Thyrotoxicosis

Yiming Zhao, MD

Department of Endocrinology and Metabolism,

the Second Affiliated Hospital ZheJiang University School of Medicine
 Introduction
• Thyrotoxicosis refers to the classic physiologic
manifestations of excessive quantities of the
thyroid hormones.
• Hyperthyroidism is reserved for disorders that
result from sustained overproduction and release
of hormone by the thyroid itself.
-Williams Textbook of Endocrinology
 Case 1 – 29 year old woman
• Presents with 5 month history of tremor,
tachycardia, 15 kg weight loss
• Testing shows TSH < 0.03 mU/L, FT4 = 90 pmol/L
(normal 9-23)
Questions:
• What clinical features are helpful in diagnosis?
• What tests do you do?
 Case 2 – 29 year old woman
• Presents with 2 month history of tachycardia, nervousness,
insomnia
• Tests show TSH< 0.03 mU/L, FT4 = 45 pmol/L (N: 9-23)
• Physical exam does not show ophthalmopathy or other
extrathyroid features of Graves’ disease
• Thyroid is only slightly increased in size, no definite nodules

Questions:
• What additional history information needed?
Anatomy
 The function of Thyroid Gland
• Generating the quantity of thyroid hormone
(thyroxine (T4) and triiodothyronine (T3))
– critical determinants of brain and somatic
development in infants and of metabolic
activity in adults
• Affecting the function of virtually every
organ system
When the Thyroid Doesn’t Work
REGULATION OF THYROID FUNCTION
REGULATION OF THYROID FUNCTION
Thyroid Hormones
Thyroid hormone biosynthesis
Transport and metabolism of thyroid
hormones
 Signs and Symptoms Of
Hyperthyroidism
Hoarseness or
Nervousness Deepening of Voice
Irritability Persistent
Sore or Dry Throat
Difficulty Sleeping Difficulty Swallowing

Rapid or Irregular Heartbeat

Bulging Eyes/Unblinking Stare

Swelling (Goiter) Infertility

Menstrual Irregularities or Weight Loss

Light Period Heat Intolerance
Frequent Bowel Movements Increased Sweating

First-Trimester Miscarriage
Warm, Moist Palms
Family History of
Excessive Vomiting in Pregnancy Thyroid Disease
or Diabetes
Symptoms and Signs of Thyrotoxicosis
Symptoms and Signs of Thyrotoxicosis
 Physical Examination
• Thyroid Gland
– Inspection: old surgical scars, distended veins, and
redness or fixation of the overlying skin
– Palpation: size, consistency, nodule, tenderness,
vascular thrill
– Auscultation: bruit
• Extrathyroidal features
– Sympathetic hyperactivity
– Ophthalmopathy
– Dermopathy
 Laboratory Evaluation
• Tests of the HPT axis
– whether TSH is suppressed,
normal, or elevated
• Serum thyroid Hormone
concentrations
– Total T4, T3 and free T4, T3
• Tests that assess the metabolic
impact of thyroid hormones
– Basal metabolic rate
– Biochemical markers of altered
thyroid status
• Serum thyroglobulin
• Thyroid autoantibodies: TRAb,
TPOAb, TgAb
 Hypothalamic-Pituitary-Thyroid Axis
FEEDBACK
Negative feedback loop
T4 * T3#

T3 is the feedback
hormone

T4 * T3#
Deiodinases in
hypothalamus ,
pituitary convert T4 to
T3 (feedback).
Peripherally,
deiodinases in liver,
thyroid, brown fat,
kidney
 TSH measurement
• TSH measurement is the BEST single screening
test for thyroid function
• Changes in TSH occur often before measurable
changes in T4 or T3 are present – reflect first
stages of hyper- or hypothyroidism
• TSH reflects the true state of Free T4, Free T3, ie
axis set-point:
• LOW TSH = hyperthyroidism
• HIGH TSH = hypothyroidism
 When TSH Values Might NOT Be
Reliable

• There are some uncommon

conditions when TSH does NOT
reliably indicate hypothyroidism or
hyperthyroidism
• TSH “normal” but hypothyroid (low
FT4):
• Hypothalamic-pituitary disease
– commonest cause is pituitary
tumors or after pituitary surgery

• NOTE: pituitary tumors are very

uncommon compared with primary
thyroid disease, so we still
recommend TSH ONLY as first
screening test for thyroid disease
 T3 versus T4
• Transport in blood: TBP * (thyroid binding protein), TBPA,
albumin; T3 = 0.3% free, T4=0.03% free)
• T3 is 3-8 x more potent than T4
• T4 is a prohormone: T3 is biologically active form
• T4 is converted to T3 in peripheral cells and liver
– T3 is an intracellular hormone and binds to nuclear
receptors
▪ The thyroid produces
– 100% T4
– 20% T3 (80% from peripheral conversion of T4)
 Half lives are important!

