Pathophysiology of Thyroid

Disease

Hypothyroidism and Hyperthyroidism

Dr GOZASHTI
ENDOCRINOLOGIST
Anatomy of the Thyroid Gland
Follicles: the Functional Units of
the Thyroid Gland

Follicles Are the Sites

Where Key Thyroid
Elements Function:
• Thyroglobulin (Tg)
• Tyrosine
• Iodine
• Thyroxine (T4)
• Triiodotyrosine (T3)
 The Thyroid Produces and
Secretes 2 Metabolic Hormones

 Two principal hormones

» Thyroxine (T4 ) and triiodothyronine (T3)
– Required for homeostasis of all cells
– Influence cell differentiation, growth, and
metabolism
» Considered the major metabolic hormones
because they target virtually every tissue
 Thyroid-Stimulating Hormone
(TSH)

 Regulates thyroid hormone, production,

secretion, and growth

 Is regulated by the negative feedback

action of T4 and T3
Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism
 Thyroid Axis
T3, T4 (-)
Hypothalamus
TRH (+)
Pituitary
T3, T4 (-)
TSH (+)
Thyroid
 Biosynthesis of T4 and T3

The process includes

 Dietary iodine (I) ingestion
 Active transport and uptake of iodide (I-) by
thyroid gland
 Oxidation of I- and iodination of thyroglobulin
(Tg) tyrosine residues
 Coupling of iodotyrosine residues (MIT and
DIT) to form T4 and T3
 Proteolysis of Tg with release of T4 and T3 into
the circulation
 Iodine Sources

 Available through certain foods

(eg, seafood, bread, dairy products),
iodized salt, or dietary supplements,
as a trace mineral
 The recommended minimum intake is
150 g/day
 Iodine deficiency is prevalent in many
mountainous regions and in central
Africa, central South America, and
northern Asia
 Cretinism is characterized by mental
and growth retardation and occurs
when children who live in iodine-
deficient regions are not treated with
iodine or thyroid hormone to restore
normal thyroid hormone levels during
early life.
 These children are often born to
mothers with iodine deficiency, and it is
likely that maternal thyroid hormone
deficiency worsens the condition.
 Oversupply of iodine, through
supplements or foods enriched in iodine
(e.g., shellfish, kelp), is associated with
an increased incidence of autoimmune
thyroid disease.
 The recommended average daily intake
of iodine is :
 150  g/d for adults
 90–120  g/d for children
 200  g/d for pregnant women.
 Urinary iodine is >10  g/dL in iodine-
sufficient populations.
Active Transport and I- Uptake by
the Thyroid

 Dietary iodine reaches the circulation

as iodide anion (I-)
 The thyroid gland transports I- to the
sites of hormone synthesis
 I- accumulation in the thyroid is an
active transport process that is
stimulated by TSH
Iodide Active Transport is Mediated by the
Sodium-Iodide Symporter (NIS)

 NIS is a membrane protein that mediates

active iodide uptake by the thyroid
» It functions as a I- concentrating mechanism
that enables I- to enter the thyroid for
hormone biosynthesis
 NIS confers basal cell membranes of thyroid
follicular cells with the ability to effect “iodide
trapping” by an active transport mechanism
 Specialized system assures that adequate
dietary I- accumulates in the follicles and
becomes available for T4 and T3 biosynthesis
 Oxidation of I- and Iodination of
Thyroglobulin (Tg) Tyrosyl Residues

 I- must be oxidized to be able to

iodinate tyrosyl residues of Tg
 Iodination of the tyrosyl residues then
forms monoiodotyrosine (MIT) and
diiodotyrosine (DIT), which are then
coupled to form either T3 or T4
 Both reactions are catalyzed by TPO
 Thyroperoxidase (TPO)

 TPO catalyzes the oxidation steps

involved in I- activation, iodination of Tg
tyrosyl residues, and coupling of
iodotyrosyl residues
 TPO has binding sites for I- and tyrosine
 TPO uses H2O2 as the oxidant to activate
I- to hypoiodate (OI-), the iodinating
species
Proteolysis of Tg With Release of
T4 and T3

 T4 and T3 are synthesized and stored within the Tg

molecule
 Proteolysis is an essential step for releasing the
hormones
 To liberate T4 and T3, Tg is resorbed into the
follicular cells in the form of colloid droplets, which
fuse with lysosomes to form phagolysosomes
 Tg is then hydrolyzed to T4 and T3, which are then
secreted into the circulation
 Source of Circulating
Thyroid Hormones

T4 T4

T3 rT3

80
Production 30 g 30
per Day g g

Serum
T3 T4 rT3
Levels 120 ng/dl 8 g/dl 30 ng/dl
 Thyroid Hormone
Pharmacokinetics

