THE ENDOCRINE SYSTEM, METABOLISM AND DISORDERS

Topic 17
Iodine Metabolism, Thyroid
Hormone Function and Disorders

Ketut Suastika et al.

Team of Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Udayana University
25th-26th April 2019
 Anatomy of thyroid

Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical Endocrinology. Gardner DG and
Shoback D (Eds.). 10th Edition, 2018
 Anatomy of thyroid

Cross-section of the neck at the level of T1, showing thyroid relationships.

Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical Endocrinology. Gardner DG and
Shoback D (Eds.). 10th Edition, 2018
 Histology of thyroid

Cellular architecture of the thyroid. (a) Low-power hematoxylin-eosin

(H&E)-stained view of thyroid showing follicles with central colloid and
thyroid capsule. (b) Medium-power H&Estained view of thyroid. Note
varying sized follicles composed of a single layer of epithelial cells
surrounding a central colloid matrix containing thyroglobulin. C cells lie
in the interfollicular zones.

Rosenthal DS and Hupart KH. 2016. Thyroid and Parathyroid Diseases. In Medical and Surgical Fernandex-Santos et al. 2012. In
Management. Terris DJ and Duke WS (Eds.). Second Edition. Thieme Publisher, New York, Thyroid Hormone.
2016. Pp. 16-23. http//doi.org/10.5772/46178.
Iodine Metabolism and
Thyroid Hormone
Synthesis and Physiology
Iodine metabolism
• Iodine is a key structural component of thyroid
hormones.
• Consequently, it is an essential micronutrient consumed
in food or water as iodide or iodate, which is converted
to iodide in the stomach.
• The World Health Organization (WHO) recommends a
daily dietary iodine intake of 150 μg for adults, 200 μg
for pregnant and lactating women, and 90 μg for
children.
• Because most iodide is excreted by the kidneys, urinary
iodide excretion is an excellent index of dietary intake.
Iodine
metabolism

The values
indicated are
representative of
those that might be
found in a healthy
subject ingesting
500 μg of iodine a
day. The actual
iodine intake
varies
considerably
among different
individuals.

Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical Endocrinology. Gardner DG and
Shoback D (Eds.). 10th Edition, 2018
Iodoamines and Thyroid
hormone synthesis
Tyrosine residues in the follicular
thyroglobulin colloid are iodinated
at the 3- and 5- positions of their
phenyl rings by oxidation and
organification of I– catalyzed by TPO
in the presence of H2O2 to form
inactive MIT and DIT. TPO then
further couples MIT and DIT by
placing an ether bond between two
rings into the active thyroid
hormones T3 and T4. H2O2,
hydrogen peroxide; TPO,
thyroperoxidase; MIT,
monoiodotyrosine; DIT,
diiodotyrosine; T3, triiodothyro-
nine; T4, tetraiodothyronine, l-
thyroxine.
Rosenthal and Hupart, 2016. Physiology of
the Thyroid Gland. In Thyroid and Parathyroid
Diseases. Medical and Surgical Management.
Terris DJ and Duke WS (Eds.). Second Edition.
Thieme Publisher, New York. Pp. 16-23.
Thyroid hormone synthesis and secretion
Effect of TSH on thyroid cells
• TSH controls thyroid cell growth and hormone production by binding to a
specific TSH receptor
• The major action of TSH
A. Changes in thyroid cell morphology
TSH rapidly induces pseudopods at the follicular cell–colloid border, accelerating TG
resorption. Colloid content is diminished as intracellular colloid droplets are formed, and
lysosome formation is stimulated, increasing TG hydrolysis and thyroid hormone release.
B. Cell growth
Individual thyroid cells increase in size; vascularity is increased; and, over a period of time,
thyroid enlargement, or goiter, develops.
C. Iodine metabolism
TSH stimulates all phases of iodide metabolism, from increased iodide uptake and transport
to increased iodination of TG and increased secretion of thyroid hormones and TG itself.
Increased NIS expression and the stimulation of cAMP production mediate increased iodide
transport, and phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis and increased
intracellular Ca2+ stimulate the iodination of TG.
D. Other effects of TSH
Other effects include increased transcription of the mRNAs for TG and TPO; increased
incorporation of iodide into MIT, DIT, T3, and T4; and increased lysosomal activity, with
increased secretion of T4 and T3 from the gland. There is also increased activity of type 1 5′-
deiodinase, which helps conserve intrathyroidal iodine.
 Thyroid hormone metabolism
• Both thyroid hormones
circulate in blood bound to
plasma proteins; only 0.04%
of T4 and 0.4% of T3 are
unbound or free, and
consequently, available for
entry and action in target
tissues.
• There are three major thyroid
hormone transport proteins:
thyroxine-binding globulin
(TBG); transthyretin, formerly
called thyroxine-binding
prealbumin (TBPA), and
albumin

Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical Endocrinology. Gardner DG and
Shoback D (Eds.). 10th Edition, 2018
 Thyroid hormone metabolism
• Major pathways of
thyroxine
metabolism in nor-
mal adult humans.
Rates are expressed
in nmol/24 h and are
approximations
based upon available
data. 100 nmol of T4
is equivalent to
approximately 75 μg.
• (rT3, reverse T3;
TETRAC,
tetraiodothyroacetic
acid

Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical Endocrinology. Gardner DG and
Shoback D (Eds.). 10th Edition, 2018
 Physiologic effects of thyroid hormones

Bowers J et al. Endocrine Rev 2013; 34: 556-589

• Fetal development • Pulmonary effects • Neuromuscular effects

• Oxygen consumption, heat • Hematopoietic effects • Effects on lipid &
production & free radical • Gastrointestinal effects carbohydrate metabolism
formation • Endocrine effects
• Skeletal effects
• Cardiovascular effects
• Sympathetic effects Cooper DS and Ladenson PW. 2018. The Thyroid Gland. In Greenspan’s Basic and Clinical
Endocrinology. Gardner DG and Shoback D (Eds.). 10 th Edition, 2018
Simplified
overview of the
HPT axis
Stimulation of the hypothalamus results
in TRH release, which increases TSH
secretion from the pituitary. TSH acts to
increase TH production and secretion
from the thyroid gland. Hypothalamic
signals can also directly influence
peripheral tissues via the SNS. THs are
secreted into the circulation, and they
enter target tissues such as liver, BAT,
and white adipose tissue (WAT). The
main form released into the blood is T4,
which in turn can be locally activated
into T3 by deiodinases D1 and 2.
Pathways of TH deactivation (involving
deiodinase D3) are not included in this
simplified schematic view of the HPT
axis, although their roles are of
particular importance in the brain for
example.

Bowers J et al. Endocrine Rev 2013; 34: 556-589

Thyroid Disorders
Screening and Work-up
of Thyroid Dysfunction
 Work-up: Structure, Function, and Etiology

• Clinical features
• Lab studies
• Screening: TSHs
• Next step: FT4
• Further lab testing: thyroid
antibodies (TRAb, Anti TPO),
thyroglobulin, calcitonin (at high
risk for medullary carcinoma of
thyroid)
• Imaging studies
• Ultrasound
• CT scan or MRI
• Radionuclide uptake and
radionuclide scan
 Benefits of Early Detection and
Treatment
• The USPSTF found inadequate evidence that screening for
thyroid dysfunction in nonpregnant, asymptomatic adults
leads to clinically important benefits. In particular, the USPSTF
found inadequate evidence to determine whether screening for
thyroid dysfunction reduces cardiovascular disease or related
morbidity and mortality.
• The USPSTF found adequate evidence that screening for and
treatment of thyroid dysfunction in non-pregnant,
asymptomatic adults does not improve quality of life or
provide clinically meaningful improvements in blood pressure,
body mass index (BMI), bone mineral density, or lipid levels. It
also does not improve cognitive function, at least through the
duration of available trials (≥1 to 2 years)
USPSTF = U.S. Preventive Services Task Force Recommendation Statement
LeFevre ML et al. Ann Intern Med. 2015;162:641-650
 Classification of thyroid
dysfunction: Biochemical Definition
TSH Level, by Condition Thyroid Hormones Comments
Overt hyperthyroidism
<0.1 mIU/L or undetectable Elevated thyroxine or triiodothyronine –

