JC40 (Medicine) - Adrenal diseases Flashcards
3 diseases that cause endocrine hypertension
Conn’s syndrome
Cushing’s syndrome
Pheochromocytoma
List all hypothalamic factors and pituitary hormones
Anterior lobe:
- Thyrotropin- releasing hormone (TRH) > Thyroid-stimulating hormone (TSH)
- Dopamine > inhibit prolactin
- Corticotropin-releasing hormone (CRH) > ACTH
- Growth-hormone releasing hormone (GHRH) > Growth hormone (GH)
- Somatostatin > inhibit Growth hormone
- Gonadotropin-releasing hormone (GnRH) > FSH and LH
Posterior lobe: Neurohypophysis from PVN and SON in thalamus
- Oxytocin
- Antidiuretic hormone (ADH)/ Vasopressin (Vp)
List all cell types in the pituitary and their secretion
Lactotrophs - Prolactin
Somatotrophs - Growth hormone
Corticotrophs - ACTH
Thyrotrophs - TSH
Gonadotrophs - FSH and LH
Causes of hypopituitarism
Hypopituitarism:
Tumor/ Mass lesion
Surgery/ radiation
Trauma
Ischemic necrosis and Sheehan syndrome
Infection/ inflammation
Action of posterior pituitary hormones
Oxytocin
- Contraction of uterine smooth muscle at pregnancy (positive feedback loop, expel fetus)
- Smooth muscle contraction around lactiferous ducts of mammary glands at lactation (milk expression)
Vasopressin/ ADH
- Increase permeability of renal collecting ducts
- Trigger by decrease BP or increase plasma osmotic pressure
Anatomical layers and composition of adrenal gland
Cortex:
- Zone glomerulosa (outer) - Mineralocorticoids: Aldosterone, DOC and 18-hydroxy DOC
- Zona fasciculata (Middle, 75% volume) - Glucocorticoids: Cortisol, corticosterone
- Zone reticularis (inner) - Mainly Androgens: Dehydroepiandrosterone, Androstenedione, Testosterone, Estrogen, Progestogens
Medulla
- Chromaffin cells and sympathetic nerve endings > Secrete Catecholamine (Epinephrine mainly)
Causes of acute and chronic adrenal gland insufficiency
Acute primary adrenal insufficiency
- Waterhouse-Friderichsen Syndrome: overwhelming bacterial infection lead to hypotension, shock, DIC and massive adrenal hemorrhage
Chronic primary adrenal insufficiency
- Addison Disease: caused by Autoimmune adrenalitis/ TB and infections/ Amyloidosis/ Metastatic cancers
Causes of adrenal hyper-function
Primary adrenal causes?
Secondary causes?
Primary adrenal causes:
- Adrenal hyperplasia
- Cortical adenomas: Conn’s syndrome (high mineralocorticoids) and Cushing’s syndrome (High Glucocorticoids)
- Pheochromocytomas or Neuroblastoma
Secondary causes:
- Function anterior pituitary adenoma (Corticotrophs)
- Iatrogenic ACTH administration
- Secondary aldosteronism: Low Na in renal tubules or low renal perfusion pressure > activate renin-angiotensin system > activate aldosterone production in adrenal cortex
List all androgens produced by zona reticularis in adrenal cortex
Dehydroepiandrosterone
Androstenedione
Testosterone
Estrogen
Progestogens
Plasma transport of steroids
Cortisol (Glucocorticoid)
- 95% protein bound to Albumin (low, affinity, high amount) and Transcortin (high affinity, low amount)
Aldosterone (Mineralocorticoid)
- 60% bind to Albumin
Sex steroids
- Sex-hormone binding globulin
- Globulin increased by estrogen and decreased by androgens
Outline the Renin-angiotensin-Aldosterone system
Systemic effects of Renin-angiotensin-aldosterone system activation
Adrenal glands > produce aldosterone for fluid and sodium retention
Kidneys > fluid and sodium retention
Heart > muscle hypertrophy and fibrosis
Brain > increase sympathetic outflow, trigger thirst sensation and ADH release
Blood vessel > Vasoconstriction
Overall effect:
