II. Epidemiology
- Addison's Disease Prevalence: 1 per 20,000 in U.S. and western europe
III. Pathophysiology
- Hypothalamic-Pituitary-Adrenal Axis (HPA) Dysfunction
- Lab features: Cortisol low, ACTH Low
- Causes
- Severe illness
- Exogenous Corticosteroid (suppression lasts months)
- All steroids forms and routes can cause adrenal suppression including Inhaled Steroids
- Adrenal suppression typically starts after 10-14 days
- Prednisone >7.5 mg/day for >3 weeks
- Dexamethasone >0.75 mg/day for >3 weeks
- Pituitary Infarction
- CNS Infection or tumor invasion
- Head Injury
- HIV Infection
- Adrenal Insufficiency
- Lab features: Cortisol low, ACTH high
- Causes
- Addison's Disease (Primary Adrenal Insufficiency)
- Primary adrenal failure of Adrenal Glands
- Mineralcorticoid deficiency
- Glucocorticoid deficiency
- Adrenal androgen deficiency
- Adrenal cortical destruction via Autoimmunity
- Isolated Adrenal Insufficiency or
- Component of Autoimmune Polyglandular Syndrome
- Primary adrenal failure of Adrenal Glands
- Idiopathic adrenal hypoplasia or destruction
- Granulomatous disease (e.g. Tuberculosis, Fungus)
- Amyloidosis
- Hemochromatosis
- Tumor
- Autoimmune Dystruction
- Drug mediated Cortisol inhibition
- Addison's Disease (Primary Adrenal Insufficiency)
IV. Stages: Autoimmune Adrenalitis
- Stage 1: Predisposing genetic risk
- HLA-B8
- HLA-DR3
- HLA-DR-4
- Stage 2: Precipitating trigger
- Environmental event such as Viral Infection
- Stage 3: Formation of 21-Hydroxylase Antibody
- Precedes symptoms and signs in 90% of cases
- Stage 4: Overt Adrenal Insufficiency (Metabolic Decompensation)
- Presents with Fatigue, Anorexia, Nausea, volume depletion and Hyperpigmentation
- Lab findings consistent with Addison's Disease (Increased ACTH, decreased 8 am Serum Cortisol)
- Stage 5: ACTH decreased response
- Addisonian Crisis presents with life-threatening Hypotension and shock
- May be unmasked by acute stress or illness
- Typically limited to primary Adrenal Insufficiency (as opposed to secondary Adrenal Insufficiency)
V. Symptoms
- Course
- Typically insidious course over years (making diagnosis difficult and cryptic)
- Constitutional (100% of cases)
- Gastrointestinal symptoms (92% of cases)
- Miscellaneous symptoms
- Salt craving (16% of cases)
- Altered Level of Consciousness (e.g. Delirium)
- Postural Dizziness (12% of cases)
- Myalgias or Arthralgias (10% of cases)
VI. Signs
- Fever
- Reduced Hair Growth
-
Hyperpigmentation (94% of cases)
- Only occurs with primary Adrenal Insufficiency
- Results from hyperstimulation of anterior pituitary Corticotrophs
- Cross-reactivity with Melatonin I receptor on Keratinocytes
- Skin with mottled areas of increased pigmentation
- Increased pigment in vermilion border of lips, vagina, Rectum as well as palmar creases, Buccal mucosa (Caucasian), nipples and scars
- Opposite findings of Vitiligo may occur in up to 10-20% of cases
- Only occurs with primary Adrenal Insufficiency
-
Hypotension (especially Postural Hypotension)
- Systolic Blood Pressure <110 mmHg in 90% of cases
- Signs of volume depletion or Dehydration
VII. Findings: Common Presentations
- Hypotension and Hypoglycemia (esp. refractory Hypoglycemia)
- Hyperkalemia and Hyponatremia
- Non-Anion Gap Metabolic Acidosis
VIII. Labs
-
Complete Blood Count
- Normochromic Normocytic Anemia
- Eosinophilia (helps differentiate from other causes)
- Serum Electrolytes
- Hyponatremia (88%)
- Hypochloremia
- Hyperkalemia (64%)
- Hypercalcemia (<33%)
- Hypoglycemia (67%)
- Helps differentiate from other causes
- Adrenal labs used in the diagnosis of Adrenal Insufficiency
- Serum Cortisol at 8 am (see diagnosis below)
- Corticotropin Stimulation Test (see diagnosis below)
- 21-hydroxylase Antibody
- ACTH
- Other adrenal labs
- Thyroid Stimulating Hormone (TSH)
- Increased TSH levels <30 mIU/L may normalize with treatment of Addison Disease
- Avoid Thyroid Replacement until Addison Disease excluded or treated (risk of Addisonian Crisis)
- Urine 17-ketosteroids low
- Urine 17-Hydroxysteroids low
- Thyroid Stimulating Hormone (TSH)
- Other findings
- Plasma renin increased (early marker in Adrenal Insufficiency)
IX. Associated Conditions: Autoimmune disorders
- At least one comorbid Autoimmune Condition accompanies Addison Disease in 50% of cases
-
Hashimoto's Thyroiditis or Graves Disease (22% lifetime Prevalence)
- Thyroid Hormone Replacement in a patient with untreated Addison Disease may result in Addisonian Crisis
- Celiac Sprue (12% lifetime Prevalence)
-
Type I Diabetes Mellitus (11% lifetimes Prevalence)
- Addison Disease may present in those with Type I Diabetes as decreased Insulin requirements and Hypoglycemia
- Hypoparathyroidism (10% lifetime Prevalence)
- Premature Ovarian Failure (10% lifetime Prevalence)
- Pernicious Anemia (5% lifetime Prevalence)
- Primary gonadal failure (2% lifetime Prevalence)
X. Diagnosis
- Initial screening (indications for Corticotropin Stimulation Test)
- Serum Cortisol level at 8 am
- Decreased to <3 mcg/dl
- Serum Potassium
- Increased in mineralcorticoid deficiency
- Serum Sodium
- Decreased in Cortisol deficiency or mineralcorticoid deficiency
- Plasma renin
- Increased (early finding of adrenal cortical dysfunction)
- ACTH
- Increased >50 pg/ml
- Serum Cortisol level at 8 am
-
Corticotropin Stimulation Test (Cosyntropin Stimulation Test)
- Must be off mineralcorticoids and Corticosteroids before test (do not withold in critically ill patients)
- Failed adrenal response (Serum Cortisol) to 250 mcg IV ACTH at 30 -60 minutes
- Low Cortisol (<18 mcg/dl) and low ACTH level suggests secondary Adrenal Insufficiency
- Low Cortisol (<18 mcg/dl) and high ACTH level suggests primary Adrenal Insufficiency (Addison's Disease)
- Obtain 21-hydroxylase Antibody level (suggests Autoimmune Adrenalitis)
- Obtain CT Abdomen of the Adrenal Glands (indicated when secondary Adrenal Insufficiency is considered)
- Adrenal Glands are small in Autoimmune Adrenalitis
- May demonstrate secondary cause such as adrenal tumor or Tuberculosis infiltration
XI. Management
- Acute Addisonian Crisis (initial severe, life-threatening presentation)
- Emergent Steroid replacement
- Fludrocortisone 0.1 mg daily AND
- Hydrocortisone
- Adults: 100 mg IV every 8 hours (or Dexamethasone 4 mg IV)
- Children: 1 to 2 mg/kg IV every 8 hours
- Newborns: 12.5 mg IV
- Infants and young children: 25 mg IV
- School Aged Children: 50 mg IV
- Teens (same as adult dosing): 100 mg IV
- Correct Electrolyte abnormalities (esp. Hyperkalemia)
- Monitor Glucose closely and correct Hypoglycemia
- D25 to D50 bolus in adults or D5NS infusion
- Hypoglycemia may be refractory until Corticosteroids are administered
- Treat Hypotension
- Start with fluid Resuscitation
- Hypotension may also be refractory until Corticosteroid administration
- Emergent Steroid replacement
- Acute stressors (e.g. illness or surgery)
- Chronic, life-long adrenal replacement
- Standard Glucocorticoid replacement (select one)
- Prednisone 3-5 mg orally daily
- Hydrocortisone 15-25 mg/day divided 2-3 times daily (with higher dose in AM)
- Backup Glucocorticoid replacement (for home IM use, when unable to tolerate oral medications)
- Dexamethasone 0.5 mg oral, IM or IV once daily
- Mineralcorticoid replacement
- Fludrocortisone 0.05 to 0.2 mg daily
- Consider increased dose for seasons with increased sweat loss
- Adjust based on Serum Sodium, Serum Potassium, Blood Pressure and plasma renin activity
- Androgen Replacement (optional)
- Dehydroepiandrosterone (DHEA) 25-50 mg daily (OTC supplement)
- Consider for improved mood and libido (especially in women)
- Times of Illness
- Mild to Moderate
- Double home dose of oral Glucocorticoid until illness resolved
- Moderate to Severe (e.g. hospitalization)
- See Stress Dose Steroid
- Start with tripling home dose for up to 3 days (or IV Hydrocortisone 25 mg every 6-8 hours)
- Taper to double home dose when improving
- Taper to home dose as illness resolves
- Mild to Moderate
- Standard Glucocorticoid replacement (select one)
XII. Resources
- National Adrenal Diseases Foundation
XIII. References
- Willis and Swaminathan in Herbert (2021) EM:Rap 21(4): 11-3
- Bleiken (2010) Am J Med Sci 339(6): 525-31 [PubMed]
- Cooper (2003) N Engl J Med 348:727-34 [PubMed]
- Michels (2014) Am Fam Physician 89(7): 563-8 [PubMed]