Hypercortisolism (Cushing’s Syndrome)

Hypercortisolism is caused by excessive glucocorticoids.

Definition of terms

Term	Definition
Cushing’s syndrome	The clinical state that is produced by chronic glucocorticoid excess, loss of the hypothalamo-pituitary-adrenal axis, and loss of circadian rhythm of cortisol secretion.
Exogenous hypercortisolism	Hypercortisolism caused by the administration of steroids to patients.
Endogenous hypercortisolism	Hypercortisolism caused by excess glucocorticoid production by the body.
Primary hypercortisolism	Inappropriate, autonomous production and secretion of cortisol (ACTH-independent)
Secondary hypercortisolism	An appropriate overproduction of cortisol (ACTH-dependent)
Cushing’s disease	Bilateral adrenal hyperplasia from an ACTH-secreting pituitary adenoma
Nelson’s syndrome	Hyperpigmentation due to increased ACTH production from pituitary enlargement (tumor) post-adrenalectomy. This responds to pituitary radiation.

Cushing’s syndrome

Category	Clinical features
Classic signs	Central obesity, weight gain, moon facies, buffalo hump, abdominal striae
Musculoskeletal	Proximal myopathy, osteopaenia, osteoporosis, avascular necrosis of the femoral head
Dermatological	Hirsutism, acne vulgaris, seborrhoeic dermatitis, thin skin with easy bruising, and poor wound healing
Endocrine	Glucose intolerance, type 2 diabetes mellitus due to cortisol-induced insulin resistance, oligomenorrhoea or amenorrhoea, decreased libido, erectile dysfunction
Neuropsychiatric	Depression, anxiety, irritability, emotional labiity, impaired memory and concentration, insomnia, hypersomnia
Cardiovascular	Hypertension, venous thromboembolism
Paediatric	Growth retardation, precocious puberty

Causes of Cushing’s syndrome
- ACTH-independent causes (primary hypercortisolism)
  - Exogenous steroids
  - Adrenal adenoma
  - Adrenal carcinoma
  - Adrenal nodular hyperplasia
  - Carney complex
  - McCune-Albright syndrome
- ACTH-dependent causes (secondary hypercortisolism)
  - Cushing’s disease
  - Ectopic ACTH production by small-cell lung cancer and carcinoid tumors
  - Ectopic CRH production by medullary thyroid or prostate cancer
Pathophysiology
- Elevated cortisol → anti-inflammatory and immunosuppressive effects
- Elevated cortisol → increased hepatic gluconeogenesis and reduced peripheral glucose uptake → hyperglycemia
- Elevated cortisol → osteoporosis
- Elevated cortisol → protein catabolism → muscle wasting
Signs and symptoms
- Weight gain
- Proximal muscle weakness
- Irregular menses
- Hirsutism
- Erectile dysfunction
- Acne
- Recurrent Achilles tendon rupture
- Virilization if female
- Depression
- Lethargy
- Irritability
- Psychosis
Physical examination
- Truncal obesity
- Plethora
- Moon face
- Buffalo hump
- Supraclavicular fat distribution
- Skin and muscle atrophy
- Bruises
- Purple abdominal striae
- Osteoporosis
- Hypertension
- Hyperglycaemia
Differentials
- Adrenal adenoma
- Ectopic ACTH syndrome
- Polycystic ovarian syndrome (PCOS)
Investigations
- Hypokalaemic metabolic acidosis
- Hyperglycaemia
- Confirm hypercortisolism
  - 24-hour urinary free cortisol
    - Elevated 24-hour urinary free cortisol
  - Midnight cortisol
    - Elevated midnight cortisol – reflects loss of diurnal variation in cortisol since it is expected to be lowest at night
  - Overnight low-dose dexamethasone suppression test
    - No cortisol suppression after an overnight 1 mg dexamethasone suppression test – this is the most useful test to diagnose hypercortisolism
- Determine the cause of hypercortisolism
  - Plasma ACTH
    - Low plasma ACTH in primary hypercortisolism (adrenal tumors)
    - High plasma ACTH from a pituitary adenoma (Cushing’s disease) or ectopic ACTH/CRH production
  - High-dose dexamethasone suppression test
    - Suppression of ACTH in a pituitary adenoma
    - No suppression of ACTH in ectopic sources of ACTH
  - CRH stimulation
    - Cortisol rises if the pituitary gland is the source
    - No change in cortisol in ectopic or adrenal sources
- Locate the source
  - CT scan or MRI
  - Adrenal vein sampling
  - Bilateral inferior petrosal sinus blood sampling
Treatment
- Stop medications if it is iatrogenic
- Treatment of Cushing’s disease
  - Trans-sphenoidal removal of pituitary tumor
  - Pituitary radiotherapy
  - Bilateral adrenalectomy if the source is unlocatable or recurs in Cushing’s disease
- Adrenalectomy for adrenal adenoma or carcinoma
  - Adjuvant radiotherapy + adrenolytic drugs (mitotane) for carcinoma
- Surgery or radiotherapy for an ectopic ACTH-producing tumor
  - Metyrapone, ketoconazole, and fluconazole can be given to reduce cortisol pre-operatively
- Intubation + mifepristone + etomidate for severe ACTH-associated psychosis
  - Mifepristone competes with cortisol at its receptors
  - Etomidate blocks cortisol synthesis
Complications of bilateral adrenalectomy
- Adrenal insufficiency
- Nelson’s syndrome

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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