Endocrine JC040: I Have Fluctuating BP: Cushing Syndrome, Adrenal Diseases And Tumours, Other Endocrine Tumours

Question 1

Hypertension

Answer 1

Types:
1. Essential hypertension (92-94%)
2. **Renal hypertension
- Parenchymal (2-3%)
- Renovascular (1-2%)
3. **Endocrine hypertension (0.3-0.4%)
- Adrenal
—> Conn’s syndrome (Hyperaldosteronism)
—> Cushing’s syndrome
—> Phaeochromocytoma

Question 2

Endocrine Hypertension

Answer 2

***Adrenal
1. Conn’s syndrome (Hyperaldosteronism)
2. Cushing’s syndrome
3. Phaeochromocytoma

Question 3

Revision: Adrenal gland

Answer 3

Cortex (記gfr):
1. Zona glomerulosa (outer)
- Aldosterone

2. Zona fasciculata (middle)
   - 75% total cortical volume
   - Corticosteroid
3. Zona reticularis (innermost)
   - Corticosteroid, Androgens

Medulla:
- Adrenaline, NE

Question 4

Adrenocortical Steroid hormones

Answer 4

1. Glucocorticoids
   - ***Cortisol (mainly)
   - Corticosterone (some)
2. Mineralocorticoids
   - ***Aldosterone (mainly)
   - Deoxycorticosterone (DOC, small amount)
   - 18-Hydroxy DOC (small amount)
3. Androgens
   - Dehydroepiandrosterone
   - Androstenedione
   - Testosterone
   - Estrogens, Progestogens (small amount)

Question 5

Plasma transport of Steroids

Answer 5

1. Cortisol
   - 95% of all circulating cortisol is **protein-bound
   —> **Transcortin: high affinity for cortisol, present in small amounts in plasma
   —> ***Albumin: much lower affinity but large amount
2. Aldosterone
   - 60% bound to Albumin
3. Androgens and Estrogens
   - bind to ***Sex hormone binding globulin (↑ by Estrogens, ↓ by Androgens)

Question 6

Aldosterone

Answer 6

• Mineralocorticoid
• Na reabsorption in **distal renal tubule + **ascending LoH by exchanging Na for K + H
• Excessive aldosterone —> **HypoK + **Alkalosis (∵ ↑ Na reabsorption + exchange of Na for K + H in renal tubules)
• Secretion mainly controlled by ***RAAS system, stimulated by Angiotensin 2 (or via ACTH)

Mineralocorticoid action:
- 50-60% from aldosterone
- 30-40% from basal cortisol secretion

Question 7

Revision: RAAS system

Answer 7

Kidney: Renin secretion
Angiotensinogen —(Renin)—> Angiotensin 1 —(ACE)—> Angiotensin 2 —>
1. **Vasoconstriction
2. Stimulate Adrenal cortex —> **Aldosterone —> act on Kidney to reabsorb Na, excrete K + H

Question 8

***Factors affecting Aldosterone secretion

Answer 8

Biochemical factors stimulation:
1. **Angiotensin 2 (via RAAS system)
2. **ACTH (short-term stimulation)
3. HypoNa
4. HyperK

Physiological stimuli (mainly mediated by RAAS system):
↑ Aldosterone:
1. Upright posture
2. Exercise
3. Sodium deprivation
4. Hypocalcaemia
5. Stress
6. Diuretics

↓ Aldosterone:
1. ↑ Age
2. Sodium loading
3. Volume overload
4. Autonomic failure

Question 9

***Causes of Primary and Secondary Hyperaldosteronism

Answer 9

Primary Hyperaldosteronism:
1. Adrenal adenoma (Conn’s syndrome) (60-70%)
2. Adrenal ***hyperplasia (20-40%)
3. Dexamethasone suppressible (1-2%)
4. Adrenal carcinoma (very rare)

Secondary Hyperaldosteronism (excessive RAAS activation):
1. **Renal artery stenosis (false sense of hypovolaemia)
2. **Congestive heart failure (↓ CO)
3. **Cirrhosis (↓ effective circulatory volume)
4. **Nephrotic syndrome
5. Salt losing states

