Hyperthyroidism

(Thyrotoxicosis)
郑州大学第一附院内分泌科
王守俊
Wang shou jun
Hyperthyroidism is only a diagnosis of
excessive TH status, never means a
concrete disease .
It is wrong to say “Graves disease (GD)”
as “hyperthyroidism ” in brief.
Regardless of the pathogenesis,
Hyperthyroidism is characterized by
Pathogenesis of Hyperthyroidism
A. Thyroidal origin
1. Graves disease (GD)
2. Multiple nodular thyrotoxicosis
3. Plummer disease (toxic thyroid adenoma)
4. Hyperfunctional thyroid nodule
5. MEN with hyperthyroidism
6. Thyroid carcinomas
7. Neonatal hyperthyroidism
8. Genetic toxic thyroid hyperplasia/goiter
9. Iodine-induced hyperthyroidism
B. Pituitary origin
1. Pituitary TSHoma
2. TH insensitivity syndrome
3. Para-carcinoma syndrome
4. HCG-related hyperthyroidism
5. Ovarian goiter with
hyperthyroidism
6. Iatrogenic hyperthyroidism
C. Transient hyperthyroidism
1. Subacute
de Quervian thyroiditis
subacute lymphocytic thyroiditis
traumatic thyroiditis
radioactive thyroiditis
2. Chronic
chronic lymphocytic thyroiditis
 TRH TRH
T3

TSH T3,T4 TSH T3,T4

I TSHR-Ab
I
Normal Feedback Graves’ Disease
GRAVES DISEASE (GD)

I. Pathogenesis
II. Histopathology
III. Clinical presentation
IV. Laboratory and special exams
V. Diagnosis and differential
diagnosis
VI. Treatment
VII. Case discussion
Graves disease
diffuse toxic goiter
Basedow disease

Subclinical hyperthyroidism
normal TH
decreased TSH
no symptoms or signs
 I. Pathogenesis

A. Abnormalities of immune system

1. Antigenic proteins in thyroid
TSH/ TPO/ Tg/NIS

2. TSH-R-Ab + TSH-R →mimic TSH

→hyperfunction/goiter.
3. functioning Ig → Th hypersensitivity →IL-1/IL-2

→ TSH-R-Ab (TRAb)
stimulating IgG hyperfunction(TSAb)
4. TRAb inhibitory IgG hypofunction/antagonist
of TSHR and TSAb (TF1Ab, TGBAb)

growth-stimulating IgG (TGI)

B. Other factors
genetic factors
infective factors
stress (physical or emotional)
C.Thyroid-associated
ophthalmopathy (TAO)
unknown(cyto-autoimmune process?)
GAG accumulation, T cell
infiltration, edema, fibrosis and sight
loss
 II. Histopathology
A. Thyroid
goiter: symmetrical, diffuse,
lobular
follicles: hyperplastic with scant colloid,
papillary projections,
vascularity: increased
infiltration: lymphocytes/plasma cells
Overactivity of the thyroid gland
The thyroid follicles are lined
by cuboidal follicular epithelium
Under high power microscope, the tall
columnar epithelium is lined by
hyperplastic infoldings
B. Eyes
orbital contents↑, with mucoprotein,
GAG (glycosaminoglycan), and lymphocytes

C. Skin (dermopathy)
1. hyaluronic acid, chondroitin sulfates↑
2. featured by separated collagen fibers,
with plague formation,
3. lymphatic drainage decreased
III.Clinical Presentation

A. General considerations
incidence 0.5%
male: female ≈ 1: 4~6
common in 30~40yrs
family onset constitution
B. Hypermetabolic states
nervousness (99%)
irritability (90%)
palpitation (88%)
tachycardia (82%)
insomnia (60%)
fatigue /weight loss (75%)
heat intolerance (70%)
voracious appetite (65%)
dysmenstruation (50%)
C. Thyroid
1. consistency
soft/firm/rubbery

