal
shown to inhibit the effect of TRH on prolactin blood flow. In contrast, vasoactive intestinal
2 Functions of Thyroid Hormones 15
PVN
TRH
T3
III ventricle
T4
TC
T3
T4
Pit
TSH
Fig. 2.2 Schematic representation of the negative feed- stimulating hormone, TRH Thyrotropin releasing hor-
back regulation of the Hypothalamic-pituitary-thyroid mone, PVN paraventricular nucleus, Pit pituitary
axis by thyroid hormones. TC Tanycyte, TSH thyroid
peptide increases the thyroid blood flow and thy- the PPII gene produced in the liver by proteolytic
roid hormone secretion [11, 12]. cleavage of membrane bound PPII . Two broad
specificity cytosolic peptidases, pyroglutamyl
Inactivation of Secreted TRH peptidase- I and prolyl endopeptidase, can also
Inactivation of secreted TRH in the brain is pri- degrade TRH. However, because there is no evi-
marily catalyzed by a membrane bound ectoen- dence for the presence of these enzymes in the
zyme, pyroglutamyl peptidase II (PPII). PPII is a extracellular space it appears that these enzymes
type II integral membrane protein comprised of a do not play a major role in the inactivation of
small, N-terminal, intracellular region and a released TRH [9, 11, 13].
large, extracellular domain containing the active
site of the enzyme. PPII produces the dipeptide Negative Feedback Regulation
HisProNH from TRH, which is further degraded of Hypophysiotropic TRH Neurons
by dipeptidyl aminopeptidase IV, or spontane- Negative feedback regulation of hypophysiotro-
ously cyclizes to His-Pro diketopiperazine. PPII pic TRH neurons is an important regulatory
is primarily synthesized by neurons, but it is also mechanism in ensuring stable thyroid hormone
produced by tanycytes, a specialized glial cell levels (Fig. 2.2). When circulating thyroid hor-
type, in the hypothalamus. Inhibition of PPII mone levels are increased, TRH gene expression
activity markedly increases the amount of TRH is decreased in hypophysiotropic neurons and
released from brain tissue slices, supporting the vice versa. Regulation of TRH transcription by
importance of thispeptidase in the metabolism of thyroid hormone is relatively rapid because the
TRH. In serum, TRH is degraded by a soluble exogenous administration of thyroid hormone
enzyme that was formerly called thyroliberinase, can suppress transcription of the TRH gene in the
but was subsequently shown to be a product of PVN within 5 h [14]. This regulatory mechanism
16 N. Dev et al.
is a unique feature of hypophysiotropic TRH neu- T3 and T4 and is abundantly expressed in endo-
rons because thyroid hormone does not regulate thelial cells of brain blood vessels, the choroid
TRH gene expression in nonhypophysiotropic plexus, and tanycytes. The activity of the HPT
TRH neurons. Thyroid hormone is sensed directly axis is not affected by the lack of OATP1C1 in
by the hypophysiotropic TRH neurons [14, 15]. KO mice, however, suggesting that this trans-
porter does not play a crucial role in feedback
regulation of TRH neurons. In contrast, the
Thyroid hormones regulate transcription of MCT8 transporter, which is preferentially
TRH gene rapidly. This is unique to hypo- expressed in neurons including hypophysiotro-
physiotropic TRH neurons as THs are pic TRH neurons has preferential affinity for T3.
sensed directly by these neurons. In MCT8 KO mice, TRH gene expression is
increased in the PVN [18].
The expression of thyroid hormones and its Thyroid hormones exert their action
functions also depend on co-regulators. through genomic and non-genomic path-
Co-activators that facilitate thyroid hormone ways. In genomic pathways the THs bind
functions are steroid receptor co activator, p160 to thyroid hormone receptors inside the
family, cAMP responsive elements (CREB) and nucleus and mediate transcription. In non-
PGC a1 acting through acetylation of histones genomic pathways they mediate their
and transcription upregulators. Co-repressors actions through second messenger systems
like NCoR and SMRT down regulate action of such as Calcium-ATPase, PI3K and AMPK
thyroid hormones by deacetylation. Although T3
18 N. Dev et al.
Table 2.1 Effect of thyroid hormones on various organs and tissues of the body
Organ/tissue Function of thyroid hormones
1. Brain Organization and function throughout life
Synaptogenesis, neurogenesis, migration, plasticity and myelination
Effect cholinergic and seretonergic activities
T3 is the predominant form acting on brain
2. Myocardium Essential for aerobic metabolism and prevention lactic acidosis
Upregulate beta adrenergic receptors and have inotropic and vasodilatory properties
Effect intracellular homeostasis of ionized calcium
Medical and surgical conditions may decrease T3 and T4 and increase reverse T3. This
phenomenon is called ‘Euthyroid sick syndrome’ (ESS)
ESS causes stunned myocardium and may cause cardiogenic shock in extreme cases.
3. Bone Important for bone growth and development
Involved in both bone formation and resorption
Hyperthyroidism causes increased porosity and decreased cortical thickness
4. Adipose tissue Important in development and function of BAT and WAT
(fat) In WAT THs regulate basal oxygen consumption, lipogenesis, lipolysis
TRα-1 gene is the predominantly expressed TR isoform in Ob17 cells
Expression of these genes is modulated by high carbohydrate diet, insulin and cAMP
5. Liver Stimulates enzymes regulating lipogenesis and lipolysis
Regulate expression of important proteins and enzymes involved in cholesterol metabolism
Deficiency causes hypercholesterolemia with elevated intermediate and LDL cholesterol
TRβ-1 is the predominant isoform in liver
Regulate gene expression of cellular pathways such as gluconeogenesis, lipogenesis, insulin
signaling, cell proliferation and apoptosis
6. Pituitary Regulate transcription of thyrotropin, prolactin mRNA
Regulate TSH synthesis
Effect on Bone
THs have important role in the critical
step of maturation of neuron. T3 affects TH is important for normal bone growth and
neurogenesis, synaptogenesis, migration, development. Hypothyroidism can cause short
plasticity, myelination and also has effect stature and delayed closure of the epiphyses.
on cholinergic and seretonergic activities THs are involved in both bone formation and
in the brain. Thyroid dysfunction is resorption [34–36]. Both osteoblast and osteo-
therefore associated with neurological clast activities are stimulated by TH. It has been
and behavioural disorders, psychomotor observed that there is enhanced calcification and
symptoms, cognitive disturbances and bone formation coupled to increased bone
neurodegeneration resorption in hyperthyroid patients. There also is
marked increase in porosity and decreased corti-
cal thickness in cortical bone in hyperthyroid
patients. TH may act on bone via TH stimulation
Effect on Myocardium of growth hormone and insulin-like growth fac-
tor I (IGF-I) or by direct effects on target genes.
Thyroid hormones are essential for proper aero- Recent studies have shown that T3 also can
bic mitochondrial function, generation of high directly stimulate IGF-I production in osteo-
energy phosphates, prevention of lactic acidosis, blasts and enhance T3 stimulation of [3H]pro-
upregulation of beta adrenergic receptors and line incorporation, alkaline phosphatase, and
have important role in intracellular homeostasis osteocalcin [36].
of ionised calcium. THs affect excitation con- Although TH increases the activities of osteo-
traction coupling, have inotropic properties and blasts and osteoclasts in vivo and in culture, little
are strong vasodilators of systemic arteries is known about its effects on the transcription of
including coronary arteries [28–30]. The acute target genes in these cells. There are a number of
changes in TH levels in the form of decreased osteoblast proteins that are stimulated by
T3 & T4 along with increased reverse T3 fol- TH. These include proteins involved in matrix
lowing acute pathogenic event(medical,surgical, formation such as alkaline phosphatase, osteo-
traumatic) is called euthyroid sick calcin, and collagen. Additionally, IGF-I and
syndrome(ESS) [31]. The ESS often depresses IGF-binding protein-2 mRNA are stimulated by
the myocardiun transiently and is sometimes T3 in rat primary cultures. However, it is not
referred to as ‘stunned myocardium’ [32]. The known whether TH directly regulates transcrip-
term is used in conditions where there is regional tion of these target genes. The T3stimulation of
or global ischemia. The effect may vary from IGF and IGFBPs suggests that TH may partici-
mild hemodynamic compromise to cardiogenic pate in osteoblast differentiation and prolifera-
shock [33]. According to current consensus, no tion by regulating growth factor synthesis and
thyroid hormone replacement is given in patients action [36, 37].
with ESS. Recent evidences however, have
shown rewarding results in 3 conditions where
ESS and myocardial stunning coexist: (a) tran- Effect on Adipose Tissue
sient regional myocardial ischemia and reperfu-
sion (b) transient global myocardial ischemia in THs plays important roles in the development
patients undergoing cardiac surgery/bypass (c) and function of brown and white adipose tis-
transient inadequate global myocardial perfu- sue (BAT and WAT) [38]. In experimental stud-
sion in brain dead potential organ donors. Under ies it has been found that T3 not only
all these conditions, administration of T3/T4 induced intracellular lipid accumulation and
rapid reversal of myocardial perfusion was various adipocyte-specific markers such as malic
found [28]. enzyme and glycerophosphate dehydrogenase,
20 N. Dev et al.
but also stimulated adipocyte cell proliferation and enhances norepinepinephrine stimulation of
and fat cell cluster formation [39]. UCP [43, 44]. The adrenergic stimulation in BAT
Studies in the adult rat have shown that T3 is predominantly, mediated by brown fat specific
plays important roles in regulating basal oxygen adrenergic β3-receptors. The dual regulation of
consumption, fat stores, lipogenesis, and lipoly- UCP by the type II deiodinase and the adrenergic
sis [40]. In WAT, T3 induces key lipogenic system suggests convergence of nuclear- and
enzymes such as acetyl CoA carboxylase, malic membrane-signaling systems in the transcrip-
enzyme, glucose-6-phosphate dehydrogenase, tional regulation of these important target genes
fatty acid synthase, and spot 14 [41]. The in BAT, but the precise relative contributions and
mechanism(s) by which T3 induces WAT differ- interplay between these regulatory systems is not
entiation currently is not known but likely yet clear [42–44].
involves transcriptional regulation of important Several human studies have shown that
target genes by TRs. Both TRα-1 and TRβ-1 are chronic hypo- and hyperthyroidism as well as
expressed in Ob17 cells, with the TRα-1 as the acute T3 treatment did not affect serum leptin
predominantly expressed TR isoform. The levels. However few have also shown that
expression of these genes is also modulated by increased leptin levels correlated with adiposity
other factors such as high-carbohydrate diet, and that T3 can decrease leptin levels but the
insulin, and cAMP [40]. Additionally, T3 also mechanism is not clear [45].
regulates lipolysis in a coordinate manner with
lipogenesis. Thus TH stimulation of lipolysis
may activate other nuclear hormone receptor sys- Effect on Liver
tems, and thereby promote differentiation [40].
Moreover, enzymes of the lipogenic pathway, TH causes stimulation of enzymes regulating
ATP-citrate lyase, malic enzyme, and fatty acid lipogenesis and lipolysis as well as oxidative pro-
synthase, are induced by T3 in differentiating cesses [46]. As described above (effect on fat)
adipocytes, suggesting T3 promotes the acquisi- some of the lipogenic enzymes that are regulated
tion of differentiated functions in white adipocyte are malic enzyme, glucose-6-phosphate dehydro-
tissue [40, 41]. genase, and fatty acid synthase [46, 47]. Of these,
Recently it has been shown that both TRα and malic enzyme has been extensively studied.
TRβ-1 are differentially expressed during the Malic enzyme has been shown to be stimulated
development of brown adipose tissue (BAT) [42], by direct action of T3 as well as secondary effect
a major contributor to facultative thermogenesis due to stimulation by other gene products that are
in rodents. Facultative thermogenesis occurs in regulated by T3. In rats it has been seen that a
response to cold exposure or overeating and number of lipogenic enzymes may be regulated
depends on T3 and adrenergic stimulation of by growth hormone, which is induced by T3.
mitochondrial uncoupling protein (UCP) synthe- Malic enzyme is very sensitive to T3 in the liver,
sis. It is not known whether these effects are but it is unresponsive in the brain, suggesting that
directly mediated by T3 or via downstream sig- tissue-specific factors are important in determin-
nals such as free fatty acids generated by lipoly- ing T3-mediated stimulation of transcription. T3
sis. The stimulation of UCP synthesis increases regulation of malic enzyme gene transcription
thermogenesis by uncoupling oxidative phos- also can be regulated by carbohydrate intake,
phorylation resulting in energy dissipation as insulin, and cAMP. For example, it has been seen
heat. Interestingly, BAT also contains a type II that T3 effects on malic enzyme gene transcrip-
deiodinase whose activity increases in response tion are minimal in fasted animals but are most
to cold, thereby enabling BAT to have the impor- pronounced in animals fed a sucrose-containing
tant ability to regulate intracellular T3 concentra- fat-free (lipogenic) diet [46, 48]. Similar interac-
tion in a tissue-specific manner. This increase in tions between T3 and dietary carbohydrate also
T3 concentration likely saturates nuclear TRs occur in the gene regulation of other lipogenic
2 Functions of Thyroid Hormones 21
sufficient enough and compensate for the fetal Effect on Lung Maturation
thyroid deficiency. This is attributed to their role THs tend to increase the expression of pulmonary
in regulating the somatotropic axis and local tis- b-adrenergic receptors and apical Na channels in
sue expression of the IGFs (insulin like growth the fetus thereby facilitationg lung fluid absorp-
factors) which have major role in fetal tissue tion at birth. It is shown that they also facilitate
accretion [57–60]. production of surfactant by synergistic action
along with cortisol [62].
Effect on Growth
The effect of low thyroid hormones on fetal Effect on Fetal Heart
growth is evidenced by studies on thyroidect- and Cardiovascular System
omised fetal animals. It is shown that the protein THs promote a switch from proliferation to
content of fetal tissues such as the heart, lung, hypertrophy and differentiation of the cardiac
and skeletal muscle is reduced by fetal thyroidec- myocytes by playing an important role in the
tomy. The growth restriction is asymmetrical in perinatal switch from b- to a-myosin heavy
the sense that greater effects are seen on the chains in the sacromeres [63].
weight of soft tissues than on the length of bones.
The appendicular skeleton is more adversely
affected than the axial skeleton. The effect on Other Important Effects
bone metabolism is affected by reducing the
osteocalcin, a marker of bone deposition rather Effect on mitochondria: The mitochondria are
than altering the calcium homeostasis in the important target for THs. They modulate mito-
body. chondrial activity through two ways: direct or
indirect. In the direct pathway, the hormone
Effect on Fetal Metabolism (Oxygen enters the cell and binds to binding sites of organ-
(O2) Consumption) elles. These organelles are responsible for regu-
THs increase O2 consumption by fetal tissues lation of mitochondrial transcription apparatus.
upto 28 % and increase umbilical blood flow. One of these binding sites, termed p43, has been
This is by inducing oxidative mechanisms by identified as a bona fide TR (nuclear receptor)
changing expression and activity of the electro- that binds to the D-loop region that contains the
genic Na–K ATPase pump or by acting on the promoters of the mitochondrial genome. Thus,
mitochondrial electron transport chain (ETC) and THs play important role in regulation of the
oxidative phosphorylation. These hormones are mitochondrial transcription apparatus. In the
necessary for normal developmental increments indirect pathway, the THs act through increased,
in hepatic glycogen and gluconeogenic enzymes. nuclear TR-dependent transcription of factors
They have an important role in maturational that modulate the expression of mitochondrial
effects of thermogenic capacity of brown adipose genes [64].
tissue as has been described earlier in the text
(see adipose tissue). Conclusion
Thyroid hormones (THs) play critical roles in
Effect on Fetal Tissue Maturation growth, differentiation and metabolism. They
Thyroid hormones also facilitate maturation are important for optimal functioning of
and differentiation of fetal tissues evidenced by almost all tissues with major effects on meta-
activation of physiological processes essential bolic rate and oxygen consumption. The thy-
for survival immediately at birth such as pulmo- roid gland secretes two biologically active
nary gas exchange, adaptations in cardiac func- thyroid hormones: thyroxine (T4) and
tion, hepatic glucogenesis and thermogenesis 3,5,3′-triiodothyronine (T3). TH synthesis
[60, 61]. and secretion is exquisitely regulated by a
2 Functions of Thyroid Hormones 23
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Iodine and the Thyroid
3
Hernando Vargas-Uricoechea,
Anilza Bonelo-Perdomo,
and Carlos Hernán Sierra-Torres
Abstract
Iodine Deficiency Disorders (IDD) are among the most significant public
health problems in the world at the present time, especially among chil-
dren and pregnant women, considered the highest risk population. These
disorders hinder socio-economic development in the affected areas. IDD
are a permanent natural occurrence that affects the entire planet, which
means that the people living in iodine-deficient areas will always be
exposed to the consequences of that deficiency, in particular increased
perinatal mortality, mental retardation and brain developmental delay.
Consequently, it is the major cause of preventable brain damage in child-
hood, and its elimination is one of the biggest challenges in public health.
Iodine is present in small amounts in the body and its main role is to act as
the substrate for thyroid hormone synthesis. When dietary requirements
are not met, the frequency of IDD increases. In general, these disorders are
underdiagnosed and, in many countries, there is no awareness of the asso-
ciated problems or of the iodine status in the population.
Introduction
iodine-“sufficient”, it is not clear whether iodine respectively). In the other WHO regions, the fig-
intake during pregnancy is appropriate; and in ures were 56.9 % for Europe; 54.1 % for Eastern
other geographical areas such as Australia, defi- Mediterranean; 42.6 % for Africa; and 39.8 %
ciency has increased as a result of a decreased use for Southeast Asia [3, 4]. Between 1990 and
of iodophors in the food industry (an iodophor is 2003, the proportion of households using iodized
defined as an iodine complex with non-ionic ten- salt increased from 10 to 66 %. As a result, the
sioactive agents that act as iodine transporters and WHO estimated that the number of countries
solubilizers in water). This lower industrial use of where iodine deficiency disorders were a public
iodophors may also explain – at least in part – health problem had dropped from 110 to 54; and
minor iodine deficiencies in the United Kingdom later it dropped from 54 to 30. On the other hand,
and the Republic of Ireland. In marginal econo- the number of “iodine-sufficient” countries
mies such as southern Asia and Sub-Saharan increased from 67 to 112. In 2006, 15 countries
Africa, the problem is greater [1, 2]. The lowest had reached the goal of sustainable elimination
frequency is found in the Americas. The most vul- of iodine deficiency disorders. The prevalence of
nerable groups are pregnant mothers and children, iodine deficiency was published in 2008 on the
and the consequences of the lack of iodine during basis of the world population estimated for
brain development in utero were the trigger that 2006 – without including data from countries
led the International Public Health Community, such as the US and Western Europe. The highest
with the support from United Nations (UN) agen- prevalence was found in Europe (52 %), fol-
cies, particularly the World Health Organization lowed by Eastern Mediterranean (47.2 %) and
(WHO) and the United Nations Children’s Fund Africa (41.5 %), taking into consideration that
(UNICEF), to adopt sustainable iodine deficiency iodine deficiency in school-age children in coun-
elimination as a goal. Food iodine content depends tries like Ethiopia is unacceptably high. The
on the amount of iodine in the soil, and soil degra- lowest prevalence was found in Southeast Asia,
dation as a result of erosion, excess cattle grazing Western Pacific and the Americas −30 %, 21.2 %
and cutting of trees is associated with significant and 11 %, respectively – [5, 6]. Despite efforts to
losses of this trace element. Consequently, food achieve universal salt iodization, there are still
grown in degraded soils has low iodine content. areas where results are conflicting – Table 3.1
The term Iodine Deficiency Disorders (IDD) is [7–9].
used to define a group of diseases resulting from a Moreover, iodine intake is more than adequate
relative loss of iodine in the diet, including multi- and even too high in at least 34 countries glob-
ple defects. The definition also encompasses the ally. Over the past decade, the number of coun-
concept that those disorders are preventable by tries with excess iodine intake increased from 5
means of an adequate iodine intake. However, to 10 as a result of very high levels of salt iodiza-
iodine-induced hyperthyroidism is a metabolic tion or poor monitoring and follow-up of the
disorder that is relatively frequent in areas with iodization programs. This is important to note
very high iodine intake; in fact, in those areas that even minor changes in iodine intake (above
where iodine intake is marginal – although not or below the normal population reference range)
iodine-deficient – moderate increases in iodine in the different geographical regions are associ-
intake may induce hyperthyroidism in individuals ated with marked differences in the frequency of
with autonomous thyroid nodules [3–5]. thyroid disorders. It has even been found that pri-
mary elimination of IDD achieved in some
regions may be accompanied by “overiodization”
Epidemiology of salt, resulting in a substantial increase in
ioduria, and highlighting the need for permanent
In an analysis of data collected in 2003, the monitoring of all IDD prevention programs.
WHO estimated that the Americas and Western Currently, 111 countries have adequate iodine
Pacific had the lowest proportion of people with dietary intake; of these, 30 remain iodine-
insufficient iodine intake (9.8 % and 24 %, deficient, nine are moderately deficient, 21 are
3 Iodine and the Thyroid 29
Table 3.1 Prevalence of iodine deficiency in numbers (millions) and percentages, in the general population (all age
groups) and in school children (6–12 years) for 2007. The percentage of households with access to iodized salt is also shown
WHO regions (193 Households with access to iodized salt (%)
member states) General population School age children not including Western Europe or the UN
Africa 312.9 (41.5 %) 57.7 (40.8 %) 66.6 %
Americans 98.6 (11 %) 11.6 (10.6 %) 86.8 %
Eastern Mediterranean 259.3 (47.2 %) 43.3 (48.8 %) 47.3 %
Europe 459.7 (52 %) 38.7 (52.4 %) 49.2 %
Southeast Asia 503.6 (30 %) 73.1 (30.3 %) 61 %
Western Pacific 374.7 (21.2 %) 41.6 (22.7 %) 89.5 %
Total 2000 (30.6 %) 263.7 (31.5 %) 70 %
Fig. 3.1 Iodine status worldwide in 2014; based on the median urinary iodine concentration
mildly deficient, and none are currently consid- UNICEF, and International Council for Control
ered severely iodine-deficient. Ten countries have of Iodine Deficiency Disorders (ICCIDD) recom-
excess iodine intake – Fig. 3.1 – [10–13]. mends an adequate daily intake of iodine aimed
at reducing IDD in the population to the largest
extent (Table 3.2). For the USA and Canada, the
efinition of IDD and Its Impact
D Institute of Medicine established Dietary
on Health and on the Population Reference Intakes (DRI) for iodine, and specifi-
cally an Adequate Intake (AI) for infants, which
Iodine deficiency emerges when iodine intake is is defined as a recommended daily intake level
below the recommended levels. The term IDD that is expected to meet or exceed the require-
refers to the consequences of iodine deficiency in ment in essentially all individuals of a specific
a population, and which may be prevented by life-stage and sex group; and an Estimated
ensuring adequate intake [14, 15]. WHO, Average Requirement (EAR) which is defined as
30 H. Vargas-Uricoechea et al.
Table 3.2 Recommendations for iodine intake by age or life-stage group and tolerable upper intake levels for iodine
WHO-UNICEF-ICCIDD Tolerable upper intake Levels for iodine
(RNI) (μg/day) USA Institute of Medicine (μg/day)
Children 0–59 90 Life Stage EAR (μg/ AI or RDA Age Groupa USA Institute ECSCb
months Group day) (μg/day) of Medicine
Children 6–12 120 Infants aged – 110–130 1–3 200 200
years 0–12 months
>12 years and 150 Children 65 90 4–6 300 250
adults Aged 1–8
years
Pregnancy and 250 Children aged 73 120 7–10 600 300
location 9–13 years
Adults aged 95 150 11–14 – 450
≥14 years
Pregnancy 160 220 15–17 and 900 500
(14–18) years
Location 200 290 Adults 1100 600
pregnant and
lactating
women
Age categories in parenthesis are for the Tolerable Upper Intake Level defined by the US Institute of Medicine
a
the average daily level of intake estimated to population –based on median ioduria and ioduria
meet the requirements of 50 % of healthy indi- concentration (or both) – are shown in Table 3.3.
viduals in a particular life-stage and sex group; It The consequences of iodine deficiency on
is usually used to assess the adequacy of nutrient health and the community may be disastrous and
intakes in populations but not individuals. And irreversible. For the WHO, iodine deficiency is
the Recommended Dietary Allowance (RDA) the primary preventable cause of brain injury –
which is defined as the average daily intake level both in fetuses and infants – as well as of delayed
sufficient to meet the requirements of nearly all psychomotor development in children; however,
(97–98 %) healthy individuals in a particular life- consequences reach beyond brain disorders, as
stage and sex group for children, adolescents, and shown in Table 3.4 [17–19].
adults. The WHO established Recommended
Nutrient Intakes (RNI) that cover the needs of
nearly all healthy individuals in a specific life- Iodine Chemistry
stage group. On the other hand, programs focus-
ing on universal salt iodization have increased the The discovery of iodine, like most discoveries,
risk of overiodized salt. This has led to the rec- was a fortuitous accident. In 1811, Bernard
ommendation of the “Tolerable Upper Intake Courtois serendipitously discovered iodine while
Levels for iodine”, bearing in mind that some extracting saltpeter (ammonium nitrate) from
populations with profound iodine deficiencies seaweed to produce gunpowder for Napoleon’s
may respond adversely to intakes far below rec- army. He mistakenly added excess sulfuric acid,
ommended levels [15, 16]. which caused a violet-colored vapor to exude and
Disorders caused either by iodine deficiency recrystallize. Iodine derives its name from the
or excess intake (measured using median ioduria Greek word iodes, which means violet.
or ioduria concentrations) occur in ranges Iodine is included in the element list of the
between <100 μg/L (insufficiency) and more lesser 1/3 in abundance and is therefore classi-
than 300 μg/L (excess). The epidemiological cri- fied as a rare element. It is classified as a non-
teria for the evaluation of iodine nutrition in a metallic element, showing that it has little of the
3 Iodine and the Thyroid 31
Table 3.3 Epidemiological criteria for dietary iodine Table 3.4 Consequences of iodine deficiency for health
contribution in a population
Age Consequence
Iodine intake Dietary iodine contribution All ages Goiter (even nodular hyperthyroid
School-age children disease); hypothyroidism in areas with
<20 μg/L Insufficient Severe deficiency moderate-to-severe deficiency; lower
20– Insufficient Moderate deficiency presence of hyperthyroidism in areas
49 μg/L with mild-to-moderate deficiency;
hyperavidity of the thyroid for iodine
50– Insufficient Mild deficiency (which increases the risk of thyroid
99 μg/L irradiation in the event of a nuclear
100– Adequate Optimal accident).
199 μg/L In-utero and Miscarriages, increased risk of fetal
200– More than Risk of iodine-induced perinatal death, congenital abnormalities,
299 μg/L adequate hyperthyroidism in state: increased perinatal mortality
susceptible groups Neonates: Endemic cretinism, increased risk of
>300 μg/L Excess Risk of harmful infant mortality
consequences for health Children and Growth delay, reduced intellectual and
(hyperthyroidism, adolescents: mental abilities
autoimmune thyroid
disease) Adults: Diminished intellectual and mental
abilities, hypothyroidism, apathy,
Pregnant women significant reduction of working
L150 μg/L Insufficient – capacity and productivity leading to
150– Adequate – poor social and economic development
249 μg/L
250– More than –
499 μg/L adequate
of the earth in a very small amounts and it is
≥500 μg/L Excessa –
known as a trace element. As a non-metallic ele-
Breastfeeding womenb ment, its atomic number is 53, it belongs under
<100 μg/L Insufficient – group 17 in the periodic table with a relative
≥100 μg/L Adequate – mass of 126.904, and it is considered the heavi-
Children <2 years of age est among halogens found in nature. Under nor-
<100 μg/L Insufficient – mal conditions, it is found in the form of a black,
≥100 μg/L Adequate – volatile, shiny solid. The chemistry of iodine, as
There is no information on dietary iodine contribution in that of other halogens, is dominated by the ease
pregnant and breastfeeding women in the UN evaluation with which the atom acquires an electron to form
table the iodide ion (I−) or a single covalent bond, and
a
The term excess means that it exceeds the amount the formation, with more electronegative ele-
required to prevent and control iodine deficiency
b
In breastfeeding women, median ioduria numbers are ments, of compounds in which the formal iodine
lower than iodine requirements due to iodine excretion in oxidation state is +1, +3, +5 or +7; however, like
breast milk the rest of halogens, it may form a large number
of compounds with other elements although it is
characteristics of metallic elements. It is a solid, in fact the least reactive of the whole group.
not a liquid or gas like the halogens above it in Despite the low concentration of iodine in sea-
the periodic table. It is however volatile and water, some algae species may extract and accu-
therefore when heated it sublimes to a purple mulate this element. In the form of calcium
vapor. It is included in the seventh column of the iodate, iodine is found in saltpeter beds in Chile,
periodic table, fourth in this halogen column. It and it is also found as iodide ion in some oil well
has a characteristic odor and a sharp acrid taste brines in California, Michigan and Japan. Iodine
[20, 21]. Like the other halogen elements it is may be obtained from iodides found in seawater
diatomic, meaning that in its atomic state there and some algae, or in the form of iodates from
are two atoms bound together to give one entity niter. Iodine exists in the form of diatomic
referred to as I2. Iodine is present on the surface molecules (I2) in solid, liquid and vapor phases,
32 H. Vargas-Uricoechea et al.
although dissociation for atom formation is quite iodine content at metamorphic temperatures.
significant at high temperatures (>200 °C). Granites, granodiorites, tonalites, and basalts are
Although it is less strong in its reactions with even lower in iodine and contain 4–9 μg/kg
other halogens (halogenides), iodine combines Iodine, almost independent of the class of mag-
directly with most of the elements, important matic rock.
exceptions being noble gases, carbon, nitrogen The planet that we know today looks very dif-
and some noble metals [22, 23]. ferent from what it was like shortly after its birth.
Iodine has several valence states and exists At that time, it was a huge clump of molten rock;
naturally in inorganic and organic forms includ- eventually, the crust cooled and turned solid.
ing iodide (I−), iodate (IO3−), elemental iodine Water pooled in the lower areas and a layer of gas
(I2), methylated forms and iodine-substituted began to form above the surface. In the mean-
humic substances. The chemical form of iodine time, lava leaked abundantly though multiple
depends on pH and the redox status of the sur- cracks in the crust and this volcanic activity
rounding environment. Iodide and organic iodine released a huge amount of gas that ended up
forms were reported as the most prevalent spe- forming a layer above the surface. Oxygen and
cies of iodine in river water while iodate is hydrogen produced water vapor during the erup-
believed to be the most common iodine form in tions; as water vapor rose through the atmo-
oceans. In soil, iodide was reported to be the sphere, it condensed, giving rise to the primordial
dominant inorganic iodine species in humid rainfall. As the first rains fell on the planet, they
acidic soils whereas iodate prevails in the arid pushed iodine into the sea, hence its substantial
oxidizing conditions [20, 24]. concentration in seawater [25–27]. Certain
marine plants and animals have developed mech-
anisms that enable them to concentrate large
Iodine Ecology and Cycle amounts of iodine in their tissues and when they
die and fall to the bottom of the sea, iodine
Close to 95 % of the crust of the earth is made of becomes part of the sediment and the sedimen-
igneous rocks that form when magma (molten tary rocks that may form later on. Part of the
rock) cools and solidifies. Those rocks contain a iodine contained in seawater evaporates and rises
definite amount of iodine – approximately 500 μg to the atmosphere, probably attached to dust par-
per kilogram of dry material (considering that ticles (Fig. 3.2).
these rocks consist mainly of silicates and are When water vapor forms clouds and then falls
covered by a fine layer of sedimentary and meta- in the form of rain or snow, the latter also contain
morphic rocks) – Soils derived from igneous iodine, completing the entire circulation cycle
rocks contain substantial amounts of iodine, as is [20, 24]. Seawater has the highest iodine concen-
to be expected. Once the rocks have formed from tration – close to 58 μg/L, iodate being the most
molten magma that rises to the surface, they may stable form which is reduced to iodide in the
go through different transformation processes. water surface through the biological activity
Moreover, they may be turned to dust by erosion, mediated by algae and phytoplankton, both of
or their fragments may give rise to sedimentary which release iodine-containing organic gases
rocks. On the other hand, they may sink or never (especially methyl iodide [CH3I] and diiodo-
rise to the surface, and become transformed by methane [CH2I2]) that rise to the atmosphere and
heat and pressure, giving rise to metamorphic undergo chemical changes under the action of
rocks. The two types of rocks and the soils they sunlight. About 400.000 ton of iodine escapes
give rise to contain varying amounts of iodine. from the oceans every year as iodide in sea spray
From among the magmatic and metamorphic or as iodide, hydrochloric acid and methyl iodide,
rocks, metasedimentary gneisses, mica schists produced by marine organisms. Much of it is
and granulites have as little as 12–25 μg/kg deposited on land where it may become part of
iodine, and have lost from 75 to >95 % of their the bio cycle. In the atmosphere, iodine migrates
3 Iodine and the Thyroid 33
Atmosphere
Soils
Fresh water Salt water: 50
Lithosphere Hydrosphere
Fig. 3.2 Iodine ecology in nature: Certain marine plants becomes part of the sediment and the sedimentary rocks
and animals have developed mechanisms that enable them that may form later on. Part of the iodine contained in sea-
to concentrate large amounts of iodine in their tissues and water evaporates and rises to the atmosphere, probably
when they die and fall to the bottom of the sea, iodine attached to dust particles (See text for more details)
to other parts of the earth and is deposited by wet of soils is most important. The amount of soil and
or dry precipitation, depending on climatic and its ability to retain it are two factors that need
topographic conditions; as a result, areas near consideration in the study of the geochemical
coastal regions tend to have a more iodine-rich pathways of iodine. There are three main forms
environment. For example, soils within 0–50 km of iodine in the soil: mobile iodine; insoluble
from the sea have a higher – though variable – iodides and fixed iodine. The property of the soil
level of iodine when compared with those found which fixes the iodine was termed Iodine Fixation
far from the sea. Iodine may become “revolatil- Potential (IFP). The IFP is particularly important
ized” from the soil and the plants, probably due for tropical soils since iron, manganese and alu-
to biological conversion to organic forms, allow- minum oxides are abundant in such soils and
ing it to travel far from the coasts until it precipi- these have the ability to fix iodine strongly. The
tates down to the earth again (Fig. 3.3). Although organic matter in the soil also absorbs iodine
organic matter plays an important role in fixing strongly and the bioavailability of iodine may
iodine in the soil, in areas known to be rich in therefore be relatively small (Fig. 3.4).
organic matter soils with high iodine content is The iodine status of a soil is a combination of
not a good source of this trace element for the the supply of iodine and the soil’s ability to retain
food chain because of strong binding of iodine to it. A soil from a coastal zone may have a high
the soil, precluding its bioavailability. From a input of iodine but if it cannot hold on to the
medical geology point of view, the iodine status iodine then it will remain deficient. The iodine
34 H. Vargas-Uricoechea et al.
Sea spray
Volatilization
(l high)
(l2 and organic-l) Lake water
River water
1 – 10 µg/g
1 – 10 µg/g
Zone of I-low
Acid soils organic - clay
I2 - rich interaction Sandy soils
Fish 1 µg/g marine plants vegetation 0.8 µg/g Zone of intense
50 µg/g leaching
Sea
58 µg/g
Lateritic formations
(I tightly bound) Groundwater flow Bed rock (I-low)
Marine sediments Decreasing I
20-200 µg/g Intrusive rock
0.24 µg/g
Fig. 3.3 Iodine cycle in nature (see text for more details)
TOTAL IODINE
INSOLUBLE
FIXED IODINE MOBILE IODINE
IODIDES
Iodine strongly
Iodine in crystal Solid soluble
sorbed in or on Soil gas
lattices inorganic inclusions
clays and colloids
Fig. 3.4 Main forms of iodine in the soil: There are three The IFP is particularly important for tropical soils since
main forms of iodine in the soil: mobile iodine, insoluble iron, manganese and aluminum oxides are abundant in
iodides and fixed iodine. The property of the soil which such soils and these have the ability to fix iodine strongly
fixes the iodine is called Iodine Fixation Potential (IFP). (See text for more details)
fixation potential of a soil is a complex mixture in the environment, considering that they repre-
of many factors that include the soil’s organic sent its bioavailability. It is suggested that a
content, the soil texture, the chemical form of the level below 3 μg/L defines iodine deficiency.
iodine, and the prevailing oxidation and acidity Finally, Iodine is primarily obtained as a by-
conditions [28, 29]. product with nitrate minerals that are associated
This means that any consideration regarding with caliche deposits in places such as the
iodine status in the population and its relation- Atacama Desert of Chile. It is present in seawa-
ship with the environment must be evaluated in ter, which contains about 0.05 parts per million
accordance with the bioavailability and not on (ppm) iodine, meaning that there is approxi-
the basis of the total iodine content. Water sur- mately 35 million metric tons of iodine in the
faces may be the best indicator of iodine status world’s oceans. Iodine was first isolated from
3 Iodine and the Thyroid 35
seaweed, and dried seaweeds (particularly those consumption of soy products that may contain
of the Liminaria family) contain as much as isoflavones (genistein and daidzein) may be asso-
0.45 % iodine. Prior to 1959, seaweed was a ciated with iodine deficiency and hypothyroid-
major source of iodine and it remains a signifi- ism. The goitrogenic effects of genistein -the
cant source for iodine in the diets of many peo- major soy isoflavone- seem to derive from a
ple around the world. Iodine is also retrieved direct interaction of this isoflavone with key path-
from underground brines (formation waters ways involved in thyroid hormones synthesis,
containing many dissolved salts and ions) which metabolism, and thyroid hormone transport pro-
are associated with natural gas and oil deposits teins. In vitro and in vivo studies showed that
as in Japan and the US [30, 31]. genistein is a potent inhibitor of Thyroid
Peroxidase (TPO). Indeed, TPO catalyzes the
iodination of thyroglobulin (Tg) and oxidative
Food Sources of Iodine coupling of diiodothyronine resulting in the thy-
roid hormone formation. Thus, inhibition of TPO
Seaweed (such as kelp, nori, kombu, and leads to a reduction of thyroid hormones levels,
wakame) is one of the best food sources of iodine, with a subsequent increment of TSH release that,
but it is highly variable in its content. Other good in turn, provides a strong growth stimulus to the
sources include seafood, dairy products (partly thyroid gland. Moreover, genistein also affects
due to the use of iodine feed supplements and the metabolism of thyroid hormones and iodide
iodophors sanitizing agents in the dairy indus- re-utilization by inhibition of sulfotransferase
try), grain products, and eggs. Dairy products, enzymes.
especially milk, and grain products are the major On the other hand, perchlorate content in
contributors of iodine to the American diet. food and its intake may affect the Symporter
Iodine is also present in human breast milk and Na/I (SNI) in the thyroid gland and reduce active
infant formulas. Fruits and vegetables contain intra-thyroid iodine transport, leading to hypo-
iodine, but the amount varies depending on the thyroidism [34, 35]. Thiocyanates are mainly the
iodine content of the soil, fertilizer use and irriga- result of the reaction of free cyanide with sulfur.
tion practices. Both leaf vegetables and fruit veg- Like perchlorate, these compounds may reduce
etables can absorb exogenous iodine from soil. active intrathyroid iodine transport through SNI
The uptake amounts increases with the applica- involvement. Thiocyanate is the main product
tion intensity of algal organic iodized fertilizer. that forms when cyanide enters the body, and it
However, uptake capacity is different for differ- is the way the body gets rid of cyanide.
ent vegetable. The leaf vegetables have a greater Thiocyanates are found in water, mainly due to
absorbing capacity than the fruit vegetables, discharges from coal processing, gold and silver
although there are variations in uptake capacity, extraction, and mining. Thiocyanates in the soil
usually less significant, between different species come from the direct application of herbicides,
within the same type vegetables. Iodine concen- pesticides and rodenticides, and the disposal of
trations in plant foods can range from as little as industrial by- products. Some vegetables like
10 mcg/kg to 1 mg/kg dry weight. This variabil- cabbage, cauliflower and Brussels sprouts are
ity in turn affects the iodine content of meat and part of a large genus called Brassica which, apart
animal products because it affects the iodine con- from their high content of diet fiber and vita-
tent of foods that the animals consume. Certain mins, also contain detectable levels of thiocya-
food sources are associated with various effects nates. In individuals that eat large amounts of
on iodine metabolism in the population [32, 33]. these vegetables may get an increased vulnera-
Universal restrictions regarding salt intake, as a bility to iodine deficiency and hypothyroidism.
way to prevent and manage diseases like hyper- Most foods and beverages for human consump-
tension, have been associated with iodine defi- tion have a low iodine concentration. Foods of
ciency, particularly in women; and the growing marine origin have the highest iodine content. In
36 H. Vargas-Uricoechea et al.
Table 3.5 Iodine content in some foods, in μg for every the world, most probably because of the high
100 g of the product (content may vary according to the
consumption of algae in the diet. It is estimated
geographical area and the content of iodine in the soil
that the daily iodine intake in this population
Foods Iodine content ranges between 5280 and 13,800 μg, 5–14 times
Red mullet (150 g) 150 higher than the upper safety limit of 1 mg for the
Calms, cockles and bi-valve mollusks 120
United States. In Japanese women, this high
in general
iodine intake is associated with low rates of goi-
Allioids (garlic) 94
Crustaceans such as shrimp, prawns 90
ter, autoimmune thyroid disease, breast cystic
and scampi disease, or breast cancer [36, 37]. Some addi-
Salmon (150 g) 60 tional sources of iodine are iodized contrast
Perciform fish (grouper) 52 media, water purification tablets and medica-
Fresh fish (150 g) 45 tions such as multivitamins, anti-arrhythmics
Pineapple (150 g) 45 like amiodarone (that contains close to 75 mg in
Lobsters and decapode crustaceans 40 each 200 mg tablet), topical disinfectants like
like king crabs povidone (10 mg/mL), and Lugol’s solution,
Tuna, bonito, sardines in oil (100 g) 37 with a content of 6 mg of iodine for every drop,
Green beans, chards 35 and saturated potassium iodide solution which
Eggs 20 contains 38 mg of iodine per drop [36].
Herbaceous plants like onions 20
Edible mushrooms 18
Whole rice (80 g) 18 Iodine Metabolism
Pleuronectiform or flat fish (sole) 17
Fabaceous plants like dry faba beans 14
Biosynthesis and secretion of thyroid hormones
and peanuts
require several steps, including the following:
Cow’s milk 9
iodide absorption from the gastrointestinal tract
Carrot-type vegetables 9
Solanaceous plants (tomatoes) 7
into the blood stream; iodide uptake in the thy-
Prunes 7
roid by the NIS and its transport into the follicu-
Lean pork 5.2 lar lumen, which is partly mediated by Pendrin
Lettuce 5 (PDS); oxidation of iodide, which involves TPO
Yogurt 3.8 and H2O2 generated by dual oxidases (DUOXs);
Potatoes 3 iodination of Tg; storage of thyroid hormones in
Lime 3 a Tg-bound form; and reabsorption and hydroly-
Spanish ham (20 g) 2.2 sis of follicular Tg and secretion of thyroid hor-
mones (Fig. 3.5).
Iodine, as a component of thyroid hormones,
general, iodine concentrations in frequently con- accounts for 65 % and 58 % of the weight of thy-
sumed foods are highly variable (3–80 μg per roxin (T4) and triiodothyronine (T3), respec-
serving). In the mid 90s in the US, mean iodine tively. When ingested, iodine is absorbed through
intake was estimated at 190–210 μg/day for the small intestine and transported in plasma to
women, the most abundant sources being milk the thyroid where it is concentrated, oxidized and
and bread. The situation is similar in other coun- incorporated into Tg to form monoiodotyronine
tries like Switzerland where the mean iodine (MIT) and diiodotyronine (DIT), and then gives
intake measured directly from food is 140 μg/ rise to T3 and T4 formation. Of the total iodine
day. Other food sources of iodine are shown in used by the body, 96–99 % is metabolized in the
Table 3.5. It is important to bear in mind that thyroid gland, while the rest is used by other
some iodophors and fertilizers may modify organs or systems like the retina and the choroid
iodine content in food. In countries like Japan, plexus. The thyroid and the kidneys remove most
iodine intake from food is among the highest in of the iodine from plasma, regardless of the
3 Iodine and the Thyroid 37
Gastrointestinal
tract
(iodine, iodide)
Plasma iodide
Hormonal metabolism in I - Trapping,
somatic cells. Conversion elevated TSH,
of T4 to T3 and to rT3 reduced KCLO4
Renal excretion
(Deiodination)
Liver
Intra-thyroid
iodide
Peroxidase
es
inas +
iod
TSH
De H2O2
IT
D
+
Intestine Oxidized
IT
M
iodine
Plasma transport of
thyroid hormones Deiodinase MIT MIT
(albumin, DIT DIT
thyroxine-binding Peroxidase
TSH +
globulin)
MIT H2O2
DIT
T4
T3 TSH
KI Tg
Tg
Fecal Loss Protease
Fig. 3.5 Iodine metabolism: When ingested, iodide is is deiodinated to T3. The hormone plays out its metabolic
trapped and oxidized in the thyroid gland and binds to effects in the cell and is finally deiodinated; iodide is
tyrosine to form iodotyrosines; the coupling of iodotyro- reutilized or excreted in the kidneys. A second cycle
syl residues forms T4 and T3; the hormone secreted by the occurs inside the thyroid through deiodination of
gland is transported in the serum, and a fraction of the T4 iodotyrosines
amount of iodine or other anions present [37, 38]. mediates active iodine transport in the thyroid
Renal clearance of iodine depends mainly on the and other tissues, such as salivary glands, stom-
glomerular filtration rate, with no evidence of a ach, lactating breast, and small intestine mediates
tubular secretion mechanism or phenomenon, or iodine transport to the inside of follicular cells in
of active transport. Reuptake is partial and pas- what is considered the first step in thyroid hor-
sive and hypothyroidism may decrease renal mone biosynthesis. In the thyroid, the transport
clearance while as hyperthyroid states may of iodide from the extracellular space to the fol-
increase it. Using a mean value of iodine intake licular lumen requires two steps: the transport in
in the diet of 150 μg/day, the thyroid clears serum the cell at the basal side and in the lumen at the
iodine at an average rate of approximately 17 mL apical side. The first step is mediated by the NIS
per minute, but rates could be as high as 100 mL/ and the second step by PDS. The NIS is located
min in iodine deficient areas. A normal thyroid at the basolateral plasma membrane of the thy-
gland maintains a free iodine concentration roid follicular cells actively transports iodide into
20–50 times higher than plasma levels – depend- the thyroid using the electrochemical gradient
ing on the amount of iodine available and gland generated by the Na,K-ATPase pump (a member
activity – the concentration gradient may be of the P-type class of ATPases, is a critical pro-
greater than 100:1 in primary hyperthyroidism. tein found in the membranes of all animal cells. It
SNI is the plasma membrane glycoprotein that functions in the active transport of sodium and
38 H. Vargas-Uricoechea et al.
potassium ions across the cell membrane against Tg and the coupling of iodotyrosyl residues to
their concentration gradients. For each ATP the generate functionally active thyroid hormones,
pump breaks down, two potassium ions are trans- T3 and T4. The single gene encoding TPO is
ported into the cell and three sodium ions out of located on chromosome 2p25 which spans at
the cell. Ion (K+) channels provide a K + −selec- least 150 kb and contains 17 exons. The matrix
tive aqueous pore for the diffusion of K+ across for the synthesis and storage of T4 and T3 is Tg,
the plasma membrane and are essential for the a large glycoprotein secreted by the thyroid fol-
function of most, if not all, mammalian cell types. licular cells. H2O2 is produced by two isoform
Voltage-gated potassium (Kv) channels are gated enzymes, DUOX1 and DUOX2 –which were ini-
(opened and closed) by changes in membrane tially identified in the thyroid as Nicotinamide
potential. They are opened by membrane depo- Adenine Dinucleotide Phosphate Oxidases
larization and are essential for the timely repolar- (NOX) that produce H2O2. DUOX1 and DUOX2
ization of excitable cells. KCNQ1-KCNE2 are a calcium dependent flavoproteins NADPH
channels are essential for the physiology of at oxidase, which requires a maturationfactor
least two types of no excitable, polarized epithe- known as DUOXA1 and DUOXA2. DUOXA1
lial cells: gastric parietal cells, which secrete gas- and DUOXA2 are required as maturation factors
tric acid, and thyroid epithelial cells. The to localize DUOX1 and DUOX2, respectively, to
requirement for KCNQ1-KCNE2 for thyroidal the cell membrane. Both DUOX and TPO colo-
iodine uptake may indicate that KCNQ1-KCNE2 calize on the apical membrane of the thyroid fol-
is necessary for adequate function of NIS, the licular epithelium. The H2O2 produced by
primary thyrocyte iodine uptake conduit (the first DUOXs is used by TPO to oxidize iodide, to
step in thyroid hormone biosynthesis requires a iodinate tyrosyl residues of Tg to form MIT and
constitutive active potassium channel promoting DIT; then, they subsequently couple to the iodo-
potassium efflux). Iodide efflux into the follicular tyrosines to form T3 and T4. Finally,
lumen is mediated in part by PDS, in conjunction Monocarboxylate Transporter 8 (MCT8,
with an as of yet unidentified channel. PDS is a SLC16A2) is a thyroid hormone transmembrane
highly hydrophobic membrane protein located at transport; MCT8 belongs to the major facilitator
the apical membrane of thyrocytes. In addition to superfamily of 12 transmembrane-spanning pro-
the thyroid, PDS is also expressed in the kidney teins and mediates energy-independent bidirec-
and in the inner ear. In the kidney, PDS plays an tional transport of iodothyronines across the
important role in acid–base metabolism as an plasma membrane [37–39].
exchanger of chloride and bicarbonate in In order to ensure the necessary supply of
β-intercalated cells. In the inner ear, PDS is iodide for thyroid hormonogenesis the iodotyro-
important for generation of the endocochlear sine deiodinase enzyme (DEHAL1) deiodinates
potential. PDS belongs to the SLC26A family, MIT and DIT, molecules that are formed in
which includes several anion transporters, as well excess within the Tg pre-hormonal matrix and
as the motor protein prestin that is expressed in become again free after hydrolysis of Tg by
outer hair cells. PDS is encoded by the SLC26A4 cathepsines, leading to the liberation and secre-
gene, which is located on chromosome 7q21-31 tion of T3 and T4. DEHAL1 then “Recovers” one
and contains 21 exons with an open reading or two iodide molecules contained in MIT and
frame of 2343 bp. At the intraluminal side, iodide DIT for further synthesis of thyroid hormones,
is oxidized, a reaction that requires H2O2 (which and this function represents an intrathyroidal
is the final electron acceptor for the biosynthesis mechanism of iodide recycling and efficient hor-
of the thyroid hormone catalyzed by TPO at the monogenesis (Fig. 3.6). This allows the re-
apical surface of thyrocytes). The oxidation of utilization of iodide within the thyroid cell. When
iodide is mediated by TPO. Human TPO is a dietary iodine is sufficient, the major product of
110 kDa membrane-bound, glycosylated, heme- the thyroid gland is T4 which is secreted at a rate
containing protein that catalyzes the iodination of of 10-fold that of T3. Thus, a rate-limiting step in
3 Iodine and the Thyroid 39
K+ 2K+
I– 2 Na+
MCT8 KCNE2 KCNQ1 –
TSH Na,K
ATPase
K–
T3
3 Na+ I– Na+
T4
DIT MIT I–
Hydrolysis Tg Tg I–
DEHAL1
Tg Tg Tg
T4 T3
DUOXA2
PDS
DUOX2
O2 H2O2
TPO
I–
Tg
T3 Tg DIT
HO CH2 H2O2
HO O CH2 H2O2 HO CH
Tg 2
Tyrosine residues
MIT TPO
T4 TPO HO CH2 HO CH
2
Tg HO O CH2
Coupling Organification
Fig. 3.6 Iodine transport mechanism: The fine balance between each of the components present in the figure, involves
the proper metabolism and transport of iodine in the thyroid follicular cell, see text for more details
thyroid hormone action is the conversion of the DIT is considered the main T4-activating enzyme,
prohormone T4 to T3. This is the major role of given its high substrate affinity. DIT-mediated T3
two enzymes –type 1 and 2 iodothyronine deio- production happens intracellularly. Subsequently,
dinases. Deiodinases exert a major metabolic T3 leaves the cells and enters the plasma com-
control of intracellular thyroid hormones concen- partment, being responsible for 70 % of all extra-
trations leading to a tissue-specific thyroid hor- thyroidal T3 production in healthy humans. The
mones bioavailability. All deiodinases are major role of DIT is to control the intracellular
membrane-anchored proteins of 29–33 kDa that T3 concentration, its availability to the nucleus,
share substantial sequence homology. They cata- and the saturation of the nuclear T3 receptor in
lyze and sequentially remove stereo-specific target tissues. It is mainly active in brain, pitu-
iodine atoms from T4, generating active and itary, and skeletal muscle. Type 3 (D3) is
inactive isomers of both T3 and DIT. The deio- expressed in the brain and other tissues. It irre-
dination of T4, T3, and other iodothyronines is an versibly inactivates T3 or prevents activation of
integral component of thyroid hormones homeo- T4 by catalyzing removal of an inner ring iodine
stasis. There are three deiodinases: Type 1 (D1), atom to generate DIT or rT3, respectively. D3 is
localized to the plasma membrane and catalyzes an integral membrane protein that exerts its role
removal of inner or outer ring iodine atoms in as a homodimer. It is recycled through a system
equimolar proportions to generate T3, reverse T3 of endosomal clathrin-coated vesicles, this might
(rT3), or DIT, depending on the substrate. Most suggest a possible mechanism for D3 reactiva-
of the circulating T3 is derived from conversion tion, and furthermore the possibility that this
of T4 to T3 by the actions of D1. Type 2 (D2), enzyme acts on both extracellular and intracellu-
which is considerably more efficient than D1, lar pools of T3 and T4. Moreover, the inactiva-
catalyzes only the removal of an outer ring iodine tion of D3 prevents thyroid hormones access to
atom from T4, generating the active product T3. specific tissues at critical times and reduces
40 H. Vargas-Uricoechea et al.
thyroid hormones receptors saturation. Given those areas where iodine intake is marginal, mod-
these functions, D3 is considered the major phys- erate increases in iodine intake may induce
iological inactivator and terminator of thyroid hyperthyroidism in individuals with autonomous
hormones action at the peripheral level [40, 41]. thyroid nodules. Consequently, clinicians must
be aware of the risk of inducing hyperthyroidism
when prescribing iodine-containing drugs such
Toxic Effects of Iodine Excess as amiodarone and iodinated contrast media [44].
Iodine-induced hyperthyroidism may be con-
In areas where the majority of the people are firmed by means of ioduria which appears ele-
iodine “sufficient”, there is high tolerance to vated and also by means of thyroid scan with
iodine intake. In general terms, the thyroid car- I-131 uptake.
ries a pool of iodine and may regulate iodine Iodine organification will depend on the
uptake within a broad margin, allowing a specific excess amount of iodine provided in a process
level of thyroid hormone synthesis (in normal that exhibits a biphasic response to iodine excess:
thyroids). In areas where dietary iodine intake is an initial phase of increased organification, and a
very high – e.g., Japan – adults may tolerate second phase of reduced organification in
amounts greater than 1,000 μg/day; however, in response to a relative blockade of this phenome-
children, amounts greater than 500 μg/day are non. This reduced iodine organification due to
associated with goiter [42]. If iodization pro- increased supplementation is known as the
grams are not appropriate or there is excess “Wolff-Chaikoff effect”, a TSH-independent
dietary salt consumption, the population will self-regulated blockade based on an intracellular
have a given risk of disorders due to excess iodine iodine molar concentration ≥10-3. Susceptibility
intake. The main consequence is iodine-induced to this phenomenon may be due either to iodine
hyperthyroidism, which usually occurs in people “trapping” mechanisms, as is the case in Graves-
with endemic goiter due to iodine deficiencies Basedow disease, or to the inability to form
supplemented with the trace element. This organic iodine, as is the case after giving radioac-
response is known as the “Jod-Basedow effect’ tive iodine therapy or during thionamide treat-
and occurs only in a small proportion of the ment, or in patients with Hashimoto’s disease.
patients at risk [43]. The best documented experi- Goiter or hypothyroidism may develop in those
ence was described in Tasmania, where a tempo- situations if iodine supply is maintained for long
rary increase in the diagnosis of thyrotoxicosis periods of time. The exact biochemical mecha-
occurred shortly after the addition of small nism underlying the Wolff-Chaikoff effect is still
amounts of iodine to bread as the selected method unclear, but it could be explained – at least par-
selected for addressing iodine deficiency. The tially- by the generation of several inhibitory sub-
analysis of that population revealed two patterns stances (such as intrathyroidal iodolactones,
of underlying thyroid dysfunction. The first pat- iodoaldehydes and/or iodolipids) on thyroid per-
tern was the presence of nodular goiter with oxidase activity, or also on the basis of triiodide
autonomous function areas, especially in elderly reaction: I− + I2↔I3−
individuals, with no finding of TSH receptor anti- At high iodide concentrations, this reaction is
bodies. The second pattern occurred in the displaced to the right due to mass action, trap-
younger population in the form of diffuse goiter ping I2, considered to be an intermediary in
and the presence of TSH receptor antibodies, iodine organification [40]. When moderate or
suggesting that the Jod-Basedow effect occurred high iodine doses are given repeatedly, organifi-
only in thyroid glands where function was inde- cation and thyroid hormone formation inhibi-
pendent from TSH-mediated stimulation. tion is partially corrected. This “escape” or
However, iodine-induced hyperthyroidism is a “adaptation” mechanism occurs because iodine
metabolic disorder that is relatively frequent in transport diminishes and thyroid iodine concen-
areas with very high iodine intake. In fact, in tration is insufficient to maintain the complete
3 Iodine and the Thyroid 41
Less Normal
a T3 and T4 b release of
released T3 and T4
↓ T2 and T4 ↓ T3 and T4
TPO TPO
Sodium-Iodide
Follicular symporter
cell
Fig. 3.7 (a, b) The Wolff–Chaikoff effect and escape ondary to elevated levels of circulating iodide. When
mechanism: Is a reduction in thyroid hormone levels moderate or high iodine doses are given repeatedly, organ-
caused by ingestion of a large amount of iodine; is an ification and thyroid hormone formation inhibition is par-
auto-regulatory phenomenon that inhibits organification tially corrected; this “escape” or “adaptation” mechanism
in the thyroid gland, the formation of thyroid hormones occurs because iodine transport diminishes and thyroid
inside the thyroid follicle, and the release of thyroid hor- iodine concentration is insufficient to maintain the com-
mones into the bloodstream. This becomes evident sec- plete Wolff-Chaikoff effect (See text for more details)
Wolff-Chaikoff effect (Fig. 3.7). This response failure to escape from the Wolff-Chaikoff effect-
is a manifestation of the thyroid self-regulated Iodine excess can cause hypothyroidism and/or
inhibition of iodine transport, preventing the goiter, but if autonomously functioning nodules
development of hypothyroid goiter in the nor- or a subclinical form of Graves’ disease are pres-
mal population [45, 46]. On occasions, the ent, it can also induce hyperthyroidism (Jod-
“escape” or “adaptation” phenomenon does not Basedow effect). Both phenomena are thought to
occur, giving rise to the persistent inhibition of lead to some thyroid destruction and hence pre-
thyroid hormone formation, leading to hypothy- sentation of the most important antigens involved
roidism and goiter (myxedema). The Wolff- in thyroid autoimmunity, such as Tg and TPO.
Chaikoff effect is short-lived because SNI Although the mechanisms are not fully eluci-
biosynthesis comes quickly to a halt, intracel- dated, excess iodine is a well-recognized envi-
lular iodine drops below the molar concentra- ronmental factor for Autoimmune Thyroid
tion of ≥10(−3), and iodine organification Disease (ATD) in autoimmune-prone individu-
resumes. This marked drop in SNI activity als, particularly Autoimmune Thyroiditis (AIT),
occurs through TSH-independent self- Toxic which is characterized by lymphocytic infiltra-
effects of iodine excess. In areas where the tion of the thyroid gland with the development of
majority of the people are iodine “sufficient”, thyroid autoantibodies and primary hypothyroid-
there is high tolerance to iodine intake. In gen- ism [47–49].
eral terms, the thyroid carries a pool of iodine Thyroid autoimmunity in the context of an
and may regulate iodine uptake within a broad iodine excess state could be induced by: (a)
margin, allowing a specific level of thyroid hor- Excess iodine induces the production of cyto-
mone synthesis (in normal thyroids). kines and chemokines that can recruit immuno-
In summary, excessive iodine intake can cause competent cells to the thyroid – has been reported
“thyroid dysfunction”, especially in patients with that high concentrations of iodine induced thy-
underlying autoimmune thyroiditis – due to a roid cell injury and subsequent inflammation
42 H. Vargas-Uricoechea et al.
with production of reactive oxygen species, Amiodarone can lead to both hypothyroidism
which may contribute to the initiation of thyroid (Amiodarone-Induced Hypothyroidism (AIH)
autoimmunity: (b) It seems that iodide preferen- with a prevalence ranging from 10 to 20 %) and,
tially induces chemokines rather than other less commonly to hyperthyroidism with a preva-
inflammatory cytokines: (c) Processing excess lence ranging from 2 to 9.6 %). Most patients
iodine in thyroid epithelial cells may result in treated with amiodarone will remain euthyroid
elevated levels of oxidative stress leading to throughout the treatment course.
harmful lipid oxidation and thyroid tissue inju-
ries: (d) Iodine incorporation in the protein chain
of thyroglobulin may augment the antigenicity of Diagnosis of Iodine Deficiency
this molecule: (e) The mechanism of iodine
excess-induced ATD is partly regarded as T There are four generally accepted and recom-
helper type 1 (Th1) cell and/or T helper type 17 mended methods for assessing the nutritional
(Th17) cell dominant autoimmune disease. Both aspects of iodine in a population: urine iodine
the hyperactivation of Th17 cells and the sup- concentration, goiter rates, Tg levels, and thyroid
pression of Th1 (and T helper type 2), and regula- stimulating hormone (THS) levels. These mea-
tory T cells may be involved in the pathogenesis surements are not exclusive but complementary
of ATD [50, 51]. since ioduria is a sensitive indicator of recent
On the other hand, amiodarone is a potent iodine intake (days), while Tg levels show iodine
class III anti-arrhythmic drug used in clinical status in the population (over weeks to months),
practice for the prophylaxis and treatment of and changes in goiter rates show long-term iodine
many cardiac rhythm disturbances, ranging nutritional status in a population (over months
from paroxysmal atrial fibrillation to life-threat- and years).
ening ventricular tachyarrhythmias. Amiodarone
often causes changes in thyroid function tests Ioduria: Essentially 90 % of the total iodine
mainly related to the inhibition of 5′-deiodinase content absorbed is cleared through the urine.
activity resulting in a decrease in the generation This is why measuring this trace element in urine
of T3 from T4, with a resulting increase in is considered a way to assess recent intake,
reverse T3 (rT3) production and a decrease in its although concentrations may vary from day to
clearance. day and even throughout the same day. Iodine
Amiodarone is a benzofuran derivative con- urine concentration may be expressed in μg/L, or
taining two atoms of iodine per molecule. This in relation with creatinine (μg/g creatinine), or
amount to 37.5 % of organic iodine by molecular also as 24 h urine concentration (μg/day).
weight, and 10 % of the drug’s iodine content is Considering that 24-h urine is impractical in pop-
released daily as free iodide. Drug doses range ulation studies, it is usually recommended to
from 200 to 600 mg daily and treatment releases measure ioduria in a urine sample taken either in
about 7–20 mg of iodide daily, which is about the morning or at random (0.5–1 mL) in a spe-
50–100 fold the optimal daily iodine intake. cific group, and it is expressed as median ioduria
Although the majority of the adverse effects of in μg/L. Although median ioduria does not reflect
amiodarone on several organs are due to deposi- thyroid function, it is clear that a low urine con-
tion of the drug in the parenchyma, its effects on centration points to an increased risk of suffering
the thyroid gland can be divided into two groups: thyroid disorders. Creatinine and creatinuria are
intrinsic effects resulting from the inherent prop- not taken into consideration in the vast majority
erties of the compound, and iodine-induced of studies designed to determine iodine status in
effects due solely to the pharmacologic effects of a population, given that creatinine concentration
a large iodine load – it has the potential to cause is low in those regions with a significant fre-
thyroid dysfunction because of its iodine-rich quency of malnutrition [52, 53]. Ioduria may be
chemical structure. used to extrapolate daily iodine intake in the
3 Iodine and the Thyroid 43
p opulation using the estimated 24-h mean uri- prevalence. In areas with moderate-to-severe
nary volume and assuming an average iodine bio- IDD, goiter screening using palpation must be
availability of 92 % on the basis of the following the option of choice because of ease of applica-
formula: tion, reproducibility and low cost. Goiter rate in
school children is an indicator of IDD severity in
Daily iodine intake = urinary iodine ( µg / L ) a specific population. A rate ≥5 % in this age
× 0.0235 × body weight ( kg ) group is an indicator of a public health problem.