Question 10

Clinical features of Primary Hyperaldosteronism

Answer 10

1. Renal (HypoK tubular damage + ADH resistance due to HypoK —> **Nephrogenic DI)
   - **Polydipsia
   - ***Polyuria
   - Nocturia
2. Neuromuscular
   - Weakness
   - ***Flaccid paralysis
   - Overt / Latent tetany
   - Paresthesia (may be partly due to Mg loss)
3. Hypertensive
   - **↑ BP
   - Headache
   - Cardiomegaly / Hypertrophy
   - **LV failure / CHF
   - Retinopathy

Question 11

***Investigations of Conn’s syndrome

Answer 11

• Exclude other causes of HypoK (**diuretics, GI loss, **renal tubular acidosis)
• Document excessive ***urinary K loss
• Ensure a reasonable Na intake (∵ Low Na intake protect against HypoK by ↓ tubular Na available for exchange)
• Stop diuretics (↓Na, ↓K), β-blockers (↑K), ACEI (↓Na, ↑K)for >=2 weeks before dynamic biochemical tests

Dynamic biochemical tests:
- Diagnosis —> **Salt loading test
- Finding out etiology (Adenoma vs Hyperplasia) —> **Postural test
- interpretation of biochemical tests can be difficult

Diagnosis: Biochemical tests + Radiological images

Question 12

DDx of Primary Aldosteronism: Adenoma vs Hyperplasia

Answer 12

Adenoma:
- Plasma K: Very low - Normal
- Basal aldosterone: High - Very high
- Basal PRA (plasma renin activity): Low / Suppressed
- Aldosterone response to standing (Postural test): **↓ 70-90% in Aldosterone (probably ∵ ↓ ACTH in diurnal rhythm)
- Adrenal venous sampling of aldosterone production: **Unilateral ↑, **Contralateral suppressed
- CT / MRI: **Unilateral tumour

Hyperplasia:
- Plasma K: Low - Normal
- Basal aldosterone: High / High normal
- Basal PRA: Low - Low normal
- Aldosterone response to standing (Postural test): **↑ 90% in Aldosterone (∵ exaggerated rise of aldosterone physiologically)
- Adrenal venous sampling of aldosterone production: **Bilateral production
- CT / MRI: Normal / Slightly enlarged

Question 13

Salt loading test

Answer 13

• 0.9% normal saline IV (500 ml/h) for 4 hours (sitting/recumbent) (i.e. 2L in 4 hours)
• Monitor pulse + BP —> watch out for signs of fluid overload
• Measure Renin / Aldosterone after salt loading
• Normal response: Suppression of renin + aldosterone levels
• Primary aldosteronism (Adenoma / Hyperplasia): ***Failure / Inadequate suppression of aldosterone level

Question 14

Postural test

Answer 14

• Measure supine / erect plasma renin + aldosterone
• Supine: at 8am after 8 hours of recumbence overnight
• Erect: at 12noon after 4 hours of ambulation
• Early morning supine position: ***High ACTH drive + Low Angiotensin drive
• Lunchtime erect position: Fallen ACTH drive + ***High Angiotensin drive

Normal response:
- Supine to Upright posture activate RAAS with ↑ in renin + aldosterone

Adenoma:
- ***very sensitive to ACTH but not Angiotensin 2 —> ↓ 70-90% in Aldosterone level in response to standing
- Aldosterone fails to ↑ from supine to erect posture (∵ fail to respond to Angiotensin)
(朝早高, 下午低)

Hyperplasia:
- respond excessively to Angiotensin 2 but not ACTH —> ↑ 90% in Aldosterone level in response to standing
- Exaggerated rise in response to standing
(朝早低, 下午高)

Question 15

Management of Aldosteronism

Answer 15

1. ***Aldosterone antagonist
   - Spironolactone
   - Epleronone (expensive) —> less gynaecomastia
2. Amiloride / Triameterene (***K sparing diuretics)
   - direct actions on distal renal tubules blocking Na reabsorption + K excretion independent of Aldosterone
3. ***Surgery in adrenal adenoma
4. ***Medical treatment in adrenal hyperplasia

