Endocrinology Flashcards
Give the anterior pituitary hormones and define hypopituitarism, differentiating between primary and secondary.
The anterior pituitary/ adenohypophysis arises from there diencephalon therefore neural tissue.
Hormones are FSH/LH, prolactin, GH, TSH, ACTH (adrenocorticotropic hormone)
Disorder in pituitary gland results in secondary endocrine gland disease.
Disorder in endocrine gland results in primary endocrine gland disease.
Hypopituitarism is the decreased production of all anterior pituitary hormones (panhypopituitarism) or specific hormones
Can be congenital (rare) or acquired
Explain congenital and acquired panhypopituitarism.
Congenital
Rare
Usually due to mutations of transcription factor genes needed for normal anterior pituitary development
e.g. PROP1 mutation - deficient in GH and at least 1 more anterior pituitary hormone.
Short stature
Hypoplastic anterior pituitary gland on MRI
Acquired
-Tumours: hypothalamic (craniopharyngiomas - squash anterior pituitary), pituitary (adenomas, metastases, cysts)
-Radiation: hypothalamic/pituitary damage
Gh most vulnerable, TSH relatively resistant
-Infection e.g. meningitis
-Traumatic brain injury
-Infiltrative disease - often involves pituitary stalk .e.g. neurosarcoidosis
-Inflammatory (hypophysitis) - autoimmune destruction of pituitary
-Pituitary apoplexy - haemorrhage (or less commonly infarction)
-Peri-partum infarction (Sheehan’s syndrome)
Describe the presentation of panhypopituitarism.
Occasionally called Simmond’s disease
Symptoms due to deficient hormones
FSH/LH secondary hypogonadism
Reduced libido
Secondary amenorrhoea
Erectile dysfunction
ACTH - secondary hypoadrenalism (cortisol deficiency)
Fatigue
TSH - secondary hypothyroidism
Fatigue
Sheehan’s syndrome
Specifically describes post-partum hypopituitarism secondary to hypotension (post partum haemorrhage - PPH)
Less common in developed countries
Anterior pituitary enlarges in pregnancy (lactotroph hyperplasia)
PPH leads to pituitary infarction = pituitary gland becomes bigger because lactrotrophs have become bigger; not enough blood flow from hypophysial artery, gland = infarction
Lethargy, anorexia, weight loss = TSH/ACTH/GH deficiency
Failure of lactation = PRL definiency (prolactin)
Failure to resume menses (periods) post-delivery
Posterior pituitary usually not affected
What is meant by pituitary apoplexy?
Intra-pituitary haemorrhage or (less commonly) infarction
Often dramatic presentation in patients with pre-existing pituitary tumours (benign adenomas) problem if enlargement
May be first presentation of a pituitary adenoma
Can be precipitated by anti-coagulants as blood thinned in coronary artery…
Severe sudden onset headache - bleed in APG, stretch in dura
Visual field defect - compressed optic chiasm, bitemporal hemianopia - lose outer fields of vision
Cavernous sinus involvement may lead to diplopia (IV, VI), ptosis (III), can squash cranial nerves, no gap between chiasm and adenoma
Explain the diagnosis of hypopituitarism.
Biochemical diagnosis 1) Basal plasma concentrations of pituitary or target endocrine gland hormones - interpretation may be limited -undetectable cortisol - what time of day? T4- circulating t1/2 6 days FSH/LH - cyclical GH/ACTH - pulsatile All fluctuating
2) stimulated (dynamic) pituitary function tests
-ACTH & GH = stress hormones
-hypoglycaemia (<2.2mM) = stress
-insulin-induced hypoglycaemia stimulates
GH release
ACTH release (cortisol measured because ACTH difficult to measure)
GH and ACTH released to increase blood glucose
-TRH stimulates TSH release
-GnRH stimulates FSH and LH release
Radiological diagnosis
Pituitary MRI
May reveal specific pituitary pathology e.g. haemorrhage (apoplexy), adenoma
Empty sella (sella turcica)- thin rim of pituitary tissue
Explain hormone replacement therapy in hypopituitarism.
Deficient hormone: replacement: check
ACTH: hydrocortison: serum cortisol
TSH: tyroxine: serum free T4
Women LH/FSH: HRT (E2 - oestrogen plus progesterone, can give endometrial cancer if unopposed oestrogen, not in balance with progesterone): symptom improvement, withdrawal bleeds (like periods)
Men LH/FSH: testosterone - gel patch, injection: symptom improvement, serum testosterone
GH: GH: IGF1, growth chart (children)
Not same as not pulsatile but constant
Explain growth hormone deficiency using growth axis.
State the causes of short stature.
List the causes of acquired GH deficiency in adults.
Somatotropin deficiency in children results in short stature (=2 SDs < mean height for children of that age and sex)
In adults, effects less clear
Causes
Genetic: Down’s syndrome, Turner’s syndrome, Prader Willi syndrome
Emotional deprivation: trauma
Systemic disease: cystic fibrosis, rheumatoid arthritis
Malnutrition
Malabsorption: coeliac disease - gut can’t absorb food properly, autoimmune problem when gluten intake (gluten intolerance)
Endocrine disorders: Cushing’s syndrome, hypothyroidism, GH deficiency, poorly controlled T1DM
Skeletal dysphasia: achondroplasia, osteogenesis imperfecta
Causes of acquired GH deficiency in adults: Trauma Pituitary tumour Pituitary surgery Cranial radiotherapy
Explain different conditions of short stature.
Prader Willi Syndrome - GH deficiency secondary to hypothalamic dysfunction
Dwarfism
Achondroplasia - mutation in fibroblast growth factor receptor 3 (FGF3), abnormality in growth plate chondrocytes (impaired linear growth), average size trunk, short arms and legs
Pituitary dwarfism - childhood GH deficiency
Larson dwarfism - high incidence in Ecuador, mutation in GH receptor, IGF-1 treatment in childhood can increase height
How is short stature diagnosed?
How is GH deficiency diagnosed?
Mid-parental height: a predicted height based on father and mother’s height, monitor height using chart
GH is random so little use, it’s pulsatile so instead use provocative challenge (stimulation test/ GH provocation test):
GNRH + arginine (marmite) i.v. In combination more effective than alone
Insulin i.v. Via hypoglycaemia, GH increases with insulin
Glucagon i.m. - vomit, stress??
Exercise - e.g. 10 min step climbing
Measure plasma GH at specific time points before and after
Explain GH treatment and the signs and symptoms of GH deficiency in adults.
Reduced lean mass, increased adiposity, increased waist:hip ratio
Reduced muscle strength and bulk, reduced exercise performance
Decreased plasma HDL-cholesterol and raised LDL-cholesterol
Impaired ‘psychological well being’ and reduced QoL
GH therapy
Preparation: human recombinant GH (somatotropin)
Administration: daily, subcutaneous injection, monitor clinical response and adjust dose to IGF-1
Benefits:
Improved body composition - decreased waist circumference, less visceral fat
Improved muscle strength and exercise capacity
More favourable lipid profile: higher HDL, lower LDL-cholesterol
Increased bone mineral density
Improved psychological well being and QoL
Risks
Increased susceptibility to cancer how’re currently no data to support
Expensive
What is meant by hyperpituitarism?
List some causes and consequences.
Excess production of adenohypophysial hormones.
Usually due to isolated pituitary tumours but can also be ectopic (from non-endocrine tissue) in origin - neuroendocrine tumours full of peptide hormones like AP hormones but elsewhere in body.
Can quite often be associated with visual field and other (e.g. cranial nerve) defects - pituitary tumour (suprasellar tumour) compressing optic chiasm -> bitemporal hemianopia (loss of peripheral vision)
As well as endocrine-related signs and symptoms
Excess -> result in
ACTH (corticotrophin) -> Cushing’s disease (too much cortisol)
TSH (thyrotrophin) -> thyrotoxicosis -
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably
Gonadotropin (LH and FSH) -> precocious puberty in children
Prolactin -> hyperprolactinaemia
GH -> gigantism, acromegaly
Explain hyperprolactineamia.
Describe the regulation of prolactin secretion.
Causes:
Physiological: pregnancy, breastfeeding
Pathological: prolactinoma - tumour of lactotrophs - most common functioning pituitary tumour
High prolactin suppresses GnRH pulsatility
Hyperprolactineamia due to pituitary adenoma
Women:
Galactorrhoea (milk production outside pregnancy)
Secondary amenorrhoea (or oligomenorrhoea)
Loss of libido
Infertility
Men: Galactorrhoea uncommon (since appropriate steroid background usually inadequate) Loss of libido Erectile dysfunction Infertility
Prolactin is the only hormone which has regulatory inhibition - dopamine.
D2 receptors are found on anterior lactotroph. Dopamine from hypothalamic dopaminergic neurones inhibits prolactin secretion through dopamine binding to these receptors. D2 receptor agonists have same effect.
Describe the treatment of hyperprolactinaemia and explain the side effects of the use of dopamine receptor agonists.
Medical treatment is 1st line
-dopamine receptor agonists (D2): decrease prolactin secretion, reduce tumour size
e.g. bromocriptine, cabergoline
oral administration
Side effects Nausea and vomiting Postural hypotension Dyskinesias Depression Impulse control disorder e.g. pathological gambling, hypersexuality, compulsive eating: due to dopmaine receptors being found elsewhere in the brain e.g. reward system - mesolimbic system
Explain the difference between gigantism and acromegaly.
Excess growth hormone in childhood:
gigantism - grow taller, no epiphyseal growth plate closure
In adults:
acromegaly - fusion of growth plate, soft tissue grows.
Explain acromegaly including clinical features and metabolic effects.
Insidious on onset (proceeding in a gradual, subtle way, but with very harmful effects)
Signs and symptoms progress gradually
(can remain undiagnosed for many years) - old photos can be used for diagnosis
Untreated, excess GH is associated with
increased morbidity and mortality: cardiovascular, respiratory (increased size of tongue), cancer
Growth in: • periosteal bone • cartilage • fibrous tissue • connective tissue • internal organs (cardiomegaly, splenomegaly, hepatomegaly, etc.)
Clinical features
Hallmarks:
-excessive sweating (hyperhidrosis) - hands
-headache
- enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features - rings/shoes don’t fit
- enlarged tongue (macroglossia)
- mandible grows causing protrusion of lower jaw (prognathism) - lantern jaw, gaps between teeth
- carpal tunnel syndrome (median nerve compression) in wrist, pins and needles in hand
- barrel chest, kyphosis
Metabolic effects
Excess growth hormone (made in response to hypoglycaemia, stress) -> increased endogenous glucose uptake -> increased insulin production = increased insulin resistance -> impaired glucose tolerance -> diabetes mellitus
Describe the complications of acromegaly.
Describe the relationship to prolactin.
Complications:
-Obstructive sleep apnoea
Bone and soft-tissue changes surrounding the upper airway lead to narrowing and subsequent collapse during sleep.
-Hypertension
Direct effects of GH and/ or IGF-1 on vascular tree
GH mediated renal sodium absorption
-Cardiomyopathy
Hypertension, DM, direct toxic effects of excess GH on myocardium
-Increased risk of cancer
Colonic polyps, regular screening with colonoscopy
Prolactin is often high in acromegaly – may
reflect tumour secreting GH AND prolactin
Hyperprolactinaemia will cause secondary
hypogonadism (see clinical features of
hyperprolactinaemia)
Describe the diagnosis and treatment of acromegaly.
Describe somatostatin analogues.
