The department of Endocrinology and metabolism Huashan Hospital, Fudan University Dr. Hongying Ye

Transcription

1 The department of Endocrinology and metabolism Huashan Hospital, Fudan University Dr. Hongying Ye

2 Main contents Basic knowledge of thyroid Overview of thyroid diseases Hyperthyroidism/Graves disease Other causes of thyroitoxicosis Hypothyroidism Thyroid nodule Case discussion

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4 Anatomy of the Thyroid Gland

5 Follicles: the Functional Units of the Thyroid Gland Follicles Are the Sites Where Key Thyroid Elements Function: Thyroglobulin (Tg) Tyrosine Iodine Thyroxine (T 4 ) Triiodotyrosine (T 3 )

6 The Thyroid Produces and Secretes 2 Metabolic Hormones Two principal hormones Thyroxine (T 4 ) and triiodothyronine (T 3 ) Required for homeostasis of all cells Influence cell differentiation, growth, and metabolism Considered the major metabolic hormones because they target virtually every tissue

7 Thyroid-Stimulating Hormone (TSH) Produced from pituitary Regulates thyroid hormone production, secretion, and growth the sodium-iodide symporter (NIS) thyroglobulin (Tg) thyroperoxidase (TPO) Is regulated by the negative feedback action of T 4 and T 3

8 Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism

9 Regulation of thyroid function HPT axon Wollf chaikoff effect others

10 Biosynthesis of T 4 and T 3 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 T 4 and T 3 Proteolysis of Tg with release of T 4 and T 3 into the circulation

11 thyroid hormone synthesis

12 Structures of thyroid hormones

13 CHARACTERISTICS OF CIRCULATING T4 AND T3 Sites of T 4 Conversion: liver, kidney, and other tissue

14 Carriers for Circulating Thyroid Hormones >99% of circulating T 4 and T 3 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

15 Free Hormone Concept Only unbound (free) hormone has metabolic activity and physiologic effects Free hormone is a tiny percentage of total hormone in plasma (about 0.03% T 4 ; 0.3% T 3 ) Total hormone concentration Normally is kept proportional to the concentration of carrier proteins Is kept appropriate to maintain a constant free hormone level

16 Changes in TBG Concentration Determine Binding and Influence T 4 and T 3 Levels Increased TBG Total serum T 4 and T 3 levels increase Free T 4 (FT 4 ), and free T 3 (FT 3 ) concentrations remain unchanged Decreased TBG Total serum T 4 and T 3 levels decrease FT 4 and FT 3 levels remain unchanged

17 Drugs and Conditions That Increase Serum T 4 and T 3 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

18 Drugs and Conditions That Decrease Serum T 4 and T 3 by Decreasing TBG Levels or Binding of Hormone to TBG Drugs that decrease serum T 4 and T 3 Glucocorticoids Androgens L-Asparaginase Salicylates Mefenamic acid Antiseizure medications, eg, phenytoin, carbama-zepine Furosemide Conditions that decrease serum T 4 and T 3 Genetic factors Acute and chronic illness

19 Thyroid Hormone Action

20 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) T 3 is bound with 10 to 15 times greater affinity than T 4

21 Mechanism of thyroid hormone receptor action

22 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

23 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

24 Physical Evaluation of the Thyroid Gland Thyroid examination Others : eyes, skin, blood pressure, heart rate,

25 Thyroid examination

26 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

27 Measurement of Thyroid Hormones TSH: TT3, TT4 FT3, FT4

28 TSH: marker of primary thyroid disease

29 exceptions pituitary diseases Euthyroid sick syndrome Medicines: pregnancy

30 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)

31 Tests to Determine The Etiology of Thyroid---autoimmune TPOAb TSH-R Ab (TRAb): TbAB, Ts Ab TGAb

32 Antithyroid Autoantibodies Antigen 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

33 radioactive iodine uptake

34 Thyroid scanning

35 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

36 Ultrasound scan

37 Evaluation of thyroid Function: hyper, hypo /euthyroidism? Primary or secondary? /Any structural abnormality? Cause?/ mlignant or benign?

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39 Overview of thyroid disorders Dysfunction hyperthyroidism hypothyroidism Abnormal structure Goiter thyroid nodule(adenoma/carcinoma) diffuse change shown in the ultrasound scan: inflamation

40 Hyperthyroidism

41 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

42 Graves disease toxic multinodular goiter toxic adenoma iodine excess ectopictsh TSHoma Thyroid disease Ectopic secretion Inflammation Subacute thyroiditis Hashimoto postpartum Hyperthyroidism Production and secreation release but production thyroitoxicosis Serum T3/T4 Factitious thyroitoxicosis

43 Causes of thyrotoxicosis

44 SIGNS AND SYMPTOMS OF THYROTOXICOSIS

45 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

46 Graves disease symptoms and signs Clinical manifestation of thyroitoxicosis goiter special signs of Graves disease thyroid ophthalmopathy ~10% thyroid dermopathy <5% thyroid acropachy <1%

47 Graves disease--specific signs Goiter ophthalmopathy dermopathy

48 Mechanism TSH Receptor highly expressed on: thyroid follicular cells orbital the lateral aspects of the shins Antibody of TSH receptor

49 Graves ophthalmopathy 10% of Graves disease infiltration of activated T cells; fibroblast activation increased synthesis of glycosaminoglycans characteristic muscle swelling, fibrosis

50 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!

51 Graves ophthalmopathy(go)

52 CT scan images of GO

53 Lab thyroid function test FT3 FT4 T4 T4 TSH Thyroid antibody: TRAb, TPOAb Thyroid ultrasound scan Radioiodine Uptake Thyroid Scanning

54 Diagnosis of hyperthyroidism Clinical manifestation of thyroitoxicosis FT3 FT4 Thyroid ultrasound scan: increased vascular signal,psv Radioiodine Uptake, Thyroid Scanning diffuse and high uptake

55 Differential diagnosis other causes of thyroitoxicosis Key point: The most important FT3 FT4 along with radioactive uptake exception: iodine excess Common diseases: Subacute thyroiditis Hashimoto thyroitoxicosis silent thyroiditis: postpartum thyroiditis

56 Diagnosis of Graves disease Based on the diagnosis of hyperthyroidism with Special signs TRAb + (~80%) Exclude other causes of hyperthyroidism

57 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

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59 Treatment for Hyperthyroidism of Graves Disease Antithyroid drugs(atd) : thionamides reduce the thyroid hormone synthesis radioiodine ( 131 I) treatment : reduce the amount of thyroid tissue subtotal thyroidectomy : reduce the amount of thyroid tissue

60 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

61 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

62 ATD-- block-replace regimen high doses ATD combined with levothyroxine supplementation Benefits?

63 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

64 ATD Advantages Effective Hypothyroidism, transient First choice in Asia and Europon First choice for pregnant or breastfeeding women Disadvantages 1.5~2ys regimen Possible side effect Frequent blood test hypothyroidism Relapse rate: 50%

65 131 I 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

66 Subtotal thyroidectomy Special preparation before operation: control of thyrotoxicosis with ATD followed 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

67 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

68 Other causes of thyroitoxicosis

69 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

70 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

71 Clinical course of subacute thyroiditis

72 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

73 Treatment of subacute thyroiditis nonsteroidal anti-inflammatory drugs(nsaid) or Glucocorticoids: 20mg~40mg/d withdrawal gradually β-adrenergic blockers

74 Hypothyroidism

75 Definition Reduced production of thyroid hormone Reduced action of thyroid hormone at the tissue level (rare)

76 CAUSES OF HYPOTHYROIDISM

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79 Special features in children with hypothyroidism slow growth delayed puberty Myopathy precocious puberty pituitary enlargement

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81 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

82 Differential Diagnosis Secondary hypothyroidism (Hypopituitarism, Hypothalamic disease) Sick Euthyroid Syndrome

83 Differential Diagnosis Secondary hypothyroidism 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 Sick Euthyroid Syndrome 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

84 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)

85 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

86 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

87 Hypothyroidism and pregnancy-2 Dose of LT4: may need to be increased by 30%~50% TSH Target :Trimester-specific reference ranges first trimester second trimester third trimester miu/l miu/l miu/l Following delivery: LT4 reduced to the patient s preconception dose monitor TSH: 6 weeks postpartum Breastfeeding : safe

88 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

89 Thyroid nodules

90 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

91 Algorithm for the evaluation of patients thyroid nodules

92 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

93 Typical images of thyroid nodules

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95 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

96 FNA

97 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)

98 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

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101 Thyroiditis

102 classification of thyroiditis

103 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

104 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:?

105 Therapy of Acute thyroiditis Antibiotics Surgery may be needed to drain an abscess Complications: Tracheal obstruction, septicemia, retropharyngeal abscess, mediastinitis, and jugular venous thrombosis

106 Subacute thyroiditis

107 Hashimoto s thyroiditis(ht)

108 Hashimoto s thyroiditis Most common cause for hypothyroidism in iodine sufficient area Etiology: genetic factors: HLADR and CTLA-4 polymorphisms environmental factors: poorly defined

109 Markers of thyroid autoimmune TPOAb TGAb TSH-R Ab: TBAb related to the atrophic form of Hashimoto s disease

110 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

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112 Manifestation of HT Goiter with or without nodules Thyroid function: euthyroidism hypothyroidism thyroitoxicosis

113 Therapy of HT Replacement therapy with LT4 when hypothyroidism Selenium: TPOAb level no evidence for its effect on preventing hypothyroidism

114 Case 1 Miss Wang, 24y What s your diagnosis? Any further examination? 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

115 Case 2 Miss Wang, 24y What s your diagnosis? Any further examination? 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

116 Case 3 Miss Wang, 24y Goiter noted for 1 week PE: goiter II ; eye sign-;hr 68bpm TFT: Thyroid antibody: Ultrasound scan: TSH FT3- FT4 TPOAb + TRAb- Goiter and diffuse change several nodules What s your diagnosis and suggestion?