Thyroid volume interpretation requires validated
Using this formula, a median ioduria of 100 μg/L reference ranges in children living in iodine “suf-
would correlate with an average mean intake of ficient” areas. In 1997, the WHO together with
150 μg. Several methods for measuring ioduria International Council for the Control of Iodine
have been described; however, these methods are Deficiency Disorders (ICCIDD) proposed refer-
not universally available. The method most ence values for thyroid volume based on data of
widely available is “Method A” which uses European children, but those reference values
ammonium persulfate and requires the use of were much higher than they actually are. Thyroid
spectrophotometry. The second is “Method B” volumes in other areas of the world (Switzerland,
which uses chloric acid, although it has the draw- the United States, Malaysia) were shown to be
back of explosion risk during the test. There are much lower than those referenced in the European
other tests, but Method A is preferred in popula- school population, although this could be
tion studies, followed by Method B [52]. explained on the basis of the residual effect from
iodine deficiency prevailing in Europe in the
early 1990s. Later, thyroid volumes were mea-
Thyroid volume: There are two methods for sured in children between 6 and 12 years of age
assessing thyroid volume: physical inspection in areas that had been “sufficient” for a long time
and palpation, and thyroid ultrasound. On palpa- in North and South America, Central Europe,
tion, goiter is considered to be present when each Eastern Mediterranean, Western Pacific Africa,
lateral lobe is longer that the distal phalanx of the and children from most ethnic majorities in the
examiner’s thumb. According to the WHO clas- world. The sample consisted of 3529 children,
sification system, grade 0 is non-palpable or vis- divided by age and gender; the median ioduria
ible thyroid gland; grade I is palpable but range was 118–288 μg/L. Significant differences
non-visible goiter with the neck in normal posi- were found in mean thyroid volume adjusted by
tion; and grade II is evidently visible goiter with age and body surface, suggesting that reference
the neck in a the normal position. This is perhaps values for a specific population in countries with
the most widely accepted classification because it long standing iodine “sufficiency” may be more
is easy to use and interpret even in the hands of an accurate than an international reference standard.
inexperienced examiner. Goiter prevalence may These reference values are recommended for goi-
be determined also with the use of thyroid ultra- ter screening during IDD monitoring, and they
sound. In those areas with mild IDD, goiter prev- are more conservative than those previously used,
alence may be low, hence the low diagnostic although it is clear that inter-observer variability
sensitivity and specificity of palpation alone. with this method is high – up to 26 % – [52, 54,
Moreover, classification error may be as high as 55]. In order to improve thyroid volume data reli-
40 %, and in those situations ultrasound may be ability and comparability on ultrasound when
more reliable than palpation. However, there are monitoring for IDD, a standardized approach has
few data comparing ultrasound with palpation in to be adopted worldwide [32, 40]. Thyroid vol-
areas where IDD is more prevalent. In fact, thy- ume is calculated by adding the volume of each
roid ultrasound is considered to have lower accu- lobe, and it does not include thyroid isthmus vol-
racy in areas with severe IDD and, consequently, ume. The following formula is used to calculate
palpation is a better way to estimate goiter the volume of each lobe:
44 H. Vargas-Uricoechea et al.
vehicle for adjusting salt intake by introducing c urrent literature does not provide unequivo-
iodine-enriched salt in the baking process. cal evidence for significant health effects for
Iodization of water and irrigation systems may populations with urinary iodine in the upper
also be useful, but this requires costly methods range of mild iodine deficiency.
that limit its application. Countries like • There is sufficient evidence to suggest that the
Switzerland and US have additional iodine known association between neurological out-
sources through milk in the diet, more because of comes and moderate and severe iodine defi-
the use of iodophors in the food industry than the ciency is likely to extend to mild iodine
deliberate addition of iodine. In countries affected deficiency. However, there is a suggestion of a
by IDD, it is considered that iodine must be dose response relationship with increasing
added routinely to complementary foods in order effects on neurological development with
to increase iodine content derived from daily higher iodine deficiency levels. Neurological
intake. In remote areas or areas of difficult access, effects associated with mild iodine deficiency
or where small-scale salt producers exist, salt include reduced IQ, increased auditory thresh-
iodization programs may not work or create the old and increased rates of attention-deficit
expected social impact. In those situations, the hyperactivity disorder. Although the relation
recommendation is to replace iodine by means of between iodine intake during pregnancy, thy-
iodized oils administered orally or intramuscu- roid function, and child neurodevelopment
larly. The oral route is easier, but the intramuscu- needs further evaluation, the evidence on the
lar route is more effective and has longer lasting safety and effectiveness of iodine supplemen-
effects. The oral dose ranges between 200 and tation during pregnancy is needed before it is
400 mg of iodine per year and it is usually admin- systematically recommended in iodine-
istered to the most vulnerable population (preg- sufficient or mildly deficient areas.
nant women, children and women in childbearing • In constructing a reasonable health-based
age). Iodine may also be given in the form of standard using the precautionary approach, it
potassium iodide or iodate drops or tablets; the is clear that urinary iodine levels below
monthly (30 mg) or biweekly (8 mg) dose of 100 μg/L, which are in the mild iodine defi-
potassium iodide may be sufficient to provide the ciency range, warrant intervention [1, 57, 58].
adequate amount of iodine, in particular to the
population at risk [52, 56]. Iodine requirements are increased ≥50 % dur-
ing pregnancy, and iodine deficiency can cause
maternal and fetal hypothyroidism and impair neu-
Impact of Iodine Supplementation rological development of the fetus. The conse-
in Deficient Populations quences depend upon the timing and severity of the
hypothyroidism. The most severe manifestation is
A review of the evidence of the health conse- cretinism. In moderate-to-severely iodine-deficient
quences of mild iodine deficiency reveals that: areas, controlled studies have demonstrated that
iodine supplementation before or during early
• There is a limited number of published studies pregnancy eliminates new cases of cretinism,
investigating the health consequences of mild increases birth weight, reduces rates of perinatal
iodine deficiency. and infant mortality and generally increases devel-
• There is reasonable evidence of an association opmental scores in young children by 10–20 %.
between mild iodine deficiency and sub- Mild maternal iodine deficiency can cause thyroid
optimal neurological development, specially dysfunction but whether it impairs cognitive and/or
reduced Intelligence Quotient (IQ). neurologic function in the offspring remains uncer-
• Of the studies that have attempted to investi- tain. To date, measures to address iodine deficiency
gate the effects of mild iodine deficiency, in populations with mild-to-moderate deficiencies
many have limitations. Consequently, the have been shown to prevent (during gestation)
46 H. Vargas-Uricoechea et al.
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The Role of Thyroid Hormones
in Neural Development 4
Alan J. Hargreaves
Abstract
A key aim of this chapter was to review the molecular events associated
with the regulation of neural development by thyroid hormones. These
molecules are produced in the thyroid gland, and secreted into the blood-
stream, where they interact with a number of carrier proteins to facilitate
distribution to target tissues. A range of transporter proteins are also pres-
ent to facilitate uptake in tissues that require TH for their normal develop-
ment. Research over several decades has shown that TH can regulate
neural gene expression both at the transcriptional and post-transcriptional
levels. This review focuses partly on the ability of TH to modulate genes
encoding cytoskeletal proteins involved in the regulation neural cell prolif-
eration and differentiation, and how dysregulation of TH is associated
with cytoskeletal disruption. It also discusses selected non-genomic mech-
anisms by which TH can influence cytoskeletal involvement in develop-
ment and other important cell functions.
I I
NH2
T4 HO O CH2CH
COOH
I I
Thyroid Hormone Transport, Uptake teins mentioned above transport bound T4 to the
and Metabolism blood brain barrier but, of these, only transthyre-
tin has been detected in large amounts in cerebro-
Due to their hydrophobic nature, after being spinal fluid, as a result of its synthesis and
secreted from the thyroid gland, THs utilise a secretion by the choroid plexus epithelial cells
number of proteins in the circulation and within [20, 25, 26]. On arrival at the blood brain barrier,
target cells that can facilitate their movements to TH requires the assistance of a number of trans-
their target tissues (e.g. brain), maternal-foetal membrane transporter proteins, which facilitate
transfer during early development, transfer uptake and release in a variety of cell types and
across the blood brain barrier in children and brain regions, to enable it to reach the appropriate
adults, and their metabolism [8, 17–20]. Major tissue [20]. Several brain TH transporter proteins
TH-binding proteins in serum include albumin, have been described, including Mct8, Mct10,
transthyretin, thyroxine-binding globulin and Lat1, Lat2 and Oatp14, which exhibit both simi-
apolipoprotein B-100 [17, 20, 21]. Collectively larities and differences in their regional distribu-
these proteins help to maintain an equilibrium tion and developmentally regulated expression
between protein-bound and free (i.e. non protein- patterns [20, 27]. It has been suggested that coor-
bound) TH, such that the necessary amount of dinated expression of TH transporters occurs in
free hormone is available in the circulation of alignment with the expression and activities of
healthy individuals [8]. deiodinases D2 and D3, in order to enable timely
While this system effectively maintains a sup- maturation of brain cells during development
ply of free TH to target cells and tissues in healthy [28, 29].
adults, during embryonic and foetal development Having crossed the blood brain barrier, T4 can
there are other barriers to TH reaching its target then be bioactivated (i.e. converted to T3) by the
tissue, namely the placental barrier. For example, deiodinase D2; alternatively T4 and T3 can be
during early development as foetal thyroid gland converted to an inactive from of TH termed
dose not secrete TH in the first 4 months of gesta- reverse T3 [20]. Deiodinases exhibit distinct dis-
tion, the foetus is dependent on the maternal sup- tribution patterns in neural cells and tissues [30,
ply of TH during this period [22]. Its transport 31], D2 being more prevalent in glial cells [32,
across the placental barrier involves TH binding 33], while D3 may be more abundant in certain
proteins, such as albumin and transthyretin, neurons [30], although developmental fluctua-
which are actually synthesised in the placental tions can occur.
trophoblast cells and are also secreted and taken On entering the cytoplasm of target cells, T3
up by them, the latter involving an LDL-mediated interacts with a thyroid hormone receptors (TRs)
receptor mediated endocytosis pathway [18, 23]. present in the nucleus [34–36]. Members of the
Transplacental transfer is further dependent on steroid-retinoic acid-thyroid hormone superfam-
the action of a number of TH transporters, which ily, TRs exist in two main forms termed TRα and
are expressed by trophobasts from 6 weeks of TRβ, each of which has at least 2 isoforms, show-
gestation [24]. On entry into the placental cells ing regional variation within the brain and dif-
T4 can be converted to T3 by deiodination medi- ferential patterns of expression during early and
ated by type III deiodinase (D3) [18]. Thus, the late development which may reflect distinct func-
delivery of T3 to the foetus is dependent on the tions at key developmental stages [35]. Like other
coordinated action of TH binding proteins, TH members of the nuclear receptor superfamily,
transporters and deiodinase activities in tropho- TRs contain an amino terminal domain, a central
plasts [4, 18]. DNA binding domain with two zinc fingers, a
The delivery of TH to the brain requires its hinge region containing the nuclear localisation
transfer across the blood brain barrier, which is signal and a carboxy terminal ligand binding
the main route of entry for T4, or the brain- domain which is essential for TH attachment
cerebrospinal fluid barrier. The four serum pro- [36]. The TRs are effectively T3-inducible
52 A.J. Hargreaves
transcription factors that, once activated, induce there is disruption of the action of neurotrophins,
changes in the expression of a variety of neural molecular organisation and signalling at gluta-
genes of importance during development and in matergic synapses in the hippocampus of adults
later life, whereas the unliganded receptors act as born from thyroxinemic mothers [44].
repressors. However, TH may interact with other A study by Chakraborty et al. [45] on neonatal
proteins in the cell membrane or the cytoplasm to rats from mothers that were treated prenatally
induce a range of rapid non-genomic effects, as with propylthiouracil (PTU) to induce mild hypo-
discussed later. thyroidism, detected a significant reduction in the
levels of the BDNF in the hippocampus. These
findings suggested that mild hypothyroidism dur-
Disruption of Brain Development ing pregnancy could contribute to the adverse
by Thyroid Hormone Depletion neurodevelopmental effects observed in later life
by causing reduced levels of BDNF in the hip-
The development of all organ systems is dis- pocampus during early postnatal development.
rupted by the lack of active TH, leading to a range In a study by Berbel et al. [46], pregnant
of developmental abnormalities [37]. However, female rats were thyroidectomised at embryonic
the brain is so severely affected that mental retar- day 18 and infused with calcitonin and parathor-
dation and other neurological effects can result mone until giving birth as a model of late mater-
from deficiencies during foetal or perinatal devel- nal hypothyroidism (LMH). Analysis of LMH
opment [4, 5, 8, 36–39]. pups revealed major disruption of the same hip-
Studies in humans have shown that TH defi- pocampal region as that affected by chemically-
ciency disrupts the normal patterns of brain induced hypothyroidism [44], as well as
development and is associated with neurological disruption of signalling pathways known to be
lesions such as attention deficit and hyperactivity important in neural cell differentiation and learn-
disorders, and impaired cognitive function [40– ing deficits. The fact that maternal administration
43]. A study performed on rats transiently treated of T4 ablated the effects of thyroidectomy sug-
with 2-mercapto-1-methylimidazole to induce gests that, although foetal thyroid function is up
hypothyroxinemia resulted in a statistically sig- and running by this stage of pregnancy, there is
nificant impairment of spatial learning in the off- still a dependence on maternal TH for normal
spring in adulthood, as determined by the water brain development in the offspring and that its
maze test, in conjunction with impairment of depletion can have serious developmental
long term potentiation (LTP) in the hippocampus, consequences.
a process which is known to be important in cog-
nitive processes such as spatial learning [44]. The
same study showed that these physiological Effects of Thyroid Hormones
changes were associated with reduced phosphor- on Neural Cell Proliferation
ylation of c-fos, an immediate early gene- and Differentiation
encoded protein which is phosphorylated at
specific sites to support its role in spatial learn- One interpretation of the above findings is that
ing. Increased levels of the post synaptic density TH plays a key role in the differentiation of spe-
protein PSD-95, the NMDA receptor NR1 with cific groups of neural cells. To address this ques-
which it normally co-localises, and the neuro- tion, a range of studies have been performed on
trophin receptor TrkB were found, although no cellular models of neural cell differentiation to
significant change was observed in the levels of determine the role of TH in the morphological
brain derived neurotrophic factor (BDNF), which development of neurons and glial cells. An early
binds to the latter. These observations, together study found that T3 stimulated the outgrowth of
with the inability of NR1 to colocalise with PSD- neurites from cultured cells of neuronal (N2a
95 in offspring from treated dams, suggest that neuroblastoma) but not glial (C6 glioma) origin,
4 The Role of Thyroid Hormones in Neural Development 53
suggesting that T3 was able to induce neuronal drite arborisation [59, 60]. Taken together, the
cell differentiation [47]. The presence of elevated above studies provide strong evidence that T3
levels of the microtubule associated protein MAP can regulate the expression of cytoskeletal and
1B on western blots of N2a cell lysates and in other proteins that play critical roles in the matu-
axon-like neurites of immunofluorescently ration of specific groups of neurons in the brain
stained cell monolayers confirmed that this effect cortex and cerebellum.
was associated with increased levels of cytoskel- It is well established that, as well as neurons,
etal proteins known to be important in axon glial cells contain TRs and that T3 can regulate
development. Interestingly, the levels of other the development of some glial cell types particu-
cytoskeletal components such as neurofilament larly in brain cortex [2, 34, 35, 61–64]. A study
proteins, which are linked to axon stabilisation, using oligodendrocyte progenitor cells derived
have also been shown to be dependent on TH from neonatal rat brain indicated that T3 partici-
during development [48, 49]. Indeed, regulation pates in the regulation of oligodendrocyte prolif-
of cytoskeletal proteins during peripheral nerve eration and differentiation, as well as in the
regeneration, which mirrors many of the cyto- regulation of cell maturation and that the two are
skeletal events of axon growth during nerve not causally linked [64]. Such differences in the
development, was also found to be regulated by responses to T3 are likely to be due to the reported
T3 [50, 51], supporting the notion that TH plays developmental changes in the patterns of expres-
a key role in the regulation of nerve repair [52]. sion of TRs [35, 65].
Enhanced outgrowth of axon-like neurites, Other studies, using primary cultures of glial
which were visualised by indirect immunofluo- cells from developing rat brain, suggested that T3
rescence staining with antibodies to the axon- could induce astroglial differentiation as deter-
enriched microtubule stabilising protein tau, mined by the outgrowth of neurites and increased
increased expression of mRNA for the synaptic levels of glial fibrillary acidic protein (GFAP)
vesicle protein synaptophysin, and enhanced cell [66–68]. Further work showed that T3 induced
survival were reported in primary cultures of rat proliferation in cerebellar astrocytes but stimu-
cerebellar neurons [53] while enhanced synthesis lated differentiation in cerebral hemisphere
of synapsin I and synaptogenesis were observed derived astrocytes, effects that may be at least
in primary cultures of foetal rat cortical neurons partly due to T3-induced synthesis of glial
[54, 55]. Garza et al. [56] found increased neurite derived neurotrophic factors [69]. Thus, T3 can
outgrowth in acetylcholinesterase (AChE) posi- directly regulate multiple key events in both
tive cells cultured from rat cerebral hemisphere astrocyte and neuronal cell development. The dif-
cultures from 15 day embryos. These morpho- ferent responses of astrocytes from these two
logical changes were associated significant dose brain regions may be due to a number of factors
dependent stimulation of choline acetyl transfer- including differences between their cellular and
ase and AChE activities from 2 to 15 days of tissue environments and variations in the regional
treatment, respectively, suggesting T3 mediated and developmental patterns of TR receptor
stimulation of cholinergic neuron differentiation. expression [35].
TH has also been shown to modulate the out- As factors secreted by glial cells can exert tro-
growth and arborisation of dendrites by differen- phic effects on neuronal cells, it is interesting to
tiating neurones [57, 58]. Furthermore, note that conditioned medium derived from pri-
developmental TH deficiency leads to disruption mary cultures of T3-treated cerebellar astrocytes
in dendrites of Ca2+/calmodulin-dependent pro- stimulates proliferation of cultured cerebellar
tein kinase II and the expression and/or neurons, particularly when the two cell types
phosphorylation-dependent activity of MAP2 were grown in co-culture, an effect that involves
and stathmin, which play opposing roles in the altered extracellular matrix deposition and acti-
stabilisation and destabilisation of MTs, respec- vation of the EGF receptor-protein kinase A sig-
tively, and are important in the regulation of den- nalling pathway [70, 71]. Thus, as well as having
54 A.J. Hargreaves
a direct effect on neuronal cells, T3 can mediate MAPs linked to dendrite outgrowth is not under
neuronal development indirectly through its the direct control of TH but involves specific
influence on glial cell activities. transcription factors or such as RORα and basic
The above mentioned studies suggest that transcription element-binding protein [57, 58,
THs regulate important developmental changes 79]. Furthermore, the stability of the mRNA
in neural cells at least in part by regulating the encoded by a number of genes including that of
synthesis and/or distribution of cytoskeletal pro- acetylcholinesterase is repressed by T3, indicat-
teins. This notion is further supported by the ing that THs are capable of regulating neural
observation of rapid T3-stimulated tubulin and/ gene expression patterns via a range of both
or actin synthesis in cultured brain explants direct and indirect mechanisms.
from late foetal and neonatal rat brain, in pri-
mary cultures of neurons and glial cells from
neonatal rat brain and fetal human brain [72– Non-genomic and Mitochondrial
74]. It has also been shown that T3 regulates the Effects of Thyroid Hormones
expression of immature (early) and mature (late)
tau isoforms during rat brain development [75]. A number of studies have indicated that THs can
The fact that T3 deprivation in development was exert non-genomic neuroprotective or neurode-
shown to down-regulate the synthesis of pro- velopmental effects on the nervous system via
teins of the neuronal axon stabilising IF proteins protein interactions at the cell surface [80–82].
∝-internexin and neurofilament light chain (in For example the state of polymerisation of micro-
addition to the GFAP in astrocytes) shows that filaments in astrocytes is regulated by thyroid hor-
the activities of all 3 cytoskeletal networks are mone and this, in turn, modulates the TH mediated
under the influence of TH [48, 49]. Given the inactivation of [83, 84]. Thyroxine treatment was
well-established importance of the cytoskeleton found to cause a rapid loss of microfilaments but
in neural form and function, it is clear that a had no effect on total cellular levels of actin in
range of genes encoding cytoskeletal proteins cultured astrocytes, suggesting a direct influence
are modulated by TH and that such regulation on the equilibrium between monomer and poly-
plays a central role in neural development and mer [83, 84]. The T4 induced depolymerisation of
function. microfilaments was associated with reduced
While the classical interpretation of the effects internalisation and hence reduced turnover of
of THs on mammalian brain development has type II iodothyronine 5′-deiodinase [83]. The
been that they are largely due to the interaction of ability to have rapid effects on microfilament
T3 with nuclear receptors, not all genes modu- dynamics may contribute to the influence of THs
lated by thyroid hormone contain TR-responsive on neurite branching, axonal transport and cell-
elements, suggesting that many are indirectly cell contact in developing brain dendrite arborisa-
regulated by TH at the post-transcriptional level. tion. Such a rapid influence may be under the
Indeed, in terms of cytoskeletal genes, the up- direct or indirect regulation of signalling events
regulation of tubulin synthesis was suggested to shown to be triggered by TH. For example, rapid
be post-transcriptionally controlled via an effect signalling at the plasma membrane in cultured rat
on mRNA stability whereas the regulation of pituitary cells, associated with modulation of the
actin was thought to be at the level of transcrip- KCNH2 potassium channel by phosphatidylino-
tion [72–74, 76, 77]. T3 was also shown to regu- sitol 3-kinase, has been shown to involve the
late the process of differential splicing of tau interaction of T3 with TRβ2 in the nucleus via a
isoforms that enables the replacement of juvenile mechanism that is independent of DNA binding
forms of tau by mature tau variants in post natal [85]. The activity of mitogen-activated protein
rat brain, an effect that is modulated by the RNA kinase, which plays a key role in the regulation of
binding protein Musashi-1 [75, 78]. It has also neurite outgrowth, is also up-regulated [86, 87].
been found that the regulation of genes for other Furthermore, protein kinase C is an important
4 The Role of Thyroid Hormones in Neural Development 55
Abnormal levels of
thyroid hormone
Elevated ROS
Fig. 4.2 Key events involved in the disruption of cell ensues, which can lead to energy deficit and elevated lev-
proliferation and differentiation in thyroid deficient brain. els of reactive oxygen species (ROS) causing oxidative
Shown is a schematic representation of key events that stress, and cytoskeletal protein dysfunction. Altered levels
contribute to the disruption of neural development as a of cytoskeletal proteins disrupt microtubule, microfila-
result of thyroid hormone imbalance. T3 induces direct or ment and intermediate filament networks that support
indirect changes in gene expression during normal devel- neural cell proliferation, differentiation and function.
opment, leading to coordinated modulation of the levels Thyroid hormones may also induce direct effects on cyto-
of many neural proteins and their activities. Disruption of skeleton proteins forming the microfilaments networks
gene expression occurs when the normal levels of hor- and other cellular events via disruption of cell signalling
mone are not maintained. If genes encoding mitochon- pathways
drial proteins are affected, mitochondrial dysfunction
modulator of the developmental events triggered activities observed in developing hypothyroid rats
by THs; it has been found that production of [49, 92, 93].
downstream messengers of this kinase such as
diacyl glycerol, which regulates cytoskeletal Conclusion
dynamics, are up-regulated in tissue slices and THs play a key role in neural development,
cultured cells exposed to T4 [88]. abnormal TH levels being associated with a
Thyroid hormones can also affect mitochon- number of neurodevelopmental abnormalities.
drial activity either by short or long term effects, A schematic representation of key events is
with higher rates of O2 consumption in mitochon- illustrated in Fig. 4.2. Disruption of key devel-
dria from hyperthyroid rats while the converse is opmental molecular events by TH deficiency
found for hypothyroid rats [87, 89]. The mito- occurs by both genomic and non-genomic
chondrial antioxidant defence system is severely pathways and may, for example, be associated
disrupted in hypothyroid rats and restored on with down-regulation of the production of
treatment with T3, suggesting that oxidative stress neurotrophins by glial cells. Not all genes
is a major contributor to abnormal development exhibiting altered expression patterns are
when thyroid levels are sub-optimal [90, 91]. The directly affected at the transcriptional level by
consequence of elevated levels of reactive oxygen T3, which can induce changes in gene expres-
species would be oxidative damage to proteins, sion or protein synthesis via other intermedi-
lipids and DNA, which could contribute to a range ary pathways such as the regulation of RNA
of cytoskeletal effects, such as the neurofilament stability. A complex combination of changes
accumulations, altered gene expression and other at the gene and protein levels leads to impaired
56 A.J. Hargreaves
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Autoimmune Thyroid Disease
(Flajani-Parry-Graves-von 5
Basedow Disease):
Etiopathogenesis, Clinical
Manifestations and Diagnosis
Hernando Vargas-Uricoechea,
Anilza Bonelo-Perdomo,
Carlos Hernán Sierra-Torres,
and Ivonne Meza-Cabrera
Abstract
Autoimmune thyroid disease is the most common organ-specific autoim-
mune disorder affecting 2–5 % of the population in Western countries.
Graves-Basedow disease is the most frequent form of hyperthyroidism in
iodine sufficient countries; while the exact etiology of thyroid autoimmu-
nity is not known, interaction between genetic susceptibility and environ-
mental factors appears to be of fundamental importance to initiate the
process of thyroid autoimmunity. The identified autoimmune thyroid dis-
ease susceptibility genes include immune-modulating genes, such as the
Major Histocompatibility Complex, Cytotoxic T Lymphocyte Antigen-4,
CD40 molecule, Protein Tyrosine Phosphatase-22, TSH receptor and
Thyroglobulin. The exact nature of the role environmental factors play in
Graves-Basedow disease is still not well known, but the involvement of
several factors such as: iodine diet, drugs, stress, and infections has been
reported. In Graves-Basedow disease the lymphocytic infiltration of the
thyroid leads to activation of TSH Receptor (TSHR)-reactive B-cells that
secrete TSHR stimulating antibodies causing hyperthyroidism. These
antibodies bind to TSH receptors on the surface of thyroid follicular cells,
leading to continuous and uncontrolled thyroid stimulation, associated
with excess synthesis of the thyroid hormones T4 and T3, and thyroid
years. The transcendental importance of the last the disease, of which 75 % are women. It is
three authors above mentioned, had established currently stated that there are about 100 types of
that exophthalmic goiter was indistinctively iden- autoimmune diseases identified, affecting a larger
tified as Parry, Graves or von Basedow disease. population than the number affected by cancer
Though it is well known that in English-speaking and heart disease. The numerical differences
countries the term Graves Disease is commonly based on the figures identified by the various
used, in most European countries the condition is associations responsible for studying autoimmune
referred to as von Basedow’s disease. In Germany diseases are due to definitions adopted for each
for instance, the description of the clinical char- particular disease; for instance, the NIH only
acteristics of the disease is attributed to von involve 24 autoimmune diseases (based on trials
Basedow; so much so, that the description of the with specific epidemiological designs); it has
so called Merseburg’s triad –exophthalmos, goi- been estimated however, that the number of dis-
ter, and tachycardia, similar to the triad described eases with some autoimmune background is close
by Robert Graves is attributed to von Basedow- to 150. Autoimmune diseases have a variable rate
[5, 6]. Currently there is little controversy about of presentation and ethnic and geographical dif-
the fact that Parry was the first to describe the ferences have been documented to impact the
disease, though historically modestly acknowl- incidence of particular autoimmune diseases.
edged. According to some of Robert Graves’s Some specific groups may be at higher risk than
biographers, this could be due to the fact that others for certain diseases with even some varia-
Graves very astutely hired the services of Armand tion among the same populations. Autoimmune
Trousseau, a very influential advertiser in France disease is highly prevalent in the pediatric popula-
at that time, in addition to the fact that he was the tion and adolescents (representing one of the ten
head of Medicine at the Hotel-Dieu hospital in most frequent causes of death among children
Paris. Trousseau was a strong admirer of Graves, 1–14 years old). Likewise, autoimmune disease is
and often quoted his work in his clinical lectures one of the ten most important causes of death
and in his multiple publications. When Grave’s among women over 65 years of age, and is the
book was translated into French, Trousseau fifth cause of death among women less than 65.
praised the author and in fact, used the term The incidence and prevalence of autoimmune dis-
Graves-Basedow Disease for the first time. It eases has been rising in the last two decades
should also be noted that most publications about worldwide, with diseases such as Diabetes
this condition are in English, thus perpetuating Mellitus Type 1 (DM1), Celiac Disease (CD),
the term “Graves’ Disease”. However, the auto- Multiple Sclerosis (MS) and Systemic Lupus
immune hyperthyroid diffuse goiter should in all Erythematous (SLE) being some of the most
fairness, and from the historical and descriptive frequent. Such a rapid rise in frequency strongly
point of view, be called “Flajani-Parry-Graves- suggests that environmental factors play a key
von Basedow Disease”. Other names used in the role in such increase, since genes do not change
medical literature to describe GD are March dis- so fast, in such short periods of time. The
ease, Parsons disease, Flajani disease and Begbie frequency of autoimmune asymptomatic thyroid
disease [6, 7]. syndrome indicates an association between the
levels of thyroid autoantibodies [Thyroid Peroxidase
(TPO) Autoantibodies and anti-Thyroglobulin
Epidemiology (Tg) Autoantibodies] and the presence of focal
thyroid inflammation in biopsy specimens and
According to the National Health Institutes (NIH) biopsies of individuals that never showed any
of the United States of America, autoimmune dis- evidence of hypothyroidism in their life.
eases affect approximately 23.5 million people in Post-mortem analyses show histopathological
the country, although the American Autoimmune evidence of autoimmune thyroiditis in over one
Related Disease Association (AARDA) estimates fourth of adult women; diffuse changes were
that there are about 50 million people affected by identified in 5 % of females and in 1 % of males;
64 H. Vargas-Uricoechea et al.
furthermore, the prevalence of thyroid antibodies females, the annual risk of spontaneous overt
among the healthy population ranges between 10 hypothyroidism was 4 % (in women with elevated
and 12 %. With regards to hypothyroidism, its fre- TSH and positive thyroid antibodies); 3 % if only
quency may vary depending on whether the diag- the TSH was elevated and 2 % when only the thy-
nosis is considered as subclinical or overt roid antibodies were positive. The likelihood of
hypothyroidism. The former shows a TSH value developing hypothyroidism was higher in women
above the upper reference limit, with a normal with TSH >2.0 mIU/L and elevated anti-TPO val-
Free T4 (FT4) level (assuming that the ues [8–10].
hypothalamic-pituitary-thyroid axis is normal, Although GD may present at any age, the inci-
and in the absence of current or recent severe criti- dence peak is found between the fifth and the sev-
cal disease). The variation in prevalence of sub- enth decade of life; the female:male ratio is
clinical hypothyroidism is consistent with the 5–10:1. The incidence of the disease varies
TSH values; for instance, The National Health depending on the series reviewed, the geographi-
and Nutrition Examination Survey (NHANES III) cal area studied, the intake of dietary iodine and
used an upper normal TSH level above 4.5 mIU/L; gender. Most series report an incidence rate from
at this cut point, the prevalence of subclinical 15 to 50 per 100,000 people/year of follow-up;
hypothyroidism was 4.3 % and the prevalence of however, trials based on the British population
overt hypothyroidism was 0.3 %. The Colorado report an incidence rate of 80 per 100,000
thyroid disease prevalence survey used an upper women/year and of 10 per 100,000 males/year.
normal TSH level of 5.0 mIU/L, and a prevalence The prevalence of the disease among the general
of 8.5 % was reported for subclinical hypothy- population is of 0.5–1.0 %. The National Health
roidism while the reported prevalence for overt and Nutrition Survey (NHANES III) showed that
hypothyroidism was 0.4 %. In the Framingham in individuals older than 12, the general preva-
trial, 5.9 % of females and 2.3 % of males over lence of hypothyroidism was 1.3 %, with a lower
60 years of age had TSH values over 10 mIU/L, prevalence in Hispanics (0.7 %) and a higher
while in the British Whickham survey, 9.3 % of prevalence among whites (1.4 %). In “The
females and 1.2 % of males had TSH values Nurses’ Health Study” the overall incidence of
exceeding 10 mIU/L. The frequency of hypothy- GD hypothyroidism was 4.6 per 1000 women in
roidism in people 85–89 years old in the 12 years of follow-up. There are limited compar-
Netherlands was 7 % among 558 people evalu- ative incidence data for males. In the “Rochester
ated. Furthermore, the incidence of hypothyroid- Epidemiology Project” trial, the age-adjusted
ism in females is established at 3.5 per 1000 incidence of ophthalmopathy due to GD was 5
individuals per year, and in males at 0.6 per 1000 times higher in white females than in males −16
individuals per year. The risk to develop hypothy- per 100,000 patients/year and 2.9 per 100,000
roidism in females with positive thyroid patients/year, respectively- In a cohort trial in
Autoantibodies and elevated TSH is 4 % per year, Stockholm between 2003 and 2005, the total
in contrast with those women that only have one incidence of hypothyroidism among the popula-
of the two conditions with a risk of 2–3 % per tion over 18 years of age was 32.7/100,000
year. For males the risk is higher in either condi- patients/year, of which 75 % had GD [10, 11].
tion, but the rate of development of overt hypothy- Changes in incidence may reflect improved diag-
roidism is still lower than the rate for women. nostic methods, rather than an actual change in
According to the 20-year follow-up Whickham the incidence rates. The higher iodine intake has
cohort, the annual average incidence of spontane- been considered a factor that impacts the inci-
ous hypothyroidism (in the 20 years of follow- dence of GD among the population in places such
up), was 3.5 per 1000 in females, and of 0.6 per as Japan, where the dietary iodine intake may be
1000 in males; the presence of elevated TSH and/ much higher than in most other countries, with an
or positive thyroid antibodies was associated with incidence of 200 per 100,000. Moreover, dietary
an increase risk of developing hypothyroidism. In iodine supplementation in mild to moderately
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 65
deficient populations may increase the number of From the genetic perspective, the studies are
GD cases. Moreover, it has been shown that in aimed at identifying an association between two
some areas with some iodine deficiency, supple- or more genetic polymorphisms and a characteris-
mentation is associated with a drop in up to 33 % tic genetic trait. Association studies differ from
in the incidence of GD [12]. binding trials where the same allele (or alleles) are
associated with that trait in a similar manner to the
population as a whole; in contrast, binding studies
Genetics and Etiopathogenesis allow for different alleles to be associated with
that trait in different families. These associated
GD is defined as an antibody-mediated autoim- studies may be done among unrelated patients
mune process that affects the thyroid gland and (cases) and healthy controls to identify markers
the extra-thyroid tissues in about 90 % of the that significantly differ between the two groups or
cases. The production of Autoantibodies tar- in family groups usually comprised of a sick indi-
geted against the TSH receptor (anti-TSHR) vidual and his/her parents. The association analy-
leads to excessive synthesis of thyroid hormones; sis is a very sensitive method to identify weak
however, the underlying inflammation and genetic risk factors and is currently the preferred
remodeling mechanisms in the extra-thyroid tis- method to study diseases with this type of pattern.
sues are still ambiguous. Family occurrence of Association analyses are based on a comparison
autoimmune thyroid disorders are frequently between a group of patients with a particular out-
identified in GD patients; for instance, in indi- come and ethnical “matched” controls; if a statis-
viduals with GD ophthalmopathy 36 % have a tically significant difference in the frequency of a
first or second degree relative affected either variable is observed between the cases and the
with GD or another Autoimmune Thyroid controls, the conclusion is that such variable is
Disease (AITD). While in monogenic diseases associated with the disease or the outcome
Monozygotic (MZ) twins show complete con- [14–16]. The most frequent type of genetic vari-
cordance, in complex inherited disorders the ability in humans occurs at specific sites in the
concordance is incomplete, but is comparatively genome where individual nucleotide variations
higher in Dizygotic twins (DZ). Cohort studies develop from one member of the population to
in twins have identified a concordance rate of another. These sites are called Single Nucleotide
0.36 and 0.03 for MZ and DZ respectively; Polymorphisms (SNPs). Most SNPs exist as alter-
moreover, the analysis of these data shows that nate alleles; i.e., A or G; in average, two randomly
79 % of the predisposition to develop GD is selected human genomes have approximately
attributable to genetics, while the specific indi- three million differences in individual nucleotides
vidual environmental factors that are not shared between them; in other words, one per one thou-
by the twins may account for the remaining 21 % sand base pairs. Generally speaking, the SNPs are
[13]. The estimated concordance for GD may be single nucleotide mutations giving rise to changes
different for the populations studied; for exam- in one amino acid in the protein – the frequency of
ple, la concordance for American twins is 0.17– the minor allele shall be more than 1 % of the
0.02 in MZ and DZ siblings, respectively, population- [17]. The identification of complex
suggesting a small contribution of genes for GD disease genes involves four phases: Phase 1:
in the American population versus Europeans. Analysis of candidate genes; Phase 2: Genome-
Studies in families and twins have clearly shown wide association studies; Phase 3: Extended
that GD is not the result of a single gene defect, genome association studies; and Phase 4: Whole
but rather that it has a complex inheritance pat- genome sequencing.
tern; consequently, the predisposition results The implementation of these technologies has
from multiple genes with individual and very led to further developments in this area, identify-
modest effects. Most of the loci identified repre- ing at least seven genes whose variants have been
sent a low risk of disease (between 1.2 and 1.5). associated with AITD, including: HLA-DR gene,
66 H. Vargas-Uricoechea et al.
immunoregulatory genes (CTLA-4, CD 40, times lower than those of CD28, but binds to
PTPN-22 y CD 25) and thyroid-specific genes: CD80 and CD86 with a dissociation constant
Tg gene and TSHR gene [16–18]. 20–50 times higher. Although a similar role was
initially attributed to CD28 in the activation of
HLA-DR Gene The available evidence suggests T-cells, the most recent experimental findings
that the HLA (6p21) region predisposes to AITD; indicate that CTLA-4 has a negative regulatory
the alleles within the HLA class II region (genes action. Some trials have established that CTLA-4
DRB1 and DQA1 are the ones with the strongest is a GD-susceptible gene; in the Chinese popula-
association to GD). An important association has tion, for instance, the A49G and CT60 polymor-
also been identified in the HLA Class I region, phisms are associated with increased susceptibility
HLA-C and HLA-B. GD Caucasian patients have for GD. The Odds Ratio (OR) for A49G was 1.49,
an increased prevalence of the DRB1*03 whilst for CT60 was 1.45 [18, 19].
DQA1*05 and DQB1*02 haplotype, though these
are not always present in other ethnic groups. In CD 40 Among the identified susceptibility
fact, it has been found that the HLA-DPB1*05:01 genes in Graves’ Disease, CD40 is the only one
is the major gene that predisposes to GD among involved with regulating the B cells response; the
the Asian population, in a sub-population of physiological ligand for CD40 is the CD154
Chinese patients with an OR = 2.3 and a popula- (CD40L) molecule, that is expressed on the sur-
tion attributable risk of 48 %. Other susceptibil- face of the T helper cells. Binding of CD40 by
ity variables with independent effects include CD40L helps to drive the resting B cell from G0
the B*46:01, DRB1*15:02 and 16:02, whilst into the cell cycle, playing an essential role in the
DRB1*12:02 and DQB1*03:02 are protective. activation and proliferation of B-lymphocytes.
Arginine in the position 74 of the HLA-DRb1 The CD40 gene has been associated with GD and
(Deb-Arg74) has been recently identified as the a plausible explanation is the a C allele may
critical DR amino acid that causes GD suscepti- induce an overexpression of the CD40 molecule,
bility. Furthermore, the presence of the glutamine leading to the activation of B-lymphocytes with a
amino acid at the position 74 of the DRb1 chain prevalence of the Th2-type immune response.
is protective against GD [15, 18]. Bases on extended genome studies, CD40 is one
of the candidates for GE. These studies have
CTLA-4 (Cytotoxic T Lymphocyte Antigen-4) involved the 20q11 chromosome region – called
The CTLA-4 attenuates T-cell activity. Its struc- GD-2 – as a susceptibility locus. The C allele in
tural resemblance to CD28, both in terms of the the rs 1883832 has been found to generate an
chromosomal localization as in terms of the exon- OR = 1.6 for Graves’ Disease among Caucasians,
intron organization, suggests that both genes though the same association has been identified
share the same origin. CD28 is a 44 KD mem- among the Japanese population [19, 20].
brane glycoprotein with a 202 amino acid
sequence, whose gene is localized in the long arm The PTPN22 Gene (Protein Tyrosine
of chromosome 2. It is the principal co-stimulating Phosphatase Nonreceptor-22) PTPN22 is
molecule in the activation of T cells, where it involved in the antigen adaptive response via the
plays a broad range of roles. One of the most dephosphorylation and inactivation of the T-cells
important effects identified is the dramatic receptor. The PTPN22 gene has been associated
increase in the production of IL-2, 4, 5 & 13, in with the presence of AITD and other autoim-
addition to other cytokines such as TNFα-, inter mune diseases; it is localized at the 1p13 chromo-
alia. These cytokines act as growth factors, with some and codes for the so-called signaling
an autocrine and paracrine action, in addition to protein Lymphoid Tyrosine Phosphatase (PTP),
reducing the T-cell response threshold and pre- which is a potent t-cell activation regulator. This
venting apoptosis. CTLA-4 is expressed in acti- protein inhibits T-cell activation through binding
vated T-cells, CD4 and CD8, at levels 10 and 100 to signal transduction molecules such as Csk
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 67
kinase that mediates T-cell activation. The best The association of SNP rs7528684 was repli-
association documented of the PTPN22 variants cated in Japanese subjects with GD and Systemic
with autoimmune diseases, including GD is with Lupus Erythematosus (SLE). The 1p21-23 cyto-
rs2476601 (C1858T). This polymorphism has band in which the FCRL resides has been identi-
been studied and considered as a candidate sus- fied as a candidate locus for several autoimmune
ceptibility gene for AITD in several ethnic groups disorders with a strong association identified for
(particularly Caucasians). The PTPN22 C1858T SNPs in that region, and increased susceptibility
polymorphism triggers a change in the 620 posi- to GD in the Japanese population. This suggests
tion from an Arginine to Tryptophan, resulting in that the origin of the association is a regulatory
a less efficient binding to Csk kinase. Hence, SNP in the FCRL3 promoter region. The
T-cells express T alleles that may be hypersensi- rs7522061 SNP in the FCRL3 gene has also been
tive and lead to autoimmune disorders. However, associated with AITD in Caucasians, and more
the association of these polymorphisms with recently the SNP rs3761959 and the rs7522061
increased susceptibility in AITD has been vari- has also been associated with GD [13, 19, 20].
able, with both negative and positive associations
due in part to the genetic heterogeneity among TSH Receptor (TSHR) TSHR and its ligand
the populations studied and to other potential -TSH- are critical thyroid activity regulators. The
confounders [19, 20]. TSHR stimulating antibodies simulate the TSH
action, resulting in the characteristic hyperthy-
Interleukin-2 Receptor α Gene (IL-2RA) This roid status. The TSHR is considered to exacer-
gene codes for the α chain of the IL-2 receptor bate the autoimmune process, as a key component
(IL-2R) complex, also known as CD25, which for the onset of GD. The TSHR is made up of 10
plays a key immunoregulatory role as an impor- exons that code for 764 amino acids of approxi-
tant auto-tolerance and immunity modulator. The mately 95 kDa. The genetic variants of the TSHR
IL-2RA gene has been associated with Graves’ probably stimulate autoimmunity in GD, particu-
disease [15, 19]. larly in individuals that exhibit other loci or gen-
eral autoimmune risk; it is then possible for the
Thyroglobulin (Tg) Tg represents one of the TSHR genetic variants to influence the post-
major auto-antigens involved in AITD; however, translational changes in the TSHR and/or the
the anti-Tg are not specific and occur in 80–90 % gene expression, thus increasing the risk for the
of the patients with Hashimoto’s disease and in TSHR to be an immune target; anti-TSHR can be
50–70 % of the patients with Graves’ disease found in 95–96 % of GD patients [15, 18].
(usually at low concentrations). The association
of Tg polymorphisms with GD has been identi- GD has a strong genetic component, and
fied with relapse of the disease following anti- hence is influenced by family history. The inter-
thyroid treatment; nonetheless, these conclusions action between genetic susceptibility and envi-
are based on studies with a small sample size that ronmental factors is extremely complex and
have not been homogenously replicated [14, 18]. poorly understood. Many of the genes associated
with the onset of the disease are involved in other
Fc Receptor-Like Gene (FCRL) This gene autoimmune diseases, including Type 1 Diabetes
codes for products that play a key role in the con- Mellitus, Rheumatoid Arthritis, and Multiple
trol of B cell signals and it has been shown to be Sclerosis. This apparent genetic susceptibility
associated with autoimmune diseases. The convergence raises the risk for autoimmunity and
FCRL3 is one of the five genes preferentially when combined with specific risk factors triggers
expressed in B-lymphocytes and are structurally autoimmune diseases [21]. Several factors have
similar to the Fc receptors. The FCRL3 plays an been suggested to increase the risk of developing
inhibitory role in the B cells signaling process, GD, including gender (the disease is more fre-
resulting in B-cells disrupted tolerance and activity. quent in females than in males), prior infections
68 H. Vargas-Uricoechea et al.
Flajani-Parry-
Genetic Autoimmunity Graves-von
Environment
predisposition promoters Grasedow
Disease
due to germs such as Yersinia enterocolítica, cells are valid candidates to explain the autoim-
Yersinia pseudotuberculosis and Mycoplasma mune modulation of thyroid disease, both during
arthritidis, iter alia. The way in which these pregnancy as during the post-partum period. The
infectious agents may trigger a specific auto- use of drugs such as amiodarone, lithium deriva-
antigenic response is controversial, though a tives, α-interferon, anti-retrovirals, and monoclo-
large number of mechanisms may be argued. One nal antibodies, increase the risk of developing
of these mechanisms is the induction of an GD. Smoking is another factor associated with
inflammatory response leading to the production the presence of GD and is considered a predictor
of pro-inflammatory cytokines that may cause of GD-related risk of hyperthyroidism. Most
the aberrant over-expression of Class III MHC, likely the existing relationship depends on the
resulting from the presentation of auto-peptides exposure time; active smokers have a higher risk
through the MHC molecules that lead to antigen- than patients who smoked in the past or those that
specific T-cell activation. The production of cyto- never smoked. These effect is also dose-
kines and their imbalance is caused by infection dependent; i.e., the larger the number of cigarette
that may trigger the immune response. The post- packs smoked per year, the higher the frequency
partum period is a potential “predisposing” fac- of Graves’ Disease, particularly in women that
tor, though clearly the pregnant woman regulates are heavy smokers [22, 23].
some genetic and autoimmune expressions that In summary, the combination of genetic, envi-
tend to activate after the end of the post-partum ronmental and endogenous factors is the etio-
period. Consequently, while the likelihood of GD pathological foundation for GD (Fig. 5.1).
expressing during the post-partum period is
higher as compared to gestation, the most plau-
sible explanation may be the “attenuation” of Clinical Manifestations
autoimmune manifestations typical of pregnancy,
rather than an increased risk during the post- The GD patient may focus on the context of a
partum period. Furthermore, during pregnancy “Hyperthyroidism Syndrome” covering the basic
fetal cells may reach the maternal circulation and signs of morphological-structural manifestations of
may somehow infiltrate various tissues – a pro- the thyroid gland (particularly goiter), alterations
cess called “fetal microchimerism”. The infiltra- triggered by excessive circulating thyroid hor-
tion of fetal cells into the maternal tissues mones (more frequently the hyperadrenegic status)
influences the maternal immune response, though and the tissue manifestations of the circulating
at a level that is difficult to quantify; these fetal TSHR expression (exophtalmos and dermopathy).
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 69
The clinical spectrum may be divided into gen- knowledge that the cardiac contractile function,
eral and tissue manifestations. The most frequent as well as the blood volume are significantly
general manifestations include the paradoxical altered in patients with thyroid disease, because
weight loss (meaning that despite the accompany- of the decreased vascular resistance that results in
ing hyperphagia, the patient experiences acceler- Renin-Angiotensin-Aldosterone system stimula-
ated and considerable weight loss), heat tion. Consequently, there is a significant increase
intolerance, diaphoresis, hyperkinesia, and emo- in sodium and water reabsorption, with the cor-
tional lability with a feeling of sadness, anxiety, responding increase in volume and preload,
and apprehension. Asthenia and adynamia may resulting in dilatation and increased cardiac out-
prevail and can be associated with difficulty to fall put. Additionally, as a direct short-term effect,
asleep and frequent awakenings, with physical there are changes in the various sodium, potas-
and intellectual performance decline as the condi- sium, and calcium channels configuration and of
tion progresses. The libido is preserved early on, their respective intracellular levels in the heart,
but as time goes by, patients express some sexual hence raising both inotropism and chronotro-
apathy and seek medical advice [24]. pism, in addition to ventricular hypertrophy due
At the cardiovascular level, palpitations, to increased protein synthesis. Failure to properly
exertion dyspnea and dyspnea at rest are overt. control these processes may lead to contractile
Arterial hypertension may be the first sign of the function and ejection fraction impairment, and
disease and it divergence may be suggestive of finally to heart failure. Furthermore, experimen-
hyperthyroidism. The cardiovascular manifesta- tal studies have shown a shorter duration of the
tions are the result of two intervening factors: the action potential and increased spontaneous activ-
direct and indirect effect of thyroid hormones on ity (automaticity), similar to the effect of the
the cardiovascular system and the interaction sinus node and in the cardiomyocytes around the
with the autonomous sympathetic system leading pulmonary veins, which may facilitate the gene-
to a hyperdynamic status called “thyrotoxic car- sis of re-entry and atrial fibrillation circuits. The
diomyopathy”, chest pain at rest and with mini- advent of Echocardiogram (EKG) has led to the
mal exertion, may be suggestive of coronary identification of images inherent to GD. Among
disease. Since cardiac manifestations may be the the most extensively described and characterized
first to be expressed, with no evidence of other using EKG are the closing time of the mitral
systemic – and even less thyroid- alterations, the valve until the opening of the aortic valve (the so-
condition is referred to as “masked thyrotoxico- called Isovolumetric Contraction Time –ICT-),
sis that mimics heart disease”. Tachycardia with the time from the opening of the aortic valve until
atrial fibrillation may be the only clinical mani- the end of ventricular systole (the left ventricular
festation in the elderly; in these patients, the pres- ejection fraction time –LVEFT-) and the time
ence of diarrhea and tachycardia may be the key from the closing of the aortic valve until the
expressions of GD. So the term “apathetic hyper- opening of the mitral valve (known as the
thyroidism” has been coined and in fact, atrial Isovolumetric Relaxation Time –IRT-). GD
fibrillation is the most frequent rhythm disorder patients exhibit increased values for these three
in GD that may be present in over one third of parameters: ICT, LVEFT, and IRT, indicating
patients over 60 years of age. The heart rate is systolic and/or diastolic dysfunction [25, 26].
usually high, the arterial pulse is jerky and broad, At the Gastrointestinal level, the acceleration
the first heart sound is accentuated and the sec- of the intestinal rhythm prevails, with hyperdef-
ond sound is often split; in patients with a classi- ecation or diarrhea. The frequency and the
cal high-output heart failure, S3 or S4 may be severity of bowel movements predisposes to
identified. Occasionally there is scratch murmur hydro-electrolytic imbalances that may impact
in the apex, called “Means-Lerman murmur” that mortality, particularly in the elderly. Flatulence
is attributed to the friction of the hyperdynamic and borborigmi are frequent manifestation. The
precordium against the pleura [25]. It is common autoimmune characteristic of GD favors the
70 H. Vargas-Uricoechea et al.
association with other equally relevant condi- myxedema is an induration of the pretibial skin
tions, including CD, that has a growing frequency and develops as a result of hyaluronic acid and
among patients with autoimmune thyroid chondroitin sulfate deposits at this level. While
disease –with a prevalence ranging from 5 to in normal skin the percentage of hyaluronic acid
10 %- Anorexia, abdominal pain, and vomiting is close to 5 %, it raises to 90 % in GD. Myxedema
are less frequent manifestation; jaundice and hep- is a rare extra-thyroid manifestation in GD; its
ato/splenomegaly are manifestations of severe frequency increases in patients with ophthal-
hyperthyroidism, although splenomegaly may mopathy, is more frequent in females and usu-
occur in the initial forms of the disease. Just as in ally manifests over the third and fourth decade of
the case of CD, GD may be associated with severe life. The underlying mechanism of myxedema is
forms of autoimmune hepatitis, ulcerative colitis, unclear, though animal studies suggest that thy-
and primary biliary cirrhosis. Paradoxical weight roid hormones affect the synthesis and catabo-
loss is a frequent manifestation and is a specific lism of mucopolysaccharides and collagen from
sign of GD, that may be explained by increased dermal fibroblasts [29, 30]. The myxedema usu-
thermogenesis and by the presence of hyperad- ally presents at sites previously injured and
renergic factor-mediated lipolysis; though rare, manifests mostly as infiltrated plaques or asym-
weigh gain may present in the hyperadrenergic metrically distributed nodules over the pretibial
status; in fact, up to 10 % of the patients with region, either of a color similar to that of the
hyperadrenergic Graves’ Disease experience a normal skin or brownish, purple or erythema-
relative weight gain [27, 28]. tous occurring in 0.5–4.5 % of patients of
Skin manifestations are very conspicuous; the GD. Diffuse myxedema presents in 43 % of the
skin looks moist and hot as a result of cutaneous patients with dermopathy and the nodular vari-
vasodilatation and diaphoresis; patients with GD ety occurs in 18 % of the patients with myx-
often present with intertrigo, facial and palmar edema. The lesions have a hard consistency, with
erythema, fine and brittle hair with excessive turn- dilatation of the follicular orifices giving the
over resulting in a marked tendency to early bald- affected surface an “orange peel” aspect; pres-
ness, with sparse fine hair, particularly on the sure on the lesions does not result in pitting.
forehead, giving rise to the expression “ash on the Whilst the classical localization is on the pretib-
forehead under flaring gaze”. Gray hair on one or ial skin area, lesions may also be found on the
both temples has been called “hyperthyroid foot dorsum, the face, the forearms, the abdomi-
Sainton tuft”. Hair loss is frequent and alopecia nal wall and the chest. Hyperhidrosis may also
areata are part of the capillary spectrum in GD be present on the affected surface, with itching,
patients. Spoon-shaped nails or koilonyquia (con- burning sensation, and pain. The combination of
cave contour with distal onycholysis) with longi- exophthalmos, pretibial myxedema, and hyper-
tudinal striae are found in 5 % of patients with trophic osteoarthopathy is referred to as “EMO
hyperthyroidism and are called “Plummer nails”. syndrome, or Diamond Syndrome” [30, 31].
Onycholysis, platonychia and onicorrhexis may At the level of the Nervous System, the mani-
be present. The elbow and knee skin tends to be festations triggered by the activation of the sym-
soft and pink; itching is very common and may be pathetic nervous system; restlessness and anxiety,
associated with atopic dermatitis; skin hyperpig- emotional lability, hyperkinesia, psychotic status
mentation is infrequent and similar to Addison’s and panic attacks are usual and may be the initial
disease, but does not affect the mucosae. The manifestations of the disease. Hypokalemic
hyperpigmentation is apparently mediated by Thyrotoxic Periodic Paralysis (HTPP) is a rare
accelerated cortisol metabolism in GD, that stim- disease that may coexist with some hyperthyroid-
ulates an excessive Adrenocorticotropic Hormone ism conditions and is frequently described in GD
(ACTH), resulting in an elevation of the patients. When HTPP occurs, patients develop
Melanocyte Stimulating Hormone (MSH), par- some degree of hypokalemia attributed to trans-
ticularly its alpha fraction (α-MSH). The pretibial cellular potassium turnover, and a subsequent
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 71
reduction of extracellular potassium. High thy- patients will express ocular manifestations of the
roid hormone levels result in an over-regulation disease, though it is clinically relevant in 20–30 %
of the ATPase activity in the muscle, the kidney, of the cases, and between 3 and 5 % of the patients
the liver, and platelets. Furthermore, there is an may have severe ocular disease. The clinical find-
increased trans-cellular potassium flow due to a ings in patients with ophthalmopathy due to GD
yet undetermined mechanism that interferes with may be segregated into two groups: thickening of
the actual ability of potassium to promote muscle the retro-lobular space due to the Glucose-
contraction. The level of hypokalemia is directly Aminoglycans (GAG) deposit or to the restriction
related to the amount of muscle weakness, para- of extra-ocular motility that is due to initial tume-
paresis and varying degrees of hemiplegia or faction and further fibrosis. The initial manifesta-
quadriplegia present in patients with HTPP. Fine tions are particularly related to foreign body
distal tremor is one of the most prevalent signs of sensation, tearing, photophobia, and retroocular
GD; tongue tremor is also frequent when pur- pain. Usually patients are diagnosed during the
posefully screened. Proximal muscle weakness initial stages of the disease with “allergic
may be present, as well as lid ptosis, which may Conjunctivitis” and transiently respond to the use
be suspicious for Myasthenia Gravis (MG). This of topical steroids. Then upper lid retraction
neurological presentation is not unusual and develops which is considered the most common
between 2 and 17.5 % of patients with MG clinical orbital characteristic in GD; this leads to
express GD associated hyperthyroidism. Some eyeball protrusion, bilateral eye protrusion
epidemiological studies have shown the co- together with upper eyelid retraction (caused by
existence of GD and ocular MG in 41 % of cases increased sympathetic activity of Müller’s muscle
and in 28 % generalized MG. The underlying and hyper function of the “superior rectus-elevator
reasons for this strong association, particularly muscle”, secondary to fibrosis-related hypophoria
for ocular MG, are not yet well established, but and contraction of the inferior rectus muscle),
immune cross-reactivity against epitopes or auto- which is pathognomonic of GD. Most GD eye
antigens that are shared by the thyroid and the expression signs and symptoms are the result of
eye muscles is suspected. The strong association orbital soft tissue expansion, resulting in increased
between GD and generalized MG may be due to pressures of the orbital cavity. Diplopia may be
the fact that both share a common genetic history, the initial symptom and results from the inflam-
and also because the HLA-B8 and DR3 expres- mation and tumefaction of the muscles involved,
sion are present in a large number of patients with mainly the inferior rectus muscle; overall, this
both entities. Other neurological manifestations sign has a restrictive pattern, and does not cause
include the carpal tunnel syndrome, the cerebel- ocular paralysis [35–37]. Diplopia is one of the
lar and pyramidal syndrome, chorea, and nonspe- most poorly tolerated signs because it is a major
cific myopathies [32–34]. Overall, patients hindrance for the patient’s performance and
respond very well to treatment (based on potas- everyday tasks. Diplopia may even be more dis-
sium electrolyte replacement and non-selective ruptive than the typical hyperadrenergic manifes-
beta blockers). Total remission is achieved when tations. Periorbital edema is very frequent at the
the underlying hyperthyroidism is finally onset of the disease and mainly affects the upper
controlled. lids (particularly in young patients, where there is
The Ocular manifestations of GD are quite the above described increase in periorbital fat).
striking, ranging from almost imperceptible man- The presence of orbital edema in GD is the reflec-
ifestations that can only be detected through tion of delayed venous drainage due to compres-
imaging techniques, up to edematous and infiltra- sion at the orbital space. Lid edema in GD differs
tive manifestation with considerable orbital dis- from hyperthyroidism edema because the latter is
figuration. Periorbital edema, lid retraction, usually localized in the lower lid. The conjuncti-
exophthalmos and diplopia are frequent signs and vas frequently present edema or chemosis; severe
symptoms. It has been estimated that 50 % of GD cases of conjuntival prolapse at the level of the
72 H. Vargas-Uricoechea et al.
lower lid are less frequent. Conjunctiva hyper- the orbital apex called “Crowded Orbital Apex
emia is particularly visible near the horizontal Syndrome” and occurs in around 5–6 % of the
rectus tendon and is indicative of the significant patients with GD ophthalmopathy who had good
underlying autoimmune disease. In the event of eyesight in the past but experienced progressive or
severe proptosis, the elevator aponeurosis may be even fast eyesight impairment. Horner’s syndrome
detached, resulting in lid ptosis that may be undis- (miosis, enophthalmos, and ptosis) is rarely present
tinguishable from the condition expressed in MG but when it occurs it is accompanied by loss of
patients. GD ophthalmopathy occurs unilaterally hemi facial sweating. Horner’s syndrome in GD
in 5–15 % of the cases and is probably the most patients indicates compression of the cervical sym-
frequent cause of unilateral ocular protrusion. The pathetic chain due to the presence of goiter. From
reason for this presentation is yet unknown, but it the ocular semiology point of view, the most rele-
may be the reflection of an early but still incom- vant signs sings described throughout history are:
plete expression of orbital antibodies. These [6, 36, 38].
patients often do not show any signs or symptoms
of hyperthyroidism (except proptosis), though the • Abadie’s sign: Spasm of the elevator palpe-
orbital imaging findings, in addition to the high brae superioris muscle
level of antibodies against the TSH receptor, • Ballet’s sign: External ophthalmoplegia with
enables the identification of this group of patients. loss of voluntary eye movements and preserva-
Exophthalmos, reduced blinking, and lid retrac- tion of the pupillary and reflex eye movements
tion give rise to exposure keratopathy of variable • Becker’s Phenomenon: Pulsation of retinal
presentation, ranging from mild forms with just a arteries visible in the eye fundus
fine punctiform de-epithelialization on the lower • Boston’s Sign: Abrupt closure of the upper
hemicornea –which is more exposed due to the eyelid when the eyeball looks downward
nocturnal lagophthalmos- to corneal-conjuntival • Cowen’s Sign: Jerky consensual pupillary
de-epithelialization resulting in stromal ulcer- light reflex
ations and eventually corneal perforation [38]. • Dalrymple’s Sign: Retraction of the upper eye-
The optical neuropathy derived from GD ophthal- lids with abnormally wide palpebral opening
mopathy is compressive in nature, and occurs in • Dieulafoy’s Sign: Patients with GD develop a
3–5 % of the patients with ocular manifestations. horror gaze (tragic eye) that sometimes is so
Optical neuropathy develops mainly in cases of marked that the eye develops a subluxation
major involvement of the orbital apex. In addition (Dieulafoy’s subluxation)
to the direct compression of the nerve in its apical • Dunphy’s Sign: The injection of the conjunc-
segment, other factors that contribute to nerve dam- tiva in front of the lateral rectus muscle
age are disruptions in venous return and stretching insertion
of the nerve in the orbit, losing the meandering tra- • Enroth’s Sign: Eyelid edema, specially the
jectory and the hypertony of the aqueous humor. upper lid close to the supraorbital rim
When the apical compression of the nerve is the • Griffith’s Sign: Lower lid lag on upward gaze
rule, the disk may look normal, edematous, or • Gifford’s Sign: Evident difficulty in averting
slightly ischemic [37, 38]. The earlier disruptions the upper eyelid
develop around color perception, since the axons • Grove’s Sign: Resistance of the upper eyelid
from the macula are more prone to injury. The pro- to do downward traction
gression of the neuropathy to absolute scotoma, the • Jellinek-Rasin Sign: Increased eyelid pig-
atrophy-cupping and stasis are dependent on the mentation, particularly of the upper lid.
ophthalmopathy due to GD proper, and on the pre- • Jendrassk-Brain Sign: Paralysis of the extra-
vious nerve circulatory status (increased sensitivity ocular muscles in GD
to compressive ischemia in patients with a history • Joffroy’s Sign: Absence of wrinkles when the
of vascular pathology). The hypertension at the gaze is forced upwards, resulting from poor
orbital apex due to increased muscle and soft tissue contraction of the frontal muscle
volume, gives rise to a compressive syndrome of • Knie’s sign: Unequal pupillary dilatation
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 73
• Kocher’s Reflex: Fixed and frightening gaze poor gaseous exchange that, in the presence of
• Lagophthalmos: Incomplete eyelid closure higher oxygen consumption typical of thyrotoxi-
due to exophthalmos cosis, expresses clinically as the initial manifesta-
• Loewi’s Sign: Pupil dilation following adren- tion of the disease. Patients with pulmonary
alin stimulation hypertension have also been identified as the ini-
• Mann’s Sign: The two eyes appear not to be tial manifestation of GD [39, 40].
on the same level due to decreased scalp Renal alterations reflect a condition of gener-
resistance. alized vasodilatation present in these patients.
• Means-Griffith-Von Koller Sign: Lower lid The renal plasma flow and glomerular filtration
lag on upward gaze are increased and polyuria –usually accompanied
• Möbius Sign: Inability to keep the eyeballs by polydipsia- seem to be mediated by increased
converged due to insufficiency of the internal levels of Angiotensin II, which causes sodium
rectus muscles and water retention by mediating aldosterone
• Rosembach’s Sign: Fine upper lid tremor release, worsening the palpebral, facial and pedal
when closing the eyes softly edema typical of GD. Thyrotoxicosis results in
• Rusell-Fraser Sign: The fold between the increased renal plasma flow and glomerular fil-
upper eyelid and eyeball is narrowed when tration, that gives rise to a decline in creatinine
closing the eyes levels. Furthermore, hyperthyroidism is associ-
• Sainton’s Sign: Frontal muscle contraction ated with a decrease in the total body water con-
on upward gaze tent and potassium turnover. Though sodium
• Snellen-Riesman Sign: Is the murmur heard turnover is increased, sodium and potassium
over the stethoscope gently placed over the serum levels are normal and those imbalances
eye closed normalize once the thyroid function is controlled
• Stellwag’s Sign: Apparent widening of the if adequately managed [41].
palpebral opening At the Bone level, the manifestations are the
• Sucker’s Sign: Deficient complementary fix- result of faster bone turnover with hypercalciuria
ation in lateral eye rotation present in many cases; hypercalcemia however is
• Tellais Sign: Eyelid pigmentation, particularly rare and is also accompanied by an increased
of the lower lids. N-telopeptide urinary excretion rate, in addition
• Topolanski’s Sign: Pericorneal eye congestion to elevated osteocalcin and alkaline phosphatase.
