Adrenal

Addison's Disease

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

  • 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. Prednisone >7.5 mg/day for >3 weeks
        2. 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
      2. Idiopathic adrenal hypoplasia or destruction
        1. Granulomatous disease (e.g. Tuberculosis, Fungus)
        2. Amyloidosis
        3. Hemochromatosis
        4. Tumor
        5. Autoimmune Dystruction
      3. Drug mediated cortisol inhibition
        1. Etomidate
        2. Ketoconazole
  • Epidemiology
  1. Prevalence: 1 per 20,000 in U.S. and western europe
  • 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)
  • 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)
  • 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
  • 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 (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)
  • 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)
  • Diagnosis
  1. Initial screening (indications for Corticotropin Stimulation Test)
    1. Serum Cortisol level at 8 am decreased to <3 mcg/dl
    2. Serum Potassium increased in mineralcorticoid deficiency
    3. Serum Sodium decreased in cortisol deficiency or mineralcorticoid deficiency
    4. Plasma renin increased (early finding of adrenal cortical dysfunction)
    5. ACTH increased >50 pg/ml
  2. Corticotropin Stimulation Test (Cosyntropin Stimulation Test)
    1. Failed adrenal response (Serum Cortisol) to 250 mcg IV ACTH at 30 -60 minutes
    2. Low cortisol (<18 mcg/dl) and low ACTH level suggests secondary Adrenal Insufficiency
    3. 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
  • Management
  1. Acute Addisonian Crisis (initial severe, life-threatening presentation)
    1. Hydrocortisone 100 mg IV every 6 hours (or Dexamethasone 4 mg IV) AND
    2. Fludrocortisone 0.1 mg daily AND
    3. Correct electrolyte abnormalities AND
    4. Monitor Glucose closely and correct Hypoglycemia (D50 in adults)
  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
    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)
  • Resources
  1. National Adrenal Diseases Foundation
    1. http://www.nadf.us