Endocrinology Flashcards
Name the two most common causes hyperthyroidism?
- Graves’ Disease
- Nodular Goitre (Plummer’s Disease) -> a benign tumour producing thyroxine
What is Graves’ Disease?
- an autoimmune disease that produces antibodies that bind to and stimulate the TSH receptor in the thyroid
- the stimulation leads to the thyroid gland becoming smoothly enlarged (goitre)
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How do patients suffering from Graves’ Disease present?
- patients will come complaining of being overactive with weight loss and sweating etc.
- on palpation, the thyroid gland will feel very diffuse and it’ll be smoothly enlarged
- a family history of hyperthyroidism
- exophthalmos - there is another antibody that binds to the growth factor receptors behind the eye -> muscles behind the eye grow and push the eyes forward (worsened by smoking)
- localised pretibial myxoedema (weird growth of soft tissue in the shin) - caused by another antibody
On further medical examination, what else would you find in a patient with Graves’ Disease?
- a rapid pulse (raised metabolic rate)
- warm
- imaging the thyroid, by giving the patient some radioactive iodine, will show up on the scintigram, showing that the iodine is going into the thyroid gland and the whole thyroid gland is active
What is Plumber’s Disease?
- a toxic nodular goitre, originating from a benign adenoma that is overactively producing thyroxine
How do patients suffering from Plumber’s Disease present?
- with generally hypothyroidism symptoms
- distinct symptoms is on palpation and examination there is a lump on one side
On further medical examination, what else would you find in a patient with Plumber’s Disease?
- because there is too much thyroxine coming from the tumour the pituitary will stop making TSH -> normal part of the thyroid will slowly shrink and stop making thyroxine
- the iodine thyroid scan you will just see a hot nodule and the rest of the thyroid scan will not be seen because of the negative feedback from the tumour
- sometimes patients may have a multinodular goitre
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What are the effects of thyroxine on the sympathetic nervous system?
- SENSITISES beta adrenoceptors to ambient levels of adrenaline and noradrenaline -> normal levels of adrenaline and noradrenaline will have much stronger effects than they should -> patients with hyperthyroidism will also have features of having too much adrenaline e.g. palpitations, tachycardia, tremor, lid lag
Name some symptoms of having too much adrenaline?
- palpitations
- tachycardia
- tremor
- lid lag
Summarise the symptoms of hyperthyroidism?
- weight loss despite increased appetite
- breathlessness
- palpitations
- tachycardia
- sweating
- heat intolerance
- diarrhoea
- lid lag and other sympathetic features
What is a Thyroid Storm (Thyrotoxic Crisis)?
- a rare but severe complication of hyperthyroidism - MEDICAL EMERGENCY (50% mortality if untreated - die of heart failure or arrhythmia)
- features of thyroid storm:
o hyperpyrexia > 41 degress
o tachycardia/arrhythmia – over 170 bpm
o cardiac failure
o delirium/frank psychosis
o hepatocellular dysfunction, jaundice
What is the cause of thyroid storm?
- hyperthyroidism that has been left untreated for long enough, two or more features of a thyroid storm = high risk of death
How is the diagnosis of a thyroid storm confirmed?
- a blood test
What are the treatment options for thyroid storm?
must be prompt and aggressive treatment
- surgery (thyroidectomy)
- radioiodine
- drugs
Name the classes of drugs used to treat hyperthyroidism?
· Thionamides (anti-thyroid drugs)
· Potassium iodide
· Radioiodine
· Beta-blockers - others reduce thyroid hormone synthesis, beta blockers simply help symptoms
What are the uses of thionamides?
- daily treatment of hyperthyroid conditions -> Graves’ or Plummer’s
- control hyperthyroidism before thyroidectomy -> don’t want to give a general anaesthetic to someone who is tachycardic with a labile heart rate
- following radioactive iodine treatment -> radioactive iodine takes a while to work so something else must control the thyroid hormone level before the radiotherapy starts to take effect
Name the 2 main thionamides.
- propylthiouracil
- carbimazole
Describe the synthesis of thyroid hormone.