• Von Graefe’s Sign (Graefe’s): Lack of syn- Intolerance to heat in these patients leads to
ergy between the eyelid and eyeball move- decreased sun exposure that together with
ments, particularly on downward gaze increased vitamin D catabolism translates into a
• Wilder’s Sign: Slight twitch of the eyeball progressive vitamin D deficiency. Such low vita-
when it changes its movement from adduction min D levels eventually result in reduced calcium
to abduction or vice versa. absorption and patients may develop mild hypo-
calcemia. Although initially the Parathormone
Enophthalmos is rare and sometimes presents (PTH) level is below the normal range, some
with orbit swelling and paresis or paralysis of the cases may present mild hypocalcemia and minor
extrinsic muscles and is sometimes called “Brain PTH elevations. All of this results in a marked
ophthalmopathy”. Orbital dull pain is considered loss of bone mass, osteopenia or osteoporosis,
a severe symptom indicative of orbital swelling with a known risk of fractures, even higher than
with subsequent distension of the tissues around in patients with prior vitamin D deficit [42, 43].
the eyeball [36–38]. Other systemic manifestations include:
The Respiratory manifestations are quite fre- Hypoalbuminemia, oligomenorrhea, polymenor-
quent with a relative weakness of the respiratory rhea, menorrhagia, hypermenorrhea and galac-
muscles, in addition to poor ventilation control torrhea. Fertility may be compromised but
due to alterations in the chemoreceptor expression pregnancy is possible, though there is a higher
and the center of respiration. All of this results in rate of abortions and a considerable increase in
74 H. Vargas-Uricoechea et al.
peripartum morbidity. Erectile dysfunction and compatible with cerebral vasculitis, venous
loss of libido are frequent in males; anemia may thromboembolism, vomiting, jaundice, pulmo-
be present with an increased mean corpuscular nary hypertension and elevated alkaline phospha-
volume (macrocytic) resulting from enhanced tase [46] (Table 5.1).
vitamin B12 and folic acid metabolism, and from
the presence of anti-intrinsic factor antibodies
and anti-parietal cells. This anemia is usually Clinical Diagnosis
asymptomatic. The presence of splenomegaly
with leukopenia-neutropenia and lymphocytosis In 1959 Crooks et al. described a statistical
has been called “Kocher Syndrome” [6, 44]. method to assist in the diagnosis of thyrotoxico-
At the thyroid level, a lobulated, soft, usually sis, using a weighted score based on 19 different
smooth gland may be found and sometimes it can signs and symptoms. The score discriminated
be nodular. In the classical GD, the gland is between individuals with and without thyrotoxi-
asymmetrical and variable in size. Thyroid gland cosis with a relatively high sensitivity. The
growth is conspicuous in some cases, even at a strength of this scoring system was that it relied
distance and seldom imperceptible to palpation on the classical symptoms of hyperthyroidism,
(in 1 % of the cases the gland is not palpable, and its weakness was the fact that most of the
either because of its small size or because it is findings were just based on the presence or
localized under the sternal manubrium). Size is absence of the factor studied. The authors also
somehow associated with the severity of the dis- used their scoring system to assess treatment and
ease, but is not infallible as a parameter since were able to contrast the efficacy of various ther-
clinically the patient may present a severe GD apeutic modalities [47, 48]. With a view to
with barely palpable goiter. In contrast, there are improving the clinical evaluation of patients
patients with mild signs and symptoms of the dis- with hyperthyroidism, the authors themselves
ease, with remarkable gland sizes. Murmur or suggested and validated the hyperthyroidism
“fremitus” are important findings, but are usually symptoms scale that was used for the diagnosis
absent; their presence is indicative of gland and treatment of Graves’ disease patients
hyperfunction [36, 45]. (Table 5.2). When newly diagnosed and untreated
GD presents some rare manifestations that GD patients are administered the above symp-
affect several organs and systems including cases toms scale; the mean score reported was
5 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease) 75
Table 5.2 Hyperthyroid symptoms scale proposed by Crooks et al. (Refs. [47, 48])
Characteristics Score
Nervousness:
0. None
1. Anxious, only under stress ——
2. Anxious at rest, occasionally
3. Frequently anxious, difficulty to complete tasks or to concentrate
4. Very nervous most of the time
Sweating:
0. Only when active
1. At rest, but under hot temperature
2. At rest in temperate climates, mainly involving the hands and intertriginous areas ——
3. At rest, involving large body areas
4. Profuse, almost constant diaphoresis
Heat Tolerance:
0. Normal tolerance
1. Periods of time when heat perception is higher than the perception by other people in the same
room
2. Extremely difficult to manage heat sensation in warm environments, constantly requiring air ——
conditioning during summer time
3. Extremely difficult to manage heat sensation, even in temperate climates
4. Extremely difficult to manage heat sensation; feels uncomfortable even in cold weather, evidenced
by the fact that no coats of blankets are needed for protection against cold.
Hyperactivity:
0. Normal level of activity
1. Increased level of activity and productivity
2. Increased productivity and less sleep hours ——
3. Performs some kind of senseless or purposeless activity
4. Frequent episodes of senseless activity unable to stay still during the examination
Tremor: Examined while the patient keeps his/her hands extended
0. Absent
1. Barely noticeable
2. Tremor easily identified during the examination ——
3. Marked tremor, but able to properly perform fine motor activities
4. Exaggerated handshake; difficulty to perform fine motor skills
Weakness:
0. Normal strength
1. Subjective weakness, but with tolerance to normal exercising
2. Reduced exercise tolerance at a near maximal activity ——
3. Reduce exercise tolerance when climbing up the stairs or standing up from a chair
4. Extreme weakness – patients are barely able to raise any objects or climb the stairs
Hyperdynamic Precordium:
0. Normal precordial activity and apical impulse
1. Tachycardia, 90 beats per minute with normal apical impulse ——
2. Tachycardia, 90 beats per minute with increased apical impulse
3. Tachycardia, 110 beats per minute with increased apical impulse
4. Tachycardia, 110 beats per minute, apical impulse and increased carotid pulse; systolic murmur
present
(continued)
76 H. Vargas-Uricoechea et al.
Characteristics Score
Diarrhea:
0. A bowel movement per day, formed stools
1. Two to four bowel movements per day, formed stools
2. One to four bowel movements per day, watery stools ——
3. Four bowel movements per day; solid feces
4. Four watery bowel movements per day
Appetite:
0. Normal appetite, no weight loss
1. Normal appetite, with weight loss
2. Increased appetite with no weight ——
loss
3. Increased appetite with weight loss
4. Decreased appetite with weight loss
Evaluation of daily function (level of disability):
0. Normal (none)
1. Minimal disruption (10 %)
2. Mild disruption (30 %) ——
3. Moderate disruption (60 %)
4. Severe disruption (90 %)
Total score: ——
sensitivity essays (0.02 mIU/L) or greater. The managed with I-131 or with surgery, since the
lower normal population level for TSH values antibody expression, regardless of the func-
ranges between 0.4 and 4.0 mIU/L (based on 95 % tional thyroid status of the mother, is a predic-
of the values identified in apparently healthy indi- tor for neonatal hyperthyroidism.
viduals). Overall, this lower range of values for F. During pregnancy, in patients treated with
TSH is not as debated as the upper normal range anti-thyroid medication or a history of prior
[50–52]. Other laboratory parameters such as the children with neonatal hyperthyroidism.
titration of the antibody against the TSH receptor Anti-TSHr titration is recommended in these
(Anti-TSHr) may be useful in some cases, but is not patients during the first trimester and at week
a prerequisite for making the diagnosis of GD [53]. 22–26 of gestation.
Some recommendations to measure anti-TSHr G. In patients with multinodular hyperthyroid-
are [53, 54]: ism goiter, with findings of ophthalmopathy
and/or dermopathy, the measurement and the
A. Since practically every GD patient expresses expression of the antibody helps in identify-
such antibodies, its detection is useful for the ing those patients with GD expressed with a
serological diagnosis of autoimmune multinodular goiter.
hyperthyroidism. H. In individuals with thyrotoxicosis within the
B. The detection of such antibodies allows for framework of Immune Reconstitution Syndrome,
the differentiation of autoimmune hyperthy- patients treated with lymphocyte-depleting
roidism from the non-autoimmune type. agents such as Alemtuzumab (AMPCATH) and
C. The antibody expression, particularly when in patients undergoing anti-retroviral therapy due
present at elevated titers, may be predictive of to HIV infection (HAART). Thyroid dysfunc-
GD ophthalmopathy. tion, hyperthyroidism and positive Anti-TSHr
D. The presence of these antibodies may predict titers may result in both cases.
relapses in patients treated with tionamides, I. Presence of unilateral orbital pathology or
though this is a debatable argument. with euthyroidism.
E. Early titration of the antibody is recommended J. Presence of orbital pathology with
in women with a history of GD, previously hyperthyroidism.
78 H. Vargas-Uricoechea et al.
goiter are called “Marine-Lenhart Syndrome”. tionamide treatment has been received.
These cases may exhibit a gland with increased dif- Microscopically, thyroid follicles in different sizes
fuse uptake, “enhancement” areas in one or several may be appreciated, either hyperplastic or too
areas that are consistent with the findings of nod- small; some follicles have a prominent papillary
ules in the scan (autonomous functional nodules in shape occasionally misperceived for thyroid papil-
GD individuals). This characteristic is present in lary carcinoma. The nucleus is rounded or oval in
0.8–2.7 % of GD patients [60, 61]. When the diag- shape, with smooth margins and localized towards
nosis of hyperthyroidism is clear (both clinical and the base; chromatin is finely granular without
biochemical) in the presence of diffuse goiter, but atypia. The nuclei in the aspirate may exhibit a
when the evolution as described upon questioning clear, marginal cytoplasmic vacuole adjacent to
the patient indicates that signs and symptoms have the nucleus; these are called flame cells that show
only been present for some weeks or a few months, small nucleoli without a nuclear bar or intra-
the presence of non-GD hypothyroidism should be nuclear vacuole. These findings are also character-
entertained. In these cases, the differential diagno- istic of papillary carcinoma. The cytoplasm of
sis should mainly be based on sub-acute or chronic thyrocytes in GD may adopt a pink or anophillic
thyroiditis in the hyperthyroid phase. Under such color, with a granular or micro-vacuolated appear-
circumstances, I-131 or I-123 uptake is extremely ance. The colloid is paler than usual, vacuolated
helpful. Uptake increases in the presence of GD, and with a scalloped shape adjacent to the epithe-
whilst it declines or will be suppressed in the case lium, indicating follicular cell activity. In long-
of thyroiditis. standing cases, mild Hürthle cells metaplasia has
been described, in contrast to what is usually
appreciated in Hashimoto’s thyroiditis. A mild
Histopathological Diagnosis increase in the lymphocytic infiltrate at the stroma
is observed, though occasionally this infiltrate may
From the macroscopic point of view, GD presents be more significant and even develop into lym-
a gland that may be mild to moderately enlarge phoid follicles [62–64]. Frequently marked edema
and is symmetrical, involves both lobules and the of the papillary and reticular dermis can be seen on
isthmus, with a vascularized surface and it is usu- the skin, with nuclear fibroblast activity. This
ally smooth, though mild nodularity is occasion- edema turns blue under alcian blue stain, showing
ally visible. The section surface is soft and reddish the positivity of mucopolysaccharides produced
due to marked vascularization of the gland. Mild by active fibroblasts secreted into the extracellular
fibrosis may be observed, usually when previous matrix (Figs. 5.2, 5.3, 5.4, 5.5, and 5.6).
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59. Piga M, Cocco MC, Serra A, Boi F, Loy M, Mariotti 64. LiVolsi VA. The pathology of autoimmune thyroid
S. The usefulness of 99mTc-sestaMIBI thyroid scan disease: a review. Thyroid. 1994;4:333–9.
Part II
Thyroid Dysfunction and
Clinical Application
Thyroiditis
6
Henrique Vara Luiz, Isabel Manita,
and Jorge Portugal
Abstract
Thyroiditis is defined by the occurrence of thyroid inflammation and
involves a diverse group of conditions. It is usually classified by the pres-
ence or absence of pain and tenderness. The most important forms include
Hashimoto’s thyroiditis, painless and postpartum thyroiditis, drug-induced
thyroiditis, Riedel’s thyroiditis, subacute and suppurative thyroiditis. Each
type has particular characteristics, such as specific epidemiological data,
etiopathogenesis, clinical features, laboratory and image results, pathol-
ogy findings, differential diagnosis and therapeutic options. It is crucial
that physicians and other health professionals be aware of the differences
between the main forms of thyroiditis, so they can make a correct and
prompt diagnosis and start the appropriate treatment.
Table 6.1 Classification of thyroiditis based on the pres- It is also reported in the literature as chronic
ence or absence of pain and tenderness
lymphocytic thyroiditis or chronic autoimmune
No thyroid pain and tenderness thyroiditis.
Hashimoto’s thyroiditis
Painless thyroiditis Etiology and Pathogenesis
Postpartum thyroiditis HT is an autoimmune disorder, thought to be
Amiodarone-associated thyroiditis caused by a combination of genetic susceptibility
Thyroiditis induced by other drugs (lithium, and environmental factors.
interferon-alpha, interleukin-2, tyrosine kinase
inhibitors)
It seems that there is no dominant gene con-
Riedel’s thyroiditis ferring major susceptibility to the disease.
Infiltrative thyroid disorders (amyloidosis, sarcoidosis) However, an association was described with
Thyroid pain and tenderness human leukocyte antigen (HLA) alleles and with
Subacute thyroiditis other genes, namely CTLA-4, thyroglobulin
Suppurative thyroiditis (Tg), PTPN22, FCRL3 and IL2RA [10, 11].
Radiation-induced thyroiditis Some precipitating factors have been identi-
Palpation or trauma-induced thyroiditis fied, but their role remains unknown. They
include infection (e.g. hepatitis C virus, human T
lymphotrophic virus-I, rubella virus, herpes sim-
Thyroiditis Without Thyroid Pain plex virus, parvovirus and Epstein-Barr virus),
and Tenderness stress, postpartum period, iodine intake, selenium
and vitamin D deficiency, drugs such as interleu-
Hashimoto’s Thyroiditis kin-2 (IL-2) and interferon-alpha (IFN-α), envi-
ronment pollutants and radiation exposure. More
Epidemiology women than men have HT, which can be
Hashimoto’s thyroiditis (HT) was first reported explained by skewed X chromosome inactiva-
in 1912 by Hakaru Hashimoto, who described tion, the role of sex steroids and fetal microchi-
four patients with a chronic disorder of the thy- merism. The prevalence of the disease increases
roid gland, termed struma lymphomatosa [3]. with age, which may reflect an increasing loss of
This entity was rarely identified for many years, tolerance to self. Smoking has a surprisingly ben-
but an increase in its incidence was noticed since eficial effect on HT, in contrast to its detrimental
1940 [4]. The diagnosis was usually made after role on Graves’ disease (GD) [11, 12].
surgery. Furthermore, the routine use of the fine Several mechanisms have been proposed to be
needle aspiration biopsy (FNAB) and measure- related to HT, namely: molecular mimicry,
ment of thyroid autoantibodies have contributed bystander activation, thyroid-cell expression of
to a significant rise in its frequency. HLA antigens with subsequent activation of T
The annual incidence of HT for women and cells, and thyroid expression of functional Fas
men is approximately 3.5 and 0.6 cases per 1000 and Fas ligand contributing to thyroid cell apop-
population, respectively [5] and its estimated tosis [13].
prevalence is about 8 cases per 1000 [6]. Women Thyroid inflammation is typically character-
are at least six to eight times more likely to ized by both T and B lymphocytes. T cells are
develop the disease. It occurs especially between thought to play the main role in the disease and
40 and 60 years of age, but it may be seen in any can act by inducing antibody production, activat-
age group, including children [5, 6]. ing cytotoxic T cells with apoptotic destruction
HT is now considered the most common cause of thyroid cells and regulating the local immune
of hypothyroidism in areas of the world where response. Type 1 and type 2 T helper cells are
dietary iodine is sufficient [7], the most frequent present in patients with HT, with a predominance
autoimmune disease [8] and one of the main of the former [14]. In addition, patients may have
endocrine disorders [9]. dysfunctional regulatory T cells [15]. B cells can
6 Thyroiditis 89
produce antibodies and nearly all individuals ence of clinical manifestations in patients with
have high serum concentrations of Tg antibodies elevated thyroid antibodies. A response to corti-
(TgAb) and thyroid peroxidase antibodies costeroids can also favor the diagnosis [25].
(TPOAb), which are polyclonal and have the Other exams may be performed and are impor-
potential to fix complement. As a result, tant in the differential diagnosis. Most patients
complement-mediated cytotoxicity may contrib- respond to steroid therapy and prognosis is usu-
ute to thyroid damage, but this is thought to be a ally good [22, 24].
second line effect [16]. Thyroid-stimulating hor-
mone receptor antibodies (TRAb) can also be Diagnostic Evaluation
identified in the serum of patients with Patients with HT usually undergo a gradual loss
HT. However, these antibodies block the action of thyroid function. Approximately 75 % have
of thyroid-stimulating hormone (TSH) rather normal thyroid function at diagnosis but they can
than activating thyroid tissue as seen in GD [17]. develop subclinical or overt hypothyroidism [18],
which is permanent in most cases. However,
Clinical Features some patients may recover and reach euthyroid-
The disease usually occurs as a painless, diffuse ism, possibly explained by the decrease over time
and gradual enlargement of the thyroid gland of TSH receptor blocking antibodies [26]. Rarely,
[18]. The goiter is often firm and symmetrical the inflammatory process in the early course of
with pyramidal lobe enlargement. The presence the disease may cause severe apoptosis and thy-
of well-defined nodules is unusual. Rare patients roid damage, with subsequent thyroid hormone
have pain and tenderness [19] or symptoms release and transient hyperthyroidism; this condi-
related to neck pressure such as dyspnea or dys- tion is termed Hashitoxicosis and usually evolves
phagia, particularly if there is a rapid thyroid into permanent hypothyroidism [18, 21].
swelling. The thyroid gland may also remain Serum concentrations of thyroid antibodies
unchanged for several years and some patients do are almost always elevated. TPOAb and TgAb
not develop goiter or have an atrophic gland. In are positive in about 95 % and 60–80 % of
fact, two forms of HT, goitrous and atrophic, patients, respectively [18].
were described representing extremes within the A cervical ultrasound (US) may display an
distribution rather than separate disorders [20]. enlarged gland with very low echogenicity, or a
The patient is usually euthyroid but symptoms suggestion of multiple ill-defined nodules. Most
and signs of mild hypothyroidism may be present commonly the gland is two to four times the nor-
[18]. Occasionally, clinical features of mild thy- mal size.
rotoxicosis can occur, especially during the early Radioactive iodine uptake (RAIU) test,
phase of the disease [21]. although rarely required, is variable and ranges
One uncommon and controversial finding of from below normal to elevated values. Thyroid
HT is Hashimoto’s encephalopathy. A review scan is not necessary in most cases and the typi-
published in 2006 identified only 121 cases in the cal finding is a diffuse or mottled uptake in an
literature [22]. Its mechanism is unknown and it enlarged gland.
does not appear to be related to thyroid dysfunc- FNAB can be useful in patients with nodular
tion, as the majority of reported patients are disease. It usually reveals lymphocytes, macro-
euthyroid at the time of presentation. Evidence phages, scant colloid and epithelial cells which
suggests an autoimmune vasculitis, but the role may show Hurthle cell features. However, some
of thyroid antibodies is not clear [23]. Patient aspirates lack inflammatory cells and consist
most often have an acute to subacute onset of almost exclusively of Hurthle cells, leading to a
confusion with alteration of consciousness and misleading result of Hurthle cell tumor [27].
other neurologic signs, such as seizures, myoclo- Histological examination often reveals lym-
nus, tremor, hyperreflexia and psychosis [22, 24]. phoplasmacytic infiltration, lymphoid follicles
The diagnosis is usually performed by the pres- with germinal center formation, epithelial cell
90 H.V. Luiz et al.
destruction, the presence of large follicular cells disorder includes, independently of the affected
with abundant granular eosinophilic cytoplasm, organ, histological features such as a dense
known as oxyphilic, Hurthle or Askanazy cells, lymphoplasmacytic infiltrate, storiform-type
and various degrees of fibrosis [18]. fibrosis and obliterative phlebitis, along with
HT is often associated with type 1 diabetes the demonstration of an increased population
mellitus (T1DM), celiac disease, Addison’s dis- of IgG4-positive plasma cells [35, 36]. Cheuk
ease, Sjögren syndrome and other autoimmune and Chan considered that it requires an increase
disorders in the context of polyglandular autoim- in the absolute number of IgG4-positive cells
mune syndromes. The link between HT and thy- of > 50 per high power field and a raised IgG4-
roid cancer remains controversial. This positive/IgG-positive ratio of > 40 % [37].
association was first described by Dailey et al. in Deshpande et al. stated that histological data
1955 [28]. Some authors reported that patients are the mainstay for diagnosis, since both ele-
with HT have a threefold increased risk of papil- vated numbers of IgG4-positive plasma cells
lary thyroid carcinoma (PTC) as compared to and IgG4/IgG ratios have been described in
non-HT patients [29], but others stated that there other inflammatory conditions and malignan-
is inconsistent evidence favoring a causal rela- cies [38]. A high serum IgG4 concentration is
tionship between these entities [30]. Thyroid can- often present but approximately 20–30 % of
cer may be associated with a less aggressive patients with classic histopathological and
disease and a better prognosis in patients with immunochemical findings of the disease have
coexisting HT [31]. normal serum levels [39].
The diagnosis of HT is usually performed in a Therefore, the IgG4 variant of HT is charac-
patient with a diffuse goiter and one other bio- terized by thyroid inflammation rich in IgG4-
chemical or histological feature, such as positive positive plasma cells and marked fibrosis
TPOAb, positive TgAb or lymphocytic infiltra- (Fig. 6.1). It is usually associated with male
tion of the thyroid gland [32]. However, goiter gender, rapid progress requiring surgery, more
can be absent and the presence of serum thyroid subclinical hypothyroidism, higher levels of
autoantibodies may be sufficient evidence of the thyroid autoantibodies and more diffuse low
diagnosis. For many years, HT has been charac- echogenicity on US, when compared with the
terized as a well-defined clinicopathologic entity. non-IgG4 variant [40]. In 2012, Kakudo et al.
However, it is now considered a heterogeneous studied 105 patients with HT and classified 28
disease, with several subtypes: classic form, cases (27 %) as IgG4 thyroiditis based on immu-
fibrous variant, IgG4-related variant, juvenile nohistochemistry [41]. We recently presented
form (presented before 18 years of age), the first case of IgG4-related HT in a non-Asian
Hashitoxicosis and painless thyroiditis, the latter patient [42] (Fig. 6.2). Since this condition
occurring either sporadically or in the postpar- seems to be more common than previously
tum period. They share the diagnostic character- thought, we suggest performing the immunos-
istics of HT but have some interesting taining in a patient who presents with these
particularities [18]. typical clinical features and with lymphoplas-
The fibrous variant accounts for 10–13 % of macytic infiltration and marked fibrosis of the
HT cases and usually affects older patients. Its thyroid gland.
diagnostic criteria were defined by Katz and
Vickery in 1974 and included a marked fibrous Differential Diagnosis
replacement of more than one-third of the thyroid HT has to be distinguished from nontoxic multi-
parenchyma and changes typical of HT in the nodular goiter, thyroid cancer and GD.
remaining tissue [33]. Most patients are hypothy- In multinodular goiter, thyroid function tests
roid at presentation. are usually normal and thyroid autoantibodies are
The IgG4-related variant of HT is a new absent or identified at low titers. Cervical US
subtype, first recognized by Li et al. in 2009 shows well-defined nodules and the thyroid scan
[34]. It may be part of the systemic IgG4- can also be helpful. FNAB can distinguish these
related disease. The diagnosis of this systemic entities but is usually not performed.
6 Thyroiditis 91
a b
c d
Fig. 6.1 Typical histopathological findings of a patient infiltration is found and atrophic follicles with oxyphilic
with the diagnosis of IgG4-related Hashimoto’s thyroiditis. cells predominate (hematoxylin and eosin, 200×). (d)
(a) Large thyroid gland with a hard consistency. (b) An Increased number of IgG4-positive plasma cells are seen,
inflammatory infiltrate is seen, along with lymphoid folli- with > 50 cells per high-power field (IgG4 immunostain-
cles with germinal centers (black arrow) and marked fibro- ing, 400×). (From Luiz et al. [42], with permission)
sis (hematoxylin and eosin, 40×). (c) Lymphoplasmacytic
Fig. 6.2 A male patient with IgG4-related Hashimoto’s thyroiditis, presenting with a diffuse neck swelling of rapid growing.
(a) anterior view. (b) lateral view
92 H.V. Luiz et al.
T4
TSH
RAIU
0 1 2 3 4 5 6 7 8 9 10 11 12
Months
Fig. 6.3 Characteristic triphasic course of painless, postpartum and subacute thyroiditis. Abbreviations: RAIU radioac-
tive iodine uptake, T4 thyroxine, TSH thyroid-stimulating hormone
pattern found in postpartum and subacute thy- remain hypothyroid. Chronic thyroid disease can
roiditis [1, 2]. However, some patients only have also appear in almost 50 % of patients during
a transient hyperthyroid or hypothyroid phase. subsequent follow-up, usually related to the
Hyperthyroid symptoms have an abrupt onset development of goiter but permanent hypothy-
over 1–2 weeks but are usually mild, lasting from roidism may occur in 6 % of patients [45, 51].
4 to 8 weeks. Hypothyroidism is also mild or Positive serum TPOAb and TgAb are present
even asymptomatic, and may be present for 2–9 in about 57 and 38 % of patients, respectively,
months [48, 49]. Some patients have no symp- with lower titers when compared to HT [46, 49].
toms or signs related to thyroid dysfunction and The white blood cell (WBC) count is often nor-
are diagnosed incidentally by routine exams. mal, and the erythrocyte sedimentation rate
The thyroid gland is not painful or tender and (ESR) and C-reactive protein (CRP) are also nor-
has a normal or slightly increased size [49, 50]. mal or slightly increased [46, 49].
The RAIU test can be performed in the hyper-
Diagnostic Evaluation thyroid phase if the diagnosis is uncertain, yield-
The diagnosis of painless thyroiditis relies on ing a low result of about 1 % [46, 48, 49].
clinical manifestations, laboratory findings and Similarly, thyroid scan shows a very low radio-
thyroid scan images. tracer accumulation in the thyroid gland.
If clinical suspicion is high, measurement of Cervical US may be helpful in some patients,
serum thyroid function is recommended. The showing a normal-sized or slightly enlarged,
results vary over the course of the disease, and heterogeneous and hypoechogenic thyroid gland.
changes in free thyroxine (T4) and triiodothyro- Color flow Doppler sonography (CFDS) is nor-
nine (T3) usually precede those of TSH. During mal or low during the hyperthyroid period.
the early period, overt or subclinical hyperthy- FNAB is not typically performed. It can reveal
roidism may be present and an increase of free lymphocytes and macrophages, thyroid epithelial
T4 over T3 is typically found. Thyroid function cells and masses of colloid.
tests should be monitored on a regular basis (e.g. Histological features are similar to those
every 4–8 weeks). Some patients may recover found in HT, but patients with painless thyroiditis
and others develop overt or subclinical hypothy- often show fewer lymphoid follicles and germi-
roidism. When inflammation subsides, euthy- nal centers, less fibrosis and lack Hurthle cells
roidism is almost always achieved, but some may [46, 52].
94 H.V. Luiz et al.
more common but also usually not severe [56, 61, Cervical US findings can be similar to those
62]. Some authors suggest a relationship between described in painless thyroiditis.
the hypothyroid phase of postpartum thyroiditis Thyroid scan is usually not necessary and spe-
and postpartum depression [63, 64], but others cial care should be taken in women who are
did not find any association [65]. There is insuf- breastfeeding. During the hyperthyroid phase,
ficient data to conclude if these entities are related RAIU is typically low.
[62]. Most women have a slightly enlarged, dif- FNAB and histological findings are also simi-
fuse, painless and nontender thyroid gland. lar to those reported for painless thyroiditis.
Recently, the first association between post-
Diagnostic Evaluation partum thyroiditis and thyroid hormone resis-
The diagnosis is based upon clinical manifesta- tance was described [71].
tions and thyroid function tests.
There is insufficient data to recommend Differential Diagnosis
screening for postpartum thyroiditis in all cases. During the hyperthyroid phase, postpartum thy-
However, measuring of TSH levels at 3 and 6 roiditis has to be distinguished from GD, which
months postpartum is recommended for women can also present during the postpartum period.
at highest risk for developing the disease, namely The former usually occurs within 3 months after
those with positive TPOAb, T1DM, chronic viral delivery and the latter often develops after 4–6
hepatitis, GD in remission and previous episode months. CFDS and serum TRAb can be useful
of postpartum thyroiditis [55]. A recent article [72]. Other clues to distinguish these entities are
suggests gestational diabetes as an additional risk discussed in the differential diagnosis of painless
factor and recommends screening for thyroid dis- thyroiditis.
orders in this group of women [66]. During the hypothyroid phase, HT should be
If clinical suspicion of postpartum thyroiditis considered. Normalization of thyroid function
is high, measurement of serum thyroid function within weeks without the need of thyroid hor-
is recommended. Given the potential association mone replacement suggests the diagnosis of post-
with postpartum depression and since hypothy- partum thyroiditis.
roidism is a reversible cause of depression, thy-
roid function tests should also be performed in Treatment
women with postpartum depression [55, 56]. The There is no recommended treatment to prevent
biochemical findings are similar to those found in the disease. Administration of L-T4 or iodine in
patients with painless thyroiditis with variable the postpartum period to women with high serum
results during the course of the disease. Overt or levels of TPOAb did not decrease the incidence
subclinical hyperthyroidism may be present dur- of postpartum thyroiditis [73]. Selenium supple-
ing the early period. Thyroid function tests mentation administered during and after preg-
should be monitored every 4–8 weeks until 1 year nancy may reduce the incidence of this disorder
postpartum to confirm resolution or to detect the in women with positive TPOAb [74]. However,
development of hypothyroidism. When inflam- the routine use of this supplementation needs fur-
mation subsides, most patients achieve euthy- ther study [56, 62].
roidism. However, some women with reversible Most women with postpartum thyroiditis do
hypothyroidism can develop permanent hypothy- not require any treatment during either the hyper-
roidism in approximately 38–64 % of cases dur- thyroid or the hypothyroid phases. If needed, the
ing long-term follow-up [62, 67, 68], especially therapeutic options are the same as were dis-
those who have high TPOAb [69]. cussed for painless thyroiditis.
Positive TPOAb are present in about 60 % of Women who have bothersome symptoms of
patients [70]. hyperthyroidism can be treated with beta-block-
The WBC count, ESR and CRP levels are ers. Propranolol is usually the preferred and saf-
typically normal, but may be slightly elevated. est drug for those who are breastfeeding because,
96 H.V. Luiz et al.
compared to other beta-blockers, it has high pro- preformed thyroid hormones into the blood-
tein binding resulting in low diffusion into breast stream. It may be followed by a transient period
milk [75]. Antithyroid drugs or radioactive iodine of hypothyroidism with recovery of normal thy-
are not indicated. roid function in most cases [77].
Women with symptomatic hypothyroidism,
TSH levels exceeding 10 mIU/L or considering Clinical Features
another pregnancy should be treated with L-T4. Manifestations of hyperthyroidism are some-
Patients not treated have to be monitored with times masked due to the beta-blocking activity of
thyroid function tests and treatment may be con- the drug. Patients may be asymptomatic or have
sidered if hypothyroidism persists [55, 56]. The weight loss along with other nonspecific symp-
decision to discontinue L-T4 should be individu- toms. However, atrial fibrillation, exacerbation of
alized. Many experts favor weaning L-T4 after ischemic heart disease or heart failure may also
6–12 months, unless the woman is pregnant, occur.
attempting pregnancy, or breastfeeding. Thyroid The thyroid gland is usually normal or mildly
function should be regularly monitored. A rise in enlarged and is usually painless and nontender
the TSH level suggests permanent hypothyroid- [77].
ism. If normal thyroid function is achieved after
thyroid hormone withdrawal, lifelong follow-up Diagnostic Evaluation
for persistent hypothyroidism is required, ini- Thyroid function should be ordered before amio-
tially more frequently and then on an annual darone is started and monitored every 3–6 months
basis [56]. during treatment. The drug has a half-life of
50–100 days and remains available for a long
period after its discontinuation. For that reason,
Amiodarone-Associated Thyroiditis thyrotoxicosis may occur after amiodarone with-
drawal and therefore assessment of thyroid func-
Epidemiology tion after treatment should be considered [83].
Amiodarone is associated with thyroid dysfunc- Type II AIT is characterized by thyroid func-
tion, including both hypothyroidism and thyro- tion tests consistent with hyperthyroidism, some-
toxicosis [76–78]. times followed by transient hypothyroidism and
The prevalence of amiodarone-induced thyro- recovery [77].
toxicosis (AIT) ranges between 5 and 12 % of Thyroid US usually shows a hypoechoic gland
treated patients [79, 80] and is more common in with absent vascularity on CFDS. RAIU is low or
men [78]. It can be related to an increased synthe- absent.
sis of thyroid hormone (type I) in iodine-deficient
regions or to a destructive thyroiditis (type II) in Differential Diagnosis
iodine-sufficient areas [76]. Only the latter will The distinction between type I and type II AIT is
be discussed in this chapter. crucial, because the therapeutic approach varies
Type II AIT usually presents in patients with- depending on the type. However, the differential
out prior thyroid disease [81]. It is the main type diagnosis may be difficult and some patients may
in the United States due to normal dietary iodine have a mixture of both mechanisms [78]. Some
intake. features help in distinguishing the two types. If
the RAIU is detectable, it suggests type I
Etiology and Pathogenesis AIT. Patients with type I often have a goiter,
The type II form is not related to iodine and whereas those with type II usually present with a
results from a direct toxic effect of the drug on normal thyroid gland. CFDS shows increased
thyroid follicular cells [76, 81, 82]. This results vascularity in type I and absent vascularity in
in a destructive thyroiditis with excess release of type II hyperthyroidism (Table 6.2) [76, 84–86].
6 Thyroiditis 97
Table 6.2 Differential diagnosis between type I and type II amiodarone-induced thyrotoxicosis (AIT)
Feature Type I AIT Type II AIT
Epidemiology Iodine-deficient areas Iodine-sufficient areas
Underlying thyroid disease Present Absent
Pathogenesis Iodine-induced hyperthyroidism Destructive thyroiditis
Hypothyroid phase Absent Sometimes present
Thyroid antibodies Often present Usually absent
Thyroid ultrasound Goiter Normal-sized and hypoechoic
thyroid gland or small goiter
Color flow Doppler sonography Increased vascularity Reduced or absent vascularity
Radioactive iodine uptake Low, normal or increased Low or absent
Spontaneous remission No Possible
Treatment Thionamides (e.g. methimazole) Glucocorticoids (e.g. prednisone)
Patients treated with this drug should have a Clinical Features, Diagnostic
thyroid physical examination and be checked for Evaluation and Differential Diagnosis
thyroid dysfunction before it is started. Thyroid Features are variable, depending on the thyroid
function has to be monitored during treatment on disorder.
a regular basis (e.g. every 6–12 months). Patients should undergo routine thyroid
screening before starting IFN-α therapy, during
Treatment treatment (usually every 3–6 months) and at least
The occurrence of thyroid dysfunction does not 6 months after withdrawal because thyroid dis-
typically require discontinuation of the drug. ease can develop later [98, 99, 102].
Therapeutic options are variable regarding the
form of thyroiditis. The development of symp- Treatment
tomatic destructive thyroiditis can be treated with IFN-α can usually be continued but in some
beta-blockers [93]. cases reduction in the dose or even cessation of
the drug may be needed, especially when
thyrotoxicosis is present [97]. Patients should
Interferon-alpha be treated according to the type of thyroid
disease. In most cases thyroid dysfunction
Epidemiology is reversible on completion of antiviral treat-
IFN-α is indicated in the treatment of chronic ment [99].
hepatitis C, in combination with ribavirin [96].
Interferon-induced thyroiditis (IIT) is a com-
mon adverse effect of the drug, accounting for up Interleukin-2
to 40 % of treated patients [97–99].
Epidemiology
Etiology and Pathogenesis The incidence of hypothyroidism in patients
IIT can be classified as autoimmune and non- treated with IL-2 alone or in combination with
autoimmune [100], and each category represents lymphokine-activated killer cells is about
50 % of cases. It is thought to occur in geneti- 20–50 % [103–105]. The occurrence of hyper-
cally predisposed individuals. The autoimmune thyroidism is less frequently found [106, 107].
form can manifest as HT in patients who have
positive thyroid antibodies before treatment and, Etiology and Pathogenesis
less frequently, as GD. A subclinical disease Hypothyroidism is caused by an autoimmune
characterized by positive thyroid autoantibodies process.
and normal thyroid function is also commonly Hyperthyroidism also seems to be induced
found. by autoimmunity and usually presents with an
Non-autoimmune IIT can occur as destruc- early phase of thyrotoxicosis followed by a
tive thyroiditis due to a direct effect of the drug period of hypothyroidism and then resolution,
on the thyroid gland. It usually starts with an similar to the pattern found in painless thyroid-
early thyrotoxic phase, caused by the release of itis [93, 107].
preformed thyroid hormones, and then pro-
gresses to a late hypothyroid period, with Clinical Features, Diagnostic
recovery in most cases. The non-autoimmune Evaluation and Differential Diagnosis
form can also present as clinical hypothyroid- These characteristics vary depending on the
ism with no detectable thyroid antibodies, pathogenesis.
also suggesting a direct effect of the drug Thyroid function should be monitored in
[100, 101]. patients receiving IL-2 [107].
6 Thyroiditis 99
to the extensive replacement of the thyroid gland The diagnostic criteria of RT were established
by fibrosis, whereas hyperthyroidism is rare by Woolner et al. in 1957, based on histological
[113, 115]. data [123]. They have been modified to include a
On physical examination, the goiter is typi- fibroinflammatory process involving all or a por-
cally nontender, firm, rock-hard, and adherent to tion of the thyroid gland, the presence of fibrous
the adjacent structures [2]. It is usually symmet- extension beyond the thyroid capsule into adja-
ric and often moves poorly with swallowing. cent anatomic structures, infiltration of inflam-
Symptoms and signs related to the involve- matory cells without giant cells, lymphoid
ment of other organs in the context of systemic follicles, oncocytes or granulomas, evidence of
fibrosclerotic disease may be present [115]. occlusive phlebitis and absence of a neoplasm.
Once the diagnosis of RT is performed, a
Diagnostic Evaluation search for related fibrotic conditions should be
Most patients have normal thyroid function tests considered. In fact, about one-third of patients
at presentation. Hypothyroidism can develop with RT may develop fibrosclerosis of other
during the course of the disease in up to 85 % of tissues, namely the retroperitoneal space,
patients, and hyperthyroidism is rarely found mediastinum, retroorbital space or the biliary
[113, 114]. tract [112].
Approximately two-thirds of patients have RT can be also associated with other autoim-
elevated serum thyroid autoantibody concentra- mune and non-autoimmune thyroid disorders
tions [113]. [115], such as HT [124], GD [125], subacute thy-
The WBC count and the ESR may be normal roiditis [126] and thyroid cancer [127].
or mildly elevated. Measurement of serum cal-
cium and phosphorus should be performed to Differential Diagnosis
screen for coexistent hypoparathyroidism. RT should be distinguished clinically and histo-
US usually reveals a diffuse hypoechoic logically from several entities, namely the fibros-
appearance with absence of vascular flow on ing variant of HT, PTC, the paucicellular variant
CFDS, due to the extensive fibrosis [119]. of anaplastic cancer, thyroid lymphoma and sar-
In patients with significant obstructive symp- coma [115, 116].
tomatology a neck computed tomography (CT) In addition, recent data suggest that some
may be ordered to establish the extent of fibrosis. characteristics can help to distinguish IgG4-
It often shows a hypodense area and extrathyroi- related HT and RT. The absence of extensive
dal invasion. Magnetic resonance imaging typi- fibrosis beyond the thyroid capsule is still the
cally identifies a homogenous hypointensity on most reliable evidence to confirm a diagnosis of
both T1 and T2 images [115, 120]. IgG4-related HT. Furthermore, when IgG4-
Thyroid radionuclide imaging is not routinely related disease occurs in a systemic pattern, the
performed and frequently shows a low uptake [116]. thyroid involvement may present as RT, since
FNAB usually yields non-diagnostic results. It IgG4-related HT is organ-specific. In addition,
may reveal inflammatory cells and fibrous tissue, obliterative phlebitis is not present in any subtype
but thyroid epithelial cells are often absent [114]. of HT [128].
Pathologic data show an intense infiltration of
lymphocytes, plasma cells and eosinophils in a Treatment
dense hyalinized fibrous tissue [116, 121]. The In the setting of clinical suspicion of RT, patients
fibrosis extends beyond the thyroid into adjacent commonly undergo surgery to improve obstruc-
tissues. Occlusive phlebitis is present and results tive symptoms, establish a definitive diagnosis
from a diffuse infiltration of the walls of small and rule out malignancy [115, 116]. Total thy-
and medium-sized veins by lymphocytes and roidectomy is often not possible because of
plasma cells [115, 122]. the lack of resection planes and the high risk of
6 Thyroiditis 101
complications. For that reason most authors pre- Etiology and Pathogenesis
fer to perform a less aggressive surgery, usually It is probably caused by a viral infection of the
an isthmusectomy to relieve constrictive pres- thyroid gland [50]. In fact, several patients have a
sure. Despite limited surgical intervention, history of an upper respiratory infection a few
approximately 39 % of patients can develop com- weeks prior to the onset of thyroiditis. Some
plications involving the vocal cords and the para- authors suggested that the disease may have a
thyroid glands [114]. higher incidence in summer, possibly related to
After establishing the diagnosis, medical the seasonal variations of viral infections [140],
treatment should be started. Glucocorticoids are but others did not identify significant differences
used as first-line therapy, usually prednisone at throughout the year [137].
an empiric dose of 100 mg daily given for long- In patients with subacute thyroiditis diagnosed
term. It can provide a dramatic improvement in during a mumps epidemic, circulating anti-
compressive symptoms, especially when initi- mumps antibodies were identified and the virus
ated early in the course of the disease [129]. In was isolated from the thyroid gland, suggesting
patients who fail to respond to steroids or relapse the mumps virus as a cause of thyroiditis [141].
after withdrawal, tamoxifen therapy can be tried Direct evidence of infection was also found for
[130, 131]. human foamy virus [142], but its implication in
Hypothyroidism, if present, should be treated subacute thyroiditis has not been confirmed
with L-T4. Patients with hypoparathyroidism [143]. Numerous attempts to culture other viruses
require treatment with calcium and calcitriol. in the thyroid gland have failed. However, viral
antibody titers were identified in these patients,
suggesting a possible association. Some exam-
Infiltrative Thyroid Disorders ples include measles, chicken pox, influenza,
rubella, adenovirus, coxsackievirus, Epstein-Barr
Several systemic infiltrative disorders can cause virus and cytomegalovirus [143].
thyroiditis without evidence of pain or tender- Approximately 70 % of patients with subacute
ness, namely amyloidosis [132, 133] and sarcoid- thyroiditis manifest HLA-B35 [144]. Therefore,
osis [134–136]. it appears that the disease might occur through
viral infections in genetically predisposed indi-
viduals. Autoimmunity does not seem to have an
Thyroiditis with Thyroid Pain important role in this disorder.
and Tenderness Inflammation and damage to thyroid follicles
occur, with development of the same thyroid dys-
Subacute Thyroiditis function pattern described for painless and post-
partum thyroiditis (Fig. 6.3).
Epidemiology
The reported overall incidence of subacute thy- Clinical Features
roiditis is 4.9 cases per 100,000/year [137]. Subacute thyroiditis is characterized by neck
Females are four to seven times more affected pain in more than 95 % of cases [137, 138]. Rare
than men. The disease is rare in children and usu- patients have minimal or absent pain [145]. The
ally occurs between 30 and 50 years of age onset can be sudden or gradual and it is usually
[137–139]. bilateral but may be located in one lobe and then
Subacute thyroiditis is used as a synonym of spreads rapidly to involve the other lobe, a pro-
subacute granulomatous thyroiditis. Other terms cess known as creeping thyroiditis. Pain may
found in the literature are subacute nonsuppura- radiate to the jaw, ears or occiput and some
tive thyroiditis, giant cell thyroiditis, painful thy- patients also complaint of dysphagia, mimicking
roiditis and de Quervain’s thyroiditis. disorders arising in these areas [48]. Sometimes
102 H.V. Luiz et al.
the clinical presentation is preceded by an upper showing absent vascularization during the
respiratory infection. hyperthyroid period [152, 153].
The thyroid gland is typically enlarged two or Rarely, FNAB is necessary to exclude infec-
three times the normal size and nearly always tion or thyroid cancer. It usually reveals neutro-
tender. Myalgia, arthralgia, tremor, sweating and phils, lymphocytes, histiocytes and giant cells,
weight loss may be present along with mild to along with follicular cells and masses of colloid.
moderate fever [137]. Histological examination shows an inflamma-
A triphasic course is often identified, charac- tory process and destruction of follicles in the
terized by hyperthyroidism followed by hypothy- early phase of the disease. The most distinctive
roidism and then recovery. At least one-half of feature is the presence of granulomas, compris-
patients have mild and transient symptoms and ing clusters of giant cells within the degenerating
signs of hyperthyroidism [139], usually subsid- thyroid follicles. Progressive destruction of the
ing in 3–6 weeks [50]. However, rare patients can thyroid parenchyma with the development of
develop severe side effects such as adverse car- fibrosis is found later in the course of this disor-
diac outcomes and thyroid storm [146]. The der [154].
hypothyroid phase occurs in about one-third of
cases and is usually asymptomatic lasting from 2 Differential Diagnosis
weeks to 6 months [50]. Subacute thyroiditis is the most common cause
of thyroid pain. However, another important con-
Diagnostic Evaluation dition to be considered is suppurative thyroiditis.
The diagnosis relies mostly on clinical findings. Some characteristics help in distinguishing these
If a patient presents with the typical symp- two disorders (Table 6.3) [155, 156].
toms and signs, thyroid function tests should be Hemorrhage into a thyroid nodule can also
performed, showing variable results over the cause severe thyroid pain and tenderness, but it is
course of the disease. Almost all patients have often more sudden and transient, and the thyroid
biochemical evidence of hyperthyroidism in abnormalities are predominantly unilateral.
the early stage of the inflammatory process. Other causes of hyperthyroidism with a low
Thyroid function tests should be monitored on RAIU, including administration of exogenous
a regular basis to confirm recovery or to iden- iodine, should be excluded based on clinical find-
tify the occurrence of overt or subclinical ings and laboratory evaluation.
hypothyroidism. Most patients achieve euthy- Rare patients with HT or GD can present with
roidism but permanent hypothyroidism can neck pain and tenderness and these entities
occur in approximately 5–15 % during follow- should also be considered.
up [137, 147]. Painless and postpartum thyroiditis are char-
A high ESR and/or CRP measurement may acterized by the same triphasic pattern of thyroid
help in confirming the diagnosis [148]. Liver dysfunction and also have a low RAIU. However,
function test abnormalities are also frequently they do not usually present with thyroid pain, and
found [149]. their ESR is often normal.
About 25 % of patients have positive serum Rarely, patients with thyroid carcinoma or
thyroid antibodies, often present at low titers lymphoma may have thyroid pain and tenderness
[138, 150]. [157]. Thyroid US and FNAB are useful in ruling
In some cases a thyroid scan can be useful. It out a malignancy.
often shows low uptake during the thyrotoxic Some authors reported the coexistence of sub-
period [151], returning to normal or even becom- acute thyroiditis and thyroid carcinoma, and
ing elevated in a late phase of the disease. noticed that US changes related to thyroiditis
Thyroid US with CFDS may help in the dif- may obscure the diagnosis of a PTC. Therefore, it
ferential diagnosis. The thyroid gland is normal is important to repeat US after recovery of the
or enlarged and typically hypoechogenic, inflammatory process and to perform a FNAB in
6 Thyroiditis 103
Therapy for hypothyroidism is also often not rence of suppurative thyroiditis by direct spread
needed. However, L-T4 treatment should be of pathogenic organisms, although this is a very
introduced in patients with symptoms or a TSH rare complication of the procedure [167, 168].
level above 10 mIU/L, and is usually discontin- Several organisms may reach the thyroid
ued after 3–12 months [50, 88]. Regular monitor- gland by hematogenous route or direct spread
ing of thyroid function should be performed to from an adjacent organ. Aerobic Gram-positive
confirm that the hypothyroidism is not bacteria are the most common pathogens, espe-
permanent. cially Staphylococcus aureus, Streptococcus pyo-
Recurrence of the inflammatory process can genes and other Staphylococcus and
occur during subsequent follow-up in 1–4 % of Streptococcus species [166, 169, 170]. In 2013,
patients with a prior episode of subacute thyroid- three cases of suppurative thyroiditis caused by
itis [137, 161]. Streptococcus milleri were published [171, 172].
This organism is associated with head and neck
abscess formation. Recently, in our hospital, we
Suppurative Thyroiditis treated two patients with thyroid infection caused
by this agent, one of them presenting with exten-
Epidemiology sive involvement of cervical structures [173] and
Suppurative thyroiditis is a rare but potentially later developing recurrent disease.
life-threatening condition, accounting for 0.1– Aerobic Gram-negative bacteria can also be
0.7 % of thyroid diseases [162]. Its incidence is associated with this disorder and include
increasing due to the higher number of immuno- Klebsiella species, Eschericia coli, Haemophilus
compromised patients. influenzae, Eikenella corrodens and Salmonella
It occurs especially in children because of the species. Anaerobic bacteria such as
association with pyriform sinus fistula, whereas Peptostreptococcus, Bacteroides, Actinomyces
about 8 % of cases are diagnosed in adults [163]. and Fusobacterium species were also identified
[166, 170].
Etiology and Pathogenesis Polymicrobial infection involving these agents
Suppurative thyroiditis is caused by an infection. is present in about 37 % of patients [173].
The thyroid gland is usually resistant to infection Organisms that are more rarely identified include
because of its encapsulation, high iodide content, Mycobacterium tuberculosis, atypical mycobacte-
rich blood supply, and extensive lymphatic drain- ria, fungal infections such as Aspergillus species,
age [1]. However, several factors may overcome Coccidioides immitis, Cryptococcus neoformans,
these mechanisms and predispose patients to this Histoplasma capsulatum, Candida species and
disorder. In children, an anomaly in the third or Pneumocystis jiroveci (previously classified as
fourth branchial arch can be related to the devel- Pneumocystis carinii) and some parasites, namely
opment of a fistula extending from the pyriform Echinococcus species and Strongyloides stercora-
sinus to the thyroid capsule. It is almost always lis [166, 170].
left-sided, explained by the fact that the right ulti-
mobranchial body is often atrophic. Pyriform Clinical Features
sinus fistula is associated with a high risk of Most cases present with a sudden onset of pain,
recurrent suppurative thyroiditis [164, 165]. often after an upper respiratory tract infection.
Patients with a thyroglossal duct remnant, and Pain is typically unilateral and may radiate to the
immunocompromised patients such as those jaw, ears or occiput. It is reduced by neck flexion
infected by the human immunodeficiency virus and worsened by neck hyperextension. Associated
(HIV) or harboring a malignancy are predisposed features include fever, hoarseness, dysphagia,
to this condition [166]. It is also most likely to dysphonia, local warmth and dermal erythema
occur in individuals with preexisting thyroid dis- [169, 174]. In general, there are no signs or symp-
ease [1]. FNAB can also contribute to the occur- toms of hyper or hypothyroidism.
6 Thyroiditis 105
a b
Fig. 6.4 Clinical features of two patients with suppurative thyroiditis presented to our hospital. (a) Streptococcus mil-
leri. (b) Mycobacterium tuberculosis
On examination, a firm, tender, red and warm A radionuclide thyroid scan shows absent or
swelling is noticed in the anterior region of the decreased uptake in the affected lobe, but is often
neck (Fig. 6.4). In children the left lobe is involved not needed [174].
in 90 % of cases due to the predominance of a Evaluation for pyriform sinus fistula is usually
left-side pyriform sinus fistula [174]. A thyroid indicated, especially in children. A barium swal-
abscess can be identified on physical exam. low study or direct laryngoscopy of the hypo-
The course of the disease is usually more pharynx can be used, and the latter may be more
indolent in patients with tuberculous and fungal sensitive [178, 179]. Thyroid US and CT may
thyroiditis, when compared to those presenting also suggest the presence of a fistula [180, 181].
with an acute bacterial infection [175, 176]. Aspiration of the lesion by FNAB or surgical
drainage should be performed to identify the
Diagnostic Evaluation causative organism, and the specimen has to be
Thyroid function tests are normal in about 90 % analyzed for Gram stain, culture of possible
of patients [174]. However, this depends on the involved organisms and cytology. For patients
causative agent. Euthyroidism is the rule in bac- presenting acutely, some authors choose to order
terial thyroiditis, but fungal infections are often blood cultures and then start empiric antibiotic
associated with hypothyroidism [171]. Patients treatment prior to thyroid aspiration. However,
with thyroid tuberculosis are usually euthyroid for hemodynamically stable patients, this proce-
but are most likely to develop hyperthyroidism, dure can be performed before starting antibiotic
whereas hypothyroidism is very rare [171, 175]. treatment [170].
Leukocytosis, high ESR and elevated CRP are In those presenting with bacterial infections,
typical [156, 174]. Screening for HIV is pathological examination reveals a polymorpho-
recommended. nuclear and lymphocytic infiltrate, often with
Cervical US often reveals a unifocal necrosis and abscess formation.
hypoechoic region and/or abscess formation,
along with effacement of the plane between the Differential Diagnosis
thyroid and perithyroid tissues. Thyroid atrophy This entity should be differentiated from thyroid
can be identified in the late inflammatory stage adenoma, goiter or subacute thyroiditis. The dif-
[177]. ferences between suppurative and subacute thy-
CT of the neck can be performed if the US is roiditis are described in Table 6.3 [155, 156]. In
unclear or if there is extension of a thyroid summary, systemic manifestations are less severe
abscess to other locations. in subacute thyroiditis and the inflammation
106 H.V. Luiz et al.
process is usually transient, whereas untreated sinus fistula, it is reasonable to continue antibi-
suppurative thyroiditis typically results in severe otic therapy until its elective correction [170].
complications. The prognosis is usually excellent and clinical
Intracystic hemorrhage, painful HT and recovery is the rule after appropriate treatment
malignancy should also be considered. The latter [170]. Rare patients develop permanent hypothy-
is usually distinguished by US and FNAB. Thyroid roidism or extension of the infection into adja-
malignancy and suppurative thyroiditis may cent structures. However, local and systemic
coexist, and the inflammatory condition can be complications may be life-threatening if therapy
the presenting manifestation disclosing the diag- is delayed or inadequate [1].
nosis of a carcinoma [182].
Epidemiology Treatment
Vigorous palpation of the thyroid gland [197], Glucocorticoids can be used to induce symptoms
manipulation during thyroid biopsy [198], neck relief [203].
surgery [199, 200] and trauma [201] can cause a
particular form of thyroid inflammation, known Conclusion
as palpation or trauma-induced thyroiditis. Several types of thyroiditis were described,
Carney et al. in 1975 identified specific patho- characterized by thyroid inflammation.
logical findings in dogs after vigorous squeezing However, each form has particular character-
of their thyroid glands. A similar disorder in istics, such as specific incidence/prevalence,
humans was believed to result from traumatic etiopathogenesis, clinical features, laboratory
injury or rupture of thyroid follicles caused by and image results, pathology findings, differ-
palpation. The authors also found the histological ential diagnosis and therapeutic options.
changes in at least 83 % of human thyroids Table 6.4 provides an overview of the main
removed surgically [197]. forms of thyroiditis.
In addition, transient hyperthyroidism has It is crucial that physicians and other health
been shown to occur postoperatively in 20–29 % professionals be aware of the classification
108
Table 6.4 Overview of the main forms of thyroiditis
Etiology and Differential
Epidemiology Pathogenesis Clinical features Diagnostic evaluation diagnosis Treatment
Hashimoto’s Incidence: 3.5 (♀) and Autoimmune Painless goiter Euthyroidism or hypothyroidism Multinodular goiter LT4
thyroiditis 0.6 (♂) /1000/year Genetic Mild High thyroid antibodies Thyroid carcinoma
♀:♂, 6:1–8:1 susceptibility hypothyroidism US: low echogenicity Lymphoma
Peak age: 40–60 years Environmental Pathology: lymphocytic Graves’ disease
factors infiltration
Painless 1–23 % of Autoimmune Variable symptoms Triphasic course Hyperthyroid No treatment
thyroiditis hyperthyroidism Genetic of thyroid (hyperthyroidism, hypothyroidism phase: Graves’ Hyperthyroid phase:
cases ♀:♂, 2:1–3:1 susceptibility dysfunction and recovery) disease consider beta-blockers
Peak age: 20–40 years Small painless US: hypoechogenicity Hypothyroid Hypothyroid phase:
goiter CFDS: normal/low flow phase: Hashimoto’s consider L-T4
(hyperthyroid phase) thyroiditis
RAIU: low (hyperthyroid phase)
Pathology: lymphocytic
infiltration
Postpartum 8 % of pregnancies Autoimmune Variable symptoms Triphasic pattern or only transient Hyperthyroid No treatment
thyroiditis Within 1 year after a Genetic of thyroid hyper or hypothyroidism phase: Graves’ Hyperthyroid phase:
delivery susceptibility dysfunction US: hypoechogenicity disease consider beta-blockers
Predisposing Small painless RAIU: low (hyperthyroid phase) Hypothyroid (propranolol)
factors goiter Pathology: lymphocytic phase: Hashimoto’s Hypothyroid phase:
infiltration thyroiditis consider L-T4
Amiodarone 5–12 % of treated Direct toxic No symptoms Transient hyperthyroidism Type I AIT Consider amiodarone
-associated patients effect of the or mild US: hypoechoic gland withdrawal
thyroiditis (type Iodine-sufficient areas drug hyperthyroidism CFDS: low flow Glucocorticoids
II AIT) (destructive Small painless RAIU: low or absent
thyroiditis) goiter
Riedel’s Incidence: 1.06/100,000 Probably a Painless, firm, Euthyroidism or hypothyroidism Fibrosing and IgG4 Limited surgical
Thyroiditis ♀:♂, 4:1–5:1 manifestation rock-hard and US: diffuse hypoechogenicity variants of intervention
Mean age: 42–48 years of a systemic adherent goiter CFDS: absent flow Hashimoto’s Glucocorticoids
fibrosclerosis Compressive RAIU: low thyroiditis Hypothyroidism: L-T4
disorder symptoms Pathology: extensive fibrosis PTC, paucicellular
triggered by Mild variant of
Thyroiditis
thyroiditis year Genetic goiter (hyperthyroidism, hypothyroidism thyroiditis Glucocorticoids (severe
♀:♂, 4:1–7:1 susceptibility Variable symptoms and recovery) Intracystic cases)
Peak age: 30–50 years of thyroid High ESR and CRP hemorrhage Hyperthyroidism:
dysfunction US: hypoechogenicity Exogenous iodine beta-blockers
CFDS: absent flow (hyperthyroid Thyroid carcinoma Hypothyroidism: L-T4
period) or lymphoma
RAIU: low (thyrotoxic period)
Pathology: granuloma, giant cells
Suppurative 0.1–0.7 % of thyroid Infection Painful/tender Euthyroidism Subacute Antibiotic therapy
thyroiditis diseases Predisposing goiter Leukocytosis, high ESR and CRP thyroiditis Surgical drainage
Children >90 % conditions Systemic US: unifocal hypoechogenicity Intracystic Surgery to repair a
symptoms and/or abscess hemorrhage pyriform sinus fistula
RAIU: low in the affected lobe Painful
Barium swallow study or direct Hashimoto’s
laryngoscopy: pyriform sinus thyroiditis
fistula Malignancy
FNAB or surgical drainage:
identify organism
Pathology: abscess formation
Radiation- 1 % in patients treated Destructive Painful/tender Transient hyperthyroidism Radioiodine failure NSAIDs or
induced for hyperthyroidism thyroiditis goiter after glucocorticoids
thyroiditis More frequent after radioiodine Hyperthyroidism:
thyroid remnant ablation Symptoms of beta-blockers
hyperthyroidism
Palpation or Unknown incidence Destructive Painful/tender Transient hyperthyroidism Graves’ disease Glucocorticoids
trauma-induced thyroiditis goiter CFDS: low flow Subacute
thyroiditis Symptoms of RAIU: low thyroiditis
hyperthyroidism Pathology: multifocal
granulomatous folliculitis
Abbreviations: AIT amiodarone-induced thyrotoxicosis, CFDS color flow Doppler sonography, CRP C-reactive protein, ESR erythrocyte sedimentation rate, FNAB fine needle
aspiration biopsy, L-T4 levothyroxine, NSAIDs nonsteroidal antiinflammatory drugs, PTC papillary thyroid carcinoma, RAIU radioactive iodine uptake, US ultrasound
109
110 H.V. Luiz et al.
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Hypothyroidism
7
Henrique Vara Luiz, Isabel Manita,
and Jorge Portugal
Abstract
Hypothyroidism can be defined by a decrease in thyroid hormone produc-
tion and/or by an impaired action of thyroid hormones on target tissues. It
is a common condition with multiple etiologies and clinical manifesta-
tions. Currently, hypothyroidism is usually diagnosed at early stages
which allow a timely treatment. Levothyroxine is still the modality of
choice and other therapeutic options are not recommended. The adminis-
tration of an appropriate hormone replacement dose leads to a normaliza-
tion of thyroid function in virtually all cases. However, patients with
severe long-standing hypothyroidism can develop life-threatening compli-
cations. Therefore, physicians must be aware of the typical clinical find-
ings in order to promptly evaluate patients with suspected hypothyroidism.
In addition, infants with congenital hypothyroidism should be properly
managed.
Primary Hypothyroidism
Hashimoto’s Thyroiditis
HT is considered the most frequent cause of
hypothyroidism in areas of the world where
dietary iodine is sufficient [27]. It is an autoim-
mune disease, usually characterized by the pres-
ence of a diffuse goiter and positive thyroid Fig. 7.1 Presence of a large goiter in a patient from an
antibodies. This disorder is discussed in the area of iodine deficiency (Courtesy of Dr. Ruby Guerrero
Chap. 6. and Dr. April Abcede)
120 H.V. Luiz et al.
Endemic cretinism refers to the presence of occurring in 4 % of cases within the first year
severe hypothyroidism in children occurring in with an additional risk during long-term follow-
regions of endemic goiter [14]. It is caused by up [43, 44]. It is also dependent on the adminis-
severe iodine deficiency during pregnancy [28, tered dose.
34, 35]. External neck irradiation performed for sev-
eral disorders can produce hypothyroidism. The
Iodine Excess estimated incidence in patients treated for
Iodine is present in the diet and in some drugs Hodgkins’ lymphoma is about 30 % [45],
such as amiodarone, kelp tablets, vitamin prep- whereas those performing irradiation for larynx
arations, topical antiseptics and radiographic or pharynx cancer develop hypothyroidism in
contrast agents. Iodine excess can also cause 13 % of cases [46]. The effect of radiation is
hypothyroidism by inhibiting iodide organifi- dose-dependent and the onset of thyroid dysfunc-
cation and thyroid hormone synthesis, a phe- tion is often gradual [47].
nomenon known as Wolff-Chaikoff effect [36].
Most subjects escape from this effect within a Drugs
few weeks. However, failure to escape may Thionamides such as methimazole and propyl-
occur especially in patients with an underlying thiouracil are used in the management of
thyroid disease such as HT, painless, postpar- hyperthyroidism. Overtreatment can cause
tum or subacute thyroiditis and in those sub- hypothyroidism.
mitted to radioiodine therapy or partial Amiodarone is associated with thyroid dys-
thyroidectomy [14, 36]. Improvement is function, including both hypothyroidism and thy-
noticed after iodine withdrawal. rotoxicosis [48–50]. Overt and subclinical
hypothyroidism develops in 5 and 26 % of treated
Iatrogenic patients, respectively [51] and is caused by iodine
Iatrogenic hypothyroidism is common in adults excess. It often affects patients living in iodine-
and can be related to thyroidectomy, radioiodine sufficient regions [52], those with an underlying
therapy and external irradiation. thyroid disorder who cannot escape from the
Hypothyroidism invariably occurs in patients Wolff-Chaikoff effect [36], and those with posi-
submitted to total thyroidectomy. After partial tive thyroid antibodies [53]. Thyroid function
thyroidectomy it develops in about 20–35 % of should be checked before amiodarone is started
cases, especially within the first year [37, 38]. and monitored every 3–6 months during treat-
However, hypothyroidism can develop later or ment. The drug has a half-life of 50–100 days and
be transient. Some authors suggested an associ- remains available for a long period after its dis-
ation between the development of hypothyroid- continuation. For that reason, thyroid dysfunc-
ism after surgery and both the presence of tion may occur after amiodarone withdrawal and
thyroid antibodies and higher preoperative TSH therefore assessment of thyroid function after
levels [37–39]. treatment should be considered [54]. If hypothy-
Radioiodine therapy is another iatrogenic roidism develops, amiodarone is usually not dis-
cause of hypothyroidism. In patients with Graves’ continued [50].
disease it is usually recommended to administer Lithium can cause goiter, hypo and hyperthy-
sufficient radiation in a single dose to render the roidism [55, 56]. The prevalence of
patient hypothyroid [40], which occurs in about hypothyroidism ranges between 6 and 52 % of
70 % of cases within the first year [41]. treated patients [56] and it can develop in those
Hypothyroidism can develop later at a rate of with or without an underlying thyroid disease.
2–3 % per year [42] and it may also be transient. Risk factors include female gender, the elderly
The development of hypothyroidism in patients and patients with positive thyroid antibodies
submitted to radioiodine therapy for toxic multi- [56–59]. Lithium-associated hypothyroidism is
nodular goiter or toxic adenoma is less common, related to the drug inhibition of thyroid hormone
7 Hypothyroidism 121
secretion and/or to the increasing of thyroid anti- sarcoidosis [76], hemochromatosis [77], sclero-
bodies [55, 56, 60]. Patients treated with this derma [78] and cystinosis [79] are rare causes of
drug should have a thyroid physical examination hypothyroidism.
and be checked for thyroid dysfunction before it Infections of the thyroid gland are also
is started. Thyroid function needs to be moni- uncommon and almost always present with nor-
tored during treatment on a regular basis (e.g. mal thyroid function. We reported an interesting
every 6–12 months). The occurrence of hypothy- case of hypothyroidism due to thyroid tuberculo-
roidism does not require discontinuation of the sis [80].
drug [56]. Riedel’s thyroiditis and infections are dis-
Interferon-alpha (IFN-α) is associated with cussed in the Chap. 6.
the occurrence of both hypo and hyperthyroidism
in about 5–10 % of treated patients [61–64]. Transient Hypothyroidism
Hypothyroidism can be autoimmune manifesting Painless, postpartum and subacute thyroiditis are
as HT, which especially affects patients with pos- characterized by a triphasic course of hyperthy-
itive thyroid antibodies before treatment. Non- roidism followed by hypothyroidism, and then
autoimmune hypothyroidism is due to a direct recovery to the euthyroid state. These entities are
effect of the drug on the thyroid gland. Patients also discussed in the Chap. 6.
should undergo routine thyroid screening before
starting IFN-α therapy, during treatment (usually Primary Congenital Hypothyroidism
every 3–6 months) and at least 6 months after It is one of the most common preventable causes
withdrawal because thyroid disease can develop of mental retardation. About 90 % of permanent
later [62, 63, 65]. IFN-α can usually be continued cases of congenital hypothyroidism are related
if thyroid dysfunction is identified. In most cases to thyroid dysgenesis. This condition manifests
hypothyroidism is reversible on completion of in about two-thirds of cases as failure of the
antiviral treatment [63]. gland to descend properly during embryologic
The incidence of hypothyroidism in patients development (ectopy), whereas absence of the
treated with interleukin-2 alone or in combina- thyroid tissue (agenesis) is found in one-third of
tion with lymphokine-activated killer cells is patients [81]. Thyroid dysgenesis is usually spo-
about 20–50 % [66–68]. It is caused by an radic, but it can be rarely associated with genetic
autoimmune process. Thyroid function should mutations in transcription factors predominantly
also be monitored in patients receiving this expressed in the thyroid gland, namely PAX8,
drug [69]. NKX2-1, FOXE1 and NKX2-5 [82]. The
Tyrosine kinase inhibitors are associated remaining 10 % of permanent cases are due to
with the development of hypo and hyperthy- thyroid dyshormonogenesis, caused by muta-
roidism [70]. Sunitinib can induce hypothy- tions in genes encoding proteins involved in
roidism in 53–85 % of patients [71, 72]. The thyroid hormone synthesis, namely the sodium-
incidence of thyroid dysfunction with sorafenib iodine symporter, thyroid peroxidase (TPO),
and other drugs from this therapeutic class is pendrin (Pendred’s syndrome), thyroglobulin
lower [70]. The pathogenesis is unknown, but (TG) and iodotyrosine deiodinase [83].
it seems that hypothyroidism can be related to Inheritance is autosomal recessive. Other
the drug induction of autoimmunity or to a patients present with resistance to TSH due to
destructive thyroiditis as a direct effect of mutations in the TSH receptor gene [84].
treatment [70]. Monitoring thyroid function Some infants may have transient congenital
during treatment is advisable. hypothyroidism, which is usually related to
iodine deficiency or excess during pregnancy
Thyroid Infiltration and Infections [85, 86], and to transplacental transfer of TSH
Infiltrative disorders such as fibrous thyroiditis receptor blocking antibodies or antithyroid
(Riedel’s thyroiditis) [73, 74], amyloidosis [75], drugs [87].
