_insufficiency stud肾上腺皮质功能不全螺柱课件

ADRENOCORTICAL INSUFFICIENCY THE ADRENAL CORTEX BASIS CONCEPTS ADRENOCORTICAL HISTOLOGY The adrenal cortex is composed of three concentric zones with distinct steroid biosynthetic capacities. nZona glomerulosa biosynthesis of mineralocorticoids nZona fasciculata biosynthesis of glucocorticoids nZona reticularis biosynthesis of adrenal androgens. STEROID BIOSYNTHESIS nSteroidogenesis results from specific sequential enzymatic conversions of cholesterol substrate into steroid hormones, which exert a wide variety of biological activities. STEROID BIOSYNTHESIS nA series of steroidogenic enzymes are compartmentalized either in the mitochondria or in the endoplastic reticulum. nSeveral of these enzymes belong to the superfamily of mixed function oxidase enzymes known as cytochrome P450. STEROID BIOSYNTHESIS nApproximately 80% of adrenal cholesterol sources are provided by circulating low density lipoprotein (LDL). nThe adrenal cells can also synthesize cholesterol de novo from acetyl coenzyme A. STEROID BIOSYNTHESIS nThe first rate-limiting step in steroidogenesis involves the removal of six carbons from the lateral chain of cholesterol by integral inner mitochondrial membrane P450 side chain cleavage (CYP11A1) enzyme to generate pregnenolone. Nomenclature for steroidogenic enzymes now utilized Trivial namePastCurrent Cholesterol side-chain cleavage enzyme; desmolase P450sccCYP11A 1 3-Hydroxysteroid dehydrogenase3-HSD3-HSD 17-Hydroxylase/17,20-lyaseP450c17CYP17 21-HydroxylaseP450c21CYP21A 2 11-HydroxylaseP450c11CYP11B 1 Aldosterone synthase; corticosterone 18- methylcorticosterone oxidase/lyase P450C11 AS CYP11B 2 Main steroid biosynthetic pathways (mineralocorticoids and glucocorticoids). cholesterolcholesterol pregnenolonepregnenolone progesteroneprogesterone 11-deoxycorticosterone 11-deoxycorticosterone (DOC)(DOC) corticosteronecorticosterone (B)(B) 18OH-corticosterone18OH-corticosterone ALDOSTERONEALDOSTERONE 3 3 -HSD II-HSD II CYP21A2CYP21A2 CYP11B2CYP11B2 1717 OH-pregnenoloneOH-pregnenolone CYP17CYP17 1717 - -hydroxylasehydroxylase 17,20-lyase17,20-lyase 1717 OH-progesteroneOH-progesterone 11-deoxycortisol11-deoxycortisol (S)(S) CORTISOLCORTISOL (F)(F) CYP11B1CYP11B1 ZONA FASTICULATAZONA FASTICULATA ZONA GLOMERULOSAZONA GLOMERULOSA 1111 - -hydroxylasehydroxylase CYP11A1CYP11A1 18-hydroxylase18-hydroxylase 18-methyloxidase18-methyloxidase Main steroid biosynthetic pathways (adernal androgens). cholesterolcholesterol pregnenolonepregnenolone progesteroneprogesterone 3 3 -HSD II-HSD II 1717 OH-OH- pregnenolonepregnenolone 1717 - - hydroxylasehydroxylase 17,20-lyase17,20-lyase 1717 OH- OH- progesteroneprogesterone ZONA ZONA RETICULARISRETICULARIS CYP11A1CYP11A1 CYP17CYP17 Dehydro-Dehydro- epiandrosteroneepiandrosterone (DHEA)(DHEA) AndrostendiolAndrostendiol 1717 -HSD -HSD 4-4- androstendioneandrostendione testosteronetestosterone estroneestroneestradiolestradiol CYP19CYP19 REGULATION OF GLUCOCORTICOID SECRETION nThe secretion of cortisol is regulated by several levels of signals and interactions between the brain, the hypothalamus, the pituitary, and the adrenal glands. Regulation of the hypothalamic-pituitary-adrenal axis. CicardianCicardian rhythmsrhythms FeedingFeeding cyclescycles stressstress HIGHER BRAIN CENTERSHIGHER BRAIN CENTERS cytocinescytocines NeurotransmittersNeurotransmitters neuropeptidesneuropeptides HYPOTHALAMUSHYPOTHALAMUS CRH-AVPCRH-AVP PITUITARY GLANDPITUITARY GLAND ACTHACTH ADRENAL CORTEXADRENAL CORTEX Cortisol-CBGCortisol-CBG Free-cortisolFree-cortisol PERIPHERIAL TISSUESPERIPHERIAL TISSUES cytokinescytokinesInflammatryInflammatry agentsagents CBGCBG + + - - + + - - + + + + - - - - - - - CORTICOTROPIN-RELEASING HORMONE (CRH) 41-aminoacid peptide synthesized by neurons in the paraventricular hypothalamic nucleus nAction: mRNA levels of pro-opiomelanocortin (POMC), the polypeptide precursor of ACTH ADRENOCORTICOTROPIC HORMONE ACTH n39-aminoacid peptide capable of stimulating secretion of glucocorticoids, androgenic steroids, and to a lesser extent of mineralocorticoids from the adrenal cortex. nIn human ACTH stimulates melanin synthesis in skin melanocytes. ADRENOCORTICOTROPIC HORMONE ACTH The acute effect of ACTH nactivation exisiting CYP11A1 to convert cholesterol to pregnenolone The chronic effects of ACTH nincrease in gene trascription of most of the steroidogenic enzymes (CYP11A1, CYP17, CYP21A2, CYP11B1) IN THE CHRONIC ABSENCE OF ACTH , THE ADRENAL CORTEX BECOMES ATROPHIC. Glucocorticoid negative feedback. nGlucocorticoids inhibit the release and synthesis of ACTH primarily by decreasing POMC gene transcription in pituitary corticotroph cells. nGlucocorticoids inhibit the production and secretion of CRH and vasopressin in hypothalamic paraventricular nuclei. ADRENOCORTICAL INSUFFICIENCY nImpairment of the adrenal production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) leads to a life- threatening situation that is often misinterpreted and neglected. ADRENOCORTICAL INSUFFICIENCY vPRIMARY (Addisons disease) damage of the adrenal glands vSECONDARY inadequate ACTH and/or CRH secretion BOTH PRIMARY AND SECONDARY ADRENAL INSUFFICIENCY ARE RARE DISEASES. The prevalence of acquired primary insufficiency is estimated at 39 to 60 cases per 1 million people, with most the cases being diagnosed in the third to fifth decade of life. Iatrogenic adrenal insufficiency, secundary to exogenous glucocorticoid therapy, includes large number of patients and implies similar risks of acute adrenal crisis. nCongenital adrenal hyperplasia (CAH) is a family of inborn errors of steroidogenesis, primarily characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex. n Complete and near-complete blocks of the 21-hydroxylase enzyme (classical form of CAH) occurs in 1 in 15 000 live births worlwide. ADRENOCORTICAL INSUFFICIENCY nFor most cases of adrenal insufficiency, impairment of hormonal production can take place over the course of many years, and the clinical picture is insidiously dominated by the features of the disorder. CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY vAutoimmune adrenalitis (80%) vInfectoius adrenalitis tuberculosis (20%) histioplasmosis, paracoccidioidomycosis, blastomycosis, coccidioidomycosis, cryptococcosis vInvasive destruction metastases lymphoma amyloidosis, sarcoidosis CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY vAIDS (infectious or invasive destruction) vAdrenal hemorrhage vIatrogenic (mitotane, ketoconazole, aminoglutethimide, metyrapone, etomidate, surgery) vCongenital and familiar Adrenoleukodystrophy Adrenal hypoplasia Familial glucocorticoid deficiency AUTOIMMUNE ADRENALITIS nThe most common cause of Addisons disease. nHumoral and cellular immunity are both involved. nAntibodies to the adrenal cortex are detected in up to 70% of idiopathic insufficiences; they inhibit adrenal steroidogenesis in vitro, and some of them are directed against enzymes of steroidogenesis. AUTOIMMUNE ADRENALITIS nLymphocytic infiltration of the adrenals gradual destruction of cortical cells and their replacement by fibrotic tissue. AUTOIMMUNE ADRENALITIS nIn 50% of the cases association to other autoimmune endocrine or nonendocrine disorders polyglandular autoimmune syndromes POLYGLADULAR AUTOIMMUNE SYNDROME Type I nOften familial, inhereted in an autosomal recessive pattern nFirst manifestation: hypoparathyroidism and/or mucocutaneous candidiasis occurring during childhood nAddisons disease develops in 60% of the cases during adolescence. Type II nThe more frequent nFamilial in half of the cases nOccurs mostly between 20 and 40 years of age nIt often develops in a sequence : Insulin type 1 Graves disease Addisons disease nHypoparathyroidism and candidiasis are absent INFECTIOUS ADRENALITIS nAdrenal tuberculosis is the second- most common cause of Addisons disease in most countries (20%). nThe adrenal gland are completely destroyed, including the medulla. caseous necrosis fibrosis INFECTIOUS ADRENALITIS nDisseminated fungal infections can destroy the adrenal glands histoplasmosis paracoccidioidomycosis South American blastomycosis nSyphilis has also become a rare cause. INVASIVE DESTRUCTION OF ADRENALS nMetastatic involvement of the adrenals lung cancer breast cancer stomach cancer colon cancer melanoma Hodgkin and non-Hodgkin lymphoma nAmyloidosis and sarcoidosis are rare invasive causes. ACQUIRED IMMUNE DEFICIENCY SYNDROME nPatients with AIDS may have adrenal insufficiency through multiple mechanism: Infection by cytomegalovirus, tuberculosis, mycobacterium avium-intracellulare, toxoplasmosis, cryptococcosis Invasion by Kaposis sarcoma and lymphoma Drugs (ketoconazole, rifampin, phenytoin) nSymptoms and signs of Addisons disease may be mistaken and imputed to AIDS itself. IATROGENIC ADRENAL DEFICIENCY Iatrogenic adrenal deficiency is a predicted situation in medically treated Cushingsyndrome. mitotane blocks the synthesis of corticosteroids and induces necrosis of the adrenal cortex aminoglutethimide, metyrapone, ketoconazole reversibly inhibit several steps of steroidogenesis. Barbiturans, rifampin, phenytoin increases cortisol metabolism they may precipitate acute crisis in cases undiagnosed adrenal insufficiency. ADRENAL HEMORRHAGE Adrenal hemorrage is a cause of rapid and total destruction of adrenal glands, leading to acute adrenal insufficiency. In adults patients on anticoagulant therapy; usually after 50 years of age In patients with severe, often life-threatening illnesses (infection with sepsis, burns, major surgery, complicated pregnancy, trauma, severe cardiovascular disease, acute renal disease). In children meningococcal or pseudomonas septicemia In neonates after complicated delivery. CONGENITAL AND FAMILIAL ETIOLOGIES Adrenoleukodystrophy defective oxidation of very long chain fatty acids (VLCFA) in peroxisomes accumulation of VLCFA in central and peripheral nervous tissue, adrenals, gonads, and other organs. CONGENITAL AND FAMILIAL ETIOLOGIES Adrenal hypoplasia Adrenal failure shortly after birth impaired development of the adult adrenal cortex CONGENITAL AND FAMILIAL ETIOLOGIES Familial glucocorticoid deficiency Rare autosomal recessive disorder unresponsiveness to ACTH (mutation of the ACTH receptor gene) ADRENOCORTICAL INSUFFICIENCY- PATHOPHYSIOLOGY Glucocorticoids deficiency decreased sense of well-being hypoglycemia gastrointestinal disturbances water retention reduced vascular adrenergic tone The decreased negative feedback by cortisol increased synthesis and secretion of ACTH and other POMC-derived peptides ADRENOCORTICAL INSUFFICIENCY- PATHOPHYSIOLOGY mineralocorticoid deficiency increased sodium renal loss hyponatremia increased renal retention of potassium and hydrogen ions hyperkaliemia and acidosis Adrenal androgen deficiency decrease in axillary and pubic hair and libido (in women) ADRENOCORTICAL INSUFFICIENCY- PATHOPHYSIOLOGY In most cases the loss of adrenal function is progressive. Symptoms and signs appear when more than 90% of the glands are destroyed. Before that point, the increased ACTH and renin maximally stimulate remaining cortical tissue normalnormal basalbasal amountsamounts ofof glucocorticoidsglucocorticoids andand mineralocorticoidsmineralocorticoids no no sufficientsufficient increaseincrease inin responseresponse to to stressstress GDuring transient state of partial steroid deficiency or decreased adrenal reserve, an acute crisis may be precipitated by surgery, trauma or infection. vThe clinical features of Addisons disease are often misleading and may go unnoticed for months. vMost of the symptoms and signs taken separately are non-specific. ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS Clinical and laboratory features of chronic primary adrenal insufficiency Weakness, malaise depression, lack of initiative, impairment of memory dizziness, postural hypotension, postural syncope myalgias, arthralgias anorexia, salt craving, weight loss hyperpigmentation hyponatremia, hyperkaliemia, azotemia eosinophilia, lymphocytosis, normochromic anemia hypoglycemia ammenorrhea with decreased axillary and pubic hair in women loss of libido in both sexes Weakness, fatigue, malaise constant complaints. Weakness occurs for usual, routine tasks and improves with rest, and it is frequently associated with myalgias and arthalgias. ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS Postural dizziness or (less often) syncope, postural hypotension with tachycardia are observed. The existence of systolic hypertension is a strong indication to exclude the diagnosis of adrenal insufficiency (moreover, spontaneous improvement of pre-existing hypertension is reported). ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS Gastrointestinal symptoms are common. Anorexia (with weight loss) is almost constantly found among patients. Salt craving, an increased thirst for iced liquids are reported ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS Spontaneous hypoglycemia is common in infants and children (infrequent in adults) It may be precipitated by infection, fever, or alcohol ingestion. ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS hyperpigmentation is a highly specific sign of chronic primary adrenal insufficiency. Vitiligo may coexist with hyperpigmentation in10% of patients with autoimmune Addisons disease. ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS The routine laboratory findings Hyponatremia Hyperkaliemia Mild acidosis Fasting blood glucose usually low to normal Mild elevation of urea and creatinine (secondary to dehydratation) Moderate eosinophilia, lymphocytosis, normochromic anemia Elevations of hepatic transaminases Mild hypercalcemia ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES GThe diagnosis is confirmed by the rapid ACTH stimulation test. This test can be done at any time of the day, since, in contrast to the circadian rhythm of basal cortisol, the stimulated cortisol concentration is independent of the time of day. ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES Diagnostic approach to primary and secondary adrenal insufficiency CONCOMITANT IN EARLY MORNINGIN EARLY MORNING BaselineBaseline plasmaplasma ACTH ACTH RapidRapid ACTH ACTH stimulationstimulation test test ADRENAL INSUFFICIENCYADRENAL INSUFFICIENCY HighHigh plasmaplasma ACTHACTH PRIMARY PRIMARY ADRENAL ADRENAL INSUFFICIENCYINSUFFICIENCY LowLow oror normalnormal plasmaplasma ACTH ACTH SECUNDARY SECUNDARY ADRENAL ADRENAL INSUFFICIENCYINSUFFICIENCY AbnormalAbnormal ACTH ACTH stimulationstimulation test testNormalNormal ACTH ACTH stimulationstimulation test test MetyraponeMetyrapone oror insulin testinsulin test AbnormalAbnormalNormalNormal NORMAL NORMAL HYPOTHALAMIC HYPOTHALAMIC PITUITARY PITUITARY ADRENAL AXISADRENAL AXIS HighHigh plasmaplasma ACTHACTH INCIPIENT INCIPIENT PRIMARY PRIMARY ADRENAL ADRENAL INSUFFICIENCYINSUFFICIENCY (rare(rare ) ) Aldosterone concentration is low, non- responsive to ACTH or to the upright position, and is associated with high renin activity. Adrenal androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androsterone) are low. ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES Adrenal CT scan should be perfomed. If bilateral adrenal enlargement is observed, futher evaluation is indicated to determine the specific cause (tuberculosis, other granulomatous diseases, metastatic cancer, or hemorrhage). ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES Adrenal autoantibodies positive autoimmune adrenalitis (evaluation of presence of other autoimmune diseases) ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES Treatment for chronic primary adrenal insufficiency includes substitutions for both glucocorticoid and mineralocorticoid function. ADRENOCORTICAL INSUFFICIENCY- TREATMENT The evaluation of glucocorticoid replacement is based on clinical judgement of a patients subjective feeling, and the aim of treatment should be to administrate the smallest dose to keeps the patients well-being at a normal level. Mineralocorticoid adequacy is obtained when blood pressure, sodium, potassium, and plasma renin levels are normal without orthostatic hypotension and tachycardia. ADRENOCORTICAL INSUFFICIENCY- TREATMENT Glucocorticoid doses must be doubled or tripled at the onset of minor illnesses for 24 or 48 hours. Moderately stressful situations: hydrocortisone i.v. (100 mg or more). In cases of severe illness or trauma, patients should be treated as in acute adrenal insufficiency. ADRENOCORTICAL INSUFFICIENCY- TREATMENT Causes of secondary adrenal insufficiency Long-term glucocorticoid administration Selective cure of Cushings syndrome Pituitary adenomas Metastatic tumors Lymphocytic hypophisitis Sarcoidosis, histiocytosis Sheehans syndrome Pituitary surgery, radiotherapy Isolated ACTH deficiency SECONDARY ADRENAL INSUFFICIENCY Clinical findings The clinical presentation of secondary adrenal insufficiency is similar to those suffering from Addisons disease, with the excepition of absent hyperpigmentation. Dehydratation, and hyperkalemia are usually absent. SECONDARY ADRENAL INSUFFICIENCY Diagnostic procedures Abnormal cortisol response to ACTH stimulation test (70%) + normal or subnormal plasma ACTH levels SECONDARY ADRENAL INSUFFICIENCY Diagnostic procedures In 30% of cases normal cortisol response to ACTH stimulation test Metyrapone test or insulin-induced hypoglycemia test: subnormal responce + normal or low ACTH levels SECONDARY ADRENAL INSUFFICIENCY Treatment Treatment for chronic secondary adrenal insufficiency is similar to that of primary deficiency, except that mineralocorticoids are seldom necessary. SECONDARY ADRENAL INSUFFICIENCY ACUTE ADRENAL INSUFFICIENCY GAcute adrenal insufficiency is a medical emergency t