内分泌疾病总论（英文版）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 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 in the interesting medical branch.D. Main subjectsI.Regulation systems of extracellular communicationII.Endocrine gland and hormone-secreting cellsIII.HormonesIV.Hormone secretion rhythmsV.Hormone synthases and its regulationVI.Endocrine regulation axesVII.Mechanisms of hormone actionVIII.Nutrient metabolismIX.Systemic examinationX.Laboratory and special examinationsXI.Therapeutic principlesI.Regulation Systems of Extra-Cellular Communicationnervous systemendocrine systemimmune systemII.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. anterior 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)，placentaB. Diffuse neuro-endocrine cells APUD(amine precursor uptake and decarboxylation) cells in GI, pancreas, adrenal medulla, etc.)C. Hormone-secreting cells in tissues atrium, endothelium, fibroblast, lipocytes, lymphocytesD. Structure of hormone-secreting cellsE. peptide/protein hormone-secreting cells:F. hormone-containing granules (激素颗粒) steroid hormone-secreting cells: lipid droplet (脂质小滴)A. Classification a. as peptide/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)III. HormonesC. Types of hormone secretionendocrine (内分泌)paracrine (旁分泌)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 transportationhalf-life: peptides and protein: minutes steroids: variable, hrs degradation in liver, kedney, other tissues, or in hormone-secreting cells.E. Hormone degradation and half-lifeA: Biological rhythms（生物节律） milliseconds: nerve impulse, membrane electrolytes. minutes: neurotransmitters hours: LH, TRH, testosterone, cortisol, GH, prolactin, TSH, etc days: FSH peaks weeks: menorrhea months: T4, 1,25-(OH)2D3, pregnancyIV. Secretion RhythmsB. 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. 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 transduction (cascade reaction) tropic-hormone (促激素) feedback cycle target cell reactionV.Hormone Synthases and Its RegulationB. Paracrine/autocrine regulation exist almost in all tissues. “point-line” (点-线式) regulation networkA. Hormone regulationA: ultra-short feedback (超短反馈) B: short feedback (短反馈)C: positive feedback (正反馈) D: long negative feedback (负反馈) : stimulating; : inhibitoryAnerve impulses/cytokinesCNShypothalamuspituitary glandtarget glandDBVI.Endocrine Regulation AxesB. Regulation axes (调节轴) a. hypothalamus-pituitary-thyroid (adrenal cortex, sexual gland) b. GIH/GHRH-GH/GHBP-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, CT,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 reabsorptionA. Acted as transcription- regulatory factors steroid hormone bindin with receptor (cytoplasm or nucleoplasm) H-R complex+DNA binding domain gene expression proteinVII. Mechanisms of Hormone ActionB. 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 (transmembrane 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.a.metabolism, anabolism and catabolismb.metabolic diseases (related to enzymes, hormones, or ion channels, etc).c.macroelement and microelement (traced element)d.micronutrient (Fe, F, Zn, Cu, Mn, I, Cr, Co, etc)e.vitaminsVIII. Nutrient MetabolismA. General concepts:A. Symptom and signs a. body height (genetic factors, GH, TH, sex hormones, IGF-1, nutrition, systemic diseases) b. obesity and weigh loss (genetic constitution, nutrition, systemic disease, GH, TH, insulin, leptin, cortisol, sex hormones) c. polydipsia and polyuria (DM, ALD , hyperparathyroidism, DI)IX. Systemic Examination d. hypertension with hypokalemia (primary hyperaldosteronism, reninoma, Cushing syndrome) e. 