122 H.V. Luiz et al.
a b
c d
Fig. 7.2 Pituitary magnetic resonance imaging performed and cavernous sinuses. Marked contrast enhancement is
in a patient with panhypopituitarism shows a large hetero- observed. (a) Sagittal T1; (b) Axial T2; (c) Coronal T2; (d)
geneous mass (5.6 × 6.0 × 6.1 cm) involving the clivus, Coronal post gadolinium. Further evaluation confirmed the
with intrasellar extension and infiltration of the sphenoid diagnosis of a solitary intrasellar plasmacytoma
7 Hypothyroidism 123
Mass lesions cause hypothyroidism by compres- hormones. Due to the resistance in peripheral tis-
sion of pituitary thyrotrophs, interruption of the sues they are usually euthyroid. Patients with pitu-
hypothalamic-pituitary portal blood flow thereby itary resistance alone are hyperthyroid as the high
preventing delivery of TRH to the pituitary, or levels of thyroid hormones have normal action
rarely by acute hemorrhage or infarction resulting peripherally. Those with predominantly peripheral
in pituitary apoplexy [89]. Several other etiologies resistance have normal TSH and thyroid hormone
are associated with central hypothyroidism, levels that are not sufficient to overcome tissue
namely postpartum pituitary necrosis (Sheehan’s hyposensitivity and usually present with symptoms
syndrome), head trauma, surgery and irradiation, and signs of hypothyroidism. We recently identified
autoimmune lymphocytic hypophysitis, infiltrative a patient with an extremely rare association of RTH
diseases (e.g. sarcoidosis, histiocytosis, hemochro- and papillary thyroid carcinoma [96]. Control of
matosis) and infections (e.g. tuberculosis, syphilis, thyroid function after total thyroidectomy was only
toxoplasmosis) [24]. possible using supraphysiological dosages of L-T4
(500 μg/day; 6 μg/kg/day).
Central Congenital Hypothyroidism
The presence of hypothalamic and pituitary Consumptive Hypothyroidism
hypothyroidism in infants is very rare. It may It is a very rare condition characterized by exces-
be caused by structural lesions such as pituitary sive degradation of thyroid hormones within
hypoplasia and septo-optic dysplasia. Some tumors such as large hemangiomas [97]. These
cases are associated with mutations in genes tumors express type 3 deiodinase (D3), which
encoding proteins that are related to TSH syn- metabolizes T4 to reverse T3 and T3 to 3,3′-diio-
thesis and release, namely TRH receptor [90], dothyronine. Consumptive hypothyroidism is
TSH [91] and pituitary transcription factors especially found in infants but adult cases were
such as POU1F1, PROP1, LHX3, LHX4, also reported [98].
HESX1 and LEPR [24]. These genetic defects
may produce hypothyroidism either isolated or
combined with other pituitary hormone Clinical Features
deficiencies.
Hypothyroidism can affect all organ systems.
Drugs The presence and severity of clinical manifesta-
Dopamine, bexarotene (retinoid X receptor ago- tions are usually dependent on the degree of hor-
nist used in the treatment of lymphoma), gluco- mone deficiency. Two mechanisms explain most
corticoids and somatostatin analogues may of the symptoms and signs: the generalized slow-
suppress serum TSH and contribute to the devel- ing of metabolic processes and the accumulation
opment of central hypothyroidism [92]. of glycosaminoglycans in the interstitial space of
many tissues [99]. To simplify the discussion the
authors decided to group the clinical features in
Other Disorders organ systems.
ceous glands are reduced, leading to dryness of tions cause narrowing of pulse pressure, diastolic
the skin. The skin is pale and cool as a result of hypertension (10–25 % of patients) and a
cutaneous vasoconstriction and/or anemia. Some decrease in blood flow to organs [101, 102]. In
patients may have hypercarotenemia, which most tissues, the reduction in blood flow is pro-
gives the skin a yellow tint. Wounds heal slowly. portional to the decrease in oxygen consumption
Easy bruising can also occur due to an increase in and therefore angina is an infrequent symptom
capillary fragility [14, 100]. [103]. When present it is usually explained by an
Head and body hair is dry and brittle, lacks underlying coronary heart disease (CHD). Serum
shine, and tends to fall out. Hair may be lost levels of homocysteine [104, 105] and creatine
from the lateral margins of the eyebrows kinase (CK) [106] may be increased in hypothy-
(Queen Anne’s sign), although this is not a spe- roidism. Dyslipidemia can be found in more than
cific feature. Eyebrows can totally disappear. 90 % of patients, usually presenting as elevations
The nails are thickened, brittle and grow slowly of total and low-density lipoprotein (LDL) cho-
(Fig. 7.3). lesterol [107]. These findings may contribute to
an increased risk of atherosclerosis.
An electrocardiogram can show sinus brady-
Cardiovascular cardia, low voltage, prolongation of the PR
interval, alterations of the ST segment, pro-
The cardiac output is decreased due to a reduc- longed QT interval and flattened or inverted T
tion in both stroke volume and heart rate, which waves [14, 100]. Torsade de pointes can rarely
can explain the symptoms of reduced exercise occur [108]. Echocardiographic evaluation may
tolerance and dyspnea. Peripheral vascular resis- reveal pericardial effusion [109], asymmetric
tance is increased. These hemodynamic altera- septal hypertrophy or other abnormalities
a b
Fig. 7.3 Features of a patient with severe hypothyroid- improvement of signs and symptoms of hypothyroidism 3
ism. (a) Clinical presentation with marked periorbital months after the introduction of levothyroxine
myxedema, dry and cool skin and fatigue. (b) Significant
7 Hypothyroidism 125
[110]. Rarely, patients can develop congestive Manifestations include mental retardation,
heart failure [111]. impaired motor development such as tremor,
rigidity and spasticity of the trunk and proximal
extremities, and also strabismus and sensorineu-
Respiratory ral hearing loss [128].
Hypothyroidism occurring in adult life is
Pleural effusions can be present and may contribute characterized by less severe neurologic manifes-
to dyspnea [100]. In severe hypothyroidism, alveo- tations. Headaches can be identified in 30 % of
lar hypoventilation and carbon dioxide retention hypothyroid patients [129]. Carpal tunnel syn-
may occur, contributing to the development of myx- drome is present in 29–38 % of cases due to
edema coma [112, 113]. Obstructive sleep apnea is compression of the median nerve by deposits of
common as a result of macroglossia [114, 115]. glycosaminoglycans [130, 131]. Body move-
ments are slow and cerebellar ataxia may be
identified [132]. The occurrence of delayed
Gastrointestinal relaxation of deep tendon reflexes may be
related to peripheral neuropathy [133]. Hearing
Appetite is usually reduced (anorexia). Modest loss, vertigo and tinnitus are frequent [134]. The
weight gain can occur due to the decreased meta- voice is husky (hoarseness), low-pitched, and
bolic rate and retention of fluid in tissues. Contrary coarse.
to popular belief, hypothyroidism is not related to The speech is slow and slurred [100]. These
an increase of fat and obesity [116]. Dysphagia or changes are caused by myxedematous infiltration
heartburn may be due to disordered esophageal of the tongue and larynx. Loss of initiative, mem-
motility, whereas dyspepsia, nausea or vomiting ory and calculation defects, reduced attention
are related to delayed gastric emptying [117]. span and poor concentration may be present.
Decreased gut motility and decreased food intake Irritability is decreased and apathy can occur.
result in constipation [118]. The latter may lead to Psychiatric disorders are common and usually
fecal impaction, megacolon and ileus [119]. The manifest as depression. However, some patients
rate of intestinal absorption is decreased and may present with psychosis and hallucinations
intestinal transit time is prolonged [120]. Ascites (myxedema madness) [135]. An association
is rarely found [121]. Gallbladder motility is between Alzheimer’s disease and hypothyroid-
decreased in hypothyroid patients [122]. ism was reported but an etiologic relationship has
In addition, measurements of serum aspartate not been established [136, 137]. Lethargy and
aminotransferase, lactate dehydrogenase [123] somnolence are sometimes found and epileptic
and carcinoembryonic antigen [124] may be ele- seizures have been reported. The patient can
vated, and pernicious anemia can be present. evolve to myxedema coma. The pathogenesis of
Celiac disease is also associated with hypothy- cognitive dysfunction in hypothyroidism is
roidism [125]. unknown. It may be related to a decrease in cere-
bral blood flow and a reduction in glucose metab-
olism [138].
Neurologic Hashimoto’s encephalopathy is a rare mani-
festation of HT [139]. Patients most often have
Thyroid hormones are crucial for the develop- an acute or subacute onset of confusion with
ment of the central nervous system. Congenital alteration of consciousness and other neurologic
hypothyroidism is related to severe and irrevers- signs, such as seizures, myoclonus, tremor,
ible neurologic abnormalities if left untreated. It hyperreflexia and psychosis [139, 140]. The
can be associated with hypoplasia of cortical diagnosis is usually performed by the presence of
neurons, retarded myelination, and altered cell these clinical manifestations in patients with ele-
migration and differentiation [126, 127]. vated thyroid antibodies [141].
126 H.V. Luiz et al.
may be reduced and both miscarriage and adverse can contribute to the delay in diagnosis. As hypo-
neonatal outcomes can occur [168]. However, thyroidism progresses, a slow intensification of
most women with untreated hypothyroidism have all clinical manifestations occur. Progressive
uneventful pregnancies and give birth to normal decrease in activity and responsiveness can
infants [169]. Hypothyroidism in adult men may finally evolve to coma. If left untreated, the length
cause decreased libido, erectile dysfunction, of time between the first symptoms and death
delayed ejaculation and defects in spermatogen- may be as long as 15 years [17]. In contrast,
esis [170, 171]. symptoms are more abrupt if an acute loss of thy-
roid function occurs, such as when replacement
therapy is discontinued or after thyroidectomy or
Energy Metabolism radioiodine therapy. Thus, the clinical course
may also be influenced by the etiology of the dis-
Energy metabolism is decreased in hypothyroid- order. One interesting and recent study found that
ism contributing to a lower energy expenditure, a diagnosis of hypothyroidism before the age of
oxygen consumption and utilization of substrates. 60 is associated with loss of labor market income
Both the synthesis and the degradation of protein and a significantly increased risk of receiving a
are decreased, but nitrogen balance is usually disability pension [175].
positive. Permeability of capillaries to protein is
increased, which explains the high levels of pro-
tein in effusions [14]. Central Hypothyroidism
Hypothyroidism is usually associated with
normal plasma glucose levels, whereas plasma The clinical manifestations are similar to those of
insulin can be increased [172]. A lower glucose primary hypothyroidism but the clinical picture is
uptake in muscles and adipose tissue was reported often milder [176]. Common symptoms of cen-
[173]. In patients with preexisting diabetes mel- tral hypothyroidism include fatigue and head-
litus who develop hypothyroidism, insulin aches [177]. Goiter is not a typical finding.
requirements may be reduced possibly due to the Clinical features associated with deficiency or
decreased insulin degradation [174]. excess of other pituitary hormones are common
Both the synthesis and the degradation of lipid and can mask those related to hypothyroidism
are reduced in hypothyroidism. As previously [24]. For example, if hypogonadism is present
noted, hypothyroidism is associated with dyslip- patients may complaint of hot flashes and the
idemia usually presenting as elevations of total cold intolerance typical of hypothyroidism is
and LDL cholesterol [107]. obscured. Acromegalic patients with central
hypothyroidsm may present with sweating
instead of dry skin.
Course of the Disease
mottled and dry skin, distended abdomen, consti- monly caused by HT. Common manifestations
pation and umbilical hernia [179]. This disorder include declining growth velocity often resulting
can also be associated with additional congenital in short stature, delayed pubertal development and
malformations especially affecting the heart the presence of a goiter [143, 182, 183].
[180]. If left untreated, prolonged hypothyroid-
ism can be associated with dwarfism, sexual
immaturity and severe neurological features, usu- Screening
ally referred as cretinism. Other characteristic
findings include disproportionately short limbs in Congenital Hypothyroidism
relation to the trunk, broad and flat nose, widely
set eyes, periorbital puffiness, and macroglossia Most developed countries perform newborn
[181] (Fig. 7.4). screening of congenital hypothyroidism, which
Endemic cretinism in iodine deficient regions is important for the early detection and treat-
may manifest in a neurologic form characterized ment of affected infants and for the prevention
by goiter, mental retardation, strabismus, deaf- of severe neurodevelopmental deficits associ-
mutism, spasticity and other motor disorders, or ated with late diagnosis. Screening programs
present as a myxedematous form with thyroid were proved to be successful and economically
atrophy, severe hypothyroidism, short stature, beneficial and are strongly recommended [184,
delayed sexual maturation and a less severe degree 185]. Blood should be collected after heel prick
of mental retardation. However, these two clinical and the best time for testing seems to be between
patterns may overlap [28, 34, 35]. Hypothyroidism 48 and 72 h of age [184]. Three screening strate-
in older children and adolescents is most com- gies can be used including the measurement of
a b
Fig. 7.4 A 26-year-old female with thyroid dyshormonogene- presence of a goiter, facial edema, evidence of a broad and
sis due to a mutation in the thyroid peroxidase gene. (a) Typical flat nose, widely set eyes and strabismus. (b) X-ray of the left
clinical findings of congenital hypothyroidism were found, hand and wrist showing a bone age of 14 years (Courtesy of
including dwarfism (height 118 cm), mental retardation, Dr. André Couto Carvalho and Dr. Cláudia Freitas)
7 Hypothyroidism 129
TSH, T4 or both [185, 186]. TSH testing better such as type 1 diabetes and pernicious anemia;
detects subclinical hypothyroidism but will not patients with first-degree relatives diagnosed
identify infants with central hypothyroidism. with an autoimmune thyroid disease; those with a
The latter can only be recognized by measuring history of radioiodine therapy, neck irradiation or
T4. The European Society of Paediatric thyroid surgery; patients with psychiatric disor-
Endocrinology guidelines consider that the ders; those with an abnormal thyroid examina-
main goal is to detect all forms of primary hypo- tion; patients taking drugs such as amiodarone or
thyroidism and therefore recommend TSH lithium; and those with hypercholesterolemia
screening [184]. In case of a high TSH concen- [16, 188]. We also suggest testing patients with
tration, confirmatory serum testing measuring Down syndrome given their risk of developing
TSH and FT4 should be performed. Thyroid hypothyroidism (Fig. 7.5).
ultrasound with color flow Doppler sonography Most organizations also recommend testing all
and/or thyroid scan can be ordered to identify individuals over a certain age. The American
dysgenesis [187]. Some infants need genetic College of Physicians suggests screening in
counseling and to perform genetic testing for women older than 50 years of age [189]. The
the mutations associated with thyroid dyshor- American Thyroid Association (ATA) recom-
monogenesis [184]. mends screening in all adults beginning at age 35
years and every 5 years thereafter [190]. Recent
guidelines for hypothyroidism in adults cospon-
Acquired Hypothyroidism sored by the American Association of Clinical
Endocrinologists (AACE) and the ATA consider
Measurement of thyroid function tests in asymp- screening of the population over the age of 60 [16].
tomatic patients is controversial but most experts TSH is the most sensitive and specific assay
do not favor screening the general population. for detecting primary hypothyroidism and should
Screening individuals at risk for hypothyroid- be used for screening. However, it may not be
ism (case finding) is recommended, including but useful if central hypothyroidism is suspected, in
not limited to those with autoimmune diseases, hospitalized patients and in those receiving drugs
that affect TSH secretion [191]. If serum TSH is
normal, no further testing is usually performed.
In patients with a high serum TSH level, subse-
quent evaluation is needed including the mea-
surement of FT4.
Diagnosis
as sex hormone binding globulin, osteocalcin, tial synthesis and secretion of T3 by the residual
total and LDL cholesterol, lipoprotein(a), CK functioning thyroid tissue and due to the increased
and ferritin should also not be used for the diag- conversion of T4 to T3 by type 2 deiodinase (D2)
nosis of hypothyroidism [16]. in hypothyroid patients [199]. As the disease pro-
In patients with suggestive symptoms or signs, gresses serum T3 concentrations may become
the serum TSH should be the initial test. If an ele- subnormal.
vated level is found, the TSH measurement should Patients with central hypothyroidism have a
be repeated along with a serum FT4. If the initial low-normal to low FT4 concentration and a serum
TSH level is normal but the patient has clear TSH that is not appropriately elevated. TSH levels
symptoms of hypothyroidism, a second measure- can be low, normal or even slightly elevated due
ment of TSH and FT4 can be performed to assess to the secretion of biologically inactive TSH [177,
for central hypothyroidism. Furthermore, if a pitu- 200]. A diurnal rhythm in TSH secretion with a
itary or hypothalamic disorder is suspected, TSH surge late at night occurs in the normal popula-
and FT4 can be initially measured. Measurements tion, whereas the nocturnal increase was found to
of serum total T3 and free T3 (FT3) are not indi- be absent in patients with central hypothyroidism
cated for the diagnosis of hypothyroidism [16]. [201, 202]. Serum total T3 and FT3 levels may be
An elevated serum TSH is usually defined as a normal or low [177].
concentration above the upper limit of the refer- After confirmation of hypothyroidism, it is
ence range for a given laboratory which typically mandatory to identify the etiology. Clinical history
lies between 4 and 5 mIU/L. Some authors found and physical examination can provide important
that more than 95 % of individuals without a thy- clues, such as a previous history of thyroid sur-
roid disease have a TSH level less than 2.5 mIU/L, gery, cervical irradiation or radioiodine treatment,
suggesting the use of a lower upper limit for the information about current and past medications
normal population [195]. TSH levels increase with and evidence of a goiter. In patients with primary
age which may warrant the consideration of a hypothyroidism TPO antibodies should be mea-
higher reference range in older patients [196, 197]. sured [16]. The presence of antibodies usually
Table 7.2 summarizes the thyroid function test indicates HT, whereas its absence suggests less
results of the main types of hypothyroidism. In common causes of hypothyroidism, such as pain-
primary hypothyroidism, the first biochemical less or subacute thyroiditis. In addition, the finding
finding is a slightly elevated serum TSH value, of a low thyroid echogenicity on ultrasound usu-
caused by a minor decrease in T4 secretion not ally indicates HT [203]. Measurement of radioac-
sufficient to produce a subnormal serum FT4 tive iodine uptake (RAIU) is rarely required. In
concentration (subclinical hypothyroidism). An patients with central hypothyroidism, a pituitary
additional decrease in T4 production results in magnetic resonance imaging should be performed
low serum FT4 values along with higher levels of (Fig. 7.2), along with the biochemical evaluation
TSH (overt hypothyroidism) [198]. If performed, of other pituitary hormones to detect hormonal
T3 levels are usually normal due to the preferen- hypersecretion and/or combined deficiencies.
Pituitary-adrenal function is usually assessed by a
Table 7.2 Patterns of thyroid function tests in the main
synacthen test. In patients with adrenal insuffi-
types of hypothyroidism ciency, glucocorticoid therapy should precede
treatment with L-T4 because the latter, if given
Type Serum TSH Serum FT4
alone, can precipitate an acute adrenal crisis.
Primary
hypothyroidism Although most patients can be managed by
Subclinical High Normal physicians from different specialties, a subset of
Overt High Low hypothyroid cases should be referred to endocri-
Central Low, normal or Low or nologists. The guidelines cosponsored by the
hypothyroidism slightly high low-normal AACE and the ATA indicate referral in the fol-
FT4 free thyroxine, TSH thyroid-stimulating hormone lowing scenarios: children and infants, pregnancy
7 Hypothyroidism 131
and women planning conception, patients in returns to normal after corticosteroid replace-
whom it is difficult to achieve euthyroidism, con- ment [208].
comitant cardiac disease, presence of goiter, nod- Some individuals were found to have antibod-
ules or other structural thyroid changes, evidence ies to the mouse immunoglobulins used in the
of other endocrine diseases such as adrenal and TSH assay, causing falsely elevated TSH levels
pituitary disorders, unusual combination of thy- [209]. Other cases were reported to have a mac-
roid function tests and uncommon causes of romolecule formed by the binding between anti-
hypothyroidism [16]. TSH immunoglobulin and TSH, which is
referred as macro-TSH. It can interfere with the
laboratory measurement of TSH, leading to high
Differential Diagnosis results [210].
Primary Hypothyroidism
Central Hypothyroidism
The differential diagnosis of primary hypothy-
roidism includes several conditions that present Central hypothyroidism presents with low-
with an elevated serum TSH level. normal to low FT4 concentrations and its differ-
RTH is characterized by nonsuppressed TSH ential diagnosis depends on the TSH levels [211].
levels which can be either normal or elevated. As previously noted, in patients with a slightly
However, it can be distinguished from primary high TSH concentration, primary hypothyroid-
hypothyroidism due to the typical high levels of ism should be considered.
serum FT3 and FT4 and because most patients If TSH levels are normal, physicians should
are euthyroid [93–96]. consider conditions related to thyroxine-binding
TSH-secreting pituitary adenomas are a rare globulin (TBG) deficiency, such as inherited
cause of hyperthyroidism. The differential diag- mutations in the TBG gene [212], androgen ther-
nosis with primary hypothyroidism relies on the apy [213], glucocorticoid excess [214], nephrotic
measurement of free thyroid hormones, since syndrome [215], and therapy with L-asparaginase
these patients also present with high concentra- [216], danazol [217] or niacin [218]. Individuals
tions of FT3 and FT4 along with a measurable with TBG deficiency usually present with low
TSH [204, 205]. total thyroid hormone levels and normal serum
Patients with nonthyroidal illness may have TSH. However, it can be distinguished from
transient elevations in the serum TSH concentra- central hypothyroidism because patients often
tion during recovery, sometimes presenting with manifest with normal serum FT4 and FT3 concen-
TSH values above 20 mIU/L [206, 207]. trations and have no symptoms or signs of thyroid
Therefore, in patients with a recent illness and dysfunction. Antiepileptic drugs such as phenyt-
altered thyroid test results, measurements of oin and carbamazepine may cause thyroid dys-
serum TSH and FT4 should be repeated 4–6 function by increasing thyroid hormone
weeks after recovery. In that situation normaliza- metabolism and competing for binding to TBG,
tion of the thyroid function usually occurs. resulting in a normal serum TSH and low total and
Patients with central hypothyroidism and bio- free thyroid hormones levels [219, 220]. In
logically inactive TSH can present with slightly patients treated with these drugs, assessment of
high TSH levels [177, 200]. High serum TPO other pituitary hormones and pituitary imaging
antibodies suggest primary hypothyroidism, may help to exclude central hypothyroidism. In
whereas abnormalities in other pituitary hormones addition, patients with drug-induced thyroid dys-
favor the diagnosis of central hypothyroidism. function have a normal TSH response to TRH
Patients with adrenal insufficiency can have a administration, whereas those with pituitary or
high level of serum TSH as a direct result of glu- hypothalamic disorders have an absent or delayed
cocorticoid deficiency. Thyroid function usually response.
132 H.V. Luiz et al.
In patients with a low TSH concentration, sub- issue to consider is patient’s schedule and prefer-
clinical hyperthyroidism may be included in the ences. For example, if neither or the two previous
differential diagnosis [221]. A high-normal options is feasible, taking the drug consistently
serum T3 level, a high-normal to high RAIU and 30 min before breakfast may also be reasonable
the presence of focal areas of increased uptake on and may promote treatment adherence.
thyroid scan favor this diagnosis, whereas the Approximately 80 % of the orally administered
presence of coexisting pituitary hormone abnor- tablet is absorbed [230]. Once-daily treatment is
malities suggests central hypothyroidism. indicated due to the long plasma half-life of L-T4
Treatment with T3 may also be considered in the of about 7 days [231]. In addition, omission of a
setting of a low serum TSH and low or low- single pill has no significant effect. Missed doses
normal T4 values. T3 containing preparations should be administered when the omission is
can promote a suppression of TSH production recognized, even on the same or subsequent
which results in a decrease in T4 secretion by the day [232].
thyroid gland. We can control thyroid function in virtually
all cases. The availability in many countries of a
multiplicity of tablet strengths ranging from 25
Treatment to 300 μg allows precise titration of the daily
L-T4 dosage. The most common cause of treat-
Primary Overt Hypothyroidism ment failure is nonadherence [233], and poorly
compliant patients may be given their total
Our therapeutic approach is in agreement with weekly dose of L-T4 once per week [234].
the ATA guidelines for the treatment of hypo- Several formulations of T4 are available with
thyroidism [222] and the European Thyroid variable absorption rates, which can explain the
Association (ETA) guidelines [223]. The treat- differences in bioequivalence between them.
ment of choice for hypothyroid patients is L-T4 Either a generic or a brand-name L-T4 is accept-
monotherapy due to its efficacy, long-term able. The use of brand-name products has the
experience, favorable side effect profile, ease of advantage of avoiding the switch between differ-
administration, good intestinal absorption, long ent formulations but will increase costs. If pos-
serum half-life, and low cost. Other treatment sible maintenance of the same generic
modalities are currently not recommended preparation is advisable. In the case of a switch
[222, 223]. to another manufacturer, it is recommended to
closely monitor the serum TSH level given the
L-T4 Monotherapy concern regarding bioequivalence [16, 222]. In
It has been considered the mainstay of thyroid addition to solid tablets that contain excipients
hormone replacement for many years. Due to the and dyes, one brand preparation is available as
peripheral conversion of the exogenous T4 into an oral gel capsule that contains only L-T4, glyc-
the active thyroid hormone T3, normal T3 levels erin, gelatin, and water [235]. Some studies sug-
are usually achieved in hypothyroid patients gested that this preparation is less affected by
receiving adequate L-T4 therapy [13, 224]. changes in gastric pH, and may be better
Absorption of L-T4 takes place along the absorbed than standard L-T4 in selected circum-
entire small intestine [225]. An acidic gastric pH stances such as the concomitant use of proton
occurring during fasting is important for a proper pump inhibitors or coffee consumption [236,
intestinal absorption, whereas co-administration 237]. Thus, the soft gel capsule may be an option
with food reduces L-T4 absorption. Thus, L-T4 for patients with suspected poor absorption,
should be taken on an empty stomach [226]. The although long-term studies are lacking [222].
best timing of administration appears to be 60 min However, a less costly option is to increase the
before breakfast or at bedtime at least 3 h after the dose of the generic L-T4 tablet with periodic
evening meal [222, 227–229]. Another important monitoring of serum TSH.
7 Hypothyroidism 133
L-T4 requirement is dependent on lean body of age-specific cutoffs may be appropriate [195–
mass and therefore ideal body weight is usually 197]. Symptoms alone lack sensitivity and speci-
used for dose calculations [238]. The average ficity and are not recommended for judging
replacement dosage in adults is approximately adequacy of treatment [222].
1.6–1.8 µg/kg of ideal body weight per day, Symptoms may start to improve in few weeks
which usually results in the prescription of after the introduction of L-T4. Serum thyroid
75–150 µg/day for women and 125–200 µg/day hormone concentrations increase first and pro-
for men. The dose per kg is higher in infants and duce a negative feedback action on the pituitary
children. Hormone requirement may also vary and hypothalamus, which results in a decrease of
according to the cause of hypothyroidism, likely TSH secretion. A steady-state TSH concentration
reflecting the amount of residual functional thy- is achieved after approximately 6 weeks of ther-
roid tissue. Patients with HT or those submitted apy. Thus, TSH and FT4 levels should be mea-
to radioiodine therapy may need less L-T4 than sured 4–6 weeks after initiation of thyroid
those who underwent thyroidectomy due to a thy- hormone replacement [222]. If the TSH value
roid cancer [239, 240]. Pretreatment serum remains above the normal reference range, the
TSH may also determine the required dose of daily dose of L-T4 can be increased by 12.5–
L-T4 [241]. 25 μg. Thyroid function should be monitored
It is recommended to start with the fully cal- every 4–6 weeks with additional changes in the
culated L-T4 dose in healthy young and middle- dose of L-T4 until normal TSH levels are
aged patients [222]. This approach leads to a achieved. After identification of the proper main-
more rapid normalization of serum TSH but a tenance dose, serum TSH can be measured in 4–6
similar time to symptom resolution [242]. months and then once yearly [222]. An increased
Thyroid hormone increases myocardial oxygen FT4 level can be identified if the blood is drawn
demand and is associated with a risk of inducing after L-T4 administration, and therefore it is usu-
cardiac arrhythmias, angina and myocardial ally suggested that collection be performed
infarction, especially in the elderly and in patients before taking the pill [245].
with CHD. Thus, a low starting dose should be TSH levels may vary in the same individual by
given to individuals older than 50–60 years (e.g. 40 % [246]. Thus, the dose of L-T4 may not be
50 μg daily) and to those with CHD (e.g. 12.5– altered in clinically euthyroid patients with
25 μg daily). A gradual dose increase is sug- slightly high or low TSH levels found in a follow-
gested until normalization of serum TSH up evaluation. These mild changes can be con-
concentration is achieved or cardiac symptoms firmed with repeat measurements of thyroid
appear, in which case less than full replacement function before adjusting the therapy. There are
dose may be reasonable. Another option to allow several conditions than can interfere with the
the administration of appropriate doses of L-T4 in L-T4 treatment and when present may warrant a
these patients is to consider additional cardiac change in the dose of thyroid hormone replace-
medical or surgical treatments such as coronary ment. The dose is usually increased during preg-
artery revascularization [16, 222]. nancy or if the patient gains weight. Individuals in
The goals of therapy are resolution of symp- whom thyroid hormone absorption is diminished
toms and signs, and normalization of the TSH may also need a higher dose, including those with
secretion [222]. TSH is the most reliable marker impaired acid secretion [247] or other gastroin-
of adequacy of replacement treatment and it testinal disorders such as celiac disease [248], and
should be kept within the normal reference range, those taking calcium carbonate [249], bile acid
which usually results in normal serum FT3 and sequestrants [250], phosphate binders [251], fer-
FT4 concentrations. However, FT3 levels may be rous sulfate [252], aluminum-containing antacids
low and FT4 values are sometimes elevated [224, [253], sucralfate [254] and proton pump inhibi-
243, 244]. As previously noted, the definition of tors [255]. Coffee was also found to reduce L-T4
a normal serum TSH is controversial and the use absorption [256]. In addition, some drugs increase
134 H.V. Luiz et al.
the metabolic clearance of L-T4 and are also General anesthesia and surgery in patients
related to a need of higher doses, including rifam- with untreated hypothyroidism are associated
picin [257], carbamazepine [258], phenytoin with minor perioperative complications [267,
[259] and sertraline [260]. Estrogen therapy in 268]. Thus, urgent surgery should not be post-
postmenopausal women is associated with a rise poned in hypothyroid patients, whereas it is pru-
in serum TBG concentrations, which can result in dent to defer elective surgical procedures until
the necessity of increasing the dose of L-T4 [261]. euthyroidism is achieved.
Thyroid function should be performed 4–8 weeks Patients treated with other therapeutic modali-
after these drugs are introduced or withdrawn ties should be switched to L-T4. For patients
[16]. However, when feasible, the best option is taking T4-T3 combination preparations, the
not to take L-T4 with interfering medications and equivalent dose of L-T4 can be calculated by the
a 4-h interval is suggested [222]. Based on our previous dose of T4 plus about three times the
experience, hypothyroid patients who develop dose of T3 [269]. In general, 1 grain of desic-
proteinuria due to nephrotic syndrome may also cated thyroid extract (60 mg) is equivalent to
need higher dose requirements. A reduction in about 88–100 μg of L-T4 [270]. In patients tak-
L-T4 dose may be needed with increasing age ing L-T4 for unclear reasons who have TSH lev-
[262], if the patient loses weight or during andro- els in the normal range, the need for hormone
gen therapy [213]. Hormone replacement is usu- replacement can be assessed by reducing the
ally performed lifelong but some etiologies of daily dose by 50 % and reevaluating the TSH and
primary hypothyroidism are related to transient FT4 levels after 4–6 weeks. If no significant
thyroid dysfunction, namely painless, postpartum increase in TSH concentration is found and FT4
and subacute thyroiditis. remains normal, residual thyroid function is most
Successful treatment with L-T4 usually likely present. L-T4 can then be withdrawn and
reverses all the symptoms and signs of hypothy- blood tests repeated in 4–6 weeks. Thyroid hor-
roidism. However, approximately 5–10 % of mone replacement is not indicated in biochemi-
patients have persistent symptoms despite a nor- cally euthyroid individuals with symptoms of
mal TSH level [223]. Most clinical features hypothyroidism, depression or obesity [222]. A
related to thyroid dysfunction are nonspecific, systematic review showed inconclusive results
and when they persist physicians should evaluate regarding the effectiveness of L-T4 in weight loss
for alternative causes [222]. Suggested explana- [271].
tions for unresolved complaints include aware- A recent survey concluded that almost all phy-
ness of a chronic disorder, presence of associated sicians (mostly endocrinologists) are using L-T4
autoimmune diseases, thyroid autoimmunity and alone as the initial therapy for hypothyroid
inadequacy of L-T4 treatment in restoring physi- patients, and half of them prefer to use brand-
ological T4 and T3 concentrations in serum and name preparations. The rate of replacement was
tissues [223]. variable among the respondents with some
Adverse effects of T4 replacement are uncom- choosing to start with a full replacement dose
monly found. Rare patients have an allergy to the while others would perform a more gradual
dye or excipients in the tablets. For dye sensitivi- increase. Physicians preferred to use age-specific
ties, using multiples of the colorant-free 50 µg TSH targets for replacement therapy [272].
tablets is an option [263]. For allergies to excipi-
ents, the soft gel capsule can be tried [222]. Some Combination T4 and T3 Therapy
studies suggested that about 40 % of older Combination therapy is not recommended for the
patients treated with L-T4 have a low TSH level majority of patients with hypothyroidism.
[264]. Subclinical and overt hyperthyroidism due Whether it is beneficial in a subset of hypothy-
to overreplacement can be associated with atrial roid individuals is uncertain [16, 222, 223].
fibrillation and osteoporosis in the elderly and in Patients who remain symptomatic during
postmenopausal women [265, 266]. L-T4 therapy despite a normal TSH level were
7 Hypothyroidism 135
thought to benefit from combination therapy. occurrence of serum T3 peaks [279]. However,
However, systematic reviews and meta-analyses longer-term controlled clinical trials are needed
showed that combined T4-T3 therapy is not sig- before considering this modality for clinical use.
nificantly superior to L-T4 monotherapy for the At the present time it is not recommended for the
management of hypothyroid symptoms [273– treatment of hypothyroidism [16, 222].
276]. The ETA guidelines considered that combi-
nation therapy may be started in compliant Desiccated Thyroid
patients treated with L-T4 who have persistent Desiccated thyroid refers to preparations that are
complaints despite normal serum TSH values, derived from the thyroid gland of animals. They
provided they have previously received support contain both T4 and T3 in a ratio of approxi-
to deal with the chronic nature of their disorder, mately 4:1, which is significantly lower than the
and associated autoimmune diseases have been ratio of secretion by the human thyroid gland
excluded [223]. The authors suggested using a [283]. The relative excess of T3 results in supra-
L-T4/liothyronine (L-T3) dose ratio between physiologic levels of serum T3 [284]. In addition,
13:1 and 20:1. Currently available combined fluctuations in serum T3 levels occur throughout
preparations have a lower ratio and are not indi- the day, with peaks occurring shortly after dosing
cated. They therefore recommended the adminis- [285]. A randomized clinical trial showed that
tration of separate L-T4 and L-T3 tablets (L-T4 desiccated thyroid was associated with more
once daily and L-T3 twice daily). The ATA weight loss when compared to L-T4 and that
guidelines suggested that combination therapy some patients preferred to be treated with thyroid
should not be used outside a formal clinical trial extracts. However, a significant improvement in
[222]. quality of life was not demonstrated [270]. Since
Patients with specific polymorphisms of the high-quality data is lacking, this modality should
D2 gene, which converts T4 into T3 may be asso- not be used in hypothyroid patients [16, 222].
ciated with better therapeutic responses to com-
bination therapy when compared to L-T4 alone Compounded Thyroid Hormones
[277]. However, additional studies are needed. Modification of the components or excipients of
Genetic testing is currently not recommended as the thyroid hormone preparations can be per-
a guide to select therapy. formed by specialized pharmacies. This has the
Furthermore, most clinical trials of combina- advantage of individualizing the medication for
tion therapy failed to mimic the physiological each patient. However, there are some concerns
serum FT4-FT3 ratios. A combination of T4 and about safety. Errors in thyroid hormone com-
sustained-release T3 preparation may better rep- pounding by the pharmacist have been reported
licate the normal ratio of T4 to T3 secretion by which resulted in thyroid storm [286]. In addi-
the thyroid gland [278, 279]. tion, it was suggested that these preparations lose
their potency in few weeks [287]. Therefore, they
L-T3 Monotherapy are not recommended and should only be consid-
L-T3 is associated with wide fluctuations in ered in some cases of allergy to an excipient
serum T3 levels which may contribute to the [222].
development of thyrotoxic symptoms [280]. The
drug half-life is approximately 1 day which Dietary Supplements, Nutraceuticals
requires two or three daily administrations [281]. and Other Over-the-Counter Products
L-T3 alone can be associated with more Dietary supplements are substances added to the
weight loss and improvement in the lipid profile diet such as vitamins, minerals, herbs and amino
when compared to L-T4, which could favor the acids. Nutraceuticals are dietary supplements
use of the former in patients with obesity and that contain a concentrated form of a presumed
dyslipidemia [282]. In addition, the use of a bioactive substance originally derived from a
sustained-release T3 preparation can avoid the food, but present in a nonfood matrix, and used to
136 H.V. Luiz et al.
enhance health in dosages exceeding those some authors consider that infants with higher
obtainable from normal foods [288, 289]. screening TSH levels (e.g above 40 mIU/L)
Patients often use such products as part of the should start treatment as soon as a venous sample
treatment of thyroid disorders [290]. Several is obtained, without waiting for the confirmatory
compounds are available in the market due to the results [184]. As in other forms of hypothyroid-
supposed capacity of enhancing thyroid function, ism, oral L-T4 alone is the treatment of choice.
including iodine-containing substances (e.g. Most authors recommend a starting dose of
kelp), tyrosine and thyroid hormone extracts or 10–15 μg/kg/day [184, 185]. The L-T4 tablet
analogs such as 3,5,3′-triiodothyroacetic acid should be crushed and administered with milk or
(TRIAC) [289]. These preparations are also not water. Although the absorption is reduced when
recommended for the treatment of hypothyroid- the drug is given with food, asking the parents to
ism [16, 222]. administer L-T4 on an empty stomach may
reduce compliance. Some authors choose to
instruct the family to give the medication consis-
Central Hypothyroidism tently at the same time of the day [293].
The goals of treatment are to restore adequate
Patients with central hypothyroidism should also levels of thyroid hormones and assure normal
be treated with L-T4, using a dose of about clinical outcomes. The serum TSH level should
1.6 μg/kg [291]. Some authors suggested that be maintained within the age-specific reference
they may need a higher dose when compared to range and the total T4 or FT4 concentrations
patients with primary hypothyroidism caused by should be kept in the upper half of the age-
HT or radioiodine therapy [239]. The dose should specific normal range. The first follow-up evalu-
be adjusted according to symptoms and to the ation with measurement of serum FT4 or total T4
serum FT4 values, aiming to maintain this bio- values and TSH levels is generally performed
chemical parameter in the upper half of the nor- 1–2 weeks after the initiation of hormone
mal range [291]. Serum TSH cannot be used to replacement, and should be repeated every
monitor therapy because it is almost always sup- 2 weeks until serum TSH level is normalized
pressed during thyroid hormone replacement [184]. The serum T4 concentration should
[292]. A randomized controlled study comparing become normal within 2 weeks and the serum
combination T4-T3 therapy with L-T4 alone in TSH level is usually within the reference range
patients with central hypothyroidism showed that after 1 month of treatment [185]. Then thyroid
the former was associated with an improvement function may be evaluated every 1–3 months
of ankle reflex time and a decrease in CK levels, until the age of 12 months, every 2–4 months
but resulted in supraphysiological levels of FT3 between 1 and 3 years of age and every 3–12
[291]. There is insufficient evidence to recom- months thereafter until growth is complete. If the
mend for combination therapy in this population L-T4 dose is changed, thyroid function should be
[222]. In patients with pituitary tumors, hypothy- monitored after 4–6 weeks [184]. Regular clini-
roidism may be reversible since surgery occa- cal evaluation for growth, puberty, psychomotor
sionally leads to an improvement of anterior and neurological development is also mandatory.
pituitary function. Lifelong treatment is usually necessary
because the disorder is permanent in most cases.
However, patients thought to have transient hypo-
Congenital Hypothyroidism thyroidism may be re-evaluated, including infants
with normal imaging exams of the thyroid gland,
Hormone replacement is mandatory in infants no confirmation of thyroid dyshormonogenesis,
after serum confirmation of overt congenital those with positive thyroid antibodies, and chil-
hypothyroidism and in some subclinical cases dren who did not require an increase in L-T4
(e.g. serum TSH above 20 mIU/L). In addition, dose since infancy. In these cases L-T4 therapy is
7 Hypothyroidism 137
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Hyperthyroidism
8
Syed Khalid Imam
Abstract
Hyperthyroidism has multiple etiologies, manifestations, and potential
therapies and untreated cases may result in significant morbidity and mor-
tality. Appropriate treatment requires an accurate diagnosis and is influ-
enced by age, coexisting medical conditions and patient preference. The
proper treatment of hyperthyroidism depends on recognition of the signs
and symptoms of the disease and determination of the etiology. The most
common cause of hyperthyroidism is Graves’ disease. Other common
causes include toxic multinodular goiter, toxic adenomas, thyroiditis and
certain medications. The diagnostic workup should begin with a thyroid-
stimulating hormone level test, the most sensitive screening test. There are
many therapeutic modalities of hyperthyroidism and selection of these
modalities depend upon the age, cause, prevailing medical condition and
patient’s preference. This chapter will provide an overview of hyperthy-
roidism in non-pregnant adults.
completely characterized. It most likely involves an the adenomas within the same multinodular goiter.
antibody reaction against the TSH receptor that This observation is consistent with studies demon-
results in activation of T cells against tissues in the strating distinct clonal origins of different thyroid
retro-orbital space that share antigenic epitopes adenomas within the same multinodular goiter
with thyroid follicular cells [21, 22]. [28]. The development of multinodular goiters had
These immune processes lead to an active been associated with a D727E germline polymor-
phase of inflammation, with lymphocyte infiltra- phism in the TSH receptor, but this finding could
tion of the orbital tissue and release of cytokines not be corroborated in other studies [29–31].
that stimulate orbital fibroblasts to multiply and
produce mucopolysaccharides (glycosaminogly- Toxic Adenoma
cans), which absorb water. Graves disease Toxic adenoma is the cause of 3–5 % of cases of
patients a have higher rate of peripheral blood thyrotoxicosis and characterized by autono-
mononuclear cell conversion into CD34+ fibro- mously functioning nodules that are found most
cytes compared with healthy controls. These commonly in younger patients and in iodine-
cells may contribute to the pathophysiology of deficient areas [24]. A toxic adenoma is a mono-
ophthalmopathy by accumulating in orbital tis- clonal, autonomously functioning thyroid
sues and producing inflammatory cytokines, nodule (AFTN) that produces supraphysiologi-
including Tumor Necrosis Factor-alha(TNF- cal amounts of T4 and/or T3 resulting in sup-
alpha) and Interleukin-6 (IL-6) [23]. pression of serum TSH. The function of the
In consequence, the extraocular muscles surrounding normal thyroid tissue is often, but
thicken and the adipose and connective tissue of not always, suppressed. Approximately 1 in
the retro-orbit increase in volume. Cigarette 10–20 solitary nodules present with hyperthy-
smoking and a high TSH receptor autoantibody roidism. The prevalence of hyperthyroidism
level are significant risk factors for ophthalmopa- appears to be more common in Europe than in
thy. In addition, patients who smoke appear to be the USA, and it is more common in women than
more likely to experience worsening of their oph- in men [32, 33]. Chronic stimulation of the
thalmopathy if treated with radioactive iodine, as cAMP cascade results in enhanced proliferation
do patients who have high pretreatment T3 levels and function of thyrocytes [33]. Hence, any
and posttherapy hypothyroidism. molecular alteration leading to constitutive acti-
vation of the cAMP pathway in a thyroid follic-
ular cell is expected to result in clonal
Other Causes of Hyperthyroidism autonomous growth and function, and ulti-
mately in a toxic adenoma [34]. In line with this
Toxic Multinodular Goiter (Plummer concept, somatic mutations were first discov-
Disease) ered in the GNAS1 gene encoding the stimula-
Toxic multinodular goiter causes 5 % of the cases tory Gs alpha subunit in toxic adenomas
of hyperthyroidism in the United States and can [34–36]. Stimulatory Gs alph amutations impair
be ten times more common in iodine-deficient the hydrolysis of guanine triphosphate (GTP) to
areas. It typically occurs in patients older than 40 guanine diphosphate (GDP), resulting in persistent
years with a long-standing goiter, and has a more activation of adenylyl cyclase. The reported preva-
insidious onset than Graves’ disease [24]. lence of TSH receptor mutations in toxic adeno-
While the mechanisms underlying the develop- mas varies widely, but is as high as 80 % [35, 36].
ment of nodules are of complex nature, it has It is now well established that somatic, consti-
become apparent that hyperfunctioning adenomas tutively activating TSH receptor mutations play a
within multinodular goiters or autonomous areas predominant role in the pathogenesis of AFTNs,
within euthyroid goiters harbor somatic gain-of- while Gs alpha mutations are less common [37].
function mutations in the TSH receptor [25–27]. It It is likely that other somatic mutations are
is noteworthy that the mutations may differ among involved in the pathogenesis of the monoclonal
8 Hyperthyroidism 151
toxic adenomas that are negative for mutations in such as interferon and interleukin- 2 (aldesleukin)
the TSH receptor and Gs alpha [38]. also can cause type II Thyroiditis [41].
Thyroiditis
Subacute: Subacute thyroiditis produces an Thyroid Hormone-Induced: Factitious hyper-
abrupt onset of thyrotoxic symptoms as hormone thyroidism is caused by the intentional or acci-
leaks from an inflamed gland. It often follows a dental ingestion of excess amounts of thyroid
viral illness. Symptoms usually resolve within 8 hormone. Some patients may take thyroid prepa-
months. This condition can be recurrent in some rations to achieve weight loss.
patients [39].
Tumors Induced Hyperthyroidism
Rare causes of hyperthyroidism include meta-
Lymphocytic and Postpartum: Lymphocytic static thyroid cancer, ovarian tumors that produce
Thyroiditis and postpartum (subacute lympho- thyroid hormone (struma ovarii), trophoblastic
cytic) thyroiditis are transient inflammatory tumors that produce human chorionic gonadotro-
causes of hyperthyroidism that, in the acute stage, phin and activate highly sensitive TSH receptors.
may be clinically indistinguishable from Graves’
disease. Postpartum thyroiditis can occur in up to TSH-Secreting Pituitary Adenoma
5–10 % of women in the first 3–6 months after TSH-secreting adenomas (TSHomas) account
delivery. A transient hypothyroidism often occurs for less than 2 % of all pituitary adenomas and
before resolution [39]. are a rare cause of thyrotoxicosis [42, 43]. The
molecular mechanisms leading to the formation
of TSHomas remain unknown. TSHomas have
Hashimoto’s Thyroiditis: Occasionally, Hashi- been shown to be monoclonal by X-inactivation
moto’s thyroiditis is accompanied by mild symp- analyses suggesting that they arise from a single
toms of thyrotoxicosis, particularly in the early cell harboring one or several mutations in genes
phases of the disease [40]. A detailed description controlling proliferation and perhaps function.
of thyroiditis is provided in Chap. 6.
Hyperthyroidism Secondary to Thyroid
Drug-Induced Hyperthyroidism Hormone Resistance
Iodine-Induced: Iodine-induced hyperthyroid- The syndrome of Resistance to Thyroid Hormone
ism can occur after intake of excess iodine in the (RTH) is defined by elevated circulating levels of
diet, exposure to radiographic contrast media, or free thyroid hormones due to reduced target tis-
medications. Excess iodine increases the synthe- sue responsiveness and normal, or elevated levels
sis and release of thyroid hormone in iodine- of TSH [44, 45].
deficient patients and in older patients with Patients with RTH typically present with goi-
preexisting multinodular goiters [41]. ter. Their metabolic state may appear euthyroid
or include signs of hypo- and hyperthyroidism.
RTH is most commonly caused by monoallelic
Amiodarone-Induced: Amiodarone induced mutations of the TRbeta gene. The mutation can
hyperthyroidism can be found in up to 12 % of be inherited in an autosomal dominant manner or
treated patients, especially those in iodine-deficient occur as de novo mutation.
areas, and occurs by two mechanisms. Because
amiodarone contains 37 % iodine, type I is an iodine Hyperthyroidism due to TSH-Receptor
induced hyperthyroidism (see above). Amiodarone Mutations
is the most common source of iodine excess in the Autosomal dominant familial hyperthyroidism
United States. Type II is a thyroiditis that occurs in without evidence of an autoimmune etiology has
patients with normal thyroid glands. Medications been first described by Thomas et al. in 1982.
152 S.K. Imam
Currently 27 families with a total of 152 affected tend to exhibit symptoms of sympathetic activa-
individuals with non-autoimmune familial hyper- tion, such as anxiety, hyperactivity, and tremor,
thyroidism have been reported . The hyperthy- while older patients have more cardiovascular
roidism is caused by monoallelic gain-of-function symptoms, including dyspnea and atrial fibrilla-
germline mutations in the TSH receptor [46, 47]. tion with unexplained weight loss [37, 49].
Affected individuals have a suppressed TSH The clinical manifestations of hyperthyroid-
and elevated peripheral hormones in the absence ism do not always correlate with the extent of the
of TSH receptor-stimulating antibodies and TPO biochemical abnormality.
antibodies. The family history is key in order to Common symptoms of hyperthyroidism
demonstrate familial clustering suggestive for an include the following:
autosomal dominant disorder. Ultimately, the
diagnosis requires sequence analysis of the TSH • Nervousness
receptor gene in order to evaluate it for the pres- • Insomnia
ence of a monalllelic mutation. • Anxiety
• Increased perspiration
• Heat intolerance
Clinical Features • Hyperactivity
• Palpitations
Generally, a constellation of information, includ- • Weight loss despite increased appetite.
ing the extent and duration of symptoms, past • Hyperdefecation
medical history, and social and family history, in • Reduction in menstrual flow or
addition to the information derived from physical oligomenorrhea
examination, help to guide the clinician to the
appropriate diagnosis. Common signs of hyperthyroidism include
The family history should include careful eval- the following:
uation of the autoimmune disease, thyroid disease
and emigration from iodine-deficient parts of the • Diffuse goiter/toxic nodule/multinodular
world. Health care provider should also review a goiter
complete list of medications and dietary supple- • Exophthalmos
ments. A number of compounds—including • Tachycardia or atrial arrhythmia
expectorants, amiodarone, iodinated contrast • Systolic hypertension
agents, and health food supplements containing • Warm, moist, smooth skin
seaweed or thyroid gland extracts—contain large • Lid lag
amounts of iodine that can induce hyperthyroid- • Stare
ism in a patient with thyroid autonomy. Rarely, • Hand tremor
iodine exposure can cause hyperthyroidism • Proximal myopathy
in a patient with an apparently healthy thyroid. • Brisk deep tendon reflexes
Hyperthyroidism presents with multiple
symptoms that vary according to the age of the Features pathognomonic of Graves’ disease
patient, duration of illness, magnitude of hormone include the following:
excess, and presence of comorbid conditions.
Symptoms are related to the thyroid hormone’s • Orbitopathy
stimulation of catabolic enzymopathic activity • Thyroid bruit
and catabolism, and enhancement of sensitivity to • Pretibial myxedema
catecholamines. Older patients often present with • Acropachy
a paucity of classic signs and symptoms, which
can make the diagnosis more difficult [41, 48].
Hyperthyroidism leads to an apparent increase Features of Graves Ophthalmopathy
in sympathetic nervous system. Younger patients Approximately 50 % of patients with Graves thy-
8 Hyperthyroidism 153
rotoxicosis have mild thyroid ophthalmopathy. and the gland is exquisitely tender on palpation
Often, this is manifested only by periorbital and often displays a substantially increased
edema, but it also can include conjunctival edema consistency.
(chemosis), injection, poor lid closure, extraocu-
lar muscle dysfunction (diplopia), and Proptosis . Hydatiform Moles and Choriocarcinoma Most
Evidence of thyroid eye disease and high thyroid women with hydatiform moles present with uter-
hormone levels confirms the diagnosis of autoim- ine bleeding in the first half of pregnancy. The
mune Grave disease. size of the uterus is large for the duration of ges-
tation [51].
Graves Dermopathy In rare instances, Graves Many women with molar pregnancies have
disease affects the skin through deposition of gly- nausea and vomiting, some have pregnancy-
cosaminoglycans in the dermis of the lower leg. induced hypertension or pre-eclampsia. The
This causes nonpitting edema, which is usually signs and symptoms of thyrotoxicosis are present
associated with erythema and thickening of the in some women, but they may be obscured
skin, without pain or pruritus. by toxemic signs. The characteristic features
belonging to Graves’ disease are missing.
Hyperthyroidism is usually not severe because of
Features Related to Other Causes a relatively short duration.
of Hyperthyroidism Women with choriocarcinomas present within
1 year after conception. The tumor may be con-
Toxic adenomas present with signs and symp- fined to the uterus, more frequently it is meta-
toms of hyperthyroidism and/or a thyroid nodule. static to multiple organs such as the liver and
The signs and symptoms of thyrotoxicosis do not lungs. In men, choriocarcinomas of the testes is
differ from other etiologies. Features suggestive often widely metastatic at initial presentation.
for Graves’ disease such as endocrine ophthal- Gynecomastia is a common finding.
mopathy, (pretibial) myxedema and acropachy
are missing. The onset of hyperthyroidism is Struma Ovarii The clinical presentation may
often insidious and more common in older include the finding of an abdominal mass, asci-
patients, who typically have larger adenomas. tes, pelvic pain, and, rarely, a pseudo-Meigs syn-
Mechanical symptoms such as dysphagia or drome with pleural effusions. A subset of women
hoarseness are uncommon. Autonomously func- present with subclinical or overt thyrotoxicosis.
tioning nodules may remain stable in size, grow, Goiter is only presented in patients with associ-
degenerate or become gradually toxic. In one ated thyroid disease. For example, coexistence of
series, 10 % of patients followed for 6 years Graves’ disease and struma ovarii has been
became thyrotoxic [32]. Thyrotoxicosis may reported [52, 53].
develop independent of age, but is much more
common in nodules over 3 cm in diameter (up to
20 %). Apathetic Hyperthyroidism
Toxic Multinodular Goiter In addition to the Hyperthyroidism in the elderly is a great mas-
signs and symptoms associated with hyperthy- querader, and even severe, life-threatening hyper-
roidism, patients with large toxic multinodular thyroidism can easily be missed in patients older
goiters may also have dysphagia, shortness of than 60 years [54]. Not uncommonly, it appears in
breath, stridor, or hoarseness. an atypical manner, and the classic symptoms are
often absent. Graves disease and toxic multinodu-
Subacute thyroiditis often present with a his- lar goiter account for most cases in the elderly,
tory of a preceding respiratory tract infection while as Solitary toxic adenomas are rare in elder
[50]. They may have fever, malaise, and soreness, patients [55–58]. Again, like hypothyroidism, the
154 S.K. Imam
symptoms of hyperthyroidism are often atypical Free T4 (FT4) and free T3 measurement is
and may mimic other common diseases in this age recommended in patients with suspected hyper-
group. They may be absent, subtle, or may be thyroidism when TSH is low. Many laboratories
obscured by coexisting diseases. Cardiac compli- do not measure FT4 directly, instead using a cal-
cations are the most common manifestations of culation to estimate the FT4 level. Serum free T4
hyperthyroidism in elderly. They are usually man- can be estimated by several different methods
ifested as atrial arrhythmias (commonly atrial such as equilibrium dialysis techniques or esti-
fibrillation with slow ventricular rates, as com- mated indirectly by calculation of the free-
pared with high rates in young patients); conges- thyroxine index (FTI):
tive heart failure (usually high output heart failure) Free-thyroxine index (FTI)
and angina pectoris. The underlying hyperthy- = Total T4 × T3 resin uptake (T3RU) %.
roidism may not be recognized, since older
patients usually do not show the classic signs/ The T3 resin uptake (T3RU) test indirectly
symptoms of thyroid overactivity [59]. Rather estimates unsaturated binding sites on thyroid
than increased appetite, weight loss with anorexia binding globulin (TBG). The patient’s serum is
may be present. Diarrhea is common in young incubated with radiolabelled T3 tracer. The
hyperthyroid patients; elderly patients may note a unbound tracer is trapped with resin, and the
correction of preexisting constipation but will value is reported as percent tracer uptake by
rarely complain of loose stools. Elderly patients resin. The greater the number of free TBG-
can present with only one symptom of hyperthy- binding sites, the lower the uptake of tracer by
roidism, sometimes referred to as monosymptom- the resin. The normal range for T3RU is between
atic hyperthyroidism. Agitation and confusion 25 % and 35 %.
can also be presenting symptoms [60]. Since Free thyroxine (FT4) and free triiodo-
thyronine (FT3) assays now available in most of
the laboratories, therefore, FTI and T3 resin
Diagnostic Modalities uptake measurement are rarely required.
Because nonthyroidal illness will produce
Hormonal Assays temporary suppression of TSH, thyroid function
tests should be repeated before therapy is insti-
Serum TSH The measurement of serum TSH tuted for subclinical disease. Hormonal changes
with a sensitive third-generation assay represents in pregnancy can complicate the interpretation of
the best biochemical marker to establish the diag- thyroid function tests. Physiologic maximum
nosis of hyperthyroidism because TSH and FT4 elevation of beta human chorionic gonadotropin
have an inverse log-linear relationship and a small (β-hCG) at the end of the first trimester of preg-
decrease or increase in FT4 is thus associated nancy is associated with a mirror-image tempo-
with an exponential change in TSH levels [61]. rary reduction in TSH. Despite the reduction in
TSH, FT4 levels usually remain normal or only
Although measurement of the TSH level is slightly above the reference range. As the preg-
the most reliable screening method for assess- nancy progresses and β-hCG plateaus at a lower
ing thyroid function, the degree of hyperthy- level, TSH levels return to normal.
roidism cannot be estimated easily in this way.
Instead, hyperthyroidism must be measured
using an assay of thyroid hormone levels in the Antibodies
plasma. Thyroid hormone circulates as triiodo-
thyronine (T3) and thyroxine (T4), with more Anti Thyroid Peroxidase(TPO) Antibody The
than 99.9 % of the hormones bound to serum most specific autoantibody test for autoimmune
proteins (especially thyroxine-binding globu- thyroiditis is an ELISA test for anti-Thyroid
lin, transthyretin or thyroxin binding prealbu- Peroxidase(TPO) antibody. The titers usually are
min, and albumin). significantly elevated in the most common type
8 Hyperthyroidism 155
Graves disease, normoechogenic and large the low uptake of thyroiditis and provides other
glands are associated with increased radiore- useful anatomic information.
sistance [67]. Following characterizes the radioisotope find-
In Graves disease ultrasound often shows a ings of common causes of hyperthyroidism : (see
diffusely enlarged thyroid gland and is often Table 8.1)
hyperechoic and of heterogeneous echotexture.
There is relative absence of nodularity in • Graves disease – Diffuse enlargement of both
uncomplicated cases. Gland may become hyper- thyroid lobes, with uniform uptake of isotope
vascular and demonstrate a “thyroid inferno” and elevated radioactive iodine uptake.
pattern on color doppler [68]. Ultrasound will • Toxic multinodular goiter – Irregular areas of
confirm the presence of a solitary nodule, ade- relatively diminished and occasionally
noma and multinodular goiter. There is no indi- increased uptake; overall radioactive iodine
cation to perform fine needle aspiration in uptake is mildly to moderately increased.
patients with toxic adenomas because the risk of • Toxic adenoma- Increased tracer uptake.
a thyroid carcinoma is extremely low and cyto- • Subacute thyroiditis –Very low radioactive
logical evaluation will not permit distinguishing iodine uptake.
between a follicular adenoma and a follicular
carcinoma [69].
MRI/CT Scan
mended for use in the first trimester of pregnancy, toms more quickly than methimazole would.
because it has been associated, albeit rarely, with Once thyroid levels have decreased to nearly nor-
cloacal and scalp (cutis aplasia) abnormalities mal values, the patient can be switched to
when given during early gestation [77, 78]. methimazole therapy.
The beta blockade can be tapered after 4–8
weeks and the methimazole adjusted, according
to clinical status and monthly free T4 or free T3 Adverse Effects of Thioamide
levels, toward an eventual maintenance dosage of Antithyroid Medications
5–10 mg per day [20, 73].
TSH levels may remain undetectable for The most common adverse effects of thioamide
months after the patient becomes euthyroid and antithyroid drugs are allergic reactions manifest-
should not be used to monitor the effects of ther- ing as fever, rash, urticaria, and arthralgia, which
apy. At 1 year, if the patient is clinically and bio- occur in 1–5 % of patients, usually within the first
chemically Euthyroid and a thyroid-stimulating few weeks of treatment. Agranulocytosis is the
antibody level is not detectable, therapy can be most serious adverse reaction of antithyroid drug
discontinued. If the thyroid-stimulating antibody therapy and is estimated to occur in 0.1–0.5 % of
level is elevated, continuation of therapy for patients treated with these drugs [76].
another year should be considered. Once anti- The risk is higher in the first several months of
thyroid drug therapy is discontinued, the patient therapy and may be higher with PTU than
should be monitored every 3 months for the first methimazole [20, 41, 63]. The onset of agranulo-
year, because relapse is more likely to occur dur- cytosis is sometimes abrupt, so patients should be
ing this time, and then annually, because relapse warned to stop taking the drug immediately if
can occur years later. If relapse occurs, radioac- they develop a sudden fever or sore throat. After
tive iodine or surgery generally is recommended, the drug is stopped, granulocyte counts usually
although antithyroid drug therapy can be start to rise within several days but may not nor-
restarted [20]. malize for 10–14 days. Granulocyte colony-
stimulating factor (G-CSF) appears to accelerate
Propylthiouracil PTU is preferred for pregnant recovery in patients with a bone marrow aspira-
women because methimazole has been associ- tion showing a granulocyte-to-erythrocyte ratio
ated with rare congenital abnormalities. The of 1:2 or greater than 0.5. In most cases, agranu-
starting dosage of PTU is 100 mg three times per locytosis is reversible with supportive treatment
day (maximum dose is 600 mg/day) with a main- [63, 72].
tenance dosage of 100–200 mg daily in two to Routine monitoring of white cell counts
three divided doses [76]. remains controversial, but results of one study
showed that close monitoring of white cell counts
If a nonpregnant woman who is receiving allowed for earlier detection of agranulocytosis.
methimazole desires pregnancy, she should be In this study, patients had white cell counts every
switched to propylthiouracil before conception. 2 weeks for the first 2 months, then monthly [79].
After 12 weeks of gestation, she can be switched Minor side effects (e.g., rash, fever, gastroin-
back to carbimazole or methimazole. testinal symptoms) sometimes can be treated
Propylthiouracil remains the drug of choice in symptomatically without discontinuation of the
uncommon situations of life-threatening severe antithyroid drug; however, if symptoms of
thyrotoxicosis (i.e., thyroid storm) because of the arthralgia occur, antithyroid drugs should be dis-
additional benefit of inhibition of T4 -to-T3 con- continued because arthralgia can be a precursor
version. In this setting, propylthiouracil should of a more serious polyarthritis syndrome. Other
be administered every 6–8 h. The reduction in serious adverse effects include aplastic anemia,
T3, which is 20–100 times more potent than T4, hepatitis, polyarthritis, and a lupus like
theoretically helps reduce the thyrotoxic symp- vasculitis.
160 S.K. Imam
The FDA recommends the following mea- by the percent of 123 I uptake in 24 h. This dose
sures for patients receiving propylthiouracil [80]: is intended to render the patient hypothyroid.
Administration of lithium in the weeks fol-
• Closely monitor patients for signs and symp- lowing radioactive iodine therapy may extend the
toms of liver injury, especially during the first retention of radioactive iodine and increase its
6 months after initiation of therapy. efficacy. This may be considered in Graves
• For suspected liver injury, promptly discon- disease patients with especially large Graves
tinue propylthiouracil, evaluate the patient for glands (>60 g) or in patients with extremely high
evidence of liver injury, and provide support- thyroidal iodine uptake (>95 % in 4 h), which is
ive care. associated with high iodine turnover in the gland.
