The department of Endocrinology and metabolismHuashan Hospital, Fudan University

Dr. Hongying Yedryehongying@hotmail.com

Main contents

Basic knowledge of thyroid

Overview of thyroid diseases

Hyperthyroidism/Graves’ disease

Other causes of thyroitoxicosis

Hypothyroidism

Thyroid nodule

Case discussion

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)

Produced from pituitary Regulates thyroid hormone production, secretion, and

growththe sodium-iodide symporter (NIS)thyroglobulin (Tg)thyroperoxidase (TPO)

Is regulated by the negative feedback action of T4 and T3

Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism

Regulation of thyroid function

HPT axon

Wollf –chaikoff effect

others

Biosynthesis of T4 and T3

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

thyroid hormone synthesis

Structures of thyroid hormones

CHARACTERISTICS OF CIRCULATING T4 AND T3

Sites of T4 Conversion: liver, kidney, and other tissue

Carriers for Circulating Thyroid Hormones >99% of circulating T4 and T3 is bound to plasma

carrier proteins Thyroxine-binding globulin (TBG) 75% Transthyretin (TTR), also called thyroxine-binding

prealbumin (TBPA) 10%-15% Albumin 7% High-density lipoproteins (HDL) 3%

Carrier proteins can be affected by physiologic changes,

drugs, and disease

Free Hormone ConceptOnly unbound (free) hormone has metabolic activity

and physiologic effects

Free hormone is a tiny percentage of total hormone in

plasma (about 0.03% T4; 0.3% T3)

Total hormone concentration

Normally is kept proportional to the concentration of carrier

proteins

Is kept appropriate to maintain a constant free hormone level

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 Oral contraceptives and

other sources of estrogen Methadone Clofibrate 5-Fluorouracil Heroin Tamoxifen

Conditions that increase TBG Pregnancy Infectious/chronic active

hepatitis HIV infection Biliary cirrhosis 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 serum T4 and T3 Glucocorticoids Androgens L-Asparaginase Salicylates Mefenamic acid Antiseizure medications, eg,

phenytoin, carbama-zepine Furosemide

Conditions that decrease serum T4 and T3

Genetic factors Acute and chronic illness

Thyroid Hormone Action

nuclear thyroid hormone receptors (TRs)

Isoform: α and ß tissue specific different function

α : brain, kidney, gonads, muscle, and heart

ß : pituitary and liver (feedback control)

T3 is bound with 10 to 15 times greater affinity than T4

Mechanism of thyroid hormone receptor action

Physiological function of thyroid hormone initiates or sustains differentiation and growth

essential for neural development and maturation and function of

the CNS

Influences Cardiovascular Hemodynamics

important for reproductive function

an important regulator of skeletal maturation at the growth plate

the major regulator of mitochondrial activity

Stimulate Metabolic Activities in Most Tissues

Calorigenic effects

Evaluation of thyroid disorders Clinical evaluation

Physical Examination

Laboratory Evaluation

Measurement of Thyroid Hormones

Tests to Determine The Etiology of Thyroid Dysfunction

Thyroid Ultrasound

Radioiodine Uptake And Thyroid Scanning

Physical Evaluation of the Thyroid Gland

Thyroid examination

Others :

eyes, skin, blood pressure, heart rate,

……

Thyroid examination

Laboratory Assessment of Thyroid Status

Measurement of Thyroid Hormones

Tests to Determine The Etiology of Thyroid Dysfunction

Thyroid Ultrasound

Radioiodine Uptake

Thyroid Scanning

fine-needle aspiration (FNA) biopsy

Measurement of Thyroid Hormones

TSH:

TT3 , TT4

FT3 , FT4

TSH:marker of primary thyroid disease

exceptions

pituitary diseases

Euthyroid sick syndrome

Medicines:

pregnancy

TT3 TT4/FT3 FT4

The direct measurement of thyroid hormone

FT3 FT4 ↑ : Thyroitoxicosis

exceptions: thyroid hormone resistance(rarely)

FT3 FT4 ↓ : hypothyroidism

exceptions: sick euthyroid syndrome, medicines

(common)

