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The department of Endocrinology and metabolismHuashan Hospital, Fudan University
Dr. Hongying [email protected]
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?