Hyperthyroidism

Tong Zhao
Department of Endocrinology, the first affiliated
hospital, School of medicine, Zhejiang university
General Introduction of Thyroid
Follicles: the Functional Units of the Thyroid Gland

Colloid

Follicle

Parafollicular Cells

Follicular Cells
Regulation of thyroid hormone
secretion
 Regulation of thyroid hormone secretion

CIRCADIAN RHYTHM

① TRH→TSH.
(Cold, Emotions)
PITUITARY

② TSH→TH.
TRH/TSH Stimulating test

③ TH→TSH
(Negative
PERIPHERAL TISSUES

feedback)
Stimulate
→ Inhibit LUNG
· Hyperthyroidism is defined as an overactive
thyroid gland, which produces and secretes excessive
amounts of thyroid hormones-t riiodothyronine (T3)
and thyroxine (T4).
· Thyrotoxicosis is clinical syndrome when
tissues are exposed to excessive concentrations of
thyroid hormones.
Etiology of thyrotoxicosis
Hyperthyroidism
- sustained overproduction and release of hormone by the thyroid itself

1. Graves disease
2. multiple nodular thyrotoxicosis
3. toxic thyroid adenoma
4. iodine-induced hyperthyroidism
5. neonatal hyperthyroidism
6. pituitary TSH adenoma
7. thyroid cancer
 GRAVES DISEASE (GD)

· It is wrong to say "Graves disease as

"hyperthyroidism " in brief.
 Etiology of thyrotoxicosis
· Non-thyroid thyrotoxicosis
- not overproduction of thyroid hormones by thyroid
1. subacute thyroiditis
2. asymptomatic thyroiditis
3. chronic lymphocytic thyroiditis
4. postpartum thyroiditis
5. HCG related hyperthyroidism
6. iatrogenic hyperthyroidism
7. Ectopic goiter with hyperthyroidism
Graves disease (GD)

· pathogenesis

· histopathology

· clinical presentation

· laboratory and special exams

· diagnosis and differential diagnosis

· treatment
Outline of GD
· Organ-specific autoimmue disease

· diffuse toxic goiter

· Symptoms: thyroid enlargement, thyrotoxicosis, exophthalmos
,pretibial myxedema

· More commonly in women, Female: Male= 4 ～ 6:1

· Subclinical hyperthyroidism is usually referred to a state with
normal T3\T4, decreased TSH, and no clinical symptoms of
hyperthyroidism
 Pathogenesis
· Abnormalities of immune system
- B cells produce TSH-R-Ab (TRAb)

- TRAb

· TSAb: stimulating lgG-----hyperfunction-- direct cause

· TSBAb: inhibitory IgG------hypofunction and antagonist of TSAb

· TGI(thyroid growth immunoglobulins): growth-stimulating IgG

- TSH-R+ TRAb

· mimic the action of TSH-------hyperfunction and goiter

 Pathogenesis
· Hereditary (genetic factors)
- HLA-B8 、 DR3 、 DQA1*0501 、 HLA-
Bw46

- CTLA-4
- GD-1,-2,and-3

· Environment and Infection

- infective factors(yersinia enterocolitica)
- stress(physical or emotional)
- Estrogen, pregnancy, childbirth
 Histopathology
• · Thyroid

- goiter: symmetrical, diffuse

- follicles: hyperplastic column with scant colloid, papillary

projections

- vascularity increased

- lymphocytes and plasma cells infiltration

Histopathology
· Ophthalmopathy
- The volume of orbital contents is enlarged because of increases in retrobulbar

connective tissue and adipose tissue

- The extraocular muscles are swollen, and some fibers exhibit loss of striation,

fragmentation,and lymphocytic infiltration

Histopathology
· Pretibial myxedema

- Skin swelling

- Glycosaminogycan accumulation in the skin and subcutaneous

tissue, collagen fiber, connective tissue damage

- Mast cells, macrophages and fibroblasts cells infiltration

Clinical Presentation
· Symptoms and signs associated with elevated

levels of thyroid hormones

· Goiter
· Ophthalmopathy

· Special manifestations
Thyrotoxicosis:
· High metabolism
· Nervous system
· Cardiovascular system
· Gastrointestinal
system · Hematopoietic
system · Gonadal
system
· Muscles
High metabolism:

Don't Evade Feeling Hot And Sweaty Patients

• Weight loss(despite normal energy intake)

• Fatigues and weakness
• Heat intolerance and low fever
• Increased sweating
• Glucose intolerance
Nervous system

