內(nèi)科學(xué)英文課件：Hyperthyroidism 甲狀腺功能亢進(jìn)癥

1、Hyperthyroidism甲狀腺功能亢進(jìn)癥Department of Endocrinology and Metabolism diseases, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University,General Introduction of Thyroid,Follicles: the Functional Units of the Thyroid Gland,Regulation of thyroid hormone secretion,Regulation of thyroid hormone se

2、cretion,TRHTSH. (Cold, Emotions) TSHTH. TRH/TSH Stimulating test THTSH (Negative feedback,Stimulate Inhibit,Hyperthyroidism（甲亢） is defined as anoveractive thyroid gland, which produces and secretes excessive amounts of thyroid hormones-triiodothyronine (T3) and thyroxine (T4,Hyperthyroidism（甲亢） is d

3、efined as anoveractive thyroid gland, which produces and secretes excessive amounts of thyroid hormones-triiodothyronine (T3) and thyroxine (T4). Thyrotoxicosis (甲狀腺毒癥,Hyperthyroidism（甲亢） is defined as anoveractive thyroid gland, which produces and secretes excessive amounts of thyroid hormones-trii

4、odothyronine (T3) and thyroxine (T4). Thyrotoxicosis (甲狀腺毒癥） is clinical syndrome when tissues are exposed to excessive concentrations of thyroid hormones,Hyperthyroidism sustained overproduction and release of hormone by the thyroid itself Graves disease multiple nodular thyrotoxicosis(多結(jié)節(jié)性毒性甲狀腺腫）

5、plummer disease/toxic thyroid adenoma（自主功能性甲狀腺腺瘤） iodine-induced hyperthyroidism (碘甲亢) neonatal hyperthyroidism (新生兒甲亢) pituitary TSHoma (垂體TSH腺瘤) others (甲狀腺癌等,Etiology of thyrotoxicosis,Non-thyroid thyrotoxicosis not overproduction of thyroid hormones by thyroid subacute thyroiditis (亞急性甲狀腺炎) asym

6、ptomatic thyroiditis (無癥狀型甲狀腺炎) chronic lymphocytic thyroiditis (橋本甲狀腺炎) postpartum thyroiditis (產(chǎn)后甲狀腺炎 PPT) HCG related hyperthyroidism (HCG 相關(guān)性甲亢) Iatrogenic hyperthyroidism (醫(yī)源性甲狀腺激素替代) Ectopic goiter with hyperthyroidism (異位甲狀腺激素產(chǎn)生,Etiology of thyrotoxicosis,GRAVES DISEASE (GD,It is wrong to say

7、 Graves disease(Graves ?。゛s hyperthyroidism (甲亢） in brief,甲亢,GD,Hyperthyroidism,Thyrotoxicosis,Graves Disease,Graves disease (GD,pathogenesis histopathology clinical presentation laboratory and special exams diagnosis and differential diagnosis treatment,Outline of GD,Organ-specific autoimmune disea

8、se Diffuse toxic goiter Symptoms：thyroid enlargement，thyrotoxicosis，exophthalmos ( 突眼）， pretibial myxedema（脛前黏液性水腫） More commonly in women，F(xiàn)emale：Male= 4 6：1 Subclinical hyperthyroidism is usually referred to a GD state with normal T3T4, decreased TSH, and no clinical symptoms of hyperthyroidism,Pat

9、hogenesis,Abnormalities of immune system B cells produce TSH-R-Ab (TRAb) TRAb TSAb: stimulating IgG-hyperfunction-直接病因 TSBAb: inhibitory IgG-hypofunction and antagonist of TSAb TGI（thyroid growth immunoglobulins）: growth-stimulating IgG TSH-R + TRAb mimic the action of TSH-hyperfunction and goiter,H

10、ereditary (genetic factors) HLA-B8、DR3、DQA1*0501、HLA-Bw46 CTLA-4 GD-1, -2, and-3 Environment and Infection infective factors ( Yersinia enterocolitica ） stress (physical or emotional) Estrogen, pregnancy, childbirth,Pathogenesis,Histopathology,Thyroid goiter: symmetrical(對(duì)稱），diffuse (彌漫性） follicles:

11、 hyperplastic column with scant colloid（濾泡細(xì)胞增生肥大，呈柱狀、膠質(zhì)少）, papillary projections（乳頭樣突起） vascularity increased (血管增生） lymphocytes and plasma cells infiltration (淋巴細(xì)胞和漿細(xì)胞浸潤,The volume of orbital contents is enlarged because of increases in retrobulbar connective tissue and adipose tissue 眼球后脂肪和結(jié)締組織水腫、