Question 16

Glucocorticoid HPA-axis

Answer 16

1. Circadian rhythm (stimulate / inhibit)
2. Stress (stimulate)
3. Pulsatility (stimulate / inhibit)
   —> Hypothalamus —> CRF
   —> Pituitary —> ACTH
   —> Adrenal cortex —> Cortisol (-ve feedback to Hypothalamus + Pituitary)

Question 17

***Etiology of Cushing’s syndrome

Answer 17

ACTH-dependent conditions (ACTH high):
1. ***Cushing’s disease
- ∵ Hypothalamic / Pituitary disease
- ↑ ACTH —> ↑ Cortisol
- Adrenal hyperplasia

2. ***Ectopic ACTH syndrome
   - ∵ Malignant / Benign non-endocrine tumour
   - ↑ ACTH —> ↑ Cortisol

ACTH-independent conditions (ACTH suppressed):
1. Adrenal ***adenoma
- ↑ Cortisol —> ACTH suppressed

2. Adrenal ***carcinoma
   - ↑ Cortisol —> ACTH suppressed
3. Iatrogenic
   - ∵ ***Exogenous steroid administration
   - ↓ Cortisol + ACTH suppressed

Question 18

***Clinical features of Cushing’s syndrome

Answer 18

Usually Spot diagnosis

1. Obesity
   - **truncal in distribution
   - **moon face
   - ***buffalo hump
   - fat pads
2. Skin changes
   - acne
   - **thin skin
   - **excessive bruising
   - **purple striae
   - **pigmentation (esp. ectopic ACTH / pituitary Cushing’s)
3. ***Proximal myopathy
4. Psychiatric disturbances
   - non-specific
   - depression
   - euphoria
   - frank pyschosis
5. ***Hirsutism, Oligo/amenorrhoea in female, Impotence in men
6. Osteoporosis
7. Hypertension
8. DM, IGT

Question 19

***Investigations of Cushing’s syndrome

Answer 19

Basal studies:
1. 24 hour urinary **Free cortisol, **17-ketosteroids
2. Plasma **cortisol + **ACTH at 9am and 12am (see if any loss of diurnal rhythm —> remains high at noon)

Screening tests:
1. Overnight dexamethasone suppression test
- for screening only, can be done on outpatient basis
- plasma basal cortisol at 9am —> ***1mg dexamethasone orally at 12am —> measure plasma cortisol at 9am next morning (see if cortisol can be suppressed)

2. Late night salivary Free cortisol
   - only available in very few centres

None of initial tests have ideal sensitivity / specificity:
- False positive: patient under a lot of stress

Diagnosis:
1. Dexamethasone suppression test
- low dose (find out whether Cushing): 0.5mg q6h for 2 days —> **No suppression in Cushing’s syndrome (i.e. there is **Autonomous glucocorticoid secretion)
- high dose (find out underlying cause): 2mg q6h for 2 days —> No suppression in Ectopic ACTH / Primary adrenal lesions but ***Pituitary Cushing’s suppressed

2. CRF test (Corticotropin releasing factor stimulation test: differentiate Pituitary Cushing’s from Ectopic ACTH)
   - 1 ug/kg IV —> serial samples for ACTH and Cortisol for 2 hours
   - Pituitary Cushing’s: **Exaggerated rise
   - Ectopic ACTH syndrome: **No significant rise above basal

Question 20

***DDx of Cushing’s syndrome

Answer 20

1. Pituitary-dependent
   - Dexamethasone suppression Low dose: Absent
   - Dexamethasone suppression High dose: **Present usually
   - ACTH: Normal - High
   - CRF test: **Exaggerated rise
2. Ectopic ACTH syndrome
   - Dexamethasone suppression Low dose: Absent
   - Dexamethasone suppression High dose: Absent usually
   - ACTH: High usually, occasionally normal
   - CRF test: No significant rise above basal
3. Adrenal adenoma
   - Dexamethasone suppression Low dose: Absent
   - Dexamethasone suppression High dose: Absent
   - ACTH: Suppressed and almost invariably undetectable
4. Adrenal carcinoma
   - Dexamethasone suppression Low dose: Absent
   - Dexamethasone suppression High dose: Absent
   - ACTH: Suppressed and almost invariably undetectable

