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Endocrinology Phase 2 Revision

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Nina De Flora

on 25 April 2013

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Transcript of Endocrinology Phase 2 Revision

Endocrinology Pituitary - Adrenal Axis Cortisol and androgen production are regulated by the hypothalamus (CRH- to pituitary) and anterior pituitary (ACTH- to adrenals)
Negative feed back from cortisol levels acts on the anterior pituitary to affect ACTH production and on the hypothalamus to affect CRH production
Hyperfunction:
Cushing’s syndrome is the result of excess cortisol (a steroid hormone)
It results in:
Protein loss:
Myopathy (muscle wasting)
Osteoporosis (fractures)
Thin skin (striae, bruising)
Altered carbohyderate/lipid metabolism (diabetes mellitus, obesity)
Altered psyche (psychosis, depression)
Excess mineralocorticoids (hypertension, oedema)
Excess androgen (virilism, hirsutism, acne, oligo/amenorrhoea)
Cortisol draws on all possible resources for energy
Cushing’s SYNDROME can be adrenal or pituitary, Cushing’s DISEASE is due to pituitary Adrenal Function The adrenals are bilateral
Normally they weigh between 4 and 5 grams
They sit superior and medial to the upper pole of the kidneys
They have an outer cortex and a central medulla
Cortex
Organised into three zones
Recognised by histological appearance
Correlates with function
Zona Glomerulosa –
Mineralocorticoids
Aldosterone
Regulated by angiotensin II and K+ (and thus Renin) -RAAS by drops in BP causing renin production. Angiotensinogen -> AI->AII (using ACE) leading to vasoconstriction and aldosterone production
Zona Fasciculata –
Glucocorticoids
Cortisol
Regulated by ACTH (and thus CRH)
Zona Reticularis –
Sex Steroids + Glucocorticoids
DHEA (precursor to testosterone)
Regulated by ACTH (and thus CRH)
Medulla:
Distinct from cortex
Innervated by pre-synaptic fibres from the sympathetic splanchnic nerves
Neuroendocrine (chromaffin) cells- secrete catecholamines (noradrenaline, adrenaline)- these reduce salts to chromium, creating a brown colour
Tyrosine -> L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline Cortisol Function Corticosteroids bind to intracellular receptors which form a receptor ligand complex
This complex binds to DNA affecting transcription
There are 6 classes of steroid receptor:
Glucocorticoid
Mineralocorticoid
Progestin
Oestrogen
Androgen
Vitamin D
Clinical application:
Suppress inflammation
Suppress immune system
Replacement treatment
Treatment for:
Allergic disease- asthma, anaphylaxis
Inflammatory disease- RA, UC, Crohns
Malignant disease Actions of cortisol:
CNS:
Mood
Euphoria
Psychosis
Decreased Libido
Bone/Connective Tissue:
Accellerates osteoporosis
Decreased serum calcium
Decreased collagen formation
Decreased wound healing
Immune:
Decreased capillary dilation and permeability
Decreased leukocyte migration
Decreased macrophage activity
Decreased inflammatory cytokine production
Metabolism:
Increased carbohydrate metabolism
Increased blood sugar
Increased lipid metabolism
Increased lipolysisI
ncreased central redistribution
Increased protein metabolism
Increased proteolysis Hypercortisolism Causes Causes:
Adrenal Hyperplasia
These may be diffuse or nodular
Diffuse are more frequently ACTH driven
Nodular are usually ACTH independent
Can be bilateral enlargement
Enlargement up to 30g
Hypersecretion
Aetiology:
ACTH Dependent (cause hyperplasia)
Pituitary (80%+) (Cushing's DISEASE)
Ectopic
Thymus
Lung (can occur in para-neoplastic syndrome with small cell cancer)
Pancreas
ACTH Independent
Malignancy of adrenal gland:
Adenoma
Carcinoma
Pseudo
Alcohol and depression
Steroid medication (including inhalers)
Non-lesional gland atrophy (hyperplasia) Congential Adrenal Hyperplasia Rare group of autosomal recessive disorders
Deficiency or lack of enzyme needed for steroid biosynthesis
Most common is 21 alpha hydroxylase deficiency (also 11B and 17a)
Aldoterone and cortisol cannot be formed from cholesterol
Altered biosynthesis leads to increased androgen (progesterone, testosterone) production
There is masculinsation and precocious puberty as a result of excess androgen
Reduced cortisol stimulates ACTH release and cortical hyperplasia
Presentation:
Classical:
Males:
Adrenal insufficiency (aroudn 2-3 weeks)
Poor weight gain
Biochemical pattern (see Addison’s)
Females:
Ambiguous genitalia
Non-classical:
Hirsutism
Acne
Oligomenorrhoea
Precocious puberty
Infertility or sub-fertility
Treatment:
Paediatrics:
Glucocorticoid replacement
Mineralocorticoid replacement if needed
Surgical correction
Help achieve maximal growth potential
Adult physician:
Control androgen excess
Restore fertility
Avoid steroid over-replacement Tumours These occur mainly in adults, can occur in younger patients with Li-Fraumeni syndrome
The numbers in males and females are equalsIt can present as a result of:
An incidental finding
Hormonal effects
Mass lesion
Distinguishing malignant and benign is difficult, metastasis is the only definite criteria
Adenoma
These are well circumscribed and encapsulate, usually small 2-3cm
They are yellow-brown
The cells resemble adrenocortical cells
The cells are well differentiated (occasionally function), with small nuclei and rare mitoses
Carcinoma
This is rare (5y survival of 20-35%)
More likely functional, virilising tumours that are usually malignant
The can closely resemble adenoma
Spread:
Local invasion: retroperitoneum, kidney
Metastases: usually vascular
Peritoneum and pleura
Regional lymph nodes
Features:
Large size (>50g, usually >20)
Frequent atypical mitoses
Lack of clear cells
Capsular or vascular invasion Symptoms Facial plethora (facial flushing)
Striae (abdominal especially)
Thin skin
Proximal myopathy
Frontal balding in women
Conjunctival oedema
Osteoporosis (this is less likely in those who are overweight, therefore if someone is obese and has osteoporosis, Cushing’s is likely)
Abdominal obesity (lemon on matchstick appearance)
Benging intercranial hypertension
Moon face
Easy bruising
Poor wound healing
Thin arms and legs
Buffalo hump
Emotional liabitlity- euphoria, depression
Tendency to hyperglycaemia
Negative nitrogen balance
Increased appetite
Increased susceptibility to infection Diagnosis Screening Tests
Overnight 1mg dexamethasone suppression test (normal adrenal should suppress cortisol when steroid is given, hypothalamus detects and suppresses CRH, pituitary suppresses ACTH)
Cortisol <50nmol/L the next morning -> normal
Cortisol >100nmol/L the next morning -> abnormal
Urine free cortisol (24h urine collection)
Total <250 is normal
Cortisol/creatinine ratio <25 is normal
Late night salivary cortisol
Diurnal cortisol variation
Highest just before waking
Lowest just after falling asleep ~midnight.
At midnight, cortisol will still be high.
If any are positive, a definitive test must be done
If negative Cushing’s is unlikely
Definitive test is the low dose DST
2 day 2mg/day dexamethasone suppression test
Cortisol <50nmol/L 6 hours after last dose implies no Cushing’s Treatment Pituitary:
Hypophysectomy (pituitary removed)
Exturnal radiotherapy if recurring (often recur)
Adrenal:
Adrenalectomy
Ectopic:
Remove source
Bilateral adrenalectomy if all else fails
Drug treatment:
Metyrapone:
Many side effects
If all other treatments fail/ while waiting for radiotherapy to work
Ketoconazole
Pasireotide
New somatostatin analogue Androgens are also produced in the adrenal cortex (Zona reticularis) - alongside corticosteroids
DHEA a precursor to testosterone is produced
Their production is also regulated by CRH and ACTH Adrenals + Cortisol Adrenals + Androgens Hypocortisolism Primary Secondary Acute Chronic Addison's Disease Rapid withdrawal of steroid treatment
Crisis in patient with chronic adrenocortical insufficency- due to stress e.g. infection without increasing steroid dose
Massive adrenal haemorrhage
Newborn
Anticoagulant treatment
DIC
Speticaemic infection- Waterhouse Friderichsen Common:
Addison's Disease
Autoimmune adrenalitis
Infection:
Fungal
HIV related
MAI
Kaposi’s
Tuberculosis
Metastatic Malignancy
Lung
Breast
Congenital Adrenal Hyperplasia
Adrenal hypoplasia (absent/dysplastic/destroyed)
Inborn error of metabolism
Uncommon:
Amyloidosis
Sarcoidosis
Haemochromatosis
CAH Epidemiology Insidious onset manifest once significant decreases occur in glucocorticoid and mineralocorticoid activity
Most common cause of primary adrenal insufficiency
Autoimmune destruction of adrenal cortex
>90% is destroyed before symptomatic
70% positive for autoantibodies
Associated with other autoimmune diseases:
Type I DM
Autoimmune thyroid disease
Pernicious anaemia Clinical Features Vague symptoms:
Weakness
Fatigue
Anorexia
Nausea
Vomiting
Weight loss
Diarrhoea
Lethargy
Hypotension
Pigementation (not seen in hypopituitarism)
Decreased mineralocorticoids:
K+ retention (hyperkalaemia)
Na+ loss (hyponatraemia)
Volume depletion
Hypotension
Decreased glucocorticoids:
Hypoglycaemia Addisonian Crisis CausesStressInfectionTraumaSurgerySymptomsVomitingAbdominal painHypotension
ComplicationsShockDeath Causes Diagnosis Suspicious biochemistry:
Hyponataemia
Hyperkalaemia
Hypoglycaemia
Short synACTHen test:
Measure plasma cortisol
Give IV ACTH injection
Measure plasma cortisol 30 mins later
Normal:
Baseline >25o nmol/L
After ACTH >480 nmol/L
High ACTH
High Renin
Low aldosterone
Adrenal autoantibodies Treatment Hydrocortisone
For cortisol replacement
If unwell, IV first
15-30mg daily
Try to mimic diurnal rhythm
Fludrocortisone
For aldosterone replacement
Monitor BP and K+
Sick day rules
Cannot stop suddenly
Need to wear identification Causes Failure to stimulate adrenal cortex
Hypothalamic pituitary disorder- hypopituitarism
Tumours
Surgery
Radiotherapy
Suppression of adrenal cortex
Steroid treatment
Most common
Negative feedback effect: stops CRH and ACTH production
High dose prednisolone
Dexamethosone
Inhaled corticosteroid Presentation Similar to Addison’s
Weakness
Fatigue
Anorexia
Nausea
Vomiting
Weight loss
Diarrhoea
Lethargy
NO increased pigment
Aldosterone intact (managed by RAAS) Management Hydrocortisone replacement only
Fluodrocortisone unneccessary Adrenals + Catecholamines Adrenal Medullary Tumours Phaeochromocytoma Aetiology Neoplasm derived from chromaffin cells of adrenal medulla
Rare tumours, difficult to diagnose
Secretes catecholamines
10% are extra-adrenal
Called paragangliomas (in th sympathetic chain)
Organs of Zuckerkandl, Carotid body
10% are bilateral (up to 50% in familial cases)
10% are biologically malignant
Defined by metastasis
More common (20-40%) in extra adrenal lesions
More often malignant (30%) if associated with germline mutation of B subunit of succinate dehydrogenase
10% are NOT associated with hypertension
Usually paroxysmal hypertension – can be fatal
25% are familial
Germline mutations in one of several known pre-disposing genes
Younger, more often bilateral
Should investigate those with family members with syndromes, resistant hypertension, young with hypertension is classical presentation
Range from small to large necrotic tumour masses and from yellow to red-brown on histology
Potassium dichromate is able to turn the tumour cells dark brown
Skeletal metastases is common Presentation Classical Triad:
Hypertension
Headache
Sweating
Labile hypertension
Postural hypertension
Paroxysmal sweating
Headache
Pallor
Tachycardia/Bradychardia
Palpitations
Breathlessness
Constipation
Anxiety
Weight loss
Pyrexia
Flushing (uncommon) Hyperglycaemia (in adrenaline secreting tumours)
Hypokalaemia
High haematocrit (raised Hb concentration)
Like hypercalcaemia
Lactic acidosis (in absence of shock)
Incidental/Family tracing
Can be asymptomatic
Rare cause of secondary hypertension
Leads to paroxysmal episodes
Triggers
Stress
Exercise
Palpation of tumour
If arising in the bladder, associated with mucturition Diagnosis Urinary excretion of catecholamines and metabolites detected
2x24hour catecholamines or metanephrines with excess
Note that secretion of catecholamines is episodic
Note that malignant and extra-adrenal tumours are less efficient at catecholamine synthesis
Note that catecholamines are also raised in heart failure
Plasma with excess catecholamines at time of symptoms
MIBG-uptake scan done - radioiodine (metaiodobenzylguanidine)
PET scan
MRI Complications Complications:
Cardiac failure
Infarction
Arrhythmia
CVA
There are surgical and pregnancy related risks
Signs of complication:
LV failure
Myocardial necrosis
Stroke
Shock
Paralytic ileus of bowel
Propensity for skeletal metastasisAlso metastasises to:
Regional lymph nodes
Liver
Lung Treatment Full alpha and beta blockade
Phenoxybenzamine
Atenolol or metoprolol
Fluid/blood replacement
Anaesthetic assesment
Surgical:
Total excision
Tumour de-bulking
Chemotherapy if malignant
Long term follow up
Genetic testing
Family tracing and investigation Associated Conditions MEN IIa MEN IIb Von Hippel Lindau Succinate Dehydrogenase Mutations Neurofibromatosis Type 1 Tuberose Sclerosis Sipple syndrome
Phaemochromocytoma (40-50%)
Phaeochromocytoma may be bilateral and occur at extra-adrenal sites
Medullary thyroid carcinoma (100%)
Parathyroid hyperplasia (10-20%)
Linked to germline gain of function mutation in RET oncogene on chromosome 10
Autosomal dominant
Activating mutation in tyrosine kinase receptor Phaemochromocytoma
Medullary thyroid carcinoma
Marfanoid habitus
Neuroma
Ganglioneuroma
Linked to germline mutation in RET oncogene- usually point mutation
Autosomal dominant Mutation in HIF 1 alphaAutosomal dominantRange of vascular tumoursFamily screening vitalAffects:CerebellumBrainstemSpinal cordRetinaInner earPancreasKidneys Types B, C, DInactivating mutationsStabilise HIF-1 alphaIn head and neck- >70% penetranceMalignant <50% penetrance Axillary freckling
Cafe au lait macules
Neurofibromas Ash leaf macules neuroblastoma Often diagnosed in infancy Arise in the adrenal medulla or along the sympathetic chainComposed of primitive cells that can show maturation and differentiation towards ganglion cellsAge and stage is important for prognosisAmplification of N-myc and expression of telomerase predict poor outcomes Adrenals + Aldosterone Aldosterone Physiology Produced by adrenal cortex (Zona Glomerulosa)
Regulated by angiotensin II (of RAAS) and K+
RAAS is activated in response to BP drop
Leads to production of renin from kidneys
This turns angiotensinogen into angiotensin I
Angiotensin I is changed into angiotensin II by angiotensin converting enzyme (ACE)
This leads to vasoconstriction and also causes aldosterone production by the adrenal glands Mineralocorticoid (aldosterone) actions:
Sodium retention (extraction from filtrate and reabsorption) in exchange for potassium and/or hydrogen ions which are lost instead
As water follows sodium, if sodium is lost, water is lost too
Too much mineralocorticoid activity:
Too much sodium retention (and water) - i.e. hypertension
Too much K+ and H+ lost
Too little mineralocorticoid activity:
Too much sodium loss (and water) - i.e. hypotension
Too much H+ and K+ retained
Aldosterone is released when the adrenal gland is stumlated by angiotensin II (after RAAS) - ie. not ACTH
Spirinolactone is a drug which can interfere with sodium loss (increase) and decrease blood pressure Hyperaldosteronism Causes This can be due to hyperplasia or hypersecretion
Hyperplasia
Bilateral Adrenal Hyperplasia
Usually (60%) associated with diffuse or nodular hyperplasia of both adrenal glands