- Increase effective circulating volume
- Increase Blood Pressure
- Increase extracellular fluid volume
Aldosterone
- MoA
- Condition caused by excess aldosterone
- Biochemical stimulating factors
MoA
- Increase Na reabsorption in DCT and ascending loop of Henle > increase exchange of Na from urine for K and H+ ions in plasma > retain Na and increase osmotic pressure in blood
Condition caused by excess aldosterone
- Excessive dumping of K and H+ ions > HypoKalemia and Alkalosis
Biochemical stimulating factors
- Angiotensin II
- ACTH (short-term stimulation)
- Plasma K: HyperKalemia
- Plasma Na: HypoNatremia
Physiological stimuli/ suppressors of aldosterone secretion
Stimuli:
- Upright posture
- Exercise
- Low Sodium
- Low blood volume
- Stress
- Diuretics
Suppressors:
- Old age
- High Sodium loading
- Volume overload
Causes of primary and secondary hyperaldosteronism
Primary:
- Adrenal adenoma - Conn’s syndrome (70%)
- Adrenal hyperplasia (30%)
- Dexamethasone-suppressible hyperaldosteronism (Familial genetic) (1%)
- Adrenal carcinoma (rare)
Secondary: reactive to low Na, low BP, low intravascular volume
- Renal artery stenosis (stimulate renin and RAA system)
- Congestive cardiac failure (cardiac RAA system)
- Liver cirrhosis (decrease albumin, hypovolemia)
- Nephrotic syndrome (sodium loss)
- Salt-losing states
Pathological Effects of primary aldosteronism
Renal: Polydipsia, Polyuria and nocturia
Neurological: HypoK causes weakness, flaccid paralysis, tetany, parasthesiae
Cardiovascular: Increase BP, Cardiac hypertrophy and fibrosis, Headache, Retinopathy, LV failure or Congestive HF
Investigations for Conn’s Syndrome
Preliminary:
- Exclude other causes of HypoK (e.g. diuretic use, GI loss, renal tubular acidosis)
- Measure urine K loss
- Maintain normal Na intake (for renal exchange of K)
- Stop diuretics, B-blocker and ACEI for >2 weeks before dynamic biochemical tests
Basal tests:
- Plasma K, Basal aldosterone, Basal Plasma Renin Activity (PRA)
Dynamic biochemical tests:
- Salt-loading test
- Postural test +/- Adrenal venous sampling
Radiological imaging: CT/ MRI
Compare the basal biochemical test results between adrenal adenoma and hyperplasia
Salt loading test
- Indication
- Procedure
- Caution
- Normal response
- Pathological response
Indication: Confirmation of primary aldosteronism
Procedure: 0.9% normal IV saline at 500mL/h for 4 hours in sitting/ recumbent position >> measure renin/ aldosterone after test
Caution: Fluid-overload, monitor pulse and BP
Normal response: Salt loading suppress renin and aldosterone
Pathological response: Failure to suppress renin and aldosterone
Postural test
- Indication
- Procedure
- Normal response
- Pathological response
Indication: D/dx adrenal hyperplasia or adrenal adenoma
Procedure: Measure supine/ erect plasma renin and aldosterone
- Supine measurement: at 8am after 8 hours of recumbence overnight
- Erect measurement: at 12 noon after 4 hours of standing
Normal response: Supine to upright posture triggers RAA system >> increase renin and aldosterone levels
Pathological response:
- Adenoma (sensitive to ACTH) - Aldosterone drop 70-90%
- Hyperplasia (sensitive to angiotensin) - Aldosterone increase 90%
Adrenal venous sampling
- Function
- Ddx
Function: measure aldosterone secretion from both adrenal glands to d/dx primary aldosteronism
Unilateral adenoma: Aldosterone high on lesion side, suppressed in contralateral side
Hyperplasia: Aldosterone high on both sides
Treatment options of Primary Aldosteronism
- Pharmacological