- iodine is taken up into the follicular cells
- under the action of thyroperoxidase with hydrogen peroxide you get iodination of tyrosine residues in the thyroglobulin
- coupling of monoiodotyrosine and diiodotyrosine to form T3 and T4, which is taken up and released by the cells into the circulation
What is the mechanism of thionamides
- INHIBIT THYROPEROXIDASE
- hence, they inhibit the iodination of thyroglobulin and the coupling of iodotyrosines therefore there is a net reduction in synthesis and secretion of thyroid hormones
- also suppress antibody production in Graves’ and diodination of T4 to T3 in peripheral tissue
How long does it take for thionamides to have an effect?
- the biochemical effects of inhibition with thionamides occurs in hours but it takes weeks before the clinical effects can be seen
- this is because there is a lot of STORED thyroid hormone in the lumen of the thyroid follicles and anti-thyroid hormones only affect the synthesis of thyroid hormones, not stored thyroid hormone
- NO CHANGE FOR 7-10 DAYS
What is the clinical consequence of the lag between giving the thyroid drug and the response?
- symptoms have to managed short-term so non-selective beta blockers are given
What are the unwanted side effects of thionamides?
- agranulocytosis/granulocytopenia (reduction or absence of granular leukocytes) - rare and reversible on withdrawal of the drug
- rashes (relatively common)
- headaches
- nausea
- jaundice
- joint pain
Describe the pharmacokinetics of thionamides.
- orally active
- plasma half-life of 6-15 hours
- crosses the placenta and is secreted in the milk
- metabolised in the liver and excreted in the urine
- carbimazole is a pro-drug which is converted to methimazole (active)
What is the significance of thionamides crossing the placenta?
- thyroid disease is common in women around reproductive age so you must consider pregnancy
- patients can conceive on thionamides but ideally on as low a dose as possible -> high doses of thionamides in a pregnant woman could cause foetal hypothyroidism
What is the significance of thionamides being secreted in milk?
- thyroid disease is common in women around reproductive age so you must consider pregnancy and neonatal period
- patients can breast-feed on thionamides but ideally on as low a dose as possible -> high doses of thionamides in a pregnant woman could cause foetal hypothyroidism
- propylthiouracil crosses into breast milk LESS than carbimazole -> breast-feeding woman are put on PTU over CBZ
How long is it aimed to keep a patient on thionamides?
18 months -> 50:50 chance of relapse after stopping
When is iodide treatment used?
o Preparation of hyperthyroid patients for surgery
o Severe thyrotoxic crisis (thyroid storm)
What compound is most commonly used in iodide treatment?
- KI
What is the mechanism of action of KI?
- Wolff-Chaikoff Effect = the temporary reduction in thyroid hormones following ingestion of large amounts of iodine
- an autoregulatory phenomenon -> the thyroid rejects the ingested iodide, hence prevents the gland from sucking up loads of iodine and making too much thyroid hormone
- KI inhibits the iodination of thyroglobulin and the generation of hydrogen peroxide
How long does it take for KI to have an affect?
- very quick, a matter of hours
- maximum effect after 10 days of contiuous administration
- over weeks it reduces the size and vascularity of the thyroid
What are the unwanted side effects of KI?
- ALLERGIC REACTION
- rashes
- fever
- angioedema
Describe how KI is given?
- given orally or Lugol’s Solution or Aqueous Iodine
What is Radioiodine 131I- high dose used to treat?
- Graves’
- Plummer’s
- Thyroid Cancer
What is Radioiodine mechanism of action?
- permanently switching off the thyroid without surgery
- the method relies on the thyroid gland taking up iodine to make thyroid hormone so thyroid follicular cells take up the radioiodine so, it accumulates in the colloid -> emits beta particles of radiation that destroy the follicular cells
What do some patients complain about as a result of radioiodine treatment?
- discomfort in the neck
What other drugs must be taken into account when prescribing someone with radioiodine?
- anti-thyroid drugs must have been discontiued 7-10 days prior to radioiodine treatment so that the thyroid gland can rev up and be really active so that it sucks up a lot of radioactive iodine when it is administered to get maximal destruction of the gland
Give the dose of radioiodine given to treat Graves’ Disease.
- oral dose of approx. 500 MBq
What is the dose of radioiodine given to patients suffering from Thyroid Cancer?
