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Activity of the Hypothalamic-Pituitary-Adrenal Axis under Normal Conditions (Panel A), during anAppropriate Response to Stress (Panel B), and during an Inappropriate Response to Critical Illness (Panel C) Cooper M and Stewart P. N Engl J Med 2003;348:727-734
Definition A disease state caused by insufficient circulating glucocorticoid and/or mineralocorticoid hormones. May be caused by abnormalities at any level of the hypothalamic-pituitary-adrenal axis. TYPES Primary Secondary Tertiary
EPIDEMIOLOGY Prevalence: 12 per 100,000 persons Incidence: 0.5 per 100,000 persons Age: may occur at any age, with peak incidence in the fourth decade Sex: Autoimmune causes: female predominance Non-autoimmune causes: equal sex distribution
Risk Factors1.Genetic: Isolated autoimmune adrenal insufficiency Congenital abnormalities of cortisol synthesis Autoimmune PGS 1: hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis PGS 2: >2 adrenal insufficiency, chronic lymphocytic thyroiditis, premature ovarian failure, type 1 diabetes mellitus, Graves’ disease, hypo-hyperthyroidism2. Medications: Rifampin, Phenytoin, Ketoconazole, etomidate, magesterol and opiates .3. Rapid withdrawal of glucocorticoids after long-term steroid therapy4. Anticoagulants5. Hypercoagulable states (adrenal infarction)6. Severe sepsis (e.g., meningococcus)
ETIOLOGYDestruction of the adrenal glands Autoimmune (~80% of cases) Isolated adrenal insufficiency Type I or II polyglandular autoimmune syndrome Infectious TB Fungal (Histoplasmosis, coccidiodomycosis, Cryptococcus) HIV/AIDS--- HIV, MAI, Cytolomegalovirus( CMV necrotizing adrenalitis) Metastatic Invasion Bilateral adrenal hemorrhage DIC, APL sepsis(Waterhouse-Friderichsen syndrome) Infiltrative (sarcoidosis, Amyloidosis, Hemochrmotosis ) Rare causes: Adrenoleukodystrophy, Adrenomyeloneuropathy, CAH. Bilateral adrenalectomy
Clinical ManifestationsUnexplained hypotension, weight loss, fatigue.Primary and Sec AI Fatigue, weakness, anorexia, weight loss N/V/D, dizziness, orthostatic hypotension Hyponatremia, hypoglycemia, EosinophiliaPrimary AI and associated conditions. Hyperpigmentation, hyperkalemia, salt craving Vitiligo, autoimmue thyroid diseaseSecondary AI & associated conditions: Pale skin, marked anemia Amenorrhea, scant pubic and axillary hairs, small testicles. Secondary hypothyroidism, delayed puberty Headache, visual symptoms, diabetes insipidus
Addison’s Disease: effect of MSH activity
DIAGNOSTIC APPROACH The diagnostic approach to adrenal insufficiency has 3 stages. Demonstration of an inappropriately low cortisol level Determination of the level of adrenal dysfunction (primary vs secondary) Identification of the specific cause of adrenal insufficiency
Adrenal autoantibodies test: for autoimmune adrenalitis Sensitivity 70%, specificity very highSTIMULATION TESTS:1. ACTH stimulation test – cortisol response to cosyntropin (250 µg followed by serial cortisol measures at 30 and 60 minutes) Cortisol <5 µg/dL – adrenal failure Cortisol >20 µg/dL – normal If cortisol ≤20 µg/dL but ≥5 µg/dL – need to evaluate for pituitary failure Simultaneous aldosterone: norm in sec AI2. Pituitary ACTH reserve testing Insulin tolerance testing Metyrapone overnight testing CT/MRI of chest, abdomen, pituitary.
Relative adrenal insufficiency Critical care and Resuscitation: Journal of the Australian Critical Care Medicine,2006 Dec;8(4):371-5 - In septic shock - Increment of < 250 nmol/L(9 µg/dL) in total serum cortisol level after administration of 250 microg corticotropin - RAI associated with increased risk of death - There is strong, but not overwhelming, evidence that administration of low doses of hydrocortisone to patients with septic shock, especially those with RAI, improves survival .
American Journal of Respiratory and Critical Care Medicine, 2006 Dec 15 In sepsis, adrenal insufficiency is likely when - Baseline cortisol levels <10 µg/dL Unlikely when - Cosyntropin-stimulated cortisol level > 44 µg/dL
Other testsCBC: anemia, moderate neutropenia, eosinophilia, relative lymphocytosisBMP: hyponatremia (90%), hyperkalemia(65%), hypoglycemia TSH, CXR plasma very long chain fatty acids S/ DHEA levels Plasma renin activity
Treatment of chronic AIMild cases hydrocortisone aloneModerate to SevereReplacement of corticosteroids and mineralocorticoidHydrocortisone----Drug of choice, 15-25 mg PO BID orPrednisone: 2-3 mg am, 1-2 mg pmFU response: normal WBC diff count with proper dose,Some patients need Florinef 0.05-0.3 qday or QOD---elevated PRA indicates need for higher dose.DHEA 50 mg PO qday: to some womenimprove sense of well being, mood and sexualityTreat infections immediately and vigorouslyIncrease dose of steroid in times of stress.Medical alert bracelet ….adrenal insuffiency ---takes hydrocortisone.
Treatment :Acute Adrenal crisis Glucocorticoid replacement1. Hydrocortisone 100 mg iv every 6 hr. for 24 hr.2. Hydrocortisone 50 mg every 6 hr. when stable3. Maintenance therapy (10 mg 3 times/days) by day 4 or 54. Increase dose to 200-400 mg/day if complication occurs5. Vasopressors may be needed. General and supportive measures1. Correct volume depletion, dehydration, hypoglycemia with iv saline and glucose2. Correct infection and other precipitating causes
Prognosis & Response totherapyLife expectancy is usually normal with good compliance.It is important to make sure that pt is taking medications regularly and knowledgeable about his condition.BP without orthostatic hypotension, normal lytes, PRA <5ng/ml/hCushing syndrome: overtreatmentPersistent fatigue consider epinephrine deficiency, suboptimal dosing, electrolyte problem.
PEARLS Mineralocorticoid deficiency is present only in primary adrenal insufficiency and accounts for hyponatremia, hyperkalemia, and salt craving. In general, a random afternoon or evening serum cortisol level is not useful for evaluation of adrenal insufficiency. A markedly elevated ACTH level in the context of a low cortisol level is useful to confirm suspected primary adrenal insufficiency. ACTH samples must be drawn in EDTA tubes, placed on ice, and processed immediately for reliable results.
ACTH stimulation testing is not useful in the evaluation of patients who have recently undergone pituitary surgery. Adrenal insufficiency is highly prevalent (~30%) in patients with AIDS who present with hyponatremia and hypovolemia. Pregnant women with adrenal insufficiency generally do not need increases in glucocorticoid or mineralocorticoid doses until labor and delivery, when stress doses are required. Prior Steroid use: at least 20mg of prednisone or its equivalent for 5 days in last 12 months. Topical steroids applied over large surface area, using occlusive dressing, high potency. inhaled steroid >0.8 mg/d for long duration