Cushing Syndrome Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: This is a key diagnosis to consider in patients with new-onset, difficult-to-control diabetes and hypertension, especially with the widespread use of traditional medications and prescription steroids.
High-Yield Definition: Cushing syndrome is a clinical state resulting from chronic exposure to excessive circulating levels of glucocorticoids. [Source: UpToDate, 2024]
Clinical One-Liner: Basically, the body is being poisoned by too much cortisol, whether we're giving it or the body is making it.
II. Etiology & Risk Factors
The most important thing to remember is the cause. Is it from the outside (exogenous) or inside (endogenous)?
Exogenous/Iatrogenic (Most Common Cause Overall):
Prolonged administration of high-dose glucocorticoids.
This is the one you'll see most often. Think patients on long-term prednisolone for autoimmune disease, or those taking potent traditional/herbal remedies (jamu) which are often adulterated with steroids. Always ask about this.
Endogenous (Rare):
ACTH-dependent (~80% of endogenous cases):
Cushing's Disease: A pituitary adenoma secreting excess ACTH. This is the most common endogenous cause.
Ectopic ACTH syndrome: A non-pituitary tumour (e.g., small cell lung cancer) is making ACTH.
ACTH-independent (~20% of endogenous cases):
An adrenal adenoma or carcinoma is producing cortisol on its own.
III. Quick Pathophysiology
It's all about too much cortisol. This excess screws up multiple systems.
Metabolic: Cortisol is a catabolic hormone. It breaks down protein (muscle wasting, thin skin) and fat (redistributes it to the face, neck, and trunk) and promotes gluconeogenesis (hyperglycaemia/diabetes).
Mineralocorticoid Effects: At high concentrations, cortisol acts on mineralocorticoid receptors, leading to sodium and water retention (hypertension, oedema) and potassium excretion (hypokalaemia).
Androgenic Effects: Can cause hirsutism and acne.
Immune Suppression: Increased risk of opportunistic infections.
IV. Clinical Assessment
Look at your patient. The diagnosis is often staring you in the face.
Red Flags & Immediate Actions:
Severe Hypokalaemia (<2.5 mmol/L) with Hypertension: Suspect ectopic ACTH production. Action → Alert senior immediately, start cardiac monitoring, arrange urgent potassium replacement.
Psychosis or Severe Mood Disturbance: Can be a manifestation of severe hypercortisolism. Action → Ensure patient safety, alert senior, consider psychiatric consult.
Evidence of Rapid Virilisation: Suggests an adrenal carcinoma. Action → Urgent endocrine and surgical review.
History:
Common (>50%): Progressive central weight gain, mood changes (depression, irritability), fatigue, proximal muscle weakness (difficulty climbing stairs), irregular menses.
Less Common (10-50%): Hirsutism, acne, easy bruising, slow wound healing.
Pertinent Negatives: Ask about fever or weight loss (may suggest malignancy in ectopic ACTH syndrome). Crucially, get a detailed drug history including traditional/herbal medications and topical/inhaled steroids.
Physical Examination:
General: "Cushingoid" features - moon facies, plethora (red cheeks), dorsal cervical fat pad ("buffalo hump"), supraclavicular fat pads.
Vitals: Check for hypertension.
Skin: Thin skin, easy bruising, broad (>1cm) purplish striae (especially on the abdomen, axillae, thighs). Look for signs of fungal skin infections.
MSK: Proximal myopathy (test by asking the patient to stand from a squat without using their arms).
Endocrine: Check for galactorrhoea (prolactin co-secretion from pituitary tumour).
Clinical Pearl: The most specific signs are proximal myopathy, wide purple striae, and easy bruising. Central obesity on its own is not enough. Anyone can be obese, but these features point specifically to excess cortisol.
V. Diagnostic Workflow
This is a step-wise process. Don't just order everything at once.
Step 1: Confirm Hypercortisolism.
Step 2: Determine if it's ACTH-dependent or independent.
Differential Diagnosis:
Metabolic Syndrome / Simple Obesity:
Points For: Central obesity, hypertension, diabetes.
Points Against: Absence of specific catabolic features (purple striae, proximal myopathy, skin thinning).
How to Differentiate: Initial screening tests for hypercortisolism will be negative.
Polycystic Ovarian Syndrome (PCOS):
Points For: Hirsutism, acne, irregular menses, central obesity.
Points Against: Lack of catabolic features.
How to Differentiate: Biochemical testing will show elevated androgens and LH:FSH ratio, with normal cortisol levels.
Investigations Plan:
Bedside / Initial (First 15 Mins):
Urine Dipstick: Check for glycosuria.
Capillary Blood Glucose: Check for hyperglycaemia.
Lying & Standing BP: Assess for hypertension.
First-Line Labs & Imaging (Screening for Hypercortisolism):
You need TWO different positive first-line tests to confirm.
Option 1: Overnight Dexamethasone Suppression Test (ODST):
How: Give Dexamethasone 1mg at 11 PM. Check serum cortisol at 8 AM the next day.
Expected Finding: In a normal person, cortisol will be suppressed (<50 nmol/L). In Cushing's, it remains high. This is the preferred initial test in most settings.
Option 2: 24-Hour Urine Free Cortisol (UFC):
How: Collect all urine over 24 hours.
Expected Finding: Elevated cortisol level. Needs at least two collections. Cumbersome but effective.
Option 3: Late-Night Salivary Cortisol:
How: Patient collects saliva sample at home between 11 PM and midnight.