GH pulsatile – so random measurement
unhelpful
Elevated serum IGF-1
Failed suppression (‘paradoxical rise’) of GH
following oral glucose load – oral glucose
tolerance test
Treatment
Surgery (trans-sphenoidal) - 1st line (up the nose)
Medical:
-somatostatin analogues e.g. octreotide (shrink tumour before operation)
-dopamine agonists e.g. cabergoline (GH secreting pituitary tumours frequently express D2 receptors)
Radiotherapy
Somatostatin analogues
‘Endocrine cyanide’
Injection: sc (short acting) or monthly depot
GI side effects common eg nausea,
diarrhoea, gallstones can occur
Reduces GH secretion and tumour size
Pre-treatment before surgery may make
resection easier
Use post-operatively if not cured or whilst
waiting for radiotherapy to take effect (slow)
Describe the hypothalamo-neurohypophysial system.
Diagram
Describe the effects of vasopressin.
Principle effect is that it’s an anti-diuretic - increases water absorption from renal cortical and medullary collecting ducts via V2 receptors
Vasopressin also known as ADH - anti-diuretic hormone
Diuresis = increase urine production
Explain how vasopressin release is regulated.
Osmoreceptors (neurones) located in organum vasculosum, project to PVN and SON (supraoptic nucleus)
Very sensitive to changes in extracellular osmolality - increase in Na+ EC increases EC osmolality
When increase in osmolality, osmoreceptor shrinks -> increased osmoreceptor firing -> vasopressin release from hypothalamic PVN and SON neurones -> increased water absorption from renal collecting ducts -> reduced urine volume, increase in urine osmolality/ reduction in serum osmolality.
Describe diabetes insipidus.
Cranial (or central): absence or lack of circulating vasopressin
Aetiology:
acquired (more common)
damage to neurohypophysial system
•Traumatic brain injury
•Pituitary surgery
•Pituitary tumours, craniopharyngioma
•Metastasis to the pituitary gland eg breast
•Granulomatous infiltration of median eminence
eg TB, sarcoidosis - vasopressin can’t pass through pituitary stalk to posterior pituitary
Congenital - rare
Nephrogenic: end-organ (kidneys) resistance to vasopressin Congenital - rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel) Acquired - Drugs (e.g. lithium) toxicity
Signs and symptoms:
• Large volumes of urine (polyuria)
• Urine very dilute (hypo-osmolar)
• Thirst and increased drinking (polydipsia)
• Dehydration (and consequences) if fluid
intake not maintained - can lead to DEATH
• Possible disruption to sleep with associated problems
Diagram
Biochemical features: Hypernatraemia Raised urea Increased plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality
Describe psychogenic polydipsia/ primary polydipsia.
Most frequently seen in psychiatric patients –
aetiology unclear, may reflect anti-cholinergic
effects of medication – ‘dry mouth’
Can be in patients told to ‘drink plenty’ by
healthcare professionals
Excess fluid intake (polydipsia) and excess
urine output (polyuria) – BUT unlike DI,
ability to secrete vasopressin in response to
osmotic stimuli is preserved
Biochemical features: Mild hyponatraemia – excess water intake Low plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality
State differences between DI and PP.
Diagram
Explain the treatment of diabetes insipidus.
When vasopressin is given exogenously, all the vasopressin receptors will be activated (V1 - liver, vascular/non-vascular smooth muscle, CNS` and V2 - kidneys, endothelial cells) therefore selective vasopressin receptor peptidergic agonists are used:
V1 - terlipressin
V2- desmopressin (DDAVP)
Desmopressin
Administration
– Nasally
– Orally
– SC - injection because nose may be inflamed from surgery up the nose
• Reduction in urine volume and
concentration in cranial DI
• CARE – to tell patient starting this NOT to
continue drinking large amounts of fluid –
risk of hyponatraemia
Treatment of nephrogenic:
Thiazides e.g. bendroflumethiazide
• Possible mechanism
– Inhibits Na+/Cl- transport in distal convoluted tubule
(→ diuretic effect)
– Volume depletion
– Compensatory increase in Na+ reabsorption from the
proximal tubule (plus small decrease in GFR, etc.)
– Increased proximal water reabsorption
– Decreased fluid reaches collecting duct
– Reduced urine volume
Explain syndrome of inappropriate ADH (SIADH).
ADH (anti-diuretic hormone) = vasopressin
By definition
the plasma vasopressin concentration
is inappropriately high for
the existing plasma osmolality e.g. due to neuroendocrine tumour in gut.
Diagram
Signs and symptoms:
Signs:
• raised urine osmolality, decreased urine
volume (initially)
• decreased p[Na+] (HYPONATRAEMIA)
mainly due to increased water reabsorption
Symptoms •can be symptomless •however if p[Na+] <120 mM: generalised weakness, poor mental function, nausea •if p[Na+] <110 mM: CONFUSION leading to COMA and ultimately DEATH
Causes • CNS – SAH, stroke, tumour, TBI • Pulmonary disease – Pneumonia, bronchiectasis • Malignancy – Lung (small cell) • Drug-related – Carbamazepine, SSRI • Idiopathic
Chest x-ray and CT scan can be done, head/ lung pathology
Describe treatment SIADH.
Appropriate treatment (e.g. surgery for tumour) if known
To reduce immediate concern, i.e. hyponatraemia
1. Immediate: fluid restriction - all water reabsorbed so might as well reduce
2. Longer-term: use drugs which prevent vasopressin
action in kidneys
e.g. induce nephrogenic DI ie reduce renal water
reabsorption - demeclocyline
inhibit action of ADH - V2 receptor antagonists
Vaptans
– Non-competitive V2 receptor antagonists
– Inhibit aquaporin2 synthesis and transport to
collecting duct apical membrane, preventing
renal water reabsorption
– Aquaresis – solute-sparing (prevent Na+ loss) renal excretion of
water, contrast with diuretics (diuresis) which
produce simultaneous electrolyte loss
– Licensed in the UK for treatment of
hyponatraemia associated with SIADH
– Very expensive – limits their current use
Explain the hypothalamic–pituitary–thyroid axis and the involvement of iodine in the production of thyroxine.
Diagram 1) Uptake of iodide - active transport 2) Iodination 3) Coupling reaction: storage in colloid 4) Endocytosis & secretion thyroperoxidase + h2o2?? peroxidase transaminase?? Healthy adult thyroid gland secretes both T4 and T3. · Tetraiodothyronine (Thyroxine, T4)
= a prohormone
converted by deiodinase enzyme into the more active
metabolite tri-iodothyronine (T3)
· Circulating T3
· 80% from deiodination of T4
· 20% from direct thyroidal secretion.
· T3 provides almost all the thyroid hormone activity in
target cells.
Describe primary hypothyroidism.
Also known as myxoedema.
Autoimmune damage to the thyroid
Thyroxine levels decline
TSH levels climb
Symptoms Deepening voice Depression and tiredness Cold intolerance Weight gain with reduced appetite Constipation Bradycardia
What is hormone replacement therapy, describing the clinical uses.
Levothyroxine sodium thyroxine sodium; thyroxine; Tetraiodothyronine; T4 usually the drug of choice
Liothyronine sodium; triiodothyronine; T3 - Less commonly used
Clinical uses of levothyroxine sodium (synthetic thyroxine)
1) Primary hypothyroidism eg autoimmune,
iatrogenic (caused by medical examination/treatment) - post-thyroidectomy, post-radioactive
iodine
Oral administration
TSH used as guidance for thyroxine dose - aim to
suppress TSH into the reference range
2) Secondary hypothyroidism – eg pituitary tumour,
post-pituitary surgery or radiotherapy
Oral administration.
TSH low due to anterior pituitary failure, so can’t use TSH as a guide to dose.
Aim for fT4 (free, not protein bound-active form) middle of reference range
Clinical use of liothyronine (synthetic trio-iodothyronine)
Myxoedema coma - a VERY RARE complication of hypothyroidism
iv initially – as onset of action faster than T4 then oral when possible
T3 very potent and acts more quickly, then oral T4
Expensive and very little evidence to support
Describe combined thyroid hormone replacement.
T4 = prohormone, converted by deiodinase action to T3
Combination T4/T3 – some reported improvement in well-being
Complicated by symptoms of ‘toxicity’ – palpitations, tremor, anxiety - often combination treatment suppresses TSH
Describe the pharmacokinetics of thyroid drugs.
i) active orally
ii) Half-life long
Levothyroxine (T4) plasma half life of 6 days
Liothyronine (T3) plasma half life 2.5 days
Approximately 99.97% of circulating T4 and 99.7%
of circulating T3 are bound to plasma proteins,
mainly thyroxine binding globulin (TBG) (NB do
NOT confuse with thyroglobulin)
Only the free (unbound) fraction of thyroid hormone is available to the tissues
- plasma binding proteins increase in pregnancy and on
prolonged treatment with oestrogens and
phenothiazines
- TBG falls with malnutrition, liver disease
- certain co-administered drugs (e.g. phenytoin,
salicylates) compete for protein binding sites.
Explain Graves’ Disease.
Autoimmune
Antibodies bind to and stimulate the TSH receptor in the thyroid and stimulates to make more thyroxine
Cause goitre (smooth) and hyperthyroidism
(Hyperthyroidism causes lid lag) - two nerves to eyes, one nerve under sympathetic control, T4 makes B receptors more sensitive to adrenaline e.g. HR increases, palpitation, tremor
Signs and symptoms
Exophthalmos - Other antibodies bind to muscles
behind the eye and cause
exophthalmos, eyelid held open by adrenaline, eyes pushed forward by growth factors.
Palpitation
Goitre -enlargement of thyroid gland, allover overactive, antibodies bind allover, follicular cells grow, feels smooth
Tremor
Pretibial myxoedema - Other antibodies cause pretibial
myxoedema (hypertrophy), The swelling (non-pitting) that occurs on the shins of patients with Graves’
disease: growth of soft tissue.
Overall antibodies causes:
1) thyroxine increases
2) myxoedema
3) exolphthalmos
Diagnosis
1) measure antibodies
2) radioactive iodine given and scanned - thyroid scan
3) smooth goitre/ eyes
Explain Plummer’s disease.
Toxic nodular goitre NOT autoimmune Benign adenoma that is overactive at making thyroxine. NO pretibial myxoedema NO exophthalmos
Large amount of thyroxine decreases TSH so normal thyroid shrinks.
Lump on one side - toxic nodule, one clone of thyroid cells grown to form benign tumour, follicular cells produce thyroxine.
What are the effects of thyroxine on the sympathetic nervous system.
Sensitises beta adrenoceptors to ambient levels of adrenaline and noradrenaline.
Thus there is apparent sympathetic activation
Tachycardia, palpitations, tremor in hands, lid lag
What are the signs and symptoms of hyperthyroidism.
Weight loss despite increased appetite Breathlessness, palpitations, tachycardia Sweating Heat intolerance Diarrhoea Lid lag and other sympathetic features
What is meant by a thyroid storm.
Medical emergency : 50% mortality untreated Blood results confirm hyperthyroidism Hyperpyrexia > 41oC accelerated tachycardia / arrhythmia cardiac failure delirium / frank psychosis - mental confusion hepatocellular dysfunction; jaundice Needs aggressive treatment
Explain viral (de Quarvain’s) thyroiditis
Painful dysphagia
Hyperthyroidism
Pyrexia (raised body temperature)
Raised ESR (erythrocyte sedimentation rate)
Virus attacks thyroid gland causing pain and tenderness
Thyroid stops making thyroxine and makes viruses instead
Thus no iodine uptake (ZERO)
Radioiodine uptake zero
Stored thyroxine released thus toxic with zero uptake
Four weeks later, stored thyroxine exhausted, so hypothyroid.
