肾上腺皮质病理生理学课件

1、ADRENOCORTICAL PATHOPHYSIOLOGY 肾上腺皮质病理生理学ADRENOCORTICAL PATHOPHYSIOLOGY The hormones(激素) of the adrenal glands(肾上腺) are essential for survival.adrenal cortex(肾上腺皮质)adrenal medulla(肾上腺髓质) ADRENOCORTICAL PATHOPHYSIOLOGY The hormones(激素) of theADRENOCORTICAL PATHOPHYSIOLOGYThe adrenal cortex(肾上腺皮质)is t

2、he source of the two important steroid hormones(类固醇激素)Cortisol (皮质醇) Aldosterone (醛固酮)ADRENOCORTICAL PATHOPHYSIOLOGY The adrenal medulla(肾上腺髓质) is embryologically (胚胎学) and histologically (组织学) distinct from the cortex. It synthesizes, stores and secretes :Adrenaline(肾上腺素)Noradrenaline(去甲肾上腺素)Dopami

3、ne(多巴胺)ADRENOCORTICAL PATHOPHYSIOLOGY The adrenal medulla(肾上腺肾上腺皮质病理生理学课件The hormones of the adrenal glandsCortisol (皮质醇) Adrenal androgens(肾上腺雄激素)Aldosterone (醛固酮)The hormones of the adrenal glCORTISOL皮质醇CORTISOL皮质醇Cortisol (皮质醇) is produced in the zona fasciculata (束状带 ) and zona reticularis (网状带)

4、 of the adrenal cortex.It is the end product of a series of hormones which make up thehypothalamic-pituitary-adrenocortical，HPA axis (下丘脑-垂体-肾上腺皮质调节轴).CortisolCortisol (皮质醇) is produced in Cortisolthe influence of cerebral factorsthe hypothalamusCorticotrophin releasing hormone (CRH) 促肾上腺皮质激素释放激素(AC

5、TH释放激素)Cortisolthe influence of cerebCortisolCRHanterior pituitary 前垂体Adrenocorticotrophic hormone（ ACTH） 促肾上腺皮质激素maintain the fascicular and reticular zones of the adrenal cortex and to stimulate the secretion of cortisol.CortisolCRH Hypothalamic secretion (下丘脑分泌 ) of CRH and pituitary secretion of

6、 ACTH are regulated by cortisol in negative feedback loops (负反馈途径).Cortisol Hypothalamic secretion (下丘脑分肾上腺皮质病理生理学课件ASSESSING THE FUNCTION OF THE HPA AXIS下丘脑-垂体-肾上腺调节轴功能的检测ASSESSING THE FUNCTION OF THE Assessing of the HPA axisCortisol secretion varies widely throughout the daysingle serum measureme

7、nts are of little value in clinical practiceDynamic tests (动态试验) of cortisol production form an important part of investigations of adrenocortical hyper-or hypo-functionAssessing of the HPA axisCortiDynamic tests(动态试验) involving stimulation of the adrenal cortex (刺激肾上腺皮质)by synthetic ACTH (Synacthen

8、)stimulation or suppression of the whole HPA axisAssessing of the HPA axisDynamic tests(动态试验) involving Adrenal cortex cells have many low-density lipoprotein receptors (LDL-R) on their surface. This enables them to take up cholesterol (胆固醇) rapidly, from which the adrenal steroid hormones are synth

9、esized.Biosynthesis of Cortisol Adrenal cortex cells have manThe conversion of cholesterol to pregnenolone (孕烯醇酮) is the rate-limiting step (限速步骤) in the biosynthesis of cortisol. This conversion is stimulated by ACTH.Biosynthesis of CortisolThe conversion of cholesterol 肾上腺皮质病理生理学课件The Role of Cort

10、isolCortisol is an important hormone with effects on many tissues in the body. It plays a major role in metabolismThe Role of CortisolCortisol iThe Role of Cortisolpromoting protein breakdown(蛋白质分解) in muscle and connective tissue(结缔组织) the release of glycerol(甘油) and free fatty acids(游离脂肪酸) from ad