Also associated with adenoma (35%) – rarely carcinoma
Hypersecretion
Conn’s syndrome
Solitary, small, bright yellow and buried within the gland – do not cause a mass lesion
Spironolactone bodies
Do not suppress ACTH so adjacent & contralateral adrenal tissue is not atrophic
Glucocorticoid remediable
Uncommon genetic disorder with production of hybrid steroids, cortisol and aldosterone
Under the influence of ACTH
Genetic mutations -rare
Unilateral Hyperplasia -rare Presenation Hypertension
Primary/Essential in >90%
<10% have secondary hypertension
Significant hypertension
Alkalosis
Hypokalaemia (sodium retention results in excess potassium loss)
Muscle weakness
Myalgia
ECG abnormalities
Autonomous production of aldosterone independent to its regulators (angiotensin II and potassium) Diagnosis Plasma aldosterone and renin levels- ratio
Ratio>750
Saline suppression test
Give saline to see if aldosterone is supressed
If suppressed less than 50%, primary aldosteronism
Do CT to see adenoma
Can do adrenal vein sampling Management Surgery
Unilateral laparoscopic adrenalectomy
Only if adrenal adenoma
Cure of hypokalaemia
Cures hypertension in 30-70%
Medical
In bilateral adrenal hyperplasia
MR (mineralocorticoid) antagonists
Spirinolactone
Eplerenone Hypoaldosteronism Acute Chronic Addison's Disease Rapid withdrawal of steroid treatment
Crisis in patient with chronic adrenocortical insufficency- due to stress e.g. infection without increasing steroid dose
Massive adrenal haemorrhage
Newborn
Anticoagulant treatment
DIC
Speticaemic infection- Waterhouse Friderichsen Common:
Addison's Disease
Autoimmune adrenalitis
Infection:
Fungal
HIV related
MAI
Kaposi’s
Tuberculosis
Metastatic Malignancy
Lung
Breast
Adrenal hypoplasia (absent/dysplastic/destroyed)
Inborn error of metabolism
Congenital Adrenal Hyperplasia
Uncommon:
Amyloidosis
Sarcoidosis
Haemochromatosis
CAH Epidemiology Insidious onset manifest once significant decreases occur in glucocorticoid and mineralocorticoid activity
Most common cause of primary adrenal insufficiency
Autoimmune destruction of adrenal cortex
>90% is destroyed before symptomatic
70% positive for autoantibodies
Associated with other autoimmune diseases:
Type I DM
Autoimmune thyroid disease
Pernicious anaemia Clinical Features Vague symptoms:
Weakness
Fatigue
Anorexia
Nausea
Vomiting
Weight loss
Diarrhoea
Lethargy
Hypotension
Pigementation (not seen in hypopituitarism)
Decreased mineralocorticoids:
K+ retention (hyperkalaemia)
Na+ loss (hyponatraemia)
Volume depletion
Hypotension
Decreased glucocorticoids:
Hypoglycaemia Addisonian Crisis Causes
Stress
Infection
Trauma
Surgery
Symptoms
Vomiting
Abdominal pain
Hypotension
Complications
Shock
Death Causes Note: pituitary disease does not usually lead to hypoaldosteronism as aldosterone production is regulated by the kidneys rather than the pituitary Diagnosis Suspicious biochemistry:
Hyponataemia
Hyperkalaemia
Hypoglycaemia
Short synACTHen test:
Measure plasma cortisol
Give IV ACTH injection
Measure plasma cortisol 30 mins later
Normal:
Baseline >25o nmol/L
After ACTH >480 nmol/L
High ACTH
High Renin
Low aldosterone
Adrenal autoantibodies Treatment Hydrocortisone
For cortisol replacement
If unwell, IV first
15-30mg daily
Try to mimic diurnal rhythm
Fludrocortisone
For aldosterone replacement
Monitor BP and K+
Sick day rules
Cannot stop suddenly
Need to wear identification Catecholamines produces in adrenal medulla (distinct from cortex)
Innervated by pre-synaptic fibres from the sympathetic splanchnic nerves
Neuroendocrine (chromaffin) cells- secrete catecholamines (noradrenaline, adrenaline)
Catecholamines reduce salts to chromium, creating a brown colour
Tyrosine -> L-DOPA -> Dopamine -> Noradrenaline -> Adrenaline Kidneys + ADH Physiology Disorders Presentation Treatment Water and sodium retention is controlled by the RAAS system and by ADH (vasopressin)
Renin is secreted by the kidneys, aldosterone by the adrenal glands these cause sodium retention
ADH (vasopressin) actions:It can also be known as AVP (argnine vasopressin)
ADH is released by the posterior pituitary in response to osmotic and non-osmotic stimuli
The posterior pituitary has a distinct vascular supply
ADH acts on renal tubules to cause water reabsorption and an anti-diuretic effect
Increased ADH -> concentrated urine (high urine osmolarity)
Decresed ADH -> dilute urine (low urine osmolarity)
Serum osmolarity is tightly regulated
Urine osmolarity has a greater range: 40mmol/kg to 1500mmol/kg Hypernatraemia Hyponatraemia The concentration of sodium depends on the Na:H2O ratio Excess Sodium Deficient Sodium Excess Water Deficient Water Increased sodium loss
Kidneys - Addison’s disease
Primary adrenal insufficinecy
Abnormal steroid hormone formation
Not enough mineralocorticoids
Low BP
Tiredness
Weight loss
Salty food cravings
Dizzy spells (especially in warmth)
Postural hypotensionIncreased pigmentation (in mouth and hand creases especially) - due to ACTH- degraded to MSH
Arrythmia
Gut- lost with water by diarrhoea,/fistula
Skin- due to burns
Decreased sodium intake
Very rarely the case Decreased water excretion
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIAD)
Often ill
No specific symptoms
Addison’s negative
ADH released due to osmotic and non-osmotic stimuli
Occurs as a result of non-osmotic stimuli
Hypovolaemia
Hypotension
Pain
Nausea
Vomiting
Increased water intake
Compulsive water drinking Very rare
Increased intake
Due to IV medications which are given as sodium salts
Near drowning in sea
Infants given high salt feeds Increased water loss
Diabetes Insipidus (urine is largely water) - due to problems with ADH secretion/action
Glycosurea- water loss greater than sodium- osmotic diuresis- too much sugar in urine, takes water with it
Decreased water intake
Elderly patients with insensible water loss Sodium is found in the plasma at about 140mmol/l, it is also found in the intracellular fluid at 4mmol/l (almost negligible)
Clinical signs of decreased ECF volume (i.e. water loss):
Increased pulse
Dry mucuous membranes
Soft/sunken eyeballs
Decreased skin turgor
Decreased consciousness
Decreased urine output
Postural hypotension
Clinical signs of increased ECF volume (i.e. water retention):
When there is heart failure or hypoalbuminurea (too little protein), the blood volume decreases
This leads to increased aldosterone and ADH secretion
Resulting in increased sodium retention and increased water retention
Leads to hyponatraemia
More water is retained than sodium
This causes OEDEMA Too little sodium?
Give sodium as saline
Too much water?
Fluid restrict - 1l/day or less
Too little water?
Give water- usually dextrose
Too much sodium (rare)?
Induce sodium (and hence water) loss with diuretics
Replace water with dextrose (rather than saline) Gonads + Reproductive Hormones Physiology Fertility Disorders Oogenesis Takes many years to complete
Begins in utero with mitotic division of oogonia
Commence 1st meitotic division of primary oocyte
Arrest in prophase
Suspended until puberty
After puberty begins again prior to ovulation
Becomes complete at fertilisation
7 million germ cells by mid trimester
2 hundred thousand at birth
40 thousand at puberty
300-400 are ovulated Menstrual Cycle On average lasts 28 days
Has 2 phases Follicular Phase Luteal Phase First half of cycle
Maturation of egg, ready for ovulation mid cycle (follicular phase ends at ovulation)
FSH stimulates folliculogenesis
Primordial follicles are recruited daily following puberty
Primary follicles have a single layer of granulosa cells
Secondary (preantral) follicles have more than 1 layer of granulosa cells - they are also called Theca cells
Theca cells develop LH receptors
They are steroidogenic (synthesise androgens- androstenedione and testosterone)
Granulosa cells develop FSH and estrogen receptors
They synthesise estrogen with aromatizing agents
There is therefore a positive feedback cycle
FSH stimulates granulosa proliferation
There are increased FSH receptors and estrogen synthesis
A dominant follicle is selected
Outer granulosa cells acquire LH receptors and can respond to the FSH surge
Tertiary (antral) follicles have an accumulation of follicular fluid in an antral space- the fluid is filled with hormones for growth, like estrogen
Estrogen stimulates thickening of endometrium
Increase serum estrogen suppresses secretion of FSH and favours LH secretion 2nd half of cycle
Development of corpus luteum
This has an orange/yellow coloured pigment
The granulosa cells are luteinsed
They produce more progestagens i.e. progesterone and 17a-hydroprogesterone
Degenerates within 14 days if not fertilised
Induces preparation of reproductive tract for pregnancy (if fertilisation occurs)
Following ovulation
Cavity of ruptured follicle is replaced with corpus luteum
Corpus luteum secretes progesterone and some estrogen
Progesterone stimulates secretory changes in the endometrium to prepare for implantation
If fertilisation does not occur
Corpus luteum regresses and production of estrogen decreases
Menstrual phase:
Corpus luteum degenerates
Cessation of progesterone and estrogen produced by corpus luteum
Endometrium degenerates and menstruation occurs
The drop in blood levels of estrogen and progesterone stimulate production of FSH and a new cycle begins GnRH FSH LH Estrogen Progeterone Gonadotrophin Releasing Hormone
Synthesised in the hypothalamus
It has a pulsatile release
Its production stimulates FSH and LH synthesis and release from the anterior pituitary
Low frequency pulses stimulate FSH
High frequency pulses stimulate LH + + Secreted by anterior pituitary
Stimulates follicular development
Folliculogenesis
Thickens endometrium Secreted by anterior pituitaryPeak stimulates ovulationStimulates corpus luteum developmentThickens endometrium LH Surge This is when oocytes resume meiosos
A secondary oocyte and plar body are generated
It stops at metaphase II
It will only complete if fertilised
There is cytoplasmic maturation
LH receptors synthesise progesterone
Ovulation occurs 36.5 hours later
The collapsed follicle forms a corpus luteum + + _ Secreted primarily by the ovaries
Also secreted by adrenal cortex
In pregnancy also secreted by placenta
Responsible for cervical mucus:
Clear, stringy, stretchable, slippery with fern patterns when dry
Maturation of ovarian follicles stimulated
Mildly accelerates sodium and water re-absorption by kidney tubules, increasing water content of the uterus
Responsible for the development of secondary sexual characteristics
High estrogen concentration inhibits secretion of FSH and prolactin (negative feedback)
Stimulates the secretion of LH
Low estrogen concentration after pregnancy, stimulates the secretion of prolactin Secreted by corpus luteum (and placenta in pregnancy)
Inhibits the secretion of LH (negative feedback)
Has a thermogenic effect (increases basal body temperature)
Relaxes smooth muscles
Responsible for infertile mucus:
Opaque, sticky, thick, non-stretchable, non-fern pattern when dry
Maintains thickness of endometrium
Maintains pregnancy + _ Spermatogenesis Structure Function Sperm take the following route:
Testes -> Epididymis -> Vas deferens -> Ejaculatory duct -> Urethra
Epididymis:
Concentrate and stores sperm
Sperm maturation
Seminal vesicles:
Produce semen which is secreted into ejaculatory duct
Supply fructose
Secrete prostaglandins (stimulates motility)
Secrete fibrinogen (clot precursor)
Prostate gland:
Produces alkaline fluid (neutralises vagina acidity)
Produces clotting enzymes to clot semen within female
Bulbourethral glands:
Secrete mucous to act as a lubricant
Sperm structure:
Acrosome at the head, is a cap containing enzymes needed for penetration of ovum (zona pellucida)
The nucleus contains genetic material
There is a tail filled with mitochondria and microtubules for motility
There is a centriole, vital to co-ordination of swimming patterns Control of the testes is by anterior pituitary hormones
Secretion of LH and FSH is stimulated by GnRH from the hypothalamus
LH
Acts on Leydig cells to regulate testosterone secretion
FSH
Acts on Sertoli cells to enhance spermatogenesis, essential for spermatid remodelling
Sertoli produce inhibin which supresses FSH secretion
Testetosterone (from Leydig cells of testes)
Able to supress GnRH bursts
Reduces sensitivity of LH secreting cells to GnRH
Brian:
Responsible for sex drive
Produces feelings
Aids memory
Bone marrow:
Produces red blood cells
Bone:
Maintains bone density
Skin:
Produces facial hair
Supports collagen production
Male sex organs:
Produces sperm
Prostate growth
Erectile function
Muscle:
Strength and muscle mass- LH Testosterone GnRH FSH + + + - - Fertilisation Cervical mucus is profuse and clear around the time of ovulation (It is thick and difficult to penetrate during the luteal phase), it easier to penetrate by sperm
The uterus contracts due to oxytocin to aid movement of the sperm
Ampulla of oviduct, the site of fertilisation has chemotaxis and thermotaxis
Freshly ejaculated sperm are incapable of fertilisation
They must first be capacitated (in the female reproductive tract)
Surface of sperm is altered by removal of glycoprotein coat
Tail movements become whip like
Biochemical changes to facilitate acrosomal reaction
There is penetration of the cumulus
There is then binding to the zona pellucida
Fertilin on the sperm binds to integrin on the secondary oocyte
There is then the acrosomal reaction- enzymes in the acrosomal tip allow sperm to burrow through the zona pellucida and corona radiata to enter the cytoplasm
The membrane changes to block polyspermy
The tail of sperm is probably lost
Final meitotic division of secondary oocyte triggered
Sperm and egg nuclei fuse to form a zygote
Cleavage of the cells occurs, then a morula is formed
Then a blastocyst is formed, it has fluid in it which becomes the amniotic fluid- it has an outer layer- the trophoblast which implants (7-10days) Causes of Infertility Female Male Ovulatory Tubular Endometriosis Hypothalamus Genetic Acquired Idiopathic hypogonadotropic hypogonadism
Absent or incomplete puberty
Low/normal LH and FSH
Low testosterone/estradiol
Normal pituitary function
Normal ferritin levels
May or may not be anosmia Kallman’s syndrome:
Large proportion of cases sporadic, but many also inherited
Have anosmia- the olfactory bulb is close to the hypothalamus in embryogenesis
Can be X-linked:
Males only
Complete absence of puberty
High frequency microphallus and cryptorchidism
Synkesia
Unilateral renal agenesis
Fully penetrant phenotype
Can be autosomal dominant:
Cleft lip/palate
Missing teeth
Family history of delayed puberty / anosmia
Females and males
Variable expressivity
Synkesia
Can be autosomal recessive Normonosmic Idiopathic Hypogonadotroic Hypogonadism:
Both sporadic 66% and genetic 33%
Can be autosomal dominant
Can be autosomal recessive
Variable pubertal development
No known associated phenotypes Acquired Hypogonadotropic Hypogonadism (hypog hypog)
Hypothalamus very sensitive
Many conditions affect hypothalamic function
Prolonged/Excessive physical exercise
Anorexia nervosa
1% of population
Commoner in females
Low BMI <19
Hair loss
Increased lanugo
Low pulse and BP
Anaemia
Low FSH
Low LH
Low estradiol
Stress
Chronic alcohol use
Chronic illness
Haemochromatosis Pituitary Loss of LH/FSH stimulation
Tumour
Non-functioning pituitary macroadenoma
Empty sella- very small pituitary, not seen on MRI
Pituitary infarction
Sheehan's Syndrome (post-partem hypopituitarism)