Overt hypothyroidism
>4.5 mIU/L Low thyroxine –

Subclinical hyperthyroidism
Normal thyroxine and triiodothyronine Clearly low serum TSH
<0.1 mIU/L
0.1–0.4 mIU/L Normal thyroxine and triiodothyronine Low but detectable

Subclinical hypothyroidism
Normal thyroxine Mildly elevated TSH
4.5–10.0 mIU/L
≥10 mIU/L Normal thyroxine Markedly elevated TSH

Rugge JB et al. Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med
2015; 162: 35-45. doi:10.7326/M14-1456.
Iodine Deficiency Disorders
 Iodine Deficiency disorders (IDD)

• Iodine deficiency is a major public

health concern throughout the world.
The main factor responsible for iodine
deficiency is a low dietary supply of
iodine.
• Iodine deficiency occurs among
populations living in areas where the
soil is deprived of iodine, which is the
result of past glaciation compounded
by the leaching effects of snow, water
and heavy rainfall.
• Iodine deficiency is the leading cause
of preventable brain damage in
childhood.

Andersson M, et al. The WHO Global Database on iodine deficiency disorders: the importance of monitoring iodine nutrition.
Scandinavian Journal of Nutrition 2003; 47 (4): 162-166
 The spectrum of iodine deficiency disorders (IDD)

Fetus Abortions
Stillbirths
Congenital anomalies
Increased perinatal mortality
Endemic cretinism

Neonate Neonatal goitre

Neonatal hypothyroidism
Endemic mental retardation
Increased susceptibility of the thyroid gland to nuclear radiation

Child and adolescent Goitre

(Subclinical) hypothyroidism-hyperthyroidism Impaired mental function
Retarded physical development
Increased susceptibility of the thyroid gland to nuclear radiation

Adult Goitre with its complications Hypothyroidism

Impaired mental function
Spontaneous hyperthyroidism in the elderly Iodine-induced hyperthyroidism
Increased susceptibility of the thyroid gland to nuclear radiation

Andersson M, et al. The WHO Global Database on iodine deficiency disorders: the importance of monitoring iodine nutrition. Scandinavian
Journal of Nutrition 2003; 47 (4): 162-166
 Epidemiological criteria for assessing iodine
nutrition based on median urinary iodine
concentrations in school-age children

Median urinary Iodine intake Iodine nutrition

iodine (mg/L)
<20 Insufficient Severe iodine deficiency
20-49 Insufficient Moderate iodine deficiency
50-99 Insufficient Mild iodine deficiency
100-199 Adequate Optimal
200-299 More than adequate Risk of iodine-induced hyperthyroidism
>300 Excessive Risk of adverse health consequences
(iodine-induced hyperthyroidism,
autoimmune thyroid disease)

Andersson M, et al. The WHO Global Database on iodine deficiency disorders: the importance of monitoring iodine nutrition.
Scandinavian Journal of Nutrition 2003; 47 (4): 162-166
 Criteria for monitoring progress towards sustainable
elimination of iodine deficiency disorders
Indicators Goals
Urinary iodine
• Proportion of population with urinary iodine levels below 100 mg/L <50%
• Proportion of population with urinary iodine levels below 50 mg/L <20%
Salt iodization coverage
• Proportion of households consuming adequately iodized salt <90%
Programmatic indicators At least 8
• National body responsible to the government for IDD elimination. It should multidisciplinary, of the 10
involving the relevant fields of nutrition, medicine, education, the salt industry, the media, and
consumers, with a chairman appointed by the Minister of Health
• Evidence of political commitment to USI and elimination of IDD
• Appointment of a responsible executive officer for the IDD elimination program
• Legislation or regulations on USI
• Commitment to regular of progress in IDD elimination, with access to laboratories able to provide
accurate data on salt and urinary iodine
• A program of public education and social mobilization on the importance of IDD and the
consumption of iodized salt
• Regular data on iodized salt at the factory, retail and household levels
• Regular laboratory data on urinary iodine in school-aged children, with appropriate sampling for
higher risk areas
• Co-operation from the salt industry in maintenance of quality control
• A database for recording of results or regular monitoring procedures particularly for salt iodine,
urinary iodine and, if available, neonatal TSH, with mandatory public reporting

