03: Clinical Lectures 2 Flashcards
Classify the steroid hormones according to their main physiological effects and the endocrine gland cell types that secrete them.
MINERALCORTICOIDS (zona medullarosa) = ALDOSTERONE
*salt balance = water balance
GLUCOCORTICOIDS (zona fasciculata) = CORTISOL
*energy balance
SEX STEROIDS (zona reticularis) = TESTOSTERONE * sex
MEDULLA (extension of sympathetic system) = Norepinephrine and epinephrine
*stress response
Outline schematically the main pathways and cellular compartments involved in the synthesis of steroid hormones; and indicate the main agents and points of control.
CHOLESTEROL
=> PROGESTERONE
- > CORTICOSTERONE > ALDOSTERONE
- > CORTISOL
(21-hydroxylase)
CHOLESTEROL
=> PROGESTERONE + DHEA => ANDROSTENEDIONE
> ESTRONE
> ANDROSTENEDIONE > TESTOSTERONE > estradiol
> DHT
- different enzymes found in different adrenal zones in order to make different enzymes
e. g. aldosterone enzymes found in zona glomerulosa
Outline diagrammatically the structure of the (compound) adrenal gland, indicating its zonation, vascularisation and innervation.
thoracic splanchnic nerve
The adrenal medulla is driven by the sympathetic nervous system via preganglionic fibers originating in the thoracic spinal cord, from vertebrae T5–T11
Justify the view that the adrenal cortex is essential for survival of the individual while the adrenal medulla is not.
Adrenal cortex produces hormones that controls sex (androgens, estrogens), salt balance in the blood (aldosterone), and sugar balance (cortisol). The adrenal medulla produces hormones involved in the fight-or-flight response (catecholamines, or adrenaline type hormones such as epinephrine and norepinephrine).
Describe the normal circadian basal rhythm in plasma total cortisol concentration & levels in pathology
high @ morning, lowest at midnight, ACTH mirrors levels
very high ACTH plasma = ectopic ACTH
very low ACTH = non-ACTH-dependent = adrenal gland
CUSHINGS (pituitary) = overlap between ectopic ACTH therefore ACTH measurement not enough to dx
Define the terms: plasma protein bound cortisol; plasma free cortisol.
95% of plasma cortisol bound to CORTISOL BINDING GLOBULIN
bind to receptors found in all nucleated cells
State the likely effect upon the plasma glucose concentration of administering cortisol to a normal subject; and list the target sites and processes underlying that effect.
Under stressful conditions, cortisol provides the body with glucose by tapping into protein stores via gluconeogenesis in the liver
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Cushing’s syndrome)
causes:
1º HYPERALDOSTERONISM:
*unilateral adenoma, bilaeral hyperplasoa
- CUSHINGS: adrenal gland = XS cortisol androgens
- tissue breakdown, sodium retention, insulin antagonism = DM, immune system suppression
=> central obesity, HT, glucose intolerance, Hirsutism, Striae
• ACTH-dependent = pit. tumour (cushing’s disease), ectopic ACTH secretion (lung carcinoid) = ⇧ACTH = XS cortisol.
or CRH secreting tumour = ⇧ACTH
• ACTH-independent = adrenal tumour (adenoma/carcinoma); corticosteroid therapy = 1º issue @ adrenal gland level
1) SCREENING: overnight dex test + 24hr free cortisol in urine
2) 24hr free urine cortisol rpt. + low dose dex test
3) ACTH monitoring @ morning-midnight
4) High dose dex test (pit or not pit.)
5) MRI sella, CT adrenal, BIPSS, CT chest
> Sx of tumour
ADRENAL HORMONE SYNTH INHIB (Ketoconazole etc.)