- oral dose of circa 3000 MBq
Describe the radioactivity of radioiodine.
o Radioactive half-life = 8 days
o Radioactivity negligible after 2 months (maximum effect 2-3 months)
What precautions must be taken after taking radioiodine?
- avoid close contact with small children for several weeks
- contra-indictaed in pregnancy and breast-feeding
What are the results of a thyroid uptake scan of Graves’ Disease?
- entire gland is active and smoothly enlarged
What are the results of a thyroid uptake scan of a patient with Plummer’s?
- single focus of activity and the rest is supressed
What are the results of a thyroid uptake scan of a patient with Thyroiditis?
- inflamed thyroid gland where there is NO activity at all
What is Viral Thyroiditis?
- caused by a virusattacking the thyroid gland and it causing a fever
- it damages the thyroid follicles and all the stored thyroxine gets released so patients present with OVERACTIVE thyroid, after a bout a month when all the thyroxine has ran out they will become hypothyroid as the damaged gland will no longer make thyroxine
What are the symptoms of viral thyroiditis?
- piainful dysphagia
- hyperthyroidism
- pyrexia
- raised erythrocyte sedimentation rate
What is the treatment for viral thyroiditis?
- you have to wait for all the thyroxine to have been used up before giving thyroxine to treat the hypothyroidism
- drugs can be given to help with the symptoms
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- all the others will control thyroid function but the lugol’s iodine, used for 10 days before the operation, will reduce the size and vascularity of the thyroid gland
What are the 6 anterior pituitary hormones?
- FSH
- LH
- GH
- TSH
- ACTH
- prolactin
Define hypopituitarism.
- decreased production of ALL anterior pituitary hormones (panhypopituitarism) or of specific hormones
How common are congeital reason for panhypopituitarism?
- rare
Name a gene mutation which leads to panhypopituitarism.
- PROP1 mutation - this is a transcription factor that allows the development of the pituitary gland to take place
- is congenital
What are the causes of acquired panhypopituitarism?
o Tumours -> hypothalamic (craniopharyngiomas) or pituitary (denomas, metastases, cysts)
o Radiation -> hypothalamic/pituitary damage (GH most vulnerable, TSH relatively resistant)
o Infection -> meningitis
o Traumatic brain injury
o Infiltrative disease -> often involves pituitary stalk (neurosarcoidosis)
o Inflammatory (hypophysitis)
o Pituitary apoplexy -> haemorrhage (or less commonly infarction)
o Peri-partum infarction (Sheehan’s syndrome)
What is the usually loss of secretion of hormones in panhypopituitarism?
o Gonadotrophins (LH and FSH)
o GH
o Thyrotrophin
o Corticotrophin
o Prolactin deficiency is uncommon/unrecognised
What are the symptoms of hypopituitarism?
o Secondary Amenorrhoea OR Oligomenorrhoea
o Impotence
o Loss of libido
o Erectile dysfunction
o Tiredness
o Waxy skin
o Loss of body hair
o Hypotension
- no really symptoms for growth hormone in adults
What is Sheehan’s Syndrome?
o develops acutely following post-partum haemorrhage resulting in PITUITARY INFARCTION
- blood loss results in vasoconstrictor spasm of hypophysial arteries and this leads to: ischaemia of the pituitary (enlarged during pregnancy due to swelling of prolactin glands) and necrosis of the pituitary
- develops very FAST
o more prevelant in less developed countries as hypotension post-partum is more common
What is the presentation of Sheehan’s Syndrome?
- lethargic
- anorexia
- weight loss
- failure of lactation
- failure to resume menses post-delivery
o posterior pituitary usually not affected
What is pituitary apoplexy?
- intra-pituitary haemorrhage or, less commonly, infarction
- often dramatic, rapid presentation in patients with pre-existing pituitary tumours (adenomas) -> may be first presentation of a pituitary adenoma
- often causes severe headaches and visual field defects (depression on the optic chiasm)
- can be precipitated by anti-coagulants
What differentiates between Sheehan’s Syndrome and pituitary apoplexy?
- pituitary apoplexy isn’t specific to women
What might be lead to if the cavermous sinus becomes involved?