2. enlargement
symmetrical

3. surface
smooth

4. thrill with audible bruit

D. Eyes
a. Ophthalmopathy
fissure widened
clera exposed
lid retraction/lid tremor
lid lay/globe lay
Staring gaze is one of the
early signs of TAO
Male, 46yrs, with TAO( exophthalmos,
double vision, inflammation of
eye-surrounding tissues)
Toxic goiter is the important
feature of GD
inflammation and hypertrophy of
the tissues around the eyes
causing swelling
b. infiltrative
ophthalmopathy
excessive tearing
exophthalmos (asymmetrical)
eyelids unclosed
blurred vision
double vision
visual acuity decreased
corneas ulcerated and infected
sight loss
c. Classification of Graves orbitopathy: NOSPECS
(American Thyroid Association)
Class Definition
0 No physical signs or symptoms
1 Only signs, no symptoms (signs limited to
upper lid retraction, stare, lid lag, and
proptosis to 22mm)
2 Soft tissue involvement (symptom and sign)
3 Proptosis>22mm
4 Extraocular muscle involvement
5 Corneal involvement
6 Sight loss (optic nerve involvement)
E. Pretibial
myxedema

Early feature
thickening
reddening
later features
thickening
plague
nodules
pigmentation
F. Others
tremor of hands and tongue
muscle wasting
rapid reflex response
liver function
wbc , and anemia,
vitiligo/hair loss
G. Complications
a. cardiopathy/heart failure
arrhythmia
heart enlargement
heart failure
disappeared after treatment
b. Thyrotoxic crisis
1. Exaggerated abruptly
2. Precipitating factors
infection, surgery, radiation,
DKA, parturition

3. Additional pictures
arrhythmia, pulmonary edema,
abdominal pain, apathy, coma, shock
c. hypokalemic periodic
paralysis
1. more common in Asia
2. abruptly paralysis with hypokalemia
3. precipitated by carbohydrate
or vigorous exercise
4. some companied by myasthenia gravis.
IV. Laboratory/special exams
A. Serum TH and TSH
FT3 and FT4
TT3 and TT4
rT3
TSH

B. TSH receptor antibodies

C. TRH stimulation test
euthyroid Graves ophthalmopathy

D. 131I uptake/T3 suppression test

E. Pathological exams
V. Diagnosis and Differential Diagnosis

A. Functional diagnosis
suspected when
weight loss diarrhea
slight fever tachycardia
atrial fibrillation fatigue
dysmenorrhea
difficult in control of DM, TB, heart
failure, CHD, liver disease
B. Types
FT3 /FT4 ↑, uTSH↓: hyperthyroidism
Only FT3 ↑, uTSH↓: T3 hyperthyroidism
Only FT4 ↑, uTSH↓: T4 hyperthyroidism
Only uTSH↓: subclinical hyperthyroidism

C. Pathogenic diagnosis
TRAb, TgAb, TPOAb, HCG, 131I uptake
 VI. Treatment
A. General management
Sedatives for restlessness/insomnia

B. Management
a. Medical
Methylthiouracil (MTU)
Propylthiouracil (PTU) 300~600mg/d

Methimazole (MM)
Carbimazole (CMZ) 30~60mg/d
b. dosage and course
1st stage (6 wks)
full dosage to control symptoms
2nd stage (4~8wks)
dosage decrease gradually
1/6 dosage/wk
3rd stage (>1yr)
PTU 50mg/MM 5mg, Qd
c. “block-replace” regimens
TH added to prevent hypothyroidism
Not recommended in general
d. drug withdrawal
goiter subsides
minimal dosage to maintain effects
TSH return to normal
TSAb negative
normal response to TRH
e. drug side-effects
Agranulocytosis
(<1%, within 2 mos)
WBC / wk-mo
C. Radioiodine (131I)
a. More commonly used than before
b. Contraindications
pregnant
young people (<20yrs)
severe exophthalmos
thyrotoxic crisis
failed to uptake I
C. Complications
hypothyroidism
radiation thyroiditis
thyrotoxic crisis
exaggerated proptosis
(smokers, >40 yrs, male)
D. Surgery
Indications
failed to medication
huge thyroid
tumor suspected
retrosternal goiter
Contraindications
severe proptosis
severe systemic diseases
early and late pregnancy
thyrotoxicosis not controlled
E. Treatment decision-
making
a. Medical treatment firstly
b. After controlled, decided by
age
run course
severity/complications
thyroid states
doctor’s experience
patient’s willings
F. Special concerns
a. minimal iodide supplement
b. treat severe proptosis with caution,
including TH supplement and prednisone