Destroy adrenocortical cells (Mitotane)
RT
Bilateral adrenalectomy
Describe the clinical features, diagnosis and management of adrenal hypofunction (Addison’s disease).
causes: adrenal dysgenesis, adrenal destruction, impaired steroidogenesis
1º ADRENAL INSUFFICIENCY
- Addison’s: AuImm, Invasion, Infiltration, Iatrogenic, Infarction
- +ve adrenal autoantibodies, lymphocytic infiltrate
- no cortisol prod > ⇧CRH (hypothal) > ⇧ACTH & ⇧MSH (due to common POMC precursor) = PIGMENTATION
- Decreased BV = postural hypotension
ADRENAL ENZYME DEFECTS
- congenital adrenal hyperplasia (21-hydroxylase deficiency)
• Low Na High K
• CORTISOL LEVELS CHECK
• SYNACTHEN TEST + BASAL ACTH: basline cortisol and ACT > synthetic ACTH (tetracosactrin) > measure over time,
= 450nmol+ over normal
= 1º adrenal insufficiency = no response
= 2º adrenal insufficiency = no CRH thus trophic diminished = stunted cortisol production
• followed by PLASMA ACTH measurements
• followed by Adrenal Antibodies + other autoimmune antibodies monitoring
+ long chain fatty acids (men) for adrenoleukodystrophy
> STEROIDS (if too unwell for SYNACTHEN)
daily: GLUCOCORTICOID (steroids) in divided doses to mimic diurnal variation (HC)
Mineralocorticoid replacement (fludrocortisone) which bind to ALDOSTERONE receptors; monitored for dose adjustment
Discuss the importance of glucocorticoids in acute stress (guidelines for the management of patients on replacement steroids).
- HYPOADRENAL PATIENTS / REPLACEMENT STEROIDS require doubling steroid doses in order to react to stresses
- Patients receiving long-term treatment and take exogenous steroids: endogenous steroid prod affected thus replacement steroids required.
- minor short lived illness or stress = 2x
- major illness/operation = 100mg HC iv
- patient education to safetynet, partners and carers taught to inject IM HC w/ sever vom and diarrhoea
Outline inborn errors of the adrenal glands (congenital adrenal hyperplasia).
21-hydroxylase defect = aldosterone and cortisol def.
*salt and glucose balance disruption
- excessive adrenal androgen production
- hyperplasia d/t nil cortisol to negative feedback ACTH and CRH = continuous adrenal cortex stimulation
Screening tests for Cushings
24hr urinary free cortisol = 14-135nmol/24hr (normal)
Overnight Dex. suppression test = <50nmol/l @ 0900 (normal)
- normal: cortisol drops
- Pituitary dependent = drops after some time (day 4) d/t high dose eliciting neg feedback
- Ectopic ACTH = cortisol levels remain high and not suppressed,
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Conn’s syndrome)
Xs ALDOSTERONE d/t adenoma or bilateral hyperplasia: normally stimulated by Angio.II (powerful vasoconstrictor) = water retention and HT
d/t
ALDOSTERONE-PRODUCING TUMOUR = renal tubules ⇧water retention etc. = ⇩renin = ⇩Angio.II =
⇧aldosterone:renin ratio
1) measure aldosterone:renin ratio, ratio >20 1º hyperaldosteronism
2) plasma renin activity (PRA) & plasma aldosterone concentration (PAC)
3) 24hr urine aldosterone w/ salt loading
4) CT adrenal, plasma 18-hydroxycorticosterone
5) adrenal venous sampling
Discuss the clinical features and biochemical diagnosis of the hyperfunction syndromes of the adrenal cortex and medulla (Phaeochromocytoma)
PHEOCROMOCYTOMA: neuroendocrine tumour in adrenal medulla = XS catecholmaines
= ⇧HR = ⇧CO = ⇧BP
= Diabetogenic d/t adrenergic effect on glucose metabolism
- HT (especially young HT) & paroxysmal attacks: headache, sweating, palpitations, tremor, pallor, anxiety,
- TUMOUR-ASSOCIATED
- HYPERGLYCAEMIC; fight or flight stress.
- MEN II (multiple endocrine neoplasia): phaecrom.
