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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 reticularis – 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 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. 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. 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. Nomenclature for steroidogenic enzymes now utilized Trivial name Past Current Cholesterol side-chain cleavage enzyme; desmolase P450scc CYP11A1 3β-Hydroxysteroid dehydrogenase 3β-HSD 3β-HSD 17α-Hydroxylase/17,20-lyase P450c17 CYP17 21-Hydroxylase P450c21 CYP21A2 11β-Hydroxylase P450c11 CYP11B1 Aldosterone synthase; P450C11AS CYP11B2 corticosterone 18-methylcorticosterone oxidase/lyase Main steroid biosynthetic pathways (mineralocorticoids and glucocorticoids). CYP17 cholesterol CYP11A1 17,20-lyase 17α-hydroxylase 17αOH-pregnenolone pregnenolone 17α OH-progesterone progesterone CYP21A2 CYP11B2 11-deoxycorticosterone (DOC) 11-deoxycortisol (S) 11β-hydroxylase corticosterone (B) 18-hydroxylase CYP11B1 18OH-corticosterone 18-methyloxidase ALDOSTERONE CORTISOL (F) ZONA FASTICULATA ZONA GLOMERULOSA 3β-HSD II Main steroid biosynthetic pathways (adernal androgens). cholesterol CYP11A1 pregnenolone CYP17 17αhydroxylase 17β-HSD 17,20-lyase 17αOHpregnenolone Dehydroepiandrosterone Androstendiol (DHEA) 3β-HSD II progesterone 17α OHprogesterone ∆4androstendione testosterone estrone estradiol CYP19 ZONA RETICULARIS 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. Regulation of the hypothalamic-pituitary-adrenal axis. Cicardian rhythms Feeding cycles cytocines stress HIGHER BRAIN CENTERS + - HYPOTHALAMUS + Neurotransmitters - neuropeptides CRH-AVP PITUITARY GLAND ACTH ADRENAL CORTEX CBG Cortisol-CBG + + cytokines - Free-cortisol PERIPHERIAL TISSUES - Inflammatry agents 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 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 skin melanocytes. ADRENOCORTICOTROPIC HORMONE [ACTH] The acute effect of The chronic effects ACTH of ACTH activation exisiting CYP11A1 to convert cholesterol to pregnenolone increase 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. 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. ADRENOCORTICAL INSUFFICIENCY Impairment of the adrenal production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone) leads to a lifethreatening situation that is often misinterpreted and neglected. ADRENOCORTICAL INSUFFICIENCY PRIMARY SECONDARY (Addison’s disease) inadequate ACTH damage of the adrenal glands 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. 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. 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. CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY Autoimmune adrenalitis (80%) Infectoius adrenalitis tuberculosis (20%) histioplasmosis, paracoccidioidomycosis, 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, etomidate, surgery) Congenital and familiar Adrenoleukodystrophy Adrenal hypoplasia Familial glucocorticoid deficiency 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. AUTOIMMUNE ADRENALITIS Lymphocytic infiltration of the adrenals gradual destruction of cortical cells and their replacement by fibrotic tissue. AUTOIMMUNE ADRENALITIS 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 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 INFECTIOUS ADRENALITIS Adrenal tuberculosis is the secondmost common cause of Addison’s disease in most countries (20%). The adrenal gland are completely destroyed, including the medulla. caseous necrosis fibrosis INFECTIOUS ADRENALITIS Disseminated fungal infections can destroy the 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 lymphoma Amyloidosis 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 Kaposi’s sarcoma and lymphoma Drugs (ketoconazole, rifampin, phenytoin) Symptoms and signs of Addison’s disease may be mistaken and imputed to AIDS itself. 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. 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 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 precipitated by surgery, trauma or infection. 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. 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 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. 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 Addison’s disease. 