Endocrine Flashcards
calcium homeostasis process
- detection of low plasma calcium by parathyroid gland cell
- release of PTH from cell by exocytosis
also postively regulated by Vit D
negatively regulated by calcitonin
PTH effects on calcium and phosphate
- increased bone resorption: immediate action on Ob expressing RANKL activating Oc -> bone resorption relating Ca into ECF
- Active reabsorption of calcium and magnesium from the distal convoluted tubule. Decreases reabsorption of phosphate.
- Increases intestinal calcium absorption by increasing activated vitamin D. Activated vitamin D increases calcium absorption
Vitamin D effects on calcium and phosphate
Increases renal tubular reabsorption and gut absorption of calcium
Increases osteoclastic activity
Increases renal phosphate reabsorption in the proximal tubule
Calcitonin effects on calcium
Inhibits osteoclast activity
Inhibits renal tubular absorption of calcium
Triiodothyronine T3
Major hormone active in target cells
Thyroxine T4
Most prevalent form in plasma, pro hormone
removal of iodine group by deiodinase enzymes to produce active T3
Process of thyroid hormone synthesis
- TSH activates cAMP
- Trapping of iodide ions converted into iodine
- iodine added onto tyrosine residues on thyroglobulin by thyroid peroxidase to make diff types of thyroid hormone
- Colloid containing thyroglobulin resorbed into follicular cell
- T3 and T4 secreted
In blood, T4 is bound to
thyroxine-binding globulin (TBG) and transthyretin (TTA), with a small amount bound to albumin
negative feedback loop of thyroid hormone
hypothalamus releases TRH
TRH acts on pituitary releasing TSH
TSH acts on thyroid releasing T3 and T4
T3 and T4 inhibit TSH release at pituitary and TRH release at hypothalamus
thyroid hormone functions
growth development, basal metabolic rate, mental process, thermogenesis in brown adipose tissue
Causes of primary hyperthyroidism
Graves, toxic multi nodular goitre, thyroiditis, toxic nodule
toxic multi nodular goitre
- multiple nodules on goitre
- overactive nodules
can get lid lag or lid retraction but no other thyroid eye disease features
thyroiditis
temporary overactivity of thyroid- thyroid damage & release all hormone already formed
- followed by period of inactivity- hypothyroidism
- trigger: preggo, infection, drugs eg. amiodarone
Endocrine hyper(hypo)tension:
caused by excess (lack):
- aldosterone from ZG
- cortisol or precursors from ZF
- catecholamines from medulla
physiological factors that control BP
vascular tone, ECF volume, cardiac output
symptoms of hyperthyroidism
– Weight loss despite good appetite (often very hungry) – Tiredness – Tremor – Hot, sweaty – Palpitations – Diarrhoea: watery – Light/absent menses – Mood: irritable, anxiety – Muscle weakness
examination findings in hyperthyroidism
– Agitated, talk fast
– Warm, sweaty
– Tremor
– Heart Rate (HR), may be in Atrial Fibrillation (AF)
– Smooth goitre (Graves) vs MNG vs single nodule vs no goitre (thyroiditis)
– Bruit (murmur over stethoscope) heard over goitre almost diagnostic of Graves
Graves eye signs
– Redness – Gritty sensation – Dry or watery eyes – Pain on eye movement – Swelling around the eyes – Proptosis (pushed forward appearance of eyes) – Double vision – Loss of colour vision
all eye signs except _ suggest Graves
lid retraction and lid lag- thyrotoxicosis
thyroid function tests indications in hyperthyroidism
TRAbs (TSH Receptor Antibodies) significantly positive indicates Graves
– TPO (thyroid peroxidase) antibodies less specific- more in hypothyroidism
– If TRAbs are negative, do scintigraphy (often technetium rather than radio-iodine uptake
antithyroid drugs
– Carbimazole and propylthiouracil (PTU)
– Decrease production of thyroid hormone (block TPO)
– Not for thyroiditis (high T4 levels are due to release of hormone stores from damaged gland, but gland is not actually overactive)
– Rare side effect of agranulocytosis (<1/500)
propanalol in hyperthyroidism treatment
good for tremor and raised HR (symptomatic)
radioactive iodine in hyperthyroidism
– Risk of long term hypothyroidism
– Avoid pregnancy for 6 months.