- Spironolactone/ Eplerenone – Aldosterone antagonists
- Amiloride/ Triameterene – Act on DCT to block Na reabsorption and K excretion
- Corticosteroid for adrenal hyperplasia
- Surgical resection- for adrenal adenoma
List causes of Cushing’s syndrome
ACTH-dependent:
- Cushing’s disease: Pituitary or Hypothalamic cause
- Ectopic ACTH production: neoplastic cause
Non-ACTH dependent
- Adrenal adenoma
- Adrenal carcinoma
- Steroid administration/ Iatrogenic
Compare the ACTH and Cortisol levels between ACTH-dependent and ACTH-independent Cushing’s syndrome
ACTH-dependent: Cushing’s disease/ Ectopic ACTH production >> High ACTH and Cortisol
ACTH-Independent:
- Adrenal adenoma and carcinoma: Low ACTH, High Cortisol
- Iatrogenic/ steroid use: Low ACTH, Low Cortisol
Clinical features of Cushing’s syndrome
Fat redistribution: Truncal obesity, moon face, buffalo hump, fat pads
Skin: Acne, Purple striae, excessive bruising, thin skin
Psychiatric: Depression, euphoria, frank psychosis
Sexual: impotence, Hirsutism, Oligo-/ Amenorrhea
MSS: Osteoporosis, Proximal myopathy
Endocrine: DM
Vascular: Hypertension
Investigations for Cushing’s syndrome
(Basal, Screening and Diagnostic tests, imaging, sampling)
Basal studies:
- 24h Urinary Free Cortisol, 17-ketosteroids
- Plasma cortisol and ACTH (at 9am and midnight)
Screening tests:
- Overnight dexamethasone suppression test (1mg oral dexamethasone at 9am and midnight, measure next day 9am)
- Late night salivary free cortisol
Diagnostic test:
- Dexamethasone suppression test
- CRF Test
Imaging:
- CXR
- MRI pituitary
- CT adrenal/ CT body scans
Sampling:
- Venous sampling for peripheral blood ACTH
- Inferior petrosal sinus sampling (for pituitary Cushing’s)
Details of Diagnostic test for Cushing Syndrome
D/dx
Dexamethasone suppression test
- Admin Dexamethasone and measure ACTH, Cortisol response
- Normal response - ACTH, Cortisol suppression
- Low dose: 0.5mg Q6H for 2 days - No suppression of Cortisol in Cushing’s Syndrome
- High dose: 2mg Q6H for 2 days - No suppression in Ectopic ACTH, Primary Adrenal Hyperplasia/ Adenoma; Suppression in Pituitary Cushing’s
CRF Test
- Differentiate Pituitary Cushing’s from ectopic ACTH production
- 1ug/kg IV CRF given, sample ACTH and Cortisol
- Pituitary Cushing’s - Exaggerated High ACTH and Cortisol
- Ectopic ACTH production - No rise in ACTH or Cortisol
Compare the diagnostic test results between Pituitary Cushing’s, Ectopic ACTH, Adrenal adenoma and carcinoma
Pituitary Cushing’s
- Dexamethasone low-dose: No suppression
- Dexamethasone high-dose: Suppression
- ACTH level: High
- CRF stimulus: Exaggerated rise
Ectopic ACTH
- Dexamethasone low-dose: No suppression
- Dexamethasone high-dose: +/- suppression
- ACTH level: High
- CRF stimulus: No change
Adrenal adenoma and carcinoma
- Dexamethasone low-dose: No suppression
- Dexamethasone high-dose: No Suppression
- ACTH level: Low/ Zero
How to localize cause of Cushing’s syndrome
Radiology:
- CXR
- MRI pituitary
- CT adrenal (renal cause)
- CT whole body (ectopic ACTH)
Sampling:
Venous sampling for peripheral ACTH
Inferior petrosal sinus sampling
e. g. Cushing’s disease - High petrosal sinus ACTH (pituitary output), low peripheral ACTH
e. g. Ectopic ACTH production - Low petrosal sinus ACTH, High peripheral ACTH
How to localize cause of Cushing’s syndrome
Radiology:
- CXR
- MRI pituitary
- CT adrenal (renal cause)
- CT whole body (ectopic ACTH)
Sampling:
- Venous sampling for peripheral ACTH
- Inferior petrosal sinus sampling