· Nervousness
· Emotional lability
· Anxiety and irritability
· Difficulty sleeping
· Hyperactivity and unable to concentrate
· Tremor and muscle weakness
· Tendon reflexes hyperactivity
· Apathy,depression and withdrawn in older patients
Cardiovascular system
• Palpitation
• Tachycardia
• Atrial fibrillation and other atrial arrhythmias
• Pulse pressure is increasing
• Accentuated heart sounds, systolic ejection or other murmurs
Gastrointestinal system

• Increased appetite
• Hyper-defecation
• Steatorrhea
• Jaundice
• Impaired of the liver function
Hematopoietic system

• Mild granulocytopenia

• lron or other hematopoietic nutrient deficiency

• anemia
Gonadal system

• Infrequent menstruation or suppressed menstruation

• Erectile dysfunction and occasionally loss of libido

• Gynecomastia
 Muscle

· Muscle weakness
· Thyrotoxic myopathy

· TPP-thyrotoxic periodic paralysis

Clinically, some young men tend to have hypokalemic periodic paralysis as the
predominant clinical manifestation
Clinical Presentation

· thyrotoxicosis(hypermetabolic state)

nervousness, irritability, palpitation, insomnia, fatigue, heat intolerance,

excessive sweating, weight loss, with voracious appetite
Clinical Presentation
thyroid goiter
(I 、Ⅱ、Ⅲ °) 、 nontender

thrill with audible bruit

We will then palpate the patient's thyroid gland

 Clinical Presentation
· Exophthalmos
- Non-infiltrating exophthalmos mild proptosis,<18mm

t
Graefe syndrome Stellwag syndrome

Joffroy syndrome

Mobius syndrome
Clinical Presentation
Exophthalmos
- Infiltrating exophthalmos(Graves ophthalmopathy)
· Symptoms: tearing, feeling sand in the eyes, photophobia, diplopia , pain,
· Signs: severe protosis(>18mm), visual acurity decrease , visual field defect, corneal
ulceration ,restriction of eye movement
Probability of the development of orbitopathy in patients with Graves’ disease
Genetics

TSH receptor Mostly similar to

autoantibody levels Graves' disease Ancestry
Few additional
Correlate with Clinical
phenotypic modifiers
Activity Score
Caucasian> Asians
Predict natural history
and reponse to therapy

Environment Gender
Development
Active and passive smoking or Progression Women —more frequent
Radioactive iodine therapy of Graves' Men — more severe
Ophthalmopathy

T₃ and T₄ levels? Thyroid dysfunction

Of questionable significance Hypothyroidism

Hyperthyroidism
Orbital anatomy?
Venous and lymphatic return?

Mechanical factors
Clinical
Presentation
· Pretibial myxedema

In the anterior tibial, dorsal foot

The skin is thick and hard, like orange peel
Special clinical
manifestations
· thyroid storm

· hyperthyroid heart disease

· apathetic hyperthyroidism

· T3\T4 type hyperthyroidism

· subclinical hyperthyroidism

· pregnancy hyperthyroidism
Thyroid storm (thyrotoxic
crisis)
· precipitating factors
- acute illness: infection, trauma, DKA
- surgery(especailly on the thyroid)
- radiation thyroiditis

· symptoms and signs exaggerated abruptly

- fever(>39℃), sweating, vomiting, diarrhea and jaundice
- increased heart rate,arrhythmias, congestive heart
failure, hypotension, shock
- restlessness, delirium ,seizures,apathy,stupor,c oma

Hyperthyroid crisis is a life threatening

form
Hyperthyroid heart
disease
· features as

- heart enlargement

- arrhythmias

- heart failure

· other causes excluded

· disappeared after treatment

 Apathetic
hyperthyroidism
· More common in older patients
· Insidious onset, high metabolic syndrome group, eye
symptoms, goiter is not obvious
· Main presentations: weight loss, heart palpitations,
fatigue, diarrhea, anorexia, apathy, atrial fibrillation
· easily be misdiagnosed
· Diagnostic clues: sudden weight loss, new onset atrial fibrillation
 T3\T4 type hyperthyroidism
· T3 hyperthyroidism
- Ratio generating T3 and T4 disorders, T3 greater than T4
- commonly in iodine deficiency region and in the elderly population
- causes:
- GD, toxic nodular thyroid tumors and high-functioning adenomas
- Remission rate is higher than the typical hyperthyroidism
· T4 hyperthyroidism
- causes
·iodine-induced hyperthyroidism
· hyperthyroidism with systemic disease (peripheral deiodinase activity
reduced or lack)
 Subclinical hyperthyroidism
· causes:
- GD, nodular goiter, thyroid adenoma and other high-functioning