– Restrict contact with children under 12 and pregnant women
– Don’t share bed with partner for 4 days
surgery in hyperthyroidism
– Risk of long term hypothyroidism or damage to recurrent laryngeal nerve and parathyroid glands (control calcium)
Graves eye disease mechanism
B cells produce TSH receptor antibodies
TSH receptor antibodies bind to TSH receptors in retro-orbital connective tissue
T cells produced inflammatory cytokine which causes swelling in muscles and tissue behind the eye= increased pressure
the distinction between active and inactive thyroid eye disease
only active disease responds to steroids
assessed with Clinical Activity Score- pain, redness, change in function, swelling
management of Graves eye disease
- achieve euthyroidism- can have active eye disease without thyroid being overactive
- smoking cessation
- topical lubricants
- selenium (antioxidant)
- steroids and other immunosuppression
further steps once active eye disease settles:
- elective decompression- resolve residual proptosis
- squint surgery if EOM restriction
- eyelid surgery if residual swelling or retraction
surgical decompression of the eye is done if
evidence of optic neuropathy and raised intraocular pressure
management for Graves
1st: ATDs
I131 or surgery for relapse
I131 and smoking can increase risk of
Graves eye disease
the initial and usually definitive imaging modality for thyroid nodule assessment
ultrasound
99mTc Pertechnetate scan nodules
Increased uptake/functionality – “hot” nodule
No uptake/non-functioning – “cold” nodule (more likely to be metastatic)
I-123: imaging of active thyroid tissue
harmless to thyroid
determine activity of the thyroid
ectopic thyroid tissue
When is CT/MRI used in the imaging of the thyroid?
Staging of suspected metastatic thyroid cancer
Assessment of metastatic thyroid cancer following treatment or on surveillance
Assessment of patients with suspected recurrence where ultrasound is negative
histological assessment of thyroid lesions is provided by
fine-needle aspiration or core biopsy
histology vs cytology
histology= solid tissue from biopsy stained, tissue architecture and cytological features cytology= aspiration using needle and smeared onto slide
multi nodular goitre histology
dilated follicles, cholesterol clefts and foamy macrophages
produced by multiple episodes of thyroid trying to produce more product- involuting
Graves disease histology
cells have more columnar appearance, papillary architecture with scalloping
Hashimotos thyroiditis histology
Lymphoid predominant inflammation, follicular cell oncocytic change and variable degrees of gland destruction
Follicular adenoma histology
Completely encapsulated (with fibrotic tissue) lesion
Made up of thyroid follicles- collapsed colloid
Clonal population but benign
when does a follicular adenoma become a follicular carcinoma?
If capsular or vascular invasion then becomes follicular carcinoma
what 3 features are papillary carcinomas diagnosed on?
- intraneuclear inclusions
- clear nuclei & nuclear irregularity
- nuclear grooves
psammoma bodies
laminated calcified bodies characteristic in papillary carcinoma
Cell to colloid ratio is a good indicator of
malignancy, colloid is reassuring
key cytological features in multinodular goitre
lots of colloid, variably sized folloicles
key cytological features in papillary carcinoma
Papillary structures, nuclear grooves & inclusions
key cytological features in medullary carcinoma
dispersed small cells
Signs of hypercalcaemia
Painful Bones
Renal Stones
Thrones- Constipation, Indigestion
Abdominal Groans - GI symptoms: Nausea, Vomiting,
Psychiatric Moans – Effects on nervous system: lethargy, fatigue, memory loss, psychosis, depression
extracellular calcium measured in either
serum- anti-coagulated or plasma- unclotted
calcium concentration is made up of 2 components, 1 of which is actively regulated:
- ionised- physiologically active, actively regulated
- calcium bound to albumin
Measuring both albumin and total calcium is required to
assess extracellular ionised Ca2+ status
ALP function
promotes mineralisation by increasing the local concentration of inorganic phosphate ions
& by hydrolysing pyrophosphate, a key inhibitor of mineralisation
pagets disease is due to
overactive osteoclasts
Rising Ca2+ ->
feeds back to the parathyroid glands and suppresses PTH secretion (negative feedback loop)
what is calcitonin secreted by?