Question 21

Diagnosis of Cushing’s syndrome

Answer 21

1. Biochemical tests
   - **Dexamethasone suppression test (Low dose)
   - **CRF test
2. Radiology
   - CXR
   - **MRI pituitary
   - **CT adrenals
   - ***CT body scans (for Ectopic ACTH syndrome)

Diagnosis of adrenal cause is easy (ACTH is suppressed), difficult part is differentiate Cushing’s disease vs Ectopic ACTH syndrome —> IPSS

3. Inferior petrosal sinus sampling (IPSS) / Venous sampling for ACTH
   - insert catheters into right + left **inferior petrosal sinuses (which drain pituitary gland)
   —> measure ACTH level
   —> Pituitary cause / Cushing’s disease: **Very high ACTH
   —> Ectopic ACTH syndrome: ACTH level not increased

Question 22

Management of Cushing’s syndrome

Answer 22

Depends on underlying cause
1. Adrenal tumours: Surgery
2. Pituitary tumours: Transphenoidal surgery

Medical treatment: essential to reduce **hypercortisolism before surgery (to reduce peri-operative complications)
1. **Metyrapone (1st line)
- block cortisol synthesis at final 11 β-hydroxylase step
- effective within 2 hours

2. ***Ketoconazole
   - inhibit cortisol + androgen secretion
   - hepatotoxicity a potential problem —> monitor LFT

Peri-operative management:
1. Control + Correct
- BP
- DM
- HypoK (∵ Cortisol mimic Aldosterone)

2. Prophylaxis
   - ***Steroid cover over peri-operative period
   - Antibiotics
   - DVT

Question 23

Adrenal Medulla

Answer 23

• Composed almost exclusively of ***Chromaffin cells —> secrete Catecholamine
• Originate from the ***neuroectoderm
• Dual blood supply:
  1. **Portal blood in corticomedullary sinuses having previously drained the adrenal cortex
  2. **Medullary arteries
• Major pathway and enzymes required for Catecholamine biosynthesis are almost identical in both adrenal medulla and in sympathetic neurons
• An additional phenylethanolamine-N-methyl-transferase promote methylation step which is required for Adrenaline synthesis from NE in adrenal medulla

Question 24

Circulating Catecholamines

Answer 24

1. Noradrenaline
   - α1 + β1 receptors
   - major circulating catecholamine under basal condition (95% derived from ***peripheral sympathetic nerve endings, small amount from adrenal medulla)
2. Adrenaline
   - β1 + β2 receptors, weak actions at α1 receptor
   - represent ***true secretion from adrenal medulla (∵ SNS does NOT secrete adrenaline)
3. Dopamine
   - released during intense adrenal medullary activity
   - most of circulating dopamine is of ***renal origin at basal condition

Question 25

Metabolism of circulating Catecholamine

Answer 25

- Metabolised predominantly ***extraneuronally to their o-methylated derivatives by Catecholamine-o-methyl transferase (***COMT: found mainly in Liver + Kidney): —> NE —(COMT)—> ***Normetanephrine —(MAO)—> MHPG —> VMA —> E —(COMT)—> ***Metanephrine —(MAO)—> MHPG —> VMA - Methylated Catecholamines —> Deaminated —> Oxidised to ***Vanillymandelic acid (VMA) —> excreted in urine - Most Catecholamines metabolism take place within same cells where they are synthesised - In sympathetic nerves, MAO is the only metabolising enzyme - In adrenal medullary Chromaffin cells and Phaochromocytoma tumour cells (where ***COMT prevails), free ***Metanephrines are main metabolic product —> metabolites produced by MAO can further metabolised by COMT