After a further month, resolution occurs (like in all viral diseases).
Patient then becomes euthyroid again.
State the treatment options available for hyperthyroidism.
Surgery (thyroidectomy) Radioiodine Drugs: 1. The thionamides (thiourylenes; anti-thyroid drugs) - propylthiouracil (PTU) - carbimazole (CBZ) 2. Potassium Iodide 3. Radioiodine 4. β-blockers First three drugs reduce thyroid hormone synthesis, B blockers help with symptoms.
Describe the use of thionamides.
i) Used as daily treatment of hyperthyroid conditions:
Graves’
Toxic thyroid nodule/toxic multinodular goitre
ii) treatment prior to surgery - decrease heart rate
iii) reduction of symptoms while waiting for
radioactive iodine to act
Mechanisms of action:
i) inhibition of thyroid peroxidase and hence T3/4 synthesis and secretion - biochemical effects takes hours, clinical effects takes weeks
Treatment regimen may include propranolol – rapidly reduces tremor, tachycardia - given in first few weeks before clinical effect
ii) may suppress antibody production in
Graves’ disease
iii) reduces conversion of T4 to T3 in peripheral tissues (PTU)
Unwanted actions Agranulocytosis (usually reduction in neutrophils) - rare and reversible on withdrawal of drug - high temperature, sore throat, check blood count rashes (relatively common)
Pharmacokinetics
i) orally active
ii) carbimazole is a pro-drug which first has to be converted to methimazole
iii) cross placenta, secreted in breastmilk (PTU
What is the role of b blockers in
thyrotoxicosis?
Several weeks for ATDs - anti-thyroid drugs to have clinical
effects eg reduced tremor, slower heart rate, less anxiety
NON-selective (ie b1 & b2) b blocker eg propranolol achieves these effects in the interim (less so with selective b1 blockers eg atenolol - more specific like for heart)
Explain the use of potassium iodide.
doses at least 30 times the average daily requirement
preparation for hyperthyroid patients for surgery
severe thyrotoxic crisis (thyroid storm) - rapid onset
Mechanisms of action:
1) inhibits iodination of thyroglobulin
2) inhibits h202 generation and thyroperoxidase
Inhibition of thyroid hormone synthesis & secretion
WOLFF–CHAIKOFF effect - presumed autoregulatory effect
Large doses of iodine shuts down thyroid gland
Hyperthyroid symptoms reduce within 1-2 says
Vascularity and size of gland reduce within 10-14 days.
Unwanted actions:
Allergic reaction .e.g rashes, fever, angio-oedema
Pharmacokinetics Given orally (Lugol's solution; aqueous iodine), maximum effects after 10 days continuous administration.
Explain the use of radioiodine.
131I given at high doses.
Treats hyperthyroidism (Graves’, toxic nodular disease), thyroid cancer
Accumulates in colloid; emits B particles, destroying follicular cells of thyroid gland, T4 decreases, TSH increases
Pharmacokinetics: Discontinue anti-thyroid drugs 7-10 days before radioiodine treatment because otherwise difficult to control Administer as a single oral dose Graves’ disease: approx 500 MBq Thyroid cancer: circa 3,000 MBq Radioactive half life of 8 days Radioactivity negligible after 2 months
Cautions:
Avoid close contact with small children for several weeks after receiving radioiodine.
Contra-indicated in pregnancy and
breast feeding, crosses placenta
Very low tracer doses of radioiodine 131I/ technetium 99
pertechnetate uses in tests of thyroid gland pathology .e.g. toxic nodule, thyroiditis vs Graves’
Administer i.v.
Negliglible cytotoxicity
Describe the clinical features of Cushing’s.
Hypersecretion of hormones of the adrenal cortex Cushing’s syndrome = excess cortisol
Too much cortisol
Centripetal obesity - cortisol synthesises fat
Moon face and buffalo hump
Proximal myopathy
Hypertension and hyperkalaemia
Red striae, thin skin and bruising - break down protein causing stretch marks
List the causes of Cushing’s.
Taking too many steroids Endogenous: Pituitary dependent Cushing's disease Ectopic ACTH from lung cancer Adrenal adenoma secreting cortisol
What are investigations to determine the cause of Cushing’s.
24 hour urine collection for urinary free cortisol
Blood diurnal cortisol levels (cortisol usually highest at 9am and lowest at midnight, if asleep)
Low dose dexamethasone suppression test - ACTH decreases, cortisol decreases, if high = Cushing’s
-0.5 mg 6 hourly for 48 hrs
-Dexamethasone = artificial steroid
-Normals will suppress cortisol to zero
-Any cause of Cushing’s will fail to
suppress
Cushing’s = Basal (9am) cortisol 800 nM
End of LDDST: 680 nM
Describe the treatment of Cushing’s.
State the drugs used in the treatment for Cushing’s.
Depends on cause
Pituitary surgery (transsphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
Inhibitors of steroid biosynthesis: metyrapone; ketoconazole
Explain the use of metyrapone.
Inhibition of 11b-hydroxylase
11-deoxycorticosterone –> corticosterone (blocked)
11-deoxycortisol –> cortisol (blocked)
•cortisol synthesis blocked
•ACTH secretion increased
•plasma deoxycortisol increased
steroid synthesis in the zona fasciculata [and
reticularis] is arrested at the 11-deoxycortisol stage
Uses:
Control of Cushing’s syndrome prior to surgery
- adjust dose (oral) according to cortisol (aim for
mean serum cortisol 150-300 nmol/L)
- improves patient’s symptoms and promotes
better post-op recovery (better wound healing,
less infection etc)
Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)
Unwanted actions:
`increased adrenal androgen production HIRSUTISM in women
deoxycorticosterone accumulates in z. glomerulosa; it
has aldosterone-like (mineralocorticoid) activity,
leading to salt retention and hypertension.
Explain the use of ketoconazole.
main use as an antifungal agent – although withdrawn in 2013 due to risk of hepatotoxicity at higher concentrations, inhibits steroidogenesis – off-label use in Cushing’s syndrome Blocks production of glucocorticoids, mineralocorticoids & sex steroids through blocking conversion of cholesterol to pregnenolone
Uses
Cushing’s syndrome - treatment and control of symptoms prior to surgery
Orally active
Unwanted actions
Liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically.
Describe Conn’s syndrome including its diagnosis.
Benign adrenal cortical tumour (zona glomerulosa)
Aldosterone in excess
Hypertension and hypokalaemia
Diagnosis
Primary hyperaldosteronism
Renin - angiotensin system should be suppressed (exclude secondary hyperaldosteronism)
Describe the treatment of Conn’s syndrome.
MR antagonist: spironolactone, epleronone
Spironolactone
Uses/ mechanism of action: Primary hyperaldosteronism (Conn’s syndrome) Converted to several active metabolites including canrenone, a competitive antagonist of the mineralocorticoid receptor (MR) Blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
Pharmacokinetics:
- orally active
- highly protein bound + metabolised in the liver.
Unwanted actions:
- menstrual irregularities (+ progesterone receptor)
- Gynaecomastia (-androgen receptor)
Epleronone
Also a mineralocorticoid receptor (MR) antagonist
Similar affinity to the MR compared to spironolactone
Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated.
Describe phaecochromocytomas.
These are tumours of the adrenal medulla which secrete catecholamines.
Sudden huge rise in bp and vasoconstriction episodes - stroke, heart attack
Clinical features
Hypertension in young people
Episodic severe hypertension (after abdominal palpating)
More common in certain inherited conditions
Severe hypertension can cause myocardial infarction or stroke
High adrenaline can cause ventricular fibrillation and death
Thus this is a medical emergency
Management
Alpha blockade is first therapeutic step
Patients may need intravenous fluid as alpha blockade commences - may have very severe drop in b.p.
Beta blockade added to prevent tachycardia
Eventually need surgery but patients needs careful prep as anaesthetic can precipitate a hypertensive crisis.
10% extra adrenal (sympathetic chain) 10% malignant 10% bilateral Extremely rare >10% genetic so screen family
Explain the synthesis from cholesterol.
Cholesterol is precursor for all adrenal steroids.
3 arms:
1) mineralocorticoid - aldosterone (retention of Na+, water and excretion of K+ from kidney)
2) glucocorticoid - cortisol
3) androgens (in humans most from gonads, some adrenal cortex), uses aromatisation -aroma tase enzyme testosterone-> oestrodial
Dehydrogenase enzymes are part of cytochrome p450 family.
All structures are similar
What are the causes of adrenocortical failure.
Adrenal glands destroyed
E.g. TB - myoconacteria have predilection to adrenals and lungs (not anymore in UK), primary adrenocortico failure more common = autoimmune
Enzymes in the steroid synthetic pathway not working - genetic mutation
Tuberculous Addison’s disease (commonest worldwide)
Autoimmune Addison’s disease (commonest in UK)
What are the consequences of adrenocortical failure.
Fall in blood pressure - decrease aldosterone, postural hypotension
Loss of salt in the urine - decrease aldosterone, Na+ out of kidney, hyponatraemia
Increased plasma potassium
Fall in glucose due to glucocorticoid deficiency - hypoglycaemia
High ACTH resulting in increased pigmentation - POMC (pro-opioid melanocortin) synthesised in pituitary and broken down to ACTH and MSH and endorphins and enkephalins and other peptides. MSH -> melanin by stimulating melanocytes e.g. scars, tan, buccal pigmentation
Eventual death due to severe hypotension - aldosterone stops blood pooling into legs when stand up therefore dizzy when stand up.
Exhaustion - low cortisol
Gonads make most sex steroids so not hugely impacted
Vitiligo - not due to Addison’s but autoimmune disease, destruction of melanocytes
What are the tests for Addison’s.
9am cortisol = low
ACTH = high
Short synACTHen test
Give 250 ug synacthen IM
Take sample of blood, ACTH causes cortisol secretion, if problem, no cortisol no matter how much.
Typical Addison’s patient:
Cortisol at 9am = 100 (270-900)
Administer injection IM of synacthen
Cortisol at 9:30 = 150 (>600)
Describe congenital adrenal hyperplasia.
Commonest is caused by 21-hydroxylase deficiency
Can be complete or partial deficiency
Complete:
Aldosterone and cortisol will be totally absent
Survive for less than 24 hours, less than few weeks, loss of salt
Sex steroids and testosterone will be I’m excess, ambiguous genitalia don’t know if male/ female
Age of presentation - as a neonate with a salt losing Addisonian crisis, before birth (while in uterus)
-foetus gets steroids across placenta
-girls might have ambiguous genitalia (virilised by adrenal testo)
Partial:
Cortisol and aldosterone are deficient
Sex steroids and testosterone in excess = hirsutism
Any age presented as they survive
Main problem in later life is hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone.
17a-Hydroxyprogesterone accumulates as this is immediately before enzyme block.
No cortisol means increase in ACTH (no negative feedback) which drives further adrenal androgen production
11-hydroxylase deficiency
Cortisol and aldosterone are deficient
Sex steroids, testosterone and 11-deoxycorticosterone are in excess.
Problems:
11 deoxycorticosterone behaves like aldosterone
In excess it can cause hypertension and hypokalaemia
Virilisation
17-hydroxylase deficiency
Cortisol and sex steroids are deficient
11-deoxycorticosterone and aldosterone (mineralocorticoids) are in excess
Problems: hypertension, low K+, sex steroid deficiency and glucocorticoid deficiency
Explain the control of adrenal steroid production.
