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A. Definitions
[Figure] "Steroid Metabolism"

  1. Primary (1°) Adrenal Insufficiency
    1. Intrinsic adrenal gland dysfunction, Addison's Disease
    2. Usually affects aldosterone, cortisol, and sex steroid production
    3. Adrenal medulla production of vasoactive amines may be normal or compromised
    4. In true autoimmune adrenal gland destruction, adrenal medulla is spared
    5. ACTH levels are elevated and skin/mucous membrane pigmentation occurs
    6. Potassium levels are high due to aldosterone deficiency
    7. Associated with hypothyroidism, diabetes mellitus type 1,
  2. Secondary (2°) Adrenal Insufficiency
    1. Hypothalamic Insufficiency - abnormal corticotropic releasing hormone (CRH)
    2. Pituitary Insufficiency - ACTH deficiency
    3. Skin and mucous membranes are pale
    4. Potassium levels are normal; sodium normal or low
    5. Other pituitary hormones may be missing
  3. Pitutiary Insufficiency
    1. Pro-opiomelanocortin is a prohormone processed to ACTH and other hormones
    2. Adrenocorticotropic hormone (ACTH) is primary stimulant of adrenal cortisol production
  4. Prevalence of adrenal insufficiency is 60-80 persons per million population
  5. May be part of polyendocrine failure syndrome; other autoimmunity should be sought [16]
  6. Mixed primary and secondary adrenal insufficiency very common in severely ill patients [3]

B. Etiology of Primary Adrenal Insufficiency

  1. Autoimmune Disease [2,10]
    1. Autoimmune adrenalitis ~90% of primary adrenal insufficiency in developed world
    2. Isolated adrenal deficiency ~40% (Addison Disease)
    3. Polyendocrine failure syndromes (autoimmune polyendocrine syndromes, APS) ~60%
    4. Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) arises in up to 15% of patients with autoimmune adrenalitis (Polyendocrine failure type I)
    5. Autoimune polyendocrine syndrome 2 includes adrenal and thyroid disease
    6. Most patients have anti-adrenal antibodies, such as anti-21-hydroxylase antibodies
    7. Associated with HLA-DR3 (~6X risk)
  2. Adrenal Hemorrhage
    1. Coagulopathy (45%)
    2. Post-operative (17%)
    3. Anti-coagulation (16%)
    4. Cardiac Disease (12%)
    5. Infection (11%) - especially meningococcus
    6. Post-partum meningococcemia (Waterhouse-Friedrickson Syndrome)
    7. Waterhouse-Friderichsen-like Syndrome reported in children with Staphylococcus aureus pneumonia and rapidly progressive multisystem failure [18]
  3. Adrenal Vein Thrombosis [15]
  4. Infection
    1. Tuberculosis - common cause only in developing world
    2. HIV Infection - decreasing incidence with current treatment
    3. Fungal Infection - mainly in immunosuppressed
  5. Adrenal Infiltration
    1. Metastatic Disease
    2. Sarcoidosis
    3. Amyloidosis
    4. Hemochromatosis
  6. Congenital Adrenal Hyperplasia [5]
    1. Usually due to defect in 21-hyroxylase
    2. Impaired production of cortisol and aldosterone
    3. Impaired development of medulla and reduced epinephrine/metanephrine production [14]
    4. Bilateral adrenal hyperplasia occurs with hyperandrogenism
    5. Salt losses, virilization (with hirsutism), adrenal crises occur
  7. Congenital Lipoid Adrenal Hyperplasia [4]
    1. Most severe genetic disorder of steroid biosynthesis
    2. Severe defect in conversion of cholesterol to pregnenolone
    3. Due to mutations in gene for steroidogenic acute regulatory protein or CYP11A
    4. Buildup of cholesterol and its esters in adrenal leads to adrenal failure
    5. Patients with karyotype 46,XY become phenotypically female
    6. May be fatal in utero; most surviving infants die within first year of life

C. Etiology of Secondary Adrenal Insufficiency

  1. Glucocorticoid Associated []
    1. Most common presentation occurs during stress following course of glucocorticoids
    2. May also occur during taper of glucocorticoids after prolonged (>2 week) therapy
    3. Glucocorticoids induce suppression of hypothalmic-pituitary-adrenal axis
    4. Adrenal suppression is dependent on total glucocorticoid dose and duration
  2. Megestrol Withdrawal
    1. Tapering of high dose megestrol acetate in patients with HIV [6]
    2. Megestrol can directly cause adrenal insufficiency as well [7]
  3. Pituitary Tumor
  4. Pituitary Infiltration
    1. Metastatic Tumor
    2. Sarcoidosis
    3. Histiocytosis
  5. Pituitary Necrosis
    1. Necrosis or bleeding into pituitary macroadenoma
    2. Shehan's Syndrome - postpartum
    3. Pituitary Radiation
  6. Pituitary Surgery
  7. Hypothalamic Tumors