Andersson M, et al. The WHO Global Database on iodine deficiency disorders: the importance of monitoring iodine nutrition. Scandinavian
Journal of Nutrition 2003; 47 (4): 162-166
Hypothyroidism:
Subclinical and Overt
 Important causes of hypothyroidism
Primary
• Hashimoto’s thyroiditis
• Radioactive iodine therapy
• Thyroidectomy
• Excessive iodide intake (kelp, radiocontrast dyes)
• Subacute thyroiditis (usually transient)
• Iodide deficiency
• Inborn errors of thyroid hormone synthesis
• Drugs: lithium, IF-alpha, amiodarone
Secondary
• Pituitary adenoma, pituitary ablative therapy, pituitary destruction
Tertiary
• Hypothalamic dysfunction (rare)
Peripheral resistance to the action of thyroid hormone
 Presenting features of Diagnosis
hypothyroidism hypothyroidism

• Exhaustion • Puffiness below the eyes • History and physical

examination
• Somnolence • Bradycardia
• Laboratory
• Slow cognition • Slow relaxing tendon
reflexes
examination
• Intolerance to cold • ↑TSHs,
• Coarsening of facial
• Constipation features • ↓FT4, FT3
• Depression • Pleural effusion • Autoantibodies
• Weight gain • Pericardial effusion • TPO antibody (+)
• Calf stiffness • Ascites • Thyroglobulin
antibody (+)
• Menstrual disturbance • Non-pitting edema of lower
leg • Radiography
• Carpal tunnel
syndrome • Hyponatraemia • Biopsy
• Hearing impairment • Hypercholesterolaemia

• Dry, thin and pale skin • Impaired consciousness

(myxoedema coma)

Vaidya B and Peacrce SHS. BMJ 2008; 337: 284-289

 Algorithm for pragmatic management of primary
hypothyroidism in non-pregnan adults
Raised thyroid stimulating hormone levels

Thyroid stimulating hormone Thyroid stimulating hormone Thyroid stimulating hormone

level >10 mU/l with or without level 5-10 mU/l with level 5-10 mU/l with
low free serum thyroxine low free serum thyroxine normal free serum thyroxine

Symptoms of hypothyroidism

Yes
No

3-6 months trial of thyroxine

Check status of thyroid peroxidase antibody

Symptom resolved?
Positive result Negative result

Yes No
Recheck thyroid Recheck thyroid
stimulating stimulating
Treat with thyroxine life Consider alternative hormone hormone level
long diagnosis level annually every three years

Vaidya B and Peacrce SHS. BMJ 2008; 337: 284-289

Factors Favoring Levothyroxine
Therapy in Patients With a TSH
Level of 5 to 10 mIU/L and normal
FT4 (Subclinical Hypothyroidism) Thyroxine therapy
• Pregnancy or intention of pregnancy • Initial dose: 50-75 mg/day
• Goiter • Patients with CAD: 12.5-25
• Therapeutic trial for possible hypothyroid mg/day
symptoms
• Patient preference • Dose can be increased
• Childhood and adolescence • TSH should be measured 4-
• 2 TSH levels >8 mIU/L 6 weeks after therapy
• Bipolar disorder, depression begun then annually once
• Infertility
the levels become stable
• Presence of antithyroid antibodies
• Progressive TSH increase
• Ovulatory dysfunction
• Young age of the patient
• Hyperlipidemia?

Fatourechi V. Mayo Clin Proc 2009; 84: 65-71

Hashimoto Thyroiditis
 Hashimoto thyroiditis: Definition

• HT: chronic inflammation of the thyroid the most

common autoimmune disease, the most common
endocrine disorder, as well as the most common
cause of hypothyroidism.
• Based on the etiology, HT can be classified into
primary and secondary forms

