Addison Disease Clinical Overview

Written By Danial Mirza

I. The "On-Call" Snapshot

  • Clinical Significance in Malaysia: A key "can't-miss" diagnosis for unexplained refractory hypotension, shock, hyponatremia, and hyperkalemia, especially in patients with a history of TB or autoimmune disease.

  • High-Yield Definition: Primary adrenal insufficiency is a clinical syndrome resulting from the destruction or dysfunction of the adrenal cortex, leading to a deficiency of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). (Source: Endocrine Society Clinical Practice Guideline, 2016).

  • Clinical One-Liner: Think of the patient who is chronically tired, getting tanned without sun exposure, craving salty foods, and has low blood pressure.

II. Etiology & Risk Factors

  • Etiology:

    • Worldwide (>80%): Autoimmune adrenalitis (destruction of the adrenal cortex by autoantibodies).

    • Malaysia & SEA: Infectious causes are still highly relevant. Always consider Tuberculosis. Other causes include metastatic disease, fungal infections (in immunocompromised), and adrenal hemorrhage.

  • Risk Factors:

    • Personal or family history of other autoimmune conditions (e.g., Type 1 DM, autoimmune thyroiditis - polyglandular autoimmune syndromes).

    • History of treated or active Tuberculosis.

    • Malignancy (esp. lung, breast, melanoma).

    • Long-term anticoagulation (risk of adrenal hemorrhage).

III. Quick Pathophysiology

It's simple. The adrenal cortex is destroyed.

  1. No Aldosterone → Can't retain sodium and water, can't excrete potassium. This leads to volume depletion, severe hypotension, hyperkalemia, and acidosis.

  2. No Cortisol → Can't mount a stress response. Can't maintain blood glucose. This leads to fatigue, weakness, hypoglycemia, and inability to cope with physiological stress (like an infection), precipitating a crisis. The feedback loop is broken, so the pituitary pumps out ACTH. ACTH is related to Melanocyte-Stimulating Hormone (MSH), causing the classic hyperpigmentation.

IV. Classification

  • Primary Adrenal Insufficiency (Addison's Disease): The adrenal gland itself is the problem. This is what we are focusing on.

  • Secondary Adrenal Insufficiency: The pituitary gland fails to secrete ACTH. Aldosterone is usually preserved. No hyperpigmentation.

  • Tertiary Adrenal Insufficiency: The hypothalamus fails to secrete CRH. Most commonly seen with abrupt withdrawal of long-term exogenous steroids.

V. Clinical Assessment

🚩 Red Flags & Immediate Actions (Addisonian Crisis)

  • Hypotension (SBP <90 mmHg) or shock, especially if refractory to fluids:

    • Action: Give IV Hydrocortisone 100mg STAT. Do not wait for labs. Start aggressive IV fluid resuscitation with Normal Saline.

    • Reason: The patient lacks endogenous cortisol to maintain vascular tone.

  • Altered Mental Status (Confusion, Coma):

    • Action: Check CBG immediately. Treat hypoglycemia if present. Give IV Hydrocortisone.

    • Reason: Can be due to hypoglycemia, severe hypotension, or electrolyte imbalance.

  • ECG changes of severe hyperkalemia (e.g., peaked T waves, wide QRS):

    • Action: Start hyperkalemia protocol (IV Calcium Gluconate, IV Insulin/Dextrose).

    • Reason: Risk of fatal arrhythmia.

History:

  • Key Diagnostic Clues: Insidious onset of symptoms over months. The classic triad is weakness/fatigue, weight loss, and hyperpigmentation.

  • Symptom Breakdown:

    • Common (>50%): Chronic fatigue, muscle weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, salt craving, postural dizziness.

    • Less Common (10-50%): Myalgia, arthralgia, diarrhea/constipation.

  • Pertinent Negatives: Absence of fever (points away from sepsis), absence of recent steroid use (points away from tertiary AI).

Physical Examination (OSCE Approach):

  • General Inspection: Look for cachexia, signs of dehydration. Note the patient's level of consciousness.