Total Serum Free Serum Serum T1/2

Concentration Concentration

T4 5-12 g/dL 1.0-2.2 ng/dL 7 days

T3 .08-.22 g/dL 0.2-0.4 ng/dL 1 day
 Thyroid Hormone Transport and
Metabolism

 Both hormones are bound to plasma

proteins, including:
1/ thyroxine-binding globulin (TBG)
2/transthyretin (TTR, thyroxine-binding
prealbumin, or TBPA)
3/albumin
Abnormalities of Thyroid Hormone
Binding Proteins

 X-linked TBG deficiency

 TBG levels are elevated by estrogen
 euthyroid hyperthyroxinemia or familial
dysalbuminemic hyperthyroxinemia
(FDH)
 Changes in TBG Concentration Determine
Binding and Influence T4 and T3 Levels

 Increased TBG
» Total serum T4 and T3 levels increase
» Free T4 (FT4), and free T3 (FT3) concentrations
remain unchanged
 Decreased TBG
» Total serum T4 and T3 levels decrease
» FT4 and FT3 levels remain unchanged
Drugs and Conditions That Increase Serum T4
and T3 Levels by Increasing TBG

 Drugs that increase TBG  Conditions that increase

» Oral contraceptives and TBG
other sources of estrogen » Pregnancy
» Methadone » Infectious/chronic active
» Clofibrate hepatitis
» 5-Fluorouracil » HIV infection
» Heroin » Biliary cirrhosis
» Tamoxifen » Acute intermittent
porphyria
» Genetic factors
Drugs and Conditions That Decrease Serum T4 and T3 by
Decreasing TBG Levels or Binding of Hormone to TBG

 Drugs that decrease  Conditions that decrease

serum T4 and T3 serum T4 and T3
» Glucocorticoids » Genetic factors
» Androgens » Acute and chronic illness
» L-Asparaginase
» Salicylates
» Mefenamic acid
» Antiseizure medications,
eg, phenytoin, carbama-
zepine
» Furosemide
 Physical Examination

 Examination of the neck begins by

inspecting the seated patient from the
front and side and noting any surgical
scars, obvious masses, or distended
veins
 thyroid can be palpated with both hands
from behind or while facing the patient,
using the thumbs to palpate each lobe.

 The patient's neck should be slightly

flexed to relax the neck muscles
 (normally 12–20 g)
 asking the patient to swallow sips of
water
 Features to be noted include thyroid
size, consistency, nodularity, and any
tenderness or fixation
 A bruit over the gland indicates
increased vascularity, as occurs in
hyperthyroidism.
 If the lower borders of the thyroid lobes
are not clearly felt, a goiter may be
retrosternal.
 Large retrosternal goiters can cause
venous distention over the neck and
difficulty breathing, especially when the
arms are raised (Pemberton's sign).
 With any central mass above the
thyroid, the tongue should be extended,
as thyroglossal cysts then move upward
Utility of Thyroid Function Tests

 Essential
» Thyroid (T4) Panel or Free T4
» TSH
 May be of help
» Total or Free T3
 Infrequent/Rare
» Plasma thyroxine binding globulin, thyroglobulin
» Anti-thyroid antibodies (15% of population)
» Thyroid stimulating immunoglobulin
» Plasma reverse T3
» T3-resin uptake test
 T4 x T3RU = FTI
Normal TBG

*T3
*T3 *T3 *T3
*T3 *T3
+ *T3 *T3
*T3
+ resin *T3 + resin
T4 T4
T4 T4
T4 T4
T4 T4
free T4 free T4
T4 T4

TBG TBG
 T4 x T3RU = FTI
Hypothyroidism

*T3
*T3 *T3
*T3
+ *T3
*T3
+ resin *T3 + resin
*T3
*T3
*T3
T4 T4
free T4 free T4
T4 T4

TBG TBG
 T4 x T3RU = FTI
Hyperthyroidism

*T3 *T3 *T3

*T3 *T3
T4 T4 *T3
+ *T3
T4 T4
+ resin
T4 + resin T4
T4 T4 *T3
*T3
T4 T4 *T3
T4 T4
T4 T4
T4
free T4 T4
free T4
TBG TBG
 T4 T3RU FTI

N N N N

Hypothy   

Hyperthy   
 T4 x T3RU = FTI
Increased TBG
*T3
*T3
*T3 *T3
*T3
*T3
+ *T3 *T3
*T3 resin
+ resin *T3 +
T4
T4
T4
T4
T4
T4
T4
T4
T4
T4
T4 free T4 T4
T4 free T4
T4
 T4 x T3RU = FTI
Normal TBG
*T3 *T3
*T3 *T3
*T3 *T3
*T3 *T3
+ *T3 *T3
T4 T4 + resin
T4 + resin T4
T4 T4
T4 T4
T4 free T4 free T4
T4