11、ipose tissue(脂肪组织). Thus, cortisol provides the substrates (底物) necessary for gluconeogenesis (葡萄糖异生) The Role of Cortisolpromoting Natural or synthetic steroids with cortisol-like effects are called glucocorticoids (糖皮质激素). GlucocorticoidsNatural or synthetic steroids So unbound cortisol is filtere

12、d into the urine.Dexamethasone suppression testCortisol excess secretion, will rapidly exceed the available capacity of cortisol binding globulin.The possibility that a patient may have Cushings syndrome frequently arises because they are obese（肥胖的 ）or hypertensive.ANDROGEN EXCESShyponatraemia (低钠血症

13、);A natural or synthetic steroid with aldosterone-like activity is called a mineralocorticoid (盐皮质激素).Dexamethasone suppression testleads to pathological sodium loss(病理性钠流失) by the kidneyAdrenal insufficiency Adrenal crisisADRENOCORTICAL PATHOPHYSIOLOGYPrimary adrenocortical insufficiency17- hydroxy

14、progesterone) are secreted in large amounts.Failure of the adrenal cortex to produce cortisol and aldosterone may be due to autoimmune or infiltrative diseases(浸润性疾病) (infiltrative carcinoma).All of the 21-hydroxylated steroids (21-羟化类固醇) have mineralocorticoid effects to varying degrees.Glucocortic

15、oidsThey can act as anti-inflammatory(抗炎) or immunosuppressive agents(免疫抑制剂). Synthetic glucocorticoids have found therapeutic applications in a wide range of clinical situations, e.g. asthma (哮喘) and connective tissue disorders (结缔组织病).So unbound cortisol is filtereADRENAL ANDROGENS肾上腺雄激素 ADRENAL A

16、NDROGENS肾上腺雄激素 The androgens (雄激素) produced by the fascicular and reticular zones of the adrenal cortex are :Androstenedione 雄烯二酮Dehydroepiandrosterone (DHA) 脱氢表雄酮DHA sulphate 脱氢表雄酮硫酸盐. Adrenal androgens The androgens (雄激素) proALDOSTERONE醛固酮ALDOSTERONE醛固酮Aldosterone (醛固酮) is produced exclusively by

17、the zona glomerulosa (球状带). primarily controlled by the renin-angiotensin system (肾素血管紧张素系统 )The metabolic pathway for the synthesis of aldosterone has many of the same enzymes involved in cortisol biosynthesis. AldosteroneAldosterone (醛固酮) is produced Other factors, including ACTH, are also involve

18、d in the regulation of aldosterone synthesis. Aldosterone is responsible for promoting sodium reabsorption and potassium excretion in the kidney.AldosteroneOther factors, including ACTH,CORTISOL皮质醇Primary adrenocortical insufficiencyHypothalamic secretion (下丘脑分Dehydration (脱水)（继发性肾上腺皮质功能不全）stimulati

19、on of the adrenal cortex (刺激肾上腺皮质)by synthetic ACTH (Synacthen)ADRENAL INSUFFICIENCY肾上腺（皮质）功能不全An initial blood sample will be taken to check the baseline level of cortisol(280-720nmol/l ).negative feedback loops (负反馈途径).Determining the causeA prolonged excessive exposure of body tissues to cortisol

20、 or any other glucocorticoid results in Cushings syndrome(库欣综合征).ALDOSTERONE EXCESS2 mmol/L (hypoglycaemia)Adrenocortical insufficiency is rare but life-threatening.1mg of Dexamethasone (地塞米松 ) taken at 23:00trauma (创伤）Insulin-induced hypoglycaemia testNauseaA natural or synthetic steroid with aldos

21、terone-like activity is called a mineralocorticoid (盐皮质激素). All of the 21-hydroxylated steroids (21-羟化类固醇) have mineralocorticoid effects to varying degrees.MineralocorticoidCORTISOL皮质醇A natural or synthCONGENITAL ADRENAL HYPERPLASIA (CAH)先天性肾上腺增生症 CONGENITAL ADRENAL HYPERPLASIAan inherited enzyme d

22、efect in corticosteroid biosynthesis. The 21-hydroxylase (21-羟化酶) is the deficient enzyme in 95% of cases of CAH The adrenals cannot secrete cortisol. If aldosterone biosynthesis is also affected , electrolyte disturbances(电解质紊乱) may lead to severe hyponatraemia and hyperkalaemia . It is life threat