P. Caturegli et al. Autoimmunity Reviews 13 (2014) 391–397

 Hashimoto thyroiditis: Pathogenesis

Compromised function to T regulatory (Treg) cells, increased activity of follicular helper T cells (Tfh), DNA fragments (frag)
released following cell death and altered microRNA (miRNA) profile result in initiation and perpetuation of the autoimmune
process. Thyroid infiltrating T and B cells result in cell cytotoxicity, apoptosis and antibody production. A large number of
cytokines are synthesised by the infiltrating inflammatory cells, which further contribute to the inflammatory process and gland
destruction
Ajjan RA and Weetman AP. Horm Metab Res 2015; 47: 702–710
Clinico-pathological spectrum of Hashimoto
thyroiditis
Primary forms Isolated •
Classic form
•
Fibrous (or fibrosing) variant
•
IgG4-related variant
•
Juvenile form
•
Hashitoxicosis variant
•
Painless (or silent, or subacute
lymphocytic) thyroiditis
• Sporadic
• Post-partum
Associated with • Other thyroid diseases (papillary
thyroid cancer)
• Other autoimmune diseases
Secondary forms to • Interferon-alpha for hepatitis C infection
the administration • CTLA-4 blocking antibody for solid tumors
of • Cancer vaccines

P. Caturegli et al. Autoimmunity Reviews 13 (2014) 391–397

Hashimoto thyroiditis: Diagnosis

• Established by a combination of clinical features, presence of

serum antibodies against thyroid antigens (mainly to
thyroperoxidase and thyroglobulin), and appearance on thyroid
sonogram.
• Thyroid uptake of radioactive iodine and cytological examination
of thyroid aspirate are used more rarely
• Clinical features
• Local manifestations originate from compression of the cervical
structures that are anatomically close to the thyroid gland, and include
dysphonia (from involvement of the recurrent laryngeal nerve), dyspnea
(from restriction of the trachea), and dysphagia (from impingement upon
the esophagus).
• Systemic manifestations originate from loss of function of the thyroid
gland and subsequent primary hypothyroidism.

P. Caturegli et al. Autoimmunity Reviews 13 (2014) 391–397

Hashimoto thyroiditis: Management

• HT is mainly a medical disease.

• Thyroidectomy is nowadays performed when there are signs
and symptoms of severe cervical compression, upon patient's
request for cosmetic reasons, or, more commonly, when the
patient has a thyroid nodule with a cytology “suspicious” for
malignancy and the clinician does not know whether the
patient has just HT (where no surgery would be required) or
HT and thyroid cancer (where instead surgery is indicated)
• The therapy of the primary and permanent hypothyroidism
seen in many forms of HT consists in the daily, lifelong, oral
administration of synthetic levo-thyroxine (L-T4), which is
given at doses of 1.6– 1.8 μg per kg of body weight

P. Caturegli et al. Autoimmunity Reviews 13 (2014) 391–397

Hyperthyroidism: Subclinical
and Overt
 Causes of Hyperthyroidism
Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the
American Thyroid Association and American Association of Clinical Endocrinologists
Thyrotoxicosis associated with a normal or elevated
radioiodine uptake over the necka
• Grave’s disease
• Toxic adenoma or Toxic multinodular goiter
• Trophoblastic disease
• TSH-producing pituitary adenomas
• Resistance to thyroid hormone (T3 receptor mutation)b
Thyrotoxicosis associated with a near-absent radioiodine
uptake over the neck
• Painless (silent) thyroiditis
• Amiodarone-induced thyroiditis
• Subacute (granulomatous, de Quervain’s) thyroiditis
• Iatrogenic thyrotoxicosis
• Factitious ingestion of thyroid hormone
• Struma ovarii
• Acute thyroiditis
• Extensive metastases from follicular thyroid cancer

a
In iodine-induced or iodine-exposed hyperthyroidism (including amiodarone type 1), the uptake may be low.
b
Patients are not uniformly clinically hyperthyroid. T3, triiodothyronine.
Bahn RS et al. Thyroid 2011; 21: 593-646
 Manifestations of hyperthyroidism
Symptoms Signs
• Hyperactivity, irritability, altered • Sinus tachycardia, atrial
mood, insomnia fibrillation
• Heat intolerance, increased • Fine tremor, hyperkinesis,
sweating hyperreflexia
• Palpitations • Warm, moist skin
• Fatigue, weakness • Palmar erythema, onycholysis
• Dyspnea • Hair loss
• Weight loss with increased • Muscle weakness and wasting
appetite (weight gain in 10 • Congestive (high-output) heart
percent of patients) failure, chorea, periodic
• Pruritus paralysis (primarily in Asian
• Increased stool frequency men), psychosis*
• Thirst and polyuria
• Oligomenorrhea or amenorrhea,
loss of libido

* These signs are rare

Weetman AP. NEJM 2000; 343: 1236-1248

 Clinical Outcomes in Mild and Severe Endogenous
Subclinical Hyperthyroidism and Possible Benefits of
Treatment

Bernadette Biondi, M.D., and David S. Cooper, N Engl J Med 2018;378:2411-9.