parafollicular or C-cells of the thyroid gland
Vitamin D synthesis
LIVER: cholecalciferol (VitD3) converted by 25-hydroxylase into 25 hydroxy-Vitamin D
KIDNEY: 25 hydroxy-Vitamin D converted by 1a- hydroxylase into 1,25 OH Vitamin D (calcetriol)- ACTIVE
Renal 1α-hydroxylase is regulated by
PTH, calcium can affect the activity
mechanism of Vit D action in the intestine
a calcium-binding protein (calbindin- D9k) is synthesised which promotes absorption of both calcium and phosphate
Calcitriol limitation of action
Calcitriol stimulates 24-hydroxlase (promotes its own inactivation)
– Calcitriol can switch off PTH gene transcription via VDR in parathyroid cells, limiting PTH action
Factitious hypercalcaemia
Raised [calcium] due to high plasma [albumin] e.g.
o Venous stasis o Dehydration o IV albumin
Primary hyperparathyroidism
presents more mildly than hypercalcemia seen in
malignancy
primary hyperparathyroidism definition and biochemical features
Primary - one parathyroid gland (or more) produces excess PTH. This may be asymptomatic or can lead to hypercalcaemia.
high calcium, low phosphate, mild raised ALP, PTH can be normal or high
secondary hyperparathyroidism definition and biochemical features
Secondary - there is increased secretion of PTH in response to low calcium because of kidney, liver, or bowel disease.
low calcium, high phosphate, low Vitamin D, high PTH
tertiary hyperparathyroidism definition and biochemical features
Tertiary - there is autonomous secretion of PTH, usually because of chronic kidney disease (CKD).
normal- high calcium, high PTH, low Vitamin D
muscle contractions in hypercalcemia
slow muscle contractions caused by less excitable neurons secondary to hypercalcemia
- seen in primary and tertiary hyperparathyroidism
Parathyroid imaging scan
Sestamibi- radionucleotide scan
treatment of primary hyperparathyroidism
rehydration, drugs to lower calcium levels
removal of parathyroid adenoma
drugs to treat hypercalcemia
o Bisphosphonates (inhibit osteoclast action and bone resorption); after re-hydration this is key drug for longer- term control o Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) o Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management o Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)
calcimimetics
bind to Ca2+ sensor and inhibit PTH release. Restricted use (e.g. parathyroid carcinomas, advanced CKD)
PTHrP
secreted by solid tumours
PTHrP shares similar actions but is distinct (PTH itself is suppressed)
• Where PTHrP is the cause= humoral hypercalcaemia of malignancy
how can some tumours can synthesise calcitriol?
