Cushing's Syndrome
Summary
Cushing's Syndrome refers to the clinical phenotype caused by chronic excess Glucocorticoids (Cortisol). The most common cause is Iatrogenic (steroid medication). Endogenous causes divide into ACTH-Dependent (Cushing's Disease = Pituitary Adenoma, or Ectopic ACTH) and ACTH-Independent (Adrenal Adenoma). It is a multisystem disorder characterized by centripetal obesity, proximal myopathy, skin fragility, diabetes, and hypertension. [1,2]
Clinical Pearls
Syndrome vs Disease: This is the most common exam trap.
- Cushing's Syndrome: Any cause of high cortisol (e.g., Prednisolone pills, Adrenal tumor, Pituitary tumor).
- Cushing's Disease: Specifically a Pituitary Adenoma secreting ACTH.
The "Ectopic" Look: Ectopic ACTH secretion (typically Small Cell Lung Cancer) is rapid and aggressive. These patients often don't have the classic moon face/hump (no time to develop fat). Instead, they present with Cachexia, Deep Pigmentation (MSH), and Profound Hypokalaemia.
Pseudo-Cushing's: Alcohol excess and severe depression can biochemically and physically mimic Cushing's. It resolves with abstinence.
Demographics
- Prevalence: Rare (Endogenous: 2-3 per million/year). Iatrogenic is common.
- Age: 20-50 years.
- Gender: F:M = 5:1 (for Pituitary/Adrenal causes). Equal in Ectopic causes.
Classification
- ACTH Dependent (High ACTH drives adrenals):
- Cushing's Disease (80%): Pituitary Microadenoma.
- Ectopic ACTH (10%): Small Cell Lung Ca, Bronchial Carcinoid.
- ACTH Independent (Adrenal drives itself):
- Adrenal Adenoma/Carcinoma (10%): Suppresses Pituitary ACTH.
- Exogenous Steroids: Suppresses Pituitary ACTH.
Mechanism of Symptoms
- Catabolic: Cortisol breaks down protein -> Muscle wasting (thin limbs), Thin skin (bruising), Striae (dermal rupture).
- Mineralocorticoid: High cortisol activates renal aldosterone receptors -> Na+ retention (HTN) and K+ loss (Hypokalaemia).
- Diabetogenic: Insulin resistance -> Diabetes.
| Feature | Cushing's Disease | Ectopic ACTH | Adrenal Adenoma |
|---|---|---|---|
| ACTH Level | Raised | Very High | Suppressed |
| High Dose Dex Test | Suppresses | No Change | No Change |
| CRH Response | Yes | No | No |
| K+ Level | Normal/Low | Very Low | Normal |
Physical Signs
Systemic
Step 1: Screening (Confirm Hypercortisolism)
Need 2 out of 3 positives to confirm diagnosis:
- Overnight Dexamethasone Suppression Test (ONDST):
- Take 1mg Dex at 11pm. Measure Cortisol at 9am.
- Normal: less than 50 nmol/L. Cushing's: >50 nmol/L.
- 24h Urine Free Cortisol: Elevated (at least 3x normal).
- Late Night Salivary Cortisol: Loss of circadian rhythm (cortisol remains high at midnight).
Step 2: Localisation (Use the ACTH)
- Measure 9am Plasma ACTH.
- Suppressed (less than 1 pmol/L): Adrenal Cause (Independent) -> Do CT Adrenals.
- Elevated (>3 pmol/L): ACTH Dependent -> Proceed to Step 3.
Step 3: Differentiation (Pituitary vs Ectopic)
- High Dose Dex Suppression: 2mg qds for 48h. Pituitary tumors retain some feedback (Cortisol drops by 50%). Ectopic tumors are autonomous (No drop).
- IPSS (Inferior Petrosal Sinus Sampling): Gold Standard. Catheterize veins draining pituitary. If Central:Peripheral ACTH gradient >2:1, it's Pituitary.