- Disease process: early stage or convalescence

· adverse outcomes
- Approximately 4-10% per year for the development of subclinical hyperthyroidism to
hyperthyroidism

- Impact on the cardiovascular system

- fracture risk
 Pregnancy hyperthyroidism
· HCG related to hyperthyroidism
- Gestational transient hyperthyroidism(GTT)
· incidence:2-3%
· increased HCG stimulates TSH receptor
· no proptosis, autoantibody(-), peaked at 3 months of pregnancy
· severe cases: can be short-term ATD therapy
· hyperthyroidism during pregnancy
- With diffuse goiter, exophthalmos, thyroid bruit or thrill, TRAB positive
- diagnosis: FT3, FT4 and TSH, not TT3/TT4
 Pregnancy hyperthyroidism

Adverse consequences
- Mother: miscarriage, premature birth, preeclampsia , placental abruption
- Fetus: preterm ,intrauterine growth retardation

- Fetal or neonatal hyperthyroidism

 Laboratory and Special Exams
· Serum TH and TSH
- TT₃ and TT₄ , FT₃ and FT₄------increased
· FT₃ and FT₄ are the direct indexes(0.3% and 0.02%)
· TT₃ and TT₄ are influenced by concentration of TBG(99.7% and 99.98%)
- rT₃-----increased
- TSH----- decreased

· TSH receptor antibodies---TRAb(+)

·
 Laboratory and Special Exams

131l uptake ------increased, peak appeared early

Normal reference range: 3h: 5-25%, 24h:20-45%

Imaging examination
- ultrasonography
- emission computered tomography(ECT)
·
Diagnosis and Differential
Diagnosis
· confirmed hyperthyroidism
- symptom
· weight loss, slight fever,diarrhea,tachycardia , atrial
fibrillation ,fatigue, with difficult in control of DM, heart failure, liver
disease
- signs
· diffuse goiter, exophthalmos
- hormone abnormal
· FT3,FT4,TSH
· pathogenic diagnosis
- TRAb, TgAb, TPOAb
- 131l uptake
- ultrasonography
- HCG
Different Diagnosis
TRAb

Graves
T3,T4 synthesis1

1311 uptake

Thyroiditis
T3,T4 release1
History:Recent onset,<3 Chronic , >3 Indeterminant
months
months

Thyrol Tenderness Diffusely Nodular Not

exam: (favors thyroiditis) en l a rg e d (one or sure

more)
High Graves' Nodular
1231 Uptake
disease thyrotoxicosis

Low

Rule out iodide excess Thiourea

1231 Uptake, Scintiscan
and exogenous drugs 土
? Uitrasound
thyroid hormone beta blockers

None
Uptake results
Thyroiditis:
2 Autoimmune, High High Low
Post-viral,
(Bacterial,
Fungal ) Toxic nodule Multiple Thyroiditis
toxic nodules Rule out
iodide excess,

1311 1311 Thyrotoxicosis

Factitia
Exogenous lodide ? Surgery (Possible (see left
thyroid hormone excess
pretreatment of figure)
portion
thiourea)
? Surgery
Symptomatic lodide-induced
treatment, Thyrotoxicosis or associated
Factitia
TPO AB hyperthyroidism

Monthly TSH,T₄ Check urinary

until stable, Check serum jodide
Watch for thyroglobulin
hypothyroidis
High Normal
m
Low Normal, high Remove source Thyroiditis
if possible,
Treat with
(see left
Thyrotoxicosis
Hyperthyroidism thiourea drugs of figure)
Factitia portion
 Treatment

· General treatment

· ATD --- reducing thyoid hormone synthesis

· Radioiodine treatment reducing the amount of

thyroid tissue

· Operation
General managment
· absolutely avoid iodine
--seafood, salt, tincture of iodine drugs [such as.
Centrum, amiodarone]
· rest enough
· energy and nutrients supplement (protein and B)
· sedatives for restlessness and insomnia
· beta blockers (propranolol) for tachycardia
- in the early stages before antithyroid drugs take effect
 ATD therapy is the first choice in
Europe and Asia

Percentage choo s ing tr ea tm en t a s pr

imary therapy

Vaidya et al Clin Endocrinol 2008

 Antithyroid drugs(ATD)

