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JC WCS > Endocrine JC040: I Have Fluctuating BP: Cushing Syndrome, Adrenal Diseases And Tumours, Other Endocrine Tumours > Flashcards

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

1
Q

Hypertension

A

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

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2
Q

Endocrine Hypertension

A

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

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3
Q

Revision: Adrenal gland

A

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

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

Medulla:
- Adrenaline, NE

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4
Q

Adrenocortical Steroid hormones

A
  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)
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5
Q

Plasma transport of Steroids

A
  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)
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6
Q

Aldosterone

A
  • 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

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7
Q

Revision: RAAS system

A

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

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8
Q

***Factors affecting Aldosterone secretion

A

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

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9
Q

***Causes of Primary and Secondary Hyperaldosteronism

A

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

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10
Q

Clinical features of Primary Hyperaldosteronism

A
  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
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11
Q

***Investigations of Conn’s syndrome

A
  • 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

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12
Q

DDx of Primary Aldosteronism: Adenoma vs Hyperplasia

A

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

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13
Q

Salt loading test

A
  • 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
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14
Q

Postural test

A
  • 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)

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15
Q

Management of Aldosteronism

A
  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
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16
Q

Glucocorticoid HPA-axis

A
  1. Circadian rhythm (stimulate / inhibit)
  2. Stress (stimulate)
  3. Pulsatility (stimulate / inhibit)
    —> Hypothalamus —> CRF
    —> Pituitary —> ACTH
    —> Adrenal cortex —> Cortisol (-ve feedback to Hypothalamus + Pituitary)
17
Q

***Etiology of Cushing’s syndrome

A

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

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

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

  1. Adrenal ***carcinoma
    - ↑ Cortisol —> ACTH suppressed
  2. Iatrogenic
    - ∵ ***Exogenous steroid administration
    - ↓ Cortisol + ACTH suppressed
18
Q

***Clinical features of Cushing’s syndrome

A

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
19
Q

***Investigations of Cushing’s syndrome

A

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)

  1. 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

  1. 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
20
Q

***DDx of Cushing’s syndrome

A
  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
21
Q

Diagnosis of Cushing’s syndrome

A
  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

  1. 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
22
Q

Management of Cushing’s syndrome

A

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

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

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

  1. Prophylaxis
    - ***Steroid cover over peri-operative period
    - Antibiotics
    - DVT
23
Q

Adrenal Medulla

A
  • 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
24
Q

Circulating Catecholamines

A
  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
25
Q

Metabolism of circulating Catecholamine

A
  • 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
26
Q

Tumours of Adrenal Medulla

A
  1. Phaeochromocytoma (most common)
  2. Ganglioneuroma (rare)
  3. Sympathoblastoma (rare)
  4. Neuroblastoma (rare)
27
Q

Phaeochromocytoma

A
  • 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)

28
Q

Diagnosis of Phaeochromocytoma

A
  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

  1. **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
29
Q

Treatment of Phaeochromocytoma

A
  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)

30
Q

Surgery for Endocrine diseases

A

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

31
Q

Laparoscopic Adrenalectomy advantages

A
  1. Safety
  2. Efficacy
  3. Shorten hospital stay
  4. Reduce analgesic requirement
  5. Hasten return to normal activities
  6. Improve overall patient satisfaction
32
Q

Adrenalectomy Complications

A
  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

JC WCS (134 decks)

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