- diplopia (IV, VI), ptosis (III)
How can hypopituitarism be diagnosed?
o Biochemical
- basal plasma values of pituitary or target endocrine gland hormones
- stimulated (dynamic) pituitary function test
o Radiological
- pituitary MRI
What is the problem for testing for basal plasma values of pituitary or target endocrine gland hormones?
- most things released from the hypothalamus are released in pulses -> single measurements are not useful -> low or high results could be physiological
What is a stimulated pituitary function test?
- done using a combined function test -> involves the administration of various releasing hormones -> releasing hormones are administered IV
- the same thing can be done with just one releasing hormone if you’re testing for a specific hypothyroidism -> the specific test for GH is the insulin-induced hypoglycaemia test
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What can be revealed by a pituitary MRI?
o specific pituitary pathology eg haemorrhage (apoplexy), adenoma
o empty sella – thin rim of pituitary tissue
What is the general treatement for hypopituitarism?
- hormone replacement therapy
What is the treatment for ACTH deficiency?
- hydrocortisone
What is the treatment for TSH deficiency?
- thyroxine
What is the treatment for GH deficiency?
- GH
What is the treatment for LH/FSH deficiency in women?
- oestrogen
- if the patient has a uterus progesterone must be given with the oestrogen - prevents endometrium hyperplasia
What is the GH also known as?
- somatotrophin
What are the effects of a lack of somatotrophin?
o children -> pituitary dwarfism
o adults -> effects are unclear
Name the causes of short stature in children?
o Lack of GH
o Genetic -> Down’s syndrome, Turner’s syndrome, Prader Willi syndrome
o Malnutrition
o Emotional deprivation (potentially due stress response effecting the growth axis)
o Endocrine disorders -> Cushing’s syndrome, Hypothyroidism, GH deficiency, poorly controlled T1DM
o Systemic disease -> Cystic Fibrosis, Rheumatoid arthritis
o Malabsorption -> Coeliac disease
o Skeletal dysplasia -> Achondroplasia, osteogenesis imperfecta
Describe the growth axis.
- GHRH is released from the hypothalamus and truggers the anterior pituitary to release GH
- GH caues growth in target tissue as well as stimulating the production of IGF I and IGF II in the liver-> IGF I mediates growth
- GH is controlled in the hypothalamus by GHRH and GH
What is Laron Dwarfism?
- a form of dwarfism caused by a GH receptor defect -> results in low IGF I levels because GH isn’t having an effect
What is the cause of teritary hypopituitarism?
- specific hypothalamic hormone defects
Give an example of tertiary hypopituitarism.
- GnRH deficiency
Name some GnRH deficiencies.
- Kallmann’s Syndrome
- Prader-Willi-Syndrome
Describe Kallmann’s Syndrome.
- caused by a genetic defect where the neurones in the embryo that will go on to produce GnRH are unable to migrate to the hypothalamus -> hypothalamus LACKS GnRH neurones
- the defect also prevents the migration of the neurones that are going to develop a sense of smell resulting in various degrees of anosmia
- hypogonadism -> untreated suffers never go through puberty
How is a diagnosis of short stature made in a child?
- if they fall below their percentile on the charts within their red book
What are the likely causes of acquired GH deficiency in adults?
- trauma
- pituitary tumour
- pituitary surgery
- cranial radiotherapy
How is GH deficiency diagnosed?
o GH provocation tests in which plasma GH is measured at specific points before and aftwerwards
- GHRH + ARGININE (IV) - (in combination more effective than each alone)
- INSULIN (IV) – via hypoglycaemia
- GLUCAGON (IM)
- EXERCISE (e.g. 10 min step climbing; when appropriate)
What is the NICE cut-off for GH deficiency in response to hypoglycaemia?