• Counsel patients to contact their health care However, studies have yielded inconsistent
provider promptly for the following signs or results, and the benefits of using lithium with
symptoms: fatigue, weakness, vague abdomi- radioactive iodine must be weighed against the
nal pain, loss of appetite, itching, easy bruis- toxicities associated with lithium. Hypothyroidism
ing, or yellowing of the eyes or skin. is considered by many experts to be the expected
goal of radioactive iodine therapy.
In several large epidemiologic studies of
Radioactive Iodine 131 Ablation radioactive iodine therapy in patients with Graves
(RAI131) disease, no evidence indicated that radioactive
iodine therapy caused the development of thyroid
Radioactive iodine therapy is the most common carcinoma [86].
treatment for Graves disease and toxic multinod- There is also no evidence that radioactive
ular goiter in adults in the United States [81]. iodine therapy for hyperthyroidism results in
In Europe and Japan, there has been a greater increased mortality for any other form of cancer,
physician preference for ATDs and/or surgery including leukemia [87].
[82]. Although its effect is less rapid than that of Long-term follow-up data of children and
antithyroid medication or thyroidectomy, it is adolescents treated with radioactive iodine are
effective and safe and does not require lacking [62, 63].
hospitalization. American Thyroid Association (ATA) guide-
Radioactive iodine is administered orally as a lines recommend avoiding131 I therapy in children
single dose in capsule or liquid form. The iodine younger than 5 years of age. In children 5–10 years
is quickly absorbed and taken up by the thyroid. old, 131 I therapy is acceptable if the calculated
No other tissue or organ in the body is capable of activity of administered131 I is less than 10 mCi. In
retaining the radioactive iodine; consequently, children older than 10 years of age, radioactive
very few adverse effects are associated with this iodine therapy is acceptable if the activity is greater
therapy. The treatment results in a thyroid- than 150 μCi/g of thyroid tissue [88].
specific inflammatory response, causing fibrosis Radioactive iodine should never be adminis-
and destruction of the thyroid over weeks to tered to pregnant women, because it can cross the
many months. placenta and ablate the fetus’s thyroid, resulting in
Radioactive iodine therapy for TMNG results hypothyroidism. Similarly, breastfeeding is a con-
in resolution of hyperthyroidism in approxi- traindication, in that the radioisotope is secreted in
mately 55 % of patients at 3 months and 80 % of breast milk. Women will continue to receive
patients at 6 months, with an average failure rate increased radiation to the breast from radioactive
of 15 % [83–85]. Goiter volume is decreased by iodine for a few months after ceasing lactation;
3 months, with further reduction observed over accordingly, initiation of this therapy should be
24 months, for a total size reduction of 40 %. delayed. It is standard practice to check for preg-
Generally, the dose of 131 I administered is nancy before starting radioactive iodine therapy
75–200 μCi/g of estimated thyroid tissue divided and to recommend that the patient not become
8 Hyperthyroidism 161
pregnant for at least 3–6 months after the treatment inhibit hormone release. Iodides also are used as
or until thyroid functions normalize. No excess adjunctive therapy before emergency nonthyroid
fetal malformations or increased miscarriage rates surgery, if beta blockers are unable to control the
have been found in women previously treated with hyperthyroidism, and to reduce gland vascularity
radioactive iodine for hyperthyroidism. before surgery for Graves’ disease [20].
Radioactive iodine usually is not administered to
patients with severe ophthalmopathy, because clini- Iodides are not used in the routine treatment
cal evidence suggests that worsening of thyroid eye of hyperthyroidism because of paradoxical
disease occurs after radioactive iodine therapy [89]. increases in hormone release that can occur with
This worsening is usually mild but occasionally prolonged use. Organic iodide radiographic
severe. The risk of ophthalmopathy is greater in contrast agents (e.g., iopanoic acid or ipodate
patients who smoke cigarettes, but it can be reduced sodium) are used more commonly than the inor-
by providing glucocorticoid therapy (prednisone ganic iodides (e.g., potassium iodide). The dos-
0.4 mg/kg for 1 month with subsequent taper) after age of either agent is 1 g per day for up to 12
radioactive iodine therapy. See algorithm for steroid weeks [95].
treatment in Graves ophthalmopathy. A saturated solution of potassium iodide
Using antithyroid drugs to achieve a euthyroid (SSKI) can be administered at a dosage of 10
state before treatment with radioactive iodine is drops twice daily, with a consequent rapid reduc-
not recommended for most patients, but it may tion in T3 levels.
improve safety for patients with severe or com- These drugs must not be administered to
plicated hyperthyroidism. It is unclear whether patients with toxic multinodular goiter or toxic
antithyroid drugs increase radioactive iodine fail- adenomas. The autonomous nature of these con-
ure rates [5, 90–92]. ditions can lead to worsening of the thyrotoxi-
If used, they should be withdrawn at least 3 days cosis in the presence of pharmacologic levels of
before radioactive iodine and can be restarted 2–3 iodide, a substrate in thyroid hormone synthe-
days later. The antithyroid drug is continued for 3 sis. This phenomenon typically presents in
months after radioactive iodine, and then tapered. patients living in iodine deficient areas who
Most of the radioactive iodine is eliminated from relocate to an iodine sufficient geographical
the body in urine, saliva, and feces within 48 h; how- area or upon ingestion of iodine (Jod-Basedow
ever, double flushing of the toilet and frequent hand syndrome).
washing are recommended for several weeks. Close
contact with others, especially children and pregnant Bile Salt Sequestrant Another drug that might
women, should be avoided for 24–72 h [93]. be considered in management of severe thyro-
Concerns about radiation exposure after ther- toxicosis would be cholestyramine, a bile salt
apy have led to the issuance of new recommenda- sequestrant. It decreases thyroid hormone levels
tions by the ATA. These recommendations are by depleting the pool by enhancing clearance
compliant with Nuclear Regulatory Commission from enterohepatic circulation. Doses up to 12 g
regulations and are a practical guide for patient in 3 divided daily doses have been used for 4
activity after radioactive iodine therapy, with the weeks.
aim of ensuring maximum radiation safety for
the family and the public [94].
Thyroidectomy
apparent pre-existing thyroid disease. An anti- Graves’ disease, toxic multinodular goiter,
arrhythmic drug amiodarone, which may and toxic adenoma can be treated with radio-
induce hyperthyroidism because of its high active iodine, antithyroid drugs, or surgery.
iodine content and/or a drug-induced thyroid- Thyroidectomy is an option when other treat-
itis. Any form of thyroiditis can be associated ments fail or are contraindicated, or when a
with a thyrotoxic phase because the disruption goiter is causing compressive symptoms.
of thyroid follicles can result in an increased Special treatment consideration must be given
release of stored iodothyronines. The thyro- to patients who are pregnant or breastfeeding,
toxic phase may be followed by transient or as well as those with Graves’ ophthalmopathy.
permanent hypothyroidism. Hyperthyroidism Patients’ desires must be considered when
in elderly may easily be missed because of deciding on appropriate therapy, and close
atypical presentation and a high index of sus- monitoring and follow up for disease status
picion is required to timely diagnose and treat and drug side effects are essential components
this life threatening condition in elderly. of management.
Risk Factors *
No Yes
131I
131I ±CS 131I + CS No 131I
Alone
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Autoimmune Thyroid Disease
(Flajani-Parry-Graves-von 9
Basedow Disease): An Overview
of Treatment
Abstract
The ideal treatment for Graves-Basedow disease should restore normal
thyroid function, avoid recurrence of hyperthyroidism, prevent develop-
ment of hypothyroidism and prevent the occurrence or progression of oph-
thalmopathy. There are basically three approaches for the treatment of
GD: anti-thyroid medical treatment, I-131 therapy and surgery. Antithyroid
drugs act principally by interfering with the organification of iodine,
thereby suppressing thyroid hormone levels. I-131 is transported into thy-
roid follicular cells resulting in cell necrosis over weeks to months.
Sometimes Antithyroid drugs are used before the administration of radio-
active iodine to promptly achieve euthyroidism and to attenuate exacerba-
tion of thyrotoxicosis. Surgery (thyroidectomy) results in rapid control of
thyrotoxicosis and has minimal risk of recurrence when a total thyroidec-
tomy is performed. Antithyroid drugs should be initiated before surgery to
reduce the risk of thyroid storm. With experienced surgeons, the risk of
permanent complications is very low. Surgery is clearly indicated in cer-
tain patients: Patients who have not responded to prolonged antithyroid
drug therapy, or who develop toxic reactions to the drug and for whatever
reason are unsuitable for 131-I therapy; patients with huge glands, which
frequently do not regress adequately after 131-I therapy; patients who pre-
fer surgery, and patients with thyroid nodules that raise a suspicion of
carcinoma.
yields better results than the “block-replacement ered a red flag. Agranulocytosis induced by these
regimen” and it has not been proven that extended agents may be mediated either by direct toxicity
with block-replacement, with a stronger trend to or by immune reaction due to IgE-mediated
present agranulocytosis and rash. The relapse hypersensitivity. The theory of an allergic back-
rate of hyperthyroidism following tionamide ground has been previously described, so in
management is 50–60 % in general with a stron- patients with a history of tionamide reactions, the
ger occurrence 3–6 months after treatment inter- potential for severe reactions with further expo-
ruption. The use of high-dose tionamides is sures has not been fully confirmed.
associated with a higher incidence of agranulocy- Agranulocytosis may present at the onset of treat-
tosis (12 %). It may then be concluded that based ment or after months of tionamide exposure
on less adverse events, the first choice for tion- (even after years of using the medication) but to
amide therapy in GD should be the “titration this date there is no real way to predict it, even
block regimen” and it should be extended for with serial measurements of neutrophil count and
12–18 months at a dose of <30 mg/day of CBZ, in short periods of time. While it is thought that
since this the dose associated with the lowest rate adverse events are MTZ-dose related, such rela-
of adverse events and is able to effectively con- tionship has not been established for PTU. The
trol thyrotoxicity. The idea of using thyroxine recommendation of frequently measuring leuko-
following the completion of tionamide therapy to cyte count while undergoing tionamide treatment
prevent relapses do not seem to be real for the is still controversial. However, in the presence of
population in general and is not reproducible; alarm signals such as fever and odynophagia,
hence its use shall not be generalized [5–8]. such recommendation is practically uncontested.
The granulocyte count in patients that developed
tionamide-induced agranulocytosis usually
Adverse Reactions recovers in a few days, though sometimes may
need several weeks. Anemia and thrombocytope-
The most frequently described tionamide adverse nia may also be present. The factors leading to a
reactions are rash and pruritus, which occur in poorer prognosis are: age >65 years, sepsis, and
5 % of the patients; other side effects triggered by neutrophil count <100/mL. The treatment of
this type of drugs are: arthralgia, fever, cervical these patients with GM-CSF (Granulocyte and
lymphadenopathy, jaundice with cholestasis pat- Macrophage Colony Stimulating Factor) in
tern, lupus-like syndrome, and hypergammaglob- asymptomatic agranulocytosis improves the rate
ulinemia. The presence of arthralgia should lead of infectious complications and mortality, with a
to the immediate discontinuation of tionamide faster recovery of the neutrophil count. However,
therapy since it could be the onset of a condition this response has not been reproduced in agranu-
called “anti-thyroid-induced arthralgia syn- locytosis and symptomatic patients. However,
drome”. Fatal reactions are fortunately rare and most experts recommend the use of G-CSF in
include neutropenia and leukopenia, aplastic ane- tionamide-induced agranulocytosis. The use of
mia, hepatitis, vasculitis, inter alia. Tionamide- antibiotics against germs such as Pseudomonas
associated liver disease and vasculitis are more aeruginosa is usually required, in addition to the
often associated with the use of PTU, and be adoption of universal measures for managing
expressed with Antineutrophil Cytoplasmic febrile neutropenia [11–14].
Antibodies (ANCA) Positive [8–11]. The inci-
dence of MTZ and PTU agranulocytosis is
0.36 % in average (though it may be higher in Radioactive Iodine Treatment
elderly patients) and the mortality secondary to
agranulocytosis may be close to 22 %. The pres- Radioactive iodine therapy is a relatively safe and
ence of fever and odynophagia should lead to the effective procedure but may be associated with
suspicion of agranulocytosis and thus be consid- some degree of exacerbation of ophthalmopathy
172 H. Vargas-Uricoechea et al.
and autoimmunity in GD patients. This treatment instance, one of them excludes the thyroid gland
method may be used as the first choice for GD size from the calculation:
management or as second choice following failed
tionamide therapy, or when hyperthyroidism per- ( 296 MBq [8 mCi] × 100 )
sists following thyroidectomy (when tionamide / ( Percentage of uptake in 24 h )
has been chosen for management). Radioactive
iodine is available as sodium iodide labeled as Another more widely used formula to estimate
I-131 (Na131I) in capsules and oral solution. the dose to be administered is based on the size of
Radioactive iodine is the result of uranium decay. the thyroid and uptake:
The efficacy of this treatment modality for hyper-
thyroidism is due to radiation-induced cell dam- ( Z × thyroid size [in grams] × 100 )
age, resulting from the high-energy beta emission. / ( Uptake percentage at 24 h )
The amount of beta emission is directly propor-
tional to the radiation dose received by the thy- In this formula, Z is the desired number of
roid with the key effect of radiation being the Becquerels administered per gram. The Z range
disruption of the follicular cells reproductive varies from 3.7 to 7.4 MBq (100–200 mCi).
capacity [15–17]. A lot has been written about Both formulae have a high success rate (defined
the best mode of I-131 administration; the as euthyroidism or hypothyroidism) after 1 year
regimes widely accepted in the literature basi- of treatment. It is difficult to determine accu-
cally describe two ways of administration: the rately the minimum dose required to achieve a
first takes into account the estimated gland weight permanent euthyroidism condition. Trying to
(in grams) and the radioactive iodine uptake in 24 approach the regimes aimed at normalizing the
h (estimated dose regimen). The doses described patient’s thyroid function may be bothersome
in this regimen ranges from 100 to 200 μCi per and discouraging. Thus, the purpose of I-131
gram. The other regimen establishes fixed I-131 treatment is to generate a chronic hypothyroid-
doses based on the gland size determined by pal- ism status using relatively high doses of I-131
pation (5, 10, or 15 mCi; equivalent to 185, 370 (550–600 MBq: 15–16 mCi) for small to
or 555 MBq, respectively). There is no general medium size glands and doses of 800–900 MBq
agreement about the dose that should be adminis- (20–25 mCi) for large glands. Those in favor of
tered to treat GD hyperthyroidism, since the vari- this management regime consider that a large
ous trials have not shown any superiority of one enough fixed dose to achieve hypothyroidism
regimen over another. According to some experts, reduces the risk of hyperthyroidism relapse and
the calculated dose regimen may also be used to hence the patient is not exposed to further I-131
help in establishing the cause of thyroiditis- doses. Moreover, hypothyroidism achieved with
related hyperthyroidism based on radioactive this modality is no different from hypothyroid-
iodine uptake (i.e., when thyroiditis related ism resulting from a different etiology. In
hyperthyroidism is also suspected). In contrast, patients that fail tionamide treatment, the bur-
those who prefer the fixed-dose regimen argue den of radiation from I-131 drops by about
that this method is simpler and less expensive 30–50 %. In any case, you should always abide
than the estimated-dose regimen [16–18]. In gen- to the principle of “As Low As Reasonably
eral, the doses used in the fixed-dose regimen Achievable” (ALARA). Notwithstanding this
range from 350 to 600 MBq. [MBq: fact, any dose administered under a particular
MegaBecquerels is the International System (IS) regime may result in a number of patients
unit to express radioactivity; mCi: is the other receiving I-131 mounts exceeding the minimal
measurement unit for radioactivity, where dose required to achieve permanent euthyroid-
1 mCi = 37 MBq]. ism [16–19]. The effective half-life of radioac-
Several formulae have been described to esti- tive iodine is defined as the period of time during
mate the I-131 dose to be administered; for which the activity of the isotope administered to
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease): An Overview of Treatment 173
the patient is cut to one half and it is considered I-131 Adverse Effects and Risk
to be around 6 to maximum 8 days. of Malignancy
Approximately 10–15 % of patients experience
a very short effective half-life, indicating fast The use of radioactive iodine may result in
iodine turnover in the thyroid. One way to radiation-related thyroiditis in up to 1 % of the
extend the effective half-life in addition to the patients and may lead to worsening of the symp-
presence of iodine inside the gland is by increas- toms of hyperthyroidism. Such symptoms may
ing the biological half-life (since the physical be mild and not require specific management of
half-life is constant). This can be achieved using pain symptoms and other adrenergic-associated
hormone-release inhibitors from the thyroid that symptoms but often occur in cases that require
may suppress the colloid formation and Tg pro- using Non-Steroid Anti-Inflammatory Agents
teolysis using lithium Carbonate that in the long (AINEs), beta blockers, and glucocorticoids to
run blocks the T3 and T4 synthesis [18–20]. The relief the symptoms. Occasionally patients pres-
ability of lithium carbonate to suppress iodine ent with dysgeusia and xerostomia that may
release is used in patients with a short effective accompany the presence of pain and swelling of
radioactive iodine half-life, thus delaying its the submaxillary, sublingual, and parotid glands.
release from the thyroid, and potentiating its The discomfort usually improves with adequate
therapeutic effect. The use of lithium Carbonate hydration and standard sialagogues (citric sub-
in GD patients must be preceded by the admin- stances, chewing gum). Several trials have
istration of radioactive iodine 3–4 days before, assessed the likelihood of developing cancer in
at an average dose of 500–700 mg/day (10 mg/ patients that received radioactive iodine therapy
kg), leading to a blood concentration of 0.4– for hyperthyroidism; some have not found an
0.8 nmol/L. The therapy shall be maintained for increased overall risk of cancer mortality, while
7 days following radioactive iodine treatment. others have described a reduced global cancer
This management protocol administered for the mortality rate, and still others report a small
recommended number of days is unlikely to increase in the risk of thyroid cancer, particularly
trigger any lithium-related adverse events. The in patients with toxic nodular goiter. Further tri-
use of beta blockers prior to the administration als report a drop in the global risk of cancer, but
of radioactive iodine may reduce and relief the with a mild increase in the risk of thyroid and
adrenergic symptoms. The use of tionamides colon cancer. Other groups report an increased
prior to I-131 may result in a milder hyperthy- risk of kidney, breast, and stomach cancer. The
roidism in the patient, and even achieve euthy- reported risk of death from cardiovascular dis-
roidism by the time the radioactive iodine ease following the use of radioactive iodine
procedure is performed. Nonetheless, when the seems to be the result of the thyrotoxic status per
patient is managed with tionamides the dose of se, rather than of the treatment itself [19–22].
I-131 should be increased to reduce the risk of Finally, the absolute contraindications to the use
treatment failure (it seems that the risk of failing of radioactive iodine are pregnancy and breast-
increases with the use of PTU versus MTZ). feeding; the relative contraindications are the
Pretreatment with Tionamides prior to the presence of thyroid nodes with some risk of
administration of I-131 is reserved for elderly malignancy or malignant, and patients under 15
patients with underlying cardiovascular condi- years of age.
tions or tachyarrhythmia and for patients with
severe hyperthyroidism [20, 21]. In general, the
use of tionamides prior to the administration of Surgical Treatment for GD
I-131 should be stopped 2–3 days prior to ther-
apy and it can be reintroduced 3 days after the Although the surgical management for GD
completion of treatment (and maintained for results in fast symptom control, with low mor-
4–6 weeks thereafter). bidity (in expert hands), it is an indication sel-
174 H. Vargas-Uricoechea et al.
dom indicated as initial treatment. In fact, the are: end-stage cancer, advanced cardiovascular
most frequent indications in clinical practice are disease, and severe lung disease. Some of the
those where other therapeutic options are contra- factors that influence the decision of surgery as
indicated and in patients with giant goiter. the first line treatment in GD are: Contraindication
Various surgical procedures have been document for the use of radioactive iodine and/or tion-
for the control of GD but two techniques have amides, rapid symptom control, and in some
prevailed: Total Thyroidectomy (TT) and pregnant women (in particular at the end of the
Subtotal Thyroidectomy (ST). While it has been second trimester). He most frequent complica-
considered that TT is the treatment of choice for tions arising for surgery in GD –in highly expe-
patients with associated thyroid cancer, the opti- rienced, high-flow centers- are hypocalcemia
mal surgical approach for GD individuals with- (<2 %), recurrent laryngeal nerve injury (<1 %);
out associated thyroid cancer is still subject to both complications may be temporary or perma-
debate. The use of TST results –at least theoreti- nent; post-surgical bleeding requiring interven-
cally- in a lower risk of the recurrent laryngeal tion (<1 %), procedure-related mortality (1 in
nerve injury and hypoparathyroidism in addition 10.000 to 5 in 1.000.000) and all the complica-
to an implicit higher probability of further pre- tions inherent to general anesthesia [24, 25]. The
serving a euthyroid state as compared to recommendation is to take the GD patient to sur-
TT. However, it also gives rise to a risk of persis- gery as close to the euthyroid status as possible;
tence of the disease since the thyroid remnant hence the use of tionamides, in particular of
may be enough to maintain the hyperthyroid sta- MTZ and the additional use of potassium iodine
tus after surgery. Based on these considerations (Lugol’s solution has 8 mg of iodide per drop
and depending on the series studied, TST is still and the recommendation is to use 1–2
recommended over TT. It has been thought that drops/0.05–0.1 mL three times per day, mixed in
TT results in a predictable risk of hypothyroid- water for 10 days prior to the thyroidectomy pro-
ism practically in every patient but it is easily cedure). Saturated Potassium Iodide solution
managed and controlled with thyroid hormone (containing 50 mg of iodide per drop and beta
supplementation; the risk is however variable blockers are key for the patient’s preoperative
according to the analysis of the results obtained control. In case of an emergency or a history of
with TST (TT has a risk of relapse or persistence adverse reactions to anti-thyroid agents, the use
of hyperthyroidism of 0 % and TST of 8 % at 5 of potassium iodide and beta-blockers are the
years). Generally speaking, the surgical inter- cornerstone of treatment. The use of potassium
vention is considered a safe and effective thera- iodide and of the saturated potassium iodide
peutic option in GD patients, with low morbidity solution reduces the risk of bleeding during sur-
and mortality rates (particularly in the hands of gery; occasionally the use of steroids may assist
experienced surgeons who perform at least 100 in the emergency preoperative prep in patients
GD surgeries per year) and with a predictable with Graves’ disease. Metimazol should be inter-
risk of hypothyroidism virtually in every patient rupted at the time of surgery and the use of beta-
(particularly with TT) with a very low rate of blockers may be downscaled in the next days,
relapses. However, the evidence is based on based on the adrenergic status of the patient
studies with a small number of patients, using [23–26]. Calcium and intact PTH (PTHi) mea-
non-standardized or inconsistent measurement surements should be performed 6–12 h after sur-
techniques. Apparently the best option to surgi- gery with a PTHi level <10–15 pg/mL in the
cally approach GD is through an interdisciplin- immediate postop predictive of the risk of symp-
ary approach that identifies the risk and benefits tomatic hypocalcemia and the need for calcium
of a particular indication and when surgery is and vitamin D supplementation. A calcium level
considered the best choice, TT should be favored >7.8 mg/dL (1.95 mmol/L) in asymptomatic
against TST [23, 24]. Some factors that may patients for hypocalcemia should be considered
contraindicate surgery one-way or other for GD as the lower limit to decide patient discharge fol-
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease): An Overview of Treatment 175
Table 9.1 Surgical indications for GD patents patient exhibits common signs and symptoms for
Indication hypothyroidism such as tachycardia, widened
Giant goiter (>80 g) or compressive symptoms pulse pressure, dry skin, heat and heat intolerance.
Suspected or documented thyroid malignancy At the initial stages of pregnancy, physiological
Low uptake of nodules on scan imaging changes develop that may mimic biochemical
Co-existing hyperparathyroidism hyperthyroidism that does not require specific
Short term pregnancy planning (i.e., less than 6 management. The diagnosis of hyperthyroidism
months) in pregnancy is done with a suppressed TSH
Moderate-severe Ophthalmopathy value, with a total T4 and T3 value within a 1.5
Rapid symptom and hyperthyroid status control fold adjusted reference range as compared to the
Thionamide adverse effects or relapse following non-pregnant women; or based on T3L and T4L
thionamide use
values above the specific range of reference for
Radioactive iodine contraindication
each trimester. Thyroid function test ranges are
Express desire stated b the patient
different throughout pregnancy and for certain
types of lab tests there may be hormonal titration
lowing thyroidectomy. Postoperative intrave- variations so the recommendation is to measure
nous calcium and magnesium should be managed the anti-TSHR titers at the time pregnancy is doc-
according to the standard management protocols umented. When the titers are elevated, the tests
[27–29]. In euthyroid patients at the time of sur- should be repeated at week 22–26 of gestation in
gery, the use of levothyroxine may be started order to guide the fetal monitoring decisions.
24–48 h after surgery. Patients undergoing emer- Human Chorionic Gonadotropin (hCG)-associ-
gency thyroidectomy shall wait a few days to ated hyperthyroidism, either resulting from a
start replacement therapy, with a dose of 1.7 μg/ molar pregnancy or because of a choriocarci-
kg/day as the reference value to begin levothy- noma, may manifest as a hyperadrenergic condi-
roxine treatment. TSH should be measured 6–8 tion with thyroid hyperactivity very similar to GD
weeks after surgery to adjust treatment. Table 9.1 but with no ophthalmopathy or dermopathy pres-
shows some of the indications for thyroidectomy ent and with negative anti-TSHR values (whilst in
in patients with GD. GD these are usually elevated). Furthermore,
serum hCG levels exceed the usual ranges present
during gestation. Nevertheless, normal pregnancy
Special Conditions may also give rise to transient hCG elevations,
with TSH suppression. Overall, the two main
Pregnancy causes of biochemical hyperthyroidism are con-
sidered to be gestational hyperthyroidism and
Hyperthyroidism results in 0.1–0.4 % pregnancy GD. The former is hCG-mediated and indicates
complications and 85 % of the cases are the cause mild biochemical hyperthyroidism in an asymp-
of these complications is GD. The treatment of tomatic woman, usually expressed during the first
GD during pregnancy is complex due to preg- trimester of pregnancy. Elevated hCG levels dur-
nancy effect on the course of the autoimmune dis- ing the first trimester causes those changes and
ease. As a general rule, subclinical hyperthyroidism usually does not result in lethality. Such changes
is not associated with major complications, whilst are the result of the thyrotropic hCG action
florid hyperthyroidism is associated with pre- through the alpha subunit late in the first trimester
eclampsia, premature labor, congestive heart fail- or early in the second trimester. A few pregnant
ure and increased rate of abortions. Uncontrolled patients with gestational hyperthyroidism develop
hyperthyroidism is also associated with low birth hyperemesis with marked thyroid function
weight and congenital malformations. The clini- changes and clinical hyperthyroidism with vari-
cal diagnosis of hyperthyroidism may be difficult able degrees of severity [29, 30]. In view of the
to pursue during pregnancy since the pregnant diagnostic safety of GD during pregnancy, the
176 H. Vargas-Uricoechea et al.
need for pharmacological treatment must be TSH values should be suppressed and thyroid
established. Anti-thyroid medications are the function tests (TSH, free and total T3 & T4)
treatment of choice, and usually PTU is preferred should be measured on a monthly basis through-
over MTZ (due to the higher risk of congenital out pregnancy in order to meet the target with the
malformations described with MTZ –in particular lowest possible dose of the anti-thyroid agent of
aplasia cutis congenital, choanal, and esophageal choice [31, 32]. Patients with uncontrolled hyper-
atresia- and presumably PTU crosses the placenta thyroidism, despite the use of anti-thyroid medi-
less readily, though this assumption has been cation, or in the presence of allergies or severe
proven wrong because both PTU and MTZ cross reactions, should be considered for surgical man-
the placenta). Historically, the use of MTZ has agement. When thyroidectomy is required, it
been recommended after the second trimester of should be performed during the second trimester
pregnancy and PTU could be administered of pregnancy because of the teratogenicity of
throughout pregnancy, but this recommendation anesthetics during the first trimester of pregnancy
is questionable on the basis of the potential liver and because of the risk of premature delivery in
involvement (toxicity). This has led to a reevalua- the third trimester. Pre-surgical preparation for
tion of such indication so that currently the rec- thyroidectomy includes a short course of potas-
ommendation is to prescribe PTU in patients sium iodide (10 days), together with anti-thyroid
during the first trimester of pregnancy or patients agents and beta-blockers.
who are intolerant or allergic to MTZ. Pregnant The administration of radioactive iodine for
women with pre-gestational GD that have been diagnostic or therapeutic purposes is
treated with anti-thyroid medications and are contraindicated in pregnancy. Following week
euthyroid before pregnancy, exhibit a low risk of 12 of gestation, once the fetal thyroid gland
activating the hyperthyroidism during pregnancy, develops the ability to concentrate iodine, con-
though the risk of relapses and post-partum thy- genital hypothyroidism may develop and has
roiditis is high. MTZ and PTU are also excreted in been document when inadvertently pregnant
breast milk but in small amounts that apparently women have been exposed in the first trimester,
do not impact the newborn thyroid function or with a 1.1 % rate of spontaneous abortion; 1.1 %
intellectual development. However, MTZ is pre- of intrauterine death; 3.3 % of neonatal hypo-
ferred over PTU during breastfeeding because of thyroidism and 2.2 % of mental retardation.
the PTU-associated liver toxicity. Therefore, This shows that hypothyroidism due to radioac-
women receiving MTZ shall be switched over to tive iodine exposure after week 12 of pregnancy
PTU as soon as pregnancy is documented –during is considerably higher than the standard inci-
the first trimester- and then switchback to MTZ dence of congenital hypothyroidism. Towards
early in the second trimester. Likewise, if the weeks 10–12 of gestation, the increase in the
patient received PTU prior to becoming pregnant, Sodium/Iodine Symporter gene (NIS) the fetal
the recommendation is to continue the medication thyroid is able to concentrate iodine, accumu-
until the beginning of the second trimester and late colloid, and produce thyroglobulin; around
then switchover to MTZ. When changing from week 20 of gestation the TSHR responds to the
one tionamide to another, the doses should be TSH stimulus (as well as to the thyroid stimu-
adjusted based on the differential strength between lating antibodies). The placenta per se is not
MTZ versus PTU (refer to the information above). permeable to TSH, but it is to iodine; active
When PTU is maintained throughout pregnancy, iodine transport through the placenta is the
liver enzymes should be monitored on a monthly result of the NIS gene expression in tropho-
basis. The goal of anti-thyroid treatment is to blasts. During the second trimester of preg-
maintain total T3 and T4 levels barely above the nancy, when the fetal thyroid produces T4, the
upper normal range of the non-pregnant patient maternal intake of iodine is critical as a back-
and free T3 and T4 levels within or slightly above ground for thyroid hormone synthesis. While
the upper normal level of a non-pregnant woman. the placental crossing of maternal antibodies to
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease): An Overview of Treatment 177
Fetal goiter
Mother with GD and poor
metabolic control.
Mother previously treated
Risk factors for fetal with radioactive iodine or
hyperthyroidism surgical, with high anti-TSHr
titers.
Fetal tachycardia.
Accelerated fetal bone age.
the fetus occurs very early in gestation, the fetal Graves’ Eye Disease
concentration of those antibodies is in fact low
until late in the second trimester. However, pla- Many of the clinical signs and symptoms previ-
cental permeability to antibodies increases sub- ously described in the eye manifestations of GD
stantially during the third trimester and thus the may be explained from a “mechanical” perspec-
fetal levels are practically identical to the mater- tive, due to the increased volume en el of intra-
nal levels. Such changes in maternal permeabil- orbital tissues typical of GD. Though much
ity and the ability of the fetal thyroid gland to patients with Graves’ disease exhibit an abnor-
respond to both TSH and anti-TSHR are the rea- mal growth of the extra ocular muscles and of the
son why fetal hyperthyroidism is expressed orbital adipose tissue, with a potential predomi-
after the second half of pregnancy [33, 34]. nant growth of one over the other, the orbital fat
Serial obstetric ultrasound imaging to measure tissue is more prevalent among youth, while there
the size of the thyroid is recommended, in addi- is a stronger predisposition to extra orbital mus-
tion to identifying the gestational age, the fetal cle growth among the elderly, with no significant
viability, the amniotic fluid volume, the fetal changes in the orbital adipose tissue. The expan-
anatomy, and the identification of any malfor- sion of both the muscle and adipose tissue around
mations. Fetal tachycardia (over 170 beats/min the orbit leads to increased intraocular pressure,
persistent for more than 10 min), growth retar- with compression of the orbital tissue contents.
dation, fetal goiter (which is an early sign of Intraocular pressure is relieved with the eyeball
fetal dysfunction, but on its own does not dif- protrusion and hence proptosis and exophthal-
ferentiate hyper from hypothyroidism – See mos should be considered a natural decompres-
Fig. 9.1), accelerated bone maturation, signs of sion phenomenon of the orbit. The level of
heart failure and hydrops fetalis, are all addi- decompression is limited by the eyeball mobility
tional considerations. The diagnosis and man- per se. The eyeball is “fixed” in place by the rec-
agement of fetal hyperthyroidism should be tus muscle and other eyelid structures [36]. The
done with a multidisciplinary approach includ- lymphocytic infiltration present in the orbital tis-
ing pediatrician, gynecologist, neonatologist, sues in GD indicates the prevalence of T CD4+
anesthesiologist, and endocrinologist. The med- and CD8+ lymphocytes, with few B cells. The
ical record, lab tests (with anti-TSHR levels), retro bulbar T cells in GD patients recognize the
ultrasound imaging and the clinical condition of autologous fibroblasts but fail to recognize the
the mother shall guide the management of fetal extracts of ocular muscles in a way restricted to
hyperthyroidism [34, 35]. See Chap. on 17 for HLA class I. The HLA-DR expression and the
further details. adhesion molecules in the orbital endothelial
178 H. Vargas-Uricoechea et al.
cells y fibroblasts are enhanced by cytokines such of eye disease refers to the presence of inflamma-
as Interleukins (IL), in particular the IL-1α, tion, while the “severity” refers to the extent of
Tumor Necrosis Factor (TNF) such as TNF-α and functional and cosmetic deficit at every level. It is
Interferon-γ. This has led to the conclusion that important to determine the GO phase in order to
the orbital fibroblast is the target of autoimmune establish proper treatment, since immune-
aggression. Since the TSHr is expressed in the modulator treatment may be effective in the pres-
messenger RNA (mRNA) and in high titers in ence of active inflammation [38–41]. There are
connective and adipose tissue proteins of the several classifications and scores aimed at accu-
orbit in GD patients versus healthy individuals, rately defining the “activity” and the “severity” of
TSHr is considered to be functional, as evidenced Graves’ eye disease and most of them evaluate
by the elevation in AMPc in response to TSH. In several aspects. The acronym used is VISA:
fact, the eye pre-adipocytes and fibroblasts dif-
ferentiation in adipocytes is associated with a Vision (the key objective is to rule out the pres-
marked enhancement of the functional TSHr ence of optic neuropathy).
expression. This concept arises from a subpopu- Inflammation(including pain, redness, swelling,
lation of eye fibroblasts that may be the target and visual function involvement).
cells in GD –called pre-adipocytes- and when Strabismus: (presence of diplopia).
these are stimulated to promote mature adipocyte Appearance/exposure: (the appearance evaluates
differentiation, high levels of TSHr are expressed the presence of eyelid retraction, proptosis,
[37, 38]. Generally speaking, GD is considered to redundant skin, and fat prolapse; the exposure
be an autoimmune disorder, triggered by autore- evaluates the presence of opacification and
active T lymphocytes that react with one or more corneal ulcer).
antigens shared between the orbit and the thyroid
gland. Consequently, these autoreactive lympho- The ocular signs of GD have been described
cytes reach the orbit, recognize the antigen (or using the NONSPECS classification that
common antigens) presented by the antigen- described the extension of the eye disease based
presenting cells (dendritic cells, macrophages, on the specific presentation of eye signs and
and B lymphocytes). Upon recognition of the symptoms, but it is of little use to monitor the
antigen, a cascade of events leads to the secretion disease process since a particular class does not
of cytokines that stimulate the proliferation of necessarily progress to the next; in other words,
fibroblasts, the differentiation of pre-adipocytes the clinical characteristics considered are not
to adipocytes, and the Glucosaminoglycans always present (Table 9.2). The natural history of
(GAG) secretion from fibroblasts, resulting in Graves’ Orbital pathology is rapid impairment,
water retention and periocular edema. An followed by gradual improvement as time pro-
increased orbital content mechanically explains gresses. The active phase is properly described in
most of the clinical manifestations in Graves’ terms of the Clinical Activity Score (CAS) that
Orbitopathy –GO- [39, 40]. During the course of
GO, the disease goes through several stages start- Table 9.2 Classification of eye changes in GD
ing with a worsening of the signs and symptoms (NONSPECS)
during the inflammatory phase. The gradual pro- Class Definition
gression of the inflammatory process may lead to 0 Absence of signs or symptoms
permanent abnormalities in function and appear- 1 Signs only, no symptoms (limited to upper lid
ance. The concept of “active” disease indicates retraction, fixed gaze)
the presence of inflammatory characteristics sug- 2 With signs and symptoms (soft tissue
gesting a potential response to anti-inflammatory involvement)
therapy. “Inactive” disease defines the phase free 3 Proptosis
of inflammation, though residual fibrosis may be 4 Extraocular muscle disruption
present. Such “inactive” phase may only be 5 Corneal involvement
changed with surgical treatment. The “activity” 6 Loss of vision (optic nerve involvement)
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease): An Overview of Treatment 179
adds one point per each clinical characteristic bypasses the last three items of the initial score
present (described under Table 9.3). The score and it is used when previous evaluations are not
ranges from 0 to 10 and predicts the response to available. Consequently, GO is considered active
anti-inflammatory treatment. A seven-point scale with a score of ≥3. Hence, hyperthyroid patients
that only present with eyelid retraction or with
Table 9.3 GO evaluation: clinical activity score (CAS) mild conjunctival erythema and lid edema, are
items not considered active GO [39–43]. The severity
Comparison of the disease is better evaluated using objective
Each against prior and quantifiable parameters that are helpful in
Items visit visits Score guiding therapy. The factors to consider when
Oppressive pain over X assessing severity are summarized in the
or behind the eyeball
in the last 4 weeks European Group on Graves’ Orbitopathy
Pain with eye X (EUGOGO) (See Table 9.4).
movements during the The diagnostic images for GO are basically
last 4 weeks ultrasound, Computed Tomography (CT) scan
Eyelid redness X and Magnetic Resonance Imaging (MRI).
Conjunctival redness X Ultrasound is a non-invasive method to rule out
Eyelid inflammation X orbital tumors and to assess the internal echo-
Chemosis (conjuntival X genicity of extra-ocular muscles and orbital fat.
edema)
The use of mode-A 2-D ultrasound is advised. A
Caruncle inflammation X
thickening of the ventral aspect of the muscle can
Increased proptosis X
≥2 mm be detected, while the scleral attachment is barely
Reduced eye X modified. It has been hypothesized that internal
movement ≥5° in reflectivity of the waves should be low in patients
every direction with active disease because of the muscle edema
Decreased visual X and high and irregular in inactive eye disease
acuity ≥1 line on the
resulting from the presence of muscle fibrosis.
snellen chart
The key advantage of mode-A ultrasound is its
CAS items, a scale with the first 7 items (excluding the
last 3) is used when no previous evaluations are available. non-invasiveness and affordability; however, it is
The Go is considered active with a CAS ≥3 not as effective as CT scan. However, CT is more
effective in the evaluation of the posterior third of Regardless of the management options, the major
the orbit due to the loss of echogenic response effort should be addressed to prevention and to
through the tissues (attenuation) and difficult avoid any progressive deterioration of the dis-
access to evaluate the inferior rectus muscle (the ease. The major key factors for GO are: prior use
structure most frequently affected) in addition to of radioactive iodine (such as hyperthyroidism
poor reproducibility. Ultrasound images of GO treatment), smoking, elevated anti-TSHr titers,
with muscle component will show marked thick- elevated T3 titers prior to treatment and uncon-
ening of the inferior, medial and lateral rectus trolled hypothyroidism following radioactive
muscles [41, 44]. CT and ultrasound are comple- iodine management. The euthyroid status shall
mentary techniques. When considering CT, take always be maintained in every patient with GD
into account that orbital fat has a negative den- and GO, or with any risk factors for the
sity, while the muscles and the optic nerve have a development of GO. GD patients with no clini-
positive density. Consequently, there is no need cally apparent GO, the management of their
to regularly use contrast agents to explore the underlying hyperthyroidism can be approached
GO, since the contrast will only be able to show with any of the universal modalities for GD man-
muscular hyper-vascularization. The CT scan agement previously described. Cigarette smok-
shall be performed with 3–5 mm sequence axial ing is the most modifiable risk factor for the
sections and 5 mm coronal sections from the eye- development of GO, hence the exposure to ciga-
lid to the sphenoid sinus, using the Salvolini- rette smoking is forbidden from the time of diag-
Cabanis plane (neuro-ocular view). The nosis. The use of glucocorticoids should be
characteristic CE findings for GO are: exophthal- considered for patients with mild activity GO and
mos, thickening of the muscle body, optic nerve no additional risk factors, for which radioactive
compression at the level of the orbital apex due to iodine will be the baseline therapy for hyperthy-
thickened muscles causing neuropathy, bone roidism. Likewise, in patients with mild GO and
bulging of the ethmoid walls, pseudo-tumoral smoking or any other associated risk factors
images on the posterior orbital third produced by should be candidates for concomitant glucocorti-
the thickened inferior rectus muscle. The axial coid use if they are going to be treated with radio-
views may show an increased fat volume and active iodine. Patients with GD and moderate to
atrophic images within the muscle. The indica- severe GO may be managed with MTZ or surgery
tions for CT-scan in GO are based on clinical for hyperthyroidism. However, patients with GD
judgment, the activity and the severity of the dis- and inactive ophthalmopathy may be managed
ease, as well as on the decision-making process with tionamides, radioactive iodine, or surgery,
for pharmacological and/or surgical management. with no need to add glucocorticoids [46–48].
MRI images do not offer any considerable advan- Treatment of hyperthyroidism with tionamides
tages for the diagnosis of GO, although they has a neutral effect on the progression of GO,
allow for the differentiation between edema and though it has an indirect positive effect on the de-
fibrosis because of the high tissue water content. escalation of anti-TSHr. Radioactive iodine is
Likewise, MRI offers a higher sensitivity for the further associated with worsening and progres-
diagnosis of the inactive phases of the disease. sion of GO, whilst surgery has a neutral effect or
Some of the advantages are the absence of ioniz- mild improvement on the progression of Graves’
ing radiation and the ability to differentiate Orbitopathy. For patients with mild active GO,
orbital structures. The major disadvantages are the recommendation is “watchful waiting” and
its high cost, lower availability, and poor quality the systematic use of corticosteroids is not
of images for studying the ethmoid bone wall accepted, except for those patients that will
since MRI does not accurately differentiate the undergo radioactive iodine management. In
shape of the bone [43–45]. The current therapeu- inactive-mild GO, rehabilitation surgery for cos-
tic approaches for GO include local measures, metic purposes or functional reasons (orbital
glucocorticoids, orbit radiation, and surgery. decompression due to exophthalmos, eye lid
9 Autoimmune Thyroid Disease (Flajani-Parry-Graves-von Basedow Disease): An Overview of Treatment 181
Moderate to
Mild
severe
GO Vision
threatening
Active Inactive Active Inactive
Orbitopathy Watch and Watch and High dose Rehabilitation Glucocorticoids and
wait wait Glucocorticoids Qx decompression QX
retraction) may be required. The use of glucocor- effective than the oral prescription. The accumu-
ticoids is not indicated on account of their inef- lated dose of intravenous glucocorticoid should
fectiveness; in fact, prophylactic glucocorticoid not exceed 6–8 grams within 6–16 weeks. The
treatment is not indicated in the absence of any use of cyclosporine, anti-TNF-α (Etanercept),
additional risk factors for the development of and intravenous immunoglobulin, as well as the
radioactive iodine-induced GO. In moderate to use of anti CD-20 monoclonal antibodies such as
severe GO, the treatment choice may be contro- Rituximab, may positively impact the pathogenic
versial; these patients should receive immediate mechanisms of GO by modulating the immune
GO therapy and glucocorticoids are the treatment burden of the disease. However, no final recom-
of choice, preferably Intravenous (IV), with or mendations are yet available for GO applications
without orbit-targeted radiation therapy. All [47–49]. Retrobulbar radiation therapy may be an
patients in this category should be euthyroid as option for the treatment of moderate-severe GO,
this is a requirement for a favorable evolution in with significant benefit over eye mobility and
the management of GO. Patients with inactive diplopia. Usually low doses are used (1 Gy per
moderate to severe GO, the baseline therapy for week versus 1 or 2 Gy day) with similar efficacy
their hyperthyroidism is established in accor- in patients with moderate-severe GO. Patients
dance with the individual patient criteria. If with diabetes mellitus and high blood pressure
radioactive iodine management is decided, glu- have a relative contraindication for the procedure
cocorticoid therapy should only be introduced if because of the high risk of post-radiation therapy
risk factors for GO are present, particularly when retinopathy [48, 49]. Figure 9.2 illustrates an
there is a history of smoking. Patients with approach for the management of hyperthyroid-
vision-threatening GO should be considered an ism and GO under various clinical settings.
endocrine emergency and high-dose intravenous
glucocorticoids should be initiated urgently, with
subsequent orbital decompression when the Pretibial Myxedema
response to glucocorticoids is poor [44–47]
Several regimes with variable IV glucocorticoid Localized myxedema or Thyroid Dermopathy
doses have been used; the response rate may (TD) is a rare manifestation in GD. The major clin-
range between 63 and 77 % and the use of IV ical characteristic is localized skin thickening, par-
glucocorticoid (methylprednisolone) is more ticularly on the pretibial area and hence the name
182 H. Vargas-Uricoechea et al.
pretibial myxedema. The key histological charac- ecchymosis and skin atrophy. The use of intra-
teristic is the accumulation of GAG on the reticular lesion steroids may result in nodular skin degen-
dermis, with an exaggerated concentration of hyal- eration from adipose tissue atrophy when standard
uronic acid as a result of fibroblast stimulation, needles are used, though probably the use of
though the reason for the stimulation and the auto- smaller gauge needles (mesotherapy-like) avoids
immune origin is not totally clear, particularly the poor results described with normal needles.
because it affects mostly the pretibial area, proba- Overall, the use of intra-lesion and systemic ste-
bly because of the venous stasis. The higher prob- roids is increasingly being neglected because of
ability for lower limb micro trauma leads to larger the poor results and of their local and systemic
mucinous deposits or may be the fibroblasts in the effects. The use of immunomodulation therapies
body have diverse regulatory mechanisms. Another such as octreotide, azathioprine, and cyclospo-
option is local edema that may enhance the secre- rine, inter alia, is not yet supported by strong evi-
tion of cytokines that further impair the GAG con- dence. TD surgery is rarely performed and in fact
centration [50, 51]. Several therapeutic modalities surgical trauma predisposes to the relapse of the
have been used, ranging from compression ban- disease and hence is only indicated in cases of
dages and topical steroids to steroid systemic ther- “cosmetically” inacceptable presentations,
apy and intradermal applications. TD typically has together with topical steroid therapy [55–59].
four distinctive presentations:
Conclusions
(a) The edematous, indurated form without pit- Treatment of Graves-Basedow disease cannot
ting accompanied by skin discolorations. yet be aimed at the cause because it is still
(b) In “Plaques”. unknown. There are three available forms of
(c) Nodular. treatment, but there is a difference of opinion
(d) Elephantiasis. as to which of these modalities is best.
Antithyroid drugs are widely used for treat-
Treatment of TD is symptomatic. As a rule, the ment on a long- term basis. Thyroidectomy is
edematous and plaque presentations may be mild a satisfactory form of therapy, if an excellent
and not annoying for the patient; most of the time surgeon is available. Currently, management
it does not require treatment but if specific man- with I-131 is considered the best treatment in
agement is adopted, topical steroids are enough adults. There is no definitive therapy in Graves-
[51–53]. The nodular and elephantiasis forms Basedow disease; rather, the treating physician
respond to management with nocturnal compres- is encouraged to discuss with the patient each
sive bandaging (at the sites affected on the ankle of the treatment options, including the logis-
or knee; sports bandages with a 20–40 mmHg tics, benefits, expected speed of recovery,
compression may be helpful. In other areas of pre- drawbacks, potential side effects and cost so
sentation, the use of medium compression ban- that the course of action incorporates both the
dages assist with management and topical steroids relevant medical considerations and the per-
(i.e., 0.05–0.1 % triamcinolone acetate in cream) sonal values and preferences of the patient.
[52–54]. Fluocinolone acetonide and clobetasol
propionate have also been used in some protocols,
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Subclinical Hyperthyroidism
10
Asim Hassan
Abstract
Because of screening tests with sensitive TSH assays, subclinical hyper-
thyroidism is being recognized more commonly. Subclinical hyperthy-
roidism is defined as undectectable thyrotrophin (TSH) concentration in
patients with normal levels of T4 and T3. Subtle symptoms and signs of
thyrotoxicosis may be present.
It be classified as endogenous in patients with thyroid hormone produc-
tion associated with nodular thyroid disease or underlying Graves’ dis-
ease; and as exogenous in those with undectectable serum thyrotropin
concentrations as a result of treatment with levothyroxine. Subclinical
hyperthyroidism is often found in older subjects with autonomous func-
tion of a multinodular goiter or nodule.
Osteoporosis and atrial fibrillation are complications of subclinical
hyperthyroidism that may be an indication for treatment. Studies suggest a
possible increase in all-cause mortality in patients with subclinical hyper-
thyroidism with an increase beyond the age of 60, especially in aging men.
In many patients with endogeneous subclinical hyperthyroidism who do
not have nodular thyroid disease or complications of excess thyroid hor-
mone, treatment is unnecessary, but thyroid-function tests should be per-
formed every 6 months. In older patients with atrial fibrillation or
osteoporosis that could have been caused or exacerbated by the mild excess
of thyroid hormone, ablative therapy with 131I is the best initial option.
In patients with exogeneous subclinical hyperthyroidism, the dose of
levothyroxine should be reduced, excluding those with prior thyroid cancer
in whom thyrotropin suppression may be required. The dose of levothyrox-
ine used for treating hypothyroidism may be reduced if the patient develops
new atrial fibrillation, angina, cardiac failure or accelerated bone loss.
Several of these patients have hypothyroid- persons over the age of 55–60 years, is presented
ism, and subclinical hyperthyroidism in them is as follows:
not the target of thyroid hormone replacement. The reported occurrence of subclinical hyper-
However, subclinical hyperthyroidism is the aim thyroidism varies among different studies
of thyroxine administration in patients with thy- because of the variability in defining the TSH
roid cancer and in some patients with thyroid level for subclinical hyperthyroidism, age of the
nodules, multinodular or diffuse goiters, or a his- patient population studied, and administration of
tory of head and neck irradiation. In these thyroid hormone. The occurrence of subclinical
patients, the advantages of TSH suppression off- hyperthyroidism in the population varies from
set the risks of subclinical hyperthyroidism. 0.7 to 12.4 %. In the U.S, the National Health and
Nutrition Examination Survey (NHANES III),
which did not include individuals with known
In the United States as many as 10 million thyroid disease, 0.7 % of 16,533 persons were
people, and possibly 200 million persons reported to have subclinical hyperthyroidism
globally, are prescribed thyroid hormone (TSH <0.1 mU/L) [18]. Subclinical hyperthy-
roidism is more widespread in areas with mild to
moderate iodine scarcity.
Endogenous Subclinical However the prevalence of subclinical hyper-
Hyperthyroidism thyroidism has been shown to be as high as 15 %
in patients older than 70 years in iodine-lacking
Independently thyroid hormone producing ade- areas [19]. It is most frequent in individuals on
nomas and multinodular goiters are the most fre- thyroid hormone treatment, where the prevalence
quent causes of endogenous or internal subclinical may be as high as 20 % [3, 4]. Moreover, sub-
hyperthyroidism. In persons over 55 years old, clinical thyroid dysfunction is more frequent in
subclinical hyperthyroidism due to multinodular females, smokers, and older persons [18, 20].
goiters was diagnosed in 57 % of patients, while
due to Graves’ disease in 6 % only [6]. One study
showed that, 22 % of patients with multinodular The condition is most frequent in individu-
goiter had subclinical hyperthyroidism, and 28 % als on thyroid hormone treatment, where
had autonomous hyperfunctioning area(s) on the prevalence may be as high as 20 %.
imaging of the thyroid gland [7]. Moreover, subclinical thyroid dysfunction
Thyroiditis can also cause subclinical hyperthy- is more frequent in females, smokers, and
roidism, and has been shown to occur in 63 % of older persons
euthyroid cases with Graves’ ophthalmopathy and
4 % of Graves’ patients in remission [8–10]. It may
also be seen in patients with early Graves’ disease Mostly subclinical hyperthyroidism will not
before the commencement of frank hyperthyroid- progress to frank hyperthyroidism. The associ-
ism. Moreover, pregnant females, mostly in the ations and the risk factors that seem to influ-
first trimester and those with hyperemesis gravi- ence the natural course include the level of TSH
darum or trophoblastic disease, with high serum inhibition and the primary cause. One prospec-
chorionic gonadotropin concentrations, may be tive study evaluated 102 females more than 60
diagnosed to have subclinical hyperthyroidism. years old with subclinical hyperthyroidism with
TSH concentrations between 0.1 and 0.4 mIU/L
[21]. Amongst these women, 2.9 % developed
Epidemiology and Natural History overt hyperthyroidism; in 3.9 % TSH levels
reduced to less than 0.1 mIU/L, with normal T3
Numerous large studies have looked into and T4 values; in 23.5 % the TSH normalized;
the prevalence of subclinical hyperthyroidism and in 69.5 % TSH levels remained within 0.1–
[11–17]. The data from these studies, mainly in 0.4 mIU/L over an average follow-up of 41
188 A. Hassan
hyperthyroidism (TSH less than 0.3–0.5 mU/L) 0.99–1.23]). In general, the increased risk of
and cardiovascular and all-cause mortality, the mortality from subclinical hyperthyroidism
risk for all-cause and cardiovascular mortality appears to be little but rises with the extent of
was not significant (relative risks [RRs] 1.12, TSH suppression.
95 % CI 0.89–1.42 and 1.19, 95 % CI 0.81–1.76,
respectively) [33]. However, another meta-
analysis showed a considerably increased risk of Bone and Mineral Metabolism
all-cause mortality (HR 1.41, 95 % CI 1.12–1.79)
[34]. Increased mortality after finding of subclin- Subclinical hyperthyroidism may decrease bone
ical hyperthyroidism depended upon age, with an mineral density (BMD), predominantly in corti-
increase beyond the age of 60 years. However, in cal bones, though the effect is possibly influenced
a subsequent population-based study, subclinical by the period of the disease, other associated risk
hyperthyroidism was associated with reduced factors for loss of bone, and the level of TSH
survival only in individuals < age 65 years [52]. inhibition. Loss of bone density with hyperthy-
The meta-analyses included both exogenous roidism is a consequence of increased bone turn-
and endogenous subclinical hyperthyroidism over due to imbalance between bone resorption
patients. Serum triiodothyronine (T3) levels are and formation, resulting in decrease in BMD and
more in persons with endogenous than exoge- increased bone turnover markers [55]. Though
nous subclinical hyperthyroidism, and this may frank hyperthyroidism is linked with increased
give a higher mortality risk [45]. In the meta- risk of fractures, the data is inconsistent for sub-
analysis of 10 prospective cohort studies (52,674 clinical hyperthyroidism.
participants, 2188 with endogenous subclinical The effect of subclinical hyperthyroidism on
hyperthyroidism) studying only patients with BMD is significant in postmenopausal women. In
endogenous subclinical hyperthyroidism, there a cross-sectional analysis of females with endog-
was an elevated risk of both all cause (HR 1.24, enous subclinical hyperthyroidism (TSH levels
95 % CI 1.06–1.46) and cardiovascular (HR 1.29, of 0.01–0.1 mIU/L), postmenopausal women had
95 % CI 1.02–1.62) mortality in patients with considerably lower BMD at the level of the femur
endogenous subclinical hyperthyroidism [53]. and lumbar regions, while premenopausal women
The risk of cardiovascular mortality was more for had only a modestly lower BMD in the femur
TSH levels <0.1 mU/L as compared to concentra- area compared with corresponding euthyroid
tions between 0.1 and 0.44 mU/L (HRs 1.84 ver- control patients [56]. A 12 studies meta-analysis
sus 1.24). also found a relationship between markedly
In a study investigating patients with exoge- decreased BMD in postmenopausal women, but
nous subclinical hyperthyroidism only, there was not in premenopausal females or males [57].
a higher risk of cardiovascular or all-cause mor- There is proof that subnormal TSH results in
tality only in patients with totally suppressed increased bone turnover markers, particularly in
TSH levels [54]. In this evaluation of 17,684 per- postmenopausal women with exogenous subclin-
sons (mean age 61.6 years) on T4 replacement ical hyperthyroidism. There is an inadequate data
treatment, TSH levels were fully suppressed on bone turnover marker in endogenous subclini-
(<0.03 mU/L) or low (0.04–0.4 mU/L) in 6 and cal hyperthyroidism; nonetheless the findings
21 % of subjects, respectively. In comparison to are similar. The data supports bone improve-
patients with normal TSH, patients with sup- ment from treating postmenopausal females with
pressed TSH levels (<0.03 mU/L) had raised car- subclinical hyperthyroidism. In one study,
diovascular morbidity and mortality (adjusted postmenopausal women with subclinical hyper-
HR 1.37, 95 % CI 1.17–1.60), while those who thyroidism (TSH levels less than 0.2 mIU/ L) due
had serum TSH concentration between 0.04 to multinodular goiter who were treated or not
and 0.4 mU/L had a lesser increase in risk that treated with radioactive iodine ablation, and fol-
was insignificant (adjusted HR 1.10 [95 % CI lowed up for 2 years [58]. Patients receiving
192 A. Hassan
radioactive iodine treatment had normal TSH In a prospective cohort study of 1864 subjects
levels and had no significant change in lumbar (mean age of 71 years and TSH of 0.1–10 mU/L),
and hip BMD, while the untreated patients with followed for an average of 12.7 years, only
low TSH levels had persistent loss of bone mass females whose TSH levels was in the lowest
of approximately 1–2 % per year. One more range had a 2.39 elevated risk of developing
study noted a prominent increase in BMD in Alzheimer disease compared with the higher lev-
patients with overt or subclinical hyperthyroid- els [61].
ism (2.8 and 1.5 %, respectively) after 6 months Similar data were noted in a population-based
of euthyroid status [59]. study of 1171 participants in whom subclinical
hyperthyroidism (TSH <0.46 mU/L) was linked
with cognitive dysfunction (HR 2.26, 95 % CI
Dementia Cognitive Function 1.32–3.91) [62].
In a community-based analysis from Scotland
The relationship between low TSH concentration (n = 2004), continuous endogenous subclinical
and dementia is contentious. Though data are hyperthyroidism (TSH <0.4 mU/L) was associ-
inconsistent, subclinical hyperthyroidism may ated with an increased risk of dementia (adjusted
also be associated with an increased possibility HR 1.79, 95 % CI 1.28–2.51) [45].
of dementia [41, 60–62]. In another prospective population based study
The prospective population-based Rotterdam from Korea, 54 out of 313 patients who showed
study analyzed a random sample of 1846 patients deterioration in cognitive function had lower
more than 55 years old, and noted that TSH con- TSH levels within the normal reference range
centrations less than 0.4 mIU/L were associated compared with subjects whose cognitive function
with a 3.5-fold elevated risk of dementia and remained stable or got better [64].
Alzheimer disease in a 2–4-year follow-up [63]. While in contradiction, cross-sectional analy-
This association was significantly stronger for sis of primary care patients in England [65], thy-
patients with both low TSH levels and positive roid cancer subjects from Korea [66], and females
antithyroid peroxidase antibodies, raising the taking T4-suppressive therapy in the United
likelihood of an autoimmune mechanism. States [67] failed to show an association of sub-
Though another study among the same popula- clinical hyperthyroidism with cognitive
tion did not confirm the relationship between function.
incident dementia or Alzheimer disease and TSH
levels in a follow-up of 5-year [63]. Another
population-based study from Italy discovered Quality of Life
that persons older than 65 years with TSH below
0.46 mIU/L had poorer Mini-Mental State Persons with subclinical hyperthyroidism may
Examination results compared with euthyroid have increased feeling of adrenergic over activity,
age-matched control patients (22.61 ± 6.88 versus especially those younger than 50 years. Quality
24.72 ± 4.52, respectively (P < .03)) [62]. of life and over activity of excess thyroid hor-
Moreover in multivariate regression analysis, mone were analyzed in 23 patients about 43 years
same patients had a more than twofold increased old, who had TSH levels less than 0.3 mIU/L
probability of cognitive impairment compared [29]. Compared with euthroid age and sex-
with age-matched control patients [62]. Further matched control patients, those with low TSH
studies are required to elucidate whether there is had a higher frequency of nervousness, tremor,
a causal link between subclinical hyperthyroid- heat intolerance, palpitations, and sweating, and
ism and cognitive deterioration, or whether the lower functional health and well-being. However,
relationship between low TSH and dementia is other studies did not find a relationship between
due to a higher occurrence of nonthyroidal illness TSH concentrations and health-related quality of
in older adults. life scores in subjects who had been treated for
10 Subclinical Hyperthyroidism 193
months after normalization of serum T4 and T3 Table 10.2 Causes of subclinical hyperthyroidism
concentrations in patients treated for hyperthy- Hyperthyroidism with a normal or high
roidism or recovering from hyperthyroidism radioiodine uptake
caused by thyroiditis and psychiatric conditions, Autonomous thyroid tissue (uptake may be low if
recent iodine load led to iodine-induced
especially emotional disorders. T4 and T3 levels
hyperthyroidism)
are generally lower in patients with these disor-
Toxic adenoma
ders, while patients with subclinical hyperthyroid- Toxic multinodular goiter
ism may have T4 and T3 concentrations in the mid Autoimmune thyroid disease
to high normal reference range. Graves’ disease
When the diagnosis of subclinical hyperthy- Hashitoxicosis
roidism is doubtful, assessment of 24-h thyroid Human chorionic gonadotropin-mediated
radioactive iodine uptake and scan may be sup- hyperthyroidism
portive. A high or relatively high 24-h uptake, rela- Hyperemesis gravidarum
tive to the low serum TSH levels or a focal area of Trophoblastic disease
increased radionuclide uptake would support the TSH-mediated hyperthyroidism
diagnosis of subclinical hyperthyroidism. TSH-producing pituitary adenoma
In patients not taking T4 who have persistent Non-neoplastic TSH-mediated hyperthyroidism
subnormal TSH values and in whom treatment is Hyperthyroidism with a near absent radioiodine
considered, a radioactive iodine uptake and scan is uptake
obtained to help establish the etiology of subclini- Exogenous thyroid hormone intake
cal hyperthyroidism (Table 10.2). Women of Excessive replacement therapy
childbearing age should have a negative pregnancy Intentional suppressive therapy
Factitious hyperthyroidism
test before having radioactive iodine scanning.
Amiodarone (also may cause iodine-induced
If the scan shows one or more focal areas of
hyperthyroidism)
increased uptake, this could explain for the low Thyroiditis
serum TSH. If there are focal areas of increased Subacute granulomatous (de Quervain’s) thyroiditis
uptake, a thyroid ultrasound would then be useful Painless thyroiditis (silent thyroiditis, lymphocytic
in determining the presence of distinct nodules. thyroiditis)
In patients with low or no uptake on radioiodine Postpartum thyroiditis
scan, the cause may be thyroiditis or recent iodine Palpation thyroiditis
exposure. Radiation thyroiditis
In postmenopausal women or other patients at Ectopic hyperthyroidism
risk for osteoporosis, a bone densitometry study Struma ovarii
may be useful in making a decision to treat sub- Metastatic follicular thyroid cancer
clinical hyperthyroidism or observe.
hyperthyroidism, antithyroid drugs lowered heart tion is advised if the bone density is normal and
rate, atrial and ventricular premature beats, left the radionuclide thyroid scan fails to show a focal
ventricular mass, inter ventricular septal thick- area of increased uptake. Observation may also
ness, and left ventricular posterior wall thickness be considered if a patient is on a beta-adrenergic
[37]. Similar benefits in hemodynamic measure- blocker for another reason. In observed patients,
ments were observed in another study with radio- check TSH, free T4, and triiodothyronine (T3)
iodine treatment [38]. every 6 months.
Similarly in two other non-randomized trials,
postmenopausal subjects with nodular goiter and
subclinical hyperthyroidism given antithyroid In persons with endogenous subclinical
drugs or radioiodine for 2 years had higher bone hyperthyroidism at high risk for cardiac or
density than matched patients who were not skeletal complications (i.e., older adults)
treated [58, 77]. and who have a TSH levels less than
Thus, in certain persons with subclinical 0.1 mU/L, treatment of the underlying
hyperthyroidism, normalization of TSH results in cause of subclinical hyperthyroidism is
improvement in surrogate outcomes. Long-term recommended. For comparable patients
clinical studies are needed to verify if correcting who have TSH concentrations between 0.1
subclinical hyperthyroidism improves and 0.5 mU/L, treatment is recommended
cardiovascular or skeletal outcomes. Due to defi- if the bone density is low and/or if the thy-
ciency of data to guide patients with endogenous roid radionuclide scan shows one or more
subclinical hyperthyroidism for therapy, it is sug- focal areas of high uptake. If bone density
gested to decide to treat on the bases of clinical is normal and the thyroid scan fails to show
risk for complications of subclinical hyperthy- a focal area of increased uptake, patients
roidism and the degree of TSH suppression. are typically observed. In these patients,
TSH, free T4, and T3 is measured every 6
months
Patients at High Risk
for Complications
Patients at Low Risk
In persons at increased risk for cardiac or skeletal for Complications
complications (e.g., old patients >65 years of
age, persons at risk factors for cardiac arrhyth- In persons at low risk for complications of hyper-
mias, and postmenopausal females with or at risk thyroidism (young subjects, premenopausal
for osteoporosis), the following approach is patients), following approach is advised:
suggested:
• If the serum TSH concentration is <0.1 mU/L,
• If the TSH level is <0.1 mU/L, treat the pri- treat the main cause of subclinical hyperthy-
mary cause of subclinical hyperthyroidism. roidism if the patient is symptomatic of hyper-
• If the TSH is 0.1–0.5 mU/L, treat if there is thyroidism and/or if a radionuclide thyroid
associated cardiovascular problem or low scan discovers one or more focal areas of high
bone density. uptake.