Hyperprolactinaemia
Micro or macro-prolactinoma
Drugs (dopamine antagonists)
Oestrogen production by ovaries decreased (also supresses GnRH)
Commonly causes galactorrhea and amenorrhoea Ovarian PCOS Polycystic Ovarian Syndrome (Group II Classification)
Menstrual irregularity
80-90% oligomenorrhoea
30% amenorrhoea
Hyperandrogenism
Hirsutism
Elevated free testosterone
Polycystic ovaries
Acne
Commonest endocrine disorder in women
Inherited
Obesity- weight gain exacerbates condition
Infertility
Diagnosed with 2 out of 3 of:
Chronic anovulation
Polycystic ovaries on ultrasound,12 or more 1-9mm folicles, increased ovarian volume >10ml
Hyperandrogenism (clinical or biochemical)
60% with elevated LH and 95% with altered FSH/LH ratios
Insulin resistance seen in 50-80%
Normal pancreatic reserve (hence, compensatory hyperinsulinaemia)
20% have frank glucose intolerance or NIDDM
Insulin acts as a co-gonadotrophin to LH
Insulin lowers SHBG levels, leading to increased free testosterone Ovarian Failure Group III Classification
High gonadotrophin levels (FSH and LH)
Low oestrogen levels (ovaries not responding)
Causes
Genetics
Congenital
Absent uterus
Vaginal atresia
Premature menopause
Autoimmune ovarian failure
Presentation
Menopause before age 40
Amenorrhea (raised FSH>30IU/L x 2 samples, low estradiol levels)
Aetiology unclear:
Family history- genetic causes
Pelvic radiotherapy, chemotherapy
Reduced ovarian reserve:
Prematurely reduced ovarian numbers
Diagnosis:
FSH increased
Low Anti-mullerian hormone (AMH)
Reduced antral follicle count on USS Genetic Causes Turner syndromeXO karyotypeCan also be mosaicismOnly affects women1 in 2000 birthsTesticular feminisationAndrogen insensitivity syndromeGenetically XY male (with tests)Phenotypically female (pseudohermaphrodites)XX gonadal dysgenesisAbsent ovariesNo chromosomal abnormalityCAHMany forms, this is non-classicalACTH diversion to androgens- rather than aldosteroneCaused by 21OH deficiencyIncreases 17-OH progesterone formed after ACTH stimulated (synACTHen test) Turner's Signs:
Short stature
Webbed neck
Shield chest
Wide spaced nipples
Cubitus valgus
Very immature ovaries
Presenting in paediatrics:
Do not progress through puberty
Normal adrenarche (pubic hair development)
May have breast development (depends when ovaries fail)3
0% have some pubertal development
Presenting in adults:
Primary or secondary amenorrhea
Infertility Constitutional:
CVS:
Coarctation of aorta
Bicuspid aortic valve
Hypoplastic left heart
GI:
Bleed (vascular malformation)
Increased Crohns/UC
Lymphatics
Lymphoedema
Endocrine
AI hypothyroidism
Musculoskeletal
Scoliosis
ENT
Otitis media1/3 have renal abnormalities Infective Non-infective Non-infectiveEndometriosisSurgical
Sterilisation
Ectopic pregnancyFibroidsPolypsCongenitalSalpingitis isthimica nodosa Pelvic inflammatory disease
Hydrosalpinx (blocked tubes) due to pelvic inflammatory disease
Abdominal/pelvic pain
Febrile
Vaginal discharge
Dyspareunia
Cervical exitation
Menhorragia/Dysmenorrhoea
Infertility
Ectopic pregnancy
Chlamydia
Gonorrhoea
Anaerobes
Syphilis
TB
Transperitoneal spread:
Appendicitis
Intra-abdominal abscess
Following procedure:
IUCD insertion
hysteroscopy
HSG In approx. 20%
Endometrial glands outside of the uterus
Retrograde menstruation is most likely a cause (altered immune function, abnormal cellular adhesion molecules, genetic)
Dysmenorrhoea (clasically before menstruation)
Dysparenuia
Menorrhagia
Painful defecation
Chronic pelvic pain
Uterus may be fixed and retroverted
Scan may show characteristic ‘chocolate cysts’
Infetility
Can be asymptomatic Miscellaneous Chronic renal failureTestosterone secreting tumourCongenital adrenal hyperplasiaThyroidDrugs:Depo-proveraExplanonOCP Idiopathic- low sperm count/quality
Varicocele- associated with reduced fertility
Non-obstructive- testicular failure- genetic (kleinfelter’s XXY), chemotherapy, radiotherapy, undescended testes, idiopathic
Low testicular volume
Reduced secondary sexual characteristics
Vas deferens present
High LH, FSH, testosterone
Obstructive (to vas deferens)- congenital absence (cystic fibrosis), infection, vasectomy
Normal testicular volume
Normal secondary sexual characteristics
Vas deferens may be absent
Normal LH, FSH and testosterone
Endocrine causes- acromegaly, Cushing’s, hyperprolactinaemia, anorexia, hyper/hypothyroidism
Erectile difficulty- diabetes, spinal cord injury, psychosexual
Semen disorders- rare specific defects in sperm- e.g. globospermia, Kartagner’s) Symptoms Hirsuitism
Excess hair
Referring to women with male pattern hair distribution
Caused by excess androgen in hair follicle
Due to increased circulating androgen
Due to increased peripheral conversion at the hair follicle
Androgen is synthesised in the ovaries and adrenal glands
Synthesis of testosterone from cholesterol
Progesterone, aldosterone, cortisol and estradiol also involved in this
Causes:
PCOS (common)
Familial (especially mediterranean)
Idiopathic
Congenital adrenal hyperplasia
Adrenal or ovarian tumour
Short history
Signs of virilisation (deep voice, clitoromegaly)
Amenorrhoea
Primary amenorrhea
Never had a period
Pubertal delay or failure to enter puberty
Likely congenital
Secondary amenorrhea
Acquired
Could be pregnant (most common)
Galactorrhoea (prolactin)
Visual Symptoms (pituitary) Classifications Anovulation Classification:
Group I -Hypothalmic pituitary failure - GnRH not secreted
Group II -Hypothalmic pituitary dysfunction -bad signalling (e.g. polycystic)
Group III -Ovarian failure - not a hormone signalling issue
Infertility:
Failure to conceive despite regular unprotected sexual intercourse over 18 months in the absence of known reproductive pathology (different from sterility)
Can be primary: Couple have never conceived
Or secondary: Couple previously conceived (although pregnancy may not have been successful: miscarriage/ectopic pregnancy)
Infertility is a disease- causes considerable psychological distress
Affects 1 in 6 couples
Incidence increasing due to:
Older women
Rise in chlamydia infectionIncreasing obesity
Increase male factor infertility
Increased awareness of treatments
Change in expectations
With increasing time, chances of spontaneous pregnancy increase (but by less and less) until it plateaus Aetiology Increased chance of conception:
Woman under 30
Previous pregnancy
Less than 3 years trying to conceive
Intercourse occurring during 6 days before ovulation, particularly 2 days before
Womans BMI between 20 and 30
Both partners non-smokers
Caffeine intake less than 2 cups of coffee daily
No use of recreational drugs
Decreased chance of conception:
Woman over 35No previous pregnancy
More than 3 years trying to conceive
Intercourse incorrectly timed, not occurring 6 days before ovulation
Womans BMI <20 or >30
One or both partners smoke
Caffeine intake more than 2 cups of coffee daily
Regular use of recreational drugs
Excessive alcohol intake in either partner
As age increases, fertility falls and number of spontaneous abortions increase Investigations Menstrual Cycle Regular: 28-35 days
Oligomenorrhea: Cycles > 35 days (i.e. less frequent)
Amenorrhoea: Absent menstruation
Primary- never menstruated
Secondary- previously menstruated, now stopped
Anovulation is associated with oligomenhorrhea and amenorrhea
Amenorrhea- check pregnancy test
Regular cycles suggest ovulaiton
Irregular cycles are probably anovulatory, further investigation needed
Tests:
Midluteal (day 21) serum progesterone (>30nmol/L) - two samples
BBT
Cervial mucous(LH predictor kits not recommended)
Biochemistry - LH, FSH Biochemistry Serum FSH -Early follicular phase (Day 2-5)
Serum LH- Early follicular phase (Day 2-5)
Serum estradiol- Early follicular phase (Day 2-5)
Serum progesterone- Early follicular phase (Day 2-5)
Serum prolactin- Early follicular phase (Day 2-5)
Serum TSH- Early follicular phase (Day 2-5)
Free androgen test (serum testosterone/serum HBG ration) testosterone is mostly inactive and bound to HBG- Early follicular phase (Day 2-5)
Midluteal progesterone (day 21)
Progesterone challenge test (menstrual bleed in response to 5 day course of progesterone- indicates normal estrogen)

Hypothalamus:
There is a low GnRH, and loss of it’s pulsatile secretion (cannot be measured)
There is a low, or low-normal LH and FSH
There is low estradiol
Pituitary:
There is a low or low-normal LH/FSH
There is low estradiol
There is a high GnRH due to negative feedback
Ovarian
High LH, very high FSH
Low estradiol
High GnRH Radiology Transvaginal ultrasound of ovaries Serial scans to look at follicular growth and ovulationMRI of pituitary fossa (tumour?)Bone density scan (premature menopause?)
Test of tubular patency
In obesity, previous pelvic surgery, Crohn’s
Laparoscopy:
Possible tubal/pelvic disease: e.g. PID
Known precious pathology (ectopic pregnancy, ruptured appendix, endometriosis)
History suggestive of pathology (dysmenorrhoea, dysparunia)
Previousy abnormal HSG
Hysteroscopy
Only performed in cases where suspected/known endometrial pathology (e.g. uterine septum, adhesions, polyp)
Ultrasound scan
Perform when abnormality on pelvic exam (e.g. enlarged uterus/adnexal mass)
When required from other investigations (e.g. possible polyp, seen at HSG) Karyotype
Visual field (if pituitary)
Auto-antibody screen (anti ovarian? adrenal?)
Endocervical swab for chlamydia
Cervical smear if due
Blood for rubella immunity
Endocrine profile
If there is an anovulatory cycle/ infrequent periods/amenhorrhoea:
Urine HCG
Prolactin
TSH
Testosterone
SHBG
FSH
LH
Estradiol
If hirsute:
Testosterone and SHBG Females Males General exam + genital exam
Semen analysis, twice over 6 weeks apart
If abnormal semen analysis:
LH
FSH
Testosterone
Prolactin
Thyroid function
If severely abnormal semen analysis/azoospermic
LH
FSH
Testosterone
Prolactin
Thyroid function
Chromosome analysis
Screen for cystic fibrosis
Testicular biopsy
If abnormality on genital exam:
Scrotal ultrasound Management Females Males Azoospermia (no sperm- sometimes in the testicle but not released, sometimes none at all)
Poor sperm quality
Adjuvants are given
If mild and moderate- IUI (intrauterine insemination- injected into uterus) or IVF
If severe IVF or ICSI (intracytoplasm sperm injection- sperm picked up and injected into egg) Peritoneal Endometriosis:
Cause:
Immune factors
Oocyte toxicity
Adhesions
Tubal dysfunction
Ovarian dysfunction
Treatment:
GnRH- usually prior to surgery
Surgical exicision
Surgical ablation:
Electrosurgical energy
Laser
Endometriomas
Cysts in the lining
Chocolate cysts Tubular Hydrosapinx:
Normal fallopian not seen on scan
Full of fluid
Due to PID/Endometriosis
Toxic to embryo
There is infertility and pregnancy loss
Treatment:
IVF
Surgical:
Restorative
Excision Uterine Ovarian Fibroids:
3 main types:
Subserous (no effect)
Submucous (remove ASAP)
Intramural (individualised)
Use myomectamy, laparotomy, hysteroscopy
Anomalies:
Septate uterus (septum in the middle)
Bicornate uterus (two parts) Depends on age and duration of infertility
Treatment:
Clomid (poor evidence)
Assisted conception- IVF
Late onset CAH
Low dose glucocorticoid to suppress ACTH drive
For pituitary
Sub-cut/pump pulsatile GnRH
FSH/LH daily injections
US monitoring General Pre-Treatment Treatment of Symptoms Clomifene Gonadotrophin Laparoscopic Diathermy Depends on symptoms:
Subfertility - ovulation induction
Oligo/amenorrhea
Hirsutism
Obesity
Acne
Alopecia
Oral contraceptive pill- regulates cycle, decreases androgens
Anti-androgens- cyproterone acetate (often combined with OCP as Dianette)
Local anti-androgens (efflornitihine - Vaniqa cream)
Cosmesis
Electrolysis
Laser phototherapy PCOS Weight loss
Risk of gestational diabetes
Poor results if BIM>30
Life style modifications- smoking, alcohol
Folic acid 400mg daily
Check prescribed drugs
Rubella immune
Normal semen analysis
Patent fallopian tubes First line
Cheap and safe
50-100mg tablet, days 2-6 of cycle
70% ovulate, 40-60% conceive, 15-20% do not ovulate on
Increased risk of twins
Cumulative conception rate rises up to 12 cycles, then plateaus
Don’t continue after 12 cycles, can lead to cancer
If clomifene resistant, options:
Metformin
Alongside lifestyle modifications
Improves insulin resistance
Reduces androgen production
Restoration of ovulation and menstruation
Does not help weight loss
Can produce a better response to clomifene or pre ovarian induction treatment
Gonadotrophin therapy
Laparoscopic ovarian drilling
Assisted conception treatment Daily injections
hMG (FSH and LH), r FSH
80% ovulate
60-70% conceive
Multiple pregnancy increased
Can be overstimulation 80% ovulate
Risk of ovarian destruction
Many singleton pregnancies
Needle put into follicle
Little holes made
How this helps is unknown Hyperprolactinaemia Premature Ovarian Failure Reduced Ovarian Reserve Hormone replacement therapy:
Check bone density
Oestrogen given
Oocyte or embryo donation
Ovarian tissue cryopreservation prior to chemo/radiotherapy when POF is anticipated
Counselling, support network Assisted conception treatment
Outcome poor
Few eggs
Those present, often of poor quality
May need donor oocytes Dopamine agonsit
Longer acting preparations- cabergoline 2x/week
Bromocriptine
These should be stopped when pregnancy occurs Ovarian Induction Aims to achieve healthy baby and mother
Consequences to both, however
Ovarian hyperstimulation
Affects 10% IVF (more so with younger polycystics)
Ranges from mild to severe
Mostly no harm, however can lead to dehydration, renal failure, DVT, PE
Multiple pregnancy
Increased maternal complications
Miscarriage
Hypertension
Gestational diabetes
Pre-eclampsia
Mode of delivery/ PPH
Increased risk to baby
Low birth weight
Prematurity
Still birth
Neonatal death
Risk of ovarian cancer- if ovulation induction used longer than 12 months Breast/Uterus
+
Oxytocin The posterior pituitary releases oxytocinThis important for the reflex of milk secretion (not production and storage, prolactin’s role)
It is also involved in uterine contractions during labour and intercourse (enabling fertilisation) Breast + Prolactin Causes Hyperprolactinaemia Presentation Investigation Treatment Dopamine from the hypothalamus inhibits prolactin secretion
Physiological causes:
Breastfeeding
Pregnancy
Stress
Sleep
Drugs:
Dopamine antagonists- e.g. metclopramide (anti-emetic)
Antipsychotics- e.g. phenothiazines (1st/2nd generation)
Antidepressants - e.g. TCA, SSRIs
Estrogen- e.g. the pill
Cocaine
Pathological:
Hypothyroidism- TRH has mild stimulatory effects on prolactin, though mainly under domaine control)- increased TRH and TSH when hypothyroid
Pituitary stalk lesions
Dopamine cannot get through to pituitary
Occurs occasionally even with non-functioning tumours
Road traffic accidents cause it
Iatrogenic causes of stalk damage
Has local effects
Prolactinoma (intrinsically releases prolactin) Can be microadenoma or macroadenoma
>1cm = macroadenoma
<1cm= microadenoma
Presents differently in women and men
More prevalent in women
Clinical symptoms and signs:
Women:
Early presentation
Galactorrhoea in 30-80%
Menstrual irregularity
Amenorrhoea
Infertility
Male:
Late presentation
Galactorrhoea in less than 30%
Visual field abnormal
Headache
Impotence (reduced testosterone)
Abnormal external eye movement
Anterior pituitary malfunction Prolactin concentration (if this is increased, then the other tests are done)
MRI of pituitary
Look for:
Microprolactinoma
Macroprolactinoma
Empty sella
Pituitary stalk (pushed to one side?)
Optic chiasma (compressed?)