• T1/2 T4 = 7 days
• T1/2 T3 = 0.75 days
• Therefore, T4 is best hormone to use for
replacement therapy
• 7 day half life means adjust treatment doses
only every ~5 half lives = 5-6 weeks
• Adjust T4 dose every 6+ weeks
recommended
 Laboratory Evaluation
• Ultrasonography
• Ultrasound-guided thyroid biopsy: Fine-needle
aspiration (FNA)
• Radioiodine Uptake and Thyroid Scanning
[radioisotopes of iodine (123I, 125I, 131I) and
99mTc pertechnetate]
Ultrasonography
• Color flow
ultrasonogram in
patient with Graves
disease. Generalized
hypervascularity is
visible throughout
gland (note red areas),
which often can be
heard as hum or bruit
with stethoscope.
Scintigraphy
• Iodine 123 (123I) nuclear
scintigraphy: 123I scans of
normal thyroid gland (A) and
common hyperthyroid
conditions with elevated
radioiodine uptake, including
Graves disease (B), toxic
multinodular goiter (C), and
toxic adenoma (D).
• Toxic multinodular goiters are
characterized by irregular areas
of relatively diminished and
occasionally increased uptake.
Overall RAIU is mildly to
moderately increased.
 Causes of Thyrotoxicosis
• Hyperthyroidism (Sustained Hormone Overproduction)
– Low TSH, High RAIU
• Graves’ disease
• Toxic multinodular goiter
• Toxic adenoma
• Chorionic gonadotropin-induced
– Gestational hyperthyroidism
Physiologic hyperthyroidism of pregnancy
Familial gestational hyperthyroidism due to TSH receptor mutations
– Trophoblastic tumors
• Inherited nonimmune hyperthyroidism associated with TSH receptor or G
protein mutations
– Low TSH, Low RAIU
• Iodide-induced hyperthyroidism (Jod-Basedow effect)
• Amiodarone-associated hyperthyroidism due to iodide release
– Struma Ovarii
– Metastatic functioning thyroid carcinoma
– Normal or Elevated TSH
• TSH-secreting pituitary tumors
• Thyroid hormone resistance with pituitary predominance
 Causes of Thyrotoxicosis
• Transient Hormone Excess
Low TSH, Low RAIU
– Thyroiditis
• Autoimmune
– Hashimoto’s disease
– Lymphocytic thyroiditis (silent thyroiditis, painless
thyroiditis,postpartum thyroiditis)
• Viral or postviral
– Subacute (granulomatous, painful, postviral) thyroiditis
• Drug-induced or associated thyroiditis
– Amiodarone
– Lithium, interferon-α, interleukin-2, GM-CSF
• Infectious thyroiditis
– Exogenous Thyroid Hormone
• Iatrogenic overreplacement
• Thyrotoxicosis factitia
• Ingestion of natural products containing thyroid hormone
 Diagnosis
▪ Symptoms/signs of hyperthyroidism
▪ Screening test: TSH decreased

FT4, FT3
(quantitate degree of hyperthyroidism)