• If the TSH is between 0.1 and 0.5 mU/L,
Also consider treatment if a thyroid radionu- observation alone is appropriate and TSH,
clide scan shows one or more focal areas of high free T4, and T3 should be measured every 6
uptake. Subclinical hyperthyroidism due to months.
autonomous nodule(s) is more likely to advance
to frank hyperthyroidism than subclinical hyper- Above guidelines are in agreement with those
thyroidism due to Graves’ disease. Only observa- of a clinical panel (comprised of representatives
10 Subclinical Hyperthyroidism 197
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Subclinical Hypothyroidism
11
Asim Hassan
Abstract
Subclinical hypothyroidism, is defined as normal serum levels of FT4 and
T3, but mildly elevated serum TSH levels, usually less than 10 mU/L. This
represents the mildest form of hypothyroidism and is a consequence of the
very sensitive feedback relationship between the thyroid and the pituitary
gland. In this situation, a small decrement in thyroid hormone output by
the thyroid gland, in which serum T4 levels are still within the normal
range, results in a serum TSH level that is elevated, albeit usually less than
10 mU/L.
Whether subclinical hypothyroidism is a significant health problem
that warrants therapy is a matter of debate. Some patients may have mild
symptoms of hypothyroidism as well as increased lipid levels and other
risk factors for atherosclerotic cardiovascular disease. There may be pro-
gression to overt hypothyroidism over time, especially if serum levels of
antithyroid antibodies are high. On the other hand, most patients are
asymptomatic, especially when TSH serum levels are less than 10 mU/L,
and the link between atherosclerosis is still controversial.
Subclinical hypothyroidism is usually due to underlying Hashimoto
thyroiditis. The major complication of Hashimoto thyroiditis is progres-
sive hypothyroidism. Most patients with Hashimoto thyroiditis initially
have a small goiter and subclinical hypothyroidism. This is in contrast to
overt hypothyroidism, in which FT4 levels are subnormal. The clinical
picture of fully developed myxedema is usually quite clear, but the symp-
toms and signs of mild or subclinical hypothyroidism may be very subtle
or absent. This has led to the recommendation by some professional orga-
nizations that screening for hypothyroidism be undertaken, especially in
high-risk groups, such as older women where the prevalence is high (up to
20 % in women >age 65), and in pregnant women, where untreated hypo-
thyroidism may cause adverse outcomes in the child.
The treatment of subclinical hypothyroidism is a matter of debate but is
often instituted because of (1) mild symptoms; (2) dyslipidemia which
could be ameliorated by T4 therapy; and (3) positive antithyroid antibody
titers, which predicts a higher chance of progression to overt hypothyroid-
ism over time. Sufficient T4 is given to normalize TSH and allow regres-
sion of the goiter.
occurrence of SCH and related metabolic risk SCH is frequent in the adult population [20].
issues such as hyperlipidemia, the American However, there is no clear proof that early diagno-
Thyroid Association advocates screening by sis and therapy with thyroxine (T4) improves out-
checking serum TSH starting at the age of 35 comes in patients with hypothyroidism diagnosed
years and every 5 years afterwards [15]. The by screening. Although thyroxine replacement
proof in favor of screening is specially convinc- treatment has few side effects when properly
ing in females, but it can also be justified for given, over-replacement with thyroxine is com-
males as a moderately cost-effective measure in mon and may be linked with adverse skeletal and
the context of the regular health evaluation. cardiovascular outcomes, particularly in older
Patients with symptoms and signs potentially persons.
related to thyroid dysfunction and those with risk There are two methods for screening asymp-
factors for its occurrence may need more fre- tomatic persons: testing all persons over a specific
quent serum TSH testing [15]. The American age (when risk of hypothyroidism rises) or evalu-
College of Physicians recognizes that treatment ating only those persons with clinical risk factors
for subclinical thyroid dysfunction is contentious for hypothyroidism. In the absence of evidence
but recommends that screening to detect thyroid favoring any screening strategy, it is advised test-
dysfunction may be indicated in females more ing patients at increased risk for hypothyroidism,
than 50 years old [16]. Because of potential con- including persons with goiter, history of autoim-
sequences of SCH for unfavorable outcome of mune disorder, past history of radioactive iodine
pregnancy and neurological and psychiatric therapy, head and neck irradiation, family history
development of the fetus, intensive case finding of thyroid disorder, and use of drugs that may
in pregnant women or in females planning preg- adversely affect thyroid function.
nancy has been advised [11, 17, 18]. However, It is recommended to measure serum thyroid-
depending only on intensive case finding results stimulating hormone (TSH) as a screening test
in missing a third of women with frank hypothy- for hypothyroidism.
roidism or SCH [19].
Before recommending routine screening of
the general population, large-scale randomized It is advised testing patients at increased
trials are needed to prove that treatment will risk for hypothyroidism, including persons
improve quality of life in otherwise healthy with goiter, history of autoimmune
patients who have mildly elevated TSH level disorder, past history of radioactive iodine
(5–10 mIU/L) typical of most SCH cases. For the therapy, head and neck irradiation, family
time being, physicians should keep a low thresh- history of thyroid disorder, and use of drugs
old for requesting a serum TSH level in females that may adversely affect thyroid function.
who have vague suggestive symptoms, who are
pregnant or anticipating pregnancy, or who have
a strong family history of autoimmune thyroid
disorder. Many endocrinologist advise routine
screening before and during pregnancy [19]. Diagnosis
more rational. For patients more than 70 years, falsely high TSH concentration (often
levels up to 6.0 or even 7.0 mIU/L with negative >100 mU/L) in euthyroid (normal free T4 and
antithyroid antibodies should not be diagnosed to triiodothyronine [T3] levels) persons [22, 28,
be hypothyroid [7]. Whatever the preferred upper 29]. Autoantibodies to TSH can be identified
limit of normal, a credible case can be made for by elimination of the IgG-TSH complexes and
closer follow-up of patients with a TSH concen- then retesting [30].
tration of 3–5 mIU/L, especially if anti thyroid • Non diagnosed and untreated adrenal
antibodies are positive. deficiency.
Different pregnancy specific normal TSH val- • Pituitary TSH-producing adenomas, thyroid
ues are suggested. The normal limits of serum hormone resistance, and rare TSH receptor
TSH levels in the first trimester of pregnancy is mutations. In patients with pituitary TSH-
0.03–2.3 mIU/L; the upper limit of normal is producing adenomas or thyroid hormone
3.5 mIU/L in the second and third trimesters. resistance, the high TSH is associated with
Pregnancy related thyroid dysfunction will be raised serum free T4 and/or T3 levels. On the
covered in separate chapters. contrary, subjects with subclinical hypothy-
roidism have normal free T4 levels. Patients
with TSH resistance due to abnormality in the
Differential Diagnosis TSH receptor have high serum TSH values
and normal or low serum free T4 and T3
There are many reasons of an elevated serum levels.
TSH values that do not exactly fit the description • Central hypothyroidism, where up to 25 % of
of subclinical hypothyroidism. These consist of subjects have a mildly raised serum TSH
the following situations: (approximately 10 mU/L) and a low or low-
normal free T4.
• During the period of recovery from nonthyroi-
dal illness, where a momentarily raised serum
TSH level is detected after a stage of TSH Evaluation
repression.
• After the hyperthyroid period of subacute, A number of persons with subclinical hypothy-
painless, or postpartum thyroiditis, when mild roidism have few non-specific symptoms of
hypothyroidism is frequently encountered. hypothyroidism, such as fatigue and constipa-
• Inconsistency of test assays. tion. Therefore, individuals with subclinical
• The occurrence of heterophilic antibodies can hypothyroidism should be inquired about symp-
hinder with TSH measurements in immuno- toms of hypothyroidism, in addition to previous
metric assays. These human anti-mouse treatment for hyperthyroidism, past history of
gamma globulins can cause falsely elevated frank hypothyroidism, and use of drugs that may
results [27]. Conversely, heterophilic antibod- disturb thyroid hormone absorption or function
ies obstruct binding of one of the mouse (Table 11.2). Moreover, they should also be
monoclonal antibodies to TSH and result in examined for the presence of thyroid gland
falsely low analysis for TSH. enlargement [31].
• Rheumatoid factors may result in same hin- Antithyroid peroxidase (anti-TPO) antibodies
drance in immunometric tests [27]. are not routinely measured in patients with sub-
• Autoantibodies to TSH have also been clinical hypothyroidism. However, the detection
detected which generate TSH-anti-TSH of antibodies may be helpful in deciding to treat
immunoglobulin G (IgG) complexes, also or monitor, and thus may be practical in individ-
called macro-TSH, which lacks biologic uals when the decision to treat or to monitor is
action but may be immunoreactive, and cause not clear.
11 Subclinical Hypothyroidism 209
Table 11.2 Drugs causing hypothyroidism ter symptom scores or enhanced memory in
Inhibition of thyroid hormone synthesis and/or one fourth of patients. Several studies have not
release – thionamides, lithium, perchlorate, shown significant improvement in anxiety,
aminoglutethimide, thalidomide, and iodine and mood, and cognition in older patients [34–36].
iodine-containing drugs including amiodarone,
radiographic agents, expectorants (Organidin, In another review available data was consid-
Combid), kelp tablets, potassium iodine solutions ered inadequate to support a benefit for levo-
(SSKI), Betadine douches, topical antiseptics thyroxine treatment in patients with SCH,
Decreased absorption of T4 – cholestyramine, specially for the cohort with TSH less than
colestipol, colesevelam, aluminum hydroxide, calcium
10 mIU/ L, and a similar conclusion was again
carbonate, sucralfate, iron sulfate, raloxifene,
omeprazole, lansoprazole, and possibly other reached later [11].
medications that impair acid secretion, sevelemer,
lanthanum carbonate, and chromium; malabsorption
syndromes can also diminish T4 absorption
Progression to Overt Hypothyroidism
Immune dysregulation – interferon-alfa, interleukin-2,
ipilimumab, alemtuzumab, pembrolizumab
Suppression of TSH – dopamine
Persons with SCH have a high incidence of
Possible destructive thyroiditis – sunitinib
development of clinically frank hypothyroid-
Increased type 3 deiodination – sorafenib
ism, 2.6 % every year if thyroperoxidase (TPO)
Increased T4 clearance and suppression of antibodies are negative and 4.3 % if they are
TSH – bexarotene positive [37]. Nevertheless, some patients do
T4 thyroxine, TSH thyroid-stimulating hormone, TBG not progress any further and a number of indi-
thyroxine-binding globulin, T3 triiodothyronine viduals normalize. A TSH level more than
10 mIU/L predicts an elevated risk of progres-
sion, and a concentration of less than 6 mIU/L
Consequences of Subclinical predicts a lower probability of any further pro-
Hypothyroidism gression. In a study in both males and females
older than 55 years with a mean follow-up of 32
Though studies have indicated to some undesir- months, the TSH level normalized in 52 % of
able effects of SCH, no agreement exists as to the subjects with a serum TSH of lower than
clinical significance of the unfavorable effects 10 mIU/L [38].
and the benefits of levothyroxine treatment, A significant percentage of patients with sub-
mainly for the 80 % of individuals with SCH who clinical hypothyroidism ultimately develop frank
have a TSH of less than 10 mIU/L, because of the hypothyroidism. In prospective studies with
different concentrations of TSH and severity of nearly 10–20 years of follow-up, the collective
thyroid dysfunction in these studies [13, 32]. incidence of overt hypothyroidism ranges from
Following is a discussion of some of the antici- 33 to 55 % [23, 37, 39]. The rate of further pro-
pated adverse effects of SCH. gression is associated with the preliminary
serum thyroid-stimulating hormone (TSH) level
(higher with TSH values >12 to >15 mU/L) and
Systemic Symptoms the detection of antithyroid peroxidase (anti-
of Hypothyroidism TPO) antibodies, [38–40]. In a study of more
than 1700 individuals followed for 20 years, for
Many randomized trials related to the effects instance, females with both elevated serum TSH
of levothyroxine therapy in persons with SCH and high thyroid antibody levels developed
are available. One study related to persons hypothyroidism at a rate of 4.3 % per year
with serum TSH levels from 5 to 10 mIU/L did (cumulative incidence 55 %) [37]. In a different
not show any advantage [33]. Some data study in which 82 females were followed for
(range of TSH level, 3–32 mIU/L) showed bet- 9.2 years, the overall incidence of frank
210 A. Hassan
hypothyroidism was zero percent for individuals [50]. Overall, the results of these 6 meta-analyses
with initial TSH levels of 4–6 mU/L [39]. indicate that a cardiovascular risk exists for indi-
The primary disorder also may be a determin- viduals less than 70 years with no effect on those
ing factor for the risk of development of overt aged 70–80 years and a perhaps a protective
hypothyroidism [23]. Subjects who have autoim- effect for those more than 80 years [5]. Therefore,
mune thyroid disease or received radioiodine the cardiovascular risk effect remains contentious
therapy or high-dose external radiation are liable and further robust trials are required to assess the
to progress to overt hypothyroidism. On the con- value of levothyroxine therapy in risk reduction.
trary, subclinical hypothyroidism is likely to con- In persons with subclinical hypothyroidism,
tinue in those who have had thyroid surgery for the results are inconsistent, possibly related to
reasons other than hyperthyroidism, or in those differences in the patient populations and study
who were given external radiation during designs. A number of but not every observational
childhood. study report a higher risk of coronary heart dis-
Natural recovery has also been seen in sub- ease (CHD) in patients with subclinical hypothy-
jects with subclinical hypothyroidism, although roidism [43, 45, 51–56]. A meta-analysis of
the incidence of this occurrence is not clear [38, seven prospective cohort studies (25,977 partici-
39, 41, 42]. In a data of 422,242 subjects without pants, 2020 with subclinical hypothyroidism)
known thyroid disease, serum TSH was elevated showed a noteworthy tendency of increased rate
(5.5 to ≤10 mU/L) in 3 % [42]. In a 5-year fol- of CHD events (nonfatal myocardial infarction,
low-up period, TSH levels normalized without CHD death, hospitalization for angina or coro-
treatment in 62 % of patients. Reversal of serum nary revascularization) with elevated serum TSH
TSH levels is more likely to occur in persons levels [57]. In comparison with euthyroid indi-
with negative antithyroid antibodies, serum TSH viduals, subjects with TSH ≥10 mU/L had a sig-
concentration <10 mU/I, and within the first 2 nificant rise in CHD events (38.4 versus 20.3
years of the diagnosis [41]. events/1000 person years, hazard ratio [HR] 1.89,
95 % CI 1.28–2.80). On the contrary, minimum
TSH rise (4.5–6.9 mU/L) were not related with
Cardiovascular Disease an increased risk (HR 1.00, 95 % CI 0.96–1.43).
The risk rates did not differ according to age,
The Rotterdam Study found an association of gender, or preexisting CVD.
SCH with myocardial infarction and aortic calci- In a combined analysis data from six prospec-
fication [43]. In contrast, the Wickham study [44] tive cohort studies (25,390 participants, 2068
showed no higher cardiac mortality in a 20-year with subclinical hypothyroidism), there was also
follow-up. Another observational study also did an important trend for higher risk of heart failure
not show any link between undetected SCH and at higher TSH levels [58]. In comparison with
cardiovascular incidents or mortality [45]. euthyroid subjects, individuals with a TSH
However, a number of meta-analyses of observa- between 10 and 19.9 mU/L had a significant rise
tional studies showed a relationship between in heart failure (40 events in 224 participants
SCH and coronary artery disease [46–48]. The [17.9 %] versus 1762 events in 22,674 controls
risk was lower when higher quality data were [7.8 %], HR 1.86, 95 % CI 1.27–2.72) [59]. The
shared [47]. An analysis of 7 cohort studies con- elevated risk of heart failure in patients with a
cluded that the relative risk of all-cause mortality serum TSH between 7.0 and 9.9 mU/L was not
was higher compared with euthyroid controls, statistically important [53], events in 422 partici-
mainly in subjects with other comorbidities [49]. pants [12.8 %], (HR 1.65, 95 % CI 0.84–3.23),
Another meta-analysis showed an increased and minimal TSH elevations (4.5–6.9 mU/L)
occurrence and incidence of cardiovascular mor- were not connected with an increased risk (HR
tality only in comparatively younger patients 1.01, 95 % CI 0.81–1.26).
11 Subclinical Hypothyroidism 211
A number of, but not all, studies show a link again, most studies were not classified for degrees
between raised TSH and total and low-density of TSH elevation, and data remain inadequate for
lipoprotein (LDL) cholesterol levels [5]. In one a TSH concentration less than 10 mIU/L but
of the biggest cross-sectional data so far (25,862 strongly indicative for a TSH level higher than
participants, median age 56 years), patients with 10 mIU/L.
modest rise in serum TSH (between 5.1 and
10 mU/L) had considerably raised mean total
cholesterol concentrations than those who had Cardiovascular Mortality
normal TSH (223 versus 216 mg/dL [5.6 versus
5.8 mmol/L]) [37]. Though, cholesterol levels In a number of [52, 53] but not all [35, 45, 68, 69]
were not adjusted for age. Moreover, it is not studies, subjects with subclinical hypothyroidism
clear whether this difference is clinically signifi- have a higher risk of cardiovascular and/or all-
cant concerning CHD risk. cause mortality. In a data from 11 prospective
Additionally, subclinical hypothyroidism has cohort studies, the risk of cardiovascular mortal-
been linked with an increase in a number of other ity, but not all-cause mortality, increased with
cardiovascular risk factors and surrogate cardio- higher concentrations of TSH and was apprecia-
vascular endpoints, including markers of inflam- bly higher in individuals with TSH concentra-
mation, vascular reactivity, endothelial function, tions ≥10 mU/L (HR 1.58, 95 % CI 1.10–2.27)
and carotid intima media thickness [59–64]. Some [57]. On the contrary, minimum rise of TSH (4.5
individuals with subclinical hypothyroidism also to 6.9 mU/L) were not related with cardiovascu-
have diastolic dysfunction and raised peripheral lar or all-cause mortality.
vascular resistance, as shown in patients with In one prospective data, older participants
frank hypothyroidism [65]. On the contrary, (>85 years) in the Netherlands with untreated
another study showed no change in left ventricu- subclinical hypothyroidism (the majority with
lar mass or function in persons with serum TSH TSH between 4.8 and 10 mU/L) in fact had a
concentrations between 3.5 and 10 mU/L in com- lower rate of cardiovascular and all-cause mortal-
parison to those with normal TSH [66]. ity [35]. Similar results were found in a retro-
spective cohort study from Denmark; subclinical
hypothyroidism with a TSH of 5–10 mIU/L was
associated with a reduced all-cause mortality
Subclinical hypothyroidism may possibly
[70]. Though, in a prospective cohort study from
be linked with an elevated risk of cardio-
the US, older persons with untreated subclinical
vascular disease (CVD) (eg, heart failure,
hypothyroidism had neither higher nor lower
coronary heart disease [CHD]), mostly
mortality over a median follow-up period of 5
when the serum TSH level is above
years [71].
10 mU/L.
Subsequently data using the NHANES III,
subclinical hypothyroidism (median TSH
6.3 mU/L) compared with euthyroidism was
Studies have also shown slowed left ventricu- linked with higher mortality in those with
lar relaxation time, increased vascular tone at heart failure but not in those without heart
rest, and left ventricular systolic dysfunction with failure [ 72 ].
exercise and abnormal endothelial function [67].
A number of studies have shown improvement of
cardiac contractibility and systolic time interval Non-alcoholic Fatty Liver Disease
with levothyroxine treatment [67]. No proof
exists to support the link between heart failure In an observational study, non-alcoholic fatty
and a serum TSH level of less than 10.0 mIU/L. Yet liver disease (NAFLD) was associated with
212 A. Hassan
raised serum TSH levels. One third of the sub- euthyroidism (TSH 2.2 mU/L) was related
jects with subclinical hypothyroidism revealed with a slightly higher baseline weight (0.51 kg
classic ultrasonographic features of NAFLD higher baseline weight per 1 mU/L higher
(versus 20 % of controls) while 20 and 26 % of TSH level) but with no change over time [86].
subjects with subclinical or overt hypothyroidism There was no link between TSH and weight in
had abnormal liver enzymes [73]. older males.
• In one study, 21 of 33 patients (64 %) with
subclinical hypothyroidism had a raised inci-
Neuropsychiatric Symptoms dence of neuromuscular complaints (weak-
ness, fatigue, paresthesias, cramps), in
Data linked to provocation of depression, bipolar comparison with 6 of 44 normal persons
disorder, and effect on cognitive function have (14 %) [87]. Conversely, in another study of
been demonstrated [74]. A study has indicated no more than 2000 older persons, functional
relationship with anxiety, depression, or cogni- mobility (walking endurance and gait speed)
tive dysfunction [34]. However, it is still rational was better in those with mild elevations in
to have a low threshold for treatment for SCH in TSH (4.5 to <7.0 mU/L) than in those with
patients with depression, bipolar disorder, and TSH concentration within the normal limits
cognitive dysfunction. (0.4 to <4.5 mU/L) [88].
Many studies indicate that subclinical hypo- • Subclinical hypothyroidism may also be
thyroidism is linked with neuropsychiatric dis- linked with shortcomings in vocal memory
eases [75–78]. Nevertheless, additional data and managerial functioning [89, 90]. These
(together with a large study of primary care defects correct with T4 therapy and are
subjects in England that failed to show an asso- thought to reflect abnormal hippocampal
ciation of subclinical hypothyroidism with function rather than general cognitive
depression, anxiety, or cognitive dysfunction) impairment.
does not support these findings [22, 34–36, 79]. • In a cross sectional study, subclinical hypo-
thyroidism was related with an higher risk of
Alzheimer disease (AD) in females but not in
Neuromuscular Dysfunction males [91].
• In one study, subjects with spontaneous deep
It has been proposed that neuromuscular symp- venous thrombosis were more liable to have
toms and dysfunction are frequent in persons subclinical hypothyroidism [92].
with SCH and can be reversed by levothyroxine • In a study, individuals with subclinical hypo-
therapy [80]. A conclusive decision will need thyroidism were more prone to have common
more trials with TSH concentrations stratified to bile duct stones, probably secondary to
less than or more than 10 mIU/L. sphincter of Oddi dysfunction [93].
• In a number of [81–83] but not all [84, 85] Subclinical hypothyroidism is more common
studies in middle-aged persons, increasing than frank hypothyroidism, occurring in 2.0–
serum TSH levels within the normal levels or 2.5 % of screened females in the US [94, 95].
slightly above normal were linked with a mod- Undiagnosed subclinical hypothyroidism in
est increase in body weight. In older females pregnancy is a risk factor for miscarriage and low
(>65 years), subclinical hypothyroidism birth weight infants, and possibly poor develop-
(mean TSH 6.7 mU/L) as compared with mental outcome in the offspring.
11 Subclinical Hypothyroidism 213
The consequences of T4 treatment on lipids is not Reducing the upper level of normal for the serum
clear. A number of studies show benefit, but the TSH concentration from 5.0 to 3.0 mIU/L is still
results are conflicting and the extent of the effect contentious. Concentration between 3 and
is of vague clinical significance [100]. In 12 clini- 5 mIU/L are unlikely to point toward a clinically
cal trials meta-analysis (nine trials with TSH significant impairment, and levothyroxine treat-
concentrations <10 or 15 mU/L), seven of the ment at these concentration may or may not pro-
studies analyzed lipid concentration after therapy vide any improvement. Though individuals with
of subclinical hypothyroidism [14]. There were a serum TSH level of 3–5 mIU/L may be at
no major effects of T4 treatment on total choles- higher risk of development of hypothyroidism,
terol, high-density lipoprotein (HDL), low- [37] no clear proof of health effect exists.
density lipoprotein (LDL), triglycerides, Actually, in a randomized, crossover, 12-week
apolipoprotein A and B, or lipoprotein (a). trial of persons with symptoms indicating hypo-
Though, in many studies of patients with subclin- thyroidism with serum TSH in the upper normal
ical hypothyroidism treated with thyroxine ver- limit, no difference in psychological and cogni-
sus placebo, serum total and LDL cholesterol tive function was shown between levothyroxine-
[59, 98, 101, 111–113] and apoprotein B-100 replacement and control groups [25]. Given these
concentrations [98, 101, 112] reduced apprecia- results, treatment cannot be proposed for this
bly, while serum HDL cholesterol, triglyceride, group, but follow-up by serum TSH testing in 1
and lipoprotein (a) levels did not change [98, year would be a sensible approach, mainly if anti-
113]. All except one of these studies included thyroid antibodies are positive.
subjects with serum TSH levels >10 mU/L.
There may be other benefits of thyroid hormone Major randomized trials to convincingly demon-
therapy, as demonstrated by the following data: strate lowering of cholesterol with levothyroxine
replacement in this subgroup are deficient. Most
• In a study of 113 patients with chronic kidney studies are not classified for various levels of
disease and subclinical hypothyroidism, serum TSH concentrations, and even though
development of renal failure was slowed by improvement of symptoms and lipid concentra-
treatment with levothyroxine [114]. tion have been demonstrated for mild thyroid
• Patients with concomitant iron-deficiency dysfunction as a group, results cannot be extrapo-
anemia and subclinical hypothyroidism had a lated to most subjects with SCH who are in this
higher rise in hemoglobin when given both subgroup [98]. Another trial of TSH concentra-
iron and thyroid hormone treatment as com- tion of 5.0–10.0 mIU/L did not demonstrate any
pared with those given only iron [115]. improvement [33].
11 Subclinical Hypothyroidism 215
Moreover, cognitive, neuropsychiatric, car- and that it is related with impairment of muscle
diac, and muscle impairment found in studies function, nerve conduction, cardiac function
including a wide range of TSH concentration in [118], and cognitive and psychological func-
SCH should be established by better randomized tion, with benefit after levothyroxine treatment
trials. The likelihood that a raised serum TSH [96–99, 118].
concentration is a cardiovascular risk factor is
still very contentious. Therefore choice for levo-
thyroxine treatment for this cluster should be Candidates for T4 Replacement
individualized and should be based on the age of
the patient (in favor of treatment for younger sub- Although almost all experts advocate therapy of
jects), comorbid medical conditions, degree of persons with serum thyroid-stimulating hormone
TSH concentration, constant and slow rise of (TSH) levels >10 mU/L, the regular treatment of
TSH, detection of antithyroid antibodies, exis- asymptomatic persons with TSH results between
tence of goiter, and hypothyroid symptoms. 4.5 and 10 mU/L remains uncertain [1, 12, 22,
Given both the findings of reduced intelligence 31, 32]
quotient in the children in females who had SCH
during pregnancy and the undesirable effects of
mild thyroid dysfunction on pregnancy result, For persons with subclinical hypothyroid-
levothyroxine replacement should be suggested ism and TSH values ≥10 mU/L, treatment
for pregnant women and women anticipating with thyroid hormone (T4) is proposed
pregnancy. Due of the benefits of thyroxine on
growth and development, levothyroxine replace-
ment for children and adolescents is also practi- In view of evidence linking subclinical hypo-
cal. Treatment may be proposed for persons with thyroidism with atherosclerosis and myocardial
a constant serum TSH concentration of more infarction, and the elevated risk of development
than 8 mIU/L because these levels are linked with of overt hypothyroidism, it is proposed that treat-
a 70 % development to a TSH level of 10 mIU/L ment of individuals with subclinical hypothy-
in 4 years. roidism and TSH concentrations more than
10 mU/L. This recommendation is in agreement
with that of a clinical consensus panel (com-
Serum TSH Concentration Greater prised of representatives from the Endocrine
Than 10 mlu/l Society, American Thyroid Association (ATA),
and the American Association of Clinical
Majority of endocrinologist are in agreement Endocrinologists) [31].
that all persons with SCH and a TSH concentra- There is some evidence to show benefit or risk
tion over 10 mIU/L must be given levothyroxine of thyroxine (T4) therapy in persons with TSH
[13, 32]. Support is more convincing for the concentration between 4.5 and 10 mU/L. The rec-
unfavorable effects of mild thyroid dysfunction ommending panel did not advocate routine replace-
in this group. Trials have demonstrated that ment for such individuals, but proposed monitoring
levothyroxine replacement results in an 8 mg TSH concentrations and replacement based upon
lowering of low-density lipoprotein levels [98, individual features (e.g., symptoms of hypothy-
116]. Amongst the causes that predict response roidism, positive thyroid peroxidase [TPO] anti-
of lipid concentration to levothyroxine replace- bodies). Though, others have proposed replacement
ment are higher results of TSH, insulin resis- for individuals with TSH results in this range
tance, higher concentration of pretreatment because undetectable symptoms may get better,
cholesterol, and type III hyperlipidemia. Some improvement of abnormal serum lipid levels are
data suggests that mild thyroid dysfunction can potentially cardioprotective, and there is little risk
worsen bipolar disorder and depression [117] linked with controlled T4 therapy [1, 12, 32, 119].
216 A. Hassan
IVF), the risk rate of miscarriage was two times roxine treatment (T4, 50 mcg daily) in TPO
higher in euthyroid women with than without positive euthyroid patients who have had repeated
positive TPO antibodies (relative risk [RR] 1.99, miscarriage, until additional evidence emerges.
95 % CI 1.42–2.78) [128]. However, in an inter- On the other hand, many experts do not regularly
vention study of thyroxine versus placebo in 72 treat euthyroid TPO positive patients with T4
euthyroid subfertile patients with positive TPO because of inadequate proof of benefit.
antibodies having assisted reproductive treatment In antibody positive euthyroid pregnant
(ART), thyroid hormone treatment did not lower female who are not given thyroid hormone, TSH
the risk of early fetal loss [129]. Though, these should be tested every month during the first half
outcomes are confounded by accompanying of pregnancy and at least once during the last tri-
additional infertility risks in women getting ART. mester to detect for the progression of hypothy-
It is uncertain if the detection of TPO antibod- roidism. Thyroid hormone should be started if
ies in euthyroid pregnant patients affects the TSH is raised above the trimester-specific refer-
behavioral or cognitive development of their off- ence level (2.5 mU/L for first, and 3.0 mU/L for
spring. In a community -based cohort data from second and third trimesters).
the Netherlands, 4770 pregnant patients had
blood extracted at 13.5 weeks of pregnancy and
cord blood was taken directly after birth in 2121 Arguments for Treatment
of the neonates [130]. All samples were tested
immediately after delivery for TSH, free T4, and Therapy will avert development of overt hypo-
thyroid peroxidase antibodies. TPO antibodies thyroidism, particularly in those with serum TSH
were raised in 4.7 %. TSH levels were more ele- concentrations higher than 10 to 15 mU/L and
vated in TPO positive than negative women (3.8 elevated serum anti-TPO antibody levels.
versus 1.5 mU/L), but TSH concentration in the Replacement in persons with minor elevations in
cord blood did not vary between positive and serum TSH levels may probably improve uncer-
negative women. Raised levels of TPO antibod- tain symptoms of hypothyroidism, such as con-
ies during gestation did not predict the vocal and stipation, depression, or fatigue, and may reduce
non vocal cognitive function of the offspring the size of goiter. Treatment may also benefit car-
when tested at 2.5 years. Nevertheless, offspring diac contractility and serum lipid levels in some
of euthyroid mothers with positive TPO antibod- individuals and additionally lower the risk of
ies were at elevated risk of attention deficit/ atherosclerosis.
hyperactivity disorder (odds ratio [OR] 1.77,
95 % CI 1.15–2.72). When the results were
adjusted for maternal TSH level, the association Arguments Against Treatment
was reduced but remained significant (OR 1.56).
The choice to treat euthyroid patients with Point of view against T4 therapy include its
raised TPO antibodies with levothyroxine (T4) or expenditure (for both the treatment and monitor-
to watch for the progression of hypothyroidism ing), the lifetime obligation to daily treatment in
during pregnancy is unclear. The majority of asymptomatic individuals, the potential risk of
pregnant patients are not likely to know their excessive treatment and producing symptoms
antithyroid antibody results because routine from extra thyroid hormone, and the likely devel-
screening is not generally done. The ATA decided opment or worsening of angina pectoris or car-
there was inadequate data to propose for or diac rhythm disturbances in vulnerable
against thyroxine treatment in Euthyroid anti- individuals [13] particularly considering data
body positive pregnant patients; though, monitor- from a population based survey demonstrating
ing for the progression for hypothyroidism was that 41 % of subjects over age 65 years on thy-
proposed [131]. roxine replacement had below normal serum
Since closely observed thyroid hormone ther- TSH [120]. Even though these apprehensions are
apy is safe, a number of experts, propose levothy- not usually enough to offset the possible benefits
218 A. Hassan
of treatment in younger subjects, a higher TSH trol the serum TSH level, usually 25–50 mcg
threshold is proposed for treating older persons, daily. This strategy will prevent excess treatment
especially since the upper limit of normal for and is most suitable in older subjects or in patients
serum TSH may be higher in this age group. If with accompanying CVD.
the patient is not treated, regular follow-up is For younger persons with Hashimoto’s thy-
indicated. roiditis who do not have autonomy (e.g., a prior
history of toxic adenoma or Graves’ disease
treated with radioiodine) and who have usual
Goals of Treatment negative feedback response, another strategy is to
start replacement at somewhat lower than full
The target of treatment is to lower the patient’s therapeutic doses (1.6 mcg/kg/day). This strategy
serum TSH levels within the normal reference prevents the need for repeated dose adjustment,
values. As the average serum TSH for the general in case there is further autoimmune damage of
population is approximately 1.4 mU/L, with the thyroid gland. On the other hand, younger
90 % with serum TSH values <3.0 mU/L, several persons can be initiated on low dose replacement,
physicians propose a clinical TSH target of 0.5– as is proposed for older subjects. Dose titration
2.5 mU/L in young and middle-aged persons. A and further follow up adjustment are similar to
TSH goal of 3–5 mU/L may be suitable in indi- the management of overt hypothyroidism.
viduals over 70 years of age.
Every person with SCH and a serum TSH level Conclusion
over 10 mIU/L and for subjects with serum TSH Subclinical hypothyroidism arises in the clini-
levels of 5.1–10.0 mIU/L in whom individualized cal scenario of a serum TSH concentration
choice for treatment is made, replacement should over the upper level of normal in spite of a
be initiated with levothyroxine. Combination of normal serum free thyroxine level. Starting
T4 plus T3 therapy is not recommended. The typi- levothyroxine treatment is advocated for all
cal required daily levothyroxine dose is 50–75 μg persons with a TSH higher than 10 mIU/L,
[132]. In anticipation of future development of even if the free thyroxine level is within nor-
thyroid dysfunction, some physicians recommend mal limits. Though, therapy of individuals
a full replacement dose. A daily dose of 25–75 μg, with a serum TSH concentration between 5
is suggested based on the age of the subject, the and 10 mIU/L remains uncertain. The stron-
results of free thyroxine, and the serum TSH con- gest reasonings for levothyroxine replacement
centration. Serum TSH should be tested after 8 are the high rate of development of frank
weeks, and the dose should be titrated. When a hypothyroidism, the potential improvement of
normal serum TSH concentration has been quality of life, and the prospect that SCH is a
reached, TSH should be analyzed again after 6 cardiovascular risk factor. Data shows that any
months and then every year. potential elevated cardiovascular risk would
be to patients less than 70 years; those between
70 and 80 years have no added risk, and those
Dose Modification Strategy more than 80 years may in fact have potential
protective benefit. High quality trials are
The advantages of modification of levothyroxine required to evaluate the effectiveness of levo-
replacement to achieve lower concentration of thyroxine replacement in the subset with TSH
TSH should be assessed with the prospect of concentration of less than 10 mIU/L. In the
undesirable effects of aggressive levothyroxine meantime, treatment of this subgroup should
treatment resulting in suppressed TSH. There are be individualized based on presence of symp-
two ways of starting T4 treatment. One approach toms, age, patient preference, and associated
is to initiate with the lowest dose required to con- medical conditions.
11 Subclinical Hypothyroidism 219
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Thyroid Emergencies
12
Syed Abbas Raza
Abstract
Thyroid gland plays a pivotal role in keeping biochemical harmony and
maintaining appropriate functioning of vital organs. Therefore any abnor-
mality in thyroid hormone regulation, can lead to wide ranging detrimen-
tal effects. This chapter is assigned for identifying and managing thyroid
conditions, which require emergent or urgent interventions. It’s not only
the biochemical status of the patient which determines this, but also the
clinical presentation can make it urgent vs emergent. This is discussed in
condition such as Thyroid storm and myxedema coma. Also, thyroid hor-
mone abnormalities during pregnancy, ICU setting, involving vital organ
(CNS, cardiovascular) or related to medicine use (lithium/amiodarone)
may pose certain acute management challenges and hence discussed in
this chapter.
Pathophysiology Signs/Symptoms
Pathophysiology behind this acute release/ Incidence of thyroid disorders varies in regional
responsiveness of thyroid hormone along with observational studies. Thyroid storm usually hap-
catecholamine surge/responsiveness is not clearly pens at the back ground of thyroid conditions
understood [1]. Levels of suppression of TSH, such as Graves’ disease, toxic multinodular goi-
Elevation of thyroxine level and thyroid scan ter, solitary toxic adenoma.
Thyroid storm is a clinical diagnosis sup-
ported by biochemical evidence.
• Cardiovascular Symptoms: Tachycardia Burch and Wartofsky scoring system for thyroid
storm
(Usually >1.5 times the resting heart rate). This
may further deteriorate into hypotension, car- Diagnostic parameters Scoring points
diac arrhythmia and cardiovascular collapse [2]. Thermoregulatory dysfunction
• Neurological Symptoms: confusion, anxiety, Temperature °F (°C)
stupor progressing to coma. 99–99.9 (37.2–37.7) 5
• Central/constitutional: Hyperpyrexia (104– 100–100.9 (37.8–38.2) 10
106 °F), moist skin and tremors. 101–101.9 (38.3–38.8) 15
• Others: GI symptoms (Vomiting, diarrhea, 102–102.9 (38.9–39.2) 20
hepatic dysfunction and abdominal pain), 103–103.9 (39.3–39.9) 25
≥104.0 (≥40.0) 30
Hyperglycemia, Hemeconcentration,
Central nervous system effects
Hypercalcemia [3].
Absent 0
Mild (agitation) 10
Establishing Diagnosis
Moderate (delirium, psychosis, 20
Although not universally accepted but most used extreme lethargy)
scoring system in evaluation of Thyroid storm was Severe (seizures, coma) 30
postulated by Burch and Wartofsky [3, 4]. This Gastrointestinal-hepatic dysfunction
scoring system helps in confirming (score of >45) Absent 0
vs unlikely (Score of <25). (See table below) Moderate (diarrhea, nausea/vomiting, 10
abdominal pain)
Scoring System Severe (unexplained jaundice) 20
A score of 45 or greater is highly suggestive of Cardiovascular dysfunction
thyroid storm; a score of 25–44 is suggestive of Tachycardia (beats/minute)
impending storm, and a score below 25 is unlikely 90–109 5
to represent thyroid storm. 110–119 10
120–129 15
Treatment 130–139 20
Management of Thyroid storm is in same lines of ≥140 25
thyrotoxicosis but dosages of medication are Congestive heart failure
higher due to higher mortality and urgency of Absent 0
treatment [5]. Mild (pedal edema) 5
Moderate (bibasilar rales) 10
• Antithyroid Medication: No one drug Severe (pulmonary edema) 15
(Thionamide) is better in management in any Atrial fibrillation
of the clinical trials. Thionamide block thy- Absent 0
Present 10
roid hormone synthesis (Onset of action <2 h)
Precipitating event
but don’t effect on the release of preformed
Absent 0
hormone. Initially, there may be required in
Present 10
higher doses to control of thyroid hormone.
Dosage required is in range of 200 mg every 4
h for Propylthiouracil (PTU) and 20 mg every form of suppository for rectal administration and
6 h for Methimazole/Carbimazole. intravenous preparation (Methimazole) can be
• PTU has additional benefit of preventing conver- requested in specialized pharmacy.
sion of T4 to T3, hence sometimes preferred in • Beta blockers: May require higher doses due
acute setting/storm [6] but less hepato toxicity to increased metabolism. They are used to
and better therapeutic control of Methimazole/ control increased adrenergic response and
Carbimazole makes them preferred choice in potentially inhibit T4 to T3 conversion
other situation/chronic use. Preparation in the (Propranolol). Usually dosage of propranolol
12 Thyroid Emergencies 227
is in range of 60–80 mg every 6 h (Provided • Plasmapheresis has been tried when tradi-
patient tolerates). Intravenous administration tional therapy has not been successful [11].
is an option but only if hemodynamic status is
continuously being monitored (Propranolol Do and Don’ts/Things Not to Be Missed
0.5–1 mg over 10 min) [7]. Esmolol is another • Don’t under estimate the mortality associated
short acting beta blocker which can be used with Thyroid storm. Thyroid storm is one of
and the usual dosage is 250–500 mcg/kg, fol- few life threatening endocrine emergencies
lowed by an infusion at 50–100 mcg/kg per [1]. Mortality associated with hyroid storm is
minute. In reactive Airway disease patient ranges between 10 and 30 % [12].
option of cardio selective beta-blockers such • Don’t miss the precipitating factor. Thyroid
as Metoprolol or Atenolol could be storm can be in a setting of precipitating event
considered. such infection, iodine exposure, acute stress or
• Iodine: Iodine solutions are sometime used to myocardial infarction.
block release of thyroid hormone (Only after • Don’t use Iodine without blocking with
initiation of Thionamide). Dosage could be Thionamide.
administered as SSKI, five drops orally every • Don’t use beta blocker in setting of Severe
6 h, or Lugol’s solution, 10 drops every 8 h Airway disease or contraindication.
[2]. Higher doses of Iodine (>960 mg iodine/ • Do monitor the patient under cardiac
day) have been linked with Esophageal/duo- surveillance.
denal ulceration/hemorrhage [8]. Iopanoic • Use of Acetaminophen is preferred over
acid and other iodinated radiocontrast agents Aspirin in acute thyroid emergency
were used for treatment in acute cases but now • Do use steroid, intravenous fluids, antibiotics
rarely used. and calcium channel blocker when indicated
• Steroids: Steroid are used for their ability to pro- in proper setting.
mote vasomotor stability (especially in condition
of relative adrenal Insufficiency) [9] and reduce Follow Up of Patients
T4 to T3 conversion. Usual dosage is • Discontinuation of Iodine and steroids after
Hydrocortisone 100 mg intravenously every 8 h. improvement of clinical parameters.
• Fluid Management: Depends on fluid over- • Reduction in dosage of beta blocker and thi-
load (Congestive heart failure) vs fluid resus- onamide with stability in thyroid function test.
citation (Dehydration). • Switching Propylthiouracil to Methimazole/
• Treatment on underlying/Precipitating Cause: Carbimazole due to PTU safety concerns.
– Fever/Pain: Acetaminophen is preferred • Planning for RAI therapy on achieving good
choice. Aspirin can potentially interfere in control over thyroid symptoms/biochemical
protein binding of T4/T3 leading to status.
increased circulating levels. • Surgery is an option for patients but not usually
– Antibiotics: Use antibiotic as indicated to recommended due to cost and association with
treat possible infection as triggering factor. more complication/longer recovery time.
Infectious should be evaluated carefully in Surgery is considered in patient with a very large
back ground of thyroid storm. or obstructive goiter or severe orbitopathy.
– Others:
– For heart rate control Diltiazem could be
considered as alternative to Beta blocker Myxedema Coma
such as asthmatic patient [10].
• Lithium use is limited by its neurological and Pathophysiology
renal side effects. The mechanism of action Diagnosis is made based on the severity of hypo-
include blocking the release of thyroid thyroidism symptoms. Level of elevation of TSH
hormone. levels and suppression of thyroxine level are not
228 S.A. Raza
benefit over starting and continuing same dos- Thyroid Dysfunction Requiring
age (100 mcg) [25]. Using T3 as initial dosage Urgent Measures
has some added benefit of having rapid onset of
action and possibly bypassing delay in T4 to T3 Thyroid Dysfunction
conversion (delayed due to decreased de-iodin- During Pregnancy
ase activity seen in severe hypothyroidism
although this has not been proven by studies). Urgency in diagnosis and treatment: There are
There is also a theoretic risk of higher mortality some unique aspects of thyroid disease during
with high T3 level [15]. Also lower dosage may pregnancy vs. non pregnant females. This dis-
be considered for patient with cardiac arrhyth- tinctive situation calls for urgency in diagnosis
mias and failure. and treatment.
• Steroid: Usual dosage is hydrocortisone intra-
venously, 100 mg every 8 h. Due to autoim- Hyperthyroidism
munity nature of hypothyroidism, adrenal • Hyperthyroidism during pregnancy is
insufficiency should always be considered. mostly attributed to Graves’ disease and
hCG-mediated hyperthyroidism. Urgency of
Do and Don’t/What Not to Miss diagnosis and treatment during pregnancy is
• Do timely investigation and diagnostic test for due to effects in fetal outcome (management
potentially fatal condition. of these are discussed in respective
• Do provide Respiratory support by mechani- chapter).
cal ventilation in respiratory compromised • Do use Propylthiouracil – PTU as preferred
patient (myxedematous infiltration of the drug during first trimester due to concerns of
pharynx, mechanical difficulties in tongue aplasia cutis, tracheoesophageal fistulas, pat-
enlargement or hypo ventilation) ent vitellointestinal duct, and choanal atresia
• Do send for biochemical evaluation (TSH, with use of methimazole/Carbimazole [26–
free T4 and cortisol) before initiation of 31]. PTU can be switched to Carbimazole/
treatment. Methimazole during second and third
• Do consider other autoimmune disorders such trimester.
adrenal insufficiency when faced with patient • Don’t use beta blockers for more than 6 weeks
with hypothyroidism. Treat empirically with for symptomatic relief/tachycardia due to
steroid before the laboratory results are concerns of fetal growth retardation and hypo-
obtained. glycemia [32–34].
• Do initiate aggressive supportive care initially as • Don’t opt for radioactive iodine, as it is abso-
it can make better outcome and lesser mortality. lute contraindication and thyroidectomy dur-
• Do use aggressively Thyroxine T4 (With or ing pregnancy is rarely necessary.
without bolus) although bolus has some addi- • In situation where other options cannot be
tional beneficial effect. Use of T3 is limited to utilized, Plasmapheresis has also been
initial management. used to rapidly control hyperthyroidism [35,
• Don’t use regular doses in patient with cardiac 36].
arrhythmias and failure.
Hypothyroidism
Follow Up of Patients • Hypothyroidism results in deleterious effect
• Discontinuation of steroids and intravenous of pregnancy out come and mental/physical
thyroxine after improvement of clinical growth of fetus.
parameters. • Don’t plan pregnancy till person (mother to
• Planning for follow up laboratory and adjust- be) is biochemically Euthyroid
ing dosage accordingly. • Do increase dosage of thyroxine by 30 % at
• Patient education and outpatient follow up. the time of conception
230 S.A. Raza
• Do monitor thyroid function every 4–6 weeks impairment) than others (cognitive functions)
during pregnancy and adjust dosage [37]. Although Seizures associated with
accordingly. Thyrotoxicosis should with improvement in
• Post-partum the Thyroxine dosage will need thyroid function but anti-seizure medication
to be adjusted and reduced again. are sometime required.
Movement Disorders
Neurological Presentation of Thyroid • Presentation: Tremor of Thyrotoxicosis
Disease should be differentiated from movement dis-
orders. Benign tremors are typically noticed
Any thyroid condition becomes an urgent one with high frequency and low amplitude [48].
when systemic symptoms including palpitations, • Myoclonus/Ballism have been reported
heat intolerance, and weight loss are accompa- although rarely in hyperthyroidism [49, 50].
nied by central and peripheral nervous system Chorea occurs in less than 2 % of patient
manifestations. effected by hyperthyroidism [51]. Chorea usu-
ally present as gradual onset. It is presented as
Cognitive Disorders and Seizures unilateral, bilateral, or multifocal and involves
• Cognitive impairment is common in hyperthy- the extremities predominantly and less often
roidism, especially in elderly population and the trunk or facial muscles [52–54]. Chorea’s
may present as one or more different syn- pathophysiology include reduction in the pro-
dromes. Study by Martin et al revealed inci- duction and turnover of the level of homova-
dence of dementia (33 %) and confusion nillic acid (metabolite of dopaminein the
(18 %) [37]. These rates were higher than cerebrospinal fluid in hyperthyroid patients)
noted in studies looking into younger popula- which results in increased sensitivity of dopa-
tion [38, 39]. mine receptors and a resulting decrease in
• It becomes a medical emergency/urgency, dopamine turnover [55]. Management of cho-
when thyrotoxic patient experience seizures rea includes correction of hyperthyroid state
along with encephalopathy. Seizure could and use of dopamine antagonist (Haloperidol),
vary from focal to generalize in clinical pre- beta-blockers and reserpine.
sentation [40–43]. Seizures are more promi-
nent in this setting and may include status Cerebrovascular Disease
epilepticus [40, 41, 43–45]. Ischemic cerebrovascular disease is a rare but
• Confirming Diagnosis: Investigation includ- recognizable complication of hyperthyroidism.
ing magnetic resonance imaging (MRI) or In a prospective cohort study by Sheu et al
computed tomography (CT) neuroimaging revealed cumulative incidence of ischemic stroke
studies and electroencephalography (EEG) was 1.0 % compared to 0.6 % in a control group
may help differentiate/diagnose thyroid con- over 5 years (HR = 1.44) [56]. Atrial fibrillation
dition with others [43, 46, 47]. Other investi- remains a recognizable risk factor for cerebral
gation such as single photon emission CT infarction related to hyperthyroidism [57]. In
(SPECT) demonstrated diffusely reduced clinical scenario of atrial fibrillation (AF), antico-
cerebral uptake with an accentuation in the agulation remains mainstay of treatment to pre-
temporoparietal regions bilaterally, which vent cerebrovascular accidents (CVA).
improved following resolution of the hyper- Another rare condition seen in thyrotoxic
thyroid state [47]. patient with a very high mortality and morbidity
• Treatment: Treating hyperthyroidism usually is cerebral venous sinus thrombosis. This usually
lead to resolution of cognitive and behavioral occurs in backdrop of dehydration, central ner-
impairments. Some symptoms resolve earlier vous system infection, or hypercoagulable states
(Agitation, inattention, and frontal lobe [58–61].
12 Thyroid Emergencies 231
Some of the other rare thyroid urgencies rarely presenting along with hyperthyroidism
include fatal stroke and bilateral carotid artery [83].
dissection [62], intracranial stenosis [63], some One of the other emergencies in hyperthyroid-
autoimmune disorders (Antiphospholipid syn- ism is involvement of peripheral nerves in myas-
drome, giant cell arteritis, and Takayasu arteritis) thenia gravis. Prevalence of this condition varies
are more common in patient with thyroid autoim- from 2 to 17 % when prevalence in general popu-
munity (although not proven) [64–67]. lation is 1 in 10,000 [84–86]. Common genetic
susceptibility (HLA antigen type, HLA-DQ3)
may explain higher prevalence [87]. The treat-
Neuromuscular Emergencies ment of Myasthenia gravis remains same regard-
ing of coexistence with thyroid state, which
Thyrotoxic patient may present with a muscular includes acetylcholinesterase inhibitors, thymec-
condition with unknown etiology which has tomy and immunosuppressive therapy [88].
acute onset of muscle weakness, muscle atrophy Although Graves’ opthalmopathy has a slow
and myalgias. The prevalence of these conditions progressive presentation but sometime can have
could be as high as 80 % in untreated patients acute phase exacerbation. This relatively com-
[68, 69]. Possible explanation of these manifesta- mon in Graves’ disease, occurring in 20–25 % of
tions is increased cellular metabolism and energy cases. Another uncommon urgent scenario may
utilization, increased catabolism and protein deg- result from thyroid gland enlargement causing
radation, reduced carnitine and inefficient energy compression of recurrent laryngeal nerve com-
utilization [70–74]. pression (respiratory stridor, vocal cord paralysis,
Others condition presenting in emergency and dysphonia) and sympathetic chain (Horner’s
room with muscular weakness include syndrome) [89, 90],
Rhabdomyolysis [75–77]. Hypokalemic periodic
paralysis present in its acquired form as
Thyrotoxic periodic paralysis. This condition is Cardiovascular Emergencies
usually preceded by generalized weakness, often
following a strenuous exercise or a high- Thyroid condition presenting with cardiovascular
carbohydrate diet. Asian race and male gender manifestation becomes an emergency due to high
are risk factor for this condition. risk and mortality. These effects are carried by
Peripheral neuropathy may be presenting the triiodothyronine (T3) on heart. T3 binds with
complaint in hyperthyroidism; these could vary nuclear receptors and transported into the cardiac
from carpel tunnel syndrome to sensory polyneu- myocyte, leading to increases in heart rate, car-
ropathy. Common presentation is symmetric dis- diac contractility, systolic and mean pulmonary
tal sensory disturbance and reduced Achilles artery pressure, cardiac output, diastolic relax-
reflexes. Carpel tunnel could be seen more com- ation, and increased myocardial oxygen con-
monly in hypothyroidism than hyperthyroidism sumption. These result in reductions in systemic
[78]. Axonal damage of thyrotoxic patient is seen vascular resistance and diastolic pressure [91,
in diagnostic testing with nerve conduction stud- 92]. Some other effects on heart are produced by
ies and EMG [79–81]. Some of the other rare pre- direct beta-adrenergic stimulation of T3 [93].
sentations seen in acute thyrotoxic/thyroid storm These positive chronotropic and ionotropic
include Basedow’s paraplegia (acute and severe effects lead to cardiac output increases by as
leg weakness and areflexia) and recovery is with much as 250 % and pulse pressure widens.
improvement in hyperthyroid state [82]. Other Patient may present with resting tachycardia
condition manifesting due to autoimmunity which is exacerbated by exercise and systolic hyper-
nature of thyrotoxicosis is Guillain-Barré syn- tension with widened pulse pressure [94]. Women,
drome and chronic inflammatory demyelinating more than men may present with angina-like chest
polyneuropathy. They are autoimmune disorders pain, with EKG changes suggesting myocardial
232 S.A. Raza
ischemia. This scenario is attributed to coronary behind this phenomenon is unusually sensitive to
vasospasm and responds to treatment with orally the inhibitory effects of iodide upon its own
administered calcium channel blockers. organification, in part due to a sustained activity
Another acute presentation of thyrotoxicosis of the sodium/iodide symporter. This sustained
is atrial fibrillation, premature supraventricular activity of the symporter results in a prolonged
depolarization, atrial premature contractions inhibition of thyroid hormone synthesis and an
(APCs), more non-sustained supraventricular increase in TSH. Hypothyroidism ensues in these
tachycardia, increased heart rate and reduced patients because of failure to escape from the
heart rate variability [95]. A detailed account of acute Wolff-Chaikoff effect. This Condition
arrhythmias is given in another chapter. associated with patient with chronic autoimmune
Thyrotoxic patient may present with heart thyroiditis, painless/postpartum/subacute granu-
failure, especially with co-existing with atrial lomatous thyroiditis and with Graves’ hyperthy-
fibrillation or prolonged tachycardia [96]. roidism previously treated either with radioactive
Usually the clinical picture improves after sinus iodine or subtotal thyroidectomy [104–106].
rhythm is restored and restoration of Euthyroid Condition such as cystic fibrosis and thalas-
status. Other condition which may result in heart semia major undergoing blood transfusion places
failure include cardiomyopathy (rate related), individual under increased risk of developing
which too disappears after restoration of euthy- iodine induced hypothyroidism [107, 108].
roidism. Treatment is primarily on rate control by
beta-adrenergic blockade.
Lithium Intoxication
Medication Exposure and Thyroid Lithium exposure has been reported to cause
Emergencies hypothyroidism as well as hyperthyroidism.
Pathophysiology of this inhibition of thyroid hor-
Acute Iodine Exposure: Jod-Basedow mone release in not clearly known, although ani-
Phenomenon/Wolff-Chaikoff Effect mal and human studies have revealed that lithium
increases intrathyroidal iodine content, inhibits
Excessive iodine exposure in patient with nodular the coupling of iodotyrosine residues to form
goiter and having underlying iodine deficiency iodothyronines (thyroxine and triiodothyronin)
(Living in areas with iodine deficiency) may and inhibits release of T4 and T3 [109–111].
result in acute onset of thyrotoxicosis. This effect Lithium induced hypothyroidism may present
is due to underlying areas of autonomy within the with or without goiter, but usually occurs during
thyroid gland. Jod-Basedow phenomenon, auton- first 2 years of lithium use, back ground of
omous areas producing thyroid hormone indepen- chronic autoimmune hyroiditis and older age
dent of normal regulatory mechanisms, results in [112–114]. It is this effect of lithium which
thyrotoxic state. These individuals may be thyro- makes it useful in treatment of hyperthyroidism.
toxic even before iodine repletion [97, 98]. This Lithium in dosage of 600–1000 mg/day quantita-
Iodine-induced thyrotoxicosis rarely occurs in tively similar to those of iodide in rapid correc-
patients without underlying thyroid disease (e.g., tion of hyperthyroidism in patient allergic to
iodine-induced thyroiditis). Common presenta- iodine or thionamide [115, 116].
tion of this thyrotoxic state is seen after iodine Miller et all and Kristensen et all have pub-
exposure in medication (Amiodarone), iodine lished data regarding two to three fold increase
based contrast (radiological procedure and car- risk of hyperthyroidism in patient using lithium
diac catherizaton) [99–103]. than general population [116, 117].
Contrast to above presentation, iodine Lithium induced goiter may lead acute com-
exposure may result in development of rapid plication (compression). Approximately 40–50%
iodine-induced hypothyroidism. Pathophysiology of individuals may experience goiter formation
12 Thyroid Emergencies 233
[118–121]. The treatment of goiter in patients may be considered for thyroidectomy, but real-
taking lithium is the same as for goiter of any izing that these patient are usually high risk.
etiology. Steroids remain the mainstay for treatment of
type II hyperthyroidism. The dosage required is
prednisone 40–60 mg/day and amiodarone could
Amiodarone-Induced Thyroid be continued [131]. Although iopanoic acid can
Emergencies be used but it is less effective than steroids [132].
Diagnosis could be challenging and possibility
Amiodarone is implicated with thyroid dysfunc- of “mixed” form of thyrotoxicosis or the under-
tion including both hypo as well as hyperthyroid- lying cause (type I or type II) may be uncertain.
ism. These conditions can present as an acute It is better to treat for both with combination of
event. This effect is attributed to amiodarone’ s prednisone (40 mg/day) and methimazole/
high iodine content (6 mg of iodine associated Carbimazole (40 mg/day).
with a 200 mg dose of amiodarone) and its direct
toxic effect on the thyroid. Iodine load can result
in the Wolff-Chaikoff effect or (hypothyroidism) Post RAI
or Jod-Basedow (excessive thyroid hormone syn-
thesis and thyrotoxicosis). Both of these are There could be a transient exacerbation of hyper-
already discussed above. thyroidism after radioiodine exposure. This
Based on the underlying thyroid status, dietary clinical emergency may be eliminated by pre-
iodine intake and/or subclinical thyroid disor- treatment and controlling hyperthyroidism clini-
ders, there is 2–30 % risk of amiodarone-induced cally and biochemically before referring for RAI
thyroid dysfunction [122–124]. therapy [133–135]. Patient with severe intoler-
Amiodarone-induced thyrotoxicosis is of two ance to hyperthyroid symptoms, having underly-
types. In type 1, there is increased synthesis of ing cardiac condition and elderly would qualify
thyroid hormone, seen in patient with pre-existing for pretreatment before RAI is offered to these
multinodular goiter or latent Graves’ disease; individuals. Coincidental use of Lithium with
whereas in type 2 there is excess release of T4 RAI may also be help full reducing transient
and T3 due to a destructive thyroiditis caused by increase in serum thyroid hormone concentra-
a direct toxic effect of amiodarone on thyroid fol- tions following radioiodine, but may not be rec-
licular epithelial cells [125–127]. ommended due to inconsistent data and lithium
Treatments of these disorders are based on the toxicity [136].
clinical scenario. In hypothyroid state thyroid
function can be easily normalized by replace-
ment with thyroxine. Amiodarone should be Thyroxine Overdose
continued.
Thionamide used in Patients with type I Ingestion of excessive amounts of thyroxine can
hyperthyroidism usually respond slowly and lead to exogenous hyperthyroidism. It could
large doses (30–40 mg daily) may be required. range from intentional (i.e., suppressive doses of
This is due to very high intrathyroidal iodine thyroxine to treat thyroid cancer) or inadvertent
stores [128]. Perchlorate, which blocks further (i.e., contamination of dietary supplements) or
iodine uptake by the thyroid, may be of benefi- surreptitious ingestion (thyrotoxicosis factitia).
cial but its association with aplastic anemia lim- These individuals present clinically as hyperthy-
its its use [129]. Sometimes lithium has been roid except exophthalmos and goiter (unless
used to expedite recovery of hyperthyroidism present since the beginning). Acute thyroxine
[130]. RAI Therapy is only used if radioactive overdose can present with all acute complication
uptake is high enough for ablation. Patient with of thyrotoxicosis such as myocardial infarction,
refractory disease to antithyroid drug therapy especially in elderly patients, and seizures in
234 S.A. Raza
children [137–139]. Chronic thyroxine overdose is same but clinically manifestations are dif-
can cause chronic overt (low serum TSH, high ferent (Hyperthyroidism vs thyroid storm,
free T4 and/or T3) or subclinical (low serum hypothyroidism vs Myxedema coma).
TSH with normal free T4) hyperthyroidism.
Laboratory investigation will reveal low serum Management of these conditions poses medi-
TSH concentrations with elevated serum thyrox- cal dilemmas which can be very challenging at
ine (T4) and/or triiodothyronine (T3). Serum thy- times. Best example could be thyroid disease
roglobulin on the other hand is suppressed unlike caused by certain medicine (amiodarone/lith-
other thyrotoxic conditions (Graves’ and thyroid- ium); in these scenarios decision regarding cessa-
itis). 24-h radioiodine uptake is low due to sup- tion of medication vs. continuation is to be made
pression of TSH secretion. Treatment could be evaluating the need for these medication. Another
challenging in different scenario. Discontinuation example is titration of doses after resolution of
or reduction in the dose of thyroid hormone is acute presentation in thyroid storm and myx-
usually the only treatment needed. Half of the edema coma.
circulating dosage is removed from circulation in
7 days’ time. T4 may take longer than T3 in
clearance (serum half-life of about 1 day). References
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Thyroid Nodule
13
Syed Hunain Riaz, Muhammad Zaman Khan Assir,
Ali Jawa, and Javed Akram
Abstract
Thyroid nodules are not an uncommon clinical problem, even in iodine suf-
ficient areas. The incidence is 2–4 per 100,000 people per year, being more
common in women and the elderly. The evaluation of thyroid nodule is
aimed at differentiating benign from malignant thyroid nodules and com-
prises of detailed history (irradiation, family history etc), examination and
biochemical, radiological and cytological investigations. Most common
diagnoses are colloid cysts and nodules (80 % of cases), benign follicular
neoplasms (10–15 % of cases) and thyroid cancer (5 % of cases).
Measurement of serum TSH is the first step in the work-up. Subnormal
TSH warrants radio-isotope scanning to exclude hyper-functioning thyroid
nodule. Patients with normal or high serum TSH undergo imaging studies
and FNA. A number of radiological modalities are used including simple
(USG) and advanced imaging studies (CT,MRI,PET). Thyroid USG is still
considered the radiological modality of choice for initial work-up. FNA is
the procedure of choice and all non-palpable/palpable nodules of >1 cm in
size warrant FNA. The indications for FNA in sub-centimeter nodules
include solid hypoechoic nodule with microcalcifications, nodules with
abnormal cervical lymph nodes detected on physical examination or imag-
ing, high risk history. Treatment of thyroid nodule depends on whether the
Increased uptake
( hyper functioning) Nodule not found
Fig. 13.1 Diagnostic algorithm for evaluation of thyroid nodule. US ultrasound, PTC papillary thyroid cancer
there may be nodules <1 cm that require eval- 3. Approximately 1–2 % of people undergoing
uation because of suspicious USG findings, 2-deoxy-2[18F] fluoro-d-glucose positron
associated lymphadenopathy, a history of emission tomography (18FDG-PET) imaging
head and neck irradiation, or a history of thy- for other reasons have thyroid nodules discov-
roid cancer or thyroid cancer syndrome (e.g. ered incidentally. Since the risk of malignancy
Cowden Syndrome, familial polyposis, in these 18FDG-positive nodules is about
Carney complex, multiple endocrine neopla- 33 % and the cancers may be more aggressive
sia [MEN] 2, Werner syndrome) in one or [23], such lesions require prompt evaluation
more first-degree relatives. [24–26].