12、浸潤、體積增大 The extraocular muscles are swollen, and some fibers exhibit loss of striation, fragmentation,and lymphocytic infiltration 眼外肌肌炎，淋巴細(xì)胞浸潤、肌纖維水腫、斷裂、壞死，眼外肌體積增大 眼肌增大及纖維化使眼肌自身的活動(dòng)障礙，引起復(fù)視。 眼瞼攣縮和眼球凸出共存，引起暴露性角膜炎。 球后組織增生，壓力增。高，壓迫視神經(jīng)引起視神經(jīng)病變。 眼眶炎癥及眶引流障礙，引起球結(jié)膜水腫和眶周水腫,Histopathology,Ophthalmopathy,Skin swe

13、lling Glycosaminoglycan accumulation in the skin and subcutaneous tissue, collagen fiber, connective tissue damage （粘蛋白沉積，膠原及結(jié)締組織損傷） Mast cells, macrophages and fibroblasts cells infiltration (肥大細(xì)胞，吞噬細(xì)胞和成纖維細(xì)胞浸潤,Histopathology,Pretibial myxedema（脛前黏液性水腫,Clinical Presentation,Symptoms and signs associ

14、ated with elevated levels of thyroid hormones Goiter Ophthalmopathy Special manifestations,High metabolism Nervous system Cardiovascular system Gastrointestinal system Hematopoietic system Gonadal system Muscles,Thyrotoxicosis,High metabolism,Dont Evade Feeling Hot And Sweaty Patients Weight loss (d

15、espite normal energy intake) Fatigues and weakness Heat intolerance and low fever Increased sweating Glucose intolerance,High metabolism,Nervous system,Nervous system,Nervousness Emotional lability Anxiety and irritability Difficulty sleeping Hyperactivity and unable to concentrate Tremor and muscle

16、 weakness Tendon reflexes hyperactivity Apathy,depression and withdrawn in older patients,Cardiovascular system,Cardiovascular system,Palpitation （心悸） Tachycardia (心動(dòng)過速 90bpm) Atrial fibrillation （房顫）and other atrial arrhythmias （室顫） Pulse pressure is increasing Accentuated heart sounds, systolic ej

17、ection or other murmurs （收縮期雜音,Gastrointestinal system,Gastrointestinal system,Increased appetite Hyperdefecation Steatorrhea (脂肪瀉） Jaundice （黃疸） Impaired of the liver function,Hematopoietic system,Hematopoietic system,Mild granulocytopenia（粒細(xì)胞減少） Iron or other hematopoietic nutrient deficiency anem

18、ia（貧血,Gonadal system（性腺,Gonadal system（性腺,Infrequent menstruation or suppressed menstruation Erectile dysfunction and occasionally loss of libido （性欲） Gynecomastia （男子乳腺發(fā)育,Muscle,Muscle,Muscle weakness Thyrotoxic myopathy （甲狀腺毒性肌?。?TPP-thyrotoxic periodic paralysis（甲亢性周期性癱瘓,Multiple system involveme

19、nt,Nervous system,肢端,Gonadal system,Cardiovascular system,Gastrointestinal system,Muscles,Skin appendages,Hematopoietic system,Endocrine system,Cardiovascular system,Gonadal system,Muscles,TPP-thyrotoxic periodic aralysis,Clinical Presentation,thyrotoxicosis (hypermetabolic state) nervousness (精神緊張

20、99%）, irritability（煩躁 90%）, palpitation（心慌 88%）, tachycardia（心動(dòng)過速 82%）,insomnia（失眠 60%）, fatigue（70%）, heat intolerance（70%）, excessive sweating（40%）, weight loss（75%）, with voracious appetite（食欲亢進(jìn) 65,Clinical Presentation,thyroid goiter（、）、nontender thrill with audible bruit( 震顫、血管雜音,Exophthalmos N

21、on-infiltrating exophthalmos,Clinical Presentation,mild proptosis, 18mm,Infiltrating exophthalmos(Graves ophthalmopathy) Symptoms: tearing , feeling sand in the eyes, photophobia(畏光）, diplopia（復(fù)視）, pain, Signs: severe protosis(18mm), visual acurity decrease（視力下降）, visual field defect（視野缺損）, corneal