c. thyroid crisis treated with NaI, PTU,

DXM, and propranolol
d. Only PTU for pregnant cases,
never makes TSH <0.5mU/L

e. Treated with digoxin may be

dangerous in some cases
 Ⅶ. Case discussion
Dear professor xxx ：
1 、 May, 2000: diagnosed as GD and treated with PTU×5
mos, TH returned to normal in Changsha.
2. June, 2001: treated with 131I in Beijing because of
repeatedly increased serum TH and lowered TSH,
showing FT4 6.8 （ 3.67-13.5 ） ,
FT33.9 （ 7.4~71.2 ） nmol/L ， and TSH
32.7 （ 0.34~5.6 ） mU/L after 6 mos.
3. Jan-Feb, 2002: Hypothyroidism was diagnosed and
replaced with L-T4 50µg/d for 4 mos. FT3 8.9, FT4
15.7nmol/L, and TSH 0.19-0.05mU/L in Feb. L-T4 then l
down to 25 µg /d.
4. March, 2002: was told to do TRH stimulation test
for determination the “relapse” reason of GD.
5. April-June, 2002: diagnosed as hyperthyroidism
and taken Tapazol (15mg/d) . Then FT3 4.3, FT4 3.0
nmol/Land TSH 83.7mU/L ， had to take thyroid
tablet(40mg/d) for hypothyroidism.
6. Aug-Oct, 2002: TSH 0.09mU/L with GD symptoms.

 Patient ：张新根
 诊断 甲亢 正常 甲低 甲低

处理 PTU I131 治 优甲乐 建议

FT4
0 0 疗后 50µg/d TRH Test
4 3
0
2
0
1

A B C D E F G
FT3
5
1
0
1 5

A B C D E F G
83.7mU/L
uTSH
0
3 5

0.1
0.09
A B C D E F G 时间
 Questions
A. What is the underlying diagnosis in this
case after 131I therapy?

B. What kind of mistakes has been made

in the diagnosis and management?
Thanks!
Pathogenesis of Hyperthyroidism
A. Thyroidal origin
1. Graves disease (GD)
2. Multiple nodular thyrotoxicosis
3. Plummer disease (toxic thyroid adenoma)
4. Hyperfunctional thyroid nodule
5. MEN with hyperthyroidism
6. Thyroid carcinomas
7. Neonatal hyperthyroidism
8. Genetic toxic thyroid hyperplasia/goiter
9. Iodine-induced hyperthyroidism
B. Pituitary origin
1. Pituitary TSHoma
2. TH insensitivity syndrome
3. Para-carcinoma syndrome
4. HCG-related hyperthyroidism
5. Ovarian goiter with
hyperthyroidism
6. Iatrogenic hyperthyroidism
C. Transient hyperthyroidism
1. Subacute
de Quervian thyroiditis
subacute lymphocytic thyroiditis
traumatic thyroiditis
radioactive thyroiditis
2. Chronic
chronic lymphocytic thyroiditis
 TRH TRH
T3

TSH T3,T4 TSH T3,T4

I TSHR-Ab
I
Normal Feedback Graves’ Disease
GRAVES DISEASE (GD)

I. Pathogenesis
II. Histopathology
III. Clinical presentation
IV. Laboratory and special exams
V. Diagnosis and differential
diagnosis
VI. Treatment
VII. Case discussion
Graves disease
diffuse toxic goiter
Basedow disease