e. g. Cushing’s disease - High petrosal sinus ACTH (pituitary output), low peripheral ACTH
e. g. Ectopic ACTH production - Low petrosal sinus ACTH, High peripheral ACTH
Treatment of Cushing’s disease
Surgical:
- Adrenal adenoma/ carcinoma - Surgical resection
- Pituitary tumors - Transphenoidal surgery
- Peri-operative: Control and correct BP, DM, HypoK
- Prophylaxis against rapid cortisol drop: Steroid cover
- Antibiotics cover
Medical:
- Reduce hypercortisolism before surgery
- Metyrapone: Block cortisol synthesis at 11 B-hydroxylase step in adrenal cortex
- Ketoconazole: Inhibit cortisol and androgen secretion
Production of adrenaline and noradrenaline
Anatomical structures involved
Catecholamine biosynthesis in Adrenal Medulla: Chromaffin cells and sympathetic nerve fibers, from neuroectoderm
Dual blood supply:
- Portal blood in corticomedullary sinuses draining adrenal cortex
- Medullary arteries
**PNMT in adrenal cortex convert Noradrenaline > Adrenaline
**PNMT is not in sympathetic nerve fiber > neurons can only make Noradrenaline
List all circulating catecholamines and origins of production
Noradrenaline
- Act on a1 and B1 receptors
- Major circulating catecholamine under BASAL condition
- 95% derived from sympathetic nerve endings, 5% from adrenal medulla
Adrenaline
- Act on B1 and B2 receptors
- 100% from adrenal medulla
Dopamine
- Released during intense adrenal medullary activity
- Mostly from kidneys
Metabolism of circulating catecholamines
Extraneuron metabolism:
Catecholamine >> catalyze by Catecholamine-o-methyl transferase (COMT) in liver and kidney
>> Methylated catecholamine oxidized >> Vanillymandelic acid (VMA)
Causes of adrenal medulla hyper-function
Tumors:
- Pheochromocytoma
- Ganglioneuroma
- Symapthoblastoma
- Neuroblastoma
Pheochromocytoma
- Cell of origin
- Etiologies
- Locations
- S/S
Cell of origin - Chromaffin cell of adrenal medulla
Etiologies - spontaneous, familial (MENII, Neurofibromatosis)
Locations - Intra-adrenal (produce noradrenaline and adrenaline) or Extra-adrenal (20%, produce noradrenaline)
S/S:
- Hypertension, Angina, Cardiac failure
- Headache
- Palpitations, Dizziness, anxiety
- Hyperhydrosis
- Pallor
- Weight loss, pyrexia
- Stroke
- Glucose intolerance, DM
Diagnosis of Pheochromocytoma
Basal test:
- Urinary Vanillymandelic acid
- Urinary catecholamines and metabolites - Metanephrine and normetanephrine
- Plasma catecholamine
Radiological:
- CT/MRI with contrast after adrenoceptor blockade (prevent pressor crisis)
- Meta-iodo-benzyl guanidine (MIBG) scan - Chromaffin uptake of RAI
Treatment of pheochromocytoma
Surgery
- Full adrenoceptor blockage before
- a blockade with Phenoxybenzamine first + B blockade with propranolol
Approaches:
- Open approach adrenalectomy: anterior transabdominal, lateral extraperitoneal, or posterior lumbar
- Minimal invasive laparoscopic adrenalectomy: Transabdominal, or Retroperitoneal
Function of alpha and beta adrenoceptors
Advantages of laparoscopic adrenalectomy
- Safe
- high efficacy
- Shorter hospital stay
- Reduce analgesic requirement
- Faster recovery
- Higher overall patient satisfaction
Complications of adrenalectomy
- Intra-operative hemorrhage - damage adrenal capsule or vena cava
- Splenic injury
- Liver injury
- Pneumothorax
- Loss of adrenal tissue/ Acute adrenal insufficiency (Need glucocorticoid replacement post-op)
- Hypertensive crisis, electrolyte disturbance
Conditions that require adrenal surgery
Conn’s syndrome
Cushing’s adenoma
Pheochromocytoma
Adrenal cortical carcinoma
Large adrenal incidentaloma
