Dexamethasone Suppression Test (DST)

Background and Rationale

Types of DST

1. Low-Dose DST - "Does the patient have Cushing syndrome?"

• Sensitivity: ~95% for Cushing syndrome
• Specificity: ~80% at 1.8 µg/dL threshold; rises to >95% if threshold raised to 5 µg/dL (140 nmol/L)

2. High-Dose DST - "What is the cause of Cushing syndrome?"

Interpretation Summary Table

Why the DST is Ordered (Clinical Indications)

• Screening/confirming Cushing syndrome (low-dose)
• Differentiating pituitary vs. ectopic vs. adrenal causes of hypercortisolism (high-dose)
• Evaluating suspected incidentally found adrenal masses (adrenal incidentalomas) for autonomous cortisol secretion

False Positives (Failure to Suppress Without True Cushing)

• Severe stress, acute/chronic illness, infection
• Obesity
• Severe depression (pseudo-Cushing syndrome)
• Alcohol abuse (alcoholic pseudo-Cushing)
• Oral contraceptives or estrogen therapy (increases cortisol-binding globulin)
• Pregnancy
• Drugs that accelerate dexamethasone metabolism: phenytoin, phenobarbital, rifampin, carbamazepine
• Failure to take the dexamethasone dose
• Renal insufficiency (invalidates the test)

Comparison with Other Cushing Screening Tests

After the DST - Next Steps

1. Plasma ACTH level - low/undetectable = adrenal source; elevated = ACTH-dependent
2. High-dose DST or CRH stimulation test - differentiate pituitary from ectopic
3. If pituitary source likely: MRI pituitary; if MRI negative, consider Bilateral Inferior Petrosal Sinus Sampling (BIPSS) - the gold standard for confirming pituitary vs. ectopic ACTH (petrosal:peripheral ratio >3 post-CRH = pituitary source)

Approach to Cushing Syndrome - Step by Step

Step 1 - Clinical Suspicion + Exclude Exogenous Cause

• Central obesity, moon facies, dorsocervical fat pad ("buffalo hump")
• Wide (>1 cm) violaceous/purple abdominal striae
• Proximal muscle weakness
• Easy bruising, facial plethora
• Hypertension, glucose intolerance
• Osteoporosis, hypogonadism

Step 2 - Screening (one of three tests)

Step 3 - Confirm Cushing Syndrome

• 2-day low-dose DST (0.5 mg q6h x 48h) - cortisol fails to suppress
• Exclude pseudo-Cushing states: major depression, chronic alcoholism, morbid obesity (these can give false positives on screening)

Step 4 - Measure Plasma ACTH (Key Branch Point)

Plasma ACTH
    |
    ├── LOW / Undetectable  (<5 pg/mL)
    │   → ACTH-INDEPENDENT Cushing syndrome
    │   → CT/MRI of adrenal glands
    │
    └── NORMAL / HIGH  (>15 pg/mL)
        → ACTH-DEPENDENT Cushing syndrome
        → Proceed to Step 5

Step 5 - Localize ACTH Source (ACTH-Dependent Only)

Step 6 - Imaging

Caveat: ~50% of patients with Cushing disease have no abnormality on pituitary MRI. Also, ~10% of the general population have incidental pituitary findings that can mislead.

Step 7 - Bilateral Inferior Petrosal Sinus Sampling (BIPSS) - Gold Standard

• ACTH-dependent Cushing confirmed but pituitary MRI is negative or equivocal
• Need to distinguish pituitary vs. ectopic ACTH with certainty

Etiology Classification (from Campbell-Walsh Urology)

Adrenal Incidentaloma - Specific Algorithm

Addison's Disease (Primary Adrenal Insufficiency)

Definition

• Secondary AI - pituitary failure → low ACTH → low cortisol (no mineralocorticoid deficiency, no hyperpigmentation)
• Tertiary AI - hypothalamic failure → low CRH → low ACTH (most often from exogenous steroid withdrawal)

HPA Axis and Types of Adrenal Insufficiency

Epidemiology

• Prevalence: ~1 in 10,000 in developed countries (39-144 per million)
• Most common in ages 30-50 years; female predominance in autoimmune form
• ~90% of cases in developed countries: autoimmune
• Worldwide: tuberculosis remains the leading cause