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, electrolytes, sugarB. hormone derivatives: VMA, 17-OHCS, 17-KSX.Laboratory and Special ExaminationsC. 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): (spironolactone 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, 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)XI. Therapeutic PrinciplesC. 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 HYPERTHYROIDISM (THYROTOXICOSIS, (THYROTOXICOSIS, 甲亢甲亢) )Hyperthyroidism is only a diagnosis of excessive 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多结节性毒性甲状腺肿)Plummer disease (toxic thyroid adenoma)automatic hyperfunctional thyroid nodules (自主自主 功能性甲状腺结节功能性甲状腺结节)multiple autoimune endocrine syndrome with hyperthyroidism (多发性自身免疫性内分泌腺多发性自身免疫性内分泌腺 病伴甲亢病伴甲亢)thyroid carcinomasneonatal hyperthyroidismgenetic toxic thyroid hyperplasia/goiteriodine-induced hyperthyroidism (碘甲亢碘甲亢)Pathogenesis of HyperthyroidismPituitary origin pituitary TSHoma thyroid hormone insensitivity 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) hymphocytic thyroiditis (postpartum, IFN, IL, Li) trumatic thyroiditis radioactive thyroiditisChronic chronic lymphocytic thyroiditisI.PathogenesisII.HistopathologyIII.Clinical presentationIV.Laboratory and special examsV.Diagnosis and differential diagnosisVI.TreatmentGRAVES DISEASE (GD)GD is also called: diffuse toxic goiter Basedow diseaseSubclinical hyperthyroidism is usually referred to a GD state with (ab)normal T3,T4, decreased TSH, and no clinical symptoms of hyperthyroidismGraves Disease (GD)A. Abnormalities of immune system a. TSH-R-Ab + TSH-R mimic the action of TSH hyperfunction and goiter. b. functioning of Ig Th hypersensitivity + IL-1, IL-2 B cells produce TSH-R-Ab (TRAb)I.Pathogenesisstimulating IgG hyperfunction(TSAb) c. TRAbinhibitory IgG hypofunction and antagonistof TSHR and TSAb (TF1Ab, TGBAb)growth-stimulating IgG (TGI)B. Other factors genetic factors infective factors stress (physical 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, vascularity increased lymphocytes and plasma cells infiltrationII. HistopathologyB. Eyes orbital contents increased, containing mucoprotein, GAG (glycosaminoglycan, 葡糖聚糖糖), lymphocytes.C. Skin (dermopathy) hyaluronic acid (透明质酸), chondroitin sulfates (硫酸软骨素) increased, collagen fibers separated nodular and plaque formation lymphatic drainage decreasedA. 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%), weight loss (75%), with voracious appetite (65%), menstrual pattern changed (50%)III.Clinical PresentationC. Thyroid diffuse goiter: absent in the elderly, consistency: soft, firm, rubbery, symmetrical enlarged, surface: smooth, lobular, thrill with audible bruit eyelid spasm or retractionD. Eyes a. 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 lossc. Classification 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 involvement5Corneal 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 (白癜风白癜风), hair loss pretibial myxedema (胫前粘液性水肿胫前粘液性水肿)F. Complications a. cardiopathy and heart failurethyrotoxicosis ,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 heart 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 companied by myasthenia gravis.A. Serum TH and TSH a. FT3 and FT4 b. TT3 and TT4 c. rT3 d. TSHB. TSH receptor antibodiesIV.Laboratory and Special ExamsC. TRH stimulation testeuthyroid Graves ophthalmopathyGD medicationD. 