Thyroid scan/iodine uptake

+TSH receptor antibodies
+ TPO antibodies
(determine cause of hyperthyroidism)
(ultrasound usually not needed)
 Graves' Disease
• One of the most common thyroid diseases,
representing 50% to 80% of all cases of
thyrotoxicosis.
• Characterized by diffuse goiter and
thyrotoxicosis; it may be accompanied by
an infiltrative orbitopathy and
ophthalmopathy and occasionally by
infiltrative dermopathy.
 Graves' Disease
• Commonest cause of hyperthyroidism
• Autoimmune: antibodies to TSH receptor
• Female:Male (7:1)
• Familial predominance
• Hyperthyroidism, goiter, extra-thyroidal
autoimmune manifestations :
– orbitopathy, pretibial myxedema,
acropachy (finger clubbing)
 Pathogenesis
• Antithyroid antibodies
• T cell activation
• Immune mechanisms
– Molecular mimicry
– Thyroid cell expression
of HLA molecules
– Bystander activation
TSHR agonists and antagonists
 Potential Risk Factors for Graves’
Disease
• Genetic Susceptibility
• Infection
• Stress
• Gender
• Pregnancy
• Iodine and Drugs
• Irradiation
 Cardiovascular System
• Tachycardia
• Palpitations
• Hyperdynamic precordium
• Systolic hypertension with widened pulse
pressure
• Exertional dyspnea
• Anginal-like chest pain, myocardial ischemia
• Increase in left ventricular mass index and left
ventricular hypertrophy
• Short QT interval
 Cardiovascular System
• Atrial fibrillation
• Heart failure
• Mitral valve prolapse
• Pulmonary hypertension
• Angina pectoris
 Metabolic / Endocrine
• Serum lipids
– Low serum total and high-density lipoprotein (HDL)
cholesterol concentrations and a low total
cholesterol/HDL cholesterol ratio.
• Hyperglycemia
– Impaired glucose tolerance
• Pituitary and Adrenocortical Function
• Reproductive Function
– Woman: menstrual irregularities, infertility, miscarriage
– Men: gynecomastia and erectile dysfunction
 Respiratory System
• Dyspnea and dyspnea on exertion
– Increased oxygen consumption and CO2
production
– Respiratory muscle weakness
– Tracheal obstruction from a large goiter
– Exacerbation of underlying asthma
– Increased Pulmonary arterial systolic pressure
 GI System
• Weight loss
– Increased calorigenesis,
– Increased gut motility, hyperdefecation and
malabsorption
– Steatorrhea.
– Celiac disease
• Hyperphagia
• Anorexia (elderly patients)
• Vomiting and abdominal pain
• Dysphagia due to goiter
• Abnormalities in liver function tests
 Hematopoietic System
• Pernicious anemia

• Decrease in the number of neutrophils

• Enhanced sensitivity to warfarin

• Coincidental autoimmune
thrombocytopenia
 Skeletal System
• Bone resorption

• Osteopenia, Osteoporosis, Fractures

• Hypercalcemia, hypercalciuria, low PTH,

low calcitriol
 Muscle
• Thyrotoxic myopathy

• Myasthenia gravis

• Periodic paralysis
Neuropsychiatric
 Geriatric Hyperthyroidism
• Apathetic

• Anorexia and weight loss

• Constipation

• Atrial fibrillation
 Skin
• Warm, erythematous
• Smooth
• Sweating
• Onycholysis (Plummer's nails) and softening of
the nails
• Hyperpigmentation
• Pruritus and hives
• Vitiligo and alopecia areata
• Thinning of the hair
 Infiltrative dermopathy
• Pretibial myxedema
• Thyroid acropachy
 Eyes
• Stare and Lid lag
• Graves’ ophthalmopathy
– Inflammation of the extraocular muscles,
orbital fat and connective tissue
– Proptosis (exophthalmos)
– More common in smokers
Graves' ophthalmopathy
 Graves' ophthalmopathy
• A sensation of grittiness, eye discomfort,
and excess tearing
• Proptosis
• Periorbital and conjunctival edema
• Diplopia
• Corneal ulceration due to lid lag and
proptosis
• Optic neuritis and even blindness
 Lid Lag in Graves’
Disease
Exopthalamos in Graves’
Disease
 "NO SPECS" scheme
• 0 = No signs or symptoms

• 1 = Only signs (lid retraction or lag), no symptoms

• 2 = Soft tissue involvement (periorbital edema)

• 3 = Proptosis

• 4 = Extraocular muscle involvement (diplopia)

• 5 = Corneal involvement

• 6 = Sight loss
Clinical Assessment of GO

Eur Thyroid J. 2022 Dec 8;11(6):e220189.

 Thyroid Storm
• It is an uncommon but serious complication, usually
occurring in association with Graves’ disease but
sometimes with toxic multinodular goiter in the
elderly patient.
• Thyroid storm is usually of abrupt onset and occurs
in patients in whom preexisting thyrotoxicosis has
been treated incompletely or not at all.
• The condition is usually precipitated by infection,
trauma, surgical emergencies, or planned
operations or, less commonly, by radiation
thyroiditis, diabetic ketoacidosis, toxemia of
pregnancy, or parturition.
1
 Treatment
• Clinical Course
• Reducing thyroid hormone synthesis,
using antithyroid drugs
• Reducing the amount of thyroid tissue
with radioiodine (131I) treatment or by
thyroidectomy
 Treatment
• Beta blockers
• Thionamides (MMI and PTU)
• Iodides
• Other medications
– Glucocorticoids, Lithium, Cholestyramine,
Carnitine, Rituximab
• Radioactive iodine
• Surgery
 Thionamides
• Methimazole(MMI), propylthiouracil (PTU), and
carbimazole

