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ADDISON’S DISEASE Nasimeh Rakhshani CC3 ADRENAL INSUFFICIENCY Addison’s Disease ADDISON’S DISEASE First described by Thomas Addison in 1855 His description referred to primary adrenal insufficiency At that time, the most common etiology was tuberculosis infiltration TB infiltration continues to be the leading cause worldwide ADRENAL INSUFFICIENCY (AI) Impairment in synthesis and/or release of adrenocortical hormones Classified as: Primary AI results from disease intrinsic to the adrenal cortex Secondary AI results from impaired release or effect of adrenocorticotropic hormone (ACTH) from the pituitary gland Tertiary AI results from the impaired release or effect of corticotropin releasing hormone (CRH) from the hypothalamus THE HPA AXIS (-) Hypothalamus CRH (-) ACTH Adrenal Gland Glucocorticoids CLINICAL MANIFESTATIONS In general, symptoms of AI include fatigue and GI complaints (nausea and vomiting) Clinical suspicion is important because the presentation of AI may be insidious and subtle Resultantly, clinical diagnosis is frequently delayed or missed early if unrecognized, may present in a life-threatening crisis with acute cardiovascular collapse (adrenal crisis) CLINICAL MANIFESTATIONS Signs and symptoms of primary adrenal insufficiency vary depending on which hormones are deficient and the severity of the defects CLINICAL MANIFESTATIONS CONT’D Glucocorticoid Deficiency Mineralocorticoid Deficiency Adrenal Androgen Deficiency Fasting hypoglycemia Hypotension Decreased axillary hair (females) Increased insulin sensitivity Dizziness Decreased pubic hair (females) Muscle weakness Salt craving Loss of libido (females) Morning headache Weight loss If prepubescent: assymptomatic ↑ production of POMC ↑ melanin Anorexia ↑pigmentation: palmer creases, gingival border,axilla Electrolyte anomalies (hypoNa, hyperK, metabolic acidosis) CLINICAL MANIFESTATIONS Adrenal Crisis Hypotension or shock Particularly if disproportionate to apparent underlying illness Serum electrolyte and metabolic abnormalities: Hyponatremia Hyperkalemia Metabolic Acidosis Hypoglycemia Vomiting and diarrhea, sometimes with severe abdominal pain Unexplained fever, weight loss and anorexia CLINICAL MANIFESTATIONS Adrenal Crisis: When to be suspicious??? In neonates, presents within 1st few days-weeks of life with vomiting, diarrhea, ↓BP, ↓Na, ↑K and ↓BG CAH (21-hydroxylase deficiency) most common cause In females with CAH is suggested by ambiguous genitalia In infants and older children with previously diagnosed AI Weight loss, serum electrolyte abnormalities +/hyperpigmentation Often a history of an antecedent precipitating stress (eg, surgery or infection) Bilateral adrenal hemorrhage or infarction Children with hypotension and shock that fail to respond to vigorous fluid resuscitation and inotropic medications Especially if have severe hyponatremia and hyperkalemia ETIOLOGY Steroidogenesis disorders: Defects within the biosynthetic pathways of glucocorticoids +/- mineralocorticoids lead to impaired synthesis of cortisol and/or aldosterone There are also drugs that inhibit cortisol synthesis (aminoglutethimide, ketoconazole, and etomidate) Adrenal damage: Injury from factors extrinsic to the adrenal gland may impair adrenal function Abnormal adrenal development: A lack of normal adrenocortical cell differentiation may result in adrenal hypoplasia Adrenal unresponsiveness to ACTH: Defects in adrenal responsiveness to ACTH results in cortisol deficiency Peroxisomal disorders: Accumulation of abnormal very long chain fatty acids within peroxisomes which may lead to adrenal impairment ETIOLOGY Steroidogenesis disdorders Adrenal damage Abnormal adrenal develop’t Unresponsive Peroxisomal to ACTH defects CAH Adrenal hemorrage X-linked AHC Familial GC deficiency X-linked ALD/AMN Defect in aldosterone production Infection (TB, HIV, fungal) Adrenal hypoplasia SF-1 defect - Allgrove syndrome (triple A syn) Neonatal ALD Defects in Autoimmune cholesterol (polyglandular biochemistry AIS) Refsum disease -Wolman dz Zellweger syndrome ETIOLOGY CONTINUED Perry et al (2005): 20 years of data, 103 patients <18 y/o Primary AI 73% congenital adrenal hyperplasia (CAH) 13% autoimmune adrenal insufficiency 5% Peroxisomal disorders 3% Wolman disease (lysosomal acid lipase deficiency) 1% Adrenal hypoplasia congenita 1% Triple A syndrome (Unresponsiveness