D. Signs and Symptoms of Primary Adrenal Insufficiency [8]

  1. Weakness and Fatigue* 100%
  2. Weight Loss* 100%
  3. Hyperpigmentation 92%
  4. Hypotension* 88%
  5. Hyponatremia* 88%
  6. Hyperkalemia* 64%
  7. Gastrointestinal Symptoms* 56%
  8. Other Symptoms and Signs*
    1. Postural dizziness, presyncope, syncope
    2. Hypercalcemia
    3. Muscle and joint pain
    4. Vitiligo
    5. Eosinophilia
  9. Reduction in sexual interest and increased anxiety
  10. *Symptoms with asterick also occur in secondary adrenal insufficiency

E. Diagnosis [1,2]

  1. Baseline AM Serum Cortisol
    1. Normal AM cortisol level is >5µg/dL
    2. Level <3µg/dL is diagnostic of adrenal insufficiency
    3. Level <15µg/dL is diagnostic of adrenal insufficiency in critically ill patients [3]
    4. For critically ill patients with levels 15-34µg/dL, stimulation test recommended [3]
  2. Stimulation Tests with ACTH Analogs [9]
    1. Give 25µg Cortrosyn or 1µg or 250µg Cosyntropin IV or IM
    2. After 30-60 minutes, should have an increase in serum cortisol to >18-24µg/dL
    3. Cortisol level <15µg/dL is invariably abnormal
    4. Failure to increase cortisol indicates primary adrenal insufficiency (~95% sensitivity)
    5. ACTH levels are typically very high in primary (1°) adrenal insufficiency
    6. ACTH stimulation has no effect on serum aldosterone levels in 1° insufficiency
    7. Failure to increase cortisol level >9µg/dL suggests insufficiency in acutely ill patients [3]
    8. These stimulation tests are ~60% sensitive for 2° insufficiency
  3. Antibodies in 1° Adrenal Insufficiency (Addison Disease) [10]
    1. Adrenal Autoantibodies are present in most cases of 1° adrenal insufficiency
    2. Usually indirect immunofluorescence test on tissue sections
    3. Majority of autoantibodies are directed against 21-hydroxylase
    4. Minority of autoantibodies directed against 17-hydroxylase
    5. Antibodies to adrenal cortical antigen (IF) also found
  4. Tests for 2° Adrenal Insufficiency
    1. These are used for patients who have normal or decreased cortisol response to ACTH
    2. Hypothalamic stimulation is used
    3. Corticotropin Releasing Hormone (CRH) - given to stimulate pituitary ACTH
    4. Metyrapone Stimulation Test
    5. ACTH stimulation increases serum aldosterone levels in 2° insufficiency
  5. Rapid Metyrapone Stimulation Test [11]
    1. Metyrapone inhibts adrenal 11-hydroxylase
    2. This leads to increased 11-deoxycortisol in normal persons
    3. Metyrapone 30mg/kg is given and serum 11-deoxycortisol measured 8 hours later
    4. Normal persons increase serum 11-deoxycortisol to >200mmol/L
    5. Test is generally well tolerated
  6. Radiologic Testing
    1. Confirm secondary cause of 2° adrenal insufficiency with MRI scans
    2. Suspect pituitary or hypothalamic anomalies in 2° adrenal insufficiency
    3. Primary adrenal insufficiency not due to autoimmune disease or infection - CT scan

