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Addison's disease (primary adrenal failure)

Addison's disease (primary adrenal failure) is caused by deficiency of cortisol with or without deficiency of aldosterone. Etiology: 1) autoimmune adrenalitis* (also see Complications: below) 2) infections of the adrenal gland a) tuberculosis b) mycosis, especially histoplasmosis c) AIDS-associated - cytomegalovirus - Mycobacterium avium - cryptococcus - primary HIV d) bacterial infection 3) hemorrhagic adrenal infarction a) precipitating factors - postoperative period - coagulation disorders - hypercoagulable states - sepsis b) symptoms - abdominal or flank pain - fever 4) amyloidosis 5) hemochromatosis 6) metastatic neoplasm a) lymphoma b) leukemia c) lung cancer d) breast cancer e) rarely cause enough adrenal destruction to result in adrenal insufficiency [4] 7) bilateral adrenalectomy 8) sarcoidosis 9) adrenoleukodystrophy 10) see adrenal insufficiency for secondary adrenal insufficiency * most common cause of primary adrenal insufficiency Pathology: 1) autoimmune adrenalitis destroys all layers of the adrenal cortex - 90% of adrenal must be destroyed before adrenal failure occurs 2) secretion of cortisol, aldosterone & DHEA affected 3) glucocorticoid deficiency a) decreased cardiac stroke volume b) heart rate increases c) cardiac output declines d) vasopressin is released e) free water retention f) inhibition of catecholamine activity g) diminished peripheral vascular resistance h) hypotension 4) aldosterone deficiency a) urinary Na+ loss b) diminished urinary K+ excretion 5) DHEA-sulfate deficiency Clinical manifestations: 1) general manifestations of glucocorticoid deficiency a) weakness & fatigue b) weight loss c) diffuse musculoskeletal pain, arthralgia d) orthostatic hypotension e) dehydration f) auricular calcifications g) symptoms of hypoglycemia h) low-grade fever [4] 2) manifestations of mineralocorticoid deficiency a) salt craving b) orthostatic hypotension c) syncope 3) manifestations of androgen deficiency in women (DHEA-sulfate deficiency) a) decreased body hair, decreased pubic & axillary hair b) amenorrhea 4) skin manifestations a) mottled skin pigmentation (hyperpigmentation* due to ACTH secretion) - buccal mucosa (Caucasians) - lips, gingival margins, buccal mucosa - elbows, knees, knuckles, palmar creases, scars - vagina, rectum b) vitiligo suggests autoimmune etiology 5) gastrointestinal a) anorexia or aversion to food b) nausea & vomiting c) abdominal pain d) diarrhea 6) psychiatric manifestations a) depression b) apathy c) confusion d) psychosis e) paranoia * image [9] Laboratory: 1) complete blood count a) normochromic normocytic anemia b) leukopenia 1] neutropenia 2] eosinophilia 3] lymphocytosis 2) serum chemistries a) low serum Na+ b) low serum Cl- c) low serum HCO3- (metabolic acidosis) [10] d) high serum K+ e) serum Ca+2: hypercalcemia, generally mild to moderate f) serum glucose: fasting hypoglycemia g) serum urea: azotemia 3) urinalysis a) low urinary 17-ketosteroids, high urinary 17-hydroxysteroids b) low 24 hour urinary free cortisol 4) serum cortisol a) generally low, but generally not useful b) only 50% of patients with adrenal insufficiency have diagnostic morning serum cortisol of < 3 ug/dL c) in the presence of severe physiologic stress, serum cortisol < 20 ug/dL suggests adrenal insufficiency d) random serum cortisol > 20 ug/dL excludes adrenal insufficiency 5) serum aldosterone is low (unnecessary if hyponatremia & hyperkalemia) [4] 6) serum DHEA-sulfate low 7) plasma ACTH a) markedly elevated in primary adrenal insufficiency b) low or inappropriately normal in secondary adrenal insufficiency 8) plasma renin activity is high 9) cosyntropin (Cortrosyn) stimulation test - test of choice - a rise in serum cortisol of > 23 ug/dL rules out adrenal insufficiency - not needed if AM serum cortisol is < 3 ug/dL with signs & symptoms of cortisol deficiency [4] 10) insulin tolerance test a) gold standard for evaluation of hypothalamic-pituitary-adrenal axis b) hazardous test 11) steroid 21-hydroxylase antibody in serum (+ in autoimmune adrenalitis) 12) PPD -> if tuberculosis is a possible etiology Radiology: 1) calcification of adrenals is rarely observed 2) computed tomography (CT) of adrenal glands a) indicated if serum ACTH is elevated b) autoimmune adrenalitis leads to small adrenal glands c) infection, hemorrhage & other causes lead to large adrenal glands 3) MRI of the brain (sella turcica) if serum ACTH is low or normal Complications: - ~50% of patients with autoimmune adrenalitis have other endocrine autoimmune diseases (autoimmune polyglandular syndrome) - testing indicated Management: 1) general: glucocorticoid + mineralocorticoid deficiency - prednisone 5 mg PO QD + fluodrocortisone 0.05 mg PO QD [4] 2) glucocorticoid deficiency a) hydrocortisone (12-15 mg/m2 daily) - 20 mg PO qAM, 10 mg qPM [8] - 10 mg TID - 12.5-25 mg/day divided BID-TID [4] - physiologic replacement of cortisol is 20 mg QD b) prednisone 2.5-5 mg PO QD c) for minor illness, stress, fever > 100 F, influenza - 2-10 times the oral maintenance dose of to avoid adrenal crisis - dosage increase of glucocorticoid crucial even with minor illness [4,5] d) for severe illness or injury - hydrocortisone 100-150 mg/day IV divided every 6 hours - hydrocortisone 100 mg IV, then 50 mg every 6 hours, rapid taper [4] - septic shock: 150-200 mg/day [4] - dexamethasone 6-8 mg IV QD divided BID/TID (alternative) e) do not use dexamethasone for chronic glucocorticoid replacement therapy [4] 3) mineralocorticoid deficiency a) fludrocortisone (Florinef) 0.05-0.1 mg PO qAM - primary adrenal insufficiency - not required if hydrocortisone dose is > 50 mg/day [4] - higher doses may be needed if prednisone is used - titrate to normal serum sodium, serum potassium & to acceptable blood pressure [4] b) liberalized salt intake 4) DHEA 25-50 mg QD - women with mood disorder or low libido 5) patient education a) Medic alert bracelet b) patients should have & be instructed on use of parenteral glucocorticoids in case of emergency 6) follow-up a) glucocorticoid replacement - appetite, well-being, body weight are the best indicators to follow - serum ACTH, cortisol & electrolytes do not reflect clinical status & do not need to be monitored - signs of Cushing's syndrome suggest over-replacement - bone mineral density measurements should be performed periodically b) mineralocorticoid replacement - plasma renin activity is the best indicator of plasma volume & should be titrated to the upper normal range - serum K+ levels should be monitored - blood pressure should be checked frequently - recumbent hypertension is a problem in patients taking fludrocortisone