Diagram
Stimuli for renin production: Hyperkalaemia Hyponatraemia Decreased renal blood flow - vasoconstriction for haemorrhage and H20 reabsorption B1-adrenoceptor stimulation
Describe the receptors for corticosteroids.
Including comparison and cortisol binding.
Members of the nuclear receptors
Glucocorticoid receptors (GR) Mineralocorticoid receptors (MR)
Comparison:
GR; MR
-wide distribution; discrete distribution (kidney)
-selective for glucocorticoids; do not distinguish between aldosterone and cortisol
-low affinity for cortisol; high affinity for cortisol
Cortisol converted to cortisone (inactive) by 11b-hydroysteroid dehydrogenase 2 (11B-HSD) to prevent from binding to MR. In Cushing’s, too much cortisol and this enzyme not very effective.
State the different corticosteroid drugs and their receptor selectivity.
Hydrocortisone
Glucocorticoid with mineralocorticoid activity at high doses (bind to MR).
Prednisolone
Glucocorticoid with weak mineralocorticoid activity.
Dexamethasone
Synthetic glucocorticoid with no mineralocorticoid activity.
Fludrocortisone
Aldosterone analogue
Used as an aldosterone substitute
Subtle changes in drug structures to bind to different receptors with different affinities
Describe the pharmacokinetics of corticosteroids.
1) Routes of administration
Oral: hydrocortisone, prednisolone, dexamethasone, fludrocortisone
Parenteral - large dose delivered quickly - acutely unwell (i.v. Or i.m.): hydrocortisone, dexamethasone
2) Distribution
Bind to plasma proteins (cortisol binding globulin, CBG and albumin) as circulating cortisol does - not many are free
3) Duration of action
Hydrocortisone - duration - 8h
Prednisolone - duration - 12h
Dexamethasone - duration - 40h
Describe corticosteroid replacement therapy.
What are additional measures needed to be considered.
1) Primary adrenocortical failure
Addison’s disease
Patients lack cortisol and aldosterone
Treat with hydrocortisone and fludrocortisone by mouth
2) Secondary adrenocortical failure (ACTH deficiency)
Patients lack cortisol but aldosterone is normal because adrenal cortex is fine and renin-angiotensin system is fine.
Treat with hydrocortisone
3) Acute adrenocortical failure - Addisonian crisis
I.v. 0.9% sodium chloroform to rehydrate patient (saline)
High dose hydrocortisone i.v. Infusion or i.m. Every 6h mineralocorticoid effect at high dose
- intervenors hydrocortisone -big dose (overwhelm HB-HSD, therefore also MR and aldosterone effects)
5% dextrose if hypoglycaemic
4) congenital adrenal hyperplasia (CAH)
Congenital lack of enzymes needed for adrenal steroid synthesis (primary adrenal cortex failure with enzymes missing)
Objectives of therapy:
-replace cortisol
-suppress ACTH and thus adrenal androgen production
-replace aldosterone in salt
Main problem is sex steroid production
Dexamethasone 1/day, pm or hydrocortisone 2-3/day, high dose
Fludrocortisone
Monitor/ optimise therapy by measuring: 17 OH progesterone Clinical assessment -Cushingoid - GC dose too high -Hirsutism - GC dose too low (and hence ACTH has risen)
Additional measures in subjects with adrenocortical failure:
Normal cortisol production - 20mg/ day
In stress production - 200-300mg/ day
Increase glucocorticoid dosage when patients are vulnerable to stress
E.g. in minor illness - 2x normal dose
Surgery - hydrocortisone .i.m. With pre-med at 6-8 hour intervals, oral once eating and drinking - general anaesthetic is stress, nil by mouth so i.m.
Patients should carry a steroid alert card and wear a MedicAlert bracelet/necklace to let others know in an emergency.
Explain the hypothalamic–pituitary–gonadal axis in both males and females.
Diagram
Describe the female menstrual cycle.
28 days
Follicular phase
Ovulation
Luteal phase
If implantation does not occur - endometrium is shed (menstruation)
If implantation does occur - pregnancy.
Define infertility and give causes for this.
The inability to conceive after 1 year of regular unprotected sex. 1:6 couples Caused by abnormalities : -in males (30%) -or females (45%) -or unknown (25%)
Causes:
1) Primary gonadal failure (testes and ovaries)
Low testosterone/ oestradiol so less negative feedback to hypothalamus giving high GnRH this high LH and FSH from pituitary.
2) Hypo/pituitary disease
Low LH and FSH hence low testosterone/ oestradiol.
Describe the gonadal disorder in males.
Hypogonadism Clinical features: -loss of libido = sexual interest/ desire -impotence -small testes -decrease muscle bulk -osteoporosis
Causes: Hypothalamic-pituitary disease -hypopituitarism -Kallmans syndrome (anosmia -failure of smell, and low GnRH) olfactory nerves migrate with GnRH neurones in embryogenesis Testes originally undescended Stature low-normal -illness/ underweight
Primary gonadal disease
- congenital: Klinefelters syndrome (XXY)
- acquired: testicular torsion, chemotherapy
Hyperprolactinaemia - switch off gonadotropin secretion e.g. pituitary tumour
Androgen receptor deficiency
Investigations: LH, FSH, testosterone -if all low >> MRI pituitary Prolactin Sperm count -Azoospermia = absence of sperm in ejaculate -oligospermia = reduced numbers of sperm in ejaculate Chromosomal analysis (Klinefelters XXY)
Treatment
Replacement testosterone for all patients
For fertility: if hypo/pit disease, subcutaneous gonadotrophins (LH and FSH) mimic using hCG and recombinant FSH respectively
Hyperprolactinaemia - dopamine agonist
What are the endogenous sites of the production of androgens?
What are the main actions of testosterone?
What are the clinical uses of testosterone?
Endogenous sites: Interstitial Leydig cells of the testes Adrenal cortex Ovaries Placenta Tumours
Main actions: Development of the male genital tract Maintains fertility in adulthood Control of secondary sexual characteristics Anabolic effects (muscle, bone)
Circulating testosterone is 98% protein bound
Tissue specific processing:
-converted to dihydrotestosterone (DHT) active form which acts via the androgen receptor (AR)
-17b-oestrodial (E2) acts via the oestrogen receptor (ER) e.g. brain and adipose tissue (found in men with obesity)
Mechanism of action of DHT and E2 via nuclear receptors
Clinical uses:
Testosterone in adulthood will increase:
-lean body mass
-muscle size and strength
-bone formation and bone mass (in young men)
-libido and potency
It will not restore fertility which requires treatment with gonadotrophins to restore normal spermatogenesis.
What are the gonadal disorders in females?
1) amenhorrhoea
2) polycystic ovarian syndrome (PCOS)
3) hyperprolactinaemia
Describe amenorrhoea.
Absence of periods
Primary amenorrhoea = failure to begin spontaneous menstruation by age 16 years.
Secondary amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles.
Oligomenorrheoa = irregular long cycles
Causes - pregnancy/ lactation -ovarian failure: Premature ovarian failure - menopause earlier, apoptosis eggs earlier, POI (primary ovarian insufficiency) Ovariectomy/ chemotherapy Ovarian dysgenesis (Turners 45 XO) - lacking one chromosome - short stature, cubitus valgus (wide carrying angle), gonadal dysgenesis, 1:5000 live F births. - gonadotrophin failure: Hypo/pit disease Kallman’s syndrome (anosmia, low GnRH) Low BMI - leptin, can’t carry baby Post pill amenorrhoea - on pill oestrogen and testosterone exogenous so own axis switches so advised to stop every 4 years -hyperprolactinaemia -androgen excess: gonadal tumours
Investigation:
Pregnancy test
LH, FSH, oestrodial - up and down because cycle differs, if all low then hypothalamic pituitary disease
Day 21 progesterone - after ovulation
Prolactin, thyroid function tests (hypothyroidism -> amenorrhoea)
Androgens (testosterone, androstenedione, DHEAS)
Chromosomal analysis (Turners 45 XO)
Ultrasound scan ovaries/ uterus
Treatment
Treat the cause (e.g. low weight)
Primary ovarian insufficiency (failure - not called anymore) - infertile, HRT (prevent osteoporosis)
Hypothalamic/pituitary disease:
-HRT for oestrogen replacement
-fertility: gonadotrophins (LH and FSH) - part of IVF treatment
Describe PCOS.
Polycystic ovarian syndrome
Incidence: 1 in 12 women of reproductive age
Associated with increased cardiovascular risk and insulin resistance (-> diabetes)
Polycystic ovaries on ultrasound scan
Criteria to diagnose PCOS Need 2 of the following: -polycystic ovaries on ultrasound scan -oligo-/anovulation -clinical/ biochemical androgen excess
Clinical features of PCOS
Hirsutism
Menstrual cycle disturbance
Increased BMI
Treatment of PCOS - fertility
Metformin - insulin sensitivity
Clomiphene - a fertility drug for irregular periods
Gonadotrophins therapy as part of IVF treatment
Clomiphene
Anti-oestrogenic in the hypothalamo-pituitary axis
Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback, resulting in an increase in the secretion of GnRH and gonadotrophins.
Describe hyperprolactinaemia.
Diagram
Causes:
Dopamine antagonist drugs
-Anti-emetics (metoclopramide)
-Anti-psychotics (phenothiazines)
Prolactinoma - usually benign
Stalk compression due to pituitary adenoma, can be detected by pituitary MRI
PCOS
Hypothyroidism - increase in TRH, increase in prolactin
Oestrogens (OCP), pregnancy, lactation
Idiopathic
Clinical features Galactorrhoea - breast milk Reduced GnRH secretion/ LH action -> hypogonadism Prolactinoma -headache -visual field defect
Treatment Treat the cause - stop drugs Dopamine agonist -bromocriptine -cabergoline
Prolactinoma
- dopamine agonist therapy
- pituitary surgery rarely needed
Describe menopause.
Permanent cessation of menstruation
Loss of ovarian follicular activity
Average age 51 (range 45-550
Climacteric: period of transition period
Symptoms Hot flushes (head, neck, upper chest) Urogenital atrophy and dyspareunia (painful sex) Sleep disturbance Depression Decreased libido Joint pain - arthralgia Symptoms usually diminish/ disappear with time.
Diagram
Ovaries release no oestradiol/ inhibit B, reducing negative feedback on hypothalamus so increased GnRH and increased LH and FSH from pituitary.
Complications of menopause Osteoporosis -oestrogen deficiency (makes bones) -loss of bone matrix -10-fold increased risk of fracture Cardiovascular disease -protected against CVD before the menopause -have the same risk as men by the age of 70
Explain hormone replacement therapy (HRT) for menopause. (Not the medications)
Control vasomotor symptoms (hot flushes)
Oestrogen and progestogen
Oestrogen:
- endometrial proliferation
- risk of endometrial carcinoma
Progestogens
Progestogen also given to prevent endometrial hyperplasia
(If hysterectomy, oestrogen only given because no risk of endometrial cancer)
Cyclical: oestrogen given every and progestogen every 12-14 days (later part of cycle)
Continuous combined
Oestrogen preparations:
-oral oestradiol (1 mg)
Oral conjugated equine oestrogen (0.625 mg)
Transdermal (patch) oestradiol (50 microgravity/ day)
Intravaginal
Oestradiol is well absorbed
Low availability (first pass metabolism)
Estrone sulphate (conjugated oestrogen)
Ethinyl estradiol - a semi-synthetic oestrogen, the ethinyl group protects the molecule from first pass metabolism,
Most oestrogens can also be administered via trasndermal skin patches.
Side effects: Breast cancer Coronary heart disease Deep vein thrombosis Stroke Gallstones The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low.
HRT and coronary heart disease, mean age 63 years, women <10 years since menopause or 50-59: no excess risk.
Effects of oestrogen and progesterone Oestrogen: Beneficial effects on lipid profile and endothelial function Synthetic progestins: Negate these effects of oestrogen Older women (>60): Atherosclerosis Susceptible to prothrombotic and proinflammatory effects of oestrogen.
Describe the medications involved in HRT in postmenopausal women.
Tibolone
Synthetic pro hormone
Oestrogenic, progestogenic and weak androgenic actions
Reduces fracture risk
Increased risk of stroke
Might increase risk of beast cancer (unknown)
Raloxifene Selective oestrogen receptor modulator Oestrogenic in bone: -reduces risk of vertebral fractures Antioestrogenic in breast and uterus -reduces breast cancer risk Does not reduce vasomotor symptoms - hot flushes Increases risk of VTE and fatal stroke
Tamoxifen
Anti-oestrogenic on breast tissue
Used to treat oestrogen-dependent breast tumours and metastatic breast cancers
Explain premature ovarian insufficiency.
Menopause occurring before the age of 40.
1% of women
Autoimmune
Surgery
Chemotherapy
Radiation
Explain contraceptives.
Combined oral contraceptives
Oestrogen (ethinyl oestradiol) + progestogen (e.g. levonorgestrel or norethisterone)
Suppress ovulation:
-oestrogen and progestogen: negative feedback andirons at hypothalamus/ pituitary
-progestogen thickens cervical mucus - more difficult for sperm to penetrate
Take for 21 says (or 12 weeks), stop for 7 days
Progesterone only contraceptive
When oestrogens contra-indicated
-smoker, > 35 years old, migraine with aura, coronary heart disease risk already high
Must be taken at the same time each day
-short half-life
-short duration of action
Long acting preparations may be given via an intra-uterine system
Emergency (post-coital) contraception
Copper IUD (intrauterine contraceptive device)
-exclude pregnancy first
-effects sperm viability and function
-effectiveness not reduced in overweight/ obese women
-5 (up to 7) days after unprotected intercourse
Levonorgestrel (within 73 hrs)
Ulipristal (up to 120 hrs after intercourse)
-anti-progestin activity
-delay ovulation by as much as 5 days
-impairs implantation
Explain semen formation and voyage.
Describe the effects of decreased aromatase.
Tubular reabsorption (induced by oestrogen from testosterone aroma tase) in testes Nutrients e.g. fructose and glycoproteins (protect sperm from hostile environment) to concentrate and secretion into epididymal fluid (induced by androgens)
Spermatozoa travel 100000x its length from Testis to Fallopian tube
In semen:
-spermatozoa
-seminal fluid
-leucocytes (potential viruses e.g. hep B, HIV)
1/100 of spermatozoa in ejaculate enter the cervix
1/10000 cervix to ovum
Overall 1/million reach ovum
Small contribution of seminal fluid from epididymis/testis Mainly from accessory sex glands: -seminal vesicles -prostate -bulbourethral glands
Decreased aromatase:
- symptoms of increased testosterone .e.g. acne
- tall, oestrogen needed for growth plate closure
- osteoporosis
Describe the capacitation of sperm.
Achieve fertilising capability in the female repro tract
Loss of glycoprotein coat
Change in surface membrane characteristics
Develop whiplash movements of tail
Describe fertilisation.
Acrosome reaction
Sperm binds to ZP3 - zona pellucida = sperm receptor
Ca2+ influx into sperm (stimulated by progesterone) from corpus luteum
Release of hyaluronidase and proteolytic enzymes (from acrosome)
Spermatozoon penetrates the Zone Pellucida
Chromosome evenly divide into 23 chromosomes each. Cytoplasm does not evenly divide, end up with small cell with 23 chromosomes - first polar body
Fertilisation occurs within the Fallopian tube
Triggers cortical reactions
Cortical granules release molecules which degrade Zona Pellucida (e.g. ZP2 and 3) therefore prevents further sperm binding as no receptors
Haploid -> diploid
Development of conceptus (embryo)
Continues to divide as it moves down Fallopian tube to uterus (3-4 days)
Receives nutrients from uterine secretions
This free-living phase can last for 9-10 days
Corpus albicans - stops producing progesterone unless pregnancy achieved, if pregnancy hCG maintains corpus luteum and acts on LH receptor.
Describe implantation.
Attachment phase: outer trophoblast cells (form placenta) contact uterine surface epithelium
Then
Decidualisation phase: changes in underlying uterine stromal tissue (within a few hours)
Requires progesterone domination in the presence of oestrogen.
Important factors for implantation: LIF - leukemia inhibiting factor IL11 - trophoblast migration, decidualisation Progesterone Diagram
Attachment
LIF from endometrial secretory glands and blastocyst? Stimulates adhesion of blastocysts to endometrial cells
Interleukin-11 also from endometrial cells is released into uterine fluid, and may be involved
Many other molecules involved in process (e.g. HB-EGF)
Decidualisation
Endometrial changes due to progesterone (provide nutrients and support for possible entry)
-glandular epithelial secretion
-glycogen accumulation in stromal cell cytoplasm
-growth of capillaries
-increased vascular permeability (-> oedema)
Factors involved:
Interleukin-11 (IL11), histamine, certain prostaglandins and TGFb (TGFb promotes angiogenesis)
What are the hormone changes and effects during pregnancy?
Hormone hCG
- trigger for ovulation in IVF
- corpus luteum maintained - source of progesterone and oestrogen
- released by placenta
Human placental lactogen - involved in metabolism, cause insulin resistance to promote nutrients to bay because mother glucose levels increase
Oestrogens (mainly oestriol)
Progesterone
Progesterone and oestrogen production during pregnancy
-first 40 days
Produced in corpus luteum (in maternal ovary) stimulated by hCG (produced by trophoblasts) which acts on LH receptors
Essential for developing fetoplacental unit
Inhibits maternal LH and FSH (-ve feedback)
-from day 40
Placenta starts to take over - hCG decreases
Maternal and foetal DHEAS are main sources of substrates that’s made into oestrogens.
Increase:
- ACTH
- adrenal steroids
- prolactin - lactotroph hyperplasia (side note: cant check prolactin in pregnancy because high anyway so visual fields checked)
- IGF1 (stimulated by placenta GH-variant)
- Iodothyronines - hCG stimulates thyroids because has common alpha subunit with TSH
- PTH related peptides - breast tissue
decrease:
- gonadotrophins
- pituitary GH
- TSH because hCG does some of job of TSH
Explain the endocrine control of lactation (breastfeeding).
Suckling (stimulus) sends signals through neural pathways to hypothalamus. Neurohypophysis (posterior PG) releases oxytocin and adenohypophysis (anterior PG) releases prolactin.
Oxytocin causes milk ejection
Prolactin causes milk synthesis
(Side note: marathon runners can get low testosterone, females can get galactorrhoea because nipple stimulation can cause high prolactin
Describe Kisspeptin neurones and prolactin.
Prolactin binds to prolactin receptors on Kisspeptin neurones which secrete Kisspeptin which bind to Kisspeptin receptors on GnRH neurones. GnRH causes LH and FSH release -> testosterone and oestrogen release.
High prolactin dowmregulates, low libido in man, amenhorrhoea in women therefore Kisspeptin given to high prolactin patients.
Kisspeptin neurones have oestrogen receptors, not GnRH neurones. If patient has anorexia, leptin is low. Kisspeptin have leptin receptors, low leptin means low Kisspeptin.
Describe role of PTH in calcium homeostasis.
Parathyroid hormone from parathyroid glands= increase serum Ca2+ after sensing low serum calcium
- acts of bone, increases reabsorption of Ca2+
- action on kidney, increases absorption of Ca2+ (increases calcitriol formation, decreases excretion of calcium)
- regulates production of active vitamin D (calcitriol) from liver, increase Ca2+ reabsorption by gut (small intestine)
Explain phosphate regulation.
Na+/PO43- enters proximal convoluted tubule cell from urine through Na+/PO43- co-transporter
3 wats decrease PO43- reabsorption:
PTH inhibits transporter therefore PO43- loss in urine, decrease reabsorption of PO43- by gut.
FGF23 also inhibits transporter and calcitriol is formed and enters blood.
(FGF23 - fibroblast growth factor 23 from osteocytes)
calcitriol also reduces reabsorption of PO43- from gut.
Explain the regulation of PTH secretion.
Parathyroid cells have Ca2+ sensing receptor.
When there’s high ECF Ca2+, Ca2+ binds to receptor, receptor activation leads to inhibition of PTH secretion
When there’s low ECF Ca2+, Ca2+ not bound to receptor so no inhibition and PTH is secreted. PTH action in body leads to increased ECF Ca2+.
Explain the role of vitamin D in calcium homeostasis.
7-dehydrocholesterol (precursor) found in skin converted to vitamin D3 (cholecalciferol) by UVB light -> 25OH-D3 in liver (not active, hydroxylated once) -> renal 1a-hydroxylase stimulated by PTH causes increased renal Ca2+ reabsorption forming calcitriol 1,25(OH)2D3.
Calcitriol causes Ca2+ absorption in gut, Ca2+ maintenance in bone, negative feedback on PTH
What are the causes of vitamin D deficiency?
Define the vitamin D deficiency state.
Lack of sunlight (UVB light)
Gi malabsorption e.g. coeliac disease, inflammatory bowel disease
Dietary insufficiency
Renal failure, liver failure
Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment)
Re-emerging as problem in UK due mainly to inadequate diet and lack of sunlight.
Definition: lack of mineralisation in bone,
Results in ‘softening’ of bone, bone deformities, bone pain; sever proximal myopathy.
In children = rickets
In adults = osteomalacia
How do changes in EC calcium affect nerve and skeletal muscle excitability?
Explain hypo and hypercalcaemia, including causes.
To generate an AP in nerves/ skeletal muscle requires Na+ influx across cell membrane
High extracellular calcium (hypercalcaemia) = Ca2+ blocks Na+ influx so less membrane excitability
Low extracellular calcium (hypocalcaemia) = enables greater Na+ influx, so more membrane excitability (not much competition)
Normal range series Ca2+ (2.2-2.6 mol/L)
Hypocalcaemia Signs and symptoms: Parasthesia (hands, mouths, feet, lips) Convulsions (seizures) Arrhythmias -heart contraction Tetany - muscles contract but can’t relax (CATs go numb) Sensitises excitable tissues, muscle cramps/ tetany, tingling
Chvostek’s sign
Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia.
Trousseau’s sign
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia.
Causes of hypocalcaemia:
Vitamin D deficiency
Low PTH levels = hypoparathyroidism
-surgical - neck surgery
-auto-immune
-magnesium deficiency - needed to make PTH
PTH resistance e.g. pseudohypoparathyroidism - make PTH but can’t use it, resistance
Renal failure
Impaired 1a hydroxylation -> decreased production of 1,25(OH)2D3
Hypercalcaemia
Signs and symptoms
‘Stones, abdominal moans and psychic groans’
Stones - renal effects
-polyuria and thirst
-nephrocalcinosis calcium stone formation in kidneys) renal colic (try to pass kidneys - painful) , chronic renal failure (kidneys keep filtering Ca2+)
Abdominal moans - GI effects
-anorexia, nausea, dyspepsia (indigestion), constipation, pancreatitis
Psychic groans - CNS effects
-fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)
Reduced neuronal excitability, atonal muscles
Causes:
- primary hyperparathyroidism
- malignancy - tumours/metastases often secrete a PTH-like peptide; calcium deposits in bone mean lots of Ca2+ released
- conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone - immobilised patient)
- vitamin D excess (rare)
Explain the diagnostic approach to hypercalcaemia.
If low Ca2+ more PTH made
If high Ca2+, low PTH - negative feedback
Primary hyperparathyroidism = high Ca2+, high PTH; no negative feedback, autonomous PTH secretion despite hypercalcaemia
-raised calcium
-low phosphate, more lost in urine
-raised (unsuppressed) PTH
Hypercalcaemia of malignancy
Raised calcium and suppressed PTH, metastatic bone deposits damaging bone therefore releasing Ca2+, appropriate negative feedback
Describe secondary hyperparathyroidism.
PTH increases to try to normalise serum calcium
Vitamin D deficiency
What are the biochemical findings in vitamin D deficiency?
Describe the treatment of vitamin D deficiency.
Describe vitamin D excess (intoxication)
Plasma [25(OH)D3] usually low (we don’t measure 1,25 dihydroxy vitamin D to assess body vitamin D stores)
Plasma [Ca2+] low (may be normal if secondary hyperparathyroidism has developed)
Plasma [PO43-] low (reduced gut absorption)
[PTH] high (2o hyperparathyroidism)
Treatment In patients with normal renal function: -give 2 hydroxy vitamin D (25(OH)D) -patient converts this to 1,25 dihydroxy vitamin D (1,25(OH)2D) via 1a hydroxylase Ergocalciferol 25 hydroxy vitamin D2 Cholecalciferol 25 hydroxy vitamin D3
In patients with renal failure:
Inadequate 1a hydroxylation, so cant activate 25 hydroxyl vitamin D preparations
Give alfacalcidol - 1a hydroxycholecalciferol (active)
Vitamin D excess:
Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium
Can occur as a result of:
-excessive treatment with active metabolites of vitamin D .e.g. alfacalcidol
-granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH)D to the active metabolite 1,25(OH)2D.
Treatment for hyperparathyrodism is parathyroidectomy.
Explain the bone components.
Organic components
Osteoid - unmineralised bone, 35% bone mass
Type 1 collagen fibres
Inorganic mineral component
65% bone mass
Calcium hydroxyapatite crystals fill the space between collagen fibrils
Cells
Osteoblasts - synthesis osteoid and participate in mineralisation/ calcification of osteoid (bone formation)
Osteoclasts - release lysosomal enzymes which break down bone (bone resorption)
Osteoclast differentiation
RANKL (ligand) expressed on osteoblast surface
RANKL binds to RANK-R to stimulate osteoclast formation and activity; activated osteoclast causes bone resorption
Osteoblasts express receptors for PTH and calcitriol - regulate balance between bone formation and resorption.
Cortical (hard) bone
Trabecular (spongy) bone
Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
Woven bone - disorganised collagen fibrils, weaker
Bone remodelling is a dynamic process
What are the effects on bone from vitamin D deficiency and hyperparathyroidism?
Vitamin D deficiency:
-inadequate mineralisation of newly formed bone matrix (osteoid)
-children - rickets
Affects cartilage of epiphysial growth plates and bone
Skeletal abnormalities and pain, growth retardation, increased fracture risk
-adults - osteomalacia
After epiphyte all clsoure, affects bone
Skeletal pain, increased fracture risk, prox myopathy
No bowing
Stress fractures from weight of skeleton
Normal stresses on abnormal bone cause insufficiency fractures - looser zones
Waddling gait - typical
Hyperparathyroidism
1) Adenoma
Primary hyperparathyroidism
Parathyroids - high PTH and high Ca2+ (no negative feedback, autonomous PTH)
2) Low plasma [Ca2+] e.g. renal failure, Vit D deficiency
Secondary hyperparathyroidism
Parathyroids - low/ normal Ca2+ so increase PTH
3) Chronic low plasma [Ca2+]
Tertiary hyperparathyroidism
Parathyroids (autonomous) high Ca2+ and PTH, 1 vs 3 - 1 is normal kidney and 3 is chronic kidney failure.
Describe relationship between renal failure and bone disease.
Decreased renal function -> decrease calcitriol -> decrease Ca2+ absorption -> hypocalcaemia -> decrease bone mineralization -> osteitis fibrosa cystica
Decreased renal function -> decrease PO43- excretion -> increase plasma [PO43-] -> hypocalcaemia -> increases PTH -> increases bone resorption -> osteitis fibrosa cystica
(Can get tertiary parathyroidism)
Increase plasma [PO43-] which binds to Ca2+ in plasma -> vascular calcification
Osteitis fibrosa cystica (hyperparathyroid bone disease) - rare = excess osteoclastic bone resorption 2o to high PTH
‘Bone tumours’ = radiolucent bone lesions
Treatment of osteitis fibrosa cystica (hyperparathyroid bone disease)
-hyperphosphataemia
Low phosphate diet
Phosphate binders - reduce GI phosphate absorption
-alphacalcidol - i.e. calcitriol analogues
-parathyroidectomy in 3o hyperparathyroidism
Indicated for hypercalcaemia and/or hyperparathyroid bone disease
Describe osteoporosis and compare with osteomalacia.
Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after mineral trauma.
Bone mineral density (BMD) > or equal to 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
BMD predicts future fracture risk
-1 to -2.5 = osteopenia
Measuring BMD
Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
Mineral (calcium) content of bone measured, the more mineral the greater the bone density (bone mass) - strength
Osteoporosis vs osteomalacia
Both predispose to fracture
Osteomalacia
-vitamin D deficiency (adults) causing inadequately mineralised bone
-serum biochemistry abdnormal (low 25(OH) Vit D, low/ low N Ca2+, high PTH (2o hyperparathyroidism)
-abnormal biochemistry issue so can diagnose using blood test
Osteoporosis
-Bone resorption exceeds formation
-Decreased bone mass
-Serum biochemistry normal - can’t diagnose with blood test
-Diagnosis via DEXA scan
Pre-disposing conditions for oesteoporosis:
-Postmenopausal oestrogen deficiency
Oestrogen deficiency leads to a loss of bone matrix
Subsequent increased risk of fracture
-Age-related deficiency in bone homeostasis (men and women) .e.g. osteoblast sensescence
-hypogonadism in young women and in men (pituitary gland)
-endocrine conditions
Cushing’s syndrome
Hyperthyroidism
Primary hyperparathyroidism
-iatrogenic
Prolonged use of glucocorticoids -steroids
Heparin
Explain the treatment options for osteoporosis.
1) Oestrogen (HRT)/ Selective oestrogen receptor modulators:
Treatment of post-menopausal women with pharmacological doses of oestrogen
-anti-resorptive effects on the skeleton
-prevents bone loss
Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/ cancer
Use limited largely due to concerns:
-increased risk of breast cancer
-venous thromboembolism
May not be good for long term
2) Bisphosphonates
- bind avidly to hydroxyapatite crystals and ingested by oestoclasts - impair ability of osteoclasts to reabsorption bone
- decrease osteoclast progenitor development and recruitment
- promote osteoclast apoptosis (programmed cell death)
- net result = reduced bone turnover
Uses of bisphosphates -osteoporosis - first line treatment -malignancy Associated hypercalcaemia Reduce bone pain from metastases -paget’s disease - reduce bony pain -severe hypercalcaemic emergency - i.v. Initially (re-hydration first)
Pharmacokinetics
- Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)
- Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years
Unwanted actions of bisphosphonates
-oesophagitis
May require switch from oral to iv preparation
-osteonecrosis of the jaw
Greatest risk in cancer patients receiving iv bisphosphates
-atypical fractures
May reflect over-suppression of bone remodelling in prolonged bisphosphate use
3)Denosumab - inhibits switching on of osteoclasts
Human monoclonal antibody
Binds RANKL, inhibiting osteoclast formation and activity
Hence inhibits osteoclast-mediated bone resorption
SC injection
2nd line bisphosphonates
3) Teriparatide
Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH
Increases bone formation and bone resorption, but formation outweighs resorption
3rd line treatment for oestoporosis
Daily s.c. injection
£££
Explain Paget’s disease (of bone).
Accelerated, localised but disorganised bone remodelling
Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) in a non-organised way.
New bone formed = WOVEN bone
-structurally disorganised
-mechanically weaker than normal adult lamellar bone
Bone frailty
Bone hypertrophy and deformity
Often positive family history - ?genetic cause
?evidence for viral origin (e.g. measles virus)
Prevalence
-highest in UK, N America, Australia and NZ
-lowest in Asian and Scandinavia
Men and women affected equally
Disease usually not apparent under age 50 yrs
Most patients are asymptomatic
Characterised by abnormal, large osteoclasts - excessive in number
Clinical features:
Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
Arthritis
Fracture
Pain
Bone deformity
Increased vascularity (warmth over affected bone) - too much activity because remodelling
Deafness -cochlear involvement
Radiculopathy - due to nerve compression
Diagnosis:
Plasma [Ca2+] normal
Plasma [alkaline phosphatase] (bone enzyme) usually increased
Plain x-rays = lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionuclide bone scan demonstrates extent of skeletal involvement
Treatment:
Bisphosphonates - very helpful for reducing bony pain and disease activity
Simple analgesia
Draw a simple diagram to summarise how the hypothalamus regulates appetite.
Diagram
Ghrelin, PYY and other gut hormones, neural input from the periphery and other brain regions, leptin -> hypothalamus -> food intake/ energy expenditure
Recall the main neuronal populations involved in the regulation of appetite.
Arcuate nucleus in rhodents, infundibular nucleus in humans
Key brain area involved in the regulation of food intake
Incomplete blood brain barrier, allows access to peripheral hormones
Integrates peripheral and central feeding signals
Two neuronal populations:
-stimulatory (NPY/ Agrp neurone) - increase appetite
-Inhibitory (POMC neurone) - alpha MSH, different enzymes to ACTH - decrease appetite
Both sets of neurones extend to other hypothalamic regions
Explain how mutations disrupting these neural systems can influence energy balance.
No NPY or Agrp mutations associated with appetite discovered in humans.
POMC deficiency and MC4-R (regulate food intake) mutations cause morbid obesity.
Mutations not responsible for the prevalence of obesity - but useful to explain signalling
Explain the role of leptin in energy homeostasis and reproduction.
Describe the role of insulin.
Recessive mutation in ob gene
Profoundly obese
Diabetic
Infertile
Stunted linear growth
Decreased body temperature
Decreased energy expenditure - don’t want to waste, want to conserve
Decreased immune function - may turn off immune system to save energy
Similar abnormalities to starved animals - on mouse thinks its starving to death therefore eats a lot
Leptin
Codes for 167 amino acid hormone
Missing in the ob/ob mouse
A way in which fat tissue can tell brain not starving to death
Low when low body fat
High when high body fat - the more fat you have, the more leptin you have - leptin coded in adipose tissue
Central or peripheral administration decreases food intake and increases thermogenesis
Activates POMC and inhibits NPY/AgRP neurones.
Leptin resistance
Leptin circulates in plasma in concentrations proportional to fat mass
Most fat humans have high leptin
Obesity due to leptin resistance - hormone is present but doesn’t signal effectively
Leptin is ineffective as a weight control drug
Absence of leptin has profound effects, including hyperphagia, lowered energy expenditure, sterility.
However, leptin is an anti-starvation hormone rather than anti-obesity hormone.
Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning-but high leptin has little effect.
