1、ADRENOCORTICAL INSUFFICIENCY,THE ADRENAL CORTEX BASIS CONCEPTS,ADRENOCORTICAL HISTOLOGY,The adrenal cortex is composed of three concentric zones with distinct steroid biosynthetic capacities. Zona glomerulosa biosynthesis of mineralocorticoids Zona fasciculata biosynthesis of glucocorticoids Zona re
2、ticularis biosynthesis of adrenal androgens.,STEROID BIOSYNTHESIS,Steroidogenesis results from specific sequential enzymatic conversions of cholesterol substrate into steroid hormones, which exert a wide variety of biological activities.,STEROID BIOSYNTHESIS,A series of steroidogenic enzymes are com
3、partmentalized either in the mitochondria or in the endoplastic reticulum. Several of these enzymes belong to the superfamily of mixed function oxidase enzymes known as cytochrome P450.,STEROID BIOSYNTHESIS,Approximately 80% of adrenal cholesterol sources are provided by circulating low density lipo
4、protein (LDL). The adrenal cells can also synthesize cholesterol de novo from acetyl coenzyme A.,STEROID BIOSYNTHESIS,The 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 cle
5、avage (CYP11A1) enzyme to generate pregnenolone.,Nomenclature for steroidogenic enzymes now utilized,Main steroid biosynthetic pathways (mineralocorticoids and glucocorticoids).,cholesterol,pregnenolone,progesterone,11-deoxycorticosterone (DOC),corticosterone (B),18OH-corticosterone,ALDOSTERONE,3-HS
6、D II,CYP21A2,CYP11B2,17OH-pregnenolone,CYP17,17-hydroxylase,17,20-lyase,17 OH-progesterone,11-deoxycortisol (S),CORTISOL (F),CYP11B1,ZONA FASTICULATA,ZONA GLOMERULOSA,11-hydroxylase,CYP11A1,18-hydroxylase,18-methyloxidase,Main steroid biosynthetic pathways (adernal androgens).,cholesterol,pregnenolo
7、ne,progesterone,3-HSD II,17OH- pregnenolone,17- hydroxylase,17,20-lyase,17 OH- progesterone,ZONA RETICULARIS,CYP11A1,CYP17,Dehydro-epiandrosterone (DHEA),Androstendiol,17-HSD,4-androstendione,testosterone,estrone,estradiol,CYP19,REGULATION OF GLUCOCORTICOID SECRETION,The secretion of cortisol is reg
8、ulated 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.,Cicardian rhythms Feeding cycles,stress,HIGHER BRAIN CENTERS,cytocines,Neurotransmitters neuropeptides,HYPOTHALAMUS,
9、CRH-AVP,PITUITARY GLAND,ACTH,ADRENAL CORTEX,Cortisol-CBG,Free-cortisol,PERIPHERIAL TISSUES,cytokines,Inflammatry agents,CBG,+,-,+,-,+,+,-,-,-,-,CORTICOTROPIN-RELEASING HORMONE (CRH), 41-aminoacid peptide synthesized by neurons in the paraventricular hypothalamic nucleus Action: mRNA levels of pro-op
10、iomelanocortin (POMC),the polypeptide precursor of ACTH,ADRENOCORTICOTROPIC HORMONE ACTH, 39-aminoacid peptide capable of stimulating secretion of glucocorticoids, androgenic steroids, and to a lesser extent of mineralocorticoids from the adrenal cortex. In human ACTH stimulates melanin synthesis in
11、 skin melanocytes.,ADRENOCORTICOTROPIC HORMONE ACTH,The acute effect of ACTH activation exisiting CYP11A1 to convert cholesterol to pregnenolone,The chronic effects of ACTH increase in gene trascription of most of the steroidogenic enzymes (CYP11A1, CYP17, CYP21A2, CYP11B1),IN THE CHRONIC ABSENCE OF
12、 ACTH , THE ADRENAL CORTEX BECOMES ATROPHIC.,Glucocorticoid negative feedback.,Glucocorticoids inhibit the release and synthesis of ACTH primarily by decreasing POMC gene transcription in pituitary corticotroph cells.Glucocorticoids inhibit the production and secretion of CRH and vasopressin in hypo
13、thalamic paraventricular nuclei.,ADRENOCORTICAL INSUFFICIENCY,Impairment of the adrenal production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) leads to a life-threatening situation that is often misinterpreted and neglected.,ADRENOCORTICAL INSUFFICIENCY,PRIMARY (Addisons disea
14、se)damage of the adrenal glands,SECONDARYinadequate 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
15、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.,Congenital adrenal hyperplasia (CAH) is a family of inborn errors of steroidogenesis, primarily characterized by
16、 a specific enzyme deficiency that impairs cortisol production by the adrenal cortex.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,For most cases of adrenal insufficiency, impairment of
17、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,Autoimmune adrenalitis (80%) Infectoius adrenalitis tuberculosis (20%) histioplasmosis, paracoccidioidom
18、ycosis, blastomycosis, coccidioidomycosis, cryptococcosis Invasive destruction metastases lymphoma amyloidosis, sarcoidosis,CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY,AIDS (infectious or invasive destruction) Adrenal hemorrhage Iatrogenic (mitotane, ketoconazole, aminoglutethimide, metyrapone, e
19、tomidate, surgery) Congenital and familiar Adrenoleukodystrophy Adrenal hypoplasia Familial glucocorticoid deficiency,AUTOIMMUNE ADRENALITIS,The most common cause of Addisons disease. Humoral and cellular immunity are both involved. Antibodies to the adrenal cortex are detected in up to 70% of idiop