Tests to Determine The Etiology of Thyroid---autoimmune

TPOAb

TSH-R Ab (TRAb): TbAB, Ts Ab

TGAb

Antithyroid AutoantibodiesAntigen Abbreviation Notes

TSH-R TSAb(TSI) Antibody that causes Graves' disease

TBAb Present in some thyroiditis patients

Thyroglobulin TgAb Often undetectable using older techniques

Thyroid peroxidase

TPOAb Useful diagnostic marker

NIS NIS-Ab Decrease iodine uptake

radioactive iodine uptake

Thyroid scanning

Thyroid Ultrasound Structure of the thyroid

Detect and monitor f nodules and cysts( >3 mm)

guide FNA biopsies and the aspiration of cystic lesions

diffuse change: chronic thyroiditis

Function ?

superior thyroid artery

Ultrasound scan

Evaluation of thyroid

Function: hyper, hypo /euthyroidism?

Primary or secondary? /Any structural abnormality?

Cause?/ mlignant or benign?

Overview of thyroid disorders

Dysfunction

hyperthyroidism

hypothyroidism

Abnormal structure

Goiter

thyroid nodule(adenoma/carcinoma)

diffuse change shown in the ultrasound scan: inflamation

Hyperthyroidism

Two definations

Hyperthyroidism: excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues

Thyrotoxicosis : defined as the state of thyroid hormone excess not synonymous with hyperthyroidism

TSHoma

Hyperthyroidism Production and secreation↑

ectopicTSH

thyroitoxicosisSerum T3/T4 ↑

Factitiousthyroitoxicosis

release ↑but production↓

InflammationSubacute thyroiditis

Hashimoto postpartum

Thyroid disease Ectopicsecretion

Graves’ diseasetoxic multinodular goiter toxic adenomaiodine excess……

Causes of thyrotoxicosis

SIGNS AND SYMPTOMS OF THYROTOXICOSIS

Graves’ disease--overview accounts for 60% to 80% of thyrotoxicosis

More common in women

Pathogenesis:

genetic factors and environmental factors

Autoimmune thyroid disease: TRAb

spontaneous autoimmune hypothyroidism may develop

in up to 15% of Graves’ patients

Graves disease—symptoms and signs

Clinical manifestation of thyroitoxicosis

goiter

special signs of Graves disease

thyroid ophthalmopathy ~10%

thyroid dermopathy <5%

thyroid acropachy <1%

Graves’ disease--specific signs

Goiterophthalmopathydermopathy

Mechanism

TSH Receptor highly expressed on:

thyroid follicular cells

orbital

the lateral aspects of the shins

Antibody of TSH receptor

Graves’ ophthalmopathy 10% of Graves disease

infiltration of activated T cells;

fibroblast activation

increased synthesis of glycosaminoglycans

characteristic muscle swelling,

fibrosis

Clinical manifestation GO a sensation of grittiness, eye discomfort, and excess tearing

proptosis, corneal exposure and damage

Periorbital edema

scleral injection

chemosis

diplopia

compression of the optic nerve

Lid retraction: sign of thyroitoxicosis!

Graves’ ophthalmopathy(GO)

CT scan images of GO

Lab thyroid function test

FT3 FT4 T4 T4 TSH

Thyroid antibody:

TRAb, TPOAb

Thyroid ultrasound scan

Radioiodine Uptake

Thyroid Scanning

Diagnosis of hyperthyroidism

Clinical manifestation of thyroitoxicosis

FT3 FT4 ↑

Thyroid ultrasound scan:

increased vascular signal ,PSV ↑

Radioiodine Uptake , Thyroid Scanning ↑

diffuse and high uptake

Differential diagnosis—other causes of thyroitoxicosis

Key point:

FT3 FT4 ↑along with radioactive uptake ↓

★exception: iodine excess

Common diseases:

Subacute thyroiditis

Hashimoto thyroitoxicosis

silent thyroiditis:

postpartum thyroiditis

The most important

Diagnosis of Graves’ disease

Based on the diagnosis of hyperthyroidism

with

Special signs

TRAb + (~80%)

Exclude other causes of hyperthyroidism

Differential diagnosis

toxic multinodular goiter

toxic adenoma:

ultrasound: nodule

Thyroid Radioiodine Scanning: hot nodule

iodine excess: history of iodine intake

radioactive iodine uptake↓

TSHoma: TSH ↑, pituitary adenome shown by MRI scan

Treatment for Hyperthyroidism of Graves’ Disease

Antithyroid drugs(ATD) : thionamides

reduce the thyroid hormone synthesis

radioiodine (131I) treatment :

reduce the amount of thyroid tissue

subtotal thyroidectomy :

reduce the amount of thyroid tissue

ATD : thionamides Propylthiouracil(PTU), carbimazole

methimazole(the active metabolite of carbimazole)

Mechanisms:

Inhibit the function of TPO

reduce oxidation and organification of iodide

reduce thyroid antibody levels (unclear mechanisms )

PTU inhibits deiodination of T4 : T3

Methimazole is perfered except pregancy, thyroid storm

ATD--- titration regimen Starting dose: (6~8W)

PTU 150mg~300mg/d q6h~q8h

methimazole 15mg~30mg/d q8h~qd

Reducing dose: gradually

Maintenance dose (~one year)

PTU 25mg~75mg/d qd~q12h

methimazole 2.5mg~7.5mg/d qqd

ATD-- block-replace regimen

high doses ATD combined with levothyroxine

supplementation

Benefits?

ATD: common side effects

Allergy : rash, urticaria

Hepatitis

Agranulocytosis(<1%)

Arthralgia, an SLE like syndrome

PTU associated vasculitis

Check hepatic function and Blood routine test before ATD therapy

ATDAdvantages Disadvantages

Effective Hypothyroidism, transient First choice in Asia and

Europon First choice for pregnant or

breastfeeding women

1.5~2ys’ regimen Possible side effect Frequent blood test hypothyroidism Relapse rate: 50%

131I treatment Mechanism: progressive destruction of thyroid cells

Dose:

fixed dose or optimal dose calculated ?

Effective, Simple and Cheap

the initial treatment in USA

High risk of hypothyroidism

Special precaution:

avoid close, prolonged contact with children and pregnant women

radiation thyroiditis

Subtotal thyroidectomy Special preparation before operation:

control of thyrotoxicosis with ATDfollowed by potassium iodide (3 drops SSKI orally tid)

effective Risk of Recurrence or Hypothyroidism major complications:

bleeding, laryngeal edema, hypoparathyroidism, and damage to the recurrent laryngeal nerves

Good choice for GD patients with severe Goiter or nodules suspected to be malignant

Management of Thyrotoxic crisis intensive monitoring

supportive care

identification and treatment of the precipitating cause:

acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis),

thyroid surgery without good preparation

radioiodine treatment

PTU: large dose (600-mg loading dose and 200 ~ 300 mg Q 6 h)

stable iodide (5 drops SSKI every 6 h) 1h after PTU

Propranolol, Glucocorticoids

Other causes of thyroitoxicosis

Subacute thyroiditis de Quervain’s thyroiditis/ granulomatous thyroiditis/

viral thyroiditis

Malaise and symptoms of an upper respiratory tract

infection may precede the thyroid-related features by

several weeks

Pathophysiology:

a characteristic patchy inflammatory infiltrate

disruption of the thyroid follicles

multinucleated giant cells

Subacute thyroiditis-clinical manifestation

Pt complains of a sore throat, fatigue

a painful and enlarged thyroid

(pain referred to the jaw or ear)

Fever

features of thyrotoxicosis or hypothyroidism

depending on the phase of the illness

Clinical course of subacute thyroiditis

Diagnosis of subacute thyroididtis Clinical manifestation:

fever, a painful and enlarged thyroid

features of thyrotoxicosis or hypothyroidism

ESR ↑ IL-6 ↑

Dysfunction of thyroid:

thyroitoxicosis/hypothyroidism

thyroid antibodies: negative

Radioactive iodine uptake: low

thyroid scan: low uptake

Treatment of subacute thyroiditis

nonsteroidal anti-inflammatory drugs(NSAID)

or Glucocorticoids:

20mg~40mg/d withdrawal gradually

β-adrenergic blockers

Hypothyroidism

Definition

Reduced production of thyroid hormone

Reduced action of thyroid hormone at the tissue level

(rare)

CAUSES OF HYPOTHYROIDISM

Special features in children with hypothyroidism

slow growth

delayed puberty

Myopathy

precocious puberty

pituitary enlargement

Diagnosis of hypothyroidism First step: confirm the diagnosis of hypothyroidism

clinical manifestation

blood test of TSH, T3,FT3,T4,FT4

Second step: try to found out the cause of hypothyroidism

medical and family history

thyroid antibodies : TPOAb, TGAb,TRAb

thyroid ultrasound scan

pituitary MRI

Differential Diagnosis

Secondary hypothyroidism

(Hypopituitarism, Hypothalamic disease)

Sick Euthyroid Syndrome

Differential DiagnosisSecondary hypothyroidism Sick Euthyroid Syndrome

TSH levels may be low, normal, or even slightly increased

FT4↓ FT3- or FT4↓ ↓ FT3 ↓decreased reverse T3

other anterior pituitary hormone deficiencies

Pituitary or hypothalamus lesion

Treatment with thyroid hormone

TSH levels may be low, normal, or even slightly increased

FT3↓ FT4-( low T3 syndrome)or FT3↓ ↓ FT4 ↓(low T4 syndrome)increased reverse T3

Any acute, severe illness The magnitude of the fall in T3

correlates with the severity of the illness

Treatment with thyroid hormone (T4 and/or T3) is controversial

Treatment of hypothyroidism--Replacement of thyroid hormone

Medicines：levothyroxine (LT4) (t1/2: 7days)

combination pill of T3 and T4

Dose: start from a low dose: LT4 25ug ~50qd

increase slowly: LT4 25ug/time

monitor TSH FT3 FT4 after fixed dose for 6weeks

adjusted according to TSH(FT3 and FT4)

Replacement of thyroid hormone factors affecting dose:

the deficiency degree of thyroid hormone

body weight

Target:

primary hypothyroidism: normal TSH

secondary hypothyroidism:

FT4 in the upper half of the reference range

Hypothyroidism and pregnancy-1 Patient education: important

Euthyroid(TSH<2.5) : necessary

prior to conception

during pregnancy

TFT monitor:

once pregnancy is confirmed

every 4 weeks during the first half of pregnancy

checked at least once between 26 and 32 weeks gestation

Hypothyroidism and pregnancy-2 Dose of LT4: may need to be increased by 30%~50%

TSH Target :Trimester-specific reference ranges

first trimester 0.1–2.5 mIU/L

second trimester 0.2–3.0 mIU/L

third trimester 0.3–3.0 mIU/L

Following delivery:

LT4 reduced to the patient’s preconception dose

monitor TSH: 6 weeks postpartum

Breastfeeding : safe

subclinical hypothyroidism(primary) Definition:

biochemical evidence of thyroid hormone

no apparent clinical features of hypothyroidism

TSH↑ but <10mIU/L; FT4/T4 normal

risk of progression to overt hypothyroidism especially

with positive TPOAb

Indication of LT4 therapy: pregnancy, goiter

Target: normal TSH

Monitor: necessary

Thyroid nodules

Thyroid nodules

common clinical problem:

palpable thyroid nodules to be ~ 5% in women and 1% in men

19%–67% of individuals with ultrasound scan

higher frequencies in women and the elderly

solitary or multiple/functional or nonfunctional

Key point: exclude thyroid cancer that occurs in 5%~10%

Further evaluation:

ultrasound scan; thyoid scan; FNA

hormone and antibodies test

MRI and CT are not indicated for routine thyroid nodule evaluation

Algorithm for the evaluation of patients thyroid nodules

Thyroid sonography performed in all patients with one or more suspected

thyroid nodules

Features associated with malignancy:

hypoechoic pattern and/or irregular margins

a more-tall-than-wide shape

microcalcifications

chaotic intranodular vascular spots

Sensitivity and Specificity: ~80% in Huashan

Typical images of thyroid nodules

FNA

the most accurate and cost effective method for

evaluating thyroid nodules

US guidance:

impalpable nodules

MNGs

in obese patients and in men with well-developed cervical

muscles

FNA

indications for FNA

>1.0 cm, solid and hypoechoic on US

Of any size with US findings suggestive of extracapsular growth or metastatic

cervical lymph nodes

Of any size with patient history of neck irradiation in childhood or adolescence;

PTC, MTC, or MEN 2 in first-degree relatives; previous thyroid surgery for

cancer; increased calcitonin levels in the absence of interfering factors

<10 mm along with US findings associated with malignancy ( 2 or more features)

Cytologic Diagnosis Thyroid smears or liquid-based cytology should be

reviewed by a cytopathologist with a special interest in

thyroid disease

5 classes of diagnosis:Nondiagnostic

Benign

Follicular lesions

Suspicious

Malignant

Thyroiditis

classification of thyroiditis

Acute thyroiditis Rare

due to suppurative infection of the thyroid

the most common cause is the presence of a piriform

sinus: predominantly left sided

thyroid pain(often referred to the throat or ears )

a small, tender goiter that may be asymmetric

Fever, dysphagia, and erythema over the thyroid

a febrile illness and lymphadenopathy

Evaluation of Acute thyroiditis

ESR and WBC ↑

thyroid function is normal

FNA biopsy: infiltration by polymorphonuclear

leukocytes; culture of the sample can identify the

organism

US: ?

Therapy of Acute thyroiditis

Antibiotics

Surgery may be needed to drain an abscess

Complications:

Tracheal obstruction, septicemia, retropharyngeal

abscess, mediastinitis, and jugular venous thrombosis

Subacute thyroiditis

Hashimoto’s thyroiditis(HT)

Hashimoto’s thyroiditis

Most common cause for hypothyroidism in iodine

sufficient area

Etiology:

genetic factors: HLADR and CTLA-4 polymorphisms

environmental factors: poorly defined

Markers of thyroid autoimmune

TPOAb

TGAb

TSH-R Ab: TBAb

related to the atrophic form of Hashimoto’s disease

Pathogenesis of HT

marked lymphocytic infiltration :

activated CD4 and CD8T cells, as well as B cells

germinal center formation

atrophy of the thyroid follicles accompanied by

oxyphil metaplasia

absence of colloid

mild to moderate fibrosis

Manifestation of HT

Goiter with or without nodules

Thyroid function:

euthyroidism

hypothyroidism

thyroitoxicosis

Therapy of HT

Replacement therapy with LT4 when hypothyroidism

Selenium: ↓TPOAb level

no evidence for its effect on preventing hypothyroidism

Case 1 Miss Wang, 24y

Presented with fatigue, sweating, weight loss(4kg),

palpitation for 2 months

PE: goiter II° ; eye sign-;HR 108bpm; tremor +

TFT: TSH↓ FT3 ↑ ↑ FT4↑ ↑

Thyroid antibody: TPOAb + TRAb+

Ultrasound scan:

Goiter and increased vascular supply

What’s your diagnosis?Any further examination?

Case 2 Miss Wang, 24y

Presented with fatigue, sweating, weight loss(1kg),

palpitation for 1 months

PE: goiter II° ; eye sign-;HR 108bpm; tremor +

TFT: TSH↓ FT3 ↑ FT4↑

Thyroid antibody: TPOAb + TRAb-

Ultrasound scan:

Goiter and diffuse change

What’s your diagnosis?Any further examination?

Case 3 Miss Wang, 24y

Goiter noted for 1 week

PE: goiter II° ; eye sign-;HR 68bpm

TFT: TSH ↑ FT3- FT4↓Thyroid antibody: TPOAb + TRAb-Ultrasound scan: Goiter and diffuse change

several nodules

What’s your diagnosis and suggestion?