haematological malignancies (esp. Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol
multiple myeloma
abundance of plasma cells- protein electrophoresis helps to identify Ig type with helps management
pepper pot skull & fractures
biochemical findings in malignant hypercalcemia
high calcium and phophate
suppressed PTH
ALP very high
GGT normal unless liver metastases
FHH
Familial hypocalciuric hypercalcaemia- low calcium in urine but high in blood
Ca2+ sensor on parathyroid glands less sensitive to Ca2+ suppression of PTH
• Altered ‘set-point’
biochemical findings in FHH
PTH high normal or slightly raised
plasma ionised calcium mild increase and low urine calcium excretion
sarcoidosis
small patches of red and swollen tissue- granulomatous disease
• ↑[calcium] with n[PTH]
• Hydroxylation of vit D in granulomas
Chvostek’s sign
tapping over parotid causes facial muscles to twitch- hyperexcitability, hypocalcemia
Trousseau’s sign
carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic
wrist flexion and fingers are drawn together- hypocalcemia
factitious hypocalcemia
Consequence of low plasma [albumin] e.g.:
• Acute phase response (low albumin)
• Malnutrition or malabsorption (protein deficiency in diet)
• Liver disease (reduced liver synthesis albumin)
• Nephrotic syndrome (albumin lost in urine)
clinical features of vitamin D deficiency
Osteomalacia (defective mineralisation), symptoms related to hypocalcemia
biochemical features of vitamin D deficiency
Low 25-D3 and 1,25-D3 (usually) • Low Ca2+ (may be normal in early stages) • High PTH (2y hyperparathyroidism) • Phosphate tends to be low • Often raised ALP
Causes of hypoparathyroidism
- iatrogenic- accidental parathyroidectomy
- radiation therapy
- autoimmune
- congenital: DiGeorge syndrome
biochemical features of hypoparathyroidism
Low Ca2+
• Inappropriately low PTH
• Phosphate may be increased
treatment of hypocalcemia
IV calcium in acute situations
oral calcium or Vit D
Vit D IM if malabsorption or rapid replenishment
active form if renal function impairment
DEXA scan
assess bone mineral density, good for osteoporosis
osteoporosis histology and biochemistry
normal for both
loss of thirst (adipsia) can occur with
hypothalamic damage, this is difficult to treat- fixed fluid intake
causes of polydipsia and polyuria
hypothalamus- primary, inhibitory/stimulatory lesions can affect this
pituitary-cranial DI, lack fo ADH
kidney- resistance to ADH (nephrogenic DI)
V1A receptors
vasopressin receptor that maintains blood volume and circulation- blood vessels
V2 receptors
appropriate retention of water, maintain osmolality- kidney
AVP receptor affinity
V2» V1> OT
vaptans act on which receptor
V2 selective
site of action of AVP
late distal tubule and collecting duct
AVP mechanism
increase water permeability by increasing apical AQP2 (move vesicles with AQP2 to cell surface)
basolateral AQP3/4 on collecting duct cell
less sensitive than AQP2 to ADH
causes of polyuria
DI (cranial or nephrogenic), psychogenic polydipsia, osmotic diuresis (hyperglycemia -DM), renal impairment (unusual)
Osmotic diuresis
substances that are not easily reabsorbed by the renal tubules are retained in the lumen, resulting an increase in osmotic pressure- increase in urination rate
water deprivation test
evaluate patients who have polydipsia Method: prevent patient drinking water ask the patient to empty their bladder hourly urine and plasma osmolalities
results of water deprivation test in psychogenic polydipsia
low starting plasma osmolality showing that the patient can concentrate their urine
results of water deprivation test in cranial DI
high starting and end plasma osmolality, low post-DDVAP plasma osmolality
results of water deprivation test in nephrogenic DI
high starting and end plasma osmolality, high post-DDVAP plasma osmolality
causes of cranial DI
idiopathic post head injury pituitary surgery craniopharyngiomas histiocytosis X
gestational DI
vasopressinase degrades AVP but not DDVAP, resolve 1w post party
causes of nephrogenic DI
- genetic: the more common form affects the vasopression (ADH) receptor, the less common form results from a mutation in the gene that encodes the aquaporin 2 channel
- electrolytes: hypercalcaemia, hypokalaemia
- lithium desensitizes the kidney’s ability to respond to ADH in the collecting ducts
- demeclocycline
treatment of cranial DI
central diabetes insipidus can be treated with desmopressin (DDVAP)
treatment of nephrogenic DI
thiazides (low ECF volume, increase water resorption at PCT but less at DCT), low salt/protein diet
first line investigations in hyponatremia
- dehydration- identify if urine is site of excess salt loss
- oedema
SIADH
hyponatraemia secondary to the dilutional effects of excessive water retention
causes of SIADH
- intracranial lesions/disease- affect intracranial pathway near hypothalamus
- intrathoracic disease esp infections- affect baroreceptor pathway: pain
- neoplasm esp lung/mediastinal
drug causes of SIADH
sulfonylureas SSRIs, tricyclics carbamazepine vincristine cyclophosphamide
Management of SIADH
- correction must be done slowly to avoid precipitating central pontine myelinolysis
- fluid restriction (1000ml/d to <800 if needed)
- demeclocycline
- ADH (vasopressin) receptor antagonists have been developed
how does aldosterone deficiency (Addisons) cause hyponatremia?
