Addison’s Disease

1. Addison’s Disease Nasimeh Rakhshani CC3

2. Adrenal Insufficiency Addison’s Disease

3. 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

4. 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

5. The HPA Axis Glucocorticoids (-) Hypothalamus CRH (-) ACTH Adrenal Gland

6. 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)

7. Clinical Manifestations • Signs and symptoms of primary adrenal insufficiency vary depending on which hormones are deficient and the severity of the defects

8. Clinical Manifestations cont’d

10. 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

11. 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

12. 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

13. Etiology

14. 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

15. 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

16. 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

17. 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

18. 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)

19. 2. Establish the level of defect • Diagnosis of Primary AI:↓ amcortisol 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

20. 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 • Measuring antibodies to other endocrine glands (thyroid, parathyroid, and islet cell antibodies) • If antibodies negative screen for other causes of 1o AI • Imaging (CT) identifying adrenal hemorrhage, calcifications, or infiltrative disease • Central AI • Evaluate for secretion of other pituitary hormones

21. Diagnostic Approach

22. Treatment of Adrenal Insufficiency • Principles: • Maintenance Therapy (Replacement) • Stressed Conditions

23. 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/ddivided 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

24. 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

25. Thank You!!! Questions???