F. Therapy [1,2]

  1. Both glucocorticoid and mineralocorticoid must be provided ± DHEA replacement
  2. Glucocorticoid Replacement [10]
    1. Lowest dose possible should be used chronically for stable patients
    2. Doses must be increased with any kind of stress
    3. Typically, hydroxycortisone (HC) 15mg qam + 10mg qpm is used
    4. Prednisone divided 5mg qam, 2.5mg qpm is also effective
    5. Cortisone 25mg qam, 12.5mg qpm
    6. Mineralocorticoid replacement is also required (even with HC or cortisone)
  3. Mineralocorticoid Replacement
    1. Required only in primary adrenal insufficiency
    2. Fludrocortisone - 0.05-0.2mg (50-200µg) qd po
    3. Underdosing is most frequent problem
    4. Underdosing is usually accompanied by orthostasis and hyperkalemia
    5. Dosing may be adjusted based on serum potassium and/or renin levels
  4. Medical or Surgical Stress / Crisis
    1. Minor: 25mg HC or 5mg methylprednisolone (MeP) on day of procedure only
    2. Moderate: 50-75mg HC or 10-15mg MeP day of procedure, taper over 1-2 days
    3. Severe: 100-150mg HC or 20-30mg MeP day of procedure, taper over 2 days
    4. Critically Ill: 50-100mg HC q6-8 hours +50µg/d fludrocortisone until shock resolved
    5. In general, HC is preferred over MeP for stress situations
  5. Androgens
    1. Dehydroepiandrosterone (DHEA) or DHEA Sulfate
    2. Testosterone - oral agents or AndroGel (5gm 1% gel applied qd to skin, up to 10gm qd max)
    3. Men 60-80 years often have low-normal serum testosterone levels (<13.7nmol/L)
    4. Testosterone supplements for 6 months did not affect functional status or cognition, but increased lean body mass and had mixed effects on metabolic parameters [19]
    5. Testosterone supplements in men with low-normal levels not recommended at this time
  6. DHEA Therapy [2,13,17]
    1. DHEA is an androgenic steroid normally made by the adrenals
    2. DHEA and other androgens are reduced in adrenal insufficiency
    3. DHEA increases serum insulin-like growth fractor 1 (IGF-1) levels
    4. DHEA is converted to androstenedione and testosterone
    5. May reduce HDL levels slightly when given to women with adrenal insufficiency
    6. Increases well being, sexual interest and thoughts
    7. Reduces feelings of anxiety and depression
    8. Acne, hair loss, hirsutism have been reported in women on standard doses
    9. Dose is DHEA-S 50mg qd or qod
  7. Emergency Therapy
    1. Acute "Addisonian Crisis" treated with high dose hydrocortisone
    2. This high dose, also called "Stress Dose", is 100mg iv stat, then 50-100mg iv q8 hours
    3. Others recommend hydrocortisone 50mg IV q 6 hours [3]
    4. Volume repletion with isotonic saline
    5. Hydrocortisone should be tapered by 25-50% per day to maintenance doses

References

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  2. Arit W and Allolio B. 2003. Lancet. 361(9372):1881 abstract
  3. Cooper MS and Stewart PM. 2003. NEJM. 348(8):727 abstract
  4. Bose HS, Sugawara T, Strauss JF III, et al. 1996. NEJM. 335(25):1870 abstract
  5. Merke DP and Cutler GB Jr. 1997. JAMA. 277(13):1073 abstract
  6. Leinung MC, Liporce R, Miller CH. 1995. Ann Intern Med. 122(11):843 abstract
  7. Subramanian S, Goker H, Kanji A, Sweeney H. 1997. Arch Intern Med. 157(9):1008 abstract
  8. Keljo DJ and Squires RH Jr. 1996. NEJM. 334(1):46 (Case Discussion) abstract
  9. Dorin RI, Qualls CR, Crapo LM. 2003. Ann Intern Med. 139(3):194 abstract
  10. Baker JR Jr. 1997. JAMA. 278(22):1931 abstract
  11. Lamberts SWJ, de Herder WW, van der Lely AJ. 1998. Lancet. 352(9122):127
  12. Krasner AS. 1999. JAMA. 282(7):671 abstract
  13. Arlt W, Callies F, van Vlijmen JC, et al. 1999. NEJM. 341(14):1013 abstract
  14. Merke DP, Chrousos GP, Eisenhofer G, et al. 2000. NEJM. 343(19):1363
  15. Vlot AJ, van der Molen AJ, Muis MJ, Fijnheer R. 2001. Lancet. 358(9279):382 (Case Report) abstract
  16. Eisenbarth GTS and Gottlieb PA. 2004. NEJM. 350(20):2068 abstract
  17. Dehydroepiandrosterone (DHEA). 2005. Med Let. 47(1208):37 abstract
  18. Adem PV, Montgomery CP, Husain AN, et al. 2005. NEJM. 353(12):1245 abstract
  19. Emmelot-Vonk MH, Verhaar HJ, Pour HR, et al. 2008. JAMA. 299(1):39 abstract