Increased TBG
*T3
*T3
*T3
*T3
+ *T3 *T3
*T3 *T3
*T3
+ resin *T3
T4 T4
T4 T4 +
T4 T4 resin
T4 T4
T4 T4
T4 free T4 T4 free T4
T4 T4
 T4 x T3RU = FTI TSH Free T4

N N N N N N

Hypothy     

Hyperthy     

 TBG   N N N

 TBG   N N N
 SCREEN

 TSH
 Abnormal TSH T4
 2 to 5% T3 toxicosis
 clinical conditions in which the use of TSH
as a screening test may be misleading

 Any severe nonthyroidal illness

 TSH-secreting pituitary tumor
 thyroid hormone resistance
 assay artifact
 suppressed TSH level, particularly <0.1
mU/L, usually indicates thyrotoxicosis

 may also be seen:

 during the first trimester of pregnancy
(due to hCG secretion)
 after treatment of hyperthyroidism
 response to certain medications (e.g.,
high doses of glucocorticoids or
dopamine).
 Importantly, secondary hypothyroidism,
caused by hypothalamic-pituitary
disease, is associated with a variable
(low to high-normal) TSH level, which is
inappropriate for the low T4 level.
 Thus, TSH should not be used to assess
thyroid function in patients with
suspected or known pituitary disease.
 About 5–15% of euthyroid women and
up to 2% of euthyroid men have thyroid
antibodies;
 such individuals are at increased risk of
developing thyroid dysfunction.
 Almost all patients with autoimmune
hypothyroidism, and up to 80% of those
with Graves' disease, have TPO
antibodies, usually at high levels
 Serum Tg

 increased in all types of thyrotoxicosis

except thyrotoxicosis factitia caused by
self-administration of thyroid hormone

 follow-up of thyroid cancer patients

 Tests Assessing Intrinsic
Thyroid Activity
Test Name Measures Factors Affecting Test
Radioactive iodine Active transport Increased:
uptake (RAIU) and organification Hyperthyroidism
of iodine Iodine Deficiency
Decreased:
Hypothyroidism
Thyroiditis
Thyroid scan Localized Hyper- or hypothyroidism
(pertechnetate, rates of active Localized inflammation &
or iodine) transport of iodine Neoplasia causes regional
suppression
 Radioactive Iodine Uptake
(RAIU)

• A small amount of 131I is given orally, and 4 & 24

hr dosimetry readings are taken from the thyroid
• Normal range: ~5-30%
• Increased RAIU
» Graves Disease
» Toxic Multinodular Goiter
» Thyroid Adenoma
• Decreased RAIU
» Subacute or Silent Thyroiditis
» Iodine-Induced
» Factitious
 Thyroid Imaging Studies

• Thyroid Scintigraphy (“Scans”)

99m
» Tc
131
» I
Normal Graves’ Multinodular
Thyroid Thyroid Goiter

• Thyroid Ultrasound
» May be useful to accurately determine size for
purposes of documenting therapeutic efficacy
 Hypothyroidism

 Definition: Deficiency of thyroid hormone

 Causes:
» Primary (TSH high) ~95%
» Secondary (TSH low) ~5%
– Pituitary disease
– Hypothalamic disease
» Thyroid Hormone Resistance (rare)
 Relatively common:
» 2% adult women, 0.2% adult men
» >60: 6% adult women; 2% adult men
» May be higher in select groups
 Wide Range of Hypothyroidism

 Asymptomatic to Severe:
» Biochemical: Very common; TSH 6-10 IU/ml, with normal T4, T3.
Treatment is controversial & should be correlated with
improvement in symptoms
» Myxedema Coma: Profound, severe hypothyroidism
 Onset: Usually Gradual
 ± Goiter
 Risk Factors: Age >60, female, history of thyroid
disease, history of radiotherapy to head/neck, family
history of thyroid disease, lithium or amiodarone
therapy.
 Subclinical hypothyroidism is found in 6–
8% of women (10% over the age of 60)
and 3% of men.
 The annual risk of developing clinical
hypothyroidism is about 4% when
subclinical hypothyroidism is associated
with positive TPO antibodies.
 Clinical Hypothyroidism

Osler’s Description of Hypothyroidism:

[There is a] “marked increase in the general bulk of the body,
inelastic swelling of the skin [non-pitting], dryness and
roughness…. Perspiration is often much decreased. …the
features are coarse and broad, the lips thick, the nostrils broad
and thick, and the mouth is enlarged. There is a striking
slowness of thought and movement. The memory becomes
defective, the patients grow irritable and suspicious, and there
may be headache. In some instances their gait is heavy and
slow.”

