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1、CLINICAL ENDOCRINOLOGY & METABOLISMINTRODUCTION AND GENERAL CONCEPTS(总论),Institute of Metabolism & Endocrinology,Eryuan Liao (廖二元),A. The rapidity and extensiveness of advances in endocrinology have made it increasingly difficult for the students and physicians to take full advantage of information
2、available for the understanding, diagnosis, and treatment of clinical disorders, not only of diseases in endocrinology, but also of that in all clinical specialties.,B. What easy to handle is that the general knowledge and the principles of endocrinology and metabolism.C. For interest, be interested
3、 in the interesting medical branch.D. Main subjects,Regulation systems of extracellular communicationEndocrine gland and hormone-secreting cellsHormonesHormone secretion rhythmsHormone synthases and its regulationEndocrine regulation axes,Mechanisms of hormone actionNutrient metabolismSystemic exami
4、nationLaboratory and special examinationsTherapeutic principles,Regulation Systems of Extra-Cellular Communication,nervous systemendocrine systemimmune system,Endocrine Gland and Hormone-Secreting Cells（激素分泌细胞）,A. Endocrine gland a. hypothalamus & posterior pituitary b. pineal gland (松果体) c. anterio
5、r and intermedial pituitary,d. thyroid e. parathyroid f. endocrine pancreas (内分泌胰腺) g. adrenal cortex and medulla h. sexual gland (testis or ovary) i. others: thymus (胸腺)，placenta,B. Diffuse neuro-endocrine cells APUD(amine precursor uptake and decarboxylation) cells in GI, pancreas, adrenal medulla
6、, etc.)C. Hormone-secreting cells in tissues atrium, endothelium, fibroblast, lipocytes, lymphocytes,Structure of hormone-secreting cells peptide/protein hormone-secreting cells: hormone-containing granules (激素颗粒) steroid hormone-secreting cells: lipid droplet (脂质小滴),A. Classification a. as peptide/
7、protein b. as derivatives of amino acid (catecholamine, 5-HT, melatonin, T3/T4) c. as derivates of cholesterol (cortisol, aldosterone, estrogen, androgen, progesterone, 1, 25-(OH)2D3)B. Storage hormone granules thyroglobulin (甲状腺球蛋白),Hormones,C. Types of hormone secretion,endocrine (内分泌)paracrine (旁
8、分泌)autocrine (自分泌)intracrine (胞内分泌)neurocrine (神经分泌)juxtacrine (并邻分泌)solinocrine (腔分泌)amphicrine (双重分泌),soluble hormone+binding protein: insulin, GH. IGF. Glucagon-like peptideinsoluble hormone+binding protein: T3, T4, sex steroids, cortisol, vitamin D.,D. Hormone transportation,half-life: peptides
9、and protein: minutes steroids: variable, hrs degradation in liver, kedney, other tissues, or in hormone-secreting cells.,E. Hormone degradation and half-life,A: Biological rhythms（生物节律） milliseconds: nerve impulse, membrane electrolytes. minutes: neurotransmitters hours: LH, TRH, testosterone, corti
10、sol, GH, prolactin, TSH, etc days: FSH peaks weeks: menorrhea months: T4, 1,25-(OH)2D3, pregnancy,Secretion Rhythms,B. Circadian rhythms (昼夜节律) biological “clock” in hypothalamus (melatonin), but lost in Cushing disease and psychosisC. 24-hr changes of serum and urine hormone (metabolic products),D.
11、 Heterogeneity of serum hormones hormone, pro-hormone (激素原), prepro-hormone (前激素原) monomer, dimer, trimer tetramer, etc. fragement of peptides.,A. Endocrine regulation active hormone molecule hormone-binding protein hormone receptor on membrane in cytoplasma in nucleolus (nucleoplasm) post-receptor
12、transduction (cascade reaction) tropic-hormone (促激素) feedback cycle target cell reaction,Hormone Synthases and Its Regulation,B. Paracrine/autocrine regulation exist almost in all tissues. “point-line” (点-线式) regulation network,A. Hormone regulationA: ultra-short feedback (超短反馈) B: short feedback (短
13、反馈)C: positive feedback (正反馈) D: long negative feedback (负反馈) : stimulating; : inhibitory,A,nerve impulses/cytokines,CNS,hypothalamus,pituitary gland,target gland,D,B,Endocrine Regulation Axes,B. Regulation axes (调节轴) a. hypothalamus-pituitary-thyroid (adrenal cortex, sexual gland) b. GIH/GHRH-GH/GH
14、BP-IGFs/IGFBPS- IGFBP/IGFBPase c. renin-AT-ALD involved in renin, AT, ALD, ANP, AVP, AM (adrenomedullin, 肾上腺髓质素),d. axis of endocrine pancreas-energy metabolism and body weight involved in insulin, glucagon, glucagon-like peptide-1, somatostatin, leptin, etc.e. PTH-CT-1,25-(OH)2D3 involved in PTH, C
15、T,1,25-(OH)2D3, serum Ca2+, Pi3-f. AVP-AVP receptor-AQP (aquaporin, 水孔蛋白) V1 receptor: related to regulation of BP V2 receptor: related to H2O reabsorption,A. Acted as transcription- regulatory factors steroid hormone bindin with receptor (cytoplasm or nucleoplasm) H-R complex+DNA binding domain gen
16、e expression protein,Mechanisms of Hormone Action,B. Acted at cell surface a. peptide hormone + membrane R postreceptor cascade reaction b. types of membrane RG-protein coupled receptor (transmenbrane 7 times) involved in PTH, AT, glucagon, LH, FSH, TSH, AVP, CT, HCG, etc.receptor kinases (transmemb
17、rane 1 time), with tyrosine kinase (activity), involved in insulin, IGF, EGF, etc.receptor-linked kinases, involved in GH, PRL, leptinreceptors of ligand-gated ion channels (transmembrane 4 or 6 times), involved in 5-HT, GABA, etc.,metabolism, anabolism and catabolismmetabolic diseases (related to e
18、nzymes, hormones, or ion channels, etc).macroelement and microelement (traced element)micronutrient (Fe, F, Zn, Cu, Mn, I, Cr, Co, etc)vitamins,Nutrient Metabolism,A. General concepts:,A. Symptom and signs a. body height (genetic factors, GH, TH, sex hormones, IGF-1, nutrition, systemic diseases) b.
19、 obesity and weigh loss (genetic constitution, nutrition, systemic disease, GH, TH, insulin, leptin, cortisol, sex hormones) c. polydipsia and polyuria (DM, ALD , hyperparathyroidism, DI),Systemic Examination,d. hypertension with hypokalemia (primary hyperaldosteronism, reninoma, Cushing syndrome) e
20、. hyperpigmentation (ACTH, MSH, estrogen, progesterone, androgen) f. hair loss or hypertrichosis (hairy, 多毛症) genetics, race, androgen. hypertrichosis: PCOS, congenital adrenal hyperplasia, Cushing disease, ovarian tumors, hypothyroidism, drugs.,hair loss: cortisol , androgen , g. gynecomastia (男性乳腺
21、发育): Klinefelter syndrome, testicular tumors, drugs.) h. exophthalmos (突眼)：Graves disease, chronic lymphocytic thyroiditis, eye diseases.) i. bone pain and fractures (osteoporosis, hyperparathyroidisim, bone or hematologic diseases),A. hormones and biomarkers (生化标志物) in serum and urine: hormones, el
22、ectrolytes, sugarB. hormone derivatives: VMA, 17-OHCS, 17-KS,Laboratory and Special Examinations,C. Dynemic tests (动态试验) stimulation test (兴奋试验)： hypofunction (hypocortisolism) inhibitory states (TSH in GD) suppression test (抑制试验)： hyperfunction (DXM for Cushing disease) therapeutic test (治疗试验): (sp