- 3mcg/L
What is the treatment for GH deficiency?
o hormone replacement therapy
- human recombinant GH
- daily, subcutaneous injection
What are the signs and symptoms of GH deficiency in adults?
o impaired ‘psychological well being’ and reduced quality of life -> only proved symptom
- reduced lean mass
- increased adiposity
- increased waist:hip ratio
- reduced muscle strength & bulk à reduced exercise performance
- decreased plasma HDL-cholesterol & raised LDL-cholesterol
State the potential benefits of GH therapy in adults.
o improved psychological well being and quality of life
- improved body composition -> decreased waist circumference, less visceral fat
- improved muscle strength and exercise capacity
- more favourable lipid profile - higher HDL-cholesterol, lower LDL-cholesterol
- increased bone mineral density
What are the potential Risks of GH Therapy in Adults?
o increased risk of cardiovascular accidents -> due to its growth promoting effects, an excess of GH can cause cardiomegaly
o increased soft tissue growth, leading to e.g. cardiomegaly
o expensive
o increased susceptibility to cancer was thought but proved wrong
Describe Hyperpituitarism.
o symptoms associated with excess production of adenohypophysial hormones
- can be due to isolated tumours but can be ectopic in origin (eg vasopressin in lung tumours)
What is hyperpituitatarism associated with?
- visuial field defects
- often accompanied with other defects particularly cranial nerve defects
Exactly, what crosses at the optic chiasm?
- fibres from the inner (nasal) part of the retinae cross
What kind of visual impairment is caused by an enlarged pituitary gland?
o bitemporal heminaopia
- you lose the temporal/peripheral vision
How are bitemporal hemianopia assessed?
o perimetry
- press button when the patient can see the flashing light which builds up a visual field
What is the difference between Cushing’s Disease and Cushing’s Syndrome?
- the syndrome is simply to much ACTH whereas the disease is due to a pituitary adenoma
Give two physiological and one pathological reason for hyperprolactinaemia.
o physiological = pregnancy and breastfeeding
o pathological = prolactinoma (often microadenomas<10nm diameter)
In terms of the gonadal axis, what does high prolactin do?
- it suppresses GnRH pulsatility
- can cause secondary hypogonadism
What are the presenting complaints/problems with hyperprolactinaemia in women?
- galactorrhoea (milk production when not breastfeeding)
- secondary amenorrhoea or oligomenorrhoea
- loss of libido
- infertility
What are the presenting complaints/problems with hyperprolactinaemia in men?
- loss of libido
- erectile dusfunction
- infertility
- galactorrhoea can occur but is very uncommon
What supresses prolactin release?
- dopamine binding to D2 receptors
How is hyperprolactinamia treated?
- 1st line = dopamine receptor agonists therefore inhibiting prolactin and reduce the tumours size
- include bromocriptine and cabergoline via oral administration
o unusual that it is medical and not surgical treatment
What are the side effects of dopamine receptor agonists?
- nausea and vomiting
- postural hypotension
- dskinesias
- depression
- pathological gambling
What does excess GH causes?
o in children = gigantism
o in adults = acromegaly
- in adults, the growth plates of the long bones have fused so there is no longer a possibility of an increase in height but you still get other effects
What is the major cause of excess GH?
- usually benign growth hormone secreting pituitary adenoma
- maybe benign but can be deadly due to pressure it can provide on cranium
Describe the signs and symptoms of acromegaly. Go onto state the issues that arise if acromegaly is left untreated.
- incidious onset -> gradual changes over many years
o increased morbidity and mortality
- > death: CVD = 60%
- > respiratory complications = 25%
- > cancer = 15%
What grows in acromegaly?
o periosteal bone
o cartilage
o fibrous tissue
o connective tissue
o internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.)
o prognathism
o enlarged supraorbital ridges
o enlarged soft tissues
State the clinical features of acromegaly.
- EXCESSIVE SWEATING (HYPERHIDROSIS)
- HEADACHES
- enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features
- enlarged tongue (macroglossia)
- mandible grows causing protrusion of lower jaw (prognathism)
- carpal tunnel syndrome (median nerve compression)
- barrel chest
- kyphosis
What are the metabolic effects of acromegaly?
excess GH -> increased endogenous glucose production and decreased muscle uptake -> increased insulin production -> increased insulin resisitance -> impaired glucose tolerance (50% of patients) -> diabetes mellitus
State 4 major clinical complications linked to acromegaly.
o obstructive sleep apnoea -> bone and soft-tissue changes surrounding the upper airway lead to narrowing and subsequent collapse during sleep
o hypertension
o cardiomyopathy -> hypertension, DM, direct toxic effects of excess GH on myocardium
o increased risk of cancer -> colonic polyps, regular screening with colonoscopy
What other hormone if often high in acromegaly?