Visual field tests:
Should be bitemporal hemionopia (not homonymous hemionopia)
Pituitary function tests Dopamine AgonistsBromocriptine 3x/dayQuinagolida (norprolac) 1x/day (oral)Cabergline 2x/week (oral)Least side effectsCommonly givenThese cause tumour shrinkageThey also bring the prolactin downThe prolactine is normalised in 96%Menstruation is regained i n 94%Pregnancy rate is 91%Return of raised prolactin within 45 days of cessation therapy - 86%Side effects (these settle with time)NauseaVomiting Tissues
+
Growth Hormone Physiology Causes Presentation Investigation Treatment Deficiency
Hyposecretion has different effects in children/young adults compared to in adults
It is less of a problem in adults
In children/young adults there is:
Decreased rate of growth- there can be dwarfism if extreme
There is loss of metabolic functions
Increased body fat
Reduced muscle strength
In adults there is:
Decreased bone density (which can also be due to physiology of the aging process
Excess
It also has more effect in children and grand adults
In children and young adults there is:
Growth, taller gigantism (overgrowth of jaw etc)
In adults there is:
Acromegaly (known as gigantism in youth)
A metabolic issue (may be diabetes) IGF1 levels- compare to standard for age and sex
Glucose tolerance test
75g given orally
Should cause GH levels to fall
In a normal person GH suppresses to less than 1 microgram/l after glucose is given
In acromegaly
GH is unchanged
There may be a paradoxical rise
GH remains above 1 microgram/l after the glucose
Visual field tests- look for bilateral hemionopia
CT or MRI pituitary scan
Pituitary function tests Giant (before epiphyseal fusion of bones at ~19 years of age)
Thickened soft tissue
Skin
Large jaw
Sweaty- grey skin
Large hands
Hypertension
Cardiac failure
Left ventricular hypertrophy
Diabetes Mellitus (insulin resistance)
Poor vision and visual fields
Hypopituitarism Vascular headaches due to increased cerebral blood flow
Snoring/ sleep apnoea
Pharynx swollen
Large tongue
Sinusitis
Lethargy
Sleepiness, headaches and aparaesthesia
Malocclusion of the teeth, clicking jaw
Joint pain
Carpal tunnel syndrome
Large spleen and liver
Polyuria
Urine calculi Non-Pharmaceutical Pituitary surgery
90% achieved if microadenoma
(<1cm diameter)
50% achieved if macroadenoma
(>=1cm diameter)
External radiotherapy to pituitary fossa
Alone: 25% at 3 years
Second line treatment
Stereotaxic may be better than standard
Retest GTT
Less than 1, clinically satisfactory
Greater than 1, drug thereapy needed Pharmaceutical Dopamine Agonist Bromocriptine 20mg/day
Cabergoline up to 3g/week
GH <2 in 15%
More efficient if co-secreting prolactin Somatostatin GH <2 in 30%
Tumour shrinks
30-50% decrease in size
Takes minimum of 6-12 months
Likely re-expands after stopping
Given by injection
Used pre-operatively
Relieves headache in 1 hr
Side Effects:
Local stinging due to subcutaneous injection
GI upset
Diarrhoea
Flatulence
Impaired GTT
Abdominal pains
Gastritis
Gall stones (stops motility of gall bladder)- risk of biliary colic
Examples
Octreotide (SC) 3xday
Sandostatin LAR (IM) 1/28days
Lanreotide autogel (IM) 1/28days Growth Hormone Antagonist Subcutaneous injection
10-30mg/day
Binds to GH receptor
Blocks GH
85% response rate
No decrease in tumour size (may be an increase)
IGF1 decreases
Serum GH concentrations may increase
Last line in therapy
Expensive Follow Up Clinically safe GH (<1) and normal IGF1
Pituitary (especially thyroid) hormone levels
Cancer surveillance
Colon
Growth of polyps
Villous adenoma
Cardiovascular risk factors:
BP
Lipids
Glucose
Sleep apnoea Known as growth hormone or somatotropin-191 amino acid protein
Made from pituitary somatotrophs
Growth hormone receptors
G protein coupled
cAMP is a secondary messenger
Has direct actions and indirect actions (involve a secondary release via insulin -like growth factors e.g. IGF-1 and IGF2)
IGF receptors are tyrosine kinase linked receptors Effects GH acts on:
Adipose tissue
To increase lipolysis (and therefore fatty acid concentration)- increased lean BM
The Liver
To increase gluconeogenesis
And to increase the release of IGFs
As a result of both, increasing plasma glucose levels
IGFs cause:
Increased growth in other soft tissue
Increased chondrocytes and long bone growth
Increased amino acid uptake and protein synthesis by muscle
Brain
Increased uptake to brain cells
Muscles
To increase amino acid uptaketo increase protein synthesis
The overall effect of GH is anabolic Controls GHRH and Somatostatin from the hypothalamus regulate GH release
GHRH
Stimulates the anterior pituitary to release GH
Somatostatin
Inhibits the anterior pituitary from releasing GH
IGF1 feeds back negatively to both the hypothalamus and pituitary
Ghrelin from the stomach also increases GH release
GH also has a direct negative feedback effect on the hypothalamus
GH levels fall with:
Increased blood glucose
Increased free amino acid level
GH levels rise with:
Decreased plasma glucose
Decreased free fatty acid concentration
Decreased amino acid
Has a pulsatile release 5 times a day
There is diurnal variation
The inputs are from the suprachiasmatic (autonomic body clock)
Peaks during sleep, prior to waking
Levels are higher during puberty
Sleep and exercise lead to increased GH release Diabetes Insipidus Causes:
Familial:
Isolated (mostly)
DIDMOAD (DI, DM, Optic atrophy, Deaf)
Acquired
Idiopathic (50%)
Trauma
RTA
Surgery
Skull fracture
Rare
Tumour
Sarcoids
External Irradiation
Meningitis
Treatment:
Desmosparay Nasally 10-60 mcg/day
Desmopressin Oral Tablet 100-1000mcg/day
Desmopressin Sublingual Tablet 60-360mcg/day
Desmopressin Injection 1-2mcg/day Hypothalamo-Pituitary Axis Structure Function Dysfunction
The anterior and posterior pituitaries are developmentally very different
Anterior
Adenohypophysis
From Rathke's pouch
Secretes trophic and non-trophic hormones
Posterior
Neurohypophysis
Extension of neural tissue with glial cells and axonal processes
Secretes ADH and vasopressin Anatomy Pituitary gland is found in a bony cavity known as the sella turcica
The hypothalamus is located just superior and posterior to it
Hypothalamus secretes hormones which affect the pituitary
Releasing hormones cause the anterior pituitary to produce other hormones
Neurosecretory cell bodies are found in the hypothalamus
They release hormone into capillaries which arrive at the anterior pituitary causing it to secrete hormones
It also secretes hormones which are then stored in and released from the posterior pituitary
The nuclei are in the hypothalamus, the nerve endings are found in the posterior pituitary
The hormones released from the pituitary go on to affect other organs around the body
Hormones produced by the peripheral endocrine organs and by the pituitary act by negative feedback on the secretion of the original hormone from the hypothalamus Embryology Histology Anterior
Islands, cords of cells
Acidophils:
Somatotrophs: GH (50%)
Mammotrophs: PRL (20%)
Basophils:
Corticotrophs: ACTH (20%)
Thyrotrophs: TSH (5%)
Gonadotrophs: FSH/LH (5%)
Chromophobes
Posterior
Nonmyelinated axons of neurosecretory neurons Hypothalamus Adenophysis Neurophysis The hypothalamus secretes releasing or inhibiting hormones which are secreted into portal veins leading to the anterior pituitary a capillary network (the median eminence)
Hormones secreted by the hypothalamus are neurohormones (cell bodies in hypothalamus)
They cause the anterior pituitary to produce other hormones
Ant. Pit hormones are tropic hormones
Releasing hormones (from the hypothalamus- stimulate the anterior pituitary to release hormones):
Growth hormone releasing hormone (GHRH) - GH
Prolactin releasing hormone (PRH)- Prolactin
Corticotrophin releasing hormone (CRH) - ACTH
Thyrotropin releasing hormone (TRH) - TSH
Gonadotrophin releasing hormone (GnRH)- LH + FSH
Inhibitory hormones (from the hypothalamus- inhibit the release of anterior pituitary hormones)
Growth hormone release inhibitor somatostatin (SS) - GH
Dopamine (DA)/Prolactin inhibitory factor (PIF)- GH/Prolactin Growth hormone/ Somatotrophin (GH)- protein (191)
Stimulates the release of insulin-like growth factors from the liver
Prolactin - protein (198)Prepares the breast for lactation
Suppresses ovulation
Adrenocorticotrophic Hormone (ACTH) - polypeptide (39)
Stimulates the release of adrenal cortical hormones
Thyroid Stimulating Hormone (TSH) - glycoprotein (201)
Stimualtes the release of thyroid hormones
Follicle Stimulating Hormone (FSH)- glycoprotein (115)
Stimulates gonadal function
Leutenizing hormone (LH) - (glycoprotein 115)
Stimulates gonadal function
Most pituitary hormones have direct effects on tissues but also stimulate the release of other circulating hormones that feedback to the hypothalamus and pituitary
TSH acts on the thyroid stimulating it to release thyroxine
LH and FSH act on the gonads stimulating the release of oestrogen, progesterone and androgens
GH stimulates the liver to release IGF-1
ACTH stimulates the adrenal glands to release cortisol The hypothalamus also secretes hormones which are then stored in and released from the posterior pituitary
The nuclei of supraoptic and paraventicular cells are found in the hypothalamus while the nerve endings are found in the posterior pituitary
The posterior pituitary releases:
Oxytocin
This important for the reflex of milk secretion (not production and storage, prolactin’s role)
Vasopressin (antidiuretic hormone - ADH)
Important for the reabsorption of water by the kidneys throughV2 receptors (without it, diabetes insipidus arises)
Also causes vasoconstriction via receptors on vascular smooth muscle and kidneys through V1 receptors
Both are short peptides (9 amino acids) to be stored in nerves Anterior Posterior Causes This is usually panhypopituitarism
It rarely affects individual hormones
There are many causes
Iatrogenic
Surgery
Radiation
Trauma- sudden haemorrhage into gland
RTA
Fractured skull
Tumours extending into sella
Pituitary tumour
Secondary metastatic leasion (lung, breast)
Local brain tumour (astrocytoma, meningioma, glioma)
Granulomatous Disease
Sarcoidosis
TB
Histiocytosis
Polyarteritis
Hypothalamic Infectious Diseases
Syphilis
Meningitis
Autoimmune
Sheehan's Syndrome Hypopituitarism Pituitary Adenoma Pituitary disorders can present as a result of:
Too much hormone
Too little hormone
Overgrowth of the gland
There may be all three- if a growth secretes and excess of one hormone while simultaneously pressing against areas of the pituitary which produce other hormones
Most pituitary tumours are benign- they are rarely carcinomas and usually adenomas
Problems resulting from non-functioning pituitary adenoma:
Compression on optic chiasm- results in bilateral hemionopia
Compression on cranial nerves (especially 3,4,6)
Hypoadrenalism
Hypothyroidism
Hypogonadism
Diabetes Insipidus
GH Deficiency Symptoms Menstrual irregularity (F)Impotence/InfertilityGynaecomastia (M)Abdominal obesityLoss of facial hair (M)Loss of axillary and pubic hair (M and F)Dry skin and hairHypothyroid faceGrowth retardation in childrenWeight loss Investigations Levels Free T4 (low)
TSH (low- can also be low in destroyed pituitary, due to negative feedback)
Estradiol (low)
Testosterone (low)
LH (low)
FSH (low)
GH (low)
IGF-1 (low)
Prolactin (low) Dynamic If it appears to be too much hormone, do a test to suppress it
If it appears to be too little hormone, do a test to stimulate it
SynACTHen test
Synthetic ACTH given
Cortisol levels measured at 0, 30 and 60 mins
If cortisol levels increase, pituitary issue, else, adrenal issue
Insulin Stress Test/Prolonged Glucagon Test
Insulin is given
Cortisol + GH levels measured every 30mins for 2-3 hours
Normal cortisol >550
Normal GH > 7ug
If GH and cortisol become normal, implies pituitary issue Treatment T4:
100-150mcg/day
Hydrocortisone:
10-25mg/day
GH:
SubCut GH nightly
Sex steroids:
Oest/Prog pill (F)
Testosterone (M) Testosterone IM injection every 3-4 weeks
Skin patches (andropatch)
Skin gel (testogel)
Prolonged IM injection 10-14 weeks (nebido)
Oral tablets (restandol) - as it is a peptide, not usually given orally
Risks:
Prostate enlargement (NOT cancer)- monitor size
Polycythaemia- monitor FBC
Hepatitis (if oral)- monitor LFTs Growth Hormone Improves quality of life
Decreases abdominal fat
Increases muscle mass, strength, exercise capacity and stamina
Improves caridac function
Decreases cholesterol
Increases LDL
Increases bone density
Given SubCut daily Hyperpituitarism Derived from cells of anterior pituitary
Relatively common (10% intra-cranial tumours)
Sporadic or associated with MEN1
Prolactin (20-30%)
Most common
Symptoms: Infertility, Lack of libido, Amenorrhoea (25%)
ACTH (10-15%)
Leads to Cushing’s disease
Usually a micro-adenoma
Bilateral adrenocortical hyperplasia occurs
FSH/LH (10-15%)
Non functioning, large gonads
GH (5%)
Second most common
Stimulates growth of bone, cartilage and connective tissue
Can produce more than one (even at sub-clinical levels)
Can be hypo / non-functional
Large adenomas
Visual field defects
Can cause pressure atrophy of surrounding normal tissue
Infarction can lead to panhypopituitarism
Carcinoma Hypofunction
Diabetes Insipidus
Lack of ADH secretion
Can lead to life threatening dehydration
Water Deprivation Test
Water not taken at length
Serum and urine osmolarities measured for 8h Again 4h after giving IM DDAVP
If urine/serum osmolarity >2, it is normal, else, <1.8 DI
Give ADH as desmospray or tablets
Hyperfunction
Syndrome of Inappropriate ADH secretion (SIADH)
Ectopic secretion of ADH by tumours
Primary disorder in the pituitary Blood Glucose + Insulin Biochemistry Disease Structure Pancreas has alpha, beta and delta cells
Exocrine- involves secretion of pancreatic digestive enzymes into SI
Endocrine- secretion of hormones into the blood stream
Exocrine cells surround Islets of Langerhans which have 3 cell types
Beta cells- secrete insulin (51aa), in the core
Alpha cells- secrete glucagon (29aa), around the periphery
Delta cells- secrete somatostatin, around the perphery
PP cells- secrete pancreatic polypeptide
Islets have capillaries within- supply core then periphery
Beta cells bathe alpha and delta cells with insulin (paracrine effect)
Parasympathetic and sympathetic innervation
Peptide Structure
Synthesized in the RER
Synthesized into a preprohormone- preproinsulin
Cleaved to form insulin
Preproinsulin contains two polypeptide chains linked by disulfide bonds (between cysteines)
One chain is lost to form proinsulin and a signaling chain
A second chain is lost to form insulin and C peptide
C peptide is a byproduct of the second cleavage- has no physiological function
Amino Acid Sequence
Similar in all species
Differences do not affect the activity if transferred between species
However, from another species, insulin is antigenic
It will induce antibody formation against the insulin Release Glucose enters beta cells through the GLUT2 transporter and is phosphorylated by glucokinase
Increased extracellular glucose leads to increased uptake/transport, increasing intracellular levels
There is more phosphorylated glucose and more ATP
Glucokinase is a glucose sensor- it is an enzyme used for glucose phosphorylation
It has a Km (affinity for the substrate - high Km means low affinity) which lies in the physiological range of concentrations
A small change in glucose concentrations leads to a dramatic change in glucokinase activity (i.e. phosphorylation)
This is not true for hexokinase, which is found in RBCs- it is virtually always at maximum capacity
Glucose then undergoes glycolysis and enters the TCA cycle to form ATP
Increased metabolism of glucose (at increased conc) leads to an increase in the intracellular ATP
ATP inhibits the ATP-sensitive K+ channel, KATP
This channel moves potassium from the inside to the outside of the cell
It is used to maintain the membrane potential
With increased glucose concentration there is increased inhibition of KATP
KATP stop pumping potassium from the inside to the outside
There is then depolarisation of the membrane
This voltage change affects the voltage gated calcium channel activity
Voltage gated calcium channels open allowing in calcium
Increased internal calcium concentration causes the mobilisation of secretory vesicles (containing insulin) within the cell
The secretory vesicles fuse with the cell membrane and insulin is released extra-cellularly Timing The insulin release is biphasic
Not just one burst
1st peak due to the secretion of insulin
This release is somewhat sustained
There is then a second phase with a second peak
There are 2 phases because there are 2 different types of vesicle
5% of insulin granules are immediately available for release in the RRP- readily releasable pool (already partly fused)
Others need to fuse with the membrane and undergo preparatory actions to be mobilised and ready for release Modulation GLP 1 helps modulate insulin secretion
GLP-1 is Glucagon-like peptide 1
It is released by the GI tract in response to food intake orally
It stimulates insulin secretion in healthy subjects
Oral glucose therefore leads to higher insulin secretion than intravenous injection
GLP-1 binding to its receptor leads to the activation of adenylate kinase and an increase in cAMP
This stimulates intermediates resulting in increased insulin- when acting in combination with other signals
PKA and Epac2 are activated
This has numerous effects on ion channel activity, calcium and exocytosis of insulin granules Inhibition KATP channel structure:
KATP consists of 2 protein subunit types- there are 4 of each
Inward rectifier subunit- Kir6.1
Sulphonylurea receptor-regulatory subunit- SUR1
Both are needed to form a functional channel
Channel has an octomeric structure
4 SUR1 receptors around 4 Kir6.1 proteins
The peptides transverse the membrane several times so some domains are inside while others are outside
Two of the inside domains on SUR1 are nucleotide binding domains
Kir moves potassium out while SUR1 regulates this movement
Intracellular ATP binds to the nucleotide binding domain on the inside of the cell on the SUR1 sub-unit
It inhibits the binding of potassium, stopping the pumping
Magnesium salt bound nucleotides (Mg2+ ATP and ADP) activate KATP by binding to the SUR1 sub-unit
Therefore ATP can inhibit OR activate pumping of potassium
KATP is directly inhibited by the sulphonylurea class of drugs (tolbutamide and glibenclamide)- they inhibit the SUR regulator by binding extracellularly , causing depolarisation and thus more insulin secretion
KATP is directly stimulated by diazoxide, which binds extracellularly to SUR1 and thus inhibits insulin secretion and increases potassium binding and transport Signalling Insulin sensitive tissues include the liver and skeletal muscle
It is a peptide and so cannot cross the plasma membrane- needs a receptor
The receptor type is a tyrosine kinase
It is dimeric
It has two extracellular alpha subunits (hormone binding domains) and two transmembrane beta subunits (ATP binding and tyrosine kinase domains)
The components are linked by disulphide bonds
The binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves
This activates catalytic activity of the receptor
Receptors are docking centres for other enzymes- recruit and activate further signalling molecules (including the RAS/MAPK pathway and gene expression)
There are several intracellular insulin receptor substrates which are phosphorylated when insulin enters the receptor
The substrate activates the PI-3K pathway
PI-3K activates protein kinase B
Protein kinase B activates glycogen synthase kinase 3 and protein phosphotase 1
Glycogen synthesis is activated
Protein kinase B also causes the movement of GLUT4 transporters from intracellular vesicles to the cell surface
This lowers blood glucose, as glucose moves into the cell
When blood glucose returns to normal transporters are endocytosed Effects Amino acid uptake in muscle
DNA synthesis
Growth responses
Glucose uptake in muscle and adipose tissue
Protein synthesis
Lipogenesis in adipose tissue and the liver
Glycogen synthesis in liver and muscle
Gene expression
Lipolysis
Gluconeogenesis in the liver Unavailability Ketone bodies are formed in liver mitochondria
They are derived from acetyl CoA from beta oxidation
They diffuse into the blood stream and into peripheral tissues
They are important for the energy metabolism of the heart and renal cortex- they are converted back to acetyl CoA which re-enters the TCA cycle
Fatty acid oxidation produces acetyl CoA which when combined with oxaloacetate can produce citrate
If oxaloacetate is consumed for gluconeogenesis, fatty acids are oxifdised to produce acetyl CoA, the excess of which, since unable to combine with oxaloacetate, forms ketone bodies
When ketone bodies accumulate they can lead to acidosis
This can cause coma and death
Ketoacidosis is associated with type 1 diabetes
There are high concentrations of insulin in type 2 and this inhibits hormone sensitive lipase so stored triglycerides are not broken down Sensing AMP (adenosine monophosphate) activated protein kinase
Maintains energy balance
Activated by metabolic stress
Inhibition of ATP production
Acceleration of ATP consumption
Activates catabolic pathways which generate ATP
Inhibits anabolic pathways which consume ATP
AMP activates the phosphorylated enzyme (kinase) allosterically
It promotes phosphorylation by upstream kinases
It inhibits dephosphorylation by protein phosphotases
It antagonises the binding of ATP
Why AMP?
Hydrolysis of ATP leads to ADP formation
However it is the AMP:ADP ratio that is important
This is because 2ADP <-> ATP + AMP
It is always close to equilibrium
Therefore the AMP:ATP ratio is a much more sensitive indicator of energy balance than ADP:ATP
After ATP production stops, there is more AMP Activation Causes of AMPK activation
Glucose Deprivation
Sensed by specialised glucose sensing cells
Pancreatic B cells
Hypothalamic cells which initiate feeding behaviour
Ischaemia and Hypoxia
AMPK is involved in oxygen sensing in specialised oxygen sensing cells
Exercise and contraction of skeletal muscle
Protect against metabolic stress caused by contraction which increases demand for ATP
Hormones and Cytokines
Role in regulation of body weight and energy balance
Targets:
Glucose uptake
Glycolysis
Fatty acid oxidation
Mitochondrial biogenesis
Effects
Activates processes that generate ATP
Inhibits processes that consume ATP
Helps maintain energy balance
Role in obesity, type 2 DM and metabolic syndrome
Low activation state of AMPK due to over-nutrition and lack of exercise may contribute to type 2 DM
Metformin indirectly activates AMPK Stimulation Insulin Increased glucose concentration in the blood causes the B cells to secrete insulin
Several other factors also stimulate the B cell to produce insulin:
Increased amino acid concentration
Increased plasma fatty acid
Increased GIP (glucose dependent insulinotopic peptide) and GLP (glucagon like peptide) in the plasma caused by increased carbohydrate in the intestine
Parasympathetic nervous system
There are also factors which inhibit insulin secretion
Sympathetic nervous stimulation, adrenaline
Somatostatin from delta cells
Sulphonylureas and Meglitinides act to directly increase insulin secretion from B cells
Acts on a tyrosine kinase receptor Glucagon Decreased plasma glucose concentration results in alpha cells being stimulated to secrete glucagon
Several other factors also stimulate alpha cells to secrete glucagon:
Decreased amino acid concentration
Decreased plasma fatty acid
Decreased GLP concentration
Stress and exercise
Sympathetic stimulation and adrenaline
Factors which inhibit glucagon release:
Insulin and somatostatin
Acts on a G protein coupled receptor with cAMP as a secondary messenger
Acts mainly on liver (not muscle and not as much adipose as insulin) In the fed state:
Increased blood glucose
Increased insulin
Glucagon increases initially and then decreases
In the post-fed state:
Blood glucose falls causing insulin to fall
When glucose levels are low, alpha cells detect this
Increased glucagon
Blood glucose maintained
If there is an increase in blood glucose, insulin increases and glucagon decreases
If there is a decrease in blood glucose, insulin decreases and glucagon increases Secretion Problem Mitochondrial Diabetes Mitochondrial metabolism problem
Attenuation of cytosolic ATP levels
Pronounces age dependent deterioration of pancreatic function Kir6.2/SUR1 Mutations In mice- overactive KATP leads to profound neonatal diabetesIn mice- inactive KATP channels lead to hyperinsulinaemiaIn humans, Kir6.2 mutations lead to neonatal diabetesThey lead to activated KATP channels and increase in KATP numbers, also increase rate of pumpingSulphonylureas like tolbutamide can inhibit these channels and allows for insulin secretionIn humans Kir6.2 and SUR1 mutations can lead to hyperinsulinsim as wellThey lead to increased insulinThere can be inhibition of transport of potassium channels into the membrane- trafficking mutationsThere can also be inhibiting mutations- pumps are inhibitedDiazoxides can help if the pumps are inhibited (but not if they are not present in the membrane) Maturity onset Diabetes in the Young Monogenic diabetes- genetic defect in beta cell function
Familial form of early onset Type II
There are mutations in 6 different genes that can cause MODY
Glucokinase
Transcription factors:
Hepatocyte nuclear factor 4alpha
Hepatocyte nuclear factor 1alpha
Insulin promoter factor 1
Hepatocyte nuclear factor 1beta
Neurogenic differentation factor 1
Over 150 different mutations can cause MODY
Enzymatic activity is impaired
Glucose sensing defect
Threshold blood glucose level for insulin secretion increased
Decrease in hepatic glycogen synthesis and storage
Increase in hepatic gluconeogenesis
Postprandial hyperglycaemia
Responsive to diet usually
Transcription factors have roles in pancreas foetal development + neogenesis
They are also important for beta cell differentiation and function Rabson Mendenhall Syndrome Rare
Autosomal Recessive
Mutations in insulin receptor gene
Severe insulin resistance
Acanthosis nigricans (hyperpigmentation)
Fasting hypoglycaemia
Postprandial hyperglycaemia and hyperinsulinaemia
Diabetic ketoacidosis
Caused by defect in insertion of insulin receptor into plasma membrane Leprechaunism (Donohue Syndrome) Rare
Autosomal recessive
Mutations in gene for insulin receptor
Severe insulin resistance
Developmental abnormalities
Elfin facial appearance
Growth retardation
Absence of subcutaneous fat
Decreased muscle mass
Caused by defects in insulin binding or receptor signaling Type 1 Diabetes Mellitus Features:
Young onset
Normal weight
Reduced insulin levels
Anti-islet antibodies
Ketoacidosis
50% Concordance with twins (genetic predisposition)
HLA linked
Pathogenesis:
Islet cell antibodies attack beta islet cells, destroying them
Loss of 1st phase insulin
Glucose intolerance
C peptide positive
C peptide negative
Autoimmune disorder (can also be idiopathic)
IA-2, IA-2B GAD65 (glutamate decarboxylase antigens)
Cause unknown- partly genetic
Possible viral aetiology
Absolute requirement for insulin
Average onset age 16
Can be found with polyglandular endocrinopathy type 2 (Addisons, hypothyroid, hypogonadism, vitiligo, Coeliac) - not just 1 gene
Can be found with type 1 endocrinopathy (Addisons, hypothyroid, hypogonadism, vitiligo, Coeliac, alopoecia, vitiligo, hypoparathyroidism)- autosomal recessive Islet Cell Tumours Glucagonomas
Weight loss
Muscle wasting
Mild DM
Catabolic
Tumours of a cells
Somatostatinomas
Mild DM
Tumours of d cells
Reduced insulin and glucagon release
Insulinoma
Hypoglycaemia
Tumour of B cells
Increase in weight Diabetes Type 2 Diabetes Mellitus Features:
Onset >30
Overweight or obese
Normal or decreased insulin
No islet antibodies
No ketoacidosis>90% concordance with twins
No HLA linkage
Family history more common
Pathogenesis:
Target cells are unresponsive to insulin secreted by beta cells
Much more common
Caused by obesity, physical inactivity, other environmental factors
Diagnosed with fasting glucose, oral glucose tolerance test or HbA1c
Insulin is not a requirement
Lifestyle helps prevent- reduce smoking, increase physical activity, improve diet- lower LDL Gestational Diabetes Pregnancy relatively insulin-resistant state
Increased resistance can cause sensitivity to become below normal in some
If those with diabetes become pregnant, diabetes much harder to controlIncreased risk of pre-eclampsia
Large babies usually ~5kg
Can be developmental defects
Hypoglycaemia life threatening for baby however Symptoms PolyuriaPolydypsiaWeight lossGeneral malaiseDiabetic ketoacidosis:VomitingAbdominal painAltered consciousnessAcidotic breathingpH<7.3Urine ketone positiveDehydratesCan lead to coma or death Complications Biochemical HONK Hyperosmolar Hyperglycaemic State/Hyperosmolar non-ketotic coma (HHS/HONK)
Relative insulin deficiency
Features:
Thirst
Frequent urination
Nausea
Disorientation
Loss of consciousness
Dehydration
Hypernatraemia
Raised plasma glucose
Increased plasma osmolarity
No ketosis/acidosis
Brain battles to retain water, if too fast leads to cerebral oedema and death, slow correction needed
Management:
Fluid electrolyte
Insulin therapy
Correct sodium then give saline Ketoacidosis Presentation ThirstFrequent urinationNauseaDisorientationLoss of consciousnessSmell funnyVomitingHigh Blood sugarRaised RRBurred visionAnorexiaWeaknessKussmaul breathingDry mouthFacial flush Management Hour 1:Litre of fluid (Unless >85/ Heart failure)Insulin- 6units/h (suppress ketones, don’t worry about blood sugar)Long acting insulinCVP lineThromboembolism prophylaxisKeep dehydratedConfirm diagnosis rapidly with BMr, ketone smellDo BM, U&E, Blood GasHours 1-43L of fluid by 4hGive dextrose once BM<14, Then give more insulinMonitor for hyperkalaemia (peaky T waves, Flat P waves)And K to IV fluids if neededAfter 4hGive insulin with meal Complications Cerebral oedema
Arterial/Venous thrombosis
Secondary infection in urine
ARDS
Thrombophlebitis
Rhabdomyelosis - creatinine kinase stuck in kidneys
Give normal meals, don’t stop insulin Non-Enzymatic Glycosylation Most proteins exist as glycoproteins, with sugar side chain
The sugar side chain affects charge, solubility and function
In extra-cellular membranes it affects stability
Sugar proteins are usually added in a regulated way
With high sugar levels sugar sticks in a non-regulated way, they accumulate and lead to over-glycosylation of protein
Protein becomes too stable and losing them function Lactic Acidosis Excessive anaerobic energy production
Lactate released into blood
Lactic acid formed Hypoglycaemia Caused by treatment
Particularly in insulin dependent (type 1) diabetics
Carbohyderate intake does not match insulin dose
Risk of coma and death
Symptoms:
Tiredness
Weakness
Headache
Shaking
Fainting
Hunger
Slow movement
Slow speech
Can be chronic when there is obsessional control of diabetes
Oral glucose is given if able to swallow, otherwise glucogel is given
If comatose, 50% 50ml dextrose IV Vascular Renal Disease Diabetes is the commonest cause
Various stages- 1 to 5
Thickening of basement membrane of glomerulus
Mesangial expansion
Hyperglycaemia causes glycosylation of matrix proteins and increased matrix production
There is glomerular sclerosis due to intraglomerular hypertension
There is increased capillary permeability
Urine protein excretion can lead to microalbuminuria- albumin in urine >300mg/day
There is increased risk for overt nephropathy Eye Disease Cataract Macroangiopathy Risk of atheroma in large arteries increased
Leads to:
7x increase in MI risk (especially if also obese or hypertensive)
Hypertension due to rigidity of vessel walls
CHD
Stroke
PVD
Stability of the extracellular matrix is increased
Diabetics also have hyperlipidaemia- lipids not taken up Microangiopathy Small arteries at increased risk of arteriosclerosis
Especially arteriosclerosis at distal parts of the ciriculation where microvascular structure is key
Poor perfusion leads to:
Gangrene
Foot ulcers
Infection with anaerobes
PVD
Structural changes
Thickening of basement membrane
Functional changes
Increased capillary permeability
Increased blood flow and viscosity
Disturbed platelet function Neural Glomerulopathy Small vessels into glomerulus, filter to excrete waste product
Filtration depends on pressure and charge on capillary wall
This is determined by basement membrane
Non-enzymatic glycosylation on basement membrane makes capillaries leaky
Protein leaks out
Leads to proteinurea
Mesangial Cells in the glomerulus at risk
Pathophysiology:
Hyperfiltration
Filtration determined by pressure
If pressure too high ,protein leaks out
Microalbuminuria
Albumin in urine
Proteinuria
ACE inhibitors to slow rate of progression of proteinuria
Reduced GFR (glomerular filtration rate)
ESRD
Treatments:
Dialysis
Co-morbidity means outcome is much worse, with CV disease etc
Kidney pancreas transplant
Islet cells needed Hypertensive Renal Disease ECF fills up glomerulus
Blood can’t flow through
Leading to filtration failure
Blood pressure needs to be reduced to slow decline of GFR and reduce proteinuria
ACEis and ARBs given to dilate efferent arteriole and reduce intraglomerular hypertension Pyelonephritis Glucose in urine makes patients more susceptible to infection
Ideal culture medium
Patients get infection
Decline much faster Papillary Necrosis Papillaries of deep medulla become ischaemic
Due to inadequate flow
Inadequate flow is due to microangiopathy Diabetes is the commonest cause of adult blindness Retinopathy Maculopathy Sclerosis of small vessels in eye due to non-enzymatic glycosylationLoss of autoregulation of blood flowVascular occlusion initially of capillaries and then of arteries and veinsRetina ischaemicNeoangiogenesis in retinaVessels grow across photoreceptorsCells will survive but function impairedEndothelial cells at risk Capillary dilatation (later with leakage)
Capillary occlusion
Microaneurysms
Blot haemorrhages- red lesions
Lipid rich hard exsudates. Background Retinopathy Cotton-wool spots (retinal ischaemia)
Venous abnormalities (loops, beading and reduplication)
Arterial abnormalities (variation of caliber, narrowing of segments and occlusion)
Intraretinal microvascular abnormalities (clusters of dilated abnormal capillaries lying within the retina. Preproliferative Retinopathy New vessels arise in the periphery and/or on the optic disc
Eventually with a fibrous tissue covering
Caused by vitreous retraction which leads to haemorrhage and to traction and detachment of the retina
Haemorrhage can be vitreous or pre-retinal
Laser photocoagulation can be used to treat Proliferative Retinopathy Rings of hard exudates approaching the fovea
Mostly in T2DM and can cause severe visual loss
There is macular oedema- focal or diffuse
There is also ischaemic maculopathy Thrombotic Glaucoma New vessels and fibrous tissue proliferating in the angle of the anterior chamber, preventing drainage of the aqueousAssociated with rubeosis iridis (neovascularisation of the iris) Causes severe pain and irreversible blindnessThis is advanced diabetic eye diseaseThere is retinal detachment with or without retinal tearsThere is neurovascular glaucoma Lens has cells with extra-cellular matrixEC matrix damaged with non-enzymatic glycosylationTransparency lostCataracts easily removed Sorbitol Accumulation The enzyme aldose reductase catalyses the reduction of glucose to its polyol, sorbitolSorbitol subsequently converted to fructoseSorbitol does not easily easily cross cell membranes and its accumulation may cause damage by osmotic effectCausing swelling of lens Features Non-enzymatic glycosylation around nerves combined with microangiopathy causes neuropathyIt affects peripheral and autonomic nervesSymptoms become clinically silentAffects 50% of patientsWith Type 1 distal polyneuropathy becomes symptomatic after many yearsWith Type 2 presents much soonerAffects preipheral nerves in stocking and glove distributionAffects autonomic neurones within GI tract,bladder and blood vesselsCan lead to hypotension, gastroparesis, diarrhoea, urinary incontinence Neurons and Schwann cells in peripheral nerves at riskAssessment:With microfilamentAt risk of developing unrecognized injury/fracture/infectionLong nerves affected first Pathophysiology Hyperglycemia causes increased levels of intracellular glucose in nerves
Leading to saturation of the normal glycolytic pathway
Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase
Accumulation of sorbitol and fructose lead to:
Reduced nerve myoinositol
Decreased membrane Na+/K+ -ATPase activity
Impaired axonal transport
Structural breakdown of nerves, causing abnormal action potential propagation
Aldose reductase inhibitors to improve nerve conduction
Nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advanced glycation end products (ACE) that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport
Increased production of free radicals in diabetes may be detrimental via several mechanisms:
Direct damage to blood vessels, such as occlusion of the vasa nervosum
Nerve ischemia
Facilitation of AGE reactions
Use of the antioxidant alpha-lipoic acid Complications Charcot foot arthropathy
Progressive condition of the musculoskeletal system
Characterized by:
Joint dislocations
Pathologic fractures
Debilitating deformities
Progressive destruction of bone and soft tissues at weight-bearing joints
Occurs at any joint; however, it occurs most commonly in the lower extremity, at the foot and ankle
Foot ulceration
Neuropathy in the presence of callus or deformity
Peripheral vascular disease
Penetration injuries
Ill fitting footwear Neuropathy Cranial Nerve Palsy
Peripheral Mononeuropathies
Amputation BMI >30
Central or peripheral
Abdominal worse, fat cells in abdomen cause fat cell glucocorticoid synthesis
Risk factor for:
Hypertension
Atheroma
Diabetes
Osteoarthritis
Gallstones
Hypoventilation
Cancer (breast, endometrial, prostate, kidney)
Psychological illness Necrobiosis lipoidica (skin)
Depression
More frequent bone fracture
Obesity: Releasing Problem Nutrition Type I:
Consistency of meal times
Timed insulin
Monitor blood glucose regularly
Type II:
Weight loss
Smaller meals and snacks
Physical activity
Monitor blood glucose and medication (if on insulin/SU)
Recommendations:
Eat 3 meals a day
Include starchy carbs at each meal but monitor intake (type I should balance)
Limit sugary food and drink
Reduce fatty food
Aim for >5 fruit and veg per day
Eat oil rich fish twice a week
Minimise salt and salty food
Limit alcohol - 2 units women, 3 units men
Potential for hypo (epsecially those with insulin/ SUs) increases insulin activity especially if there is no food intake to compensate
Food have a glycaemic index- ranks the rate at which food makes blood glucose rise
Consider portion sizes Insulin Devices PensOralInhaledPreprandialPumpsInto subcutaneous tissueSlow clearanceLeads to post meal hyperglycaemic spike
Basal insulins must have:Flat profileDuration beyond 2hLow variabilitySafeClinical effectivenessPancreas transplantation- usually only with renal failure Durations Rapid:
Aspart, Lispro, Glulisine
Analogues
Onset 15mins
Peak 1 h
Lasts 3-4h
Short:
Soluble Insulin
Actrapid, Humulin S
Onset 30mins
Peak: 2-3h
Lasts 8h
Intermediate:
NPH,Humulin, Novolin
Long:
Detemir
Small peak
Lasts 22-24h
Long:
Glargine
Almost no peak
Lasts 22-24h
Basal:
Insulin Degludec
Lasts about 40h Pharmaceuticals Insulin Sensitizers Incretin Secretagogues Act on:
Impaired peripheral glucose uptake
Increased hepatic glucose output
Reduce insulin resistance
Don't cause hypoglyaemia Biguanides Prescribing 1st line for the overweight or obese in Type II DM
Metformin (Glucophage)
Derived from guanidine
Metformin is the only available biguanide(Phenformin withdrawn)
Usually start with 500mg (low dose)
Little evidence for >1g
Can also be found as modified release and liquid
Safe in pregnancy
Tablets with food Mechanisms Improves hepatic insulin sensitivity
Reduces endogenous glucose production
May increase muscle glucose uptake via GLUT4
Increases AMPK activity
Alleviates hyperglycaemic symptoms
Reduces HbA1c
Minimises hypoglycaemia
Low risk with monotherapy
May cause slight weight loss
Reduces microvascular complications
Reduces macrovascular complications
Safe if prescribed appropriately Side Effects GI Side Effects
Anorexia
Nausea
Vomiting
Diarrhoea
Abdominal pain
Taste disturbance
In upto 25%
Lactic acidosis
Rarely de novo
Caution acute CCF
Septic
Acute MI
Respriatory failure
Hypotension
Peri-operative- stop if eGFR<30 and creatinine>150
Temporarily withhold if IV contast being used
Discontinue if risk of lactic acidosis- encephalopathy, alcohol excess
Interference with vitamin B12 and folic acid absorption
Liver toxicity
Discontinue with cirrhosis/liver failure Thiazolidinediones Pioglitazone (Actos)
Peroxisome proliferator- activated receptor gamma (PPARY)
Improve insulin sensitivity/decreased resistance
Only available agent is piogitazone 15-45mg
Usually 2nd or 3rd line in T2DM
Used in combination with metformin or SU
Used with insulin under special supervision
Mechanism:
Affects transcription of insulin sensitive genes- so glucose and fatty acids enter
Reduces HbA1c but takes 2-3months to work
Low risk of hypoglycaemia as monotherapy
Reduces triglycerides and LDL
Causes weight gain!
Probably reduces micro and macrovascular complecations
Not sure if safe
Side Effects:
Fluid retention
Fractures- avoid in those with osteoporosis
Possible bladder cancer risk Management Act on impaired insulin secretion Sulphonylureas 1st generation:
Chlorpropamide
Tolbutamide
2nd generation:
Glicazide 40-160mg 2x/day
Glibenclamide
Glimepiride
Mechanism:
Binding causes K+ channels to close
Ca2+ enters
Insulin released
Reduces HbA1c
Risk of hypoglycaemia- especially if elderly/long acting (glibenclamide)
Causes weight gain
Reduces microvascular complications
May reduce macrovascular complications
Safe if prescribed appropriately
Avoid in liver failure
SUs first line in non-overweight T2DM patients and those intolerant of metformin (thin type 2 probably have more of a problem with secretion than sensitivity) Metglitinide Analogues Repaglinide and Nateglinide (Prandin and Starlix)
Mechanism:
Bind to different subunit of beta cell than SUs
Insulin release is more glucose dependent
More rapid onset (must eat just after taking)
Shorter duration of action Alpha Glucosidase Inhibitors Alpha glucosidase:
Brush border enzyme metabolising oligo-disaccharides in the small intestine
Acarbose with meals reduces glucose absorption
Low risk hypoglycaemia
Modest effect on HbA1cSide Effects:
FlatulenceDiarrhoea
(Due to undigested complex carbohyderates reaching the colon)
These effects are relatively rare Incretin Based Therapy Incretins:
GIP: gastric inhibitory polypeptide
GLP1: glucagon-like polypeptide
Promotes satiety, reduces appetite
Acts on alpha cells to decrease post-prandial glucagon secretion
Acts on liver to reduce hepatic glucose output
Acts on stomach to slow gastric emptying- feel full
Acts on beta cells to produce glucose dependent insulin secretion
DPP4: degrages GLP1
GIP and GLP-1 account for most of the incretin effect
Released from gut, act on pancreas
Suppress glucagon
GLP-1 from L cells
Incretin effect diminished in T2DM
Resistance to GIP
Deficiency of GLP-1
Types:
Incretin mimetics
GLP1 receptor agonists
DPP4 inhibitors GLP-1 Enhancers Secretion impaired in T2DM
Natural GLP-1 has short half life
Treat with GLP-1 analogue with long half life- not degraded by DPP4
Injectible (subcutaneous)
Exenatide
Liraglutide
Used in combination with oral agents
SU, metformin, both
Or with TZDs
3rd line / if BMI>35
Weight Loss
Improved HbA1c
Improve beta cell mass
Decreased BP
Improved lipid profile
Side Effects:
Nausea
Diarrhoea
Hypoglycaemia (in conjunction with SUs)
Injection
Pancreatitis DPP4 Blockers OralSitagliptinSaxagliptinVildagliptin2nd line treatment after metforminOr if there is concern over hypos/weight gainWeight neutralModest affect on HbA1cNo hypoglycaemia as monotherapyLong term safety unknown Weight Loss Orlistat Bariatric Surgery Weight loss drug
Adjunct to lifestyle intervention
Many side effects- lack of anal tone If BMI is > 35 or with co-morbiditeis
Helps with:
Hyperlipidaemia
Hypertension
Sleep apnoea
Type 2 DM
Overall mortality
HbA1c Thyroid + Thyroxine Physiology Pathology Control of Thyroid (Hyp-Pit) The thyroid consists of two lobes joined by the isthmus
It is anterior to the trachea, thus an enlarged thyroid can lead to stridor
On the back, 4 parathyroid glands are found and these regulate calcium
It is found just below the larynx
Recurrent laryngeal nerve runs very close, if damaged there can be a hoarse voice
The thyroid cells exist in follicles
There are follicular cells that run along the outside of the follicle
There is colloid- this are tyrosine containing throglobulin filled spheres enclosed by the follicular cells
There are also parafollicular C cells which secrete calcitonin
The colloid containing thyroglobulin has T3 and T4
These pass through the follicular cells to enter the blood streamIodine passes from the blood stream to the colloid
TRH from the hypothalamus stimulates the pituitary to release TSH which stimulates the thyroid to release T3 and T4 Control by Thyroid (Hormones) Synthesis T4- thyroxine, accounts for about 90% of secreted thyroid hormone and is used in treatment
T3- tri-iodothyronine accounts for about 10% of thyroid hormones secreted- it is the active component and is 4 times more potent than T4
T4 is converted to T3 by the kidney
Biosynthesis
Iodine is required for the formation of thyroxine
Iodine is taken up by follicular cells
Iodine is then attached to tyrosine residues on thyroglobulin (this can be inhibited by carbimazole and propylthiouracil used to treat hyperthyroidism
Monoiodotyrosine (MIT) and Di-iodotyrosine (DIT) are formed
MIT and DIT are coupled to form triiodothyronine (T3 - 3Is) or 2 DITs are coupled to form thyroxine (T4-4Is)
T3 and T4 are stored in colloid thyroglobulin until required
Regulation:
Thyrotrophin releasing hormone (TRH) is released from the hypothalamus
It stimulates the anterior pituitary to release thyroid stimulating hormone (TSH)
TSH enters follicular cells and stimualtes thyroid to release T3 and T4
T3 and T4 are secreted from the colloid via the follicular cells into the boodstream
Negative feedback to control the release of TRH and TSH
These act on nuclear receptors in their target cells
They are both hydrophobic/lipophilic Transport They bind to plasma proteins
Thyroxine binding globulin (TBG) 70%
Thyroxine binding pre-albumin (TBPA) 20%
Albumin 5%
It is only biologically active when unbound
They are almost entirely bound by plasma proteins
T3 is bound 10-20 times less avidly by TBG and not significantly to TTR
As a result it has a more rapid onset and offset of actions
Only free hormone is available to tissues
The metabolic state correlates more with the free concentration than with the total concentration
Concentration of total hormone may not vary with that of free hormone
Increase in TBG does not necessarily mean there is also an increase in free T4
This binding allow the body to better maintain free hormone levels
Variations of plasma protein affect the level TBG increase?
(without freeT4 increase) PregnancyNewborn stateOCP (and other forms of oestrogen)TamoxifenHepatitis A (decreased albumin)Chronic active hepatits (decreased albumin)Biliary cirrhosis (decreased albumin)Acute intermittent porphyriaGeneticsClofibrateHeroin TBG decrease
(without freeT4 decrease) AndrogensLarge doses of glucocorticoidsCushingsActive acromegalySevere systemic illnessChronic liver diseaseNephrotic syndromeGenetically determinedPheytoinCarbamzepine Effects Metabolism Increase in thyroid hormone increases the basal metabolic rate
Increased number and size of mitochondira
Increased oxygen use and ATP hydrolysis rate
Increased synthesis of respiratory chain enzymes
Increase in thyroid hormones increases thermogenesis
There is about a 30% temperature rise due to thyroid thermagonesis
Hyperthyroid- feel hot
Hypothyroid- feel cold
Increased thyroid hormone increases carbohyderate metabolism
Increased blood glucose due to stimulation of glycogenolysis and gluconeogenesis
Increased insulin-dependent glucose uptake into cells
Increased thyroid hormone increases lipid metabolism
Mobilise fats from adipose tissue
Increases fatty acid oxidation in tissues
Increase thyroid hormone increases protein metabolism
There is increased protein synthesis Growth GHRH production and secretion requires thyroid hormonesGlucocorticoid induced GHRH release also depends on thyroid hormonesGH and stomatomedins require the presence of thyroid hormone for activity Development It also has a role in foetal development and that of the neonatal brainMyelinogenesis and axonal growth require thyroid hormonesIt also has a role in normal CNS activity:Hypothyroidism- slow intellectual functionHyperthyroidism- Nervousness hyperkinesis and emotional lability Behaviour Permissive sympathomimetic action:
Thyroid hormones increase responsiveness to adrenaline and noradrenaline
This is done by increasing the number of receptors
Cardiovascular responsiveness increases with increased thyroid hormone
Increased force and rate of construction with increased thyroid hormone
Increased thyroid hormone means there is an increased likelihood of atrial fibrillation
As a result, in hyperthyroidism beta blockers are needed Influences Low temperature:
In babies and young children exposure to the cold stimulates the release of TRH thus stimulating TSH release and so T3 and T4 release
Stress:
Inhibits TRH and TSH release
Circadian rhythm:
Thyroid hormones are high late at nights and lowest in the day Carcinoma Thyroid cancers are the most common type of malignant endocrine tumourIt can affect younger individualsThere are various types of cancer affecting each of the cell types Papillary Cells Differentiated Their histological appearance and physiological characteristics are differentiated
Mostly take up iodine and secrete thyroglobulin
They are TSH driven
They have a better prognosis comapred with others
They are more common in females- 2 to 3 times
The rate in females increases between 15 and 40
In males there is a steady increase in the rate with age
They are uncommon in childhood
There is a strong association with exposure to radiation, including childhood radiotherapy
No association with diet, other malignancies, family history, smoking or other lifestyle factors
Best prognosis of all cancers except non-melanoma skin cancer
Treated with surgery, TRA and suppressive T4
Needs life long-follow up after treatment
Recurrent and metastatic disease still have a good prognosis if iodine uptake is still evident Papillary The majority of thyroid cancersThese are the most commonClasically spread via lymphaticsHaematogenous spread to lungs, bone, live and brainPrognosis usually good Follicular Second most commonIncidence higher in regios with iodine deficiencyTends to spread haematogenouslyGood prognosis Presentation Commonly:
Palapable nodule
Rarely:
Cough
Hoarseness
Dysphagia
5% with local (lymph node usually) or disseminated metastases
Some are chance findings on thyroidectomy Undifferentiated Anaplastic RareAccounts for 40% of thyroid cancer deathsUsually in the elderlyFemale to males 3:1Invasive- local and distantPoor prognosis- 5y survival <10%Treatment is usually palliative C-cells Medullary Usually present with neck lumpFrom parafollicular C cellsSecrete calcitonin75% sporadic25% inheritedFamilial MTCMEN2 Lymphocytes Lymphoma Causes Prognosis Increased chances of malignancy if:
New thyroid nodule at age x<20 or x>50
Male (cancers more common in women, increased malignancy in men)
Nodule increasing in size
Lesion >4cm in diameter
History of head and neck irradiation
Vocal cord palsy
Best prognosis with differentiated papillary cancers
Prognosis for differentiated follicular cancers is similar Diagnosis Ultrasound guided Fine Needle AspirateFine Needle Aspirate Cytology (FNAC) used to determine malignancy:Thy1-Non-diagnosticThy2-Non-neoplasticThy3-Follicular lesion/suspected follicular neoplasmThy4- Suspicious of malignancyThy5- Diagnostic of malignancyExcision biopsy of lymph nodeNo need for:Isotope thyroid scanCTMRIPre-operative laryngoscopy if vocal cord palsy suspected Treatment Extent of surgery controversial
Types:
Thyroid lobectomy (including isthmusectomy)
If low risk follicular or papillary <1cm diameter
Can also be used for minimally invasive follicular carcinoma
Used for low risk AMES patients
Near-total thyroidectomy
Differentiated cancer with extra-thyroid spread
Bilateral or multifocal differentiated thyroid cancer
Differentiated cancer with distant metastases or with nodal involvement
High risk AMES patients
Total thyroidectomy
Most cases
Differentiated cancer with extra-thyroid spread
Bilateral or multifocal differentiated thyroid cancer
Differentiated cancer with distant metastases or with nodal involvement
High risk AMES patients
Lymph node surgery:
Degree is controversial
Spread depends on histology
Used on those with macroscopic lymph node disease
Central lymph node clearance in follicular cancer
Often followed up with RAI/TRA if differentiated, if not, no role Recurrence Detected by rising Tg or imaging
Recurrence in cervival lymph nodes more common in papillary cancer
Haematogenous spread to lungs, bones and brain more common in follicular lesions
Recurrence rate at 30%
Difficulty with those with rising Tg but negative whole body iodine scan
Increasing evidence of role in PET to identify sites of disease in these patients Risk Stratification AMES system
A: Ages
M:Metastases
E: Extent of priamary tumour
S: Size of primary tumour
Low risk:
Younger patients (men <40, women <50)
Older patients with intrathyroidal papillary lesion/minimally invasice follicular lasion and primary tumour <5cm and no distant metastases 20y survival~ 99%
High risk:
Those with distant metastases
Extrathyroidal disease in those with papillary cancer
Significant capsular invasion in those with follicular carcinoma
Primary tumour >5cm in older patients
20y survival ~ 61% Thyroxine Patient discharged on T3 or T4Whole body iodine scan in those with sub-total or total thyroidectomy- usually 3-6m post-opT4 stopped 4 weeks priorT3 stopped 2 weeks priorrhTSH is an alternativeShould be TSH>20 (ensure that TSH is elevated)Then iodine givenIn lead lined room with mains sewerageHigher dose iodine capsule administeedDisposable cutlery, sheets and clothingLittle contact with nurses and visitorsDischarged when count rate <500cpm at 1mIf uptake >0.1% of ingested activity, throid remnant ablation (TRA) neededAblate residual tissue to destroy microfoci80% is excreted in the first 24hPost-therapy scan prior to dischargeDischarged on T3 or T4 depending on chances of requiring a further scanPermit predictively useful scanning in whole body scans and give high dose therapy if neededAllows for thyroglobulin to be used as a tumour markerOnly used/produced in throid tissueMeasured pre-op (as some do not secrete Tg)Reuslts are affected by thyroid status- raised TSH can increase Tg levelsAnti-thyroglobulin antibodies are meaure at the same time as the titre may affectthe interpretation of results Side Effects Side effects of high dose iodine:
Sialadentis (inflammation of salivary gland)
Sore throat
Long term effects:
Small increase in AML
No convincing evidence of increase in incidence of other solid tumours
No evidence of subsequent genetic abnormality or infertility Calcium Calcitonin is the marker for medullary tumours
Calcium
Calcium checked within 24h
Calcium replcement initiated if levels <2mmol/l
Intravous calcium for levles <1.8mmol  or if symptomatic Monitoring Goitre Adenoma Follicular cells
Benign
Discrete solitary mass
Encapsulated by cllagen cuff
Composed of neoplastic thyroid follicles
Follicles smaller but very proliferative An enlargement of the thyroid gland
Commonly due to lack of dietary iodine
Can be diffuse (all of gland- normal hormone production and release)
Can be multi-nodular
Parts of gland expand
Tumour
Colloid
Large follicles full of colloid) Hyperthyroidism Causes Grave's Autoimmune
Positive for thyrotropin receptor antibody (TRAB)
60-80% of all cases of hyperthyroidism
Found in a younger age group
Associated opthalmology and dermopathy (gritty eyes, exopthalmus, pretibial myxedema)
Possibly associated with other autoimmune disease- e.g. Pernicious anaemia Multinodular Goitre Found in older patients
F:M = 3:1
5% of cases are toxic (i.e. secrete hormone) Thyroiditis Inflammatory probelm
Lymphocytic infiltrate
May or may not be fibrosis
Associations:
Post-viral (subacute/De Quervain’s)
May be pain/tenderness of gland
Post partum
1/20 pregnancies
Reidel’s
Acute infections
Hashimoto’s (this is hypo with a goitre)
With scans, more iodine is not taken up (low uptake)
Can be mild to debilitating
Usually recover in 12 months Drugs Amiodarone
IF
Lithium Receptor Constitutive TSH receptor activation
McCune Albright Syndrome
TSH receptor pathway is abnormal
TSH is constantly secreted Toxic Adenoma
Carcinoma
Iodine toxicity
TSHoma
hCG
Teratoma
T4 (secretes T3) (rare) (TSH secreting tumour) (tumour with any cell type) (Thyrotocicosis factitia) Presentation Symptoms Signs Dysphagia
Dyspnoea
Discomfort
Heat intolerace
Sweaty
Pruritis
Anxious
Nervous
Insomnia
Full of energy -> Tiredness
Palpitations
Appetite increased
Weight decreased
Diarrhoea
Amenorrhoea
Muscle weakness
Thirst
Eye symptoms (Graves’)
Hair problems
Itching
Neck lump
Squint
Tremor Muscle wastingGoitreBruitTremorWarm moist skinOnycholysisPalmar erythemaTachycardia
Atrial FibrillationBrisk reflexesHair lossClubbingPretibial myxoedemaEye signs Investigations Laboratory Thyroid Function Tests:T4: highfT4: highT3: highfT3: highTSH: low (suppressed)Thyroid antibodies:Thyroid peroxidase (TPO):
positiveThyrotropin receptor antibody (TRAB):
positive Imaging Isotope Scan:
Size of thyroid
Activity
Hot/Cold nodules
Should be classic butterfly shape
Graves: Increased uptake, darker colour, wider
Multinodular: Not butterfly shaped, all over
Single nodule (thyroiditis): One spot
Ultrasound:
Cysts
Nodules
Helps decide if FNA needed
Fine Needle Aspirate:
Any nodule >1.5cm or obviously increasing in size
More so with cancer, sometimes multinodular goitre
Xray:
Thoracic inlet Complications Acute Chronic Crisis Features:
Unwell
Nausea
Vomiting
High fever
Arrythmia
Psychosis
Precipitants:
Surgery
Infection
Post partum
Contrast
MI/PTE
Management:
PTU 300mg /6h
Start KI 6h later
Beta blockers
Glucocorticoids
Cool
Chloropromazine to sedate
IV fluids
Consider antibiotics
Treat underlying cause Anaemia
Hypercalcaemia
Myopathy
Cardiomyopathy
Osteoporosis Eye Disease Inflammatory disorder
Rarely in euthyroid patients Pretibial myxoedema
Lesions
Bilateral
Firm
Non-pitting
Asymmetrical
Shiny pink- purple-brown
Plaques or nodules
Commonly onset after 1-2 years of disease
On lateral or anterior aspect of legs
May occur in thighs, shoulders, hands, forehead or any other skin surface
Occurs in areas of recent or prior trauma or skin graft donor sites Dermopathy Symptoms Dry painful eyes
Gritty
Inflamed
Blurred vision
Painful eye movements
Decreased colour Signs HyperaemiaChemosisTearsLid retractionLid lagExopthalmosProptosis (eyeballs bulge)Opthalmoplegia Management Stop smoking
Control thyroid
Moisturising eye drops/ointment
Tape eyes closed at night
Steroids
Local radiotherapy
Decompression surgery (into sinuses)
Corrective surgery (lids/muscles, once inflammation has settled)
Corrective prisms Treatment Drugs Beta Blockers Propanolol, Nadolol
Blocks peripheral action
No effect on thyroid
Often only treatment in thyroiditis with NSAIDs etc
Stop the conversion of T3 to T4 Iodides Potassium iodide, Lugol’s iodide
Temporary treatment
Suppress organification of iodine
May decrease bleeding
Beyond 14 days may increase risk of resistance hyperthyroidism
Used in those where carbimazole didn’t work
Iodides stop proteolysis of MIT and DIT to form T3 and T4 Thionamides Carbimazole, Propylthiouracil (PTU)
Prevents synthesis of thyroid hormones
Takes weeks to deplete thyroid store
Some immunosuppressive effect
PTU preferred in pregnancy
PTU stops conversion of T4 to T3
Not effective in thyroiditis Carbimazole Dosing:
Start at high dose (20-60mg)
Two systems:
Dose titration:
Reduce to minim dose to maintain euthyroid
Block and Replace:
Maintain high dose and add thyroxine as soon as they become underactive
Side Effects:
Nausea
Rashes
Arthralgia
Hepatitis
Myopathies
Bone Marrow Suppression- Agranulocytosis Radiotherapy For toxic multinodular goitre and for adenoma
For relapsed Graves’
Iodine is taken up by the thyroid exclusively
Burns out thyroid
Leads to hypothyroidism, usually within 12 months
Long term follow-up needed
No risk of teratogenesis/tumours/leukaemia in over 40 years of usage
Contamination to children avoided
Can exacerbate opthalmopathy Surgery Indications
Large gland
Radioiodine unlikely to work
Possible malignancy
Patient preference
Risks
Hypothyroidism
Hypocalcaemia (transient/permanent)
Damage to recurrent laryngeal nerve (leading to dysphonia)
Surgical complications (infection, pain, scar) Graves’: drugs cure, otherwise radioiodine/surgery, requiring long-term levothyroxine
MNG: drugs lifelong, otherwise radioiodine/surgery, requiring long-term levothyroxine Amiodarone Usually 150-200ug daily
High concentration of iodine
Long half life
Lipophylic
Thyroid problems in 50% of patients
2% develop thyrotoxicosis
13% develop hypothyroidism
Amiodarone induced thyrotoxicosis occurs frequently in areas of low iodine intake
Amiodarone induced hypothyroidism occurs frequently in areas of high iodine intake
More develop hypothyroidism than thyrotoxicosis
Promotes auto-immune response
With amiodarone induced thyrotoxicosis:
Looks like thyroiditis
Discontinue amiodarone if possible
Give prednisolone 40mg/day for 8-12weeks
If mixed form, add carbimazole or PTU maybe with potassium perchlorate Hypothyroidism Causes Presentation Diagnosis Complications Treatment Primary Secondary Thyroid
Goitrous
Chronic thyroiditis- Hashimoto’s
Hereditary biosynthetic defects
Maternally transmitted
Iodine deficiency
Drug induced
Non-Goitrous
Congenital developmental defect
Atrophic thyroiditis
Post-ablative
Postradiation (e.g. for lymphoma)
Self-limiting
Following withdrawal of suppressive thyroid therapy
Subacute thyroiditis and chronic thyroiditis with transient hypothyroidism
Post-partum thyroiditis Hashimoto's Most common
Autoimmune destruction of thyroid gland
Resulting in reduced hormone production
Chracterized by:
Thyroid peroxidase antibodies
T-cell inifiltrate and inflammation on microscopy
Progresses very slowly Drugs Amiodarone
Lithium
Iodides
Aminosalicylic acid
Aminoglutethimide
Pheybutazone
Thalidomide
Bexarotene Hypothalamus
Congenital
Infection (encephalitis)
Infiltration (sarcoid)
Malignancy (craniopharyngioma)
Pituitary
Panhypopituitarism
Trauma
Infection
Infiltration
Malignancy
Isolated TSH deficiency Coarse, sparse hair
Dull expressionless face
Peri-orbital puffiness
Pale cool skin that feels doughy
Cold intolerance
Pitting oedema
Associated with other autoimmune disease:
Vitiligo
Coeliac
Diabetes
Hypercarotenaemia
May also be causd by hyperlipidaemia, DM and porphyria CNS Decreased intellectual and motor activities
If in utero-baby not exposed to enough hormone
Depression, psychosis and others
Muscle stiffness and cramps
Peripheral neuropathy
Prolonged relaxation of deep tendon jerks
Carpal tunnel syndrome
Cerebellar ataxia
Encephalopathy
Decreased visual acuity Respiratory Deep hoarse voice
Macroglossia
Obstructive sleep apnoea Cardiovascular Reduced heart rate
Hyperlipidaemia
Cardiac dilation
Pericardial effusion
Worsening heart failure
Cardiac system slows down Gastrointestinal Decrease appetite
Weight gain
Constipation
Mega-colon and intestinal obstruction
Ascites Gynaecology Menorrhagia
Oligo/amenorrhoea
Hyperprolactinaemia
Increase TRH, Increased prolactin Primary Hypothyroidism Secondary Hypothyroidism Subclinical Hypothyroidism Low free T4
High TSH
Thyroid gland is failing
Pituitary gland responds and tries to stimulate more thyroid hormone production
Increase TSH in response to this
Fewer have overt than subclinical
Incidence higher in hispanics and african american populations
Higher incidence in areas of high iodine intake
Laboratory investigations:
Macrocytosis typical
Elevated creatinine kinase (affects muscle metabolism)
High LDL cholesterol
Hyponatramia
Reduced renal tubular water loss
Less commonly due to co-existing cortisol deficiency
Hyperprolactinaemia
Increased TRH causes increased prolactin secretion
Thyroid antibodies- anti TPO, anti-thyroglobulin, can even be TSH receptor antibody- rare Low free T4
Low TSH
This is rare
Pituitary gland fails and stops producing TSH
This results in a loss of stimulus to the thyroid
There is thus low T4
It is possible that the TSH and free T3 levels may still be normal
TSH is not a useful index of therapeutic success- will remain low if T4 therapy is given
Use T4 to monitor treatment High TSH
Low normal free T4
The thyroid gland begins to fail
The pituitary responds and stimulates more
TSH production to try to increase T4 production
It just manages to sustain levels within the normal limit
If TSH is less than 4.5:
Measure TSH every 6-12 months
If TSH is between 4.5-10:
And pregnant/contemplating pregnancy/symptomatic:
Levothyroxine tretment
And fT4 < 12
Measure TSH every 6-12 months
If TSH >10 / antibody positive/ other autoimmune disease / previous treatment of Graves’
Levothyroxine treatment Myxoedema Coma Causes Rare
Typically in elderly women with long standing but unrecognised and untreated hypothyroidism
Mortality up to 60% despite early diagnosis and treatment
Precipitated by:
Trauma
Hypothermia
Infection
Cardiac or cerebrovascular disease
Discontinuation of thyroxine replacement therapy
CNS depressant drugs
Anti-depressants
Anaesthetics
Sedatives
Opiates
Lithium
Amiodarone Manifestations Abnormal ECG
BradychardiaLow voltage complexes
Varying degrees of heart block
T wave inversion
Prolonged QT interval
Type II Respiratory Failure:
Hypoxia
Hypercarbia
Respiratory acidosis
Coexisting adrenal failure in 10% of patients
Primary
Secondary (to pituitary disease)
Suggested (due to hyponatraemia, hyperkalaemia, hypoglycaemia and raised urea) Management Intensive care
ABCDE
Monitor arrythmias
Blood cultures to check for infection
Fluid restriction if hyponatraemic
Broad spectrum Abx
IV hydrocortisone 50-100mg/6-8h
IV T4 300-500ug then 50-100ug
If inadequate T4 response add T3
Stop T3 and resume T4 once conscious Myxoedema (this is DIFFERENT TO PRETIBIAL MYOEDEMA):
Refers to severe hypothyroidism
Myxoedema coma
Pretibial myxoedema used to describe dermopathy with Graves’ Normal BMR should be restored gradually
Rapid restoration of metabolic rate may precipitate cardiac arrythmias
Younger patients start thyroxine at 50-100ug/day
Older patients start thyroxine at 25-50ug/day (adjust every 4 weeks)
Check TSH 2 months after any dose change
Once stable, check TSH every 12-18 months
Follow T4 measurements
Increase dose requirement by 25-50% in pregnancy (increased TBG)
No benefit of combining T4 and T3
T4 preferably taken prior to breakfast
T3 therapy rarely used, 20ug T3 = 100ug T4
T3 effects develop in a few hours and disappear within 1-2 days of discontinuing
TSH to measure success of treatment in primary but not secondary
Factor interfering with absorption: Coeliac
Atrophic gastritis in H. pylori infection
Drugs:
Omeprazole
Cholestyramine
Sucralfate
Aluminium hydroxide
Caclium carbonate
Iron
Rifampicin
Phenytoin
If failure to respond to treatment:
Check compliance
Check for coeliac antibodies
Check other malabsorption Parathyroid + Calcium Normal Calcium physiology
Calcium arrives at Calcium Sensing Receptors (CaSR) on the parathyroid glands
These secrete parathyroid hormone as a result
Parathyroid hormone causes the reabsorption of calcium by the kidneys and bones as well as the absorption of calcium by the intestines
This increases the serum calcium
Vitamin D physiology
Dehydro-cholesterol from the sun goes to the skin
Cholecalciferol (d3) is formed
This then becomes 25 (OH) Vitamin D
This then becomes 1,25 (OH) Vitamin D
This acts on the parathyroid, the kidney, the bones and the intestines allowing calcium absorption Physiology Abnormal Hypercalcaemia Presentation Stones, groans, bones and moans
Acute symptoms:
Thirsy
Polyuria
Dehydration
Confusion
Chronic symptoms:
Myopathy
Osteopaenia
Fractures
Depression
Hypertenstion
Abdominal pain
Pancratitis
Ulcers
Renal stones
Bone (especially back) pain - metastasis Causes Primary hyperparathyroidism (major)
Malignancy (major)
Drugs (Vitamin D, thiazides)
Granulomatous Disease (Sarcoid, TB)
Familial hypocalciuric hypercalcaemia
High turnover- bed ridden, thyrotoxic, Paget’s
Tertiary hyperparathyroidism

Mechanisms:
Metastatic bone destruction
PTHrp from solid tumour
Osteoclast activating factors Diagnosis Hypercalcaemia
Hyperalbuminuria
Elevated urea- Dehydration
Normal urea- Cuffed sample
Normal albumin
Elevated phosphate- Bone pathology
Elevated Alkaline phosphatase- Bone metastases, Sarcoidosis
Reduced Alkaline phosphatase- Myeloma, Vitamin D excess, Mild alkali syndrome
Normal/low phosphate- Primary/Tertiary hyperparathyroidism Familial Hypercalciuric
Hypercalcaemia Familial
Autosomal dominant
Usually benign/asymptomatic
Diagnosis:
Mild hypercalcaemia
Reduced urine calcium excretion
PTH marginally high (sometimes)
Genetic screening
Deactivating mutation in the CaSR Hyperparathyroidism Cause Cause is usually a small adenoma
Other causes:
Hyperplasia (typically involves all the glands)
May be associated with MEN I and MEN IIA
Carcinoma Diagnosis Calcium levels (high)
Alkaline phosphatase (high)
Serum PTH (high, or inappropriately normal)
Hypercalciuria (high urine calcium)
X-ray
CT scan
Isotope bone scan
Sestamibi scan (to determine if parathyroid ois the cause) Treatment Hyperparathyroid with mild hypercalcaemia
Not too problematic
No benefit of diet and drugs
Hyperparathyroid with significant hypercalcaemia
Fluids- 0.9% saline (4-6L/24h)
Loop diuretics once rehydrated (NOT thiazides)
Bisphosphonates- single dose lowers over several days
Steroids occasionally (including prednisolone for sarcoidosis)
Salmon calcitonin (rare)
Chemotherapy (may reduce in malignant disease)
Surgery
Not always required
Parathyroidectomy indicated with:
There is end organ damage
Bone disease- osteitis fibrosa et cystica- brown tumours, pepper pot skull
Gastric ulcers
Renal stones
Osteoporosis
Very high calcium >2.85
Under age 50
eGFR < 60mL/min Hypocalcaemia Presentation Paraesthesia (pins and needles)- fingers, toes, peri-oral
Muscle cramps
Tetany (muscle spasms)
Muscle weakness
Fatigue
Bronchospasm
Laryngospasm
Fits
Chovsteks sign (tapping over facial nerve- angle of mandible)
Trousseau sign (carpopedal spasm)
ECG showing QT prolongation Causes Hypoparathyroidism (major)
Vitamin D deficiency (major) - osteomalacia, rickets)
Chronic renal failure (major)
Hyperventilation
Metastases
Pancreatitis
Osteoblastic bone
Rhabdomyolysis (destruction of muscle cells) Complications A medical emergency
Give IV calcium gluconate
10ml 10% over 10 mins in 50ml saline/dextrose
Infusion of 10ml 10% in 100ml infusate at 50ml/h Vitamin D Deficiency Hypoparathyroidism Cause Usually post-operative (removal/damage)
Congenital Abscence
Di George's syndrome-absent thymus
Destruction
Surgery
Radiotherapy
Malignancy
Autoimmune
Hypomagnesaemia
Idiopathic
Familial
Associated with:
Primary adrenal insufficiency
Mucocutaneous candidiasis Similar Disease Treatment Calcium supplement (1-2g/day)
Vitamin D
Tablets:
1alphacalcidol (0.5-1 mcg)
Depot injection:
cholecalciferol 300,000 units/6 months Acute Hypocalcaemia Pseudohypoparathyroidism Hormone resistant syndrome
Looks like hypoparathyroidism
Genetic defect (dysfunction of G protein alpha subunit)
Low calcium
PTH high
Due to PTH resistance
Bone abnormalities (McCune Albright) - at risk of fracture
Obesity (short, round face and abdomen)
Subcutaneous calcification
Mental retardation
Brachdactyly (4th metacarpal) - short, same length as pinkie, classic sign Pseudo-pseudohypoparathyroidism Shows the clinical features of hypoparathyroidism
Normal calcium
Normal PTH
Patients can change between pseudo and pseudo-pseudo
Mild form of pseudo
Normal biochemistry Biochemistry Vitamin D comes from the sun (as D2) and diets (as D2 and D3)In the liver it is metabolised to 25(OH)- vitamin DIn the kidney it is metabolised to 1.25 (OH) vitamin DRickets and ostemalacia are the result of a vitamin D deficiency Causes Dietary deficiency
Malabsorption
Gastric surgery
Coeliac disease
Liver disease
Pancreatic failure
Chronic renal failure
Can present with:
Vitamin D deficiency (not being processed to 1,25 (OH) vitD
Secondary hyperparathyroidism (as a result of low calcium, due to low vitamin D)
May have high 25 (OH) VitD
Titrate treatment to PTH levels
Lack of sunlight
Can present with:
Low calcium
Low phosphate
High Alkaline phosphatase (trying to make bone)
Low vitamin D
High PTH
Drugs
Anticonvulsants Complications Deminerlisaition
Fractures
Osteomalacia
Rickets
Malignancy
Especially colon
Heart disease
Diabetes Osteomalacia Low calcium
Muscle wasting- proximal myopathy
Dental defects- caries, enamel
Bone tenderness
Rib fractures/deformity
Limb deformity
Pseudofractures (thinning of the bone)
Looser’s Zones Treatment Vitamin D
Vitamin D3 tablets
400-800IU/day after 3200IU per day for 3 weeks
Calcitriol
Alfacalcitriol
Combined calcium + Vitamin D
Note: replacing vitamin D after deficiency does not reduce risk of complication Paget's Pathogenesis This is abnormality of bone remodelling
There is thick but weak bone
Bone structure is disorganised and chaotic
It has a viral aetiology with a genetic predisposition Presentation Asymptomatic (seen on X-ray)
Bone pain
Fractures
Nerve compression
Deafness
Cord compression Diagnosis X ray
Raised alkaline phosphatase
Increased osteoblasts
Isotope Bone Scan Management Oral bisphosphonate
High dose for 2-6 months
Risendrodate
Alendrodate
Calcitonin
Sub cut
Nasal spray Osteoporosis Epidemiology Pathophysiology Aetiology Investigation Management Osteoporotic fractures are a major cause of pain disability and death
50% of hip fracture patients lose the ability to live independently
Around 20% of hip fracture patients die within a year of their fracture
1/2 women >50 develop osteoporosis
1/6 men >50 develop osteoporosis Progressive systemic skeletal disease
Low bone mass
Microarchitectural deterioration of bone tissue
Consequent increase in bone fragility and susceptibility to fracture
The human skeleton is made of:
80% cortical bone (dense, for stiffness and strength)
20% trabecular bone (porous, sponge like)- decreases in thickness and strength with age
Bone undergoes continual remodelling at distinct sites called remodelling units
About 10% of the adult skeleton is remodelled each year
Osteoclasts are used for activation and resorption- break down
Osteoblasts are used for reversal formation- build up Factors affecting peak bone mass:
Genetics
Body weight
Sex hormones
Diet
Exercise
Factors affecting bone loss:
Sex hormone deficiency
Body weight
Genetics
Diet
Immobility
Diseases
Drugs (e.g. glucocorticoids, aromatase inhibitors, glitazones)
Age
In time there is a decrease in trabecular thickness (30y)
Later the connections between vertical trabeculae will decrease in number (80y)
There will be a decrease in trabecular strength (80y)
Secondary causes:
Endocrine (hyperthyroidism, hyperparathyroidism, Cushing’s disease, Type 1 diabetes)
Gastrointestinal e.g. Coeliac disease, IBD, Chronic liver disease, Chronic pancreatitis)
Respiratory (e.g. CF, COPD)
Chronic kidney disease Fracture Complication Risk Factors
Previous fragility fractures
Current or previous frequent use of oral glucocorticosteroids
These reduce osteoblast activity and lifespan (less building)
The suppress the replication of osteoblast precursors (less building)
They reduce calcium absorption
Indirectly, they inhibit gonadal and adrenal steroid production
There is a dose dependent fracture risk, but no safe dose
There is a rapid loss of BMD (bone mineral density)
History of falls
Family history of hip fracture
Other secondary causes of osteoporosis
Low BMI
Smoking
High alcohol intake
After a Colles fracture there is risk of double hip fracture
After one hip fracture there is increased risk to the other hip Bone mineral density:
Predicts risk independently of other factors
DEXA scans are the most widely used method of measuring bone density
Measure by number of standard deviations from the mean
T score- young adult female population mean
Z score- age matched- female population mean
Normal BMD is within 1 standard deviation
Osteopenia 1<x<2.5 deviations below T
Osteoporosis >2.5 deviations below T
If they are younger than 20, only Z score is reported
As T score falls, fracture risk increases
Difficulty with scanning:
Hip
Previous fracture
Difficulty positioning
Spine
Degenerative changes
Obesity
Wrist
Inflammatory arthropathy
Previous fracture
U+Es
Liver function tests (autoimmune liver disease)
TSH
FBC
Testosterone (in men) Lifestyle Exercise:
High intensity strength trainingLow impact weight bearing exercise (standing, 1 foot on the floor)Avoidance of excess alcoholAvoidance of smokingFall preventionDiet:Post menopausal women to increase dietary calcium intake from 700mg to 1000Can also use non-dairy sources- cerela, bread, bony fish, nuts, greens, beans Pharmaceutical Treat after T score is <= -2.5If ongoing steroid is needed, treat with T score < -1.5 (osteopenic) Supplements Mainly for post-menopausal women unable to achieve 1000mg from dietVitamin D not required for people <65 years with adequate sun exposure10 microgram vitamin D supplement for over 65 yo20 microgram vitamin D supplement for frail, elderly, housebound women Bisphosphonates Anti-resorptive agents
Alendronate, Risendronate
Prevent bone loss at all sites vulnerable to osteoporosis
Reduce risk of hip and spine fracture
Taken first in morning on empty stomach
Common side effect of GI irritation
Adsorb onto bone within the matrix
Ingested by osteoclasts, kill osteoclasts
Filling of resorption sites by new bone increases BMD by 5-8%
If oral bisphosphonates not tolerated:
Zoledronate (iv) Hormone Replacement Selective estrogen receptor modulators (SERMs)
e.g. Raloxifene
Testosterone Strontium Ranelate Anti-resorptive agent
2nd/3rd line agent as fracture risk reduction is less than with bisphosphonates
Contraindicated with thromboembolic disease Teriparatide Recombinant synthetic parathyroid hormone
Stimulates bone growth rather than reducing bone loss
Given to those:
Over 65 with T score <-4
Over 65 with a T score <-3.5 and > 2 fractures
Age 55-64 with T score <-4 and >2 fractures
Self-administered once daily subcut
Treatment for 18-24 months Denosumab Fully human monoclonal antibody
Targets and binds with high specificity to RANKL
Inhibits development and activity of osteoclasts
Decreased bone resorption and increased bone density
Subcut injection 6 monthly
Not with eczema or cellulitis
No increase risk of cancer or infection
Expensive (Teriparatide is more expensive)
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