Addison's Disease

Aka: Addison's Disease, Addisons Disease, Addison Disease, Addisonian Crisis, Adrenal Cortical Insufficiency, Adrenal Insufficiency, Adrenal Hypofunction, Illness Induced Adrenal Insufficiency, Autoimmune Adrenalitis

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II. Epidemiology

  1. Addison's Disease Prevalence: 1 per 20,000 in U.S. and western europe

III. Pathophysiology

  1. Hypothalamic-Pituitary-Adrenal Axis (HPA) Dysfunction
    1. Lab features: Cortisol low, ACTH Low
    2. Causes
      1. Severe illness
      2. Exogenous Corticosteroid (suppression lasts months)
        1. All steroids forms and routes can cause adrenal suppression including Inhaled Steroids
        2. Adrenal suppression typically starts after 10-14 days
        3. Prednisone >7.5 mg/day for >3 weeks
        4. Dexamethasone >0.75 mg/day for >3 weeks
      3. Pituitary Infarction
      4. CNS Infection or tumor invasion
      5. Head Injury
      6. HIV Infection
  2. Adrenal Insufficiency
    1. Lab features: Cortisol low, ACTH high
    2. Causes
      1. Addison's Disease (Primary Adrenal Insufficiency)
        1. Primary adrenal failure of Adrenal Glands
          1. Mineralcorticoid deficiency
          2. Glucocorticoid deficiency
          3. Adrenal androgen deficiency
        2. Adrenal cortical destruction via Autoimmunity
          1. Isolated Adrenal Insufficiency or
          2. Component of Autoimmune Polyglandular Syndrome
            1. Autoimmune Polyglandular Syndrome, Type I
            2. Autoimmune Polyglandular Syndrome, Type II
      2. Cancer-Related
        1. Metastatic cancer resulting in adrenal Hemorrhage
        2. Checkpoint Inhibitors (e.g. CTLA-4 inhibitor, PD-1 Inhibitor)
      3. Idiopathic adrenal hypoplasia or destruction
        1. Granulomatous disease (e.g. Tuberculosis, Fungus)
        2. Amyloidosis
        3. Hemochromatosis
        4. Autoimmune Dystruction
      4. Drug mediated Cortisol inhibition
        1. Etomidate
        2. Ketoconazole

IV. Stages: Autoimmune Adrenalitis

  1. Stage 1: Predisposing genetic risk
    1. HLA-B8
    2. HLA-DR3
    3. HLA-DR-4
  2. Stage 2: Precipitating trigger
    1. Environmental event such as Viral Infection
  3. Stage 3: Formation of 21-Hydroxylase Antibody
    1. Precedes symptoms and signs in 90% of cases
  4. Stage 4: Overt Adrenal Insufficiency (Metabolic Decompensation)
    1. Presents with Fatigue, Anorexia, Nausea, volume depletion and Hyperpigmentation
    2. Lab findings consistent with Addison's Disease (Increased ACTH, decreased 8 am Serum Cortisol)
  5. Stage 5: ACTH decreased response
    1. Addisonian Crisis presents with life-threatening Hypotension and shock
    2. May be unmasked by acute stress or illness
    3. Typically limited to primary Adrenal Insufficiency (as opposed to secondary Adrenal Insufficiency)

V. Symptoms

  1. Course
    1. Typically insidious course over years (making diagnosis difficult and cryptic)
  2. Constitutional (100% of cases)
    1. Anorexia or weight loss
    2. Weakness
    3. Fatigue or Lethargy
  3. Gastrointestinal symptoms (92% of cases)
    1. Nausea or Vomiting
    2. Diarrhea
    3. Abdominal Pain
  4. Miscellaneous symptoms
    1. Salt craving (16% of cases)
    2. Altered Level of Consciousness (e.g. Delirium)
    3. Postural Dizziness (12% of cases)
    4. Myalgias or Arthralgias (10% of cases)

VI. Signs

  1. Fever
  2. Reduced Hair Growth
  3. Hyperpigmentation (94% of cases)
    1. Only occurs with primary Adrenal Insufficiency
      1. Results from hyperstimulation of anterior pituitary Corticotrophs
      2. Cross-reactivity with Melatonin I receptor on Keratinocytes
    2. Skin with mottled areas of increased pigmentation
    3. Increased pigment in vermilion border of lips, vagina, Rectum as well as palmar creases, Buccal mucosa (Caucasian), nipples and scars
    4. Opposite findings of Vitiligo may occur in up to 10-20% of cases
  4. Hypotension (especially Postural Hypotension)
    1. Systolic Blood Pressure <110 mmHg in 90% of cases
    2. Signs of volume depletion or Dehydration
    3. Fluid refractory Hypotension

VII. Findings: Common Presentations

  1. Hypotension and Hypoglycemia (esp. refractory Hypoglycemia)
  2. Hyperkalemia and Hyponatremia
  3. Non-Anion Gap Metabolic Acidosis

VIII. Labs

  1. Complete Blood Count
    1. Normochromic Normocytic Anemia
    2. Eosinophilia (helps differentiate from other causes)
  2. Serum Electrolytes
    1. Hyponatremia (88%)
    2. Hypochloremia
    3. Hyperkalemia (64%)
    4. Hypercalcemia (<33%)
    5. Hypoglycemia (67%)
      1. Helps differentiate from other causes
  3. Adrenal labs used in the diagnosis of Adrenal Insufficiency
    1. Serum Cortisol at 8 am decreased (see diagnosis below)
    2. Corticotropin Stimulation Test (see diagnosis below)
    3. 21-hydroxylase Antibody
    4. ACTH
  4. Other adrenal labs
    1. Thyroid Stimulating Hormone (TSH)
      1. Increased TSH levels <30 mIU/L may normalize with treatment of Addison Disease
      2. Avoid Thyroid Replacement until Addison Disease excluded or treated (risk of Addisonian Crisis)
    2. Urine 17-ketosteroids low
    3. Urine 17-Hydroxysteroids low
  5. Other findings
    1. Plasma renin increased (early marker in Adrenal Insufficiency)

IX. Associated Conditions: Autoimmune disorders

  1. At least one comorbid Autoimmune Condition accompanies Addison Disease in 50% of cases
  2. Hashimoto's Thyroiditis or Graves Disease (22% lifetime Prevalence)
    1. Thyroid Hormone Replacement in a patient with untreated Addison Disease may result in Addisonian Crisis
  3. Celiac Sprue (12% lifetime Prevalence)
  4. Type I Diabetes Mellitus (11% lifetimes Prevalence)
    1. Addison Disease may present in those with Type I Diabetes as decreased Insulin requirements and Hypoglycemia
  5. Hypoparathyroidism (10% lifetime Prevalence)
  6. Premature Ovarian Failure (10% lifetime Prevalence)
  7. Pernicious Anemia (5% lifetime Prevalence)
  8. Primary gonadal failure (2% lifetime Prevalence)

X. Diagnosis

  1. Initial screening (indications for Corticotropin Stimulation Test)
    1. Serum Cortisol level at 8 am
      1. Decreased to <3 mcg/dl
    2. Serum Potassium
      1. Increased in mineralcorticoid deficiency
    3. Serum Sodium
      1. Decreased in Cortisol deficiency or mineralcorticoid deficiency
    4. Plasma renin
      1. Increased (early finding of adrenal cortical dysfunction)
    5. ACTH
      1. Increased >50 pg/ml
  2. Corticotropin Stimulation Test (Cosyntropin Stimulation Test)
    1. Must be off mineralcorticoids and Corticosteroids before test (do not withold in critically ill patients)
    2. Failed adrenal response (Serum Cortisol) to 250 mcg IV ACTH at 30 -60 minutes
    3. Low Cortisol (<18 mcg/dl) and low ACTH level suggests secondary Adrenal Insufficiency
    4. Low Cortisol (<18 mcg/dl) and high ACTH level suggests primary Adrenal Insufficiency (Addison's Disease)
      1. Obtain 21-hydroxylase Antibody level (suggests Autoimmune Adrenalitis)
      2. Obtain CT Abdomen of the Adrenal Glands (indicated when secondary Adrenal Insufficiency is considered)
        1. Adrenal Glands are small in Autoimmune Adrenalitis
        2. May demonstrate secondary cause such as adrenal tumor or Tuberculosis infiltration

XI. Management

  1. Acute Addisonian Crisis (initial severe, life-threatening presentation)
    1. Emergent Steroid replacement
      1. Fludrocortisone 0.1 mg daily AND
      2. Hydrocortisone
        1. Adults: 100 mg IV, then 50 mg IV every 8 hours (or Dexamethasone 4 mg IV)
          1. Continuous infusion 200 mg IV over 24 hours may be used as an alternative
        2. Children: 1 to 2 mg/kg IV every 8 hours
          1. Newborns: 12.5 mg IV
          2. Infants and young children: 25 mg IV
          3. School Aged Children: 50 mg IV
          4. Teens (same as adult dosing): 100 mg IV
    2. Correct Electrolyte abnormalities (esp. Hyperkalemia)
      1. See Hyperkalemia Management
    3. Monitor Glucose closely and correct Hypoglycemia
      1. D25 to D50 bolus in adults or D5NS infusion
      2. Hypoglycemia may be refractory until Corticosteroids are administered
    4. Treat Hypotension
      1. Start with fluid Resuscitation
      2. Hypotension may also be refractory until Corticosteroid administration
  2. Acute stressors (e.g. illness or surgery)
    1. See Stress Dose Steroid
  3. Chronic, life-long adrenal replacement
    1. Standard Glucocorticoid replacement (select one)
      1. Prednisone 3-5 mg orally daily
      2. Hydrocortisone 15-25 mg/day divided 2-3 times daily (with higher dose in AM)
    2. Backup Glucocorticoid replacement (for home IM use, when unable to tolerate oral medications)
      1. Dexamethasone 0.5 mg oral, IM or IV once daily
    3. Mineralcorticoid replacement
      1. Fludrocortisone 0.05 to 0.2 mg daily
      2. Consider increased dose for seasons with increased sweat loss
      3. Adjust based on Serum Sodium, Serum Potassium, Blood Pressure and plasma renin activity
    4. Androgen Replacement (optional)
      1. Dehydroepiandrosterone (DHEA) 25-50 mg daily (OTC supplement)
      2. Consider for improved mood and libido (especially in women)
    5. Times of Illness
      1. Mild to Moderate
        1. Double home dose of oral Glucocorticoid until illness resolved
      2. Moderate to Severe (e.g. hospitalization)
        1. See Stress Dose Steroid
        2. Start with tripling home dose for up to 3 days (or IV Hydrocortisone 25 mg every 6-8 hours)
        3. Taper to double home dose when improving
        4. Taper to home dose as illness resolves

XII. Resources

  1. National Adrenal Diseases Foundation
    1. http://www.nadf.us

XIII. References

  1. Willis and Swaminathan in Herbert (2021) EM:Rap 21(4): 11-3
  2. Bleiken (2010) Am J Med Sci 339(6): 525-31 [PubMed]
  3. Cooper (2003) N Engl J Med 348:727-34 [PubMed]
  4. Michels (2014) Am Fam Physician 89(7): 563-8 [PubMed]

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