Cushing's Disease and Syndrome Flashcards
What are the functions of cortisol?
Functions of cortisol
1. Carbohydrate metabolism - increases glucose production, antagonises insulin action
- Gluconeogenesis and glycogenolysis
- Stimulates lipolysis
- Protein catabolism
- Inhibits protein synthesis, increases protein breakdown
- Reduces muscle mass via protein catabolism - Immunologic and inflammatory response
- Reduces inflammatory factors and phagocytic activitiy
- Reduces proliferation and deposition of collagen fibres
- Reduce T cell proliferation and antibody formation - Maintenance of blood pressure
Describe the regulation of cortisol
Regulation of cortisol
1. Hypothalamus-pituitary-adrenal axis (HPAA) and negative feedback loop
- Hypothalamus secretes corticotropin-releasing hormone (CRH) and ADH
- CRH stimulates anterior pituitary to secrete adrenocorticotropin (ACTH)
- ACTH stimulates adrenal glands to produce cortisol
- Cortisol in body provides negative feedback loop suppressing CRH and ACTH secretion
- Circadian rhythm production (diurnal - meaning: during the day)
- Non-stress condition: higher levels in morning, lower levels at night
- Stressed condition: loss of circadian variation
What are the stress factors triggering cortisol release?
- Trauma or major surgery
- Infection
- Major haemorrhage
- Hypoglycaemia
- Cold
- Fever
- Emotional stress
What is Cushing’s syndrome vs Cushing’s disease?
Cushing’s syndrome - excessive and prolonged exposure to circulating free glucocorticoids
Cushing’s disease - endogenous excessive glucocorticoids due to hyperexcretion of ACTH by pituitary adenoma
What are the causes of Cushing’s syndrome?
90:10 rule - 90% exogenous, 10% endogenous - In endogenous, 90% ACTH-dependent, 10% ACTH-independent - In ACTH-dependent, 90% pituitary, 10% ectopic ACTH - In pituitary lesions, 90% microadenoma, 10% macroadenoma Commonest cause: 1. Syndrome - exogenous 2. Disease - pituitary adenoma
A. Exogenous - 90% of the causes
1. Iatrogenic corticosteroids - oral, topical, inhaled
2. Traditional medications - contains dexa
B. Endogenous - 10% of the causes
> ACTH-dependent
1. Pituitary adenoma (Cushing’s disease)
2. Ectopic ACTH-producing tumours (small cell ca, Phaeochromocytoma, Carcinoid)
> Non-ACTH dependent
3. Adrenal adenoma or carcinoma
4. McCune-Albright syndrome
5. Carney complex
6. Micronodular adrenal dysplasia
C. Pseudo-Cushing - increased CRH neuron activity
1. Alcoholism
2. Poorly controlled DM
3. Obesity
4. Depression, anxiety
5. Oral contraceptives
Clinical Features of Cushing’s syndrome
- Inappropriate fat deposition
- Weight gain
- Moon facies
- Central obesity and fat pad - Protein catabolism
- Proximal muscle weakness (myopathy)
- Abdominal striae
- Skin atrophy and bruising - Hyperglycaemia and insulin resistance
- Diabetes mellitus
- Cataracts - Hyperandrogenism
- Acne
- Hirsutism
- PCOS or amenorrhoea
- Reduced libido
- Abnormal genital virilisation, precocious or delayed puberty - Mineralocorticoid mimicking activity
- Hypokalaemia - Melanocyte stimulation
- Skin hyperpigmentation - Immunosuppression
- Recurrent infection
- Poor wound healing - Phospholipase inhibition
- Loss of prostaglandin, mucosal healing -> peptic ulcer disease - Vitamin D antagonism
- Osteoporosis
- Nephrolithiasis - Hypertension
- Disruption of diurnal cortisol rhythm
- Insomnia
- Psychiatry disturbance - depression, anxiety
- Fatigue
- Stunted growth, short stature
Cushing’s syndrome dance
Upper Limbs
1. Finger clubbing
2. Tar staining – chronic smoker (small cell ca releases steroids)
3. Dorsum hyperpigmentation (ectopic ACTH production)
4. Easy bruising and skin atrophy (thin skin)
5. Muscle wasting and proximal myopathy
Face
1. Cushingoid facies - moon facies, plethora, telangiectasia, anaemia, buccal hyperpigmentation, hirsutism, acne
2. Oral thrush and candida infection
3. Acne vulgaris
Chest, abdomen, back
1. Supraclavicular and interscapular fat pad (buffalo hump)
2. Acanthosis nigricans over the back
3. Truncal obesity