23、ironolactone treatment in suspected hyperaldosteronism),provocation test (glucagon test for diagnosis of pheochromocytoma)X-ray film (bone diseases, kedney stones)CT&MRI (morphologic changes)radionuclear tomography (thyroid, pancreas, adrenal cortex and medulla, parathyroid, etc)type B US (thyroid,
24、adrenal cortex, ovary, testis),A. Pathogenic therapy: supplement of nutrients, gene treatment.B. Hypofunction: 1. hormone replacement therapy (Addison disease, hypothyroidism; hypogonadism) 2. drugs to stimulate hormone secretion (sulfonylurea for type 2 DM) 3. transplantation (organ, tissue, cells)
25、,Therapeutic Principles,C. Hyperfunction 1. drugs to suppress hormone secretion (iodide for GD, spironolactone for hyperaldosteronism. SS for insulinoma) 2. radioactive therapy (131I for GD, - knife for pituitary tumors),HYPERTHYROIDISM (THYROTOXICOSIS, 甲亢),Hyperthyroidism is only a diagnosis of exc
26、essive thyroid hormone status, not a concrete disease or a syndrome.It is wrong to say “Graves disease (Graves病)” as “hyperthyroidism (甲亢)” in brief.,Thyroidal origin Graves disease multiple nodular thyrotoxicosis (多结节性毒性甲状腺肿)Plummer disease (toxic thyroid adenoma)automatic hyperfunctional thyroid n
27、odules (自主 功能性甲状腺结节)multiple autoimune endocrine syndrome with hyperthyroidism (多发性自身免疫性内分泌腺 病伴甲亢)thyroid carcinomasneonatal hyperthyroidismgenetic toxic thyroid hyperplasia/goiteriodine-induced hyperthyroidism (碘甲亢),Pathogenesis of Hyperthyroidism,Pituitary origin pituitary TSHoma thyroid hormone i
28、nsensitivity syndrome (pituitary type, 垂体型TH不敏感综合征) paracarcinoma syndrome HCG-related hyperthyroidism carcinomas (lung, GI, pancreas) with hyperthyroidism Ovarian goiter with hyperthyroidism Iatrogenic hyperthyroidism (医源性甲亢),Transient hyperthyroidismSubacute de Quervian thyroiditis (肉芽肿性甲状腺炎) hymp
29、hocytic thyroiditis (postpartum, IFN, IL, Li) trumatic thyroiditis radioactive thyroiditisChronic chronic lymphocytic thyroiditis,PathogenesisHistopathologyClinical presentationLaboratory and special examsDiagnosis and differential diagnosisTreatment,GRAVES DISEASE (GD),GD is also called: diffuse to
30、xic goiter Basedow diseaseSubclinical hyperthyroidism is usually referred to a GD state with (ab)normal T3,T4, decreased TSH, and no clinical symptoms of hyperthyroidism,Graves Disease (GD),A. Abnormalities of immune system a. TSH-R-Ab + TSH-R mimic the action of TSH hyperfunction and goiter. b. fun
31、ctioning of Ig Th hypersensitivity + IL-1, IL-2 B cells produce TSH-R-Ab (TRAb),Pathogenesis,stimulating IgG hyperfunction(TSAb) c. TRAbinhibitory IgG hypofunction and antagonistof TSHR andTSAb (TF1Ab, TGBAb)growth-stimulating IgG (TGI),B. Other factors genetic factors infective factors stress (phys
32、ical or emotional),C. Thyroid-associated ophthalmopathy (TAO) unknown GAG (葡萄聚糖) accumulation, T cell infiltration, edema, fibrosis and sight loss.,A. Thyroid goiter: symmetrical, diffuse, soft enlarged after treatment: lobular follicles: hyperplastic column with scant colloid, papillary projections
33、, vascularity increased lymphocytes and plasma cells infiltration,Histopathology,B. Eyes orbital contents increased, containing mucoprotein, GAG (glycosaminoglycan, 葡糖聚糖), lymphocytes.C. Skin (dermopathy) hyaluronic acid (透明质酸), chondroitin sulfates (硫酸软骨素) increased, collagen fibers separated nodul
34、ar and plaque formation lymphatic drainage decreased,A. General considerations male: female 1: 46, common in 3040yrs.B. Hypermetabolic states nervousness (99%). irritability (90%), palpatation (88%), tachycardia (82%), insomnia (60%), fatigue (70%), heat intolerance (70%), excessive sweating (40%),
35、weight loss (75%), with voracious appetite (65%), menstrual pattern changed (50%),Clinical Presentation,C. Thyroid diffuse goiter: absent in the elderly, consistency: soft, firm, rubbery, symmetrical enlarged, surface: smooth, lobular, thrill with audible bruit eyelid spasm or retraction,D. Eyes a.