· agents
- methylthiouracil(MTU) or propylthiouracil(PTU) 300-600mg/d

- methimazole(MM) or carbimazole(CMZ) 30-60mg/d

· mechanism

- inhibit the function of TPO, reducing oxidation and organification of iodide

- reduce thyroid antibody levels(mechanisms unclear)

- Inhibition of thyroid follicular epithelial cell function and growth

- PTU inhibits deiodination of T4 to T3

· severe thyrotoxisis
Antithyroid drugs (ATD)

· Indications

- mild to moderate patients

- thyroid mild to moderate swelling

- young people(<20 yrs)

- pregnant women, the elderly patients

- not suitable for surgery or radioactive iodine treatment

- preparation before surgery or radioactive iodine therapy

- recurrence after surgery

Antithyroid drugs (ATD)
· dosage and course
>1st stage (6 wks): full dosage to control symptoms
> 2nd stage (4-8 wks): dosage decrease gradually
>3rd stage(1yr or more):minimal dosage to maintain treated effects. "block-replace"
regimens
>TH added to prevention of hypothyroidism
>regulation of immune
· drug withdrawal
goiter subsides
TSH return to normal
>TSAb/TRAb negtive

>maximum remission rates are achieved by 18-24

Antithyroid drugs(ATD)
· side effects
- Low dose of MMI rarely have side effects while PTU can cause it in any dose
- common: rash, urticaria ,fever, and arthralgia (1-5% of patients)
- hepatitis, an SLE-like syndrome
- Leukocytopenia and agranulocytosis (<1%,within 2 months)
· can be caused by hyperthyroidism itself, so take a blood
routine before treatment
- Anti-Neutrophil Cytoplasmic Antibodies(ANCA) positive
vasculities, Aplastic anemia
monitor blood counts and live function: wk or mo

most of them were transient that needn' t stop the

Antithyroid drugs (ATD)
Agranulocytosis
· The incidence rate is 0.2%-0.5%, the most severe side effect, both

PTU and MMI can cause it

· normally happens within 3 months of treatment

· Sore throat, fever, infection etc.

· WBC<3×10 12/L, neutrophil cells <1.5×10⁹/L should stop drug

instantly, with broad-spectrum antibiotics, glucocorticoid and colony cell stimulating

factor (G-CSF)

· Glucocorticoid has no definite therapeutic effect, G-CSF should be

the first choice.

Radioiodine

·causes progressive destruction of thyroid cells

· be used as initial treatment or for relapses after antithyroid drugs

· The risk of thyrotoxic crisis can be avoided by pretreatment

with antithyroid drugs for at least a month before treatment.
· Antithyroid drugs must be stopped 3 to 5 days before

radioiodine administration to achieve optimum iodine uptake.

 Radioiodine
Indication Contraindication
[Link] hyperthyroidism 1. Pregnancy or lactation
[Link] appropriate for antithyroid drugs 2. Lower than 20 years
[Link] after operation 3. Severe heart 、 liver or kidney
4. Have heart disease dysfunction, active tuberculosis
5. WBC in low level 4. Severe or active infiltrating
6. Old people exophthalmos
[Link] multinodular goiter 5 . Neutropenia
6. Hyperthyroid crisis
7. Failed to I uptake
 Radioiodine
· Complications
- permanent hypothyroidism(40-70% 10yrs)
- radiation thyroidiis(7-10 days after treatment)
- thyrotoxic crisis
- exaggerated proptosis

· Its dosage should be calculated by specialist

Thyroid w eight assessment * (60~ 120 uCi)
*100%
24-hour iodine uptake rate

· For serious condition, it can use MMI control symptoms at first - its inhibition of 131l uptake
disappear after 24 hours (several weeks for PTU)
 Surgery

Indication Contraindication
1 . Severe or rapid development of
1 .Moderate or severe hyperthyroidism, not
exophthalmos
appropriate for antithyroid drugs 2 . Accompanied by severe disease who can
2 . Immense goiter accompanied by not tolerate operation
compressive symptoms 3. At early or late stage of pregnancy
[Link] behind sternum
accompanied by hyperthyroidism
[Link] goiter accompanied by
hyperthyroidism
[Link] not exclude thyroid carcinoma
6. Children and pregnancy
Surgery

· Preparation
· Take ATD and β-block before operation
· careful control of thyrotoicosis

· Take lugol's solution

·avoid thyroid crisis

· reduce the vascularity of the gland

Complication
· Nerve injury

· Permanent hypothyroidism

· Hypoparathyroidism
 Managment of thyrotoxic crisis
· intensive monitoring and supportive care
· identification and treatment of the precipitating cause
· therapy for thyroid
- large dosed of PTU(600mg loading dose and 200-300mg/6hrs
· inhibitory acting on T4 to T3 conversion and thyroid hormone synthesis
- potassium iodide(5 drops/6h)
·one hour after the first dose of PTU ·
block thyroid hormone release