131I uptake and T3 suppression testE. pathological examsA. Functional diagnosis GD 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 diseaseV.Diagnosis and Differential DiagnosisB. TypesFT3 、FT4 , sTSH (uTSH) : hyperthyroidismFT3(orTT3) , FT4(TT4) normal, sTSH : T3 hyperthyroidism FT4(orTT4) , FT3 (TT3) normal, sTSH : T4 hyperthyroidismFT3 and FT4 (ab)normal, sTSH : subclinical hyperthyroidismC. Pathogenic diagnosis TRAb, TgAb, TPOAb, HCG, 131I uptake, TSHA. General management rest enough, energy and nutrients supplement, sedatives for restlessness and insomnia.B. Management of hyperthyroidism a. medical antithyroid agents: methylthiouracil (MTU) or propylthiouracil (PTU) 300600mg/d methimazole (MM) or carbimazole (CMZ) 3060mg/dVI. Treatmentb. dosage and course1st stage (ca.6 wks): full dosage to control symptoms2nd stage (ca. 48wks): dosage decrease gradually 1/6 dosage/wk3rd stage (ca 1yr or more)PTU 50mg(or MM 5mg), Qdc. “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 to TRHe. drug side-effectsprimary and secondary failureagranulocytosis (1%, within 2 mos)WBC count/ wk or moC. 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 uptake dosage should be calculated by specialistC. Complicationshypothyroidismradiation thyroiditisthyrotoxic crisisexaggarated proptosis (smoking)D. Surgery indications: failed to antithyroidal agent huge thyroid or suspected with tumors retrosternal goiter contraindications: severe proptosis severe systemic diseases early and late pregnancy thyrotoxicosis not controlledE. Treatment decision-making a. firstly, treated with medications for all patients b. after controlled, decided byagerun course of diseaseseverity & complicationsthyroid statesdoctors experiencepatients willings and special entitiesF. 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 pregnancy, never makes TSH 0.5U/L e. heart failure treated with digoxin may be dangerous in some cases高敏TSHTSH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，离心后取血清置20保存。检测方法FT3，FT4用放免法，药盒由天津协和试剂公司提供，TSH用免放法，药盒由天津协和试剂公司提供。1.3 统计学处理率的比较采用X2检验。2 结果4518份标本中，FT3、FT4均增高，TSH降低者有1596份，占总数的35.25%；FT3增高，TSH降低，FT4正常者有564份，占总数的12.46%；FT4、FT4正常，仅有TSH降低者有736份，占总数的16.25%；三项结果均正常者有820份，占总数的18.11%；FT3、FT4正常，而TSH升高者有338份，占总数的7.46%；FT3、FT4降低，TSH升高者有46份，占总数的1.02%；FT4降低，TSH升高，FT3正常者有314分，占总数的6.93%；FT4增高，TSH降低，FT3正常者有46份，占总数的1.02%；其他各种组合有29份，占总数的0.64%。2.1 在诊断甲亢方面以TSH降低为诊断指标，其阳性率为65.33% （2952/4518），以FT3升高为诊断指标，阳性率为47.80%（2160/4518）经X2检验，差异有显著性（P0.001），说明以TSH降低为诊断指标，阳性率为36.56%（1652/4518），明显低于TSH和FT3的阳性率（均P0.001），提示在诊断甲亢时，FT4的敏感性最低。2.2 在诊断甲低方面以TSH升高为诊断指标，其阳性率为15.45% （698/4518），以FT4降低为诊断指标，其阳性率为7.97%（360/4518），明显低于前者 （ P0.001） ； 如 以 FT3降 低 为 诊 断 指 标 ， 其 阳 性 率 为1.02%（46/4518），远低于前二者的阳性率（均P0.001）。3 讨论甲状腺功能异常是一组常见的临床症群，它已成了继溏尿病之后的第二个常见的内分泌疾病，包括有甲状腺机能亢进症、亚临床甲亢、甲状腺机能减退症和亚临床甲减。典型的甲亢或甲减因有其明显的临床症状而不易漏诊，但亚临床甲状腺疾病常常没有典型的临床症状或仅有一些非特异的临床表现，易被误或漏诊。此时，恰当的实验室检查对诊断十分有益。Volpe在复习了大量文献后提出，如果为了筛选甲状腺功能异常的患者，TSH是最开始需要做的，若TSH降低，则需进一步做FT3和FT4，必要时还可做TRH兴奋试验；若TSH升高，则需进一步做FT4和甲状腺抗体（TAb）。从本文的统计结果亦可看出，高敏TSH对依断甲亢或甲低的敏感性均高于FT3、FT4，提示临床上需判断甲状腺功能时，应首选TSH检查。甲亢患者服药治疗，其间甲状腺功能的监测对药物剂量的调整十分重要。从本文的统计结果可看出，当TSH已经升高时，其FT3、FT4水平尚在正常范围（338/4518），如果此时药物剂量不改变，可能会加重药物性甲低；相反，FT3、FT4水平在正常范围的一部分病人，TSH水平低于正常，如此时仅根据FT3、FT4水平而停用抗甲亢药，又会导致甲亢复发，提示在治疗监测过程中，也应以TSH为首选检查。此外，TSH检查在甲低的诊断及治疗监测中也十分重要。Ayala等认为，对只有TSH升高的甲低患者也应予甲状腺素治疗，以纠正血脂异常或改善临床神经系统症状；Smallridge也认为，当TSH大于10mIU/L高度提示应使用甲状腺素治疗，且治疗的目的是使TSH恢复正常。我们的结果提示，在体外试验中，判断甲状腺功能方面，TSH是最敏感的，而FT3对诊断甲亢最敏感，FT4对诊断甲减最敏感 ，与国外报道一致。思 考 题一、判断1、甲亢 = Graves 病2、甲状腺性甲亢时，TSH降低的阳性率为65.33%3、原发性甲减时，TSH升高的阳性率为15.45%4、判断甲状腺功能时，TSH最敏感，而FT3对诊 断甲亢最敏感，FT4对诊断甲减最敏感。二、论文评价5、如根据科学性（50%）、先进性（10%）、实用性（20%）和创新性（20%）来评价此文，您给多少分？教授： 我于2000年5月在附二院检查出甲亢，经治疗，到10月指标基本正常。后到北京工作，经中日友好医院检查发现有反复，药物（丙硫）的用量降不下来。2001年6月20日在中日友好医院做碘131治疗。12月月13日日检检查查：FT3：6.84（3.67-13.5），FT4：3-91（7.4671.1），TSH：32.69（0.345.6）。原主治医师诊断为甲低，处方为优甲乐：50g/日，2002年1月16日检查FT3：8.92；FT4：15.76；TSH：0.19。今年2月27日检查FT3：8.13，FT4：20.85，TSH：0.14。经电话请教原131治疗主治医师，建议改为优甲乐：25g/日。3月27日检查：TSH：0.05（0.49-4.67）；FT3：3.29（1.453.48）；FT4：1.62(0.711.85)。内分泌科教授要求作TRH兴奋试验。4月2日，另一位教授用她的经典处方（心跳88次/分，甲状腺不大）治疗，处方为他巴唑（3次/日，5mg/次）和维生素AD。