Subclinical hyperthyroidism
normal TH
decreased TSH
no symptoms or signs
 I. Pathogenesis

A. Abnormalities of immune system

1. Antigenic proteins in thyroid
TSH/ TPO/ Tg/NIS

2. TSH-R-Ab + TSH-R →mimic TSH

→hyperfunction/goiter.
3. functioning Ig → Th hypersensitivity →IL-1/IL-2

→ TSH-R-Ab (TRAb)
stimulating IgG hyperfunction(TSAb)
4. TRAb inhibitory IgG hypofunction/antagonist
of TSHR and TSAb (TF1Ab, TGBAb)

growth-stimulating IgG (TGI)

B. Other factors
genetic factors
infective factors
stress (physical or emotional)
 Graves disease

Genetic environment

disorder of
Immune system

TRab

Hyperthyroidism
C.Thyroid-associated
ophthalmopathy (TAO)
unknown(cyto-autoimmune process?)
GAG accumulation, T cell
infiltration, edema, fibrosis and sight
loss
 II. Histopathology
A. Thyroid
goiter: symmetrical, diffuse,
lobular
follicles: hyperplastic with scant colloid,
papillary projections,
vascularity: increased
infiltration: lymphocytes/plasma cells
Overactivity of the thyroid gland
The thyroid follicles are lined
by cuboidal follicular epithelium
Under high power microscope, the tall
columnar epithelium is lined by
hyperplastic infoldings
B. Eyes
orbital contents↑, with mucoprotein,
GAG (glycosaminoglycan), and lymphocytes

C. Skin (dermopathy)
1. hyaluronic acid, chondroitin sulfates↑
2. featured by separated collagen fibers,
with plague formation,
3. lymphatic drainage decreased
III.Clinical Presentation

A. General considerations
incidence 0.5%
male: female ≈ 1: 4~6
common in 30~40yrs
family onset constitution
B. Hypermetabolic states
nervousness (99%)
irritability (90%)
palpitation (88%)
tachycardia (82%)
insomnia (60%)
fatigue /weight loss (75%)
heat intolerance (70%)
voracious appetite (65%)
dysmenstruation (50%)
C. Thyroid
1. consistency
soft/firm/rubbery

2. enlargement
symmetrical

3. surface
smooth

4. thrill with audible bruit

D. Eyes
a. Ophthalmopathy
fissure widened
clera exposed
lid retraction/lid tremor
lid lay/globe lay
 Graves disease
Clinical manifestations
三、 Eye Sign 甲亢病人约 25-50% 伴有突眼

交感神经兴奋眼外肌和 球后组织增生，淋巴细胞
上睑肌使其张力增高 浸润，眼肌水肿增粗

良性突眼 恶性突眼
（非浸润性突眼） （浸润性突眼）
（单纯性突眼） (infiltrating exophthalmos
 Graves disease
Clinical manifestations
良性突眼
1 、 轻度突眼 ( 眼球突出，小于 18mm ）
2 、上眼睑挛缩
3 、 Dalrymple 症 （眼裂增宽）
4 、 Von Graefe sign （上眼睑活动滞缓）
5 、 Stellwag sign （瞬目减少和凝视）
6 、 Joffroy sign （ 向上看时，额部皮肤不能皱起）
7 、 Mobius sign （ 两眼球不能内聚 ）
8 、 staring of frightened expression （惊恐眼
神）
 Graves disease
Clinical manifestations
infiltrating exophthalmos( 恶性突眼 ) 性突眼