Graves’ Disease
 Theoretical Model of Intrathyroidal Graves’ Disease

Smith TJ and Hegedüs L. N Engl J Med 2016;375:1552-65.

 Theoretical Model of the Pathogenesis of Thyroid-
Associated Ophthalmopathy

Smith TJ and Hegedüs L. N Engl J Med 2016;375:1552-65.

 Manifestations of Graves’ Disease 1
• Diffuse goiter
• Ophthalmopathy
• A feeling of grittiness and discomfort in
the eye
• Retrobulbar pressure or pain
• Eyelid lag or retraction Bartalena L and Tanda ML. NEJM 2009; 360: 994-1001

• Periorbital edema, chemosis, scleral

injection
• Exophthalmos (proptosis)
• Extraocular-muscle dysfunction
• Exposure keratitis
• Optic neuropathy
• Localized dermopathy
• Lymphoid hyperplasia
• Thyroid acropachy
Weetman AP. NEJM 2000; 343: 1236-1248

Fatourechi V et al. JCEM 2002; 87: 5435-5441 Schwartz KM et al. JCEM 2002; 87: 438-446
 Management of Graves disease

• Anti-thyroid drugs:
PTU, Carbimazole, Methimazole/Thiamazole
• Radioactive iodine
• Surgery
 Options for the management of Graves disease include antithyroid drug
therapy such as methimazole, radioactive iodine (RAI) treatment, and surgery

ATD actions:
Intrathyroidal inhibition of: Iodine oxidation/organification , Iodotyrosine coupling , Thyroglobulin biosynthesis, Follicular cell growth
Extrathyroidal inhibition of T4/T3 conversion (PTU)

Burch HB and Cooper DS. JAMA. 2015;314(23):2544-2554

 Algorithm for the management of a patient
with Graves’ hyperthyroidism (ETA, 2018)

Persistent
Untreated GD Hyperthyroidism Relapse
Recent onset At 18 (36) months
After stopping MMI
(adults & children) Positive TSH-R-Ab

MMI (CBZ) Long-term

MMI for Definitive
Adults: 18 months further 12 or treatment
or low-dose
Children: 36 months MMI
months

-MMI intolerance Personal Then TSH-R-Ab

- Noncompliance or decision measuremen
RAI Tx
negative positive
RAI Tx
-Small thyroid or - Nodul
- No/inactive - Goiter >50 mL Stop RAI or
-GO - Active GO MMI TX

Kahaly GJ et al. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J 2018;7:167–186
 Adverse events of antithyroid drugs

Common (1.0–5.0%) Rare (0.2–1.0%) Very rare (<0.1%)

• Skin rash • Gastrointestinal • Aplastic anemia (PTU,
• Urticaria • Abnormalities of CBZ)
• Arthralgia, taste and smell • Thrombocytopenia
polyarthritis • Agranulocytosis (PTU, CBZ)
• Fever • Vasculitis, lupus-like,
• Transient mild ANCA+ (PTU)
leukopenia • Hepatitis (PTU)
• Hypoglycemia (anti-
insulin Abs; PTU)
• Cholestatic jaundice
(CBZ/MMI)

ANCA, antineutrophil cytoplasmic antibody.