Osler, W., McCrae, T. The Principles and Practice of Medicine, 9th edition, 1920.
 Clinical Features: Hypothyroidism

 Constitutional Symptoms:
» Cold Intolerance
» Fatigue, Lethargy
» Hoarseness
 Integument:
» Thickened/yellowed, Dry, Non-pitting Edema (=“Myxedema”) of
hands/feet/periorbital region, Cool,  Perspiration, Alopecia.
 Cardiovascular:
»  contractility,  rate,  cardiac output, pericardial/pleural
effusions,  peripheral vascular resistance. CHF rare.
 Clinical Features: Hypothyroidism

 Gastrointestinal:
»  Appetite, Constipation, Weight Gain (5-10% increase)
 Gynecologic:
» Menorrhagia, Menstrual Irregularities
 Musculoskeletal:
» Myalgias, Arthralgias ,stiffness, cramps, and pain
 Hematologic:
» Anemia
 Neurologic:
» Delayed relaxation phase of DTRs, Difficulty Concentrating, Poor
Memory, Somnolence, Depression, Headache, Paresthesia
 Clinical Features of
Hypothyroidism

Tiredness Puffy Eyes

Forgetfulness/Slower Thinking Enlarged Thyroid (Goiter)

Moodiness/ Irritability Hoarseness/
Deepening of Voice
Depression
Persistent Dry or Sore Throat
Inability to Concentrate
Thinning Hair/Hair Loss Difficulty Swallowing
Loss of Body Hair Slower Heartbeat

Dry, Patchy Skin Menstrual Irregularities/

Heavy Period
Weight Gain Infertility
Cold Intolerance
Elevated Cholesterol Constipation
Muscle Weakness/
Family History of Thyroid Cramps
Disease or Diabetes
 hoarse voice and occasionally clumsy
speech of hypothyroidism reflect fluid
accumulation in the vocal cords and
tongue.
autoimmune hypothyroidism may be associated with
signs or symptoms of other autoimmune diseases

 vitiligo, pernicious anemia, Addison's

disease, alopecia areata, and type 1
diabetes mellitus.
 Less-common associations include
celiac disease, dermatitis herpetiformis,
chronic active hepatitis, rheumatoid
arthritis, systemic lupus erythematosus
(SLE), and Sjögren's syndrome.
 Thyroid-associated ophthalmopathy,
which usually occurs in Graves' disease
,occurs in about 5% of patients with
autoimmune hypothyroidism
 Myxedema

Robbins’ Pathology Online

Laboratory Diagnosis: Hypothyroidism

TSH Free T4 T3
Primary Hypothyroidism:
Subclinical Hypothyroidism  N N
Mild Hypothyroidism  N/ N/
Overt Hypothyroidism   N/

Secondary Hypothyroidism /N  N/

 Etiologies of Primary
Hypothyroidism

 Loss of Functional Thyroid Tissue

» Chronic/Autoimmune thyroiditis (Hashimoto’s thyroiditis)
» Transient Thyroiditis (post-partum, silent, painful)
» Transient or Permanent Iatrogenic hypothyroidism, 2º to
surgery or following 131I thyroid ablation therapy
» Congenital Thyroid Agenesis/Dysgenesis
 Interference with T4/T3 Production
» Drug-Induced Defects in T4 Biosynthesis
– Anti-thyroid drugs, lithium, iodide, amiodarone
» Iodine Deficiency (rare in US, common in 3rd world)
» Congenital Defects in Thyroid Hormone Production (rare)
Autoimmune Thyroiditis (Hashimoto’s,
Chronic Lymphocytic)

 Autoimmune destruction of thyroid tissue

» High titers of anti-thyroid antibodies
» Lymphocytic Infiltration of thyroid gland, fibrosis

 Firm, non-tender diffuse goiter

 #1 cause of hypothyroidism (70%)
 Usually permanent
 Other Types of Thyroiditis

 Painful (Subacute, DeQuervain’s) Thyroiditis

 Silent (Painless) Thyroiditis
» Post Partum Thyroiditis

 Uncommon:
» Riedel’s Thyroiditis
» Acute Suppurative Thyroiditis
Effect of Silent/Subacute Thyroiditis
on Thyroid Function Tests

Thyrotoxic Nml
Thyrotoxic Hypothyroid Recovery

T3
T4

Normal
~70%

TSH ~30%

Months

Modified from Nickolai, T.F., Werner & Ingbar’s The Thyroid,

Chapter 36, Braverman & Utiger, ed., 6th Edition, 1991.
 Hypothyroidism in Pregnancy
• Fetal thyroid forms at ~11th week of life
• Maternal/Fetal placental transfer:
» T4/T3 is limited
» No TSH
» Limited anti-thyroid drugs
» TSI Antibodies can cross: may cause transient neonatal
Graves’
 Maternal thyroid status may be important for cognitive
development during the first trimester.
 Maternal T4 needs may increase by 10-25% during
pregnancy
Hypothyroidism in Infants
 Delayed Growth & Development
 Poor Feeding
 Prolonged Neonatal Jaundice
 Umbilical Hernia
 Protruding Tongue
 Delayed Bone Age
 majority of infants appear normal
at birth, and <10% are diagnosed
based on clinical features
Hypothyroidism in Infants