1 、眼球高度突出（大于 19mm ），甚至达 30mm 。

2 、两眼球突出度不等，相差约 2--5mm 。
3 、不但有眼部体征，还有明显的眼部症状：如眼部疲
劳，怕光，流泪，异物感 ，眼部疼痛，斜视，复视，甚
至眼球固定，突眼严重者眼球不能闭合。
甲亢眼征
良、恶性突眼的鉴别
Staring gaze is one of the
early signs of TAO
Male, 46yrs, with TAO( exophthalmos,
double vision, inflammation of
eye-surrounding tissues)
Toxic goiter is the important
feature of GD
inflammation and hypertrophy of
the tissues around the eyes
causing swelling
b. infiltrative
ophthalmopathy
excessive tearing
exophthalmos (asymmetrical)
eyelids unclosed
blurred vision
double vision
visual acuity decreased
corneas ulcerated and infected
sight loss
c. Classification of Graves orbitopathy: NOSPECS
(American Thyroid Association)
Class Definition
0 No physical signs or symptoms
1 Only signs, no symptoms (signs limited to
upper lid retraction, stare, lid lag, and
proptosis to 22mm)
2 Soft tissue involvement (symptom and sign)
3 Proptosis>22mm
4 Extraocular muscle involvement
5 Corneal involvement
6 Sight loss (optic nerve involvement)
E. Pretibial
myxedema

Early feature
thickening
reddening
later features
thickening
plague
nodules
pigmentation
F. Others
tremor of hands and tongue
muscle wasting
rapid reflex response
liver function
wbc , and anemia,
vitiligo/hair loss
 Special types

G. Complications
a. cardiopathy/heart failure
arrhythmia
heart enlargement
heart failure
disappeared after treatment
Graves disease
b. Thyrotoxic crisis
1. Exaggerated abruptly
2. Precipitating factors
infection, surgery, radiation,
DKA, parturition

3. Additional pictures
arrhythmia, pulmonary edema,
abdominal pain, apathy, coma, shock
c. hypokalemic periodic
paralysis
1. more common in Asia
2. abruptly paralysis with hypokalemia
3. precipitated by carbohydrate
or vigorous exercise
4. some acompanied by myasthenia gravis.
IV. Laboratory/special exams
A. Serum TH and TSH
FT3 and FT4
TT3 and TT4
rT3
TSH

B. TSH receptor antibodies

C. TRH stimulation test
euthyroid Graves ophthalmopathy

D. 131I uptake/T3 suppression test

E. Pathological exams
Normal
Graves disease

multinodular Adenoma
正常甲状腺
热结节
热结节
冷结节
甲状腺外肿块
 Graves disease
manifestation

suppressed TSH

And/or high T4/T3

Etiology
diagnosis
Hyperthyroidism
V. Diagnosis and Differential Diagnosis

A. Functional diagnosis
suspected when
weight loss diarrhea
slight fever tachycardia
atrial fibrillation fatigue
dysmenorrhea
difficult in control of DM, heart
failure, CHD, liver disease
B. Types
FT3 /FT4 ↑, uTSH↓: hyperthyroidism
Only FT3 ↑, uTSH↓: T3 hyperthyroidism
Only FT4 ↑, uTSH↓: T4 hyperthyroidism
Only uTSH↓: subclinical hyperthyroidism

C. Pathogenic diagnosis
TRAb, TgAb, TPOAb, HCG, 131I uptake
 VI. Treatment
A. General management
Sedatives for restlessness/insomnia

B. Management
a. Medical
Methylthiouracil (MTU)
Propylthiouracil (PTU) 300~600mg/d

Methimazole (MM) 30~60mg/d

Carbimazole (CMZ)
b. dosage and course
1st stage (6 wks)
full dosage to control symptoms
2nd stage (4~8wks)
dosage decrease gradually
1/6 dosage/wk
3rd stage (>1yr)
PTU 50mg/MM 5mg, Qd
c. “block-replace” regimens
TH added to prevent hypothyroidism
Not recommended in general
d. drug withdrawal
goiter subsides
minimal dosage to maintain effects
TSH return to normal
TSAb negative
normal response to TRH
e. drug side-effects
Agranulocytosis
(<1%, within 2 mos)
WBC / wk-mo
C. Radioiodine (131I)
a. More commonly used than before
b. Contraindications
pregnant
young people (<20yrs)
severe exophthalmos
thyrotoxic crisis
failed to uptake I
%