23、ening.CAH(先天性肾上腺增生症) an inherited enzyme defect in Because of the lack of cortisol negative feedback to the pituitary is absent ACTH secretion continues to stimulate steroid biosynthesis Cortisol precursors (皮质醇前体) (e.g. 17- hydroxyprogesterone) are secreted in large amounts.CAH(先天性肾上腺增生症)Because of

24、 the lack of cortisoHere, large amounts of 17- hydroxyprogesterone (17-羟孕酮)are secreted lead to virilization (男性化) in baby girl or precocious puberty(早熟性青春期) in boy CAH(先天性肾上腺增生症)Here, large amounts of 17- hydSUMMARYSUMMARY The adrenal glands comprise three separate hormone systems: the zona glomeru

25、losa which secretes aldosterone. the zona fasciculata and reticularis which secrete cortisol and the adrenal androgens the adrenal medulla which secretes adrenaline.SUMMARY (ADRENOCORTICAL PATHOPHYSIOLOGY) The adrenal glands compriseSteroids with cortisol-like activity are known as glucocorticoids;

26、they are potent metabolic regulators and immunosuppressants.Steroids with aldosterone-like activity are called mineralocorticoids; they promote renal sodium retention.SUMMARY (ADRENOCORTICAL PATHOPHYSIOLOGY)Steroids with cortisol-like ac Adrenal steroid concentrations in serum fluctuate widely. Sing

27、le measurements are therefore of limited value in clinical investigations, and dynamic tests are widely used in diagnosis Congenital adrenal hyperplasia（先天性肾上腺增生症） is an inherited enzyme defect in corticosteroid biosynthesis which can be fatal unless diagnosed early.SUMMARY (ADRENOCORTICAL PATHOPHYS

28、IOLOGY) Adrenal steroid concentration21-hydroxylase deficiency is the most commonly encountered form of CAH. The finding of a raised plasma 17-hydroxyprogesterone confirms the diagnosis.SUMMARY (ADRENOCORTICAL PATHOPHYSIOLOGY)21-hydroxylase deficiency is tADRENAL INSUFFICIENCY肾上腺（皮质）功能不全 ADRENAL INS

29、UFFICIENCY肾上腺（皮质）功Acute adrenal insufficiency (急性肾上腺功能不全) is a rare condition which if unrecognized is potentially fatal (引起死亡的). It is often relatively simple to treat once the diagnosis has been made and patients can lead a normal life. Adrenal insufficiencyAcute adrenal insufficiency (急The main c

30、linical features of Adrenal insufficiencylack of aldosteroneHyponatraemia (低钠血症)Hyperkalaemia (高钾血症)lack of cortisolLethargy(嗜睡）Anorexia（厌食）Abdominal painWeight lossPigmentation (色素沉着)The main clinical features of Adrenal crisis (肾上腺危象)Infectionoperation stress trauma (创伤）Adrenal insufficiency Adren

31、al crisis (life-threatening) Postural hypotension (体位性低血压 ) Vomiting Nausea Dehydration (脱水) Adrenal crisis (肾上腺危象)Infecti肾上腺皮质病理生理学课件Primary adrenocortical insufficiency原发性肾上腺皮质功能不全Secondary adrenocortical insufficiency继发性肾上腺皮质功能不全Adrenal insufficiencyPrimary adrenocortical insuffiPrimary adrenocor

32、tical insufficiency（原发性肾上腺皮质功能不全）Adrenal gland destruction was often due to tuberculosis (结核病) and auto-immune disease (自身免疫病).Both cortisol and aldosterone production may be affected.Adrenal insufficiencyPrimary adrenocortical insuffiSecondary adrenocortical insufficiency（继发性肾上腺皮质功能不全）Secondary adr

33、enal failure is frequently due to therapeutic administration of corticosteroids（皮质类固醇）. long-standing suppression（长期抑制） and the impairment（损害）of the HPA axisAdrenal insufficiencySecondary adrenocortical insufFollowing are the causes of adrenal insufficiencyFollowing are the causes of adBiochemical f