Expected Finding: Loss of normal diurnal rhythm, so cortisol is high when it should be at its lowest. Not commonly available in most government centres.
Also send:
FBC, BUSE/RP: Look for hypokalaemia, metabolic alkalosis, neutrophilia.
HbA1c: Assess for secondary diabetes.
Confirmatory / Second-Line (To find the cause):
Plasma ACTH Level (8 AM sample): This is the crucial next step after confirming hypercortisolism.
Suppressed/Undetectable ACTH (<5 pg/mL): The problem is in the adrenals (ACTH-independent). Proceed to CT Adrenals.
Normal to High ACTH (>20 pg/mL): The problem is either the pituitary or an ectopic source (ACTH-dependent). Proceed with brain imaging.
Imaging:
MRI Pituitary Gland (with gadolinium): To look for a pituitary adenoma (Cushing's disease).
CT Thorax/Abdomen/Pelvis: If MRI pituitary is negative or ACTH levels are extremely high, search for an ectopic source like a lung tumour.
VI. Staging & Severity Assessment
We don't "stage" Cushing's like cancer, but we assess its severity by the degree of end-organ damage.
Mild: Minimal clinical features, mild biochemical abnormalities.
Moderate: Clear clinical features with complications like controlled hypertension or diabetes.
Severe: Florid features with poorly controlled complications, significant hypokalaemia, osteoporosis with fractures, or psychosis. This determines the urgency of treatment.
VII. Management Plan
Management depends entirely on the cause. This is a multidisciplinary team (MDT) effort involving endocrinology, surgery (neuro or general), and radiology.
Immediate Stabilisation (For severely unwell patients):
A (Airway), B (Breathing), C (Circulation): Manage as per standard protocols.
D (Disability/Metabolic):
Severe Hyperglycaemia: Start insulin infusion.
Severe Hypokalaemia: Aggressive IV potassium replacement with cardiac monitoring.
Severe Hypertension: Requires IV anti-hypertensives.
Consider medical therapy to block cortisol production (e.g., Metyrapone or Ketoconazole) as a bridge to definitive treatment, but this is a specialist decision.
Definitive Treatment (The Ward Round Plan):
Iatrogenic/Exogenous: The only "cure" is to slowly and carefully taper the offending steroid under medical supervision to avoid adrenal crisis.
Cushing's Disease (Pituitary Adenoma):
First-Line: Trans-sphenoidal surgery (TSS) to resect the adenoma.
Adrenal Tumour (Adenoma/Carcinoma):
First-Line: Unilateral adrenalectomy (usually laparoscopic).
Ectopic ACTH Syndrome:
First-Line: Resect the primary tumour if it can be found and is resectable.
Long-Term & Discharge Plan:
All patients who undergo surgery will need post-operative glucocorticoid replacement (e.g., Hydrocortisone) as their normal HPA axis is suppressed. This is tapered over months to years.
Manage comorbidities aggressively: hypertension, diabetes, osteoporosis.
Provide a steroid dependency card/bracelet.
VIII. Complications
Immediate (Peri-operative):
Adrenal Crisis: Life-threatening hypocortisolism post-op if steroid replacement is inadequate. Management: IV hydrocortisone, IV fluids.
Venous Thromboembolism (VTE): Cushing's is a pro-thrombotic state. Management: Prophylactic LMWH.
Long-Term:
Cardiovascular Disease: Increased risk of MI and stroke.
Osteoporosis: High risk of pathological fractures.
Psychiatric: Persistent depression or cognitive issues.
Nelson's Syndrome: Rapid growth of a pituitary adenoma after bilateral adrenalectomy.
IX. Prognosis
Iatrogenic: Excellent if steroids can be safely withdrawn.
Adrenal Adenoma / Cushing's Disease: Generally good cure rates (>80%) with successful surgery.
Adrenal Carcinoma / Ectopic ACTH from Malignancy: Prognosis is poor and depends on the underlying cancer.
Top Prognostic Factors:
Underlying cause (benign vs. malignant).
Successful surgical remission.
Severity of comorbidities at diagnosis.
X. How to Present to Your Senior
Be concise and structured.
"Dr., for review please. This is Puan Siti in Bed 10, a 55-year-old lady with a 6-month history of progressive weight gain, fatigue, and new-onset diabetes. On exam, she has central obesity, moon facies, and purple abdominal striae. Her BP is 160/100 mmHg and her potassium is 3.1 mmol/L. My main differential is Cushing Syndrome. I have sent off a baseline FBC and BUSE/RP. I would like to plan for an overnight dexamethasone suppression test to confirm. Could you review her with me?"
XI. Summary & Further Reading
Top 3 Takeaways:
The most common cause of Cushing Syndrome is prescribed or surreptitious steroid use. Always take a detailed drug history.
The diagnostic workflow is stepwise: first, prove there is too much cortisol; second, find out where it's coming from using an ACTH level.
The most specific clinical signs are catabolic: proximal muscle weakness, thin skin with easy bruising, and broad, purple striae.
Key Resources:
UpToDate: Search for "Diagnosis of Cushing syndrome" and "Overview of the treatment of Cushing syndrome". This is your best friend. https://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushing-syndrome
Amboss: Good for quick review and question banks. https://www.amboss.com/us/knowledge/cushing_syndrome
Key Review Article: Nieman, L. K. (2022). Cushing's Syndrome: Aetiology, Diagnosis and Treatment. Neuroendocrinology. A good overview of recent advances. (You can find this on PubMed).