- prolactin
State and explain the ‘gold standard’ test for acromegaly.
- oral glucose tolerance
o paradoxical rise of GH following oral gluscose load
What is the treatment for acromegaly.
o SURGERY is the main treatment - transphenoidal hypophysectomy
o Radiotherapy - problem is that over a long period of time the patient ends up hypopituitary as a result
o Chemotherapy/Drugs -> somatostatin analogues or dopamine Agonists
Name a somatostatin analogue.
- octreotide
Name two dopamine agonsits.
- bromocriptine
- cabergoline
What is the clincal use of octreotide?
- short-term treatment before pituitary surgery -> reduces the size of the tumour to make surgery easier
- treatment of other neuroendocrine tumours e.g. carcinoid tumours
How are somatostain analogues administed?
- subcutaneous or intramuscular
What are the side effecst of somatostatin analogues?
o GI tract disturbances (somatostatin is produced by the small intestine) -> gallstones
o initial reduction in insulin secretion - transient hyperglycaemia -> inhibits the production of insulin by beta cells leading to transient hyperglycaemia
What does the posterior pituitary look like on MRI?
- is the bright spot at the back of pituitray gland
What two hormones are produced in the neurohypophysis/posterior pituitary?
- vasopressin (ADH)
- oxytocin
What is the role of oxytocin?
- constriction of myometrium at parturition
- milk ejection reflex
How is vasopressin regulated?
- osmoreceptors in the organum vasculosum
What are the two types of diabetes insipidus?
o central/cranial -> absense or lack of circulating vasopressin
o nephrogenic -> end-organ (kindeys) resistence to vasopressin
What are the causes of cranial diabetes insipidus?
o acquired (more common) -> damage to neurohypophysial system
- traumatic brain injury
- pituitary surgery
- pituitary tumours, craniopharyngioma
- metastasis to the pituitary gland - e.g. breast
- granulomatous infiltration of median eminence - e.g. TB, sarcoidosis
o Congenital – rare
- usually receptor gene mutations
What are the causes of nephrogenic diabetes insipidus?
- familial (rare)
- drugs -> LITHIUM (used to treat bi-polar disorder), dimethyl chlortetracycline (DMCT)
What are the signs and symptoms of diabetes insipidus?
- polyuria
- very dilute urine (hypo-osmolar)
- thirst and increased drinking (polydipsia)
- dehydration (and consequences) if fluid intake is not maintained
- possible disruption of sleep with associated problems
- possible electrolyte imbalance
What is the cycle of diabetes insipidus?
What happens to the usual cycle of diabetes insipidus if the patient doesnt have access to water?
Name a disease which presents with similar symptoms to DI?
- psychogenic polydipsia
What is the cycle of patients suffering from psychogenic polydipsia?
How can DI and psychogenic polydipsia be distinguished between?
o normal person has a tightly maintained osmolality (270-290 mOsm/kg H2O)
o diabetes insipidus = high osmolality
o psychogenic polydipsia = low osmolality
What is the ‘gold standard’ test to diagnose diabetes insipidus?
o fluid deprivation test
What are the biochemical features of DI?
- hypernatraemia
- raised urea
- increased plasma osmolality
- dilute (hypo-osmolar) urine - ie low urine osmolality
State the biochemical features of psychogenic polydipsia.
- mild hyponatraemia -> excess water intake
- low plasma osmolality
- dilute (hypo-osmolar) urine -> ie low urine osmolality
What is the treatment for cranial DI?
- V2 receptor agonists -> desmopressin (DDAVP)
What is the clinical use of terlipressin?
- is V1 receptor agonist -> used to treat GI bleeds
How is desmopressin administrated?
- nasally or orally
- produces a prompt sustained decrease in urine volume and increase in urine osmolarity -> has a very long effect so you don’t need to take desmopressin too often
Apart from cranial DI, what else can desmopressin be used to treat?
- nocturnal eneuresis (bedwetting)
- haemophilia - you need V2 receptor stimulation
What are the side effects of desmopressin?
- fluid retention and hyponatraemia
- abdominal pain
- headaches
- nausea
What is the treatemnt for nephrogenic diabetes insipidus?
- thiazide diuretic
Define SIADH.