34、eatures of adrenocortical insufficiency In addition to the clinical observations, a number of biochemical results may help in the diagnosis of adrenocortical insufficiency. These are: hyponatraemia (低钠血症); hyperkalaemia (高钾血症); elevated serum urea; These are the biochemical features in many patients

35、 with Addisons Disease阿狄森氏病(primary adrenocortical insufficiency).Biochemical features of adren In primary adrenal insufficiency, patients become hyponatraemic(低钠血症 )for two reasons:lack of aldosterone leads to pathological sodium loss(病理性钠流失) by the kidney contraction of the ECF (细胞外液) volumecausin

36、g hypotension and pre-renal uraemia Patients may develop life-threatening sodium depletion（钠流失 ）and potassium retention（钾潴留）Biochemical featuresHyponatraemic In primary adrenal inshypovolaemia（低血容量）and hypotension stimulate arginine vasopressin， AVP（精氨酸加压素） secretioncausing water retention（水潴留）In th

37、e absence of cortisol, the kidneys ability to excrete (排泄) a water load is impaired thus leading to hyponatraemiaBiochemical featuresHyponatraemichypovolaemia（低血容量）and hypotensPigmentationLack of negative feedback of cortisol on the anterior pituitary （垂体前叶）results in an excessive secretion of ACTH.

38、 Biochemical featuresPigmentationPigmentationBiochemical featuBiochemical featuresPigmentationSince the structure of ACTH contains part of the amino acid sequence of melanocyte-stimulating hormone促黑(素细胞)激素so an excessive ACTH secretion leads to the darkening of the patients skin and mucous membranes

39、(皮肤和黏膜变黑) Pigmentation（色素沉着）Biochemical featuresPigmentatDiagnosis of adrenocortical insufficiencyIf a patient is suspected to be suffering from adrenal insufficiency, it is essential to ensure that they have an adequate sodium intake before investigations. Serum aldosterone measurements have no rol

40、e to play in the initial diagnosis of adrenal insufficiency.Diagnosis of adrenocortical in Synacthen tests Synacthen tests Synacthen is a synthetic analogue of ACTH(合成ACTH类似物) There are two kind of Synacthen teststhe short Synacthen test the depot Synacthen testSynacthen tests in the diagnosis of ad

41、renocortical insufficiency Synacthen is a synthetic analShort Synacthen test procedureAn initial blood sample will be taken to check the baseline level of cortisol(280-720nmol/l ).0.25mg Synacthen is administered intravenously (iv injection) to stimulate your own body production of cortisol. A blood

42、 sample will be taken at 30 minutes and 60 minutes after the stimulation to measure the cortisol level.Short Synacthen test procedureNormally, the resting value is within the reference range 280720nmol/l at 08:0010:00 Am. There should be an increment of more than 200nmol/L after Synacthen the final

43、value should be greater than 500 nmol/L. Diagnostic criteria of Short Synacthen test Normally, the resting value isAll criteria must be met. Failure to meet any of the criteria indicates adrenocortical inadequacy.A normal response to the Synacthen test excludes primary hypofunction. Diagnostic crite

44、ria of Short Synacthen test All criteria must be met. DiagIf a patient with an impaired response to the Synacthen test. An elevated ACTH concentration will confirm the diagnosis of primary adrenal failure in such a patient.Diagnostic criteria of Short Synacthen testIf a patient with an impaired Pati

45、ents with equivocal responses(不明确应答) to the short Synacthen testafter stimulation of the adrenal cortex with depot Synacthen ( long-acting material长效的). the short Synacthen test may be retested.The depot Synacthen testPatients with equivocal respThis depot Synacthen is given intramuscularly (IM inje

46、ction) for 3 days. On the fourth day a short Synacthen test is carried out as before.If the normal criteria for the short Synacthen test are satisfied on the second testing, it is not primary but secondary adrenocortical insufficiency.Depot Synacthen test procedureThis depot Synacthen is given an ex

47、cellent diagnostic test for adrenal insufficiencyused to check the amount of cortisol in the body and how well it can produce It also indicates the ability of adrenal cortex to respond to ACTH. Synacthen tests in the diagnosis of adrenocortical insufficiencyan excellent diagnostic test fThe HPA axis