• Inhibiting the function of TPO, reducing

oxidation and organification of iodide

• Inhibiting deiodination of T4 to T3 (PTU)

• Immunomodulatory activity
 Thionamides
Factor PTU MMI

Response time Slower Faster

Toxicity ?dose-related, Dose-related,

hepatitis, rare side-effects
vasculitis less common
Compliance Worse (divided Better (single-
doses) daily-dose)
Effect on Decreases effect No effect
radioiodine
outcome
 Use of Thionamides
• Methimazole should be used in virtually
every patient who chooses antithyroid drug
therapy for GD, except during the first
trimester of pregnancy when
propylthiouracil is preferred, in the
treatment of thyroid storm, and in patients
with minor reactions to methimazole who
refuse radioactive iodine therapy or
surgery.
 Use of Thionamides
• Patients should be informed of side effects
of antithyroid drugs and the necessity of
informing the physician promptly if they
should develop side effects of ATDs.
• Prior to initiating antithyroid drug therapy,
we suggest that patients have a baseline
complete blood count, including white
count with differential, and a liver profile
including bilirubin and transaminases
Side Effects Of Anti-thyroid Drugs
 Use of Thionamides
• The starting dose of antithyroid drugs can be gradually reduced
(titration regimen) as thyrotoxicosis improves.

• Alternatively, high doses may be given combined with

levothyroxine supplementation (block-replace regimen) .

• Monitoring of patients taking antithyroid drugs

• The medication should be continued for approximately 12–18
months, then tapered or discontinued if the TSH is normal at that
time.
• Measurement of TRAb levels prior to stopping antithyroid drug
therapy
 Radioactive Iodine
• Preparation for 131I therapy
– beta-adrenergic blockade, MMI
• Administration of 131I
– radiation safety precautions
• Complications
– thyroid cancer, hypothyroidism, radiation
thyroiditis, orbitopathy
• Follow-up
 Surgery
• Preparation for surgery
• Near-total or total thyroidectomy
• Complications
– permanent recurrent laryngeal nerve (RLN)
injury, permanent hypoparathyroidism,
bleeding necessitating reoperation
• Follow-up: L-thyroxine replacement
 Contraindications
• ATDs: previous known major adverse
reactions to ATDs
• 131I therapy: pregnancy, lactation,
coexisting thyroid cancer, or suspicion of
thyroid cancer, individuals unable to comply
with radiation safety guidelines and females
planning a pregnancy within 4–6 months
• Surgery: substantial comorbidity; pregnancy
Choice of Therapy
Graves' disease in pregnancy
Graves' disease in pregnancy
• Propylthiouracil (PTU)-the first-line drug
during the first trimester of pregnancy
• Thyroid function monitoring at 2- to 4-wk
intervals
• Fetal thyroid function screening
• Postpartum Period
• Breast-feeding
 Thyroid Storm
• Treatment aims to correct both the severe
thyrotoxicosis and the precipitating illness
and to provide general support.
• Large doses of an anti-thyroid agent (up to
400 mg of PTU every 4 to 6 hours)
• Iodide
• Glucocorticoids
• Beta blockers (propranolol 40 to 80 mg
orally every 6 hours)
 Ophthalmopathy
• Reversal of hyperthyroidism
• Symptomatic treatment
– artificial tears, eye ointment, and the use of dark
glasses with side frames
– Periorbital edema: upright sleeping position or diuretics
• Glucocorticoids
• Immunosuppressive drugs
• Orbital decompression
• External beam radiotherapy
 Ophthalmopathy

Eur Thyroid J. 2022 Dec 8;11(6):e220189.