Kahaly GJ et al. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J 2018;7:167–186
Beta-Adrenergic Receptor Blockade in the Treatment of
Thyrotoxicosis
2016 American Thyroid Association Guidelines for Diagnosis and Management of
Hyperthyroidism and Other Causes of Thyrotoxicosis
Drug Dosage Frequency Considerations
Propanolol 10–40 mg 3–4 times per Nonselective b-adrenergic receptor blockade
day Longest experience
May block T4 to T3 conversion at high doses
Preferred agent for nursing and pregnant
mothers
Atenolol 25-100 mg 1–2 times per Relative b-1 selectivity
day Increased compliance
Avoid during pregnancy
Metoprolol 25-50 mg 2–3 times per Relative b-1 selectivity
day
Nadolol 40-160 mg 1 times per day Nonselective b-adrenergic receptor blockade
Once daily
Least experience to date
May block T4 to T3 conversion at high doses
Esmolol IV pump 50– In intensive care unit setting of severe
100 lg/kg/min thyrotoxicosis or storm

Ross DS et al. THYROID Volume 26, Number 10, 2016. DOI: 10.1089/thy.2016.0229
Considerations when deciding upon a treatment plan
in young patients with Graves’ Disease
Key circumstances when ATD may be the most appropriate treatment for Graves’ disease in the young

• Most patients – as initial therapy – on the basis that this is the only potential route to a life of long-term
medication
• The older patient where ATD is more likely to result in disease remission
• Relatively mild disease – biochemically and immunologically

Key circumstances when thyroidectomy may be the most appropriate treatment for Graves’ disease in the young

• Very young age (<10) and unable to tolerate ATD

• Eye disease (Graves orbitopathy)
• Large gland
• When rapid resolution of hyperthyroid state is desirable
• Where there are concerns about increased malignancy risk/particular concerns about the impact of ionizing
radiation
• Where ATD is no longer an option and avoiding close contact with family members presents particular problems

Key circumstances when radioiodine may be the most appropriate treatment for Graves’ disease in the young

• Where ATD is no longer an option and avoiding close contact with family members presents particular problems
• Key circumstances when radioiodine may be the most appropriate treatment for Graves’ disease in the young
• Patients unable to report key side effects of ATD such as a sore throat
• Patients requesting or requiring definitive treatment who do not want an operation.
• Older patients at high risk of recurrent relapse

Cheetham T and Bliss R. Clinical Endocrinology (2016) 85, 161–164

The recommended frequency of thyroid function testing
for patients receiving different anti- thyroid treatments
Anti-thyroid treatment Recommended frequency of thyroid function testing
Frequency of Period during which thyroid function is
testing tested
Carbimazole Every 4–6 weeks From starting carbimazole until
euthyroidism has been established on a
maintenance dose of 5–15 mg daily
Every 3 months From establishing euthyroidism on a
maintenance dose until 1 year after
stopping carbimazole
Annually If euthyroidism persists 1 year after
stopping carbimazole
Radioiodine and Initial test Check thyroid function 4–8 weeks after
subtotal thyroidectomy treatment
Every 3 months From 4 to 8 weeks after treatment until 1
year after treatment
Annually If euthyroidism persists 1 year after
treatment

Grayston F. InnovAiT, Vol. 4, No. 12, pp. 698–705, 2011

THYROID NODULES:
Diagnosis
 What is a thyroid nodule?
• The term thyroid nodule refers to an abnormal growth of thyroid cells
that forms a lump within the thyroid gland. Although the vast majority
of thyroid nodules are benign (noncancerous), a small proportion of
thyroid nodules do contain thyroid cancer. In order to diagnose and
treat thyroid cancer at the earliest stage, most thyroid nodules need
some type of evaluation.

ATA, www.thyroid.org. 2014

 Thyroid nodules: epidemiology
• Prevalence of palpable thyroid nodules: approximately 5% in women, 1% in
men living in iodine-sufficient part of the world
• By high-resolution ultrasound can detect thyroid nodules in 19%-68% of
randomly selected individuals, with higher frequencies in women and the
elderly
• Thyroid cancer: 7%-15% of case, depending on age, sex, radiation exposure
history, family history, and other factors
• Nonpaplpable nodules “incidentalomas” (<1 cm)
• Nodules are more likely to be malignant in patients <20 or >60 years of age.
Thyroid nodules are more common in women but approximately 4× more likely
to be malignant in men.