· therapy for peripheral effects of thyroid hormone

- propranolol(40-60mg/4h,orally; 2mg/4h, intravenously)
· reduce tachycardia and other adrenergic manifestations
- glucocorticoids
Therapy for Ophthalmophthy

· yes or no

Graves Grading Criteria for Ophthalmology, American Thyroid Association (ATA), 1997

· active or inactive
In 2008, the GO European Research Group (EUGOGO) proposed a scoring method
for judging GO activities (clinical activity score (CAS)

· severity

In 2008, EUGOGO proposed criteria for assessing the severity of GO's condition

Bartalena L, et al. Thyroid 2008, 8(3):333-347

 Classification of Graves orbitopathy: NOSPECS
Class definition

O N no signs or symptoms

1 0 only signs

2 S soft-tissue involvement

3 P proptosis
4 E extraocular muscle involvement

5 C corneal involvement
6 S sight loss

3-6 CAN BE DIAGNOSED GO

Assessment of the activity of GO
Clinical Activity Score(CAS)
① Spontaneous retrobulbar pain
② Pain on eye movement
③ Eyelid erythema
④ Conjunctival injection
⑤ Chemosis
⑥ Swelling of the caruncle
⑦ Eyelid edema or fullness
Assessment of the severity of GO (UGOGO)

grade Upper eyelid Soft tissue exophthalmos diplopia Corneal Optic nerve
retraction involvement exposure compression

Mild <2mm Mild <3mm None or No No

transient

moderate- ≥2mm moderate- ≥3mm Intermittent Mild No

severe severe or
persistent

Sight- Severe Yes

threatening

N o r m a l e x o p h t h a l m o s i s o f t h e C h i n e s e g r o u p ： 1 8 . 6 mm

ATA/AACE:Guidelines for the management of hyperthyroidism 2010

 Eyelid retraction

Soft tissue inflammation

Exophthalmos

Corneal exposure

Courtesy of Dr. Petros Ocular motility disorders

 Management of nonsevere
GO
Management Signs or symptoms

Sunglasses Photophobia
Artificial tears and ointments Foreign body sensation
b-Blocking eye drops Eyelid retraction; increased
intraocular pressure
Nocturnal taping of the eyes Lagophthalmos
Prisms Mild diplopia
Correction of hyper-or
hypothyroidism
Elimination of risk factors
(smoking)

LUIGI BARTALENA,ER 2000

Management of severe
GO
· Established methods:
· Glucocorticoids (Oral, Intravenous, Local)
· Supervoltage orbital radiotherapy
· Rehabilitative surgery (Orbital decompression,
Extraocular muscle surgery, Eyelid surgery)

· Novel treatments under investigation:

· Somatostatin Analogues
· Octreotide
· Lanreotide
· Intravenous immunoglobulins

· Nonestablished methods:
· Cyclosporinea
· Plasmapheresis

LUIGI BARTALENA,ER 2000

Graves' disease in pregnancy

· Antithyroid drugs are the treatment choice

- PTU is preferred

- The lowest possible dose of drug should be used to maintain the

mother's thyroid function at the upper limit of normal.

· pregnancy has an ameliorative effect

- breast feeding is safe with low doses of drugs

· Surgery

- if necessary, it is best done during the second trimester(4-6th)

· absolute contraindications: radioiodine treatment

Neonatal hyperthyroidism

· mother' TSAb through the placenta

· mild cases: self-limiting, no treatment

· severe cases: PTU10-25mg,q8h

lodine-induced hyperthyroidism

· Avoid excessive intake of iodine

· Apply the β-blockers relieve symptoms

· plus MMI
- severe cases
- three months without remission
· Thyroid nodules can be surgically removed

· Radioactive iodine treatment is not considered before

Iodine is drained
Questions

· definition: thyrotoxicosis, hyperthyroidism

· Graves disease

· managment of thyrotoxic crisis

 (D2) Hypothalamus
T₄ +T₃
T4→T
(-) ₃ TRH(+)
SRIH(-)

(D2)
T4→T ₃ (-) Pituitary
T₃ (-)
T ₄ +T ₃
T,L,K(D1)
T, T₄→T TSH(+)
SM,CM(D2) } ₃
T₄(T₃)
D1+D2 Thyroid
Thank you ! !