- plasma vasopressin concentration is INAPPROPRIATE for the existing plasma osmolarity -> too much ADH for current osmolarity
Show the pathway of SIADH.
What are the signs and symptoms of SIADH?
o Signs of SIADH:
- raised urine osmolarity
- decreased urine volume (initially)
- hyponatraemia - decrease in plasma sodium concentration due to increased water reabsorption
o Symptoms of SIADH:
- often asymptomatic
- when Na+ concentration falls < 120mM = generalised weakness, nausea and poor mental function
- when Na+ conc. falls <110mM = confusion, coma and death
What are the causes of SIADH?
- tumours (ectopic secretion)
- neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease)
- pulmonary disease (e.g. pneumonia)
- malignancy (in particular small cell lung cancer)
- endocrine disease (e.g. Addison’s disease)
- physiological - it can happen under quite normal circumstances where AVP release is stimulated by non-osmotic stimuli (e.g. hypovolaemia, pain, surgery)
- drugs (e.g. chlorpropamide)
- idiopathic
What is the treatment of SIADH?
- treat the cause (e.g. tumour)
- if someone is already hyponatraemic, you need to deal with that as quickly as possible: -> immediate = fluid restriction and longer-term = drugs that prevent vasopressin action in the kidneys (e.g. lithium, dimethyl chlortetracycline (DMCT), V2 receptor antagonists)
What are Vaptans?
- non-peptide vasopressin analogues
- tolvaptan - V2 receptor antagonist
o can be used for SIADH but are very expensive so are rarely used
What is another disease (not SIADH) that vaptans could be used for)
- congestive heart failure
What drugs affect ADH secretion?
- increase = nicotine
- decrease = alcohol and glucocorticoids
What are the symptoms of primary hypothyroidism?
o Tongue gets thick
o Speech slows down
o Deepening of the voice
o Basal Metabolic Rate falls
o Bradycardia
o General weakness
o Depression
o Cold intolerance
o Weight gain and reduced appetite
o Constipation
- Eventual myzoedema coma
What happens to TSH in primary hypothyroidism?
- it goes up to try and stimulate the thyroid
What enzyme converts T4 to T3?
- deiodinase
What percentage of hormones are made in the thyroid?
- 80% is deiodination of T4
- 20% is direct thyroidal secretion of T3
Describe the mechanism of thyroid hormones.
- thyroxine enters the target cell and is converted to T3 by deiodinase (can also be T3 that enters directly)
- T3 moves to the nucleus and binds to the thyroid hormone receptor and then heterodimerises with a Retinoid X Receptor
- this complex then binds to the Thyroid Response Element that causes a change in gene expression
What is used in thyroid hormone replacement therapy?
- the usual thyroxine replacement is levothyroxine sodium or direct thyroxine (T4)
- rarely liothyroxine sodium is used as a T3 replacement
What is levothyroxine sodium used to treat?
- primary hypothyroidism - autoimmune or iatrogenic (post-thyroidectomy or post-radioactive iodine)
- secondary hypothyridsim (pituitary tumour, post-pituitary surgery/radiotherapy)
What is used as reference to thyroxine dose in primary hypothyroidism?
- TSH levels
What is used as a reference for thyroxine dose in secondary hypothyroidism?
- isn’t any TSH (or is very low) so middle of T4 reference range is used
What is the clincal use of liothyronine?
- to treat MYXOEDEMA COMA - a very rare complication of hypothyroidism
- IV liothyronine (T3) is given in this situation because the onset of action is faster than T4
- then when the patient has recovered from the coma oral thyroxine replacement is given
As well as being expensive, name another reason why T3 hormone replacement therapy is not favoured.
- T3 is very potent -> very difficult to get the dose right
- high T3 switches off TSH and patients show thyrotoxicosis symptoms = palpatations, tremors and anxiety
- combined thyroid hormone replacement does exsist but again isn’t favoured
How does T3 and T4 circulate in the blood plasma?
- 99.97% of T4 and 99.7% of T3 are bound to thyroxine binding globulin (TBG) (not to be confused with thyroglobulin in the colloid of follicular cells)
What factors affect plasma protein production?