Haugen BR et al. 2015 ATA management guideline for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2016; 26. DOI: 10.1089/thy.2015.0020
Oxford American Handbook of Endocrinology and Diabetes. Edited by Boris Draznin et al., 2011
 Etiology of thyroid nodules
Clinical features raising
Etiology suspicion of thyroid malignancy
Common causes Uncommon causes
• Colloid nodule • Granulomatous
thyroiditis • Age (<20 or >60 years)
• Cyst • Infections
• Lymphocytic thyroiditis • Malignancy
• Rapidly enlarging nodule
• Medullary
• Anaplastic
• Local symptoms including
• Metastatic dysphagia, stridor, or
• Lymphoma hoarseness
• Benign neoplasms
• Hurthle cell • Previous exposure to radiation
• Follicular
• Malignancy
• Positive family history of
• Papillary thyroid cancer or multiple
• Follicular endocrine neoplasia (MEN)
syndrome

Oxford American Handbook of Endocrinology and Diabetes. Edited by Boris Draznin et al., 2011
 Ultrasound-based diagnostic
classification
Solid thyroid nodules Partially cystic thyroid nodules

A. Benign A. Benign
B. Probably benign B. Probably benign
C. Boderline C. Possibly malignant
D. Possibly malignant D. Malignant
E. Malignant

The US-based diagnostic criteria for solid thyroid nodules were as follows:
1) benign (SN-US class I): solid thyroid nodules with > 3 US features of benignancy and no
malignant or borderline US features;
2) probably benign (SN-US class II): solid thyroid nodules with 1 or 2 US features of
benignancy and no malignant or borderline US features;
3) borderline (SN-US class III): solid thyroid nodules with 1 border- line US feature and no US
features of malignancy, regardless of benign US features;
4) possibly malignant (SN-US class IV): solid thyroid nodules with 1 US feature of
malignancy, regardless of borderline or benign US features;
5) malignant (SN-US class V): solid thyroid nodules with > 2 US features of malignancy,
regardless of borderline or benign US features.
The criteria underlying the US diagnosis of PCTNs were as follows:
1) benign (PCTN-US class I): PCTNs with > 3 US features of benignancy and no
features of malignancy;
2) probably benign (PCTN-US class II): PCTNs with 1 or 2 US features of
benignancy and no features of malignancy;
3) possibly malignant (PCTN-US class III): PCTNs with 1 US feature of
malignancy, regard- less of other benign features;
4) malignant (PCTN-US class IV): PCTNs with > 2 US features of malignancy,
regardless of other benign features.

Kim DW et al. AJNR 2012; 33: 1144-1149

ATA nodule
sonographic
patterns and risk
of malignancy, and
FNA guidance for
thyroid nodules
Sonographic FNA size cutoff (largest
pattern dimension)
High suspicion FNA at > 1 cm
Intermediate FNA at >1 cm
suspicion
Low suspicion FNA at > 1.5 cm
Very low Consider FNA at > 2 cm
suspicion Observation without FNA is
also a reasonable option

Benign No biopsy

Haugen BR et al. 2015 ATA management guideline for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2016; 26. DOI: 10.1089/thy.2015.0020
 Multinodular thyroid glands
Multiple thyroid nodules have the same risk of
malignancy as those with solitary nodules
(solitary>multiple)
Strong recommendation
• Patients with multiple thyroid nodules >1 cm should be
evaluated in the same fashion as patients with a solitary
nodule >1cm, excepting that each nodule that is >1cm
carries an independent risk of malignancy and therefore
multiple nodules may require FNA.
• When multiple nodules >1 cm are present, FNA should
be performed preferentially based upon nodule
sonographic pattern and respective size cutoff

Haugen BR et al. 2015 ATA management guideline for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2016; 26. DOI: 10.1089/thy.2015.0020
 Thyroid carcinoma
Approximate frequency of malignant thyroid tumors
• Papillary carcinoma (including mixed papillary and 80%
follicular)
• Follicular carcinoma (including Hûrthle cell carcinoma) 10%
• Medullary carcinoma 5%
• Undifferentiated (anaplastic) carcinomas 3%
• Miscellaneous (including lymphoma, fibrosarcoma,
squamous cell carcinoma, malignant 1%
hemangioendothelioma, teratomas, and metastatic
carcinomas)

Cooper DS and Ladenson PW. The Thyroid Gland. Greenspan’s Basic & Clinical Endocrinology. 10th Edition, 2018