Age: 6 mos 4 mos after L-T4

Behrman: Nelson Textbook of Pediatrics, 15th ed., 1996

 Hypothyroidism in Children

 Short Stature, Delayed

Bone Age
 Increased Wt for Ht Age
 School performance
often does not suffer
 Other symptoms/signs
similar to adults
 Pituitary enlargement
may occur

Fisher, D., Hypothyroidism, Rudolph’s Pediatrics, 21st Ed, 2002

Treatment of Hypothyroidism

Replace with levo-thyroxine (L-T4)

(Example Brands: Synthroid®, Levoxyl®,
Levothroid®, Unithroid®)

Monitor thyroid function tests every 6-8

weeks until steady dose is achieved; goal
is to normalize TSH in most cases

Therapy with T3 (cytomel) or other thyroid

preparations is rarely indicated.
Severe Hypothyroidism
(Myxedema Coma)

Chronic non-compliance or
undiagnosed hypothyroidism
Precipitating Factors:
» Severe Illness
– Infection
– Cerebrovascular Accident
– Seizure
– GI Hemorrhage
» Surgery
» Sedative Drugs, Anesthetics
 Severe Hypothyroidism
(Myxedema Coma)

“Myxedema Coma” - A clinical diagnosis

at the end of a hypothryoid continuum
» Bradycardia, Hypotension
» Hypothermia
» Hypoventilation
» Stupor, Coma
» Delayed deep tendon reflexes
» Dry, puffy skin
» History of thyroid surgery, T4
supplementation, or RAI
 Severe Hypothyroidism
(Myxedema Coma)

Emergent Treatment:
» Treat underlying disorder
» Thyroid hormone dose is controversial:
– L-thyroxine 50-100 mcg IV q 8°-12° initially,
then 75-100 mcg qd
– Monitor cardiac rhythm, EKG; supportive care
– Avoid T3 if possible due to risk of myocardial
ischemia
» Hydrocortisone 100 mg IV q 8°
 Now that the treatment of
Hypothyroidism has been covered….

Brian Narelle, Petaluma, CA

 Thyrotoxicosis

 Thyrotoxicosis is defined as the state of

thyroid hormone excess and is not
synonymous with hyperthyroidism,
which is the result of excessive thyroid
function.
 Hyperthyroidism:
Clinical Features

» Cardiac
– Sinus Tachycardia/Atrial Fibrillation
– Congestive heart failure (high-output)
– Angina
– Increased pulse pressure
» Musculoskeletal
– Tremor
– Proximal Muscle Weakness (Myopathy)
» Neurologic/Psychiatric
– Anxiety, Hyperactivity, Mania
– Disorientation, Coma
– Rarely, seizures/convulsions
 Signs and Symptoms of
Hyperthyroidism

Nervousness/Tremor Hoarseness/
Deepening of Voice
Mental Disturbances/ Persistent Dry or Sore Throat
Irritability
Difficulty Swallowing
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/ Palpitations/
Vision Changes Tachycardia

Enlarged Thyroid (Goiter) Impaired Fertility

Weight Loss or Gain
Menstrual Irregularities/
Light Period Heat Intolerance
Increased Sweating
Frequent Bowel Movements
Sudden Paralysis
Warm, Moist Palms

Family History of
First-Trimester Miscarriage/ Thyroid Disease
Excessive Vomiting in Pregnancy or Diabetes
 Diagnosis of Hyperthyroidism

• Physical Examination
• Laboratory Tests:
» Common:
– Thyroid Stimulating Hormone (TSH)
– T4 Panel (Total T4, %TUptake, Free T4 Index)
or
Free T4
» Less Common:
– Total T3 (Free T3)
» Infrequently:
– TSI, Thyroid antibodies
Laboratory Diagnosis: Hyperthyroidism

TSH T4 Free T4 T3
Primary:
Subclinical Hyperthyroidism  N N N
Hyperthyroidism    
T3 thyrotoxicosis  N N 

Secondary Hyperthyroidism    
(TSH Secreting Adenoma-Rare!)
 Causes of Hyperthyroidism

 Toxic Diffuse Goiter (Grave’s) ~70%

 Multinodular Goiter ~20%
 Toxic Adenoma (nodule) ~ 5%

 Non Goitrous causes:

» Thyroiditis
» Thyroid hormone use
» Uncommon/Rare disorders
 Graves’ Disease
(Toxic Diffuse Goiter)