- Aldo reduced but ADH normal
- non osmotic ADH stimuli: reduced vol, nausea, pain
- reduced GC effects- impair water loss
metabolic products that stimulate GH secretion
amino acids eg. arginine- inhibit somatostatin release
demeclocycline
reduces the responsiveness of the collecting tubule cells to ADH
GHRH- where is it synthesised and released from?
the arcuate nucleus, and released from neurosecretory terminals at the median eminence
GHRH function
stimulate GH synthesis and release form stored pools
somatostatin synthesised in
periventricular nucleus
somatostatin function
inhibits secretion of GH from somatotrophs and inhibits the secretion of GHRH
GH negative regulation
- glucocorticoids- initial stimulatory effect but later suppressed
- IGF-1 and somatostatin
GH postitive regulation
- thyroid hormone
- catecholamines
- ghrelin
- oestrogen- decreased IGF-1 production
hypothyroidism in childhood effect on growth
poor growth, blunting of GH
responses to stimuli & reduced pituitary GH levels
growth hormone secretion type
Growth hormone secretion is pulsatile and has circadian rhythm
peak in slow wave sleep
which gender has higher growth hormone secretion?
female
GH levels in obesity
GH levels are lower in obesity and are restored by massive weight loss
exercise and GH
exercise- stimulant for GH secretion, occurs around 10-15 mins after start
may be mediated by Ach, adrenaline and endogenous opioids
GH signalling process
- One GH molecule binds to 2 GHR molecules leading to dimerisation of receptors
- Activation of receptor-associated Janus kinase, followed by STAT phosphorylation
- Translocates to nucleus and acts as a transcription factor
- Insulin-like growth factor-1 (IGF-1) gene activation
direct effects of GH
- inhibits glycogen synthesis in muscle
- anabolic- acts to increase blood pressure
- increasing lipolysis and gluconeogenesis
indirect effects of GH
Most growth promoting effects of GH due to IGF-1- autocrine/paracrine effect probably most responsible fro linear growth
where is IGF-1 secreted from?
liver and other tissue
what is puberty growth driven by?
in puberty growth is driven by GH and sex steroid, high amount of growth hormone is important in growth spurts.
what is childhood growth driven by?
GH and thyroxine
causes of short stature and poor growth in childhood
nutrition Chronic disease Genetic conditions (Turner syndrome, Trisomy 21, Noonan syndrome, skeletal dysplasias) Steroids Hypothyroidism Psychosocial deprivation
Central causes of short stature and poor growth in childhood
Pituitary abnormalities
- GH deficiency
- TSH deficiency: hypothyroidism
- Gonadotrophin deficiency: poor pubertal growth
These can be caused by tumours, irradiation, trauma, or genetic reasons
adult GH deficiency symptoms
decreased energy, social isolation, depressed mood
adult GH deficiency clinical features
increased body fat, decreased muscle mass, decreased bone density, increased risk of fracture
Impaired cardiac function
Decreased insulin sensitivity and impaired glucose tolerance
what other abnormalities does adult GH deficiency present with?
pituitary hormone abnormalities due to new adult pituitary tumours (macroadenomas, craniopharyngiomas)
GH excess present before epiphyses have fused
gigantism
GH excess present after growing ends of long bones have fused:
acromegaly