4. Thick, violaceous abdominal striae
5. Kyphoscoliosis - osteoporosis and vertebral collapse
6. Osteoporosis and compression fracture, hip AVN
7. Lower limb oedema
8. Diabetic dermopathy
9. Adrenalectomy scar (at the back)
Fundoscopy
Cataracts, hypertensive retinopathy, diabetic retinopathy, papillodema
Clues
1. SLE steroid induced Cushing’s - malar rashes
2. Inhaled steroids - COPD, asthma, fibrosis
3. Lifelong IST, transplant scars - kidney, liver
4. Splenomegaly - AIHA
5. Adrenal mass - adrenal adenoma/carcinoma
6. Bitemporal hemianopia - pituitary adenoma
7. Finger pricks, lipodystrophy - diabetes mellitus
Wishlist/Complete Examination
1. Vitals and BP
2. Random glucose
3. Urine dipstick
Feature sepcificity of Cushing’s syndrome
Specific but less common
1. Easy bruising and thin skin
2. Facial plethora
3. Violaceous striae
4. Proximal muscle weakness
5. Hypokalaemia
6. Osteoporosis
Common but less specific
1. Hypertension
2. Weight gain
3. Impaired glucose tolerance or DM
4. Depression, irritability
5. Peripheral oedema
6. Acne, hirsutism
7. Reduced libido, menstrual irregularities
Explain the pathophysiology of excessive hair growth
What is another condition that can cause such issue?
ACTH overstimulation leading to excessive adrenal androgen production
ADrenal cancer - also excessive production of glucocorticoids and androgens
What are the causes of death in Cushing’s syndrome?
- Cardiovascular disease
- Infection
Age and gender predisposition to Cushing’s syndrome
Female - pituitary tumour (80%)
Male - ectopic ACTH syndrome
Children - malignant adrenal tumours
20-40 years - Cushing’s disease
40-60 years - ectopic ACTH syndrome
Investigations for Cushing’s syndrome
Screening Investigations
1. Overnight LDDST :
- PO dexamethasone 1mg at 11pm
- Measure 8am cortisol cm
> Healthy: suppression of CRH, ACTH and cortisol
> Endogenous Cushing: no suppression, elevated cortisol
- Evening/midnight salivary cortisol
- Healthy: low (cortisol nadir at midnight)
- Cushing: high - loss of diurnal rhythm - 24-hour urine free cortisol
- Done x3, result x3 above upper limit - Serum calcium level - elevated in MEN-1, hyperparathyroidism
Definitive Investigations
1. ACTH level or DHEAS
- Normal to high: ACTH-secreting pituitary adenoma, ectopic ACTH, small carcinoid tumours
- Suppressed: cortisol-producing adrenal tumours (ACTH-independent Cushing)
- CRH administration test immediately post-LDDST
- Pituitary Cushing: low ACTH and cortisol -> rise of both ACTH and cortisol > 20%
- Adrenal or ectopic Cushing: not affected
> Adrenal (low ACTH, high cortisol)
> Ectopic (high ACTH, high cortisol) - HDDST - differentiates pituitary from ectopic
- PO dexamethasone 2mg Q6H for 48 hours
- Pituitary adenoma (Cushing’s disease): suppression in 75% patients
- Adrenal and ectopic Cushing (same as CRH test)
(Some 10-25% ectopic Cushing may still be suppressed) - Bilateral inferior petrosal sinus sampling
Imaging
1. MRI pituitary: pituitary tumour
2. MRI adrenals
Bilateral inferior pertrosal sinus sampling (IPSS) for ACTH
- Bilateral femoral vein catheterisation up till inferior petrosal sinuses (drains pituitary gland)
1A. +/- injection CRH stimulation - Collect blood sample for ACTH
If ACTH in petrosal sinuses higher than peripheral sample
> Pituitarty gland as source of excessive ACTH
- Trans-sphenoidal surgery
If no gradient -> elsewhere - Carcinoid tumour
- Suggest for CT thorax and abdomen
- Possible sites: lungs, pancreas, intestines, adrenal glands
Reliability of LDDST
High rates of false positive:
1. Acute or chronic illness
2. Depression
3. Alcoholism
Stressors activate HPA axis and thus resistant to dexamethasone suppression
Sensitivity and specificity of MRI pituitary gland
Most corticotroph adenomas are tiny and not visible on MRI (> 50% of the scans are negative)
Patient with abnormal MRI has 90% chance of having ACTH- secreting pituitary tumour
- MRI is only diagnostic only if large tumour > 6mm
- 10% healthy adults have non-functioning pituitary lesion < 6mm.