Pathophysiology: Autoimmune Disease

Thyroid stimulating immunoglobulins (TSI)
activate the TSH receptor in thyroid cells

TSH TSI

TSH-R TSH-R

Normal Graves’ Disease

 Graves’ Disease
(Toxic Diffuse Goiter)

• Epidemiology
» Principally a disease of young females (20-50), although it
can occur in neonates and elderly
» Female:Male 5:1-10:1
» Incidence 15-50 persons/100,000 per year
» Graves' disease accounts for 60–80% of
thyrotoxicosis
 The prevalence varies among populations, depending
mainly on iodine intake
 (high iodine intake is associated with an increased
prevalence of Graves' disease).
 Graves' disease occurs in up to 2% of women but is
one-tenth as frequent in men.
 Graves’ Disease
(Toxic Diffuse Goiter)

Clinical Features of Graves’ Disease:

» Diffusely enlarged, non-tender goiter, usually
symmetric, sometimes associated with thyroid
bruit or thrill
» Graves’ Ophthalmopathy (~30%)
» Graves’ Dermopathy (~2%)
» Acropachy (1-2%)
 Lid retraction,:
causing a staring appearance, can occur
in any form of thyrotoxicosis and is the
result of sympathetic overactivity
 Graves' ophthalmopathy

 occurs in the absence of Graves'

disease in 10% of patients.
 Most of these individuals have
autoimmune hypothyroidism or thyroid
antibodies.
 The onset of Graves' ophthalmopathy occurs
within the year before or after the diagnosis of
thyrotoxicosis in 75% of patients but can
sometimes precede or follow thyrotoxicosis by
several years
 The earliest manifestations of ophthalmopathy are
usually a sensation of grittiness, eye discomfort, and
excess tearing.
 About a third of patients have proptosis, best
detected by visualization of the sclera between the
lower border of the iris and the lower eyelid, with the
eyes in the primary position.
 Proptosis can be measured using an
exophthalmometer
 In severe cases, proptosis may cause corneal
exposure and damage, especially if the lids
fail to close during sleep.
 Periorbital edema, scleral injection, and
chemosis are also frequent.
 In 5–10% of patients, the muscle swelling is
so severe that diplopia results, typically but
not exclusively when the patient looks up and
laterally.
 The most serious manifestation is
compression of the optic nerve at the
apex of the orbit, leading to papilledema,
peripheral field defects, and, if left
untreated, permanent loss of vision.
 Graves’ Disease
(Toxic Diffuse Goiter)

Clinical Features of Graves’ Disease:

Wartofsky, Harrison’s Textbook of Medicine Online, 2004

 Graves’ Disease
(Toxic Diffuse Goiter)

• Laboratory Tests
» No laboratory test is specific for Grave’s Disease
» RAIU elevated (4 and/or 24 hour uptake %)
» Thyroid Scintigraphy: diffuse increased uptake
» Thyroid Stimulating Immunoglobulins (TSI) fairly
specific, somewhat sensitive, but not usually
indicated.
 Graves’ Disease
(Toxic Diffuse Goiter)

• Clinical Course
» Variable
– Subclinical
– Single episode that quickly resolves
– Severe, permanent hyperthyroidism
– Recurrent remissions and relapses
» Favorable prognostic indicators for remission:
– female
– small goiter
– early diagnosis/treatment
 Toxic Multinodular Goiter

• Pathogenesis
» Final phase of evolution of goiter over time
» Nodules gradually acquire autonomy
» Influenced by growth factors, goitrogens, iodine,
and genetic/hereditary factors. There may also be
a role of the immune system, but this is not clear.

» Some mutations have been identified in the TSH

receptor, or cytogenetic abnormalities observed.
 Toxic Multinodular Goiter

TSH

Hormone secretion by
Normal Range normal follicles Hormone secretion
of T4/T3 by Autonomous Follicles

Thyroid Gland

Euthyroid State Hyperthyroidism

After Studer & Gerber, The Thyroid (ed Braverman & Utiger), 6th Edition, 1991
 Toxic Multinodular Goiter

 Epidemiology
» Typically seen in older populations
» Often preceded by several year history of
euthyroid multinodular goiter.
» Incidence ~ 5-15 persons/100,000 per year
 Pathogenesis
» Final phase of evolution of goiter over time
» Nodules gradually acquire autonomy
Toxic Multinodular Goiter

 Clinical Features & Diagnosis

» Often large, assymetric, nodular gland
» Other stigmata of Grave’s Disease absent
» No lab test is specific for Toxic MNG
» RAIU usually  (4/24 hr uptake %)
» Thyroid Scintigraphy: diffuse patchy uptake
» Thyroid Ultrasound: multiple nodules
 Clinical Course
» Variable. Initially  TSH with normal T4/3.
» Compressive symptoms
 Toxic Adenoma (Nodule)