Etiology

Autoimmune (Most Common in Developed World)

• Autoimmune adrenalitis with 21-hydroxylase antibodies (anti-adrenal antibodies)
• Often part of Autoimmune Polyglandular Syndrome (APS):
  • APS type 2 (~70%): Addison + Type 1 DM + autoimmune thyroid disease (autosomal dominant, HLA-DRB1)
  • APS type 1 (~10%): Addison + chronic mucocutaneous candidiasis + hypoparathyroidism (autosomal recessive, AIRE gene, chromosome 21q22.3)
  • ~10% isolated Addison's (no associated APS)

Infectious

• TB (most common worldwide; adrenal involvement in ~6% of active TB)
• Disseminated fungal infections (histoplasmosis, cryptococcosis, coccidioidomycosis)
• HIV-related infections (CMV, MAI, toxoplasmosis)

Other Causes

Symptoms appear only after >90% of adrenal tissue is destroyed - explaining the insidious onset.

Pathophysiology

Clinical Features

Chronic Presentation (Insidious Onset)

• Fatigue, weakness (most common)
• Anorexia, weight loss
• Nausea, vomiting, diarrhea
• Myalgia, arthralgia
• Depression, apathy
• Mild fever
• Hypotension (BP ≤ 110/70 mmHg)

• Hyperpigmentation - most striking sign
  • Sun-exposed areas (face, neck, hands)
  • Sites of pressure/friction (knees, elbows, knuckles, spine)
  • Palmar creases, nipples, areolae, axillae, genitalia, perineum
  • Oral/buccal mucosa (gums, inner cheeks)
  • Recent scars
• Salt craving
• Orthostatic hypotension, syncope
• Vitiligo (associated autoimmune depigmentation)
• Hyperkalemia, hyperchloremic metabolic acidosis
• Hypoglycemia

Laboratory Findings

Diagnostic Algorithm

Step-by-Step Diagnostic Approach:

1. Morning plasma cortisol (or stress cortisol x1 / AM cortisol x2):
   • < 5 µg/dL → abnormal → proceed to cosyntropin test
   • 5-18 µg/dL → indeterminate → proceed to cosyntropin test
   • ≥ 18-20 µg/dL → normal (if low suspicion → ruled out)
2. 1-hour cosyntropin (ACTH) stimulation test (standard test):
   • Give 250 µg synthetic ACTH (cosyntropin) IV/IM
   • Measure cortisol at 0, 30, and 60 min
   • Normal response: Peak cortisol ≥ 18-20 µg/dL AND Δ ≥ 7-10 µg/dL → rules out cortisol deficiency
   • Abnormal response: Cortisol < 18-20 µg/dL or Δ < 7-10 µg/dL → proceed to prolonged test
3. Multi-day cosyntropin stimulation (prolonged protocol):
   • Differentiates primary (Addison) from secondary/central AI
   • Cortisol fails to rise + ACTH high → Addison disease (primary)
   • Cortisol eventually rises + ACTH normal/low → Central glucocorticoid deficiency (secondary/pituitary)
4. Clinical Addisonian crisis (no need to wait for labs):
   • Cortisol < 5 µg/dL + ↓Na⁺ + ↑K⁺ + acidosis + shock → Treat immediately

If adrenal crisis is suspected, treat first - test later. Use dexamethasone (not hydrocortisone) if you still want to draw a cortisol level, as dexamethasone does not cross-react with cortisol assays.

Adrenal Crisis (Addisonian Crisis)

• Infection, surgery, trauma, physical/emotional stress
• Abrupt steroid withdrawal in a patient on chronic steroids
• First presentation in previously undiagnosed Addison's

Treatment

Acute Adrenal Crisis

Chronic Maintenance Therapy

Sick Day Rules ("Stress Dosing")

• Minor illness/fever: Double the daily hydrocortisone dose
• Major illness/surgery/procedural stress: Hydrocortisone 100 mg IV
• Patients should wear a medical alert bracelet and carry an emergency injection kit

Primary vs. Secondary AI - Key Distinctions

The Synacthen Test - Simply Explained

What is Synacthen?