100
90
80
70 hyperthyroidism
60
50
normal
40
30
20
10 hypothyroidism
0
2 4 6 24 H

RAIU
 Graves 病接受 I131 治疗的分
布
%
40

女 (308)
30

男 (81)
20
10

20 30 40 50 60 70 80

年龄 J.inter Med. 1996;239:1651

G.Berg et al.
C. Complications
hypothyroidism
radiation thyroiditis
thyrotoxic crisis
exaggerated proptosis
(smokers, >40 yrs, male)
60

40
手术治疗组
131I治疗组
20

0
0 2 5 10 15 20 25 30

incidence of hypofunction after131I therapy and operation

（ Frantlyn et al.)
 Graves 病接受 I131 治疗的分
布
%
40

女 (308)
30

男 (81)
20
10

20 30 40 50 60 70 80

年龄 J.inter Med. 1996;239:1651

G.Berg et al.
D. Surgery
Indications
failed to medication
huge thyroid
tumor suspected
retrosternal goiter
Contraindications
severe proptosis
severe systemic diseases
early and late pregnancy
thyrotoxicosis not controlled
B. GD in pregnancy
1.Radioiodine uptake and scanning
are absolutely contraindicated.
2.Propylthiouracil(PTU) is ued in
usual dosage and then decreased to
lowest effective dosage to control the GD.
3 .MM is contraincidated because of
its cross the placenta. Caused the fetal
goitr/ or hypothyroidism.
B. GD In Adolescence.
Three treatment methods
posttreatment hypothyroidismshould be
promptly.
E. Treatment decision-
making
a. Medical treatment firstly
b. After controlled, decided by
age
run course
severity/complications
thyroid states
doctor’s experience
patient’s willings
F. Special concerns
a. minimal iodine supplement
b. treat severe proptosis with caution,
including TH supplement and prednisone

c. thyroid crisis treated with NaI, PTU,

DXM, and propranolol
d. Only PTU for pregnant cases,
never makes TSH <0.5mU/L

e. Treated with digoxin may be

dangerous in some cases
 Ⅶ. Case discussion
Dear professor xxx ：
1 、 May, 2000: diagnosed as GD and treated with PTU×5
mos, TH returned to normal in Changsha.
2. June, 2001: treated with 131I in Beijing because of
repeatedly increased serum TH and lowered TSH,
showing FT4 6.8 （ 3.67-13.5 ） ,
FT33.9 （ 7.4~71.2 ） nmol/L ， and TSH
32.7 （ 0.34~5.6 ） mU/L after 6 mos.
3. Jan-Feb, 2002: Hypothyroidism was diagnosed and
replaced with L-T4 50µg/d for 4 mos. FT3 8.9, FT4
15.7nmol/L, and TSH 0.19-0.05mU/L in Feb. L-T4 then l
down to 25 µg /d.
4. March, 2002: was told to do TRH stimulation test
for determination the “relapse” reason of GD.
5. April-June, 2002: diagnosed as hyperthyroidism
and taken Tapazol (15mg/d) . Then FT3 4.3, FT4 3.0
nmol/Land TSH 83.7mU/L ， had to take thyroid
tablet(40mg/d) for hypothyroidism.
6. Aug-Oct, 2002: TSH 0.09mU/L with GD symptoms.

 Patient ：张新根
 诊断 甲亢 正常 甲低 甲低

处理 PTU I131 治 优甲乐 建议

FT4
0 0 疗后 50µg/d TRH Test
4 3
0
2
0
1

A B C D E F G
FT3
5
1
0
1 5

A B C D E F G
83.7mU/L
uTSH
0
3 5

0.1
0.09
A B C D E F G 时间
 Questions
A. What is the underlying diagnosis in this
case after 131I therapy?

B. What kind of mistakes has been made

in the diagnosis and management?
Thanks!