Question 26

Tumours of Adrenal Medulla

Answer 26

1. Phaeochromocytoma (most common) 2. Ganglioneuroma (rare) 3. Sympathoblastoma (rare) 4. Neuroblastoma (rare)

Question 27

Phaeochromocytoma

Answer 27

- Arise from Chromaffin cells - “Rule of 10”: No longer valid - 20% extra-adrenal - 24% familial (MEN2, Neurofibromatosis) - up to 36% malignant - ***Extra-adrenal tumours: tend to produce NE - ***Adrenal tumours: produce both NE + E S/S: 1. ***Hypertension (paroxysmal / sustained) 2. ***Headache, palpitations 3. ***Hyperhidrosis 4. Dizziness, anxiety 5. Pallor 6. ***Weight loss, Hypermetabolism, Pyrexia 7. ***Angina, Cardiac failure, Stroke 8. ***Glucose intolerance, DM (NE / E ↑ gluconeogenesis, ↑ glycogenolysis)

Question 28

Diagnosis of Phaeochromocytoma

Answer 28

1. Urinary ***VMA 2. ***Urinary Catecholamines and their metabolites (***Metanephrine, ***Normetanephrine) - beware of drug and dietary interference (e.g. β-blockers, methyldopa) 3. ***Plasma Catecholamines (available in some centres) Localisation 4. CT / MRI - contrast injection may induce a pressor crisis —> patients should be prepared with complete ***adrenoceptor blockade before scan 5. ***MIBG scan (Meta-iodo-benzyl guanidine) - taken up by Chromaffin tissue —> ***↑ uptake by phaeochromocytoma - labelled with radioactive ***iodine and results in adrenomedullary images 24-48 hours after injection

Question 29

Treatment of Phaeochromocytoma

Answer 29

1. Surgery to remove tumour 2. Full α + β blockade before surgery / any procedures to prevent ***hypertensive crisis - α blockade with ***Phenoxybenzamine first —> β blockade with ***Propranolol - if β blockade first —> ***unopposed α-adrenoceptor activity —> vasoconstriction —> exacerbate hypertension - α blockade first —> allow ***vasodilation first before β blockade (vasoconstriction) (α1 receptor: smooth muscle contraction + vasoconstriction in many blood vessels β2 receptor: dilate arteries to skeletal muscles)

Question 30

Surgery for Endocrine diseases

Answer 30

Principles: 1. Confirm the endocrine diagnosis 2. Localise the tumour 3. ***Render the patient medically fit before surgery 4. Establish the need to operate 5. Surgical tactics Adrenal surgery indications: 1. Conn’s syndrome 2. Cushing’s adenoma 3. Phaeochromocytoma 4. Adrenocortical carcinoma 5. Adrenal incidentaloma Conventional open approach: 1. Anterior transabdominal 2. Lateral extraperitoneal 3. Posterior lumbar Minimal invasive approach: 1. Anterior / Lateral Transabdominal 2. Posterior / Lateral Retroperitoneal Choice of approach depends on: 1. Pathology 2. Size, Location 3. Concomitant procedure 4. Surgical expertise

Question 31

Laparoscopic Adrenalectomy advantages

Answer 31

1. Safety 2. Efficacy 3. Shorten hospital stay 4. Reduce analgesic requirement 5. Hasten return to normal activities 6. Improve overall patient satisfaction

Question 32

Adrenalectomy Complications

Answer 32

1. ***Intraoperative haemorrhage - adrenal capsular - vena cava 2. Splenic injury 3. Liver injury 4. Pneumothorax 5. Loss of adrenal tissue 6. ***Hypertensive crisis - Phaeochromocytoma —> Full α + β blockade before surgery 7. ***Acute adrenal insufficiency - Cushing’s syndrome due to Adrenal adenoma —> given Steroid cover peri-operatively - Contralateral suppressed adrenal gland —> given Cortisol replacement post-operatively until remaining adrenal gland recover 8. Electrolyte disturbance 9. Others