13 Thyroid Nodule 243
Table 13.1 Summary of revised American Thyroid Association 2009 recommendations on the evaluation of thyroid
nodule
Investigation/ Recommendation
Sr # condition Recommendation rating
1 Serum TSH Measure serum TSH in the initial evaluation of a patient A
with a thyroid nodule. If the serum TSH is subnormal, a
radionuclide thyroid scan should be performed using either
technetium 99mTc pertechnetate or 123I
2 Thyroid sonography Thyroid sonography should be performed in all patients A
with known or suspected thyroid nodules
3 Serum thyroglobulin Routine measurement of serum Tg for initial evaluation of F
(Tg) thyroid nodules is not recommended
4 Serum calcitonin The panel cannot recommend either for or against the I
routine measurement of serum calcitonin
5 FNA (a) FNA is the procedure of choice in the evaluation of A
thyroid nodules
(b) US guidance for FNA is recommended for those nodules B
that are nonpalpable, predominantly cystic, or located
posteriorly in the thyroid lobe
(c) US guidance should be used when repeating the FNA A
procedure for a nodule with an initial nondiagnostic
cytology result
6 Cytology: diagnostic (a) If a cytology result is diagnostic of or suspicious for A
of or suspicious PTC, surgery is recommended
for PTC (b) If the reading is “suspicious for papillary carcinoma” or A
“Hurthle cell neoplasm,” a radionuclide scan is not needed,
and either lobectomy or total thyroidectomy is recommended,
depending on the lesion’s size and other risk factors
7 Cytology: (a) The use of molecular markers (e.g., BRAF, RAS, C
indeterminate RET = PTC, Pax8-PPARg, or galectin-3) may be considered
for patients with indeterminate cytology on FNA to help
guide management
(b) The panel cannot recommend for or against routine I
clinical use of 18FDG-PET scan to improve diagnostic
accuracy of indeterminate thyroid nodules
8 Cytology: follicular If the cytology reading reports a follicular neoplasm, a 123I C
neoplasm thyroid scan may be considered, if not already done,
especially if the serum TSH is in the low-normal range. If a
concordant autonomously functioning nodule is not seen,
lobectomy or total thyroidectomy should be considered
9 Cytology: benign (a) If the nodule is benign on cytology, further immediate A
diagnostic studies or treatment are not routinely required
(b) It is recommended that all benign thyroid nodules be C
followed with serial US examinations 6–18 months after the
initial FNA. If nodule size is stable (i.e., no more than a 50 %
change in volume or <20 % increase in at least two nodule
dimensions in solid nodules or in the solid portion of mixed
cystic–solid nodules), the interval before the next follow-up
clinical examination or US may be longer, e.g., every 3–5 years
(c) If there is evidence for nodule growth either by palpation B
or sonographically (more than a 50 % change in volume or a
20 % increase in at least two nodule dimensions with a
minimal increase of 2 mm in solid nodules or in the solid
portion of mixed cystic–solid nodules), the FNA should be
repeated, preferably with US guidance
(continued)
244 S.H. Riaz et al.
identification of a benign thyroid nodule [37]. Other apy for a period of 1–2 months. Gadolinium con-
features suggestive of a benign nodule include mac- trast used with MRI does not interfere with
rocalcifications, comet-tail shadowing and hyper- thyroid uptake of radiotracer, but it is signifi-
echoic mass with peripheral vascularity. cantly more expensive than CT or ultrasound.
Diagnostic Ultrasound of the thyroid provides 18F-fluorodeoxyglucose positron emission
useful information as whether the nodule is cys- tomography-computed tomography (18FDG-
tic, solid or mixed (solid plus cystic). Cystic nod- PET/CT) can be used to improve diagnostic
ules were earlier on thought to be predominantly accuracy of indeterminate thyroid nodules. ATA
benign and conservative management was sug- guidelines do not recommend for or against the
gested [38]. However it has been seen recently use of 18FDG-PET scan.
that cystic thyroid nodules also carry an equal or
even greater risk than solid nodules to harbor
malignancy [39]. Cysts that are larger in size Fine Needle Aspiration
(>33 mm), have a blood component in them, have
recurrences after repeated aspirations and previ- The American Thyroid Association recom-
ous history of neck irradiation are all consider- mends FNA biopsy as the procedure of choice
ations for surgery. To improve the accuracy of the for evaluating thyroid nodules and selecting
FNAC in such nodules, it should be carried out candidates for surgery. FNA is the most accurate
under Ultrasound guidance because when done and cost-effective method for evaluating thyroid
blindly, there is possibility of geographically nodules. It has advantages of cost-effectiveness,
missing the area with malignancy [40, 41]. easy to learn and can be performed on out-
Similarly the diagnostic accuracy of FNA per- patient basis. FNA is performed with or without
formed by palpation is low in posteriorly located local lidocaine anesthesia [42], by repetitively
nodules and in these cases, ultrasound guided moving a 23–27-gauge (most commonly
FNA of thyroid nodule is recommended. 25-gauge) needle through the nodule. Biopsy
Additionally, US guidance should be used when can be guided by palpation only or by ultra-
repeating the FNA procedure for a nodule with sound. Ultrasound guidance is recommended in
an initial non-diagnostic cytology result. The rate case of posteriorly located nodule, nodule with
of malignancy in nodules in thyroid glands mixed solid and cystic components and repeat
involved with Hashimoto’s thyroiditis is as least FNA. Fine-needle capillary sampling (FNC,
as high as or possibly higher than normal thyroid also called fine-needle non-aspiration biopsy) is
gland. The nodularity of thyroid gland in the set- a variation of FNA in which the sample is
ting of Hashimoto’s thyroiditis may represent obtained by repetitively moving within the nod-
focal enlargement from lymphocytic infiltrates, ule a 25–27-gauge needle that is not attached to
TSH-induced hyperplasia of follicular tissue, or a a syringe [43, 44]. After the needle is removed
thyroid tumor and thyroid ultrasound may help to from the nodule, a syringe containing air is used
distinguish among these possibilities. to express the sample on a slide, which is
smeared, stained, and submitted for cytologic
interpretation. If FNA is scheduled antiplatelets
Other Imaging Studies and anticoagulants should ideally be discontin-
ued 5–7 days before the procedure, however cli-
Computed tomography (CT) and magnetic reso- nician should weigh the risk of discontinuing
nance imaging (MRI) are not routinely recom- these drugs and current use of these medications
mended for the work up of a thyroid nodule. does not preclude FNA. FNA is a simple and
They are useful in the evaluation of retro-sternal safe procedure. Local pain and hematomas are
thyroid. It is important to note that iodinated con- the most common complications, while serious
trast material utilized for CT scan should be adverse events are rare.
avoided because its use prevents scintigraphy or Routine FNA is not recommended for nodules
administration of radioactive iodine (RAI) ther- <1 cm in size. The indications for FNA in sub-
13 Thyroid Nodule 247
centimeter nodules include solid hypoechoic ectomy with discovery of thyroid cancer) and
nodule with microcalcifications, nodules with 18FDGPET–positive thyroid nodules (Fig. 13.2).
abnormal cervical lymph nodes detected on Criteria for cytological adequacy of FNA
physical examination or imaging, high risk his- include the presence of at least six follicular cell
tory (family history of PTC [45]; history of exter- groups, each containing 10–15 cells derived from
nal beam radiation exposure as a child [46]; at least two aspirates of a nodule [48].
exposure to ionizing radiation in childhood or FNA biopsy results are divided into six catego-
adolescence [47]; history of prior hemi thyroid- ries: Non-diagnostic, benign, follicular lesion of
Thyroid nodule
High-risk history?
Yes No
FNA if nodule
>5mm with or
without Abnormal cervical
suspicious US lymph nodes?
features
No Yes
Regardless of
nodule size
perform FNA of
Sonographic lymph node
features?
Fig. 13.2 A step wise approach to the decision of FNA in both the size and high risk characteristics (high risk his-
a thyroid nodule based on ATA guidelines. The decision to tory, physical examination and suspicious ultrasono-
obtain FNA in a thyroid nodule takes into consideration graphic findings)
248 S.H. Riaz et al.
undetermined significance, follicular neoplasm, and FNAC of thyroid nodule. The next step in
suspicious for malignancy and malignant. Non- management depends on whether the nodule is
diagnostic biopsies are those that fail to meet speci- benign, malignant or has suspicious features on
fied criteria for cytologic adequacy. In case of any of the diagnostic modalities. The following
non-diagnostic FNA biopsy results, ultrasound algorithm shows the approach to diagnosis of a
guided repeat biopsy is indicated. It is important to solitary Thyroid Nodule (Fig. 13.1).
note that absence of malignant cells should not be
interpreted as ‘negative’. Benign lesions include
macrofollicular or “colloid” adenomas, chronic Overview of Treatment Options
lymphocytic (Hashimoto’s) thyroiditis, or sub- for Solitary Thyroid Nodules
acute granulomatous thyroiditis. Follicular lesions
of undetermined significance are those lesions that Thyroid nodules with gross presentations like
are not convincingly benign but do not have defini- rapidly increasing size, pressure symptoms or
tive features of a follicular neoplasm and are not suspicion of malignancy on FNAC warrant treat-
highly suspicious of malignancy. This category ment without ambiguity, however solitary thy-
includes lesions with mild atypia, mixed macro- roid nodule which are quiescent are the ones
and microfollicular lesions where the proportion of which represent a diagnostic dilemma at times. It
micro- and macrofollicles is similar, and specimens has been seen that majority of non-functioning
that are compromised because of poor fixation or benign nodules grow with time, particularly
obscuring blood. Follicular lesions include micro- those which are solid [53]. Before we have a
follicular or cellular adenomas. The category ‘sus- look at the treatment options for solitary Thyroid
picious for malignancy’ includes lesions with some nodule, we will look at the differentiation of
features suggestive of but not definitive for thyroid these nodules on basis of their nature (solid/cys-
cancer. The malignant category includes papillary tic/mixed) and also on whether they are benign
cancer, medullary cancer, thyroid lymphoma, ana- or malignant.
plastic cancer, and cancer metastatic to the thyroid. We will now discuss the treatment options for
The only malignant pathology reliably diagnosed small thyroid nodule:
through fine needle aspiration is papillary thyroid
carcinoma, as features such as ‘Orphan Annie’
nuclei, nuclear grooves, intra-nuclear inclusions, Surgery
and psammoma bodies can be sufficient for a diag-
nosis. Medullary carcinoma, anaplastic carcinoma, Surgery is generally the treatment of choice for
lymphoma, poorly differentiated carcinoma, and nodules which have high risk clinical or cytological
metastatic disease have also been reported to be features or have symptoms suggestive of cancer
classified on the basis of cytology [49]. [54]. Near total or total thyroidectomy is preferred
A number of genetic markers (BRAF, Ras, for patients with diagnosis of malignancy on histo-
RET/PTC) and protein markers (galectin-3) have pathology and is >1 cm [55] along with other risk
been shown to improve preoperative diagnostic factors such as lymphadenopathy, family history of
accuracy for patients with indeterminate thyroid differentiated thyroid cancer or radiotherapy to
nodules [50–52]. head and neck region. A large study showed that
total thyroidectomy improved recurrence and sur-
vival rates in nodules >1 cm [55]. Comprehensive
Treatment bilateral central lymph node dissection is done
(especially in PTC) which improves survival and
The management of a thyroid nodule depends on reduces recurrences [56]. In those patients where
decisions taken on basis of thorough history tak- histology is indeterminate (follicular or Hurthle
ing, physical examination, TSH values, thyroid cell neoplasm) or non-diagnostic, Thyroid
radionuclide scan, ultrasonography of thyroid Lobectomy is the initial approach. However when
13 Thyroid Nodule 249
there are high risk features of size >4 cm and nodules [59]. The mechanism proposed for its
atypia, total thyroidectomy can be performed [22]. use is local coagulative necrosis and thrombosis
For those patients of cystic thyroid nodules of small vessels. However this procedure requires
with subsequent recurrent symptomatic cystic skill and experience and obviously a benign
fluid accumulation, surgical removal, generally cytology to begin with [7]. There is risk of local
by hemi thyroidectomy is an option. pain and other side effects.
The current data suggests that multiple injec-
Pro’s and Con’s There is complete relief of tions of ethanol (a median of four) can achieve a
symptoms and histological diagnosis while on complete cure (i.e., a normalization of results of
the hind side there is need for hospitalization and radionuclide scanning and serum thyrotropin
the risks associated with surgery such as vocal measures) in majority of the patients with hyper-
cord palsy (<1 %), hypoparathyroidism and functioning nodules and functioning nodules
hypothyroidism (both <1 %) [16]. without hyperthyroidism. In solid non-
functioning benign nodules, a single ethanol
injection can reduce the size of a thyroid nodule
Radio-Iodine by up to half [53]. Evidence shows that there is
no recurrence on ultrasonography following
It is an option for a functioning thyroid nodule with treatment [60].
or without biochemical hyperthyroidism. There is
normalization of thyroid nuclide scanning and Pro’s and Con’s There is no need for hospital-
serum thyrotropin levels in up to 75 % cases and ization and the cost is less. There is around half
the thyroid volume decreases up to 40 % from reduction in size of thyroid nodules following
baseline after a single dose of iodine-131 aiming at treatment in 6 months. It requires considerable
a level of 100 Gy, independent of pretreatment thy- skill and experience. There is local pain, risk of
roid function [57, 58]. There is risk of developing vocal cord paralysis (in up to 2 %) and thyrotoxi-
hypothyroidism post-treatment in 10 % of patients cosis. After treatment, histology interpretation of
in 5 years, and the frequency of risk increases with the nodule is obscured [8].
time. Post treatment, the thyroid function should be
monitored on a yearly basis to diagnose hypothy-
roidism. Post-treatment, thyroid nodules rarely Levothyroxine
grow. If they do, then a biopsy should be done to
assess histology. Radio-iodine is contraindicated in Treatment with levothyroxine is based on the
pregnant or breast feeding women. principle that suppression of thyrotropin prevents
growth of benign thyroid nodule. However defin-
Pro’s and Con’s There is no need for hospital- itive evidence for its support is lacking. The
ization and the cost is less. There is significant objective of treatment is to suppress thyrotropin
reduction in thyroid volume. However the reduc- to <0.3 mU/l.
tion in thyroid volume is very gradual and there is A meta-analysis suggested that after 6–12
a risk of radiation induced thyroiditis or months of suppressive therapy, there was no sig-
thyrotoxicosis. Fertile women will need contra- nificant difference in nodule growth in patients
ception before and after treatment [8]. on levothyroxine and those on no treatment [61].
The chances of nodule size reduction are greater
with suppression of thyrotropin to <0.1 mU/l as
Percutaneous Ethanol Injection compared to <0.3 mU/l [61]. In a randomized
trial, levothryroxine suppression showed decrease
This involves injection of Ethanol under ultra- in the frequency of appearance of new thyroid
sound guidance in benign functioning/non- nodules when thyrotropin was suppressed to
functioning solid nodules and also in cystic <0.1 mU [62]. Of note is the fact that nodule re-
250 S.H. Riaz et al.
growth occurs after cessation of treatment and it 3. Singer PA, Cooper DS, Daniels GH, Ladenson PW,
Greenspan FS, Levy EG, et al. Treatment guidelines for
does not have effect on cyst recurrence after aspi-
patients with thyroid nodules and well-differentiated
ration [63]. However, suppression to such a low thyroid cancer. American Thyroid Association. Arch
level of thyrotropin does not come without haz- Intern Med. 1996;156(19):2165–72.
ards of developing complications such as atrial 4. Wong CK, Wheeler MH. Thyroid nodules: rational
management. World J Surg. 2000;24(8):934–41.
fibrillation.
5. Mazzaferri EL. Management of a solitary thyroid
nodule. N Engl J Med. 1993;328(8):553–9.
Pro’s and Con’s Does not need hospitalization 6. Tan GH, Gharib H. Thyroid incidentalomas: manage-
and the cost is less. It ‘may’ reduce nodule size ment approaches to nonpalpable nodules discovered
incidentally on thyroid imaging. Ann Intern Med.
and prevent new nodule formation. However the
1997;126(3):226–31.
gross drawback is that the nodules regrow after 7. Hegedus L, Bonnema SJ, Bennedbaek
cessation of treatment and there is high risk of FN. Management of simple nodular goiter: current
developing atrial fibrillation and osteoporosis status and future perspectives. Endocr Rev.
2003;24(1):102–32.
with this degree of thyrotropin suppression. And
8. Hegedüs L. The thyroid nodule. N Engl J Med.
lastly, it is of no utility in those patients who 2004;351(17):1764–71.
already have a suppressed or low thyrotropin [8]. 9. Sherman SI. Thyroid carcinoma. Lancet.
2003;361(9356):501–11.
10. Davies L, Welch HG. Increasing incidence of thyroid
Conclusion
cancer in the United States, 1973–2002. JAMA.
The purpose of evaluation of thyroid nodule is 2006;295(18):2164–7.
to identify the malignant lesions on the basis 11. Leenhardt L, Bernier MO, Boin-Pineau MH, Conte
of detailed history, physical examination, bio- Devolx B, Marechaud R, Niccoli-Sire P, et al.
Advances in diagnostic practices affect thyroid cancer
chemical, radiological and cytological investi-
incidence in France. Eur J Endocrinol.
gations. Clinical evaluation alone is 2004;150(2):133–9.
insufficient in identification of malignant 12. Valeix P, Faure P, Bertrais S, Vergnaud AC, Dauchet
lesions. The risk of harboring a malignancy in L, Hercberg S. Effects of light to moderate alcohol
consumption on thyroid volume and thyroid function.
nodules with subnormal serum TSH and high
Clin Endocrinol (Oxf). 2008;68(6):988–95.
radio-isotope uptake is low and FNA is not 13. Volzke H, Friedrich N, Schipf S, et al. Association
required in these cases. Patients with normal between serum insulin-like growth factor-I levels and
or high serum TSH are evaluated with thyroid thyroid disorders in a population-based study. J Clin
Endocrinol Metabol. 2007;92(10):4039–45.
ultrasound and FNA. FNA is the investigation
14. Knudsen N, Bülow I, Laurberg P, et al. Low goitre
of choice for initial workup and is indicated in prevalence among users of oral contraceptives in a
nodules >1 cm, nodules with high risk history, population sample of 3712 women. Clinical
examination and suspicious ultrasound find- Endocrinol (Oxf). 2002;57:71.
15. Cappelli C, Castellano M, Pirola I, De Martino E,
ings. Surgery is generally the treatment of
Gandossi E, Delbarba A, et al. Reduced thyroid vol-
choice for nodules which have high risk clini- ume and nodularity in dyslipidaemic patients on statin
cal or cytological features or have symptoms treatment. Clin Endocrinol (Oxf). 2008;68(1):16–21.
suggestive of cancer. 16. Hagag P, Strauss S, Weiss M. Role of ultrasound-
guided fine-needle aspiration biopsy in evaluation of
nonpalpable thyroid nodules. Thyroid.
1998;8(11):989–95.
17. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G,
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Thyroid Cancer
14
Zakir Alavi
Abstract
The incidence of thyroid cancer is rising in most regions of the world. This
rise is mostly made up of small, low risk papillary thyroid cancers with
little effect on mortality. Overall the mortality for differentiated thyroid
cancers is low, with a 10 year survival greater than 95 %. Although there is
debate regarding the extent of surgery, need for lymph node dissection and
the need for or dose of radioactive iodine, the traditional triad of treatment
for differentiated thyroid cancer i.e. surgery, radioactive iodine ablation and
TSH suppression with thyroxine, is still the standard recommendation. In
the absence of strong trial evidence it is difficult to judge the benefits of
these treatment modalities against the potential harm of over treatment.
Recent times have seen an explosion in our understanding of the molec-
ular mechanism involved in thyroid cancer. Molecular analysis of FNA
biopsy has lead to better preoperative diagnosis. Novel new tyrosine
kinase inhibiting drugs such as sorafinib and sunitinib (for non-iodine avid
progressive differentiated thyroid cancers) and vanditinib (for medullary
thyroid cancers) have helped halt the progress of these cancers and
improved survival rates.
Genetic screening of family members of patients with the familial type
of medullary thyroid cancer (either without associated endocrine disease or
as part of multiple endocrine neoplasia syndromes), and prophylactic sur-
gery have resulted in survival comparable to differentiated thyroid cancer.
Introduction
calcitonin. The follicular cells give rise to well- (D) Miscellaneous including:
differentiated thyroid cancers i.e. papillary thy- (a) Lymphoma
roid cancer (PTC), follicular thyroid cancer (b) Fibrosarcoma
(FTC) as well as Hurthle cell cancer (HCC) and (c) Squamous cell carcinoma
anaplastic thyroid cancers. The parafollicular (d) Teratoma
cells are the cells of origin for medullary thyroid (e) Metastatic lesions
carcinoma.
Thyroid cancer is the most common endocrine
malignancy and is one of fastest growing diagno- Differentiated Thyroid Cancers
sis. Worldwide thyroid cancer is 16th most com-
mon cancer, with around 298,000 new cases Papillary Cell Carcinoma
diagnosed in 2012 (2 % of total), with highest
incidence reported in North America and lowest Epidemiology
in Western Africa [1]. Papillary thyroid cancer (PTC) is the most com-
The incidence of thyroid cancer specifically mon endocrine malignancy. PTC constitutes about
PTC has increased rapidly over last three decades 80 % of all thyroid cancers including 85 % of
[2], the majority of these are small PTCs however those induced by radiation. However in countries
increased incidences have been exhibited for all where the incidence of endemic goiter is high, a
sizes and stages of PTC in both genders and all greater portion are follicular or anaplastic.
ethnic groups [3]. It has been suggested that this PTC largely accounts for the increase in new
surge of new cases is due to development and use diagnosis of thyroid cancer. As stated earlier the
of imaging technologies capable of detecting a reason for this increase is believed to be largely
large reservoir of subclinical disease [4]. This due to wide spread use of radiology tests done for
notion is supported by cadaveric studies, where a other reasons that detect small none palpable thy-
third of patients who died from non-thyroid roid cancers. Consistent with this theory is that
related conditions were found to have thyroid death rate from thyroid cancer has remained sta-
cancer [5]. ble despite the increase in cases. However a
Despite its high prevalence thyroid cancer is recent analysis suggests that all stages of thyroid
an uncommon cause of death. The discrepancy cancer are increasing, a finding that may not be
between high number of cases and relatively low explained by surveillance alone [6]. It has been
deaths reflects the indolent nature and excellent suggested that the increase in the incidence of
long-term survival associated with thyroid malig- thyroid cancer might also reflect a new risk factor
nancies. Overall greater than 90 % of patients are not yet identified, it could be increased exposure
alive 10 years after diagnosis. to low dose ionizing radiation from radiographic
imaging as well as hormonal or nutritional fac-
tors. However the association of these risk factors
Calcification with low risk thyroid cancer is weak and
inconsistent.
(A) Differentiated thyroid cancer
(a) Papillary adenocarcinoma (Variants: Pathology
Follicular variant of papillary carci- Papillary carcinoma typically presents as a nod-
noma, Tall cell, columnar cells, ule that is firm and solid on ultrasound, some-
Oxyphyl, Solid sclerosing) times with internal calcifications. It is usually
(b) Follicular adenocarcinoma (variants: the dominant nodule in a multi-nodular goiter
Hurthle cell carcinoma, Clear cell carci- and with suspicious ultrasound characteristics.
noma, Insular carcinoma) However, especially in children it may sometimes
(B) Medullary Carcinoma present with enlarged cervical lymph nodes.
(C) Undifferentiated (Anaplastic Carcinoma) Occasionally there is hemorrhage, necrosis and
14 Thyroid Cancer 255
cyst formation in a malignant nodule on ultra- the world [8]. It tended to be more common in
sound. In such cases FNAC of the solid compo- areas of iodine deficiency and endemic goiter.
nent will reveal the underlying malignancy. It However owing to changing diagnostic criteria,
may also be found incidentally when the gland is rising incidence of PTC and iodine supplementa-
removed for another reason. tion, it frequency is decreasing. It occurs at a
PTCs usually are nonencapsulated, sharply slightly older age group than PTC and is rare in
circumscribed tumors. A small percentage may children. It occurs infrequently after radiation
spread directly through the thyroid capsule into exposure and is not commonly found at autopsy
the surrounding structures. as an occult inconsequential tumor.
The size of the primary lesion is important for
prognosis. Tumors <1.5 cm rarely metastasize Pathology
and virtually never cause death [7]. FTC is characterized histologically by the pres-
Microscopically, papillary cancer usually con- ence of small follicles with poor colloid forma-
sists of single layer of thyroid cells arranged in tion. ‘Minimally invasive’ FTC is an encapsulated
vascular stocks, with papillary projections tumor whose growth pattern resembles that of a
extending into microscopic cyst like spaces. The trabecular or solid, microfollicular, or atypical
nuclei of the cells are large and pale (“Orphan adenoma. FTC is distinguished from benign ade-
Annie Eye” nuclei) and frequently contain clear, noma microscopically by the presence of capsule
glassy intranuclear inclusion bodies. Psammoma and/or vascular invasion within the tumor cap-
bodies are calcified concentric laminated spheres sule. Such tumors have an indolent course similar
within or near the tumor and in nearby lymph to low-grade PTC. “Widely invasive” form of
nodes, these occur in about half the cases and are FTC may be partially encapsulated, however the
pathognomic of papillary carcinoma. margins are infiltrative even on gross examina-
A tumors is designated as follicular variant of tion and vascular invasion is often extensive.
PTC if the lining cells of the neoplastic follicles Such cancers are aggressive and have the poten-
have the same nuclear features as typical PTC tial for distant metastasis to bone, brain, lung and
and the follicular predominance over the papillae other organs.
is complete. When more than 75 % of cells in an FTC
Most PTCs remain confined to the thyroid exhibit Hurthle cell or oncocytic features (char-
gland and local lymph nodes. However these can- acterized by large individual cells with pink
cers can exhibit intraglandular metastasis and staining cytoplasm filled with mitochondria) the
lymph node spread. More aggressive tumors tumor is classified as Hurthle cell neoplasm.
especially in older patients can spread locally
into adjacent muscles nerves and the trachea. In Molecular Biology of Differentiated
later stages it may metastasize to the lungs, brain, Thyroid Cancer
bones and other organs. Two intracellular pathways have been identified
Anaplastic transformation may occur in well that play a role in thyroid cancer – the MAPK
differentiated PTC resulting in aggressive local (mitogen activated protein kinase) and PI3-AKT-
invasion of tumor and widespread rapidly fatal MTOR (phosphatidylinositide 3-kinase-protein
metastasis. kinase B-mammalian target of rapamycin) path-
ways. Aberrant activation of MAPK pathway
results in tumor promotion, whereas mutations in
Follicular Thyroid Carcinoma the PI3K-AKT-MTOR pathway decrease expres-
sion of tumor suppressor genes [9].
Epidemiology PTC is likely caused by mutations in genes in
Follicular thyroid carcinoma (FTC) is an unusual the MAPK signaling pathway, especially the
thyroid cancer comprising approximately 5–10 % BRAF mutation. Another common finding in
of thyroid cancers in nonendemic goiter areas of PTCs, especially after radiation exposure, are
256 Z. Alavi
gene rearrangements in which a portion of the is solid, or cystic with solid component or purely
RET gene (a receptor tyrosine kinase not nor- cystic (unlikely to be malignant), measures the
mally expressed in the thyroid), is linked to a size of the nodule, and identifies features suspi-
portion of one of several unrelated genes, produc- cious of malignancy and the presence or absence
ing a constitutively active chimeric RET receptor. of cervical lymphadenopathy. Sonographic char-
Subsequently loss of P53 suppressor gene may acteristics suspicious of malignancy include nod-
allow progression to anaplastic carcinoma. ule ecogenecity, increased nodular vascularity,
Activating mutations of RAS oncogene and irregular infiltrating margins, the presence of
loss of function of PTEN a tumor suppressor gene, microcalcifications, absent halo and a shape
are common in benign follicular adenomas. which is taller than width. Typically sonographic
Progression to follicular carcinoma may occur features of PTC and FTC differ. A PTC is gener-
after another genetic event involving a chromo- ally solid or predominantly solid and hyperechoic,
somal translocation forming a fusion gene between often with infiltrative irregular margins and
the thyroid transcription factor PAX8 and PPARɣ increased vascularity. Microcalcifications if pres-
gene (PAX8-PPARɣ). Further loss of suppressor ent are highly specific for PTC. Conversely FTC
gene P53 may allow progression to anaplastic is more often isoechoic and has a thick irregular
carcinoma. halo but no microcalcification. Certain sono-
graphic characteristics may also be highly predic-
Diagnosis tive of a benign nature of a nodule.
Most thyroid cancers present as a lump in the thy-
roid region detected by the patient or detected by Fine Needle Aspiration (FNA) Biopsy FNA is
physician on examination or incidentally found on the procedure of choice for evaluating a thyroid
radiological examination of the neck done for an nodule [10]. Ultrasound directed FNA is recom-
unrelated reason. There is a 5–10 % chance of a mended for those nodules which are non-palpable,
nodule to be malignant, most are benign. High risk predominantly cystic or located posteriorly in the
factors for malignancy are, extremes of age, family thyroid gland. FNA biopsy is the most accurate,
history of thyroid cancer, history of rapid increase safe and cost effective method of evaluating a thy-
in size of nodule, dyspnea, dysphagia, hoarseness roid nodule. Traditionally FNA results are divided
of voice. On examination large size of the nodule, into four categories, non-diagnostic, malignant,
hard nodule, lack of mobility, adherence to struc- intermediate or suspicious and benign.
tures, and ipsilateral lymphadenopathy. Routine FNA is not recommended for subcen-
timeter nodules. In suspicious subcentimeter
Investigations nodules sonography of lateral neck and central
Thyroid Function Tests when a thyroid nodule neck lymph nodes must be performed. Detection
is discovered a Serum TSH should be obtained to of abnormal lymph nodes should lead to FNA of
identify thyroid dysfunction but not to differenti- the lymph nodes. Other groups of patient for
ate between benign and malignant. If the TSH is whom consideration of FNA of subcentimeter
suppressed, a radionuclide thyroid scan should be node include, patients with high risk history;
performed to document whether the nodule is family history of PTC, history of external beam
hyper-functioning, or non-functioning. Since irradiation exposure as a child, exposure to ion-
hyper-functioning nodules rarely harbor malig- izing radiation in childhood or adolescence, prior
nancy, no cytological evaluation is necessary [10] history of hemithyroidectomy with discovery of
carcinoma, FDG-PET-positive nodules.
Thyroid Ultrasound diagnostic ultrasound is
one of the most useful adjunct to clinical exam for Molecular Markers molecular markers (eg
assessing thyroid nodules. It should be performed BRAF, RET/PTC, PAX8-PPARɣ, galactin-3)
in all patients with known or suspected thyroid may be considered for patients with intermediate
nodule [10]. It helps in determining if the nodule cytology on FNA to help guide management.
14 Thyroid Cancer 257
Table 14.1 TNM classification for differentiated thyroid to destroy any remaining thyroid cells, normal or
carcinoma
malignant. RAI improves the specificity of future
Definition surveillance imaging to detect recurrent disease.
T1 Tumor diameter 2 cm or smaller It also allows clinicians to monitor serum thyro-
T2 Primary tumor diameter >2–4 cm globulin, a protein made by thyroid follicular
T3 Primary tumor diameter >4 cm limited to the cells, as a marker of disease.
thyroid or minimal extrathyroidal extension
RAI ablation is recommended for all patients
T4a Tumor of any size extending beyond the
thyroid capsule to invade subcutaneous
with known distant metastases, gross extrathyroi-
soft tissues, larynx, trachea, esophagus, or dal extension of the tumor regardless of tumor
recurrent laryngeal nerve size, or primary tumor size >4 cm even in the
T4b Tumor invades prevertebral fascia or absence of other higher risk features. RAI abla-
encases carotid artery or mediastinal vessels tion is also recommended for selected patients
TX Primary tumor size unknown, but without with 1–4 cm thyroid cancers confined to the thy-
extrathyroidal invasion
roid, who have documented lymph node metasta-
N0 No metastatic nodes
ses, or other higher risk features when the
N1a Metastases to level VI (pretracheal,
paratracheal, and prelaryngeal/Delphian combination of age, tumor size, lymph node sta-
lymph nodes) tus, and individual histology predicts an interme-
N1b Metastasis to unilateral, bilateral, diate to high risk of recurrence or death from
contralateral cervical or superior thyroid cancer.
mediastinal nodes
RAI ablation is not recommended for patients
NX Nodes not assessed at surgery
with unifocal cancer <1 cm without other higher
M0 No distant metastasis
risk features or for patients with multifocal can-
M1 Distant metastasis
cer when all foci are <1 cm in the absence other
MX Distance metastasis not assessed
higher risk features.
Stages Patient age <45 Patient age >45
Stage I Any T, any N, M0 T1, N0, M0
Preparation for RAI Thyroid stimulating hor-
Stage II Any T, any N, M1 T2, N0, M0
mone (TSH) stimulation increases iodine uptake
Stage III T3, N0, M0
in the thyroid cell hence an elevated TSH is
T1, N1a, M0
T2, N1a, M0
required to achieve maximal uptake of RAI into
T3, N1a, M0
the remnant. This can be achieved by using injec-
Stage T4a, N0, M0 tion of recombinant human TSH (rhTSHThyro-
IVA genTM) given to the patient in the euthyroid state.
T4a, N1a, M0 Alternatively, TSH stimulation can be achieved
T1, N1b, M0 by withdrawing the patient from thyroxine ther-
T2, N1b, M0 apy which causes transient clinical hypothyroid-
T3, N1b, M0 ism (in such a case T3 is often prescribed
T4a, N1b, M0 temporarily at a dose of 25–50 μg daily in divided
Stage T4b, any N, M0 doses for 2–4 weeks; the medication is then with-
IVB drawn for 2 week, and the patient quickly
Stage Any T, any N, M1 becomes hypothyroid prior to RAI). In general
IVC
rhTSH is preferred, since hypothyroidism is
The source of this material is the AJCC Cancer Staging
avoided and whole body radiation exposure is
Manual, Sixth Edition
lower as radioiodine is cleared from the body
more rapidly. ThyrogenTM injection (0.9 mg) is
Radioactive Iodine (RAI) given as an intramuscular injection on two con-
secutive days followed by RAI on third day.
A small amount of thyroid tissue, called the thy- Regardless of how the patient achieves the ele-
roid remnant, is often left after total thyroidec- vated TSH a low iodine diet is prescribed for 2
tomy. RAI can be administered postoperatively weeks to enhance uptake of RAI.
14 Thyroid Cancer 259
Pretherapy scan may be useful when the extent should be done to look for residual cancer, and if
of thyroid remnant cannot be accurately ascer- found, additional surgery may be warranted. If
tained or when results would alter the decision to stimulated thyroglobulin is greater than 20 ng/ml
treat or the RAI dose. Following thyroid hormone and other imaging studies are negative, some
withdrawal or rhTSH stimulation, the serum thy- experts recommend empiric RAI therapy because
roglobulin level is determined, and the patient is of the high suspicion of residual disease.
scanned 24–72 h after a low dose RAI (1–4 mCi Follow-up at intervals of 6–12 months should
of 131I or 1–2 mCi of 123I). If the decision is to give include local neck exam, sometimes including
ablative RAI then 131I is administered in a dose of ultrasound exam looking for recurrent mass or
30–100 mCi depending on the size and invasive- cervical lymph nodes. If abnormal lymph nodes
ness of the primary tumor. are discovered an FNAB is indicated. The patients
A posttherapy scan is recommended following TSH should be checked to see if adequately sup-
RAI remnant ablation. This is typically done pressed. The serum thyroglobulin should be peri-
2–10 days after the therapeutic dose is adminis- odically checked to be certain it is undetectable.
tered, to be sure no additional areas of radioio- A rise in serum thyroglobulin while the TSH is
dine uptake are revealed. suppressed suggests tumor recurrence and imag-
ing studies such as ultrasound, CT, MRI should
TSH Suppression Therapy be done. A PET scan can be especially useful in
Similar to normal follicular cells, thyroid cancer such situations when other imaging studies are
cells express thyrotropin receptors and respond negative.
to TSH by increasing cell growth. Lifelong sup- Thyroglobulin antibodies interfere with the
pression of TSH using supra-physiological doses thyroglobulin assay and result in falsely low thy-
of thyroxine, is commonly used to treat patients roglobulin result. Hence patients who are positive
with thyroid cancer in an effort to decrease the for these antibodies should be followed up with
risk of recurrence. Initial TSH suppression to ultrasound or CT.
below 0.1 mU/L is recommended for high risk
and intermediate risk thyroid cancer patients, Treatment Options for Advanced DTC
while maintaining a TSH slightly below normal Patients with progressive DTCs that are not
(0.1–0.5 mU/L) is appropriate for low risk responsive to standard treatment require addi-
patients. tional therapy. Neck dissection should be consid-
ered even in metastatic disease. External beam
Long Term Management radiation (EBRT) may help provide local control.
Nine to twelve months later rhTSH is adminis- Doxorubicin is approved for treatment of thyroid
tered or thyroid hormone therapy is withdrawn, cancer, however response rates are low and short
and a radioiodine scan and thyroglobulin are lived. Doxorubicin may act as a radiation sensi-
repeated to document ablation of all functioning tizer in some cancers of thyroid origin.
thyroid tissue. An undetectable thyroglobulin at a
time when TSH is elevated is the most sensitive Novel Therapies
evidence that all thyroid tissue has been In recent years, new targeted agents for the treat-
eradicated. ment of advanced thyroid cancer have emerged.
If the patients TSH stimulated thyroglobulin The rationale for these agents is that they target
(usually achieved by giving rhTSH) is less than and block known aberrancies in thyroid carci-
1 ng/ml and the whole body radioiodine scan is noma, namely constitutive activation of the
negative, the patient is considered to be disease MAPK and/or PI3 pathway and vascular endo-
free. On the other hand, if the serum thyroglobu- thelial growth factor receptors (VEGFRs). Most
lin concentration rises above 2 ng/ml and/or if the of these novel agents are tyrosine kinase inhibi-
radioiodine scan is positive, the patient is likely tors and include Axitinib, Motesanib, Sorafenib,
to have either persistent thyroid tissue or residual Sunitinib and Pazopanib. Thalidomide and
thyroid cancer. Neck sonography, CT or MRI Lenalidomide are inhibitors of angiogenesis.
260 Z. Alavi
Some of these agents are still in phase II and Presentation and Diagnosis
phase III trials while others have established effi-
cacies. The role of these agents in the manage- The clinical symptoms at the time of presentation
ment of advanced radioiodine refractory cancers vary. MTC usually appears as a hard nodule or
is emergent and needs to be clarified as to which mass in the thyroid gland or as an enlargement of
patients may benefit most from these agents. the regional lymph nodes. The neck mass is fre-
quently painful and often located in the upper
two thirds of each lobe of the gland, reflecting the
Medullary Thyroid Cancer anatomic location of the parafollicular cells.
Patients with familial MTC who are identified on
Epidemiology and Pathology screening are usually identified before develop-
ment of macroscopic disease. Differentiation of
Medullary thyroid cancer (MTC) account for 3–6 % sporadic MTC from other types of thyroid nod-
of thyroid cancer [8]. It arises from the parafollicu- ules on clinical grounds may be difficult. In a
lar or C cell of the thyroid gland. MTC tumors are patient with a family history of thyroid cancer
usually firm and non-encapsulated. On histologic associated with hypertension or hyperparathy-
examination the tumor is composed of cells that roidism, the MEN 2A syndrome should be sus-
vary in their morphologic features and arrange- pected. In MEN2A hyperparathyroidism occurs
ments. Round polyhedral and spindle shaped cells late. Pheochromocytomas invariably occur later
form solid and trabecular glandular like structures. than MTC and are often bilateral and may be
An amyloid like stroma is commonly present [15]. clinically silent. In MEN 2B, MTC and pheo-
Gross or microscopic foci of carcinoma may be chromocytoma are associated with multiple
present in other parts of the gland, and blood vessels mucosal neuromas (‘Bumpy lip syndrome’), a
may be invaded. The tumors typically produces Marfinoid habitus and typical facies, but they do
early biochemical signals and are capable of secret- not have hyperparathyroidism.
ing calcitonin, carcinoembryonic antigen (CEA), FNAB has made it possible to diagnose MTC
histamine, prostaglandins, serotonin, VIP, cortico- prior to surgery. Positive immunocytochemical
trophin and other peptides. staining for calcitonin allows confirmation of
MTC is typically more aggressive than DTC, diagnosis. Basal plasma calcitonin levels are ele-
extending locally to cervical lymph nodes and vated in virtually all the patients with MTC. If
into surrounding tissues. It may also invade lym- MTC is diagnosed in a patient on FNAB or at
phatics and blood vessels, and metastasize to surgery, it is essential that the patient be screened
other viscera. Serum calcitonin (which is invari- for one of the familial MTC syndromes by DNA
ably secreted by the tumor) and CEA are useful analysis for mutations in the RET protoonco-
markers for diagnosis and follow up. gene. If screening is negative then the tumor is
MTC occurs in both sporadic and familial most likely sporadic and other family members
forms. The familial form make up approximately need not be screened. On the other hand family
20 % of the total. There are three familial forms; members of a patient with an RET oncogene
(1) Familial medullary cancer without associated should be screened.
endocrine disease; (2) Multiple endocrine neopla-
sia 2A (MEN 2A), consisting of medullary thyroid
carcinoma, pheochromocytoma and hyperparathy- Treatment
roidism; and (3) MEN 2B, consisting of medullary
thyroid cancer, pheochromocytoma, multiple Early and adequate initial thyroidectomy and
mucosal neuromas (bumpy lip syndrome), as well regional node dissection is the best therapy for
as intestinal ganglioneuromatosis. These familial MTC. More extensive surgery may be warranted,
syndromes are due to RET protooncogene muta- depending on the extent and invasiveness of the
tions mostly in exon 10, 11 or 16. tumor. Patient with MTC should be evaluated for
14 Thyroid Cancer 261
Abstract
Psychiatric manifestations are not uncommon presentation of thyroid dys-
function. Although, depression and anxiety are likely to occur in both hypo
and hyperthyroidism, there are much more mental symptoms which may
take place within a course of thyroid dysfunction. Those symptoms may
present as a mood, psychotic, cognitive and anxiety in character. The mech-
anism of such mental symptoms in relation to thyroid abnormalities is still
unclear. Proper management is expected to bring about good outcome.
corrective utilization of thyroid hormones (TH). Table 15.1 Psychiatric disorders related to thyroid
dysfunction
This observation encouraged clinicians to experi-
ence the efficacy of these hormones in the treat- Psychiatric
ment of depression [4]. disorder Type
Thyroid hormone is required for the metabolic Mood Major depressive disorder
disorders Dysthymia
activity of every cell in the body. When patients
Atypical depression
experience symptoms related to abnormal func-
Bipolar Type I and type II
tioning of the hypothalamic-pituitary-thyroid disorder Cyclothymia
axis, psychiatrists often are the first professionals
Anxiety Generalized anxiety disorder
they consult. Diagnosis of thyroid disorders is disorder Social phobia
based on biochemical and clinical data which
Panic disorder
might not be congruent. Clinical symptoms of
Phobias
hypothyroidism, for example, are notoriously
Psychotic Schizophrenia
variable. Severe biochemical hypothyroidism disorder Schizophreniform disorder,
may be associated with mild clinical symptoms, Schizoaffective disorder,
whereas mild biochemical hypothyroidism may Brief psychotic disorder,
be associated with severe symptoms [5]. Delusional disorder,
Mental state examination of a hypothyroid Chronic hallucinatory psychosis
patient may reveal a broad spectrum of dysfunc- Cognitive Attention, concentration, memory,
tion, ranging from mild attention impairment to a disorder problem solving etc
significant agitated delirium or psychosis.
Patients with thyrotoxicosis may experience
behavioral and personality changes, such as psy- will be defined generically as something actually
chosis, agitation, and depression. Less overt man- wrong with a subject. It might be a condition, an
ifestations that are more common in less severe abnormality, a sign or a symptom. On the other
thyrotoxicosis include anxiety, restlessness, irrita- hand, disease is a definite pathological process hav-
bility, emotional labiality and insomnia [6]. ing a characteristic set of signs and symptoms [7].
Consequently psychiatric manifestations of Psychiatry also deals with spectrum disorder
thyroid dysfunction diverge much (see Table 15.1 which includes a range of disorders containing
below). They could be classified globally into core manifestations in their clinical presentation.
mood, cognitive, psychotic and anxiety disor- A spectrum disorder is a mental disorder that
ders. In this chapter, those psychiatric manifesta- includes a range of linked conditions. The differ-
tions or disorders will be detailed and clarified. ent elements of a spectrum either have a similar
The neurophysiological basis and possible mech- appearance or are thought to be caused by the
anisms for psychiatric symptoms will be dis- same underlying mechanism. The spectrum may
cussed. Management and outcome of such represent a range of severity, comprising rela-
disorders will be covered as well. tively “severe” mental disorders through to rela-
tively “mild and nonclinical deficits” [8, 9].
“default system” of cortical areas that include the the amygdale and the mammillary bodies are
dorsal prefrontal cortex, mid- and posterior cin- thought to be involved in certain kinds of mem-
gulated cortex, anterior temporal cortex, and ory and cognition. For example, the hippocampus
entorhinal and parahippocampal cortex. is believed to be involved in spatial learning and
Dysfunctions within and between structures in declarative learning. Damage to certain areas in
this circuit may induce disturbances in emotional patients and animal models and subsequent
behavior and other cognitive aspects of depres- memory deficits is a primary source of informa-
sive syndromes in humans [10]. tion. The dorsolateral prefrontal and posterior
Norepinephrine, serotonin, dopamine and ace- parietal cortex are two components of the cortical
tylcholine are involved with mood regulation. network controlling attention, working memory
The limbic cortex is linked with both the neocor- and executive function [14].
tex, which subserves higher symbolic functions, Acetylcholine, norepinephrine, serotonin,
the midbrain and lower brain centers, which are GABA, histamine, adenosine, nitric oxide and
involved in autonomic control, hormonal produc- choleystokinin play role in memory and learning
tion, and sleep and wakefulness. Nor epinephrine- in animals.
containing neurons are involved in many of the
functions that are profoundly disturbed in melan-
cholia, including mood, arousal, appetite, reward, Mood Disorders
and drives. Other neurotransmitters that mediate
such functions are the catecholamine dopamine, Mood disorder is a group of diagnoses where a
especially important for psychomotor activity, disturbance in the person’s mood is hypothesized
and the indoleamine serotonin, involved in mood to be the main underlying feature. They are
and sleep and inhibitory control. Cholinergic broadly classified into unipolar and bipolar disor-
neurons, secreting acetylcholine at their dendritic der. In unipolar depression there are episodes of
terminals, are generally antagonistic in function depressive symptoms while in Bipolar disorders
to catecholaminergic neurons [11]. there are episodes of depression and others of
Anxiety disorders have been linked to dis- mania or hypomania [15].
rupted functional connectivity of the amygdala Mood is defined as Pervasive and sustained
and it’s processing of fear and anxiety. Sensory feeling tone that is experienced internally and
information enters the amygdala through the that in the extreme, can markedly influence virtu-
nuclei of the basolateral complex (consisting of ally all aspects of a person’s behavior and percep-
lateral, basal and accessory basal nuclei) [12]. tion of the world. While affect is the subjective
The three major neurotransmitters associated and immediate experience of emotion attached to
with anxiety on the bases of animal studies and ideas or mental representations of objects. Affect
responses to drug treatment are nor epinephrine, has outward manifestations that can be classified
serotonin, and gamma amino butyric acid as restricted, blunted, flattened, broad, labile,
(GABA). Much of the basic neuroscience infor- appropriate or inappropriate.
mation about anxiety comes from animal experi- Patients with thyroid disturbance and psychiatric
ments involving behavioral paradigms and symptoms most often are diagnosed with mood
psychoactive agents. changes usually related to depressive-spectrum [5].
In Schizophrenia, studies using neurophysi- Depressive affect has been reported as a frequent
ologic tests and brain imaging such as MRI and association with hypothyroidism and a regular fea-
PET to examine the functional differences in ture of early cases of hypothyroidism [16].
brain activity have shown that differences seem Several of the metabolic and behavioral
to most commonly occur in frontal lobes, hippo- changes seen in hypothyroidism are common
campus and temporal lobes [13]. to depression, suggesting that changes in the
As regards cognitive functions, brain areas pituitary–thyroid system may play a role in the
such as the prefrontal cortex, the hippocampus, modulation of mood [17].
266 E. Elmaghraby
Patients with subclinical hypothyroidism have of reproductive age; however, late-onset mania
higher prevalence of depression than the general associated with hypothyroidism in an elderly
population and it has been proposed that this clin- woman has been reported [26, 27].
ical entity shares with overt hypothyroidism the Mood Disorders could occur with either hypo
capability of causing depression, being consid- or hyper function of thyroid gland. In DSM.5
ered one of the main risk factors in non-elderly they are classified as mood disorder due to
women with 56 % prevalence of life time depres- another medical condition [28].
sion in this population as compared to 20 % in the Several studies have suggested that mild
euthyroid population [18]. symptoms of hypothyroidism are commoner and
In another study by Haggert and Prange scores on measures of depression and anxiety
reported that 15–20 % of depressed patients show higher in patients with subclinical hypothyroid-
subclinical hypothyroidism and also show poor ism than in age-matched controls. These find-
response to antidepressant therapy [19]. In case ings, however, are inconsistent with other studies
of refractory depression are these rates are even that have found no significant differences . Mild
higher. hypothyroidism is also more frequent in rapid
Howland, in his review of six studies, found a cycling bipolar disorder, occurring in up to 25 %
mean rate of 52 % as compared to 8–17 % in gen- of cases. Thyroxin supplementation of estab-
eral population and concluded that subclinical lished treatment for bipolar disorder has been
hypothyroidism is significantly associated with shown to reduce the number of episodes.
refractory depression [20]. In a large epidemiological study involved
In a study of twins, autoimmune thyroiditis 30,175 individuals, no associations were found
was related to bipolar disorder and the genetic between antithyroid antibodies and depression or
tendency to develop bipolar disorder. The authors anxiety [29].
suggest that autoimmune thyroiditis, using the Generally hypothyroid patients usually meet
marker of thyroperoxidase antibodies, is a possi- several criteria for a major depressive episode—
ble endophenotype for bipolar disorder [21]. such as concentration difficulties, lassitude, low
Another study evaluating outpatients with libido, and sometimes pessimism or sadness.
bipolar disorder found thyroid autoimmunity to Symptoms improve after sustained thyroid hor-
be highly prevalent. The presence of thyroperoxi- mone replacement therapy [30]. In one study no
dase antibodies appeared to be an independent statistical association between thyroid dysfunc-
risk factor for the development of hypothyroid- tion and the presence of depression or anxiety
ism, particularly in women with bipolar disorder disorder was found [31].
[22]. While another study showed association
Thyroid dysfunction is more common in between estimated free thyroxine level and sever-
patients with rapid cycling bipolar disorder (i.e., ity of depression [32].
having 4 or more mood swings or episodes in a
12-month period) or mixed states (i.e., an episode
that simultaneously presents symptoms of both Antidepressant Effects on Thyroid
depression and mania) than in patients with clas- Function
sic mania [23].
Levothyroxine may decrease the severity and Associations between lithium, the gold-standard
frequency of manic and depressive episodes [24]. for treatment of bipolar disorder, and thyroid
In addition, triiodothyronine has been effec- function have been recognized for some time.
tively used as an augmentation agent in treatment- A review of the literature found that Inhibition of
resistant bipolar depression [25]. thyroid hormone release is critical for the devel-
While hyperthyroidism is typically associated opment of hypothyroidism and goiter;
with mania, there are case reports of mania or Hypothyroidism may occur in the early years of
hypomania associated with hypothyroidism. lithium use, in middle-aged women, and when
These reports typically occurred in young women thyroid autoimmunity is present; The outcome of
15 Thyroid Dysfunction and Mental Disorders 267
thyroid dysfunction in patients who have been on intervention. All recovered completely. Such
lithium for many years is not greatly different patients often had a personal or family history of
from that observed in the general population, and psychiatric disorder and had frequently been
Hyperthyroidism and thyroid cancer are uncom- depressed or delusional prior to starting
mon during treatment with lithium. The authors treatment [37].
recommend that thyroid function tests to be per- Psychosis is an uncommon association of hyper-
formed at baseline prior to lithium initiation and thyroidism, which may occasionally be the present-
repeated after 1 year. An annual TSH may then ing feature and lead directly to psychiatric referral.
be sufficient to detect hypothyroidism. Thyroid A study of thyrotoxic psychosis from New Zealand
function abnormalities are not a contraindication suggested that in contemporary practice approxi-
to lithium treatment and lithium should not be mately 1 % of thyrotoxic patients are first diagnosed
discontinued if thyroid abnormalities occur [33]. with a major psychiatric illness [38].
A recent nested, matched, case–control study The diagnostic distinctions between the affec-
of patients with bipolar disorder and incident tive and schizophrenic reactions are often blurred,
hypothyroidism found that lithium, carbamaze- and an admixture of organic psychiatric features
pine and valproate increased the risk for hypothy- is relatively common.
roidism. Combination of agents (especially
lithium and valproate) further heightened risk for
hypothyroidism. Based on these results, the Cognitive Changes
authors recommend regular monitoring of thy-
roid function and monotherapy of mood stabiliz- Cognitive functions is a broad term which encom-
ers for treatment of bipolar disorders [34]. pass a variety of integrated brain functions e.g.,
attention, concentration, memory, perception, lan-
guage, information processing, orientation and
Psychosis decision making. Initially in thyroid dysfunctions
cognitive changes are non-specific and ill-defined.
Psychosis refers to an abnormal condition of the Cognitive disturbances include the inability to
mind, and is a generic psychiatric term for a men- concentrate, poor attention, bradyphrenia, calcu-
tal state often described as involving a “loss of lation difficulties and difficulty understanding
contact with reality. The term “psychosis” is very complex questions. Memory is often affected
broad and can mean anything from relatively nor- from an early stage, with failure to register events
mal aberrant experiences through to the complex and forgetfulness for day-to-day events. Memory
and catatonic expressions of schizophrenia and for remote events may also deteriorate in chronic
bipolar disorder [35]. cases. Psychomotor retardation is seen and fatiga-
Patients with thyroid dysfunction may develop bility ability is conspicuous. Elderly patients may
a spectrum of psychotic presentation e.g., schizo- have a less activated presentation with depression
phrenia, schizoaffective disorder and delusional and lethargy, so-called apathetic thyrotoxicosis .
disorder. In one review of elderly patients with hyperthy-
Very occasionally in treatment of hyperthy- roidism, dementia and confusion were found in
roidism the initiation of treatment is accompa- 33 and 18 % of patients respectively [39].
nied by the emergence of psychotic disorder, Studies in younger individuals with newly-
which interestingly usually takes the form of diagnosed hyperthyroidism have found lower
mania. Josephson and Mackenzie (1980) referred cognitive scores compared with controls [40, 41].
to 18 examples in the literature, 12 being manic With chronic thyroid dysfunctions, the ability
illnesses and the others mixed affective or depres- to perform everyday routine tasks is decreased
sive disorders [36]. and such tasks take a progressively longer time to
The symptoms usually began within 4–7 days be completed. Patients become less concerned
of starting thyroxin treatment, resolving over about and less responsive to others, and there is
1–2 weeks irrespective of further therapeutic marked inability to sustain mental exertion. The
268 E. Elmaghraby
patient also becomes less capable of learning and recurring worry about common events; and
performing new tasks. Speech is reduced and physical symptoms, such as muscle tension,
perseverations are frequently seen. Alterations in insomnia, and fatigue [43].
the accuracy of perception may also develop [5]. Anxiety disorders are common in the setting
Acute organic reactions accompany ‘thyroid of medical disease and are associated with sev-
crises’ and show the typical picture of delirium, eral types of psychosomatic presentations [44].
usually are accompanied by fever. They were for- Generalized anxiety has been reported in 80 %
merly one of the commonest forms of major of those who have hyperthyroidism. An associa-
mental illness encountered in the disease, but are tion with panic disorder and the earlier ‘atypical
now very rare because of modern methods of organic brain syndrome’ and ‘organic anxiety
treatment. They constitute a grave emergency syndrome’ has been described as well [45, 46].
and warrant urgent intervention [3, 42].
In a study included 1,327 adolescents 13–16
years old in the United States, subclinical hypo- Mechanism of Psychiatric Disorders
thyroidism, subclinical hyperthyroidism and Associated with Thyroid
euthyroid groups were defined. Cognitive perfor- Dysfunction
mance was assessed using the subscales of the
Wide Range Achievement Test-Revised The question of whether the cerebral hypome-
(WRAT-R) and the Wechsler Intelligence Scale tabolism seen in hypothyroidism is a conse-
for Children-Revised (WISC-R). Results showed quence of a direct action of thyroid hormones on
that subclinical hypothyroidism was found in neurons or is secondary to altered cerebral blood
1.7 % and subclinical hyperthyroidism was found flow remains unanswered and will perhaps await
in 2.3 % of the adolescents. Cognitive assessment the development of techniques to directly
scores on average tended to be lower in adoles- measure CNS thyroid metabolism in vivo.
cents with subclinical hyperthyroidism and Nevertheless, the associated mental symptom-
higher in those with subclinical hypothyroidism atology can be largely ascribed to changes in
than the score for the euthyroid group. cerebral metabolism, regardless of cause. Cases
Adolescents with subclinical hypothyroidism of major affective disorder and schizophrenia are
had significantly better scores in block design likely to be determined by both organic factors,
and reading than the euthyroid subjects even after genetic and environmental factors. In the rare
adjustment for a number of variables including examples where organic features are entirely
sex, age and family income level. It was con- absent from the mental state, the cerebral meta-
cluded that subclinical hypothyroidism was asso- bolic defect has probably served merely as a
ciated with better performance in some areas of precipitant. However, the situation is not entirely
cognitive functions while subclinical hyperthy- straightforward, since patients with purely
roidism could be a potential risk factor [40]. depressive symptomatology with no evidence of
hypothyroidism have been found to respond to
thyroxine, often after other forms of treatment
Anxiety Disorders have failed entirely [47].
This is followed by evaluating types and severity of levothyroxine and would require larger doses
of functional impairment with quality of life of of the drug. The selective serotonin reuptake
the patient. Coordination of the patient’s care inhibitor (SSRI) sertraline widely prescribed for
with other clinicians should be arranged. It is depression, has been associated with a decrease
central to define the goals of the treatment and to in the effect of levothyroxine. Further studies are
monitor the patient’s psychiatric status. It is also needed on this, and on any similar effects of other
vital to keep an eye on the patient’s adherence to SSRIs. Levothyroxine increases receptor sensi-
the treatment plan and to overcome the obstacles tivity to catecholamines thus accelerating the
which diminish compliance. Providing education response to tricyclic antidepressants. St. John’s
to the patient and, when appropriate, to the fam- wort(antidepressant) is also an enzyme inducer.
ily is crucial and mandatory in determining the One study found that it may increase levothyrox-
success of the management plan. ine metabolism. Taking the two drugs should be
In psychiatry the management plan usually go avoided, since it may cause hypothyroidism [49].
through three consecutive phases. The acute Lithium is used as an integral component in
phase followed by continuation and maintenance the management of acute mania, unipolar and
phases. Treatment in the acute phase should be bipolar depressive disorder. It is also used as
aimed at inducing remission of the major depres- long-term prophylaxis of bipolar disorders.
sive episode and achieving a full return to the Thyroid abnormalities associated with lithium
patient’s baseline level of functioning [48]. treatment have been widely reported in the
During the continuation phase of treatment, medical literature over the last five decades.
the patient should be carefully monitored for These include hypothyroidism, hyperthyroidism,
signs of possible relapse. Systematic assessment unmasking or induction of autoimmune thyroid-
of symptoms, side effects, adherence, and func- itis and goiter [50, 51].
tional status is essential and may be facilitated Despite adequate therapy with thyroxine and
through the use of clinician- and/or patient TSH within the desired range, many hypothyroid
administered rating scales. patients complain of persistent lethargy and other
Maintenance therapy should also be consid- persisting psychological symptoms. A random-
ered for patients with additional risk factors for ized clinical trial has suggested that combined
recurrence, such as the presence of residual therapy with tri-iodothyronine and thyroxine
symptoms, ongoing psychosocial stressors, early leads to improved cognitive performance, mood
age at onset, and family history of mood and physiological well-being compared with
disorders. treatment with thyroxine alone [52].
It is important to recognize and address the However, subsequent randomized clinical tri-
potential interplay between Psychiatric disorder als have failed to replicate these findings, leading
and thyroid dysfunction. Communication with to suggestions that it is perhaps only patients with
other clinicians who treat the patient is recom- complete absence of thyroid function alone who
mended. The clinical assessment should include may benefit from combined therapy [53, 54].
identifying any potential interactions between Optimum treatment of persistent psychologi-
medications used to treat depression and those cal symptoms and mood disturbance therefore
used to treat thyroid dysfunction. In addition, the currently remains unclear.
psychiatrist should consider the effects of pre-
scribed psychotropic medications on the patient’s
general medical conditions, as well as the effects Outcome of Mental Disturbances
of interventions for such disorders on the patient’s
psychiatric condition. The treatment of hypothyroidism is usually highly
Drugs used to treat seizures including carbam- rewarding, with behavioral disturbances responding
azepine, oxcarbazepine, phenobarbital, primi- well to adequate thyroxin therapy, although supple-
done and phenytoin can increase the metabolism mentation with an antidepressant or neuroleptic is
270 E. Elmaghraby
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Thyroid Dysfunction
and Arrhythmias 16
Sonia Marrakchi Meziou, Faouzi Kanoun,
Dania Idriss Marrakchi, Ikram Kammoun,
and Salem Kachboura
Abstract
Context: Arrhythmia is a major cause of morbidity and mortality in Europe
and in the United States. The aim of this review article was to assess the
results of the prospective studies that evaluated the risk of arrhythmia in
patients with overt and subclinical thyroid disease and discuss the man-
agement of this arrhythmia.
Evidence Acquisition: Reports published with the following search terms
were searched: thyroid, hypothyroidism, hyperthyroidism, subclinical
hyperthyroidism, subclinical hypothyroidism, levothyroxine, triiodothyro-
nine, antithyroid drugs, radioiodine, deiodinases, atrial flutter, supraven-
tricular arrhythmia, ventricular arrhythmia, ventricular tachycardia,
ventricular fibrillation, torsade de pointe, amiodarone and atrial fibrilla-
tion. The investigation was restricted to reports published in English.
Evidence Synthesis: The outcome of this analysis suggests that patients with
untreated overt thyroid dysfunction are at increased risk of arrhythmia.
Conclusions: The timely recognition and effective treatment of thyroid
dysfunction in patients with arrhythmia is mandatory because the long-
term and prognosis of arrythmias may be improved with the appropriate
treatment of thyroid dysfunction.
Abbreviations
S. Marrakchi Meziou, MD (*) • I. Kammoun
S. Kachboura AF Atrial fibrillation
Cardiology Department, Abderrahman Mami AIT Amiodarone-induced
Hospital, Ariana, Tunisia
thyrotoxicosis
e-mail: marrakchi.sonia@yahoo.fr
AP Action potential
F. Kanoun
EAD Early afterdepolarization
Endocrinology Department, La Rabta Hospital,
Tunis, Tunisia ECG Electrocardiogram
FT4 Free thyroxine
D. Idriss Marrakchi
Department of Molecular Biology, University Manar IK Delayed rectifier potassium
2 of Tunis, Tunis, Tunisia current
In the ventricle, the transcription of the beta controversy regarding the relative contributions
myosine heavy chain (β-MHC) antisense (AS) of various ionic currents, it is becoming clear that
gene appears to be associated with and linked to the a variety of ionic currents are responsible for
transcription of the α-MHC gene; both are induced pacemaker activity in various regions of the
in the presence of T3. However, in atria this expres- heart. Sun et al. [18] demonstrated through elec-
sion appears to be uncoupled. As observed in the trophysiological recordings that thyroid hormone
ventricles, the expression of the β-MHC AS gene increases the pacemaker rate of these myocytes
in the atria is inversely correlated, while the expres- by increasing the slope of spontaneous depolar-
sion of the α-MHC gene is not thyroid hormone ization. Under voltage clamp conditions, Sun
responsive and highly expressed in all thyroid et al. focused on several ionic currents that may
states. This observation demonstrates for the first be involved in pacemaker activity in atrial cells,
time that the previously identified shared promoter including ICa, If and INa/Ca. of the ionic cur-
region that lies in the intergenic region between the rents studied, the electrogenic Na+−Ca2+
b-MHC and a-MHC genes is differentially regu- exchange current was the only candidate to be
lated in a tissue-specific manner [10]. Exploration changed by T3 and which may have altered the
of the differences in cofactors and potential epigen- slope of spontaneous depolarization. They sug-
etic influences in this shared intergenic promoter gest that, of the ionic currents studied, T3 might
region in atria and ventricles may provide addi- accelerate diastolic depolarization and pace-
tional information regarding the potential mecha- maker activity (at least in part) by an up-
nism by which T3 influences the MHC genes in the regulation of the Na+−Ca2+ exchanger.
human heart [12]. Several ionic currents may contribute to pace-
maker activity in this tissue, including If, the
delayed rectifier potassium current (IK) [19–21],
Non Genomic Action of Thyroid both the L-type (ICa,L) and T-type (ICa,T) cal-
Hormone on Heart cium currents [20] and a background Na+ current
(Ib) [19]. The electrogenic Na+−Ca2+ exchanger,
In addition to the well-characterized nuclear triggered as a result of SR Ca2+ release, may also
effects of thyroid hormone, some cardiac responses contribute to the initial phases of diastolic depo-
to thyroid hormone appear to be mediated through larization in the sinoatrial (SA) node [22]. Thus,
non genomic mechanisms [16], as suggested by the positive chronotropic action of thyroid hor-
relatively rapid onset of action-faster than can be mones is potentially caused by modulation of any
accounted for by changes in gene expression and of these electrogenic ion conductances and/or by
protein synthesis and failure to be affected by alterations in intracellular calcium homeostasis.
inhibitors of gene transcription. The significance Early experimental studies of thyroid hor-
of these diverse actions remains to be established, mone effects on transmembrane potentials of
but may explain the ability of acute T3 to alter car- sinoatrial node cells and atrial muscle cells
diovascular hemodynamics. They may alter the showed an increased rate of diastolic depolariza-
functional proprieties of membrane ion channels tion and decreased duration of action potential in
and pumps, including the sodium channel and thyrotoxic animals, suggesting that conductance
inward rectifying potassium current (IK) [17]. of K1 ions may be altered [23, 24].
Thyroid hormones have profound effects on the Recent evidence has shown that thyroid hor-
cardiovascular system. The mechanism of pace- mones exert effects on the cardiovascular system
maker activity in adult cardiac tissue is increas- that are not mediated by alterations in gene
ingly well documented. Although there is some expression. Sakaguchi and co-workers [25]
276 S. Marrakchi Meziou et al.
showed that T3 caused a shortening of the action myosin heavy chain isoform expression and the
potential duration in guinea pig ventricular myo- relative abundance of the sarcoplasmic reticulum
cytes by increasing whole cell inward rectifier (SR) calcium pumps (SR Ca2+-ATPase) and its
potassium current (IK1). phosphoprotein inhibitor, phospholamban,
In the rat ventricular myocyte, two primary although other thyroid hormone–mediated effects,
depolarization-activated outward currents are such as those reported for L-type calcium channels
important in regulating action potential duration: and Na+/K+-ATPase pumps cannot be excluded.
the Ca21-independent transient outward K1 cur- Thyroid hormone potentiates the effect of
rent (Ito) and a slowly inactivating K1 current adrenergic system on heart. Catecholamine levels
(IK) [26]. are either normal or decreased in thyrotoxicosis.