48、 may be investigated by performing an insulin tolerance test (ITT) (胰岛素耐量试验). ITT is used in diagnosis of pituitary insufficiency (垂体机能减退) which may lead to secondary failure of the adrenal cortex.Diagnosis of adrenocortical insufficiencyThe HPA axis may be investigatSUMMARY(Adrenal insufficiency) A

49、drenocortical insufficiency is rare but life-threatening. Failure of the adrenal cortex to produce cortisol and aldosterone may be due to autoimmune or infiltrative diseases(浸润性疾病) (infiltrative carcinoma).SUMMARY(Adrenal insufficiency The Synacthen test is used in diagnosis of primary adrenocortica

50、l failure. The insulin tolerance test is used in diagnosis of pituitary insufficiency which may lead to secondary failure of the adrenal cortex.SUMMARY(Adrenal insufficiency) The Synacthen test is used inHYPERFUNCTION OF THE ADRENAL CORTEX肾上腺皮质功能亢进HYPERFUNCTION OF THE ADRENAL C Hyperfunction of the

51、adrenal cortex can be conveniently discussed in terms of the overproduction of the three main products:Cortisol (皮质醇)Adrenal androgens (肾上腺雄激素) Aldosterone (醛固酮) Hyperfunction of the adrenal cortex Hyperfunction of the adCORTISOL EXCESSCORTISOL EXCESSA prolonged excessive exposure of body tissues to

52、 cortisol or any other glucocorticoid results in Cushings syndrome(库欣综合征).It is one of the most difficult endocrine diagnoses to make. Cortisol excessA prolonged excessive exposureThe main clinical features of Cushings syndromeDisorders of lipid metabolismDisorders of protein metabolism Disorders of

53、 glycometabolism Electrolyte disturbances HypertensionBreakdown of immune function sexual disturbance The main clinical features of 肾上腺皮质病理生理学课件 In any investigation of Cushings syndrome the clinician should ask two questions:Does the patient actually have Cushings syndrome? The possibility that a p

54、atient may have Cushings syndrome frequently arises because they are obese（肥胖的 ）or hypertensive. Cortisol excess In any investigation ofOnce the diagnosis of Cushings syndrome is established, then a second question may be asked:What is the cause of the excess cortical secretion?Cortisol excessOnce t

55、he diagnosis of CushinDiagnosis of Cortisol excess（1）Iatrogenic（医源性） Cushings syndrome should be diagnosed from the patient history and clinical examination (the steroid may have been taken)Cortisol excess secretion, will rapidly exceed the available capacity of cortisol binding globulin. Diagnosis

56、of Cortisol excess（1So unbound cortisol is filtered into the urine.Urinary free cortisol(尿游离皮质醇) in a 24h collectionor assessed as a cortisol / creatinine ratio(皮质醇/肌酐) in an early morning urine sampleIt is the initial screening test in a patient suspected of adrenocortical hyperfunction. Diagnosis

57、of Cortisol excess（2）So unbound cortisol is filteRepeatedly high early morning urine cortisol / creatinine ratios are evidence enough to proceed with further investigations of the patient. If the test is negative on three occasions, Cushings syndrome may be excluded from the differential diagnosis.D

58、iagnostic criteriaRepeatedly high early morning Disappearance of circadian rhythm Cortisol concentrations measured at 08:00 and 22:00 normally show a circadian rhythm（昼夜节律） the evening sample having a lower value than that in the morning. This difference is usually not apparent in the patient with C

59、ushings syndrome. Diagnosis of Cortisol excess（3） Disappearance of circadian rhDexamethasone suppression test地塞米松抑制试验Insulin-induced hypoglycaemia testDiagnosis of Cortisol excess（4）Dexamethasone suppression testDexamethasone suppression test1mg of Dexamethasone (地塞米松 ) taken at 23:00 to suppress th

60、e serum cortisol level at 08:00 the following morningor to suppress the urinary cortisol secretion overnight (as measured by an early morning urine cortisol / creatinine ratio)Dexamethasone suppression testIf failure to the suppression of dexamethasoneIt is another indicator of Cushings syndrome.Dex