- Von Hippel-Landau
- MEN III
1) 24hr urine for metanephrines & plasma metanephrines
2) discontinue any contributing medications
3) Adrenal CT/MRI
4) Radionecleotide scan: selective uptake and localisation of lesion
+genetic testing w/ family hx > tumour evaluation (expression studies)
> Sx risk of crisis release of hormone release
thus
• alpha-adrenergic blockade > THEN beta blocker (lols)
Adrenal Mass Dx Algorithm
1) endocrine workup: free metanephrine plasma/urine, dex test, ALD:PRA
= Sx if functional and secretory
2) CT or MRI (non-functional, need to id malignant or benign)
3) surveillance or surgery
Congenital adrenal Hyperplasia
21-hydroxylase def.
Xs of precursors and shunted pathway to TESTOSTERONE
*lack of cortisol = no neg feedback = ⇧ACTH = adrenal hyperplasia
- neonatal salt loss crisis
- ambiguous genitalia (girls)
- hirsutism (women)
Calcium distirbution & adjustment
dietary calcium forms salts and thus majorly excreted
BONE calcium reservoir
PLASMA calcium: 45% of plasma calcium is free/ionised and bio active
* total calcium needs to be adjusted
* albumin levels; binds to calcium thus dictate active calcium levels
- 2.20-2.6mmol/l
- ADJUST BY 0.1mmol/L FOR EACH 5G/L reduction in albumin from 40g/l
e.g. albumin of 30g/l = 0.2mmol INCREASE d/t to LOSS in albumin = above normal range
Parathyroid Glands
CHIEF CELLS: PTH
OXYPHIL CELLS: larger and less abundant;
*calcium-sensing receptors indicate and dictate PTH levels depending on plasma calcium
Vitamin D Metabolism
Inactive vitamin D (25-hydroxylase vitamin d) synthesised from precursors (obtained from sun metabolism @ skin or diet)
Activated (1,25) in kidney, controlled by PTH
acts on gut and serum calcium
- inactive vitamin D is circulating form, long 1/2L
- patients with renal impairment or chronic kidney disease REQUIRE ACTIVATED VITAMIN D
>ALFACALCIDOL or CALCITRIOL prescribed (hydroxylated derivatives)
hypocalcaemia: signs, causes, dx, mgmt
tetany + cardiac features (acute)
paraesthesia, twitching and spasm
*CHOVSTEK’S SIGN
*TROSSEAU’S SIGN
ectopic calcification, parkinsonism, dementia (chronic)
- vit d deficiency (common)
- Mg2+ deficiency interfere with PTH (GI Pt., diarrhoea, alcohol abuse, omperazole)
- Cytotox drugs
- genetic disorders
- Bisphosphonates, calcitonin
1) Confirm adjusted calcium levels
2) PTH levels
3) Mg (⇩PTH) or Urea and Creatinine (⇧PTH)
4) Vitamin D
* ⇩phosphates & ⇧PTH in Vtamin D def.
* ⇧phosphates in hypoparathyroidism
combination of treatments (mild) >1.9mmol > oral calcium tablets > vitamin D > Mg2+ replacement > remove offending meds
severe <1.9mmol/L
MEDICAL EMERGENCY
> IV Calcium gluconate + ECg monitoring
> solve underlying cause
hypoparathyroidism
inappt. low PTH in presence of hypocalcaemia
* common surgical cause, followed by autoimmune
pseudohypoparathyroidism
presents in childhood, obesity, short stature, shortening of metacarpals
*hypocalcaemia + ⇧PTH
ACUTE HYPERCALCAEMIA
<3.0mmol - MILD. OFTEN ASYMPTOMATIC, URGENT CORRECTION
3-3.5mmol - MOD. TOLERATED, SYMPTOMATIC, PROMPT TREATMENT
>3.5mmol - URGENT CORRECT, RISK OF COMA
HYPERCALCAEMIA
1º Hyperparathyroidism, or non-parathyroid MALIGNANCY,
*drug induced (thiazide diuretics, Vit D & calcium supplements)
?hyperthyroidism
?milk alkali syndrome, antacid
- polyuria, polydipsia, renal stones, anorexia, N&V, constipation
- neuro: poor concentration, brain fog, confusion
- cvd: shortening QT, bradycardia
1) PTH
2) Calcium, albumin
(1)
> Rehydration
> IV bisphosphonates (zolendronic acid) - will take a few days, repeated.