The Simple Concept - Think of it as a "Fire Drill"

Normal situation:
Pituitary rings the alarm (ACTH) → Adrenal glands respond → Cortisol produced ✅

In Addison's disease:
Pituitary rings the alarm (ACTH) → Adrenal glands are DAMAGED → No cortisol ❌

• If the adrenal glands respond well → they are healthy → no Addison's
• If they don't respond → they are damaged → Addison's confirmed

How the Test is Done - Step by Step

Step 1:  Draw blood → measure baseline cortisol (8 AM fasting)

Step 2:  Inject Synacthen 250 µg  →  IV or IM
         (This is the "alarm bell")

Step 3:  Wait 30–60 minutes

Step 4:  Draw blood again → measure cortisol level

How to Read the Result

But Wait - What If the Test is Abnormal? WHO is to Blame?

Is it the ADRENAL GLAND'S fault?  →  Primary AI (Addison's disease)
           OR
Is it the PITUITARY'S fault?       →  Secondary AI

• Addison's = The fire station itself is burnt down. Even if you ring the alarm (Synacthen), no trucks come out.
• Secondary AI = The fire station is fine, but it hasn't been used in so long (low ACTH from pituitary) that it has gone "rusty/lazy."

How to tell them apart after a failed test:

Why Check ACTH Alongside?

ACTH very HIGH  →  Pituitary is screaming for help but adrenals can't respond
                →  ADDISON'S DISEASE ✅

ACTH low/normal →  Pituitary is not sending the signal properly
                →  SECONDARY (pituitary) AI ✅

The Whole Picture in One Diagram

                    INJECT SYNACTHEN (250 µg)
                           |
              ┌────────────┴────────────┐
              ↓                         ↓
       Cortisol RISES             Cortisol STAYS LOW
       (≥18-20 µg/dL)             (<18-20 µg/dL)
              ↓                         ↓
       NORMAL ✅                  ADRENAL INSUFFICIENCY
                                         ↓
                                  Check ACTH level
                              ┌──────────┴──────────┐
                              ↓                      ↓
                         ACTH HIGH             ACTH LOW/Normal
                              ↓                      ↓
                       ADDISON'S             SECONDARY AI
                      (adrenal              (pituitary/
                       damage)               steroid use)

When Should You NOT Do This Test?

• Active adrenal crisis → Don't wait for the test, treat immediately with hydrocortisone 100 mg IV
• If you're suspicious of crisis but still want to test → use dexamethasone instead of hydrocortisone for treatment, since dex doesn't interfere with the cortisol assay

One-Line Summary

The Synacthen test = Give fake ACTH, measure if adrenals respond. No response = adrenal insufficiency. Then check ACTH level to find out whose fault it is.

Step-by-Step Approach to Addison's Disease

Step 1 - Clinical Suspicion

Step 2 - Is it a Crisis?

• YES (crisis): Cortisol < 5 µg/dL + ↓Na + ↑K + refractory hypotension → Treat first, test later
  • Hydrocortisone 100 mg IV bolus
  • Aggressive IV Normal Saline
  • Dextrose if hypoglycaemic
  • Identify & treat the precipitant (infection, surgery, missed doses)
• NO (stable): Proceed with investigation

Step 3 - Morning Cortisol (8 AM)

Step 4 - Synacthen (Cosyntropin) Test

• PASS (Cortisol ≥ 18-20 µg/dL AND rises by ≥ 7-10 µg/dL) → Adrenal insufficiency excluded ✅
• FAIL (Cortisol stays low, barely rises) → Adrenal insufficiency confirmed → Go to Step 5

Step 5 - Measure Plasma ACTH (The Key Branch Point)

ACTH very HIGH  →  Adrenal gland is damaged
                →  PRIMARY AI = ADDISON'S DISEASE

ACTH LOW/Normal →  Pituitary not sending the signal
                →  SECONDARY AI (not Addison's)

Step 6 - Find the Cause of Addison's

• 21-hydroxylase antibodies positive → Autoimmune Addison's (most common in developed world)
• Antibodies negative → Look for other cause:
  • CT adrenals: calcification = TB; bilateral enlargement = metastases/lymphoma; bilateral haemorrhage
  • VLFCA levels (for adrenoleukodystrophy in young males)
  • Screen for APS (thyroid, diabetes, parathyroid)

Step 7 - Treatment

The One Key Difference to Always Remember