JC40 (Medicine) - Adrenal diseases Flashcards by Max Kam

3 diseases that cause endocrine hypertension

Conn’s syndrome
Cushing’s syndrome
Pheochromocytoma

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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)

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List all cell types in the pituitary and their secretion

Lactotrophs - Prolactin

Somatotrophs - Growth hormone

Corticotrophs - ACTH

Thyrotrophs - TSH

Gonadotrophs - FSH and LH

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Causes of hypopituitarism

Hypopituitarism:

Tumor/ Mass lesion

Surgery/ radiation

Trauma

Ischemic necrosis and Sheehan syndrome

Infection/ inflammation

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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

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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)

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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

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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

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List all androgens produced by zona reticularis in adrenal cortex

Dehydroepiandrosterone

Androstenedione

Testosterone

Estrogen

Progestogens

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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

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Outline the Renin-angiotensin-Aldosterone system

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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

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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

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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

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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

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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

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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

1. Safe 2. high efficacy 3. Shorter hospital stay 4. Reduce analgesic requirement 5. Faster recovery 6. Higher overall patient satisfaction

Complications of adrenalectomy

1. Intra-operative hemorrhage - damage adrenal capsule or vena cava 2. Splenic injury 3. Liver injury 4. Pneumothorax 5. Loss of adrenal tissue/ Acute adrenal insufficiency (Need glucocorticoid replacement post-op) 6. Hypertensive crisis, electrolyte disturbance

Conditions that require adrenal surgery

Conn's syndrome Cushing's adenoma Pheochromocytoma Adrenal cortical carcinoma Large adrenal incidentaloma