(2)
> GLUCOCORTICOIDS - lymphoma, granulomatous disease
> CALCITONIN - poor biphosphonate response
> CALCIMIMETICS
> PARATHYROIDECTOMY
Testing for Hypercalcaemia
Calcium & *PTH* Glucose, TFTs PO4 Serum ACE - sarcoidosis CXR = secretory malignancies
?medication
1º Hyperparathyroidism: Present., Causes, Investigations, Tx
Asympt. Associated w/ irradiation = parathyroid adenoma and gland hyperplasia. F > M
1) PTH
UE: renal function
2) USS - localise and aid Sx
3) SESTAMIBI: nuclear trace.
65+ 4D-CT, high dose
> Surgery for <65yo, >0.25mmol over recommended, osteoporosis on DEXA, eGFR <60
!hypocalcaemia (temporary)
> Fluid intake & Vit D replacement
Cinacalcet mimics calcium receptor action = ⇩PTH
FHH
Familial Hypocalciuric Hypercalcaemia, AD
= ⇩urinary calcium
•normal/elevated PTH
Multiple Endocrine Neoplasia
MEN, AD = 1º Hyperparathyroidism, pancreatic
*family history & genetic testing!
Discuss the concept of neoplasms of the endocrine system as being functional (ie, secreting hormones) and non-functional (ie, non-secretory)
*adenomas, carcinoma etc.
FUNCTIONAL
- secretes hormones
- Thyroid Medullary carcinoma
NON-FUNCTIONAL
- non-secretory
- follicular adenoma: most non-functioning, encapsulated tumour, small microfollicles
*Endocrine organs have high reserve capacity and can be extensively damaged/reduced in volume before disease manifests
Discuss the concept of neoplasms being benign and malignant, in the context of the endocrine system.
Benign
Often circumscribed, localised, cannot invade, don’t usually transform
Malignant
Synonymous with cancer, invades, metastasises, if untreated, will often prove fatal
Discuss the presentation, investigation and management of thyroid cancer.
a
Hashimoto’s Thyroiditis
F > M, adults
AuIm attack of thyroid epithelial cells
= lymphocytic infiltrate + circulating AuAb(thyroglobulin & thyroid perox.)
- wt gain, bradycardia, dry skin, constip, intolerance to cold, slowed speech
- HISTO: HURTHLE CELL CHANGE (dmg); intense infiltrate
Goitre
Enlarged thyroid
MULTI-NOD
- I2 def, goitrogens = impaired T3, T4 = ⇧TSH = hypertrophy and hyperplasia of thyroid epithelium
- simple => multinodular
- HISTO: ⇧follicles - crowded, distended colloid, fibrotic change
- Toxic nodule may develop
DOMINANT NODULE in MULTI-NOD
CYST
FOLLICULAR ADENOMA
CARCINOMA: family hx, chronic inflamm, radiation, obesity
- Differentiated Thyroid carcinoma
- Papillary carcinoma
Thyroid Nodule Investigations
TFT
USS
FNA - cytology
Follicular carcinoma
Invasive, solitary, mets: blood, bone with RAS mutation
F>M, 10% thyroid malignancy
Papillary carcinoma
Radiation, BRAF mutation, <50yrs
- lymphatic spread, good prognosis
- HISTO: empty nuclei, papillary projections, psammoma bodies (calcium deposits)
Thyroid Medullary carcinoma
malignant chief cells,
CALCITONIN+ - promotes bony absorption of calcium and prevents bone resorption
ACTH+
sporadic, MEN2A, 2B
> Sx
Radioactive Iodine
RT
ChemoT
2º Hyperparathyroidism
Response to ⇩Ca2+ d/t renal failure
Pituitary Adenoma: hyperfunction & hypofunction
common cause: pituitary adenoma, with carcinomas are rare
- 35-60y/o, sporadic
- soft well-circumscribed lesion
- functionning: hormone excess: prolactinoma (galactorrhoea, menstrual disorders), GH++, ACTH++ (cushings disease)