22、ulceration（角膜潰瘍）, restriction of eye movement,Clinical Presentation,Exophthalmos,Probability of the development of orbitopathy in patients with Graves disease,Pretibial myxedema,Clinical Presentation,In the anterior tibial, dorsal foot 多見于脛前、足背 The skin is thick and hard, like orange peel 皮膚厚而硬，酷似橘皮

23、,thyroid storm hyperthyroid heart disease apathetic hyperthyroidism T3T4 type hyperthyroidism subclinical hyperthyroidism pregnancy hyperthyroidism,Special clinical manifestations,complications,Thyroid storm (thyrotoxic crisis,precipitating factors acute illness: infection, trauma(創(chuàng)傷), DKA surgery(e

24、specailly on the thyroid) radiation thyroiditis symptoms and signs exaggerated abruptly fever(39), sweating, vomiting, diarrhea and jaundice（黃疸） increased heart rate, arrhythmias（心律失常），congestive heart failure（充血性心衰），hypotension, shock restlessness(煩躁），delirium(譫妄）, seizures（抽搐）, apathy（淡漠）, stupor（

25、木僵）,coma（昏迷） Hyperthyroid crisis is a life threatening form,Hyperthyroid heart disease,features as heart enlargement arrhythmias heart failure other causes excluded disappeared after treatment,Apathetic hyperthyroidism,More common in older patients Insidious onset, high metabolic syndrome group, eye

26、 symptoms, goiter is not obvious Main presentations: weight loss, heart palpitations, fatigue, diarrhea, anorexia(厭食）, apathy（淡漠）, atrial fibrillation easily be misdiagnosed Diagnostic clues: sudden weight loss, new onset atrial fibrillation,T3T4 type hyperthyroidism,T3 hyperthyroidism Only 5% of hy

27、perthyroidism Ratio generating T3 and T4 disorders, T3 T4 commonly in iodine deficiency region and in the elderly population causes: GD, toxic nodular thyroid tumors and high-functioning adenomas Remission rate is higher than the typical hyperthyroidism T4 hyperthyroidism causes iodine-induced hyper

28、thyroidism hyperthyroidism with systemic disease (peripheral deiodinase activity reduced or lack,Subclinical hyperthyroidism,causes: GD, nodular goiter, thyroid adenoma and other high-functioning disease process: early stage or convalescence(恢復(fù)期） adverse outcomes Approximately 4-10% per year for the

29、 development of sub-clinical hyperthyroidism to hyperthyroidism Impact on the cardiovascular system Osteoporosis, fracture risk,Pregnancy hyperthyroidism,HCG related to hyperthyroidism Gestational transient hyperthyroidism (GTT) incidence: 2-3% increased HCG stimulates TSH receptor no proptosis, aut

30、oantibody(-), peaked at 3 months of pregnancy severe cases: can be short-term ATD therapy hyperthyroidism during pregnancy With diffuse goiter, exophthalmos, thyroid bruit or thrill, TRAB positive diagnosis: FT3, FT4 and TSH, not TT3/TT4 adverse consequences Mother: miscarriage, premature birth, pre

31、eclampsia（先兆子癇), placental abruption(胎盤早剝） Fetus: preterm(早產(chǎn)）, intrauterine growth retardation（宮內(nèi)生長遲緩） Fetal or neonatal（新生兒） hyperthyroidism,Laboratory and Special Exams,Serum TH and TSH TT3 and TT4, FT3 and FT4-increased FT3 and FT4 are the direct indexes(0.3% and 0.02%) TT3 and TT4 are influenced

32、 by concentration of TBG(99.7% and 99.98%) rT3-increased TSH-decreased TSH receptor antibodies-TRAb（+） 131I uptake -increased，peak appeared before Normal reference range: 3h: 5-25%, 24h: 20-45% Imaging examination ultrasonography emission computerized tomography(ECT,Diagnosis and Differential Diagno

33、sis,confirmed hyperthyroidism symptom weight loss, slight fever, diarrhea, tachycardia（心動(dòng)過速）, atrial fibrillation（房顫）, fatigue, with difficult in control of DM, heart failure, liver disease signs diffuse goiter, exophthalmos hormone abnormal FT3, FT4, TSH pathogenic diagnosis TRAb, TgAb(甲狀腺球蛋白抗體), T

34、POAb(甲狀腺過氧化物酶抗體) 131I uptake ultrasonography HCG,Different Diagnosis,TRAb Graves甲亢 T3,T4 synthesis Thyroiditis T3,T4 release,131I uptake,Treatment,General treatment ATD -reducing thyroid hormone synthesis Radioiodine treatment reducing the amount of thyroid tissue Operation,General managment,absolut