Insulin circulates at levels proportional to body fat - high fat can get insulin resistance like leptin
Receptors in hypothalamus
Central administration reduces food intake
Insulin and leptin signal to regulate long term food intake.
The GI tract signals to regulate short-term food intake.
Specific neuronal circuits in the hypothalamus and other brain regions regulate food intake.
Describe the role of gastrointestinal hormones in the regulation of appetite.
The GI tract is the body’s largest endocrine organ.
Releases more than 20 different regulatory peptide hormones.
Influence processes including gut motility, secretion of other hormones, appetite
Release regulated by gut nutrient content
From duodenum: Cholecystokinin -gall bladder contraction -gastrointestinal motility -pancreatic exocrine secretion Secretin -pancreatic exocrine secretion GIP -Incretin activity Motilin -gastrointestinal motility
From stomach: Ghrelin -hunger -growth hormone release Gastrin -acid secretion
From pancreas: Insulin and glucagon -glucose homeostasis Pancreatic polypeptide -gastric motility -satiation Amylin -glucose homeostasis -gastric motility
From colon: GLP-1 -incretin activity -satiation GLP-2 -gastrointestinal motility and growth Oxyntomodulin -satiation -acid secretion PYY3-36 -satiation
Hormones released from basal side of epithelial cells in gut wall
Paracrine effects - affect cells nearby
Modulation of neuronal function - enteric nervous system; vagus nerve
Endocrine effects - pancreas
L cells (flask shape) secrete PYY and GLP-1 If something from lumen enters (signal), secretory granules released Open endocrine cells, contact with lumen of gut
Peptide YY - 36aa
Post-prandial (lunch/dinner) secretion of PYY - the more calories you eat, the more PYY is released
PPY3-36 directly modulates neurones in the arcuate nucleus:
-inhibits NPY release
-stimulates POMC neurones
-decreases appetite
Brain tricked that you’ve just had a meal, PYY3-36 reduces food intake
Explain the effects of ghrelin and glucagon-like peptide-1 on food intake.
28aa gastric hormone
Ghrelin O-acyltransferase - attach fatty acids to it, fatty acid chain binds to receptor/ proteins in circulation
Ghrelin directly modulates neurones in the arcuate nucleus
- stimulates NPY/ Agrp neurones
- inhibits POMC neurones
- increases appetite
Ghrelin increases food intake in humans
Glucagon-like peptide-1
Gut hormone coded for by the preproglucagon gene (same gene that codes for glucagon) and released post-prandially
Processing of pro-glucagon in intestinal L cells
GLP-1 to agonist (active) by prohormone convertase 1 then inactive by DP-IV.
Well characterised incretin role (decrees glucose) in stimulating glucose-stimulated insulin release and also reduces food intake.
Saxenda
Long -acting glucagon-like peptide-1 receptor agonist (liraglutide)
Double the dose used for T2DM
Used for weight loss
Only small part of it effective, short half-life
Side effect = nausea so build up dosage
Dietary manipulation?
Synthetic nutrients to stimulate nutrient receptors
Delivering nutrients to specific regions of the gut
What are the three types of satiety action by gut hormones.
1)post-prandial
Reduces food intake following a meal
2) chronic
Gut disease - chronic elevation suppresses appetite to allow gut to recover
3) acute nausea
Toxin ingestion - acutely very high levels
Demonstrate awareness of theories which aim to explain the causes of the obesity epidemic in the context of the homeostatic control of energy balance.
Obesity is associated with comorbidities
- depression
- stroke
- sleep apnoea
- diabetes
- hypertension
Thrifty gene hypothesis
Specific genes selected for to increase metabolic efficiency and fat storage. In the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes.
Evolutionarily sensible to put on weight.
Thin humans didn’t survive famines, so didn’t pass their genes on to modern humans.
Evidence? Populations historically prone to starvation become most obese when exposed to Western diet and sedentary lifestyle e.g. Pacific Islanders
Weakness: not everyone is fat
Adaptive drift (drifty gene) hypothesis
Normal distribution of body weight: the fat are eaten, the thin starve
10-20000 years ago, humans learned to defend against predators
Thus obesity not selected against
Putting on body fat then a neutral change (genetic drift). (Though unlikely to put on much weight)
In current context, the inheritors of these genes became obese
Example of genetic effect within a specific environment - obesity driven by the effects of environment on genetic background
Describe the ambiguity of diabetes.
Autoimmune ‘type 1’ diabetes leading to insulin deficiency can present > decades of life = latent autoimmune diabetes in adults (LADA) -antibodies against pancreas, now type 1
T2DM may present in childhood, increasing because of obesity epidemic
Diabetic ketoacidosis is a feature of T2DM
Monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (e.g. MODY, mitochondrial diabetes) -strong genetic family history
Diabetes may present following pancreatic damage or other endocrine disease - pheochromocytoma (tumour of adrenal gland), Cushing’s syndrome increase glucose
Describe the classification for diabetes.
Type 1
Environmental trigger and genetics -> autoimmune destruction of islet cells -> insulin deficiency -> hyperglycaemia
Type 2
Genetics and obesity -> insulin resistance -> B cell failure -> hyperglycaemia
Explain the autoimmune basis of type 1 diabetes.
Describe the effect of the genetics and the environment.
State the markers used for diabetes.
- Increased prevalence of other autoimmune disease .e.g coeliac disease, Addison’s
- Risk of autoimmunity in relatives
- More complete destruction of B-cells
- Auto antibodies can be useful clinically
- Immune modulation offers the possibility of novel treatments - still in reasearch
Genetic susceptibility - different HLA-DR alleles on chromosome 6
Environment - bacterial/viral conditions increase type 1 prevalence?
Markers
- islet cell antibodies (ICA) - group O human pancreas
- insulin antibodies (IAA)
- glutamic acid decarboxylase (GADA) - widespread neurotransmitter
- insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family
Explain the presentation of diabetes.
Symptoms
- polyuria
- nocturia
- polydipsia
- blurring of vision
- ‘thrush’ - yeast growth
- weight loss
- fatigue
Signs
- dehydration
- cachexia
- hyperventilation - Kussmaul breaking, metabolic acidosis therefore more CO2
- smell of ketones
- glycosuria
- ketonuria
Explain the role of insulin, glucagon, catecholamines, growth hormone and cortisol in liver, muscle and adipocyte.
Diagram
State the aims of treatment in type 1 diabetes.
Reduce early mortality Avoid acute metabolic decompensation Prevent long term complications -retinopathy - micro -nephropathy - micro -neuropathy - micro -vascular disease - macro
Explain the treatment of type 1 diabetes.
Needs exogenous insulin to preserve life. Ketones define insulin deficiency.
Diet
- reduce calories as fat
- reduce calories as refined carbohydrate
- increase calories as complex carbohydrate
- increase soluble fibre
- balanced distribution of food over course of day with regular meals and snacks
Insulin given during meals and also as background insulin.
With meals
-short acting
-human insulin
-insulin analogue (lispro, aspart, glulisine)
Background
- long acting
- non-c bound to zinc or protamine
- insulin analogue (Glargine, determir, degludec)
Genetic engineering to alter absorption, distribution, metabolism and excretion
Insulin pump (in abdomen)
Continuous insulin delivery
Preprogrammed basal rates and bolus for meals
Does NOT measure glucose, no completion of feedback loop
Islet cell transplants
Immunosuppressants
How do we know how successful the treatment for diabetes is?
Capillary monitoring
Continuous glucose monitoring
Measure capillary glucose levels
Capillary glucose not as accurate as venous glucose.
HbA1c red cells react with glucose as it does with all proteins. Irreversible, non-covalent depends on:
-lifespan of red cell, about 120 days e.g. thalassemia, sickle cell have short life span therefore test not as reflective
-rate of glycation, faster in some individuals
-Hb opathy, renal failure .etc.
-level of glucose
-forms ideal measure of long term glycemic control and has been shown to be related to risk of complications
-furthermore lowering HbA1c associated lower risk of complication particularly microvascular complication
<42 mmol = normal
> 48 mmol = diabetic
42-48 mmol = prediabetic
Explain the acute complications in type 1 diabetes.
Ketoacidosis
- rapid decompensation (deteriorating functional system) of type 1 diabetes
- hyperglycaemia - reduced tissue glucose utilisation; increased hepatic glucose production
- metabolic acidosis - circulating acetoacetate and hydroxybutyrate osmotic dehydration and poor tissue perfusion (pH decreases, bicarbonate decreases)
Hypoglycaemia
- occasional hypos inevitable as a result of treating diabetes
- major cause of anxiety in patients and families
- source of major misconceptions in media e.g. coma
Definitions:
Hypoglycaemia - plasma glucose of <3.6 mmol/l
Severe hypoglycaemia - any hypo requiring help of another person to treat
- most mental processes impaired at <3 mmol/l
- consciousness impaired at <2 mmol/l
- severe hypoglycaemia may contribute to arrhythmia and sudden death
- may have long term-effects on the brain .e.g. cerebral cortex
- recurrent hypos result in loss of warnings
- hypoglycaemic unawareness
Who is affected by hypoglycaemia? When are people affected? Why are people affected? What are the signs and symptoms? What are the treatments?
Who
- Main risk factor is quality of glycaemic control
- More frequent in patients with low HbA1c
When
- can occur at anytime but often a clear pattern
- pre-lunch hypos common
- nocturnal hypos very common and often not recognised - increase adrenaline when hypoglycaemic at night therefore high glucose in morning
Why
- Unaccustomed exercise
- Missed meals
- inadequate snacks
- alcohol
- inappropriate insulin regime
Symptoms and signs Due to increased autonomic innervation: -palpitations (tachycardia) -tremor -sweating -pallor/ cold extremities -anxiety
Due to impaired CNS function:
- drowsiness
- confusion
- altered behaviour
- focal neurology
- coma
Treatment
Oral (feed the patient):
-glucose - rapidly absorbed as solution or tablets
-complex CHO - to maintain blood glucose after initial treatment
Parenteral (give it consciousness impaired)
- IV dextrose e.g. 10% glucose infusion
- 1 mg glucagon IM - if fasting, glucose reserves low therefore may not work so if cachexic give i.v.
- avoid concentrated solutions if possible (e.g. 50% glucose)
Define diabetes.
What are the ranges for impaired fasting glucose and impaired glucose tolerance.
Diabetes mellitus is the state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves and arteries.
Impaired fasting glucose: 6-7 mmol
Impaired glucose tolerance: 7.8 -1 mmol
Describe maturity onset diabetes of the young (MODY).
Several hereditary forms (1-8) - single gene defects
Autosomal dominant
Ineffective pancreatic B cell insulin production
Mutations of transcription factor genes, glucokinase gene - mechanism by which B cell recognises a particular glucose conc.
Positive family history, no obesity
Specific treatment for type
Explain the metabolism of T2DM.
Heterogenous Obesity Insulin resistance and insulin secretion deficit Hyperglycaemia and dyslipidaemia Acute and chronic complications
Insulin secretion deteriorates with progressive impairment of glucose tolerance - less able to make first phase insulin
Diagram
Adipocytes are a major endocrine organ as they make lots of hormones. These hormones are important in the mechanism of diabetes, not the cause of diabetes
Enough insulin to switch off ketone production but not enough to switch off hepatic glucose output.
Explain obesity song gut microbiota in T2DM.
Central or omental obesity
Insulin resistance
Fatty acids released by bacteria into omental circulation can alter liver metabolism
What is the presentation of T2DM?
Explain the complications.