- acromegaly,
- moon face, buffalo hump, bruise easily
- non-functionning: not as much common
- MASS PRESSURE EFFECT: ⇧ICP, visual field abn.,
- compression damage = hypopituitrism (75% loss); alt. Trauma, infection (TB, sarcoidosis), Post-partum ischaemic necrosis: Sheehan’s Syndrome
Adrenal Glands & Masses
Mass lesion: late effect
Hyperplasia, atrophy, mass of the glands
Masses: Adrenal Cortical Hyperfunction Syndromes
HYPERCORTISOLISM = CUSHINGS SYNDROME
exo iatrogenic vs endogenous ACTH (pit adenoma vs adrenal adenoma)
HYPERALDOSTERONISM = CONN’S SYNDROME
bilateral idiopathic hyperplasia, or functionning adrenal adenoma
ADRENOGENITAL SYNDROMES
functionning adrenal tumour, congenital adrenal hyperplasia
Adrenal Insufficiency
WATERHOUSE FRIDERICHSEN: acute meningococcal septicaemia = destruction
ADDISON’S DISEASE: chronic autoimmune nature or: infection, replacement, atrophy (therapy)
Adrenocortical Tumours
ADENOMA: functionnal = hyperadrenal syndromes + atrophy of adjacent cortex
CARCINOMA: rarer
- functional: virilising
- invades via adrenal vein = lung breast
Adrenal Medullary Tumour - PHAEOCHROMOCYTOMA: medulla neuroendocrine cells, catecholamine+++, bilateral, inherited
MEN
multiple endocrine neoplasia: inherited, hyperplasia, younger age
MEN1 WERMER SYNDROME: parathyroid hyperplasia and adenomas, pit. adenoma = prolactinoma
MEN2A SIPPLE SYNDROME: parathyroid hyperplasia, phaeochromocytoma
MEN2B: neuroma of skin, mucosal neuroma
Outline the main mechanisms and long-term pathological complications of diabetes mellitus.
DM1:
- HLA mut = autoimmune attack via T cells = beta cell destruction
- environmental triggers
- molecular mimicry: the activation of auto-aggressive T cells in T1D as the result of a virus carrying an epitope that strongly resembles certain structures on the beta cells, and which consequently induces a cross-reactive autoimmune response
DM2:
- ⇩tissue sens to insulin (resistance) + inability to secrete sig. levels of insulin
- gene variant factor affecting insulin secretion (pancreas)
1) ⇧⇧visceral fat = ⇧FFA
2) ⇩insulin receptor sens.
3) ⇧⇧Pancreas demand to mobilise glucose into cells
=> PERIPHERAL HYPERINSULINAEMIA
4) Genes: Poor beta cell high end function
=> INSULIN SECRETION CANNOT COUNTERACT THE INSULIN RESISTANCE CAUSED BY CENTRAL ADIPOSITY
Be able to describe the pathogenesis, appearances, and consequences of diabetic macro and micro vascular disease
*MI commonest cause of death (LT complciation)
MACROVASCULAR
- acceleration of atherosclerosis; glc attachment to LDL preventing liver uptake = HYPERLIPIDAEMIA
MICROVASCULAR - ARTERIOLES
- buildup of molecules in subendothelial space resulting in basal lamina thickening
- buildup of albumin and collagens
= HYALINE CHANGE: widespread narrowing arteriole = ischaemia
- kidney, peripheral tissue, retina, arterioles supplying nerves
- AMPUTATION
- END STAGE RENAL DISEASE
- BLINDNESS
MICROVASCULAR - CAPILLARIES
⇧connective tissue around capillaries creating lesions
- GLYCOSYLATION of proteins (reversible) > Advanced Glycosylation End-products (irreversible)
- Glycosylated collagen binds albumin in subendothelial space
- AGE protein cross-linking,