36、non-infiltrative orbitopathy: fissure widened, sclera exposed, lid retraction, lid tremor, lid lay, globe lay.,b. infiltrative orbitopathy: excessive tearingexophthalmos (asymmetrical)eyelids unclosedblurred visiondouble visionvisual acuity decreasedcorneas ulcerated, infectedsight loss,c. Classific
37、ation of Graves orbitopathy: NOSPECS (from: American Thyroid Association)ClassDefinition0No physical signs or symptoms1Only signs, no symptoms (signs limited to upper lid retraction, stare, lid lag, and proptosis to 22mm)2Soft tissue involvement (symptom and sign)3Proptosis22mm4Extraocular muscle in
38、volvement5Corneal involvement6Sight loss (optic nerve involvement),E. Others tremor of the hands and tongue muscle wasting rapid reflex response diarrhea liver function wbc , and anemia, vitiligo (白癜风), hair loss pretibial myxedema (胫前粘液性水肿),F. Complications a. cardiopathy and heart failurethyrotoxi
39、cosis ,arrhythmia, heart enlargement and heart failure, and all disappeared after treatment b. Thyrotoxic crisissymptoms and signs exaggerated abruptlyprecipitating factors: infection, trauma, surgeryradiation thyroiditis, DKA, parturtionAdditional pictures: arrhythmias, pulmonary edema,congestive h
40、eart failure, restlessness, delirium,nausea, vomiting, abdominal pain, apathy, stupor,coma, hypotension, shock, etc.,c. hypokalemic periodic paralysismore common in Asiaabruptly paralysis with hypokalemiaprecipitated by dextrose, oral carbohydrateor vigorous exercise.attacks last 7-27 hrs.some compa
41、nied by myasthenia gravis.,A. Serum TH and TSH a. FT3 and FT4 b. TT3 and TT4 c. rT3 d. TSHB. TSH receptor antibodies,Laboratory and Special Exams,C. TRH stimulation testeuthyroid Graves ophthalmopathyGD medicationD. 131I uptake and T3 suppression testE. pathological exams,A. Functional diagnosis GD
42、suspected: (1)weight loss; (2)slight fever; (3)diarrhea; (4)tachycardia; (5)atrial fibrillation; (6)fatigue; (7)dysmenorrhea; (8)with difficult in control of DM, TB, heart failure, CHD, liver disease,Diagnosis and Differential Diagnosis,B. TypesFT3 、FT4 , sTSH (uTSH) : hyperthyroidismFT3(orTT3) , FT
43、4(TT4) normal, sTSH : T3 hyperthyroidism FT4(orTT4) , FT3 (TT3) normal, sTSH : T4 hyperthyroidismFT3 and FT4 (ab)normal, sTSH : subclinical hyperthyroidism,C. Pathogenic diagnosis TRAb, TgAb, TPOAb, HCG, 131I uptake, TSH,A. General management rest enough, energy and nutrients supplement, sedatives f
44、or restlessness and insomnia.B. Management of hyperthyroidism a. medical antithyroid agents: methylthiouracil (MTU) or propylthiouracil (PTU) 300600mg/d methimazole (MM) or carbimazole (CMZ) 3060mg/d,Treatment,b. dosage and course1st stage (ca.6 wks): full dosage to control symptoms2nd stage (ca. 48
45、wks): dosage decrease gradually 1/6 dosage/wk3rd stage (ca 1yr or more)PTU 50mg(or MM 5mg), Qd,c. “block-replace” regimensTH added to prevention of hypothyroidism. T4 50g, Qd.d. drug withdrawalgoiter subsidesminimal dosage to maintain treated effectsTSH return to normalTSAb negativenormal response t
46、o TRH,e. drug side-effectsprimary and secondary failureagranulocytosis (1%, within 2 mos)WBC count/ wk or mo,C. Radioiodine (131I) a. more active than before, more(USA) VS less (Euro) b. contraindications: pregnant thyrotoxicosis young people (20yrs) severe exophthalmos thyrotoxic crisis failed to I
47、 uptake dosage should be calculated by specialist,C. Complicationshypothyroidismradiation thyroiditisthyrotoxic crisisexaggarated proptosis (smoking),D. Surgery indications: failed to antithyroidal agent huge thyroid or suspected with tumors retrosternal goiter contraindications: severe proptosis se
48、vere systemic diseases early and late pregnancy thyrotoxicosis not controlled,E. Treatment decision-making a. firstly, treated with medications for all patients b. after controlled, decided byagerun course of diseaseseverity & complicationsthyroid statesdoctors experiencepatients willings and specia
49、l entities,F. Special concerns a. minimal iodide supplement, iodo-NaCl is not suitable for GD b. severe proptosis treated with caution, including TH supplement and prednisone c. thyroid crisis treated with NaI, PTU, DXM, and propranolol,d. PTU is the treatment of choice for hyperthyroidism in pregna
50、ncy, never makes TSH 0.5U/L e. heart failure treated with digoxin may be dangerous in some cases,高敏TSH检测在甲状腺功能诊断及监测中的意义,甲状腺功能异常是临床上常见的一组疾病。有研究表明，高敏TSH在甲状腺功能诊断方面最为敏感。1999年9月2000年11月在我科实验室所做的5100人次甲状腺功能检查，以了解三项检测指标在甲状腺功能诊断及监测中的意义。1 资料和方法1.1 实验对象我科临床诊断为甲亢的病人及甲亢服药复查的病人共4518份血标本。1.2 实验方法标本收集每次抽肘静脉血3ml，离心