  • Vitals: Postural hypotension is key (drop in SBP >20mmHg on standing). Tachycardia. Usually afebrile unless there is a concurrent infection.

  • Disease-Specific Examination:

    • Look:

      • Hyperpigmentation: Diffuse tanning, especially in sun-exposed areas. Look specifically at buccal mucosa, palmar creases, nail beds, and recent scars.

      • Vitiligo may be present if the cause is autoimmune.

    • Feel: Check skin turgor for dehydration.

  • Examination for Differentials: Look for a source of infection to rule out sepsis. Check thyroid for goiter (autoimmune context).

VI. Diagnostic Workflow

  • Differential Diagnosis:

    1. Sepsis:

      • Points For: Hypotension, tachycardia, malaise.

      • Points Against: Often no fever, lack of a clear infectious source, presence of hyperpigmentation, specific electrolyte pattern (hypoNa, hyperK).

      • How to Differentiate: Blood cultures, inflammatory markers (CRP/procalcitonin), and a random cortisol level (inappropriately low in the context of shock).

    2. Severe Acute Gastroenteritis (AGE):

      • Points For: Nausea, vomiting, abdominal pain, dehydration, hypotension.

      • Points Against: Chronic history of weight loss and fatigue, hyperpigmentation.

      • How to Differentiate: History and the characteristic electrolyte disturbance.

    3. Hypopituitarism (Secondary AI):

      • Points For: Weakness, hypotension, hypoglycemia.

      • Points Against: No hyperpigmentation, aldosterone is intact so electrolytes are often normal.

      • How to Differentiate: ACTH level will be low (not high), and other pituitary hormone deficiencies will be present.

  • Investigations Plan:

    • Bedside / Initial (First 15 Mins):

      • ECG: Look for signs of hyperkalemia.

      • CBG: Rule out hypoglycemia.

      • Urine dipstick: May show low sodium.

    • First-Line Labs & Imaging:

      • Urea & Electrolytes (U&E): The classic pattern is hyponatremia, hyperkalemia, metabolic acidosis, and high urea (pre-renal).

      • Random Serum Cortisol: In a critically ill patient, cortisol should be high (>500 nmol/L). A random cortisol <140 nmol/L is highly suggestive of AI. A level in between is indeterminate. Do not delay treatment waiting for this.

      • FBC: May show normocytic anemia, eosinophilia.

      • CXR: Look for a small heart (volume depletion) or evidence of TB.

    • Confirmatory / Gold Standard:

      • Short Synacthen Test (SST) / ACTH Stimulation Test: This is the definitive test.

        • Procedure: Take baseline serum cortisol. Administer 250mcg of synthetic ACTH (Synacthen) IV/IM. Measure cortisol again at 30 and 60 minutes.

        • Interpretation: A normal response is a peak cortisol level >500-550 nmol/L. Failure to mount this response confirms adrenal insufficiency.

        • Important: Perform this test after the patient is stable, or draw the baseline sample before giving stress-dose steroids if a crisis is suspected.

VII. Staging & Severity Assessment

This is less about staging and more about a spectrum of disease.

  • Chronic Stable Addison's: Patient is on replacement therapy, ambulant, and well.

  • Impending Crisis: Patient has an intercurrent illness (e.g., infection) and has not increased their steroid dose. They may present with worsening fatigue, vomiting, and postural symptoms.

  • Acute Adrenal (Addisonian) Crisis: A life-threatening emergency characterized by shock, hypoglycemia, and severe electrolyte imbalance.

VIII. Management Plan

A. Principle of Management:

  1. In crisis: Reverse shock, correct electrolytes, and provide high-dose glucocorticoids.

  2. Chronic: Replace missing hormones (glucocorticoid and mineralocorticoid) and educate the patient on sick-day management.

B. Immediate Stabilisation (The ABCDE Plan for Adrenal Crisis):

  • Airway: Ensure patent.

  • Breathing: Administer high-flow oxygen.

  • Circulation:

    • Secure two large-bore IV cannulas.

    • IV Hydrocortisone 100mg STAT.

    • IV Normal Saline 0.9% 1 Litre STAT over 30-60 minutes, then continue aggressive resuscitation based on response. Most patients need 2-3 litres in the first 12 hours.

    • Send bloods (U&E, Cortisol, FBC, Cultures) before giving steroids if possible, but do not delay treatment.

  • Disability:

    • Check CBG. If low, give IV Dextrose 50%.

    • Monitor GCS.

  • Exposure:

    • Look for the precipitant (e.g., signs of infection). Start empirical antibiotics if sepsis is suspected.

    • Keep the patient warm.

C. Definitive Treatment (The Ward Round Plan):

  • Acute Phase (Post-Crisis):

    • Continue IV Hydrocortisone 50mg QDS or as a continuous infusion of 200mg/24 hours.

    • Continue IV fluids. Taper as haemodynamics and electrolytes normalize.

    • Once the patient is stable, eating, and drinking, transition to oral steroids.

  • Chronic Replacement Therapy (Long-term):

    • Glucocorticoid: Hydrocortisone. Total dose 15-25mg per day, given in 2-3 divided doses to mimic diurnal rhythm (e.g., 10mg morning, 5mg evening).

    • Mineralocorticoid: Fludrocortisone 50-200 mcg OM. Dose is titrated based on postural BP and electrolytes (aim for normal sodium and potassium).

  • Patient Education & Sick Day Rules (CRITICAL):

    • Minor illness (e.g., cold): DOUBLE the daily hydrocortisone dose.

    • Major illness (e.g., fever >38°C, vomiting, surgery): Take 20mg Hydrocortisone orally immediately and seek medical attention. They will need IV/IM hydrocortisone.

    • All patients must have a steroid card and a medical alert bracelet.

IX. Complications

  • Immediate: Adrenal crisis (shock, death). Severe hypoglycemia. Cardiac arrhythmias from hyperkalemia.

  • Long-Term:

    • Overtreatment with steroids: Iatrogenic Cushing's syndrome, osteoporosis, diabetes, hypertension.

    • Undertreatment: Chronic ill health, recurrent adrenal crises.

X. Prognosis

  • With proper replacement therapy and patient education, the prognosis is excellent, and life expectancy is near-normal.

  • The mortality risk is from adrenal crisis, which carries a mortality rate of ~5-10% even when treated.

  • Top Prognostic Factor: Patient's ability to manage their sick day rules.

XI. How to Present to Your Senior

Use the SBAR format.

  • Situation: "Dr, I'm calling about Patient [Name/Age/Location]. I am concerned they are in an adrenal crisis."

  • Background: "They presented with hypotension and confusion. Background of [e.g., weight loss and fatigue for 3 months]. On examination, they are hypotensive at 80/50, tachycardic at 120, and have buccal hyperpigmentation."

  • Assessment: "The key issues are refractory shock with hyponatremia of 125 and hyperkalemia of 6.0. My primary differential is an Addisonian crisis, likely precipitated by an infection."

  • Recommendation: "I have already administered 1L of Normal Saline and given IV Hydrocortisone 100mg STAT. I have sent blood cultures and a baseline cortisol. I need you to review the patient urgently."

XII. Summary & Further Reading

  • Top 3 Takeaways:

    1. Suspect Addison's in any patient with unexplained shock, especially with hyponatremia and hyperkalemia.

    2. In a suspected crisis, give IV Hydrocortisone 100mg and IV fluids immediately. Do not wait for diagnostic tests.

    3. Patient education on sick day rules is the most important factor in preventing mortality.

  • Key Resources:

    • Guideline: Endocrine Society Clinical Practice Guideline on Adrenal Insufficiency (2016) - This is the key international document used in local practice.

    • UpToDate: "Treatment of adrenal insufficiency in adults"

    • Amboss: "Primary adrenal insufficiency (Addison disease)"

Danial Mirza
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