to ACTH) 6% No diagnosis identified DIAGNOSIS 3 Step Process: Confirm adrenal insufficiency demonstrating inappropriately low cortisol secretion Determine whether the cortisol deficiency is primary or central AI Determine the cause of the underlying disorder DIAGNOSTIC TESTS Static Tests Cortisol, ACTH, Adrenal Androgens Mineralocorticoid status Serum electrolytes Plasma renin activity (PRA), direct [renin] Dynamic Tests Short ACTH stimulation test: Serum cortisol levels are measured before and 60 minutes after the rapid IV infusion of synthetic ACTH (cosyntropin) Tests of ACTH secretory ability Insulin-induced hypoglycemia Glucagon Metyrapone test CRH stimulation test: helps determine if 2o or 3o AI 1. CONFIRMING AI Initial step: measurement of serum ACTH and cortisol in the morning (8 a.m.) and in the fasting state If serum cortisol is low and serum ACTH is high likely primary AI and diagnosis can be confirmed with an ACTH stimulation test If low cortisol and normal lytes the rapid ACTH stimulation test often performed simultaneously If serum ACTH is also low, serum cortisol is indeterminate or pituitary disease is suspected likely central AI tests of ACTH secretory ability 1. CONFIRMING AI CONT’D In patients suspected of adrenal crisis: Immediate treatment crucial and must not postpone until diagnosis confirmed Draw required samples and initiate therapy (saline and GC replacement) Cortisol, ACTH, electrolytes, PRA, renin, etc. May perform a short ACTH stimulation test following treatment in these patients if: Treatment has been given for < a few days (no adrenal suppression secondary to treatment) Dexamethasone used to treat (not detected in cortisol assay unlike hydrocortisone and cortisone) 2. ESTABLISH THE LEVEL OF DEFECT Diagnosis of Primary AI:↓ am cortisol and ↑ am ACTH levels + ↓ or absent cortisol in response to ACTH stimulation test Often evidence of mineralocorticoid deficiency hyponatremia, hyperkalemia, ↑ PRA and/or ↑ [renin] Diagnosis of Central AI: ↓ Basal and ACTH stimulated cortisol secretion and ↓ Basal ACTH tests of ACTH secretory ability +/- CRF stimulation test Practically, not always necessary to determine if AI is 2o or 3o treatment is often the same Plasma levels of renin and aldosterone are usually unaffected in central AI 3. EVALUATION OF CAUSE Primary AI Evaluate for CAH (most common cause of 1o AI ) adrenal androgens Measure adrenal antibodies if +ive screen for autoimmune polyglandular syndromes If antibodies negative screen for other causes of 1o AI Measuring antibodies to other endocrine glands (thyroid, parathyroid, and islet cell antibodies) Imaging (CT) identifying adrenal hemorrhage, calcifications, or infiltrative disease Central AI Evaluate for secretion of other pituitary hormones DIAGNOSTIC APPROACH TREATMENT OF ADRENAL INSUFFICIENCY Principles: Maintenance Therapy (Replacement) Stressed Conditions TREATMENT CONT’D Maintenance Therapy Glucocorticoid Therapy Calculated according to body surface area Often hydrocortisone is preferred because of its short duration of action and low potency ease in titration to optimal dose (5-16 mg/m2/d divided into 3 doses) During follow-up must ensure adequate somatic growth (weight, BA, height and weight velocities) and screen for symptoms of insufficiency Must also screen for symptoms of GC excess Mineralocorticoid Therapy Fludrocortisone (Florinef) 0.05-0.2 mg/d do not vary by age or surface area because aldosterone secretion rate is nearly constant throughout the lifespan Monitor for signs of inadequate replacement: dehydration, poor weight gain, salt-craving, and hyponatremia with hyperkalemia TREATMENT CONT’D Stress Conditions Primary goal is to avoid serious consequences of an adrenal crisis always wear identification Illness: Minor stress (e.g. sore throat, rhinorrhea, T < 38ºC) may not require ∆ dose Moderate stress (e.g. severe URTI) double the GC replacement dose Major stress (e.g. T > 38ºC and/or vomiting), three to four times the GC replacement dose If child unable to keep down oral dose administer IM GC Surgery: During general anesthesia, +/- surgery, the GC requirements increases greatly Protocols vary depending on nature of surgery, length of surgery, age of patient etc Stress dosing is generally continued until the patient can tolerate oral intake, is afebrile, and is hemodynamically stable THANK YOU!!! 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