- increase in pregnancy and with prolonged treatment with oestrogens and phenothiazides
decreased with liver disease or if you are severely malnourished
Name two drug classes that can compete for binding sites of TBG.
- phenytoin
- salicylates (e.g. aspirin)
What is the most common cause of hypothyroidism?
- autoimmune -> 5% of people suffer from this in their life
What are the adverse effects of thyroid hormone over-replacement?
o usually associated with a low/suppressed TSH
o Skeletal -> increased bone turnover, reduction in bone mineral density therefore risk of osteoporosis
o Cardiac -> tachycardia, risk of Dysrrhythmia (particularly atrial fibrilation)
o Metabolism - increased energy expenditure, weight loss
o Increase b-adrenergic sensitivity -> tremors, nervousness
ARE ALL SYMPTOMS OF THYROTOXICOSIS
- D
- D
What is Cushing’s Syndrome?
- too much cortisol
What are the clinical features of Cushing’s Syndrome?
- centripetal obesity
- moon face
- buffalo hump
- proximal myopathy
- hypertension
- hypokalaemia
- red striae
- thin skin and bruising
- osteoporosis
- diabetes
What are the causes of Cushing’s Syndrome?
o exogenous
- taking too many steroids
o endogenous
- pituitary dependent cushing’s disease (pituitary produces too much ACTH causing adrenal growth therefore too much cortisol)
- ectopic ACTH from lung cancer
- adrenal adenoma secreting cortisol
What is the pattern of cortisol release?
- diurnal rhythm
Compare the release of cortisol throughout the day between a normal person and someone with Cushing’s Syndrome.
What are the methods of diagnosing Cushing’s Syndrome?
- 24h urine collection for urinary free cortisol
- blood diurnal cortisol levels
- low dose dexamethasone suppression test
Describe the low dose dexamethasone suppression test.
- 0.5mg of dexamethasone (artificial steroid) every 6hrs for 48hrs
- normally this suppress cortisol to 0
- in any cause of Cushing’s Syndrome this will fail to suppress it to 0
o GOLD STANDARD
Barring surgery, what treatments are available for Cushing’s Syndrome?
- inhibitors of sterid biosynthesis -> metyrapne, ketoconazole
Barring surgery, what treatments are available for Conn’s Syndrome?
- mineralocorticoid receptor (MR) antagonists -> spironolactone, epleronone
What is the mechanism of metyrapone?
- inhibition of 11beta-hydroxylase therefore blocking steroid synthesis in the zona fasciculata
- causes ACTH to rise as no cortisol is made so no negative feedback
What are the clinical scenarios in which metyrapone is used?
o Control of Cushing’s syndrome prior to surgery
- cushing’s patients are not good surgical candidates because they are predisposed to infection and have very thin skin
- metyrapone is used to improve the patient’s symptoms and promotes better post-op recovery (better wound healing, less infection)
- oral metyrapone is dosed according to cortisol production (aim for mean serum cholesterol of 150-300 nmol/L)
o Control of Cushing’s symptoms after radiotherapy
- radiotherapy is usually quite slow to work so you would give metyrapone after radiotherapy until the effects of the radiotherapy start to come about
State two biological/mechanical negative aspects about metyrapone.
o accumulation of 11-deoxycorticosterone which has mineralcorticoid properties -> sodium retention and potassium secretion -> salt retention -> hypertension
o all precursors are channeled towards sex steroid synthesis -> increase in adrenal androgens -> hirsutism and acne (more unpleasant for women is general)
What are the side effects of metyrapone?
- nausea, vomiting, dizziness
- sedation
- hypoadrenalism
- hypertension on long-term administration
- hirsuitism
How does ketoconazole function?
- inhibits Cytochrome P450 side chain cleavage enzymes meaning that glucocorticoid, mineralocorticoid and sex steroid production is blocked
What are the uses of ketoconazole?
- treatment and control of symptoms prior to surgery
- an anti-fungal (not licensed anymore due to its reduction on cortisol)
What are the side effects of ketoconazole?
- nausea, vomiting
- abdominal pain
- alopecia
- gynaecomastia, oligospermia, impotence, decreased libido -> due to reduction of sex steroid production
- ventricular tachycardias
- hepatotoxicity -> can be fatal - patients are monitored with regular liver function tests