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ADRENOCORTICAL INSUFFICIENCY

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

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ADRENOCORTICAL INSUFFICIENCY

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  1. ADRENOCORTICAL INSUFFICIENCY

  2. THE ADRENALCORTEXBASIS CONCEPTS

  3. 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 reticularis – biosynthesis of adrenal androgens.

  4. STEROID BIOSYNTHESIS • Steroidogenesis results from specific sequential enzymatic conversions of cholesterol substrate into steroid hormones, which exert a wide variety of biological activities.

  5. STEROID BIOSYNTHESIS • A series of steroidogenic enzymes are compartmentalized 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.

  6. STEROID BIOSYNTHESIS • Approximately ~80% of adrenal cholesterol sources are provided by circulating low density lipoprotein (LDL). • The adrenal cells can also synthesize cholesterol de novo from acetyl coenzyme A.

  7. 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 cleavage (CYP11A1) enzyme to generate pregnenolone.

  8. Nomenclature for steroidogenic enzymes now utilized

  9. Main steroid biosynthetic pathways (mineralocorticoids and glucocorticoids). CYP17 cholesterol 17,20-lyase CYP11A1 17α-hydroxylase 17αOH-pregnenolone pregnenolone 3β-HSD II 17α OH-progesterone progesterone CYP21A2 11-deoxycorticosterone (DOC) 11-deoxycortisol (S) CYP11B2 ZONA GLOMERULOSA 11β-hydroxylase CYP11B1 ZONA FASTICULATA corticosterone (B) 18-hydroxylase 18OH-corticosterone CORTISOL (F) 18-methyloxidase ALDOSTERONE

  10. Main steroid biosynthetic pathways (adernal androgens). cholesterol CYP17 17β-HSD 17α- hydroxylase 17,20-lyase CYP11A1 Dehydro-epiandrosterone (DHEA) 17αOH- pregnenolone Androstendiol pregnenolone 3β-HSD II 17α OH- progesterone progesterone ∆4-androstendione testosterone CYP19 estrone estradiol ZONA RETICULARIS

  11. REGULATION OF GLUCOCORTICOID SECRETION • The secretion of cortisol is regulated by several levels of signals and interactions between the brain, the hypothalamus, the pituitary, and the adrenal glands.

  12. Regulation of the hypothalamic-pituitary-adrenal axis. Cicardian rhythms Feeding cycles stress HIGHER BRAIN CENTERS + Neurotransmitters neuropeptides + HYPOTHALAMUS cytocines - - CRH-AVP PITUITARY GLAND ACTH ADRENAL CORTEX CBG Cortisol-CBG - - + + Free-cortisol - - cytokines Inflammatry agents PERIPHERIAL TISSUES

  13. CORTICOTROPIN-RELEASING HORMONE(CRH)  41-aminoacid peptide synthesized by neurons in the paraventricular hypothalamic nucleus • Action:  • mRNA levels of pro-opiomelanocortin (POMC), the polypeptide precursor of ACTH

  14. 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 skin melanocytes. ADRENOCORTICOTROPIC HORMONE [ACTH]

  15. 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) ADRENOCORTICOTROPIC HORMONE [ACTH]

  16. IN THE CHRONIC ABSENCE OF ACTH , THE ADRENAL CORTEX BECOMES ATROPHIC.

  17. 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 hypothalamic paraventricular nuclei.

  18. ADRENOCORTICALINSUFFICIENCY • Impairment of the adrenal production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) leads to a life-threatening situation that is often misinterpreted and neglected.

  19. PRIMARY (Addison’s disease) damage of the adrenal glands SECONDARY inadequate ACTH and/or CRH secretion ADRENOCORTICAL INSUFFICIENCY

  20. 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.

  21. Iatrogenic adrenal insufficiency, secundary to exogenous glucocorticoid therapy, includes large number of patients and implies similar risks of acute adrenal crisis.