35、ely avoid iodine seafood, salt, tincture of iodine(碘酒), drugs such as Centrum(善存), amiodarone(胺碘酮) rest enough energy and nutrients supplement(protein and vB) sedatives(鎮(zhèn)靜劑) for restlessness and insomnia(失眠) beta blockers (propranolol) for tachycardia in the early stages before antithyroid drugs tak

36、e effect,Vaidya et al Clin Endocrinol 2008,ATD therapy is the first choice in Europe and Asia,Antithyroid drugs (ATD,agents methylthiouracil(MTU) or propylthiouracil(PTU) 300-600mg/d methimazole(MM) or carbimazole(CMZ) 30-60mg/d mechanism inhibit the function of TPO, reducing oxidation and organific

37、ation of iodide reduce thyroid antibody levels (mechanisms unclear) Inhibition of thyroid follicular epithelial cell function and growth PTU inhibits deiodination of T4 to T3 severe thyrotoxisis,Indications mild to moderate patients thyroid mild to moderate swelling young people (20 yrs) pregnant wo

38、men, the elderly patients not suitable for surgery or radioactive iodine treatment preparation before surgery or radioactive iodine therapy recurrence after surgery,Antithyroid drugs (ATD,dosage and course 1st stage (6 wks)： full dosage to control symptoms 2nd stage (4-8 wks): dosage decrease gradua

39、lly 3rd stage (1yr or more）：minimal dosage to maintain treated effects block-replace regimens TH added to prevention of hypothyroidism regulation of immune drug withdrawal goiter subsides TSH return to normal TSAb/TRAb negtive maximum remission rates are achieved by 18-24 months,Antithyroid drugs (A

40、TD,side effects Low dose of MMI rarely have side effects while PTU can cause it in any dose common: rash (皮疹）, urticaria（蕁麻疹）, fever, and arthralgia（關(guān)節(jié)痛）（1-5% of patients) hepatitis, an SLE-like syndrome Leukocytopenia (粒細(xì)胞減少）and agranulocytosis (粒細(xì)胞缺乏癥） （1%, within 2 months) can be caused by hypert

41、hyroidism itself, so take a blood routine before treatment Anti-Neutrophil Cytoplasmic Antibodies（ANCA） positive vasculities, Aplastic anemia (再生障礙性貧血） monitor blood counts and live function: wk or mo most of them were transient that neednt stop the treatment,Antithyroid drugs (ATD,Agranulocytosis (

42、粒細(xì)胞缺乏癥） The incidence rate is 0.2%-0.5%, the most severe side effect, both PTU and MMI can cause it normally happens within 3 months of treatment Sore throat, fever, infection etc. WBC 3 x 109 / L, neutrophil cells 1.5 x 109 /L should stop drug instantly, with broad-spectrum antibiotics, glucocortic

43、oid and colony cell stimulating factor (G-CSF) Glucocorticoid has no definite therapeutic effect, G-CSF should be the first choice,Antithyroid drugs (ATD,Compare MMI and PTU,Radioiodine,causes progressive destruction of thyroid cells be used as initial treatment or for relapses after antithyroid dru

44、gs The risk of thyrotoxic crisis can be avoided by pretreatment with antithyroid drugs for at least a month before treatment. Antithyroid drugs must be stopped 3 to 5 days before radioiodine administration to achieve optimum iodine uptake,Radioiodine,Indication 1. Moderate hyperthyroidism 2. Not app

45、ropriate for antithyroid drugs 3. Reccurence after operation 4. Have heart disease 5. WBC in low level 6. Old people 7. Toxic multinodular goiter,Contraindication 1. Pregnancy or lactation(哺乳） 2. Lower than 20 years 3. Severe heart、liver 、kidney dysfunction，active tuberculosis 4. Severe or active in

46、filtrating exophthalmos 5. Neutropenia（粒細(xì)胞減少） 6. Hyperthyroid crisis 7. failed to I uptake,Complications permanent hypothyroidism (40-70% 10yrs) radiation thyroiditis (7-10 days after treatment) thyrotoxic crisis exaggarated proptosis Its dosage should be calculated by specialist For serious conditi

47、on, it can use MMI control symptoms at first its inhibition of 131I uptake disappear after 24 hours (several weeks for PTU,Radioiodine,甲狀腺估重*（60120uCi） *100% 24小時(shí)攝碘率,131I治療前使用ATD藥物的效果,Prospective study of MMI resumption Bonnema S EJE 2003,Surgery,Indication Moderate or severe hyperthyroidism,not app

48、ropriate for antithyroid drugs Immense goiter accompanied by compressive symptoms Goiter behind sternum (胸骨） accompanied by hyperthyroidism Nodular goiter accompanied by hyperthyroidism Can not exclude thyroid carcinoma Children and pregnancy,Contraindication 1. Severe or rapid development of exopht

49、halmos 2. Accompanied by severe disease who can not tolerate operation 3. At early or late stage of pregnancy,Surgery,Preparation Take ATD and -block before operation careful control of thyrotoxicosis Take lugols solution avoid thyroid crisis reduce the vascularity of the gland Complication Nerve in

50、jury Permanent hypothyroidism Hypoparathyroidism,intensive monitoring and supportive care identificationg and treatment of the precipitating cause therapy for thyroid large dosed of PTU(600mg loading dose and 200-300mg/6hrs inhibitory acting on T4 to T3 conversion and thyroid hormone synthesis potas

51、sium iodide (5 drops/6h) one hour after the first dose of PTU block thyroid hormone release therapy for peripheral effects of thyroid hormone propranolol (40-60mg/4h,orally; 2mg/4h, intravenously) reduce tachycardia and other adrenergic manifestations glucocorticoids,Managment of thyrotoxic crisis,T

52、herapy for Ophthalmophthy,yes or no 1997年美國甲狀腺學(xué)會(huì)（ATA）的Graves眼病分級(jí)標(biāo)準(zhǔn) active or inactive 2008年GO歐洲研究組（EUGOGO）提出的判斷GO活動(dòng)的評(píng)分方法（clinical activity score,CAS） severity 2008年EUGOGO提出GO病情嚴(yán)重度評(píng)估標(biāo)準(zhǔn),Bartalena L, et al. Thyroid 2008, 8(3):333-347,Classification of Graves orbitopathy: NOSPECS,3-6 CAN BE DIAGNOSED GO

53、,Assessment of the activity of GO,Clinical Activity Score（CAS） Spontaneous retrobulbar(球后) pain Pain on eye movement Eyelid erythema(眼瞼發(fā)紅) Conjunctival injection(結(jié)膜充血) Chemosis(球結(jié)膜水腫) Swelling of the caruncle(眼阜腫脹) Eyelid edema(水腫) or fullness Each manifestation assigned 1 point， CAS3分為GO活動(dòng) The high

54、er CAS, the higher activity,Assessment of the severity of GO (UGOGO,中國人群的正常突眼度：18.6mm,ATA/AACE：甲亢處理指南 2010,角膜外露,Courtesy of Dr. Petros Perros,Management of nonsevere GO,LUIGI BARTALENA,ER 2000,Management of severe GO,Established methods: Glucocorticoids (Oral , Intravenous , Local) Supervoltage orbi

55、tal radiotherapy（超高壓眼眶放射治療） Rehabilitative（康復(fù)） surgery (Orbital decompression 眶減壓, Extraocular muscle surgery, Eyelid surgery) Novel treatments under investigation: Somatostatin Analogues（生長抑素類似物） Octreotide（奧曲肽） Lanreotide（蘭瑞肽） Intravenous immunoglobulins（免疫球蛋白） Nonestablished methods: Cyclosporine

56、a（環(huán)孢素） Plasmapheresis（血漿置換,LUIGI BARTALENA,ER 2000,GO患者,改善甲狀腺功能 力勸戒煙 ?？漆t(yī)院就診 局部檢查 鼓勵(lì)患者,輕度,中至重度,威脅視力,局部檢查 等待-觀察,康復(fù)手術(shù) (必要時(shí),穩(wěn)定無活動(dòng),有活動(dòng),無活動(dòng),糖皮質(zhì)激素治療 (+/- 眶放療,立即減壓手術(shù),療效欠佳 (1-2 周,仍有活動(dòng),病情進(jìn)展,穩(wěn)定無活動(dòng),穩(wěn)定無活動(dòng),康復(fù)手術(shù),康復(fù)手術(shù),糖皮質(zhì)激素治療,糖皮質(zhì)激素治療 (+/- 眶放療,Bartalena & EUGOGO, Thyroid & EJE 2008,Treatment of subclinical hyperthyroidism,If a sustained TSH suppression (0.1 mU/L)is established,then managment should be based on an individual program. For example, patients with 65yrs, symptoms, atrial fibrillation, unexplained weight loss, multinodular goiter, women with osteoporosis,