GO - Pathogenesis
GO – Treatment

1. Eur Thyroid J. 2022 Dec 8;11(6):e220189.

2. Eur J Endocrinol.2021;185:G43-G67
GO – Clinical Trials
Toxic multinodular goiter
• Toxic multinodular
goiter is a disorder in
which hyperthyroidism
arises in a
multinodular goiter,
usually one of long
standing.
• Laboratory Tests
• Treatment
Toxic adenoma
• A solitary,
autonomously
functioning thyroid
nodule
• Laboratory Tests
• Treatment
 Thyroiditis
• Thyroiditis is a term indicating the presence of
thyroid inflammation.
• Absence of iodine 123 (123I) radioactive iodine
uptake in patient with thyrotoxicosis and subacute
painless or lymphocytic thyroiditis
Subacute granulomatous thyroiditis
• Subacute granulomatous thyroiditis is
characterized by neck pain, a tender
diffuse goiter, and a predictable course of
thyroid function evolution.
• Hyperthyroidism is typically the
presentation followed by euthyroidism,
hypothyroidism and ultimately restoration
of normal thyroid function.
Subacute granulomatous thyroiditis
Subacute granulomatous thyroiditis
• Diagnosis
– History
– PE
– Lab findings
– Ultrasound
– RAIU
• Treatment
– Antiinflammatory therapy (nonsteroidal antiinflammatory
drug or prednisone)
– beta blocker
– L-T4 replacement
 Infectious thyroiditis
• Suppurative thyroiditis
• The sudden onset of neck pain and
tenderness, accompanied by fever, chills
and other symptoms and signs of infection
• Unilateral neck mass, which may be
fluctuant
• Evaluation: ultrasonography, FNA
• Management: drainage, antibiotic therapy
 Amiodarone Effects on Thyroid
Function
• Antiarrhythmic drug that contains 37%
iodine
– Direct effects of amiodarone on the thyroid
– High iodine content
• Thytotoxicosis: thyroiditis or iodine-induced
hyperthyroidism
• Hypothyroidism: antithyroid action of iodine
 Case 1 – 29 year old woman
• Presents with 5 month history of tremor,
tachycardia, 15 kg weight loss
• Testing shows TSH < 0.03 mU/L, FT4 = 90 pmol/L
(normal 9-23)
Questions:
• What clinical features are helpful in diagnosis?
• What tests do you do?
 Case 1 – 29 year old woman
• Clinical features:
• Hyperthyroid features not specific eg tachycardia, tremor
• Look for specific physical features:
- extrathyroidal manifestations of Graves’ disease:
3 - opthalmopathy, acropachy, pretibial myxedema
- character of goitre: - diffuse (Graves’) or nodular
- tender (viral thyroiditis) or
nontender (everything else)
 Case 1 – 29 year old woman
• Clinical features:
• Large, symmetrical (diffuse) fairly soft goitre
• Obvious proptosis, no pretibial myxedema or
acropachy

• Clinical Diagnosis: most likely Graves’ disease

 Case 1 – 29 year old woman
• Lab testing: Expected result:
• thyroid scan or 131I uptake increased
• TSH receptor antibodies positive

• (Note: TPO antibodies likely positive, but are nonspecific

as they are also positive in Hashimoto’s thyroiditis)

• Treatment: 131I, antithyroid drugs, or surgery

 Case 2 – 29 year old woman
• Presents with 2 month history of tachycardia, nervousness,
insomnia
• Tests show TSH< 0.03 mU/L, FT4 = 45 pmol/L (N: 9-23)
• Physical exam does not show ophthalmopathy or other
extrathyroid features of Graves’ disease
• Thyroid is only slightly increased in size, no definite nodules

Questions:
• What additional history information needed?
 Case 2 – 29 year old woman
• History:
• Is thyroid painful? Yes: viral thyroiditis
• No: other causes

• Iodine exposure? Yes: probable iodine-

induced hyperthyroidism
• Drug use: amiodarone, lithium,
interferon
• Has she been pregnant? Yes: postpartum
thyroiditis or Graves’
 Case 2 – 29 year old woman
• History:
• She does not have any of the prior etiologic factors
• Thyroid not tender on examination

• What testing is needed?

• Thyroid scan or 131I uptake
• TSH receptor antibodies
• TPO antibodies
 Case 2 – 29 year old woman
• Results:

• Thyroid scan increased: Graves’,

toxic nodule(s)
• decreased: other causes

• TSH receptor antibodies positive : Graves’ disease

• TPO antibodies positive : Graves’ or
Hashimoto’s thyroiditis
 Case 2 – 29 year old woman
• Results on this patient:

• Thyroid scan: decreased uptake

• TSH receptor antibodies: negative
• TPO antibodies positive

• Diagnosis: transient (silent) thyroiditis in

person with Hashimoto’s thyroiditis
 Key Points
• Differential diagnosis of thyrotoxicosis.
• The most common causes of an overactive
thyroid are Graves disease and toxic
multinodular goiter.
• Graves disease is caused by the
development of TRAb.
• The treatment of hyperthyroidism is best
initiated with the antithyroid drug
methimazole.
THANK YOU!