Although thyroid hormone has been shown to Facilitation of action of catecholamines is by
regulate the expression of numerous cardiac- increasing tissue sensitivity by increased tran-
specific genes, Sun et al. [27] show that T3 short- scription of beta adrenergic receptors and struc-
ens the action potential duration (APD) in tural similarity to catecholamines. Hyperthyroidism
hypothyroid rats due at least in part to the increase is associated with reduced vagal activity and
of the delayed rectifier current IK. The Ito appears reduced heart rate variability which can persist
to be regulated by thyroid hormone at the tran- despite restoration of euthyroidism [32]. Ojamaa
scriptional level, whereas the IK is regulated by a et al. [33] indicate that an analysis confined to the
nongenomic mechanism of action. changes in 13-adrenergic receptor expression is
insufficient to ascertain the role of catecholamines
as mediators of thyroid hormone--dependent
Relation Between Thyroid Hormone effects on cardiac autonomic responsiveness. It is
and Adrenergic System important to consider all three components, the
β3-adrenergic receptor, G-coupled protein, and
Many of the cardiovascular manifestations of thy- catalytic subunit expression, in assessing adrener-
roid hormone excess resemble those produced by gic responsiveness of target tissues.
sympathoadrenal stimulation. Since plasma cate-
cholamine levels and turnover rates are not
increased in hyperthyroidism [28], it has been Mechanism Underlying the Effect
argued that the effects of thyroid hormone result of Thyroid Hormone (TH)
partly from increased responsiveness to catechol- on the Arrhythmogenesis
amines. This hypothesis is supported by studies
that indicate that β-aderenergic receptor (βAR) Thyroid hormone has been shown to have several
number and sensitivity are increased in isolated cardiovascular effects, and hyperthyroidism has
hearts and cultured cells from experimental ani- been known to be an important factor in the
mals (most often the rat) treated with thyroid hor- etiology of atria and ventricles arrhythmias [5].
mone [29, 30]. The influence of thyroid hormone In fact, there are always three main ingredients
on adrenergic responsiveness is particularly con- required for the production of a clinical arrhyth-
troversial in large animals and humans but Brian mia: (1). the arrhythmogenic substrate; (2). the
et al. [31] suggest that the cardiac mechanical trigger factor; (3). the modulation factors of
effects of hyperthyroidism cannot be explained by which the most common is the autonomic ner-
enhanced sensitivity to catecholamines. Despite vous system [34]. The cardiovascular manifesta-
significant increases in basal heart rate and rates of tions of thyroid dysfunction is due to three
left ventricular (LV) contraction and relaxation, potential mechanisms by which thyroid hor-
the response to β-adrenergic agonists was not mones might exert their cardiovascular actions
increased in hyperthyroid baboons. Increased by direct effects at the cellular level, by interact-
basal indices of LV contraction and relaxation in ing with the sympathetic nervous system, through
this model are more clearly related to changes in alterations of the peripheral circulation and
16 Thyroid Dysfunction and Arrhythmias 277
energy metabolism [5]. Thyroid hormones have ism, a shortening of the refractory period in asso-
been shown to alter cardiac excitability, which ciation with a facilitation of the atrial conduction
may lead to arrhythmias [8]. delay could be expected to increase the propen-
sity for AF, and a pre-existent arrhythmogenic
substrate might not be essential to the genesis of
Effects of Thyroid Hormones Excess AF. These findings suggest that the agents that
on the Atrias prolong the atrial effective refractory period are
effective against AF in patients with hyperthy-
Hyperthyroidism has been known to be an roidism [40].
important factor in the etiology of paroxysmal
atrial fibrillation (AF) [5]. The pathogenesis of
AF in these patients is postulated to result from Effects of Thyroid Hormones Excess
shortening of the action potential (AP) duration on the Ventricles
in the atrial myocardium from excess thyroid
hormone facilitating formation of multiple reen- The onset of tachycardia or ventricular fibrilla-
try circuits [35, 36]. Graves’ disease is one of the tion (VF) has been reported within a thyrotoxic
most common causes of hyperthyroidism. The storm [41]. The presentation of these arrhythmias
prevalence of AF in patients with Graves’ dis- in the initial phase of the disease is much less
ease, as in all other forms of hyperthyroidism, common, and only a few isolated cases are
increases with age [36]. Shortening of the AP described in the scientific literature. The majority
duration also decreases the refractoriness of car- [42, 43] occur in the context of thyrotoxic peri-
diomyocytes, which may facilitate the mainte- odic paralysis with severe hypokalemia [44].
nance of multiple reentrant circuits in heart. There has been an occasional patient in whom the
Using voltage clamp methods, several ionic cur- ventricular arrhythmia were related to coronary
rents have been investigated in cardiomyocytes. spasm [45].
Calcium currents and delayed rectified potas- Nevertheless, the shortening of the Q–T inter-
sium currents of ventricular cardiomyocytes val and the effect of TH on the autonomic ner-
were increased in hyperthyroidism [37]. vous system may affect ventricular
Moreover, transient outward potassium currents arrhythmogenesis [46]. TH interacts with the
and inward rectified currents have also been sympathetic nervous system by altering respon-
demonstrated to be increased in hyperthyroid siveness to sympathetic stimulation presumably
ventricular cardiomyocytes [36]. by modulating adrenergic receptor function and/
Pulmonary veins (PVs) have been demon- or density [5]. The density of myocardial adren-
strated to be important sources of ectopic beats ergic binding sites has been shown to be enhanced
with the initiation of paroxysmal AF or the foci by chronic as well as acute treatment with thyroid
of ectopic atrial tachycardia and focal AF [38]. hormone in hypothyroidism [47]. Thyroid hor-
Previous studies have demonstrated that PVs mone, in addition, induces a rate-dependent
have pacemaker cells in several species [39]. lengthening of the Purkinje fiber action potential
Thyroid hormone changes the electrophysiologi- while ventricular action potential shortens [48].
cal activity of the Pulmonary vein cardiomyo- Consequently, these differences can enhance dis-
cytes. Increased automaticity and enhanced persion of myocardial repolarization and facili-
triggered activity may increase the arrhythmo- tate re-entrant arrhythmias including ventricular
genic activity of PVs in hyperthyroidism [36]. fibrillation (VF) [49]. It should also be noted that
Chen et al. suggest in their study that the electro- hyperthyroidism may affect myocardial electrical
physiological features of paroxysmal AF associ- stability [50] due to increased excitability linked
ated with hyperthyroidism are essentially to triggered activity [51] resulting in ventricular
different from those of lone paroxysmal AF. In premature beats (VPB) [52] that often initiate
patients with paroxysmal AF and hyperthyroid- malignant arrhythmias [53].
278 S. Marrakchi Meziou et al.
On the other hand, it has been suggested that incidence is reduced in hypothyroidism [62]
hypothyroidism might confer a protection against depression of TH levels seems to be beneficial
arrhythmias because they are rarely encountered in patients with angina and acute myocardial
in hypothyroid patients. Only atrioventricular infarction [53, 63].
blocks, sinus bradycardia, and rare episodes of Finally, thyroid hormones may trigger arrhyth-
“torsade de pointes” have been reported to be mias mostly at the level of the atria, and there is
associated with clinical hypothyroidism [3]. In an some evidence that tissue hypothyroidism may
animal model of ventricular fibrillation, hypothy- increase the fibrillation threshold of the ventri-
roidism has been shown to increase the fibrilla- cles. However, there are no clear data in humans
tory threshold of the ventricles [5]. indicating that hypothyroidism confers a protec-
In humans, the prolongation of the QTc inter- tion against ventricular or atrial arrhythmias [5].
val encountered in hypothyroid patients is similar
to that seen in euthyroid patients on class III anti-
arrhythmic agents [54]. In this regard, it has been Supraventricular Arrhythmia
suggested that the antiarrhythmic effect of amio-
darone parallels its blocking effect on the periph- Atrial Arrhythmia
eral thyroid hormone metabolism, suggesting
that tissue hypothyroidism may have some anti- The atrial arrhythmia includes AF, atrial flutter
arrhythmic properties [55]. However, this con- and atrial tachycardia. Atrial fibrillation is the
cept has been challenged by several observations. most frequent atrial arrhythmia. Hyperthyroidism
Tri-iodothyronine T3 administration to euthyroid has been associated with atrial tachyarrhythmias
patients treated with amiodarone for benign atrial [64] and with sustained AF occurring in 20–30 %
or ventricular arrhythmias does not increase the of patients even after return to the euthyroid state
frequency of arrhythmias [52]. In patients with [64]. The risk of atrial fibrillation or flutter in
hypothyroidism, thyroid replacement therapy did hyperthyroidism was higher in men than in
not increase significantly the frequency of benign women, and the risk of atrial fibrillation in hyper-
atrial or ventricular premature beats [56]. thyroidism increased by increasing age during
Many patients with overt hypothyroidism the age range of 20–89 years. The presence of
have Q–T interval lengthening, which reflects ischemic heart disease, congestive heart failure,
the prolonged ventricular action potential due to and heart valve disease was also associated with
electrical remodeling [57]. It renders the heart an increased risk of atrial fibrillation [65].
prone to ventricular arrhythmias, such as poten- We could not differentiate atrial fibrillation
tially lethal polymorphic tachycardia “Torsade from atrial flutter because in the literature and a
de Pointes” [58]. The incidence of arrhythmia lot of articles didn’t differentiate the two arrhyth-
precedes the occurrence of early after depolar- mias. In fact, they had the same ICD-10 code
ization (EAD) usually triggered in the setting of [66]. In other hand, there is a low proportion of
hypokalemia. EAD-induced triggered responses patients with pure atrial flutter these represent
are traditionally thought to be involved in the approximately 5 % of the recorded cases
generation of ventricular arrhythmias under [37–39, 67].
long Q–T conditions. Dispersion of ventricular
refractoriness resulting from heterogeneous Hyperthyroidism
myocardial structural remodeling [59] predis- Thyrotoxicosis is a common disorder with a prev-
poses to Q–T dispersion and consequently to alence of 3 % in females and 0.3 % in males in
ventricular arrhythmias particularly in patients iodine-replete areas such as the United Kingdom
with subclinical hypothyroidism that are treated and the United States [68]. It is known to induce
with L-thyroxine [60]. Furthermore, in hypothy- many cardiovascular effects such as sinus tachy-
roidism an atrioventricular block of different cardia, systolic hypertension, changes in ventricu-
degrees may occur [61]. Nevertheless, the VF lar systolic and diastolic function, and
16 Thyroid Dysfunction and Arrhythmias 279
4–8 % in people older than 60 years of age. tionated heparin (UFH) has been documented,
Subclinical hypothyroidism has some clinical however Badawi [83] reported an interaction
consequences like an increase in the prevalence between thyroid function and UFH. Nakazawa
of atria fibrillation [77]. However, Klemperer et al. [84] suggested that spontaneous reversion
et al. [78] found that perioperative T3 administra- of atrial fibrillation to sinus rhythm is highly
tion in Cardiopulmonary bypass in euthyroid unlikely if the duration of atrial fibrillation before
patients decreased the incidence and need for the euthyroid state is achieved exceeds 13
treatment of postoperative atrial fibrillation. This months, or if it is still present after the patient has
finding still unexplained. Kim et al. [79] did not been in a euthyroid state for 4 months,
identify a significant association between hypo- Cardioversion should be performed at about the
thyroidism and 10-year risk of incident AF in a 16th week after the euthyroid state is achieved.
community-based study from the Framingham
heart study. Arrhythmia and Amiodarone-Induced
Hyperthyroidism
Euthyroid Range in Older Adults Amiodarone is the most commonly used antiar-
Cappola et al. [80] examined the relationship rhythmic drug worldwide [85]. It is effective in
between thyroid function testing within the the treatment of both supraventricular and ven-
euthyroid range and outcomes encompassing the tricular tachyarrhythmias and has the added
cardiovascular system in cohort of community- advantage of being well tolerated in patients with
dwelling individuals aged 65 years and older. both normal and impaired left ventricular systolic
They found increased risk of atrial Fibrillation at function [85]. The majority of patients (>70 %)
higher concentrations of FT4 and they suggested on amiodarone will remain euthyroid. However,
that there is no optimal set of thyroid function treatment may lead to either amiodarone-induced
tests within current reference ranges to reflect the hypothyroidism (AIH) or amiodarone-induced
euthyroid ideal in the age group. Cappola et al. thyrotoxicosis (AIT), with AIH more common in
[80] proposed that the optimal TSH may need to iodine-sufficient populations and AIT in iodine-
be higher in older people than the currently deficient populations [86].
defined references ranges. Amiodarone-induced thyroid dysfunction
occurs in 15–20 % of amiodarone-treated
Should We Anticoagulate and Attempt patients [87]. Amiodarone-induced hypothyroid-
Cardioversion in Those with AF? ism (AIH) does not pose relevant problems, is
Anticoagulation of patients with hyperthyroid- easily controlled by L-thyroxine replacement,
ism and AF is controversial [81] as the risk for and does not require amiodarone withdrawal.
systemic thromboembolic events in the setting of Most frequently, AIH develops in patients with
thyrotoxicosis is not well defined [82], and anti- chronic autoimmune thyroiditis. Amiodarone-
coagulation drugs such as warfarin, are associ- induced thyrotoxicosis (AIT) is most frequently
ated with a significant risk of bleeding due to destructive thyroiditis (type 2 AIT) caus-
complications and other side effects [82]. There ing release of thyroid hormones from the dam-
are beliefs that in patients with hyperthyroidism aged, but otherwise substantially normal gland.
it is advancing age rather than the presence of AF Less frequently AIT is a form of hyperthyroidism
that is the main risk factor [81] for a thromboem- (type 1 AIT) caused by the iodine load in a
bolic event, and in younger patients without diseased gland (nodular goiter, Graves’ disease).
organic heart disease, hypertension, or other A clear-cut differentiation between the two main
independent risk factors for embolization, the forms is not always possible, despite recent diag-
benefits of anticoagulation may actually be out- nostic advances. As a matter of fact, mixed or
weighed by the risks [69]. In our knowledge, no indefinite forms do exist, contributed to by both
interaction between thyroid function and unfrac- thyroid damage and increased thyroid hormone
16 Thyroid Dysfunction and Arrhythmias 281
synthesis. Treatment of type 1 (and mixed forms) and reentrant A-V nodal tachycardia are highly
AIT is based on the use of thionamides, a short prevalent in females.
course of potassium perchlorate and, if treatment In patients with reentrant A-V nodal tachycar-
is not rapidly effective, oral glucocorticoids. dia, at least two functionally distinct A-V nodal
Glucocorticoids are the first-line treatment for conduction patterns are demonstrable [90, 91].
type 2 AIT. Amiodarone should be discontinued, One pathway, referred to as the fast pathway, is
if feasible from a cardiac standpoint. Continuation characterized by rapid conduction velocity and
of amiodarone has recently been associated with relatively long refractoriness. The second or slow
a delayed restoration of euthyroidism and a pathway typically shows slow conduction veloc-
higher chance of recurrence after glucocorticoid ity and short refractoriness. During sinus rhythm,
withdrawal. Whether amiodarone treatment can the electric impulse is expected to reach the His
be safely reinstituted after restoration of euthy- bundle and the ventricle preferentially over the
roidism is still unknown. In rare cases of AIT faster-conducting pathway with the frequent evi-
resistance to standard treatments, or when a rapid dence of a short P-R interval. A-V nodal reentry
restoration of euthyroidism is advisable, total of the common type (slow-fast) is typically initi-
thyroidectomy represents a valid alternative. ated by an atrial premature beat that conducts
Radioiodine treatment is usually not feasible due down only through the slow pathway because of
to the low thyroidal iodine uptake [4]. functional block of the fast pathway, and reenters
Dronedarone was approved in 2009 for the treat- back through the fast pathway because of recov-
ment of patients with atrial fibrillation. Like ami- ery of its excitability. Conceivably, thyroid hor-
odarone, dronedarone is a benzofuran derivative mones might increase the occurrence of reentrant
with similar electrophysiologic properties. In A-V nodal tachycardia in predisposed subjects
contrast to amiodarone, however, dronedarone is because of the enhancement of atrial excitability,
structurally devoid of iodine and has a notably with consequent increase of the number of atrial
shorter half-life. Dronedarone proved to be asso- premature beats and the shortening of the refrac-
ciated with significantly fewer adverse effects tory period of the conducting tissues. Thus, reen-
than amiodarone, making it a more attractive trant A-V nodal tachycardia might be triggered in
choice for patients with atrial fibrillation or flut- patients in whom L-T4 is exogenously adminis-
ter, who are at risk of developing amiodarone- tered to lower TSH [46].
induced thyroid dysfunction [88]. Abbasoglu et al. [92] reported a case of
Neonatal thyrotoxicosis with concurrent supra-
ventricular tachycardia caused by the transpla-
Other Supraventricular Arrhythmia cental passage of thyroid stimulating
immunoglobulins from mothers with Graves’
Biondi et al. [46] reported the possibility that thy- disease. The heart rate was between 260 and 300
roid hormones may also induce other kinds of beats/min. Matthew et al. [93] described a case
supraventricular arrhythmias not frequently of 43 year old woman who presented in supra-
described in hyperthyroid patients, such as reen- ventricular tachycardia and acute pulmonary
trant atrioventricular (A-V) nodal tachycardia. edema and died without any evident cause of
This report also showed that reentrant A-V nodal mortality. At autopsy the significant positive
tachycardia may be triggered by thyroid hormone macroscopic findings were confined to the lungs
in predisposed subjects. The reentrant A-V nodal (acute pulmonary edema) and thyroid (diffusely
tachycardia is a relatively common cause of enlarged). Histology revealed features typical of
regular, narrow QRS complex tachycardia, and it Graves’ disease while post mortem thyroid func-
is more prevalent in women than in men with a tion tests supported a diagnosis of thyrotoxic cri-
ratio of 7:1 respectively [89]. Epidemiologically, sis in the setting of undiagnosed Graves’
it must be emphasized that both thyroid disease disease.
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Part III
Pregnancy and Thyroid Dysfunction
Pregnancy and Hypothyroidism
17
Aqiba Sarfaraz
Abstract
Pregnancy is a state that causes massive physiological stress on both the
mother and the fetus. When pregnancy is associated with endocrine disor-
ders such as hypothyroidism, the risk for maternal and fetal adverse out-
comes can be enormous. While a lot of attention has been focused on the
adverse fetal outcomes consequent to hypothyroidism, it is being gradually
directed towards the adverse maternal outcomes. Timely diagnosis and
treatment of thyroid disorders in pregnancy is very important. Subclinical
hypothyroidism also needs to be detected and treated to prevent adverse
outcomes. Symptoms of SCH may vary from being asymptomatic to having
mild nonspecific symptoms. This condition occurs in 3–8 % of the general
population. It is more common in women than men, and its prevalence
increases with age. In patients with SCH, 80 % have a serum TSH of less
than 10 mIU/L. The most important implication of SCH is high likelihood
of progression to clinical hypothyroidism during pregnancy and these
patients needs thyroxine replacement during pregnancy to reduce adverse
fetal outcomes. The risk of progression to overt hypothyroidism is related to
a number of factors including initial serum TSH concentration, presence of
auto antibodies (anti TPO), family history and presence of goiter. Women
who already on thyroxine prior to pregnancy usually need to increase their
daily dosage, on an average, by 30–50 % above preconception dosage.
Introduction
with adverse outcomes during pregnancy, and deficiency. Production of thyroxine (T4) and triio-
treatment is an essential part of prenatal care to dothyronine (T3) increases by 50 %, along with a
ensure maternal and fetal well-being. 50 % increase in the daily iodine requirement.
While a lot of attention has been focused on These physiological changes may result in hypo-
the adverse fetal outcomes consequent to hypo- thyroidism in the later stages of pregnancy in
thyroidism, it is being gradually directed towards iodine-deficient women who were euthyroid in
the adverse maternal outcomes. Subclinical the first trimester. The range of thyrotropin
hypothyroidism also needs to be detected and (TSH), under the impact of placental human cho-
treated to prevent adverse outcomes [1]. rionic gonadotropin (hCG), is decreased through-
Since the treatment of hypothyroidism is easy, out pregnancy with the lower normal TSH level
timely detection and treatment of the disorder in the first trimester being defined as an upper
could reduce the burden of adverse fetal and limit of 2.5 mIU/L [3] See Table 17.1.
maternal outcomes. Thyroid disease in pregnancy The most notable change is the increase in thy-
can affect the health of the mother as well as the roxine-binding globulin (TBG). This begins early
child before and after delivery. The harmful effects in the first trimester, plateaus during mid gestation,
of thyroid dysfunction can also extend beyond and persists until shortly after delivery. This is due
pregnancy and delivery to affect neuro-intellectual to stimulation of TBG synthesis by elevated mater-
development in the early life of the child [2]. nal estrogen levels, and more importantly, due to a
Thyroid gland influences almost all of the reduced hepatic clearance of TBG because of
metabolic processes in our body. Thyroid disor- estrogen-induced sialylation [4]. This increased
ders can range from a small and harmless goiter TBG concentration leads to an expansion of the
(enlarged gland) that needs no treatment to life- extra-thyroidal pool and results in elevated total
threatening cancer. The most common thyroid T3 and T4 levels. T4 metabolism is enhanced in
problems involve abnormal production of thyroid the second and third trimesters, due to a rise in pla-
hormones. Excessive amount of thyroid hormone cental type II and type III deiodinases, which con-
results in a condition known as hyperthyroidism. vert T4 to T3 and T4 to reverse T3. Plasma iodide
Insufficient hormone production leads to hypo- levels decrease due to both increased thyroxine
thyroidism. Although the effects can be unpleas- metabolism and increased renal iodide clearance
ant or uncomfortable, most thyroid problems can [5]. All these changes lead to an increase in the
be managed well if properly diagnosed and size of the thyroid gland in 15 % of pregnant
treated. This review will mainly focus on hypo- women, which returns to normal in the post-par-
thyroidism during pregnancy. tum period. Serum hCG has intrinsic thyrotropic
activity, which increases after fertilization and
peaks at 10–12 weeks. Hence, in the first trimester,
Physiologic Changes in Thyroid free T3 and T4 levels increase slightly and TSH
Function During Pregnancy levels decrease in the first trimester with a read-
justment in the second and third trimesters, when
Pregnancy has a profound impact on the thyroid hCG levels decrease. As a consequence, cut-offs
gland and thyroid function. The gland increases to determine hypothyroidism in pregnancy are dif-
10 % in size during pregnancy in iodine-replete ferent in the first trimester and the rest of the preg-
countries and by 20–40 % in areas of iodine nancy. See table [3, 6].
Thyroid Function and the Fetus SCH pre pregnancy or during pregnancy over
another, for improving maternal, fetal, neonatal
The fetal thyroid begins concentrating iodine at and childhood outcomes. Thyroid hormone dis-
10–12 weeks of gestation and is controlled by pitu- turbances have known to have adverse effect in
itary TSH by approximately 20 weeks of gestation. pregnancy outcomes. That is why thyroid func-
Fetal serum levels of TSH, TBG, FT4, and free tri- tion assessment is relevant in reproductive dys-
iodothyronine (FT3) increase throughout gestation, function [15]. One review of literature revealed
reaching mean adult levels at approximately that SCH increased the rate of miscarriage/fetal
36 weeks of gestation [7]. Thyroid stimulating hor- death and later it adversely affects the cognitive
mone does not cross the placenta, and only small development of offspring [16–18].
amounts of thyroxine (T4) and triiodothyronine Though universal screening for thyroid hor-
(T3) cross the placenta. In neonates with congenital mone abnormalities in pregnancy is not routinely
hypothyroidism, enough maternal thyroid hormone recommended at present, but thyroid function
crosses the placenta to prevent the overt stigmata of must be assessed in those having reproductive
hypothyroidism at birth and maintain cord blood dysfunction and must be treated appropriately.
thyroid hormone levels at 25–50 % of normal [8]. Although it is evident from current literature that
However, thyrotropin releasing hormone (TRH), pregnancy outcomes are worse in women with
iodine, and TSH receptor immunoglobulins do overt hypothyroidism versus SCH. Studies done
cross the placenta, as do the thioamides propylthio- in individuals with SCH showed an increased
uracil (PTU) and methimazole. risk of preterm birth, miscarriage, severe pre-
eclampsia and impaired cognitive development
in children [19].
Subclinical Hypothyroidism
During Pregnancy
Thyroid Autoimmunity
Subclinical hypothyroidism (SCH) is biochemi- and Subclinical Hypothyroidism
cally diagnosed when there is a persistently high
TSH level, while circulating free thyroid hor- It has been observed that the autoimmune thyroid
mone levels are within range [9, 10]. Other terms disease without overt hypothyroidism is associ-
for this condition are mild hypothyroidism, early ated with a higher miscarriage rate. One study
thyroid failure, preclinical hypothyroidism, and done by Negro et al showed that euthyroid
decreased thyroid reserve [11]. Thyroid diseases Caucasian women with positive anti – thyroid
are one of the most common endocrine disorders peroxidase (anti-TPO) antibodies who were
and most prevalent in iodine deficient areas. treated with LT4 during the first trimester had
During the first trimester, approximately one in lower miscarriage rates than those who were not
ten pregnant women develop antibodies to TPO treated. These women also had lower rates of pre-
or to thyroglobulin, and hypothyroidism devel- mature delivery, comparable to rates in women
ops in roughly 16 % of these women. The preva- without thyroid antibodies [20].
lence of hypothyroidism in pregnancy is around In a meta-analysis of 3 studies involving 220
2.5 % according to the Western literature [12]. women with subclinical hypothyroidism or thy-
There are a few reports of prevalence of sub- roid autoimmunity who were undergoing assisted
clinical hypothyroidism during pregnancy from reproduction technologies, Velkeniers et al con-
India with prevalence rates ranging from 4.8– cluded that treatment with LT4 should be recom-
11 % [13, 14]. mended to improve pregnancy outcomes [21]. In
Data on the prevalence of thyroid dysfunction this meta-analysis, LT4 treatment resulted in a
during pregnancy is lacking in Asian-Indian pop- significantly higher delivery rate and a signifi-
ulation. There is insufficient evidence to recom- cantly lower miscarriage rate. Such findings, if
mend the use of one intervention for clinical or confirmed by sufficient data, would provide an
292 A. Sarfaraz
indication for treating Euthyroid pregnant women • Increased risk of spontaneous abortion
who have thyroid antibodies. • Preeclampsia
• Low birth weight
• Impaired cognitive development in the fetus
Hypothyroidism in Pregnancy • Fetal mortality
• Postpartum hemorrhage
The prevalence of hypothyroidism during preg- • Anemia
nancy is estimated to be 0.3–0.5 % for overt
hypothyroidism and 2–3 % for subclinical hypo-
thyroidism. Autoimmune thyroiditis is the com- Screening
monest cause of hypothyroidism during
pregnancy [22]. Other causes include radioiodine Despite the possibility of poor fetal outcomes,
ablation of thyroid while treating hyperthyroid- routine screening for thyroid dysfunction is not
ism or thyroid cancer, surgery of the thyroid performed in the United States and remains a
tumors and rarely, central hypothyroidism. On controversial topic [25–27].The Endocrine
the other hand, globally, iodine deficiency still Society recommends screening only pregnant
remains one of the leading causes of hypothy- women at high risk of thyroid disease using
roidism, both overt and subclinical [1]. serum TSH measurement [2, 3].
Hypothyroidism commonly manifests as a
slowing in physical and mental activity but may
Feto-maternal Risk be asymptomatic. Symptoms and signs of this
disease are often subtle and neither sensitive nor
Women with hypothyroidism have decreased fer- specific. Classic signs and symptoms such as
tility; even if they conceive, risk of abortion is cold intolerance, puffiness, decreased sweating,
increased, and risk of gestational hypertension, and coarse skin may not be present as commonly
anemia, abruptio placenta and postpartum hem- as was once believed. See chap. 17 for clinical
orrhage is increased [23]. manifestation of hypothyroidism.
The risk of these complications is greater in
women with overt than subclinical hypothyroid-
ism. Untreated maternal hypothyroidism can Diagnosis
lead to preterm birth, low birth weight, and
respiratory distress in the neonate. Enough evi- Thyroid function tests are the mainstay. Serum
dence has accumulated over the years about the TSH elevation indicates primary hypothyroidism.
role of thyroxine in normal development of the Free thyroxine (FT4) and free triiodothyronine
fetal brain [1]. Various studied proved that chil- (FT3) levels are estimated, as total hormone levels
dren born to mothers with hypothyroidism had a are elevated due to changes in TBG levels.
significantly increased risk of impairment in
intelligence quotient (IQ) scores, neuropsycho-
logical developmental indices and learning abili- Indications for Thyroid Testing
ties. Children born to untreated hypothyroid in Pregnancy [28]
women had an IQ score that was seven points
below the mean IQ of children born to healthy
women and women given thyroxine supple- History of thyroid dysfunction
ments. This risk applies to children born not only Family history of autoimmune thyroid disease
of untreated women, but also women with sub- High-dose neck radiation
optimal supplementation [24]. Postpartum thyroid dysfunction
Previous delivery of infant with thyroid disease
Adverse outcome of hypothyroidism in preg-
Type 1 diabetes mellitus
nancy can be summarized as follows;
17 Pregnancy and Hypothyroidism 293
4–6 weeks with free T4 and TSH value, till Preconception Counseling
delivery, to facilitate periodic adjustment of LT4
supplementation. If hypothyroidism has not Women with hypothyroidism should be coun-
been diagnosed until the end of the first trimes- seled about the importance of achieving euthy-
ter, offspring may display impairment in final roidism before conception because of the risk of
intellectual and cognitive abilities, thus under- decreased fertility and miscarriage. They must
scoring the importance of early diagnosis and also understand the importance of immediate
treatment. monitoring at the onset of pregnancy, because by
the first prenatal visit, many of these patients will
already have an elevated TSH level consistent
Prognosis with uncontrolled hypothyroidism. Euthyroid
women who are taking a stable dosage of levothy-
• Prognosis for mother and fetus is excellent roxine should be counseled to notify their physi-
with appropriate treatment. cian and independently increase their medication
• However, there is a small increase in stillbirth by two additional doses per week after a missed
rate and fetal assessment in the third trimester menstrual cycle or positive home pregnancy test.
is necessary. In a study of 48 women treated for hypothyroid-
• Recent research has suggested an increased ism with a normal prepregnancy serum TSH level,
risk of neurocognitive difficulties in children increasing levothyroxine by two doses per week
of women with hypothyroidism, even with a prevented maternal TSH elevation above 2.5
euthyroid fetus, as maternal thyroid hormone mIU/L and above 5 mIU/L in 85–100 % of
is needed for neuronal development until patients, respectively, with only two patients
12–13 weeks. requiring a subsequent dose reduction [33].
their children at 25–30 months. Clin Endocrinol implications for population screening. J Med Screen.
(Oxf). 2010;72:825–9. 2000;7:127–30.
20. Negro R, Formoso G, Mangieri T, et al. Levothyroxine 27. Vaidya B, Anthony S, Bilous M, et al. Detection of
treatment in euthyroid pregnant women with autoim- thyroid dysfunction in early pregnancy: universal
mune thyroid disease: effects on obstetrical compli- screening or targeted high-risk case finding? J Clin
cations. J Clin Endocrinol Metab. 2006;91(7): Endocrinol Metab. 2007;92:203–7.
2587–91. 28. De Groot L, Abalovich M, Alexander EK, et al.
21. Velkeniers B, Van Meerhaeghe A, Poppe K, et al. Management of thyroid dysfunction during pregnancy
Levothyroxine treatment and pregnancy outcome in and postpartum: an endocrine society clinical practice
women with subclinical hypothyroidism undergoing guideline. J Clin Endocrinol Metab. 2012;97(8):
assisted reproduction technologies: systematic review 2543–65.
and meta-analysis of RCTs. Hum Reprod Update. 29. Beverly MS, Bridget AK, Anita VH, et al. Five-Year
2013;19(3):251–8. follow-up for women with subclinical hypothyroid-
22. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos ism in pregnancy. J Clin Endocrinol Metab
RJ, Pulkkinen A, et al. Prevalence of thyroid defi- 2013;98:E1941–E1945.
ciency in pregnant women. Clin Endocrinol (Oxf). 30. Abalovich M, Vazquez A, Alcaraz G, et al. Adequate
1991;35:41–6. levothyroxine doses for the treatment of hypothyroid-
23. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, ism newly discovered during pregnancy. Thyroid.
Garcia A, Levalle O. Overt and subclinical hypothy- 2013;23(11):1479–83.
roidism complicating pregnancy. Thyroid. 2002;12: 31. Monahan M, et al. Costs and benefits of iodine sup-
63–6. plementation for pregnant women in a mildly to mod-
24. Rovet JF. Neurodevelopmental consequences of erately iodine-deficient population: a modelling
maternal hypothyroidism during pregnancy (abstract analysis. Lancet Diabetes Endocrinol. 2015;3:715–22.
88;annual meeting of the American Thyroid doi:10.1016/S2213-8587(15)00212-0.
Association). Thyroid. 2004;14:710. 32. Pearce E. Iodine deficiency in pregnant women in the
25. Blat AJ, Nakamoto JM, Kaufman HW. National status UK: the costs of inaction. Lancet Diabetes Endocrinol.
of testing for hypothyroidism during pregnancy and 2015;3:671–2. doi:10.1016/S2213-8587(15)00228-4.
postpartum. J Clin Endocrinol Metab. 2012;97(3): 33. Yassa L, Marqusee E, Fawcett R, Alexander
777–84. EK. Thyroid hormone early adjustment in pregnancy
26. Allan WC, Haddow JE, Palomaki GE, et al. Maternal (the THERAPY) trial. J Clin Endocrinol Metab.
thyroid deficiency and pregnancy complications: 2010;95(7):3234–41.
Pregnancy and Hyperthyroidism
18
Aisha Sheikh
Abstract
Hyperthyroidism during pregnancy is coupled with diagnostic and treat-
ment dilemmas since there are several causes of hyperthyroidism during
pregnancy including Gestational Transient Thyrotoxicosis (GTT) which is
a self- limiting condition. The symptoms of pregnancy mimic that of
hyperthyroidism, thus cannot be entirely relied upon. The lack of consen-
sus on the lower limit of Thyroid Stimulating Hormone (TSH) during
pregnancy and lack of universal availability of trimester-specific reference
ranges for thyroid function tests in most of laboratories; add more to diag-
nostic confusion. Any unnecessary treatment with anti-thyroid drugs can
lead to adverse effects on the fetus, same is true for uncontrolled hyperthy-
roidism. All this calls for vigilance in diagnosing and managing pregnancy
complicated by hyperthyroidism.
and method-specific reference ranges [2, 4]. The The thyroidal T3 production is high in Graves’
lower limit of TSH during pregnancy is still ill- and serum T3 or free T3 concentrations are typi-
defined with studies reporting lower normal TSH cally more raised than serum T4 or free T4 con-
at 0.03 or 0.08 mIU/L [13, 14]. The American centrations [17]. However, GTT is unique in
Thyroid Association (ATA) suggests that a TSH many ways i.e. absence of prepregnancy thyro-
that is within detection is unlikely to be clinically toxic symptoms, lack of thyrotorpin receptor
significant as subclinical hyperthyroidism is not antibodies (TRAbs), absence of a goiter with
associated with adverse pregnancy outcomes [4, bruit, and absence of Graves’ Ophthalmopathy
15]. The total T4 and total Triiodothyronine (T3) (Table 18.3).
levels during pregnancy are 1.5 folds higher than Radionuclide imaging is contraindicated in
in non-pregnant women due to thyroxine binding pregnancy [4]. Thyroid ultrasound with Doppler
globulin (TBG) excess [1, 3, 4]. In clinical practice flow may help to distinguish Graves’ disease
if the trimester specific reference ranges are not from painless or postpartum thyroiditis [19]
available then besides the TSH and FT4 levels one However, the utility of thyroid ultrasound with
has to rely on total T3 and total T4 levels as well to Doppler in diagnosing hCG-mediated hyperthy-
confirm or refute the diagnosis of hyperthyroidism roidism is unknown.
in pregnancy [6]. Alternatively, thyroid-binding Women who have a history of Graves’ disease
globulin or another measure of T4-binding (e.g. in past whether they are in remission [following
T3 resin uptake test) can be done and used to antithyroid drug (ATD) use] or had received a
adjust the total T3 and T4 values obtained to cor- definitive treatment [Radioactive iodine (RAI)
respond to the non-pregnant range [16]. treatment or thyroidectomy] and now are on
L-thyroxine replacement should undergo thyroid
function testing either at preconception period or
Establishing the Cause in early antenatal period [6, 7].
of Hyperthyroidism
During Pregnancy
Gestational Transient
The main differential is either the Graves’ disease Thyrotoxicosis
or GTT as other causes of hyperthyroidism are
rare in pregnancy. If is important to differentiate Gestational Transient Thyrotoxicosis or GTT can
between the two conditions as the management, be caused by excessive stimulation of thyroid gland
outcomes and clinical course of both differ. induced by elevated human chorionic gonadotropin
300 A. Sheikh
(hCG). hCG is a glycoprotein that shares a com- 100,000 per year in women older than 30 years.
mon alpha subunit with TSH and thus acts as a While the risk is much lower in women younger
TSH agonist. In GTT the hCG concentrations are than 20 years; an incidence of 35–50 cases per
generally higher than 200,000 IU/L [2, 4]. 100,000 per year is reported in women aged
Risk factors for GTT include hyperemesis 20–29 years [27, 28]. Thus, the risk of a woman
gravidarum, multiple gestations, hydatiform getting pregnant with Graves’ hyperthyroidism
mole, and choriocarcinoma [20, 21]. Biochemical is 1.3 % at age 40 years and 0.5 % at age 30
results show a suppressed TSH with an elevated years [6].
FT4/ Total T4 levels similar to Graves’ Disease.
GTT presents in the 1st trimester at a time when
peak levels of hCG are evident and characteristi- Pre-pregnancy Counseling
cally resolves spontaneously by mid-trimester as
hCG levels decline. Usually GTT is seen in women All women with Hyperthyroidism should avoid
with Hyperemesis Gravidarum (vomiting, dehy- conception till their hyperthyroidism is well
dration, weight low of >5 % body weight, ketonu- under control as uncontrolled thyrotoxicosis can
ria and hospitalization and intravenous hydration) lead to wide array of maternal and fetal compli-
but can be seen in women with morning sickness. cations [4, 29] (Table 18.4). Well before concep-
A state of thyrotoxicosis is seen in about 50 % of tion, the woman is offered a definitive treatment
patients with hyperemesis gravidarum [22–25]. of her thyrotoxicosis either with surgery or radio-
As GTT resolves spontaneously, there is no active iodine (RAI) ablation and alternatively she
need to treat these women with Antithyroid drugs may wish to continue with ATDs. The pros and
(ATDs) [4–6]. ATDs can potentially induce cons of each of these management options should
maternal hypothyroidism which can have be thoroughly discussed with the woman that will
deleterious effects on fetal development and via- help her in making the decision [4, 6].
bility. It is therefore crucial to differentiate GTT
from Graves’ disease as only Graves’s disease Radioactive Iodine Ablation or Surgery
will need ATDs. If a woman is very symptomatic A woman who opts for RAI ablation needs to
then small doses of beta-blockers can be given understand that:
for a short while [4, 6]. Supportive management
for hyperemesis gravidarum is the mainstay of • Before getting the RAI, a proof of negative
therapy and hospitalization may be required in pregnancy test should be available at least
severe cases [26]. within 48 h before the RAI treatment.
A woman with GTT needs to be followed up • After RAI, she needs to avoid conception for at
with Thyroid Function tests done at an interval of least 6 months and let the L-thyroxine replace-
3–4 weeks and by mid-gestation these show a ment be sufficient enough to bring the TSH
trend towards euthyroidism along with symptom- within a normal range required for conception
atic improvement i.e. hyperemesis subsides and i.e. ≤2.5 mIU/L (range 0.3–2.5 mIU/L) [4].
the woman starts to regain her weight. FT4 con-
centrations tend to show a progressive decline If the woman has high titres of TRAbs, the
while the TSH may remain partially or totally titres are likely to rise after RAI treatment for 1
suppressed for several weeks [25]. year and remain elevated for several years
before finally disappearing [30]. In a 5 year pro-
spective randomized study, medical therapy
Graves’ Disease with ATDs and surgery was followed by a grad-
ual decline in TRAb in serum, with the disap-
Graves’ disease is the most common cause of pearance of TRAb in 70–80 % of the patients
hyperthyroidism in women of childbearing age. after 18 months. On the other hand, RAI led to a
The incidence is roughly 55–80 cases per 1-year long worsening of autoimmunity against
18 Pregnancy and Hyperthyroidism 301
the TSH receptor, and the number of patients hyperthyroidism from Danish nationwide regis-
entering remission of TSH-receptor autoimmu- ters is reported as 65/100,000/year. This incident
nity with the disappearance of TRAb from ratio was high in first 3 months of pregnancy
serum during the following years was consider- [incidence rate ratio (IRR) vs the remaining study
ably lower than with the other types of therapy period: 1.50 (95 % CI 1.09–2.06]), very low in
[31]. So if the woman has high levels of TRAb last 3 months of pregnancy [0.26 (0.15–0.44)]
and she is planning pregnancy in near future; and reached the highest level 7–9 months post-
surgery could be a better option as this will partum [3.80 (2.88–5.0)]. Such particular pattern
reduce the TRAbs earlier than RAI. was not observed for other diseases of autoim-
mune origin [32].
Antithyroid Drugs [4, 6, 29] Poorly controlled thyrotoxicosis is associated
If the woman chooses to opt for ATDs then she with miscarriages, pregnancy induced hyperten-
should be counseled about: sion, intrauterine growth restriction, prematurity,
low birth weight, still birth, maternal congestive
• The ideal time to conceive is when hyperthy- heart failure and thyroid storm (Tables 18.2 and
roidism is well controlled preferably with 18.4).
small doses of ATDs.
• The risks (maternal and fetal) associated with
both ATDs should be discussed. Treating Graves’ Disease
• She will be switched to Propylthiouracil dur- in Pregnancy
ing the 1st trimester of pregnancy to reduce the
risk to fetus. However, she will be switched During pregnancy ATDs are the ideal treatment
back to Carbimazole/methimazole after 1st for Graves’ Disease. ATDs reduce thyroid hor-
trimester of pregnancy to avoid PTU associ- mone synthesis by virtue of reducing iodine
ated hepatotoxicity in mother. organification and coupling of mono- and diiodo-
tyrosine. In non-pregnant individuals the most
Incidence of Hyperthyroidism frequently encountered side effects are allergic
During Pregnancy reactions occurring in 3–5 % of patients [8]. The
Maternal hyperthyroidism is reported to occur at rare side effects are agranulocytosis and PTU
a frequency of around 0.2 %. The incidence of associated hepatotoxicity [8].
hyperthyroidism fluctuates widely in and around During pregnancy there is a risk of teratogenic
pregnancy. The overall incident ratio of maternal effects with the use of ATDs especially
302 A. Sheikh
Carbimazole/methimazole (CMZ/MMI) [33]. The initial doses of ATDs depend upon the
CMZ/MMI exposure at the time of embryogenesis severity of hyperthyroidism but usually these are
can lead to congenital malformations. Generally it started at a lower dose as compared to a non-
is associated with aplasia cutis or a rare “MMI pregnant individual [4–6]. CMZ is the precursor
embryopathy” consisting of esophageal or choanal of MMI and is converted to MMI rapidly in
atresia, dysmorphic facies and omphalomesenteric serum. (10 mg of CMZ is metabolized to approx-
anomalies [34–36]. Such complications however imately 6 mg of MMI). Generally the initial
are not reported with the use of PTU yet there is doses could vary from MMI 5–15 mg/day; CMZ
possible association of birth defect in the face and 10–15 mg/day; or PTU 50–300 mg/day. MMI or
neck region (periauricular and branchial sinus/fis- NMZ can be given in once daily dose while PTU
tula/cyst) and in the urinary system (single cyst of should be given in divided doses [4–6, 8].
kidney and hydronephrosis). In a study from If the woman is overtly symptomatic then
Denmark; the adjusted Hazard Ratio of having a Beta adrenergic blocking agents like propranolol
birth defect in the face and neck region was 4.92 10–40 mg every 6–8 hourly can be given to con-
(95 % CI 2.04–11.86) and in the urinary system trol symptoms. Depending upon the clinical con-
2.73 (1.22–6.07) [37]. These defects tend to be dition, the drug should then be tapered off over
less severe than the defects observed after CMZ/ next 2–6 weeks [4–6]. Beta blockers can lead to
MMI exposure [38]. Infants of mothers with diag- fetal intrauterine growth restriction, fetal brady-
nosed thyrotoxicosis or ATD use during preg- cardia and neonatal hypoglycemia thus long-term
nancy; were more likely to be preterm and admitted use during pregnancy should be avoided [4–6].
to the neonatal intensive care unit [39]. The fre- Use of Block-replace regimen is contraindi-
quency of PTU associated hepatotoxicity was 1.8 cated in pregnancy as it can lead to fetal hypothy-
per 1000 delivered pregnancies [39]. Due to PTU- roidism. The only exception is for treatment of
associated hepatotoxicity, the FDA advisory com- fetal hyperthyroidism [4].
mittee has recommended limiting its use to 1st
trimester of pregnancy, in those who are allergic to Monitoring a Pregnant Woman on ATDs
MMI/CMZ and in the management of thyroid (Table 18.5)
storm [4, 5, 8, 40]. Similarly if PTU is not avail- ATDs cross the placenta and can lead to fetal
able or the patient is intolerant of PTU, it is accept- hypothyroidism thus the aim of treating hyper-
able to proceed with MMI/CMZ in the lowest thyroidism during pregnancy is to keep the low-
possible effective dose [6]. est possible doses of ATDs to keep the FT4 values
It is important to bear in mind that the risk of at, or just above the trimester specific reference
complications in an untreated or undertreated range [4, 42]. Avoiding over treatment can reduce
hyperthyroid patient far outweighs the small and the occurrence of fetal hypothyroidism and fetal
potential risk associated with maternal ATD use goiter [4–6]. If the trimester and method-specific
[10]. Thus, it is important to treat Graves’ disease reference ranges are not available for different
in pregnancy [7]. populations, thus in such situations the ATA sug-
It is prudent to get a baseline Complete Blood gests to rely on the non-pregnant FT4 reference
Count and Liver function tests before starting range for ATD dose adjustment [4].
ATDs [8]. Patients need to be advised that in the The rationale for keeping the FT4 around the
event of fever, pharyngitis or oral ulcers they upper limit of normal is twofolds [4–6]:
should get their White Cell Count and report to
their doctor [8]. If there is any evidence of agran- 1. The available evidence suggests that subclini-
ulocytosis, then the ATD has to be stopped imme- cal hyperthyroidism is not associated with
diately and should not be replaced by the other adverse maternal or fetal effects.
ATD since these drugs exhibit cross reactivity [8, 2. Keeping the lowest possible maternal ATD
41]. Similarly if the patient develops nausea, dose reduces the trans-placental passage of
vomiting, jaundice, upper abdominal pain then the ATD and thus reduces the risk of fetal/
liver function tests should be done [8]. neonatal hypothyroidism [33, 42].
18 Pregnancy and Hyperthyroidism 303
Table 18.5 Graves’ hyperthyroidism in pregnancy and the balance between maternal and fetal thyroid function
1. TSH-receptor stimulating antibodies (TRAbs) produced in the mother and inducing maternal hyperthyroidism
pass the placenta, and they stimulate the fetal thyroid
2. If the mother has an intact thyroid, her thyroid function mirrors the thyroid function of the fetus
3. Antithyroid drugs (methimazole/carbimazole or propylthiouracil) pass the placenta and induce a block of both
the maternal and the fetal thyroid hormone production
4. At a given dose of propylthiouracil or methimazole/carbimazole the block of fetal thyroid is more effective than
of the maternal thyroid
5. During antithyroid drug therapy the thyroid function of the mother should be kept around or slightly above the
upper normal to avoid fetal hypothyroidism in the last part of pregnancy
6. Thyroid hormones only pass the placenta barrier to a very limited degree
7. A combination of antithyroid drug and L-thyroxine given to the mother to keep her euthyroid (block + replace
therapy) may mask fetal hypothyroidism induced by the antithyroid drugs
8. The combination of block (of fetal thyroid) + replacement (of the hypothyroid mother) is only appropriate in a
hypothyroid mother (after previous surgery or radioiodine therapy for Graves’ hyperthyroidism) with a
hyperthyroid fetus from persistent maternal production of TSH-receptor stimulating antibodies
Adapted from Laurberg et al. [18]
FT4 and TSH should be measured every 2–4 improvement in the second and third trimester of
weeks at initiation of therapy. Generally it pregnancy due to falling titres of TRAb and pos-
takes 2–6 weeks for thyroid function tests to sible presence of thyroid receptor blocking anti-
improve and at that time the dose can be cut by bodies [44, 45]. This calls for ATD dose reduction
50 % in many patients [4, 6]. Thereafter, FT4 accordingly; some 20–30 % of women can go off
levels should be checked at 2–4 weekly inter- their ATDs in third trimester [42]. However,
vals and ATD dose should be adjusted accord- women with very high TRAbs should be contin-
ingly [6]. TSH may remain suppressed longer ued on their ATDs [6]. After delivery, generally
and thus FT4 remains the best test to help with an exacerbation of Graves’ Disease is seen, thus
ATD dose adjustment during pregnancy [4, 6]. it is prudent to closely follow the woman with
Normalizing the TSH is not the goal of treat- FT4 levels in the postpartum period and make
ment as it will lead to fetal goiter and fetal ATD dose adjustments accordingly.
hypothyroidism [4]. Serum total T3 monitor-
ing is not recommended as normalization of T3 Thyroidectomy for Graves’ Disease
can lead to elevated serum TSH in the neonate During Pregnancy
at birth [4]. The only exception is T3-toxicosis Thyroidectomy is rarely indicated during preg-
in the setting of a nodular goiter. However, the nancy but following are the indications for thy-
optimum maternal T3 concentration that con- roidectomy [4–6]:
trols maternal hyperthyroidism with minimal
fetal thyroidal exposure is unknown [6]. • If the woman is having allergies or intolerance
to both ATDs.
Natural Course of Graves’ Disease • If both ATDs are contraindicated.
During Pregnancy • If the woman requires persistently high doses
Graves’ disease tends to exacerbate during the of ATDs and still remain poorly controlled
first trimester of pregnancy in some women. This threatening her health.
deterioration in clinical features of Graves’ dis- • If the woman is having compliance issue with
ease in first trimester may occur due to stimula- intake of ATD.
tion of thyroid both by hCG and TRAb [43]. A
high TBG state may also contribute to deteriora- The relatively safe time for thyroidectomy is
tion. Later on, there is a trend towards gradual the second trimester of pregnancy. The decision
304 A. Sheikh
should be made in close consultation of the sur- untreated then it is associated with increased fetal
geon and obstetrician. The woman should be and neonatal morbidity and mortality [47]. In a
properly counseled about the need of thyroidec- study from Japan; in women who had received RAI
tomy is her clinical situation [6]. Beta blockers in the past for severe and intractable Graves’ dis-
and short course of potassium iodide solution ease; an incidence of neonatal hyperthyroidism as
(50–100 mg/day) is recommended in prepara- high as 11.3 % is reported [48]. Mothers who have
tion for surgery [4]. Maternal TRAbs levels had received RAI in the past for severe and intrac-
should be tested at the time of surgery which table Graves’ disease are more likely to exhibit
will help in risk assessment of fetal hyperthy- higher TRAb titres in pregnancy and subsequent
roidism [6]. TRAb disappears slowly after sur- risk of neonatal hyperthyroidism. Still others have
gical thyroidectomy, with only about half of the reported a 30 % occurrence of neonatal hyperthy-
patients being TRAb negative after a year [31]. roidism in TRAb positive women [48, 49].
Thus, a woman may have undergone thyroidec- TRAb titres decrease with the progression of
tomy and is off ATDs and now receiving pregnancy. It is recommended to test for serum
L-thyroxine but due to her high TRAb, the fetus TRAb at 24–28 weeks of gestation and if the lev-
may be hyperthyroid [18]. All this calls for a els are elevated three times the upper limit of nor-
systematic and careful follow-up evaluation of mal then close fetal monitoring by fetal medicine
the fetal thyroid state. physicians should be done [4, 6].
Radioactive iodine treatment is contraindi-
cated in pregnancy because it destroys the fetal Fetal Monitoring in a Woman
thyroid gland, resulting in permanent hypothy- with Graves’s Disease
roidism in the newborn [2, 4]. In most cases, the diagnosis of fetal hyperthy-
roidism should be made on clinical grounds
based on maternal history, serum TRAb levels,
Metarnal TRAb and Its Impact and fetal ultrasonography.
on the Fetus Fetal surveillance with serial ultrasound
examinations may be performed for the assess-
TRAb are present in over 95 % of patients with ment of gestational age, fetal viability, amniotic
active Graves’ Disease and even following RAI fluid volume, fetal anatomy, and detection of
ablation; TRAb remains elevated for many months malformations. Fetal well-being may be compro-
[31]. High titres of TRAb can lead to fetal or neo- mised in the presence of elevated TRAb, uncon-
natal hyperthyroidism [46–48]. TRAb determina- trolled hyperthyroidism, and pre-eclampsia
tion is advisable in following condition [4–6]: [4–6].
Signs of potential fetal hyperthyroidism that
• Maternal active hyperthyroidism may be detected by ultrasonography include fetal
• Past history of treatment with RAI or thyroid- tachycardia (>160 beats/min, persistent for over
ectomy for Graves’ disease 10 min), intrauterine growth restriction, presence
• Past history of delivering an infant with of fetal goiter (the earliest sonographic sign of
hyperthyroidism fetal thyroid dysfunction), accelerated bone mat-
• Thyroidectomy during pregnancy for treat- uration, signs of congestive heart failure, and
ment of Graves’ Disease fetal hydrops [6, 47]. A team approach is recom-
mended for the management of these patients.
The team should include an experienced obstetri-
Fetal and Neonatal Hyperthyroidism cian or maternal–fetal medicine specialist, neo-
natologist, and anesthesiologist.
The prevalence of fetal or neonatal hyperthyroidism In extremely rare circumstances; cordocente-
is 1–5 % in women with active or past history of sis or umbilical cord sampling can be performed
Graves’ disease but if remains unrecognized or to detect whether the fetus is hypothyroid or
18 Pregnancy and Hyperthyroidism 305
hyperthyroid [4, 6]. The indications are for a months post-partum and relapse is expected in
woman who is having high TRAb and is being 84 % of women after a pregnancy [58].
treated with ATDs and fetal goiter is visualized
on ultrasonography but the thyroid status of the Conclusion
fetus is undetermined [4, 6]. Cordocentesis car- Uncontrolled hyperthyroidism in pregnancy is
ries significant fetal morbidity and mortality so associated with adverse maternal and fetal
should be offered and performed only in appro- outcomes. Wherever available; trimester-spe-
priate setting. cific and method-specific reference ranges for
None of the infants born to TRAb negative thyroid function tests should be used. It is
mothers develop neonatal hyperthyroidism. At important to differentiate between the two
birth, taking a cord blood sample for TRAb esti- common causes of hyperthyroidism in preg-
mation in the neonate helps in risk prediction for nancy i.e. GTT and Graves’ disease as the for-
development of neonatal hyperthyroidism [50, mer condition is largely self-limiting and
51]. FT4 measurement at birth should be repeated requires only supportive care. ATDs stay as
between days 3 and 5 (and by day 7 at the latest); the first line treatment for Graves’ disease dur-
rapid FT4 elevation during the first postnatal ing pregnancy, PTU in the first trimester and
week is predictive of hyperthyroidism and war- CMZ/MMI for rest of gestation. It is impor-
rants ATD therapy [52]. tant to keep the lowest possible doses of ATDs
to keep the FT4 at or just above the reference
range. TSH may remain suppressed through-
ATDs Use in Lactation out pregnancy thus ATD dose adjustment
should be done mainly on the basis of 2–4
Both ATDs are secreted in human milk. In gen- weekly FT4 levels. Maternal TRAbs estima-
eral, there is no evidence to advice mothers tion in the third trimester helps in assessing
against breast-feeding when taking antithyroid the risk of fetal and neonatal hyperthyroidism.
drugs [53]. Moderate dose of ATDs are safe in There is a risk of Graves’ disease relapse in
lactating mothers. MMI/CMZ stay as first line the post-partum period.
agents with doses up to 20–30 mg/day; while
PTU as second line with doses up to 300 mg/day
during lactation [54]. Mothers should be advised
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Index
A hyperthyroidism, 154–155
Abadie’s sign, 72 against TSH receptor, 72
Acetylcholinesterase (AChE), 53 Anticoagulation, 230, 280
Acquired hypothyroidism, 128–129 Antithyroid drugs (ATDs), 300, 301
Adipose tissue in lactation, 305
atrophy, 182 monitoring pregnant woman on, 302–303
brown, 20, 22 Anti-thyroid medications
orbital, 177 Graves’ disease, 170–171
THs in, 19–20 hyperthyroidism, 158–160
white, 19–20 bile salt sequestrant, 161
Adrenergic system, 20, 276 carbimazole, 158–159
Aerobic Gram-negative/-positive bacteria, 104 iodides, 161
AF. See Atrial fibrillation (AF) methimazole, 158–159
AFTN. See Autonomously functioning thyroid propylthiouracil, 159
nodule (AFTN) thioamides, 158
Agranulocytosis, 159, 171, 302 Antithyroid peroxidase (anti-TPO) antibodies
AIH. See Amiodarone-induced hyperthyroidism (AIH) hyperthyroidism, 154–155
AITD. See Autoimmune thyroid disease (AITD) subclinical hypothyroidism, 208
American Academy of Family Physicians, 8 Anxiety disorders, 265, 268
American Association of Clinical Endocrinologists Apathetic hyperthyroidism, 69, 153–154
(AACE), 7, 129, 195, 197, 215 Apathetic thyrotoxicosis, 267
American College of Obstetricians and Gynecologists, 7 Appendages, 123–124
American College of Physicians, 7, 129, 206 Arrhythmias
American Thyroid Association (ATA), 7, 129, 160, atrial, 278–281
206, 299 in hyperthyroidism, 274
fine needle aspiration, 246 thyroid dysfunction (see Thyroid dysfunction)
hyperthyroidism, 299 ventricular, 282
iodine replacement, 293 Arrhythmogenesis, 276–278
management guidelines, 257 As Low As Reasonably Achievable
pregnancy, 299 (ALARA), 172
thyroid nodule, 241, 243 Atrial arrhythmia, 278–281
Amiodarone-associated thyroiditis amiodarone-induced hyperthyroidism, 280–281
clinical features, 96 anticoagulation, 280
diagnostic evaluation, 96 euthyroid range in older adults, 280
differential diagnosis, 96–97 hyperthyroidism, 278–279
epidemiology, 96 hypothyroidism, 279–280
etiology, 96 subclinical hypothyroidism, 279–280
pathogenesis, 96 Atrial fibrillation (AF)
treatment, 97 anticoagulation, 280
Amiodarone-induced hyperthyroidism pathogenesis, 277
(AIH), 151, 233, 280–281 to sinus rhythm, 279–280
AMP-activated protein kinase (AMPK) pathway, 17 subclinical hyperthyroidism, 190
Anaplastic thyroid carcinoma (ATC), 261 tachycardia with, 69
Antibodies triiodothyronine on, 275
Autoimmune thyroid disease (AITD), 41, 42, 65, 148 acquired pituitary and hypothalamic disorders,
Graves’ disease (see Graves’ disease (GD)) 122–123
radioiodine therapy, 210 central congenital hypothyroidism, 123
susceptibility genes, 149 course of disease, 127
without overt hypothyroidism, 291 definitions, 118
Autoimmune thyroiditis (AIT), 41, 63, 154, 266, 292 diagnosis, 129–131
Autonomic nervous system, 14–15, 277 differential diagnosis, 131–132
Autonomously functioning thyroid nodule disorders, 123
(AFTN), 150, 157 drugs, 123
Avicenna, 62 epidemiology, 118
treatment, 136
Cerebrovascular disease, thyroid emergencies, 230–231
B CFDS. See Color flow Doppler sonography (CFDS)
Ballet’s sign, 72 Chemotherapy, melignant thyroid lymphoma, 261–262
B cells, 155 Clinical activity score (CAS), GO, 179
Hashimoto’s thyroiditis, 88–89 Cocaine and amphetamine regulated transcript
signaling process, 67 (CART), 14
BDNF. See Brain derived neurotrophic factor (BDNF) Color flow Doppler sonography (CFDS)
Becker’s sign, 72 amiodarone-associated thyroiditis, 96
Beta blockers Graves’ disease, 78
hyperthyroidism, 157, 159 painless thyroiditis, 93, 94
subclinical hyperthyroidism, 197 postpartum thyroiditis, 95
thyroid storm, 226–227 Riedel’s thyroiditis, 100
Bile salt sequestrant, 161 subacute thyroiditis, 102
Biochemical tests, 5, 244–245 Complete blood count (CBC), 155
Bone mineral density (BMD) Computed tomography (CT)
subclinical hyperthyroidism, 191–192 Graves’ opthalmopathy, 179–180
THs in, 19 hyperthyroidism, 156–157
Boston’s sign, 72 Riedel’s thyroiditis, 100
Brain derived neurotrophic factor (BDNF), 52 suppurative thyroiditis, 106
Brain development thyroid nodule, 245, 246
disruption, 52 Congenital hypothyroidism
iodine lack during, 28 central, 123
secreted TRH, inactivation of, 15 primary, 121
THs in, 18 screening, 128–129
Brassica, 35 treatment, 136–137
Brown adipose tissue (BAT), 20, 22 Coronary heart disease (CHD)
Hashimoto’s thyroiditis, 92
subclinical hyperthyroidism, 190
C subclinical hypothyroidism, 210
Calcium channel blockers, hyperthyroidism, 157 Cowen’s sign, 72
Canadian Task Force on the Periodic Health Cytotoxic T lymphocyte antigen-4 (CTLA-4), 66
Examination, 7
Canon of Avicenna, 62
Carbimazole (CMZ), 170–171 D
Graves’ disease, 302 Dalrymple’s sign, 72
hyperthyroidism, 158–159 Deiodinases, 16, 39, 51
Cardiovascular disease (CVD) Dementia, 192, 230, 270
contractile properties, 274 2-deoxy-2[18F] Fluoro-d-glucose positron emission
Graves’ disease, 69 tomography (18FDG-PET) imaging, 242, 246
hypothyroidism, 124–125 Desiccated thyroid, 135
subclinical hyperthyroidism, 189–191 Diarrhea, 69, 154
subclinical hypothyroidism, 210–211 Dietary supplements, 135–136, 152
THR, 213–214 Dieulafoy’s sign, 72
thyroid emergencies, 231–232 Differentiated thyroid cancer (DTC), 240
and thyroid function, 6 follicular thyroid carcinoma
thyroid hormone, 22, 274–276 diagnosis, 256
Catecholamine, 3, 152, 265, 276 epidemiology, 255
CD40 gene, 66 investigations, 256
Central hypothyroidism pathology, 255
Index 311
R Screening
Radiation-induced thyroiditis acquired hypothyroidism, 128–129
diagnostic evaluation, 107 advantage of, 194
differential diagnosis, 107 congenital hypothyroidism, 128–129
epidemiology, 106 hypothyroidism, 128–129
etiology, 106 pregnancy in hypothyroidism, 292
pathogenesis, 106 for subclinical hyperthyroidism, 194–195
treatment, 107 subclinical hypothyroidism, 205–206
Radioactive iodine (RAI) therapy Selective serotonin reuptake inhibitor (SSRI), 269
differentiated thyroid cancers, 258–260 Single Nucleotide Polymorphisms (SNPs), 65
long term management, 259 Sinus rhythm
novel therapies, 259–260 atrial fibrillation to, 279–280
preparation, 258–259 supraventricular arrhythmia during, 281
TSH suppression therapy, 259 thyroid emergencies, 232
Graves’ disease, 171–173 Skin
hyperthyroidism, 160–161, 300–301 Graves’ disease, 70
primary hypothyroidism, 120 hypothyroidism, 123–124
thyroid emergencies, 233 Snellen-Riesman sign, 73
thyroid nodule, 249 ST. See Subtotal thyroidectomy (ST)
Radioactive iodine uptake (RAIU) test Stellwag’s sign, 73
amiodarone-associated thyroiditis, 96 Steroids
Hashimoto’s thyroiditis, 89 amiodarone-induced thyroid emergencies, 233
painless thyroiditis, 93, 94 myxedema coma, 229
Radionuclide scanning, thyroid nodule, 245–246 thyroid storm, 227
Recommended Dietary Allowance (RDA), 30 Struma lymphomatosa, 118
Recommended Nutrient Intakes (RNI), 30 Struma ovarii
Recurrent laryngeal nerve (RLN) injury, 162 cause-specific treatment, 163
Renal system clinical features, 153
Graves’ disease, 73 Stunned myocardium, 19
hypothyroidism, 126 Subacute thyroiditis
Renin-Angiotensin-Aldosterone system, 69 clinical features, 101–102, 153
Reproductive system, hypothyroidism, 126–127 diagnostic evaluation, 102
Resistance to thyroid hormone (RTH), 118, 123, 151 differential diagnosis, 102–103
differential diagnosis, 131 epidemiology, 101
hyperthyroidism, 151 etiology, 101, 151
primary hypothyroidism, 131 pathogenesis, 101
Respiratory system radioisotope findings, 156
Graves’ disease, 73 treatment, 103–104
hypothyroidism, 125 Subclinical hyperthyroidism, 6
Riedel’s thyroiditis (RT) atrial fibrillation, 190
clinical features, 99–100 bone and mineral metabolism, 191–192
diagnostic evaluation, 100 cardiovascular abnormalities of, 189–191
differential diagnosis, 100 causes, 186, 194
epidemiology, 99 clinical findings, 189
etiology, 99 community-based analysis, 192
pathogenesis, 99 complications
treatment, 100–101 high risk for, 196
Rituximab, 163, 181 low risk for, 196–197
RLN injury. See Recurrent laryngeal nerve coronary heart disease, 190
(RLN) injury dementia cognitive function, 192
Rosembach’s sign, 73 diagnosis, 193–194
RTH. See Resistance to thyroid hormone (RTH) endogenous, 187, 195–196
Rusell-Fraser sign, 73 epidemiology, 187–188
etiology of, 197
evaluation, 193
S exogenous, 186–187
Sainton’s sign, 73 heart failure, 190
Saturated solution of potassium iodide management, 195–198
(SSKI), 161, 162, 227 multivariate regression analysis, 192
Schizophrenia, 265 natural history, 187–188
Index 317