Interactions

disease interactions

Related

17 hydroxycorticosteroid 17 ketosteroid aldosterone (Electrocortin, Aldocortin) congenital adrenal hypoplasia cortisol; hydrocortisone (Cortef, Solu-Cortef, Alphaderm, Cetacort, Cortenema, Nutracort) cosyntropin (ACTH, Cortrosyn) stimulation test (delta cortisol test) hypoglycemia insulin tolerance test (ITT) potassium (K+) in serum/plasma renin; angiotensinogenase (REN)

Specific

hypoadrenal (Addisonian) crisis; acute adrenal insufficiency X-linked adrenal hypoplasia congenital

General

adrenal insufficiency

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 474
  2. DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg 862
  3. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 653-656
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022.
  5. Chakera AJ, Vaidya B. Addison disease in adults: diagnosis and management. Am J Med. 2010 May;123(5):409-13. PMID: 20399314
  6. Neary N, Nieman L Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):217-23. Review. PMID: 20375886 Free PMC Article
  7. Kong MF, Jeffcoate W. Eighty-six cases of Addison's disease. Clin Endocrinol (Oxf). 1994 Dec;41(6):757-61. PMID: 7889611
  8. Werumeus Buning J, van Faassen M, Brummelman P et al. Effects of hydrocortisone on the regulation of blood pressure: Results from a randomized controlled trial. J Clin Endocrinol Metab 2016 Oct; 101:3691 PMID: 27490921
  9. Mohamed F, Raal FJ. Images in Clinical Medicine Hyperpigmentation from Addison's Disease. N Engl J Med 2021; 384:1752. May 6 PMID: 33951364 https://www.nejm.org/doi/full/10.1056/NEJMicm2018221
  10. NEJM Knowledge+ Endocrinology
  11. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Adrenal Insufficiency & Addison's Disease https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease