What causes intermittent Addison's disease?

Causes of Intermittent Addison's Disease

Intermittent Addison's disease is most commonly caused by precipitating events such as infections, surgical procedures, injuries, severe allergic reactions, and gastrointestinal disturbances that trigger temporary adrenal insufficiency in predisposed individuals. 1

Primary Causes

Autoimmune Factors

• Autoimmune adrenalitis (accounts for ~85% of PAI cases in Western countries) 1
  • Presence of 21-hydroxylase autoantibodies (21OH-Ab) indicates autoimmune etiology
  • Autoimmune destruction may be gradual, leading to intermittent symptoms before complete adrenal failure

Precipitating Factors for Intermittent Symptoms

• Gastrointestinal disturbances (vomiting/diarrhea) - most common trigger 1
  • Prevents absorption of oral medication when increased doses are needed
• Infections (bacterial or viral)
• Surgical procedures or invasive medical interventions
• Physical injuries or trauma
• Severe allergic reactions
• Severe hypoglycemia (especially in diabetic patients)
• Myocardial infarction
• Strenuous physical activity without appropriate medication adjustment 1

Secondary Causes

Medication-Related Factors

• Immune checkpoint inhibitors (ICPIs) - can cause immune-related adrenal insufficiency 1
  • May present with fluctuating symptoms as the immune response varies
• Drugs affecting glucocorticoid synthesis, action, or metabolism 2
• Inadequate stress dosing during periods of physiological stress 1, 3

Unusual Presentations

• Neurological manifestations - may present with intermittent confusion or neurological deterioration 4
  • Can be misdiagnosed as primary neurological disorder
• Patients may maintain normal electrolyte profiles despite hypoaldosteronism 4
  • Makes diagnosis challenging as classic electrolyte abnormalities may be absent

Diagnostic Approach for Intermittent Symptoms

1. Morning cortisol and ACTH levels 3

   • Low cortisol (<3 μg/dL) with elevated ACTH (>2-3× upper limit normal) suggests primary adrenal insufficiency

2. Cosyntropin (ACTH) stimulation test 1, 3

   • Gold standard for diagnosis
   • Serum cortisol should exceed 550 nmol/L (20 μg/dL) at 30 or 60 minutes after ACTH administration

3. Evaluate for precipitating causes 1

   • Infection workup
   • Medication review
   • Recent stressors or surgical procedures

4. Additional testing

   • 21-hydroxylase antibodies (21OH-Ab) to confirm autoimmune etiology 1
   • Adrenal CT scan to rule out hemorrhage, tumors, or calcifications 1
   • Basic metabolic panel (sodium, potassium, CO2, glucose) 1
   • Renin and aldosterone levels 1

Management Considerations

Acute Management During Intermittent Episodes

• Immediate administration of hydrocortisone (100 mg IV/IM) 1
• Isotonic (0.9%) saline infusion (1 L over first hour) 1
• Identify and treat precipitating conditions 1
• Continue parenteral glucocorticoids until able to tolerate oral medication 1

Prevention of Intermittent Episodes

• Patient education on stress dosing is critical 3

  • Double oral dose during minor illness or stress
  • Triple oral dose for moderate illness with fever
  • Injectable hydrocortisone for severe illness or inability to take oral medication

• Medication adjustments for specific situations 1:

  • Major surgery: 100 mg hydrocortisone IM before anesthesia, continue every 6 hours until oral intake resumes
  • Minor procedures: Extra morning dose 1 hour prior to procedure
  • Strenuous exercise: Additional 5 mg hydrocortisone before activity

Long-term Management

• Regular endocrinology follow-up to adjust treatment regimens 3
• Medical alert bracelet or card identifying adrenal insufficiency 1
• Monitoring for development of other autoimmune disorders (up to 50% develop another autoimmune condition) 5

Common Pitfalls to Avoid

• Delayed diagnosis due to non-specific symptoms 2

  • Fatigue, anorexia, nausea, and orthostasis may be attributed to other conditions

• Failure to recognize adrenal crisis during intermittent episodes 1

  • Symptoms include hypotension, dehydration, abdominal pain, and altered mental status

• Inadequate stress dosing during illness or procedures 1, 3

  • Patients and healthcare providers must understand the importance of increasing glucocorticoid doses

• Confounding factors in diagnosis 4

  • Recent administration of dexamethasone or etomidate can suppress adrenal function
  • Any unusually low cortisol level merits thorough investigation

• Overlooking diagnosis in absence of classic signs 4

  • Hyperpigmentation or hyperkalemia may not be present in intermittent cases