Osmotic symptoms - polyuria, polydipsia
Infections - high sugar for organisms to feed on
Screening test - try to do earlier but often at time of complication so too late
At presentation of complication
- acute: hyperosmolar coma
-chronic: ischaemic heart disease, retinopathy
Complications Microvascular -retinopathy -nephropathy -neuropathy
Microvascular
- ischaemic heart disease
- cerebrovascular
- renal artery stenosis
- PVD
Metabolic
- lactic acidosis
- hyperosmolar
Treatment
-hypoglycaemia
What are the 4 ways to manage T2DM?
1) education
2) diet
3) pharmacological treatment
4) complication screening
Explain the role of education and diet in the management of T2DM.
Education
- know symptoms
- reduce chance of acute metabolic complications
- reduce change of long term complications
Diet
- control total calories/ increase exercise (weight)
- reduce refined carbohydrates (less sugar)
- increase complex carbohydrate (more rice etc)
- reduce fat as proportion of calories (less IR)
- increase unsaturated fat as proportion of fat (IHD)
- increase soluble fibre (longer to absorb CHO)
- address salt (BP risk)
Explain the use of pharmacological treatment in managing T2DM.
Metformin -Biguanide, insulin sensitiser -overweight patient with T2DM where diet alone has not succeeded -reduces insulin resistance Reduced hepatic glucose output Increases peripheral glucose disposal -GI side effects -do not use if severe liver, severe cardiac or mild renal failure
Acarbose
- alpha glucosidase inhibitor
- prolongs absorption of oligosaccharides
- allows insulin secretion to cope, following defective first phase insulin
- as effective as metformin
- side effects flatus - fermentation of sugars in large bowel causes flatus
Thiazolidinediones
- peroxisome proliferator-activated receptor agonists (PPAR-gamma)
- pioglitazone
- insulin sensitiser, mainly peripheral
- adipocyte differentiation modified, weight gain but peripheral not central
- improvement in glycaemia and lipids
- Side effects of older types - hepatitis, heart failure
Sulfonylureas
- e.g. glibenclamide
- block K+ channel causing Ca2+ to enter so insulin increases
- side effect = weight gain
Glucagon like peptide-1 (GLP-1) -secreted in response to nutrients in gut -transcription product of proglucagon gene, mostly from L cell -stimulates insulin, suppresses glucagon -increases satiety -restores B cell glucose sensitivity -short half life, rapid degradation from enzyme dipeptidyl peptides-4 (DPPG-4 inhibitor) Two types: GLP-1 agonist -exenatide, liraglutide -injectable -long acting GLP-1 agonist -decrease glucagon -decrease glucose -weight loss Gliptins (DPPG-4 inhibitor) -increase half life of exogenous GLP-1 -increase GLP-1 -decrease glucagon -decrease glucose -neutral on weight
Empaglifozin
- inhibits Na-Glu transporter, increases glycosuria
- HbA1c lower
- can lower risk of heart failure - affect on Na+ transport in heart
What other aspects other than hyperglycaemia do we need to control in T2DM?
Blood pressure
Diabetic dyslipidaemia
-cholesterol high
-triglyceride high
HDL-cholesterol low
Describe screening for diabetes.
Problem?
Mortality, morbidity, cost
Diagnosis?
Glucose, fasted or stimulated?
High risk?
Screen?
Specifics of program unclear, which test how often in who?
Treatment?
All aspects of control
What factors are microvascular complications dependent on?
- severity of hyperglycaemia - glucose can damage through protein kinase C, AGEs, hexosamine, Polyol pathway
- hypertension
- genetic
- hyperglycamic memory- those with better control of their diabetes for longer have better outcomes
- tissue damage through originally reversible and later irreversible alterations in proteins
Where are the sites of microvascular complications?
- retinal arteries - retinopathy
- glomerular arterioles (kidney) - nephropathy
- vasa nervorum (tiny blood vessels that supply nerves) - neuropathy
Explain diabetic retinopathy.
Diabetic retinopathy is the main cause of visual loss in people with diabetes and the main cause of blindness in people of working age.
E.g. hyperglycaemia -> PKC activation -> vascular endothelial dysfunction -> vascular permeability -> retinal neovascularisation
Background diabetic retinopathy:
Hard exudates (cheese colour, lipid)
Microaneurysms (“dots”)
Blot haemorrhages
Pre-proliferative diabetic retinopathy (if you don’t treat background retinopathy):
Cotton wool spots also called soft exudates
Represent retinal ischaemic - vessels become more ischaemic
Proliferation retinopathy (next stage):
Visible new vessels
On disk or elsewhere in retina
Maculopathy:
Hard exudates near the macula
Same disease as background, but happens to be near macula
This can threaten direct vision
Management of diabetic retinopathy
Background:
Improve control of blood glucose
Warn patient that warning signs are present
Pre-proliferative:
Suggests general ischaemia
If left alone, new vessels will grow
Needs: pan retinal photocoagulation (laser beams fired at back of retina to prevent new vessels from forming)
Proliferation:
Also needs pan retinal photocoagulation
Maculopathy:
Only have problem around macula
Needs only a GRID of photocoagulation (not pan retinal photocoagulation)
Explain nephropathy.
Hypertension
Progressively increasing proteinuria
Progressively deteriorating kidney function
Classic histological features
Histological features Glomerular Mesangial expansion Basement membrane thickening - cells become very rigid Glomerulosclerosis
Vascular
Tubulointerstitial
Epidemiology Age at development of disease Racial factors Age at presentation Loss due to cardiovascular morbidity
Clinical features:
Progressive proteinuria
Increased blood pressure
Deranged renal function
Normal GFR >90
40-90 = chronic kidney disease
Strategies for intervention: Diabetic control Blood pressure control Inhibition of the activity of RAS system Stopping smoking
Explain the effects of angiotensin 2 and the renin/angiotensin system.
Angiotensin 2
- vasoactive effects
- mediation of glomerular hyperfiltration
- increased tubular uptake of proteins
- podocyte effects
- induction of pro inflammatory cytokines
Diagram
Explain diabetic neuropathy.
Diabetes is the most common cause of neuropathy and therefore lower limb amputation.
Small vessels supplying nerves are called vasa nervorum.
Neuropathy results when these get blocked.
Diabetic neuropathy:
- peripheral polyneuropathy - most common
- mononeuropathy
- mononeuritis multiplex
- radiculopathy
- autonomic neuropathy
- diabetic amyotrophy
1) peripheral neuropathy Longest nerves supply feet Loss of sensation More common in tall people Danger is that patients will not sense an injury to foot e.g. stepping on a nail More likely to occur in: -tall patients -patients with poor glucose control Loss of ankle jerks Loss of vibration sense (using tuning fork) Multiple fractures on foot x-ray (Charcot’s joint = tender red areas of inflammation) - step on one part of foot more than another = fracture Monofilament examination used
2) mononeuropathy Usually sudden motor loss Wrist drop, foot drop Cranial nerve palsy Double vision due to 3rd nerve palsy
3) mononeuritis multiplex
A random combination of peripheral nerve lesions
4) radiculopathy
Pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall.
5) autonomic neuropathy
Loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system - gastroparesis, incontinence, arrhythmia
GI tract:
-difficulty swallowing
-delayed gastric emptying
-constipation/ nocturnal diarrhoea
-bladder dysfunction
Postural hypotension - can be disabling: collapsing on standing
Cardiac autonomic supply - sudden cardiac death
Measure changes in HR in response to Valsalva manoeuvre - blow into syringe, build up of pressure, measure HR
Normally thee is a change in HR
Look at ECG and compare R-R intervals
Explain third nerve palsy.
Pupil sparing third nerve palsy:
Eye is usually “down and out”
6th nerve pulls eye out and 4th nerve pulls it down
Pupil does respond to light
Parasympathetic fibres on outside thus they do not easily lose blood supply in diabetes.
Aneurysm causing third nerve palsy
Space occupying lesion
Will press on parasympathetic fibres first causing fixed dilated pupil
What are the macrovascular complications involved in diabetes?
Ischaemic heart disease - the major cause of morbidity and mortality in diabetes
Cerebrovascular disease - earlier than without diabetes, more widespread (stroke)
Renal artery stenosis - May contribute to hypertension and renal failure
Peripheral vascular disease - contributes to diabetic foot problems and neuropathy (narrowing of armies to leg - emboli/ ischaemic)
What are the key concepts involved in macrovascular disease in diabetes?
Hyperlgycaemia is associated with significantly reduced life expenctancy
Microvascular disease causes morbidity; macrovascular disease causes morbidity and mortality
Macrovascular disease is a systemic disease and is commonly present in multiple arterial beds
Treatment targeted to hyperglycaemia alone has minor effect on increased risk of cardiovascular disease
Prevention of macrovascular disease requires aggressive management of multiple risk factors Insulin resistance before hyperglycaemia itself contributes Risk factors: Non modifiable -age -sex -birth weight -FH/ genes
Modifiable
- dyslipidaemia
- high blood pressure
- smoking
- diabetes (sugar)
What are the complications of diabetes predisposing to foot disease.
Neuropathy; sensory, motor and autonomic
Peripheral vascular disease
What is the pathway to foot ulceration?
1) sensory neuropathy
2) motor neuropathy - imbalance between long extensors to foot and short flexors, clawing of foot, knuckles of toes scratch against shoe, metatarsal head of big toe have lots of pressure - hard to balance weight of foot
3) limited join mobility - glycosylation of collagen, can’t bend feet properly
4) autonomic neuropathy - dry - sweat glands grease and moisture lost
5) peripheral vascular disease - loss of arteries, not enough blood supply to leg, can surgically bypass
6) trauma - repeated minor/ discrete episode
7) reduced resistance to infection - Candida fungal infection
8) other diabetic complications e.g. retinopathy
Describe foot ulceration.
The neuropathic foot = numb, warm, dry, palpable foot pulses, ulcers at points of high pressure loading
The ischaemic foot = cold, pulseless, ulcers at the food margins- extremities e.g. toes
The neuro-ischaemic foot = numb, cold, dry, pulseless, ulcers at points of high pressure loading and at foot margins.
How do you assess the foot of a diabetic patient?
Appearance - deformity, callus - bears weight incorrectly -> ulcerated -> ulcerates -> dry and thick skin around prevent healing
Feel - hold/cold, dry
Foot pulses - dorsalis pedis/ posterior tibial pulse
Neuropathy - vibration sensation, temperature, ankle jerk reflex, fine touch sensation
Explain the management of the diabetic foot.
Hyperglycaemia
Hypertension
Dyslipidaemia
Tackled by stopping smoking, education .etc.
Preventative management
- control diabetes
- inspect feet daily
- have feet measured when buying shoes
- buy shoes with laces and square toe box
- inspect inside of shoes for foreign objects attend chiropodist
- cut nails straight across
- care with heat
- never walk barefoot
Management of foot ulceration:
Relief of pressure
- bed rest (risk of DVT, heel ulceration)
- redistribution of pressure/ total contact case
Antibiotics, possibly long term (can cause resistance) e.g. for osteomyelitis
Debridement - dead tissue needs to be removed
MTD Diabetes nurse Diabetologist Chiropodist Vascular surgeon Orthopaedic surgery
Revascularisation
-angioplasty
-arterial bypass surgery
Amputation
Describe Charcot’s foot.
Charcot foot is a condition causing weakening of the bones in the foot that can occur in people who have significant nerve damage (neuropathy). The bones are weakened enough to fracture, and with continued walking (not painful because neuropathic), the foot eventually changes shape. (Also ulceration and inflammation)