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 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 rhythm of basal cortisol, the stimulated cortisol concentration is independent of the time of day. Diagnostic approach to primary and secondary adrenal insufficiency CONCOMITANT Baseline plasma ACTH IN EARLY MORNING Rapid ACTH stimulation test Normal ACTH stimulation test High plasma ACTH Abnormal ACTH stimulation test ADRENAL INSUFFICIENCY Metyrapone or insulin test INCIPIENT PRIMARY ADRENAL INSUFFICIENCY (rare) Normal Abnormal NORMAL HYPOTHALAMIC PITUITARY ADRENAL AXIS Low or normal plasma ACTH High plasma ACTH PRIMARY SECUNDARY ADRENAL INSUFFICIENCY ADRENAL INSUFFICIENCY ADRENOCORTICAL INSUFFICIENCY- DIAGNOSTIC PROCEDURES Aldosterone concentration is low, nonresponsive 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- TREATMENT 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 patient’s subjective feeling, and the aim of treatment should be to administrate the smallest dose to keeps the patient’s 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. SECONDARY ADRENAL INSUFFICIENCY Causes of secondary adrenal insufficiency Long-term glucocorticoid administration Selective cure of Cushing’s syndrome Pituitary adenomas Metastatic tumors Lymphocytic hypophisitis Sarcoidosis, histiocytosis Sheehan’s 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 Addison’s 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. ACUTE ADRENAL INSUFFICIENCY Acute adrenal insufficiency is a medical emergency that is too often misdiagnosed. It may occur in a patient with known and treated adrenal insufficiency, in the presence of a stressfull situation if: the dose of glucocorticoid treatment has not been appropriately increased, or the patients cannot retain medication because of vomiting. ACUTE ADRENAL INSUFFICIENCY Acute adrenal insufficiency develops rapidly (not days but hours). Symptoms and signs: gastrointestinal symptoms fever Hypotension hyponatremia, hyperkaliemia, lymphocytosis, and eosinophilia ACUTE ADRENAL INSUFFICIENCY Gastrointestinal symptoms anorexia nausea vomiting abdominal pain mimics an acute surgical abdomen ACUTE ADRENAL INSUFFICIENCY Fever is commonly associated Hypoadrenalism itself infection ACUTE ADRENAL INSUFFICIENCY Hypotension may develop into hypovolemic shock with apathy and confusion. ACUTE ADRENAL INSUFFICIENCY In the previously undiagnosed patient, clinical features are highly misleading. The presence of hyperpigmentation (primary adrenal disease) suggests the diagnosis. ACUTE ADRENAL INSUFFICIENCY In the cause of adrenal hemorrhage causing acute destruction of the glands, the presenting features are abdominal or flank pain, in addition to rapidly developing signs of acute adrenal insufficiency (hiperpigmentation is absent). ACUTE ADRENAL INSUFFICIENCY The confirmation of the diagnosis should not delay the institution of therapy. ACUTE ADRENAL INSUFFICIENCY In the majority of cases, it is sufficient to obtain a plasma sample for assay of cortisol (and ACTH) ACUTE ADRENAL INSUFFICIENCY If the plasma cortisol level is below 20 g/dl (SI=0.56 mol/l) in the face of hypovolemia or shock the diagnosis is confirmed. ACUTE ADRENAL INSUFFICIENCY A rapid (30-minute) ACTH stimulation test may be obtained, without delaying the appropriate therapy by use of dexamethasone as a starting glucocorticoid ACUTE ADRENAL INSUFFICIENCY TREATMENT In the face of a strong clinical suspicion for acute adrenal insufficiency, blood is drown for the measurement of electrolytes, glucose, cortisol and (if possible) ACTH, and treatment is instituted immediately, without waiting for the results. ACUTE ADRENAL INSUFFICIENCY TREATMENT Vigorous intravenous rehydration: saline 0.9% or 5% glucose in 0.9% saline e.g., 2 liters in 3 hours; continued at a lower rate for the next 24 to 48 hours ACUTE ADRENAL INSUFFICIENCY TREATMENT Hydrocortisone iv 100 mg is injected as soon as possible, and given every 6 hours iv or imm at the same dose for the first 24 hours. Mineralocorticoids are not necessary. ACUTE ADRENAL INSUFFICIENCY TREATMENT Any precipitating illness should be explored and appropriately treated. ACUTE ADRENAL INSUFFICIENCY TREATMENT In the absence of complications, treatment can be tapered within 3 to 5 days and oral mineralocorticoids (9-fluorocortisol 0.1 mg/day) are started when the patient is able to take food and when hydrocortisone has been decreased to less than 60 mg per day.