• Epidemiology
» Incidence is variable, ranging from 2-5 persons/
100,000 per year
» Vast majority of these nodules are >2.5 cm
 Toxic Adenoma (Nodule)

• Pathogenesis
» Monoclonal expansion of thyroid follicular cells
» The adenoma escapes regulation by TSH, some
studies have found mutations causing constitutive
activation of the thyrotropin receptor.
» Almost never malignant
» May suppress the size of the rest of the gland
 Toxic Adenoma (Nodule)

• Clinical Features & Diagnosis

» Solitary nodule on exam, usually >2.5 cm
» Other stigmata of Grave’s Disease absent
» No lab test is specific for toxic adenoma goiter
» RAIU usually elevated (4 / 24 hour uptake %)
» Thyroid Scintigraphy reveals a solitary hot nodule
» Thyroid Ultrasound reveals a solitary nodule
Thyroid Scans of Toxic Multinodular
Goiter & Toxic Adenoma

Multinodular Goiter Toxic Adenoma

Comprensive Clinical Endocrinology, 3rd Ed., Besser & Thorner, 2002

Thyroiditis
 Acute Thyroiditis

 Rare
 the most common cause is the presence
of a piriform sinus
 patient presents with thyroid pain, often
referred to the throat or ears, and a
small, tender goiter that may be
asymmetric.
 Fever, dysphagia, and erythema over
the thyroid are common, as are systemic
symptoms of a febrile illness and
lymphadenopathy.
 ESR and CBC
 FNA
 Antibiotic treatment
 surgery
 Subacute Thyroiditis ,de Quervain's
thyroiditis, granulomatous thyroiditis, or
viral thyroiditis

 mumps, coxsackie, influenza, adenoviruses, and

echoviruses
 painful and enlarged thyroid, sometimes accompanied
by fever
 The patient typically complains of a sore throat, and
examination reveals a small goiter that is exquisitely
tender.
 Pain is often referred to the jaw or ear
 (1) thyrotoxic phase
 (2) hypothyroid phase
 (3) recovery phase
 In the thyrotoxic phase, T4 and T3
levels are increased, reflecting their
discharge from the damaged thyroid
cells, and TSH is suppressed.
 The diagnosis is confirmed by a high
ESR and low radioiodine uptake
Treatment:
 aspirin (e.g., 600 mg every 4–6 h) or
NSAIDs
 glucocorticoids
 Silent Thyroiditis ,Painless
thyroiditis

 The condition occurs in up to 5% of women 3–6

months after pregnancy and is then termed
postpartum thyroiditis.
 Typically, patients have a brief phase of thyrotoxicosis
lasting 2–4 weeks,
 followed by hypothyroidism for 4–12 weeks,
 and then resolution;
 often, however, only one phase is apparent
 The condition is associated with the
presence of TPO antibodies antepartum,
and it is three times more common in
women with type 1 diabetes mellitus
 Anti-Thyroid Drugs

• Methimazole & Propythiouracil

• Block production of T4/T3 at several levels.
• Take several weeks to reach full therapeutic
effectiveness.
• Do not affect the size of the goiter, only the
level of thyroid hormone production.
 Anti-Thyroid Drugs

Methimazole Propylthiouracil
(Tapazole®) (PTU)

Dosage Range: 5-20 mg qd, BID, TID 50-200 mg TID

Half Life: 4-6 hours 75 minutes
Pregnancy/Lactation: ± preferred

Cost: ~$20-40/month ~$10-20/month:

Treatment of Hyperthyroidism

• Anti-thyroid Drugs
» Methimazole (Tapazole®)
» Propylthiouracil
• Radioactive Iodine
• Surgery
• Ancillary Drugs:
» Iodine
 Anti-thyroid Drugs:
Side Effects
Rash ~2-4%
Muscle/Joint Aches ~2%
Headache ~2%
Nausea/Upset Stomach ~2%
Altered Taste Sensation ~2%
Fever ~1%
Hair loss ~1%
Liver Damage (Hepatitis) <1%
Kidney Damage (Nephritis) <1%
* Agranulocytosis 0.2-0.3%*

* (about 1 out of 300 to 500 persons)

 Anti-Thyroid Drugs:
Agranulocytosis

• Idiosyncratic Reaction, impossible to predict.