  22. Congenital 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. • Complete and near-complete blocks of the 21-hydroxylase enzyme (classical form of CAH) occurs in 1 in 15 000 live births worlwide.

  23. ADRENOCORTICAL INSUFFICIENCY • For 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.

  24. CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY • Autoimmune adrenalitis (80%) • Infectoius adrenalitis • tuberculosis (20%) • histioplasmosis, paracoccidioidomycosis, blastomycosis, coccidioidomycosis, cryptococcosis • Invasive destruction • metastases • lymphoma • amyloidosis, sarcoidosis

  25. CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY • AIDS (infectious or invasive destruction) • Adrenal hemorrhage • Iatrogenic (mitotane, ketoconazole, aminoglutethimide, metyrapone, etomidate, surgery) • Congenital and familiar • Adrenoleukodystrophy • Adrenal hypoplasia • Familial glucocorticoid deficiency

  26. AUTOIMMUNE ADRENALITIS • The most common cause of Addison’s disease. • Humoral and cellular immunity are both involved. • Antibodies 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.

  27. AUTOIMMUNE ADRENALITIS • Lymphocytic infiltration of the adrenals  gradual destruction of cortical cells and their replacement by fibrotic tissue.

  28. AUTOIMMUNE ADRENALITIS • In 50% of the cases  association to other autoimmune endocrine or nonendocrine disorders  polyglandular autoimmune syndromes

  29. Type I Often familial, inhereted in an autosomal recessive pattern First manifestation: hypoparathyroidism and/or mucocutaneous candidiasis occurring during childhood Addison’s 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 Addison’s disease Hypoparathyroidism and candidiasis are absent POLYGLADULAR AUTOIMMUNE SYNDROME

  30. INFECTIOUS ADRENALITIS • Adrenal tuberculosis is the second-most common cause of Addison’s disease in most countries (20%). • The adrenal gland are completely destroyed, including the medulla.  caseous necrosis  fibrosis

  31. INFECTIOUS ADRENALITIS • Disseminated fungal infections can destroy the adrenal glands  histoplasmosis paracoccidioidomycosis South American blastomycosis • Syphilis has also become a rare cause.

  32. INVASIVE DESTRUCTION OF ADRENALS • Metastatic involvement of the adrenals  • lung cancer • breast cancer • stomach cancer • colon cancer • melanoma • Hodgkin and non-Hodgkin lymphoma • Amyloidosis and sarcoidosis are rare invasive causes.

  33. 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 Kaposi’s sarcoma and lymphoma • Drugs (ketoconazole, rifampin, phenytoin) • Symptoms and signs of Addison’s disease may be mistaken and imputed to AIDS itself.

  34. IATROGENIC ADRENAL DEFICIENCY Iatrogenic adrenal deficiency is a predicted situation in medically treated Cushing’syndrome. • 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.

  35. 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.

  36. 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.

  37. CONGENITAL AND FAMILIAL ETIOLOGIES Adrenal hypoplasia Adrenal failure shortly after birth  impaired development of the adult adrenal cortex

  38. CONGENITAL AND FAMILIAL ETIOLOGIES Familial glucocorticoid deficiency Rare autosomal recessive disorder  unresponsiveness to ACTH (mutation of the ACTH receptor gene)

  39. 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

  40. 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)

  41. 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 no sufficient increase in response to stress normal basal amounts of glucocorticoids and mineralocorticoids

  42. During transient state of partial steroid deficiency or decreased adrenal reserve, an acute crisis may be precipitated by surgery, trauma or infection.

  43. ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS • The clinical features of Addison’s disease are often misleading and may go unnoticed for months. • Most of the symptoms and signs taken separately are non-specific.

  44. 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

  45. ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS Weakness, fatigue, malaise  constant complaints. Weakness occurs for usual, routine tasks and improves with rest, and it is frequently associated with myalgias and arthalgias.

  46. 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).

  47. 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

  48. 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.

  49. 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 Addison’s disease.

  50. ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC PROCEDURES 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

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