Hyperthyroidism

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. 2. 3. 4. 5.

Pituitary TSHoma TH insensitivity syndrome Para-carcinoma syndrome HCG-related hyperthyroidism 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

TSH

TRH T3 TSH

T3,T4

I Normal Feedback

I

T3,T4

TSHR-Ab

Graves’ Disease

GRAVES DISEASE (GD) I. II. III. IV. V. VI. VII.

Pathogenesis Histopathology Clinical presentation Laboratory and special exams Diagnosis and differential diagnosis Treatment 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) 4. TRAb

stimulating IgG hyperfunction(TSAb) 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 lymphocy

C. Skin (dermopathy)

1. hyaluronic acid, chondroitin sulfates 2. featured by separated collagen fiber 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 0 1 2 3 4 5 6

Definition

No physical signs or symptoms Only signs, no symptoms (signs limited to upper lid retraction, stare, lid lag, and proptosis to 22mm) Soft tissue involvement (symptom and sign) Proptosis>22mm Extraocular muscle involvement Corneal involvement 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.

131

I 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, 131 I 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 decisionmaking 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. LT4 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

4 3 0 0

FT4

甲低

甲低

处理 PTU I131 治 优甲乐 建议 疗后 50µg/d TRH Test

2 0 1 0

FT3

B

C

D

E

F

A

B

C

D

E

F 83.7mU/L

G

1 5

A

1 0 5

uTSH

G

3 0 5 0.1

0.09 A

B

C

D

E

F

G

 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. 2. 3. 4. 5.

Pituitary TSHoma TH insensitivity syndrome Para-carcinoma syndrome HCG-related hyperthyroidism 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

TSH

TRH T3 TSH

T3,T4

I Normal Feedback

I

T3,T4

TSHR-Ab

Graves’ Disease

GRAVES DISEASE (GD) I. II. III. IV. V. VI. VII.

Pathogenesis Histopathology Clinical presentation Laboratory and special exams Diagnosis and differential diagnosis Treatment 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) 4. TRAb

stimulating IgG hyperfunction(TSAb) 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 lymphocy

C. Skin (dermopathy)

1. hyaluronic acid, chondroitin sulfates 2. featured by separated collagen fiber 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 上睑肌使其张力增高

良性突眼 （非浸润性突眼） （单纯性突眼）

球后组织增生，淋巴细胞 浸润，眼肌水肿增粗

恶性突眼 （浸润性突眼） (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 0 1 2 3 4 5 6

Definition

No physical signs or symptoms Only signs, no symptoms (signs limited to upper lid retraction, stare, lid lag, and proptosis to 22mm) Soft tissue involvement (symptom and sign) Proptosis>22mm Extraocular muscle involvement Corneal involvement 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.

131

I uptake/T3 suppression test

E. Pathological exams

Normal

multinodular

Graves disease

Adenoma

冷结节

甲状腺外肿块

Graves disease

manifestation

suppressed TSH

And/or high T4/T3

Hyperthyroidism

Etiology diagnosis

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, 131 I 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

% 100 90 80 70 60 50 40 30 20 10 0

hyperthyroidism

normal

hypothyroidism 2

4

6

RAIU

24

H

40

%

Graves 病接受 I131 治疗的分 布 女 (308)

30

男 (81)

20 10 20

30

40

50

60

70

80

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 after131 I therapy and operation

（ Frantlyn et al.)

40

%

Graves 病接受 I131 治疗的分 布 女 (308)

30

男 (81)

20 10 20

30

40

50

60

70

80

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 decisionmaking 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. LT4 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

4 3 0 0

FT4

甲低

甲低

处理 PTU I131 治 优甲乐 建议 疗后 50µg/d TRH Test

2 0 1 0

FT3

B

C

D

E

F

A

B

C

D

E

F 83.7mU/L

G

1 5

A

1 0 5

uTSH

G

3 0 5 0.1

0.09 A

B

C

D

E

F

G

 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!