• Routine “surveillance” CBC not helpful.
• Most likely to occur shortly after starting therapy,
but may develop anytime thereafter.
• Very unlikely to develop on low doses of
methimazole; threshold for PTU unclear.
• Tell patients to stop the medicine if they ever
develop a fever or sore throat, and check a CBC
with differential.
 131
Radioactive Iodine: I

• Safe; no evidence of increased thyroid CA risk

• Effective 70-90% of cases (can re-treat prn).
• Control achieved in several weeks to months.
• Major drawback: Hypothyroidism
• ~ 50% within 3 years, and cumulatively develops at
a rate of ~2% per year thereafter.
• Grave’s ophthalmopathy may be exacerbated
 Hyperthyroidism:
Adjunctive Therapy

 Iodine: Severe Hyperthyroidism

» Inhibits thyroid hormone synthesis/release,
» Decrease the vascularity of the thyroid gland
» Should not be used for long-term therapy , Will delay 131I

» SSKI (50 mg iodide/drop)

» Lugol’s Solution (5-10% KI, 8 mg iodide/drop)

 Beta Blockers: For palpitations

» Propranolol, 10-40 mg TID-QID (can ability to block T4 to T3)
» Atenolol 25-100 mg qd
» Esmolol (IV titrate to effect)
 Severe Hyperthyroidism

 “Thyroid Storm” – A clinical diagnosis at the

end of a hyperthryoid continuum
» Fever
» Mental Status Changes
» Cardiovascular Collapse
 Precipitatants in hyperthyroid patients:
» surgery
» sepsis
» iodine loads
» post-partum
 Endocrine emergency (Mortality 20-50%)
 Severe Hyperthyroidism
(“Thyroid Storm”)

Emergent Treatment:
• Propylthiouracil (PTU) 300 mg po (pr) q 8°
• Iodine (2 hrs after PTU)
» SSKI 2 gtt po q 8° or
» 1-2 mg IV q 5 minutes to 10 mg
• Propranolol (avoid in heart failure)
• Dexamethasone 2 mg po or IV q 6°
• Treat underlying cause(s)
Thyroid Dysfunction: Summary

 Hypothyroidism
» TSH (or T4, if pituitary disease)
» L-T4 Rx, F/U as appropriate
» adjust L-T4; normalize TSH in most cases
 Hyperthyroidism
» T4, TSH (T3?) establish diagnosis/baseline
» Auxiliary tests as needed (RAI, ??other)
» Determine therapy based on cause & pt
 Diffuse Nontoxic (Simple) Goiter

 When diffuse enlargement of the thyroid occurs in the

absence of nodules and hyperthyroidism, it is referred
to as a diffuse nontoxic goiter
 diffuse goiter is most commonly caused by iodine
deficiency and is termed endemic goiter when it
affects >5% of the population.
 sporadic goiter occurs, and the cause is usually
unknown
 In iodine-deficient areas,:
 thyroid enlargement reflects a compensatory effort to
trap iodide and produce sufficient hormone under
conditions in which hormone synthesis is relatively
inefficient
 TSH levels are usually normal or only
slightly increased
 goitrogens such as cassava root, which
contains a thiocyanate; vegetables of
the Cruciferae family (e.g., brussels
sprouts, cabbage, and cauliflower); and
milk from regions where goitrogens are
present in grass
 Clinical Manifestations and
Diagnosis

 most goiters are asymptomatic

 Goiter is defined, as a lateral lobe with a
volume greater than the thumb of the
individual being examined
 If the thyroid is markedly enlarged, it can
cause tracheal or esophageal
compression
 Substernal goiter may obstruct the thoracic inlet.

 Pemberton's sign refers to symptoms of faintness

with evidence of facial congestion and external jugular
venous obstruction when the arms are raised above
the head, a maneuver that draws the thyroid into the
thoracic inlet
 Treatment

 Iodine or thyroid hormone replacement

induces variable regression of goiter
 Surgery
 Nontoxic Multinodular Goiter

 MNG occurs in up to 12% of adults.

 MNG is more common in women than men and

increases in prevalence with age.

 It is more common in iodine-deficient regions but also

occurs in regions of iodine sufficiency
 Clinical Manifestations

 asymptomatic
 euthyroid
 If the goiter is large enough, it can ultimately
lead to compressive symptoms including
difficulty swallowing, respiratory distress
(tracheal compression), or plethora (venous
congestion), but these symptoms are
uncommon
 A TSH level should be measured to
exclude subclinical hyper- or
hypothyroidism, but thyroid function is
usually normal.
 TREATMENT

 T4 suppression is rarely effective

 I131
 surgery
Approach to the Patient: A Thyroid
Nodule

 found in about 5% of adults

 nodules are more common in iodine-
deficient areas, in women, and with
aging.
 Most palpable nodules are >1 cm in
diameter
 Thyroid Cancer

 Thyroid carcinoma is the most common

malignancy of the endocrine system
 Differentiated tumors:
 such as papillary thyroid cancer (PTC)
 follicular thyroid cancer (FTC)
 are often curable, and the prognosis is
good for patients identified with early-
stage disease.
 In contrast, anaplastic thyroid cancer
(ATC) is aggressive, responds poorly to
treatment, and is associated with a
bleak prognosis.
 Medullary Thyroid Carcinoma
Question