Management Algorithm
CONFIRMED CUSHING'S
↓
CHECK ACTH
┌─────────┴─────────┐
SUPPRESSED ELEVATED
(Adrenal) (ACTH Dependent)
↓ ↓
CT ADRENALS MRI PITUITARY
↓ ↓
ADRENALECTOMY TRANS-SPHENOIDAL
(Curative) SURGERY (TSS)
↓
FAILED?
┌─────┴─────┐
RADIOTHERAPY BILATERAL
ADRENALECTOMY
Medical Therapy (Pre-op or Palliative)
- Metyrapone / Ketoconazole: Block adrenal steroidogenesis. Used to normalize cortisol before surgery to reduce complications (infection/healing).
- Pasireotide: Somatostatin analogue for Cushing's Disease.
Surgical
- Trans-Sphenoidal Surgery (TSS): Treatment of choice for Pituitary. 80% cure.
- Laparoscopic Adrenalectomy: For adenomas.
- Note: Post-op patients become hypocortisolaemic (as the other adrenal/pituitary is asleep) and need Hydrocortisone replacement for months.
- Nelson's Syndrome: Post-bilateral adrenalectomy, the pituitary tumor (no longer restrained by cortisol feedback) grows rapidly. Causes visual field defects and hyperpigmentation.
- Cardiovascular: MI/Stroke risk remains elevated even after cure due to residual metabolic changes.
- Osteoporotic Fractures.
- Untreated: 50% mortality at 5 years.
- Treated: Excellent, but recurrence of Pituitary Cushing's is common (20-30%).
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Cushing's Diagnosis | Endocrine Society (2008) | Use ONDST as first line screen. |
| Management | Pituitary Society | Surgical pathways and IPSS criteria. |
Landmark Evidence
1. Nieman et al (J Clin Endocrinol Metab 2008)
- The definitive guideline establishing the 3-tier diagnostic approach (Screen -> Localise -> Differentiate).
What is Cushing's?
It is a condition where your body has too much Cortisol. Cortisol is a vital "stress hormone", but too much of it is toxic. It causes rapid weight gain on the tummy and face, thins the skin causing bruises, and weakens muscles and bones.
What causes it?
The most common cause is taking steroid tablets (like Prednisolone) for other conditions. If your body is making it itself, it is usually due to a small benign lump in the pituitary gland (behind the nose) or the adrenal gland (above the kidney).
How do we test for it?
It is tricky to diagnose because Cortisol levels fluctuate wildly normally. We usually give you a tablet (Dexamethasone) at night and check your blood in the morning to see if your body "switches off" its own production like it should. In Cushing's, it doesn't.
Can it be cured?
Yes. We usually perform keyhole surgery to remove the small lump responsible. After surgery, you will actually be low on cortisol for a while and need tablets until your body wakes up again.
Primary Sources
- Nieman LK, et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008.
- Newell-Price J, et al. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev. 1998.
- Lacroix A, et al. Cushing's syndrome. Lancet. 2015.
Common Exam Questions
- Diagnosis: "Failure to suppress on ONDST + High ACTH?"
- Answer: ACTH Dependent Cushing's (Pituitary or Ectopic).
- Differentiation: "Suppresses on High Dose Dex?"
- Answer: Pituitary (Cushing's Disease).
- Complication: "Pigmentation after Adrenalectomy?"
- Answer: Nelson's Syndrome.
- Electrolytes: "Hypokalaemic Alkalosis?"
- Answer: Ectopic ACTH (Mineralocorticoid effect).
Viva Points
- Why Pigmentation?: ACTH is a precursor to MSH (Melanocyte Stimulating Hormone). Only ACTH-dependent causes (High ACTH) cause tanning. Adrenal adenomas (Low ACTH) do not.
- Pseudo-Cushing's: Conditions that drive the HPA axis (Alcohol, Depression, Severe Obesity). Use the Insulin Stress Test to differentiate (Pseudo-Cushing's patients will still have a response to hypoglycaemia).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.