20、athic insufficiences; they inhibit adrenal steroidogenesis in vitro, and some of them are directed against enzymes of steroidogenesis.,AUTOIMMUNE ADRENALITIS,Lymphocytic infiltration of the adrenals gradual destruction of cortical cells and their replacement by fibrotic tissue.,AUTOIMMUNE ADRENALITI
21、S,In 50% of the cases association to other autoimmune endocrine or nonendocrine disorders polyglandular autoimmune syndromes,POLYGLADULAR AUTOIMMUNE SYNDROME,Type I Often familial, inhereted in an autosomal recessive pattern First manifestation: hypoparathyroidism and/or mucocutaneous candidiasis oc
22、curring during childhood Addisons disease develops in 60% of the cases during adolescence.,Type II The more frequent Familial in half of the cases Occurs mostly between 20 and 40 years of age It often develops in a sequence : Insulin type 1 Graves disease Addisons disease Hypoparathyroidism and cand
23、idiasis are absent,INFECTIOUS ADRENALITIS,Adrenal tuberculosis is the second-most common cause of Addisons disease in most countries (20%). The adrenal gland are completely destroyed, including the medulla. caseous necrosis fibrosis,INFECTIOUS ADRENALITIS,Disseminated fungal infections can destroy t
24、he adrenal glands histoplasmosis paracoccidioidomycosis South American blastomycosis Syphilis has also become a rare cause.,INVASIVE DESTRUCTION OF ADRENALS,Metastatic involvement of the adrenals lung cancer breast cancer stomach cancer colon cancer melanoma Hodgkin and non-Hodgkin lymphomaAmyloidos
25、is and sarcoidosis are rare invasive causes.,ACQUIRED IMMUNE DEFICIENCY SYNDROME,Patients with AIDS may have adrenal insufficiency through multiple mechanism: Infection by cytomegalovirus, tuberculosis, mycobacterium avium-intracellulare, toxoplasmosis, cryptococcosis Invasion by Kaposis sarcoma and
26、 lymphoma Drugs (ketoconazole, rifampin, phenytoin) Symptoms 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 corticoste
27、roids 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 HEMORR
28、HAGE,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
29、, complicated pregnancy, trauma, severe cardiovascular disease, acute renal disease). In children meningococcal or pseudomonas septicemia In neonates after complicated delivery.,CONGENITAL AND FAMILIAL ETIOLOGIES,Adrenoleukodystrophydefective oxidation of very long chain fatty acids (VLCFA) in perox
30、isomesaccumulation of VLCFA in central and peripheral nervous tissue, adrenals, gonads, and other organs.,CONGENITAL AND FAMILIAL ETIOLOGIES,Adrenal hypoplasiaAdrenal failure shortly after birth impaired development of the adult adrenal cortex,CONGENITAL AND FAMILIAL ETIOLOGIES,Familial glucocortico
31、id deficiencyRare 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 t
32、oneThe 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 hyperk
33、aliemia and acidosisAdrenal 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 poi
34、nt, the increased ACTH and renin maximally stimulate remaining cortical tissue,normal basal amounts of glucocorticoids and mineralocorticoids,no sufficient increase in response to stress,During transient state of partial steroid deficiency or decreased adrenal reserve, an acute crisis may be precipi
35、tated by surgery, trauma or infection.,The clinical features of Addisons disease are often misleading and may go unnoticed for months. Most of the symptoms and signs taken separately are non-specific.,ADRENOCORTICAL INSUFFICIENCY- CLINICAL FINDINGS,Clinical and laboratory features of chronic primary
36、 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
37、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 IN
38、SUFFICIENCY- 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 hypertensio
39、n 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 hypog
40、lycemia 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 hyperpigmen
41、tation 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
42、eosinophilia, lymphocytosis, normochromic anemia Elevations of hepatic transaminases Mild hypercalcemia,ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES,The 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
43、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 MORNING,Baseline plasma ACTH,Rapid ACTH stimulation test,ADRE
44、NAL INSUFFICIENCY,High plasma ACTH,PRIMARY ADRENAL INSUFFICIENCY,Low or normal plasma ACTH,SECUNDARY ADRENAL INSUFFICIENCY,Abnormal ACTH stimulation test,Normal ACTH stimulation test,Metyrapone or insulin test,Abnormal,Normal,NORMAL HYPOTHALAMIC PITUITARY ADRENAL AXIS,High plasma ACTH,INCIPIENT PRIM
45、ARY ADRENAL INSUFFICIENCY(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- DIAGNOS
46、TIC 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 a
47、utoantibodies 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 IN
48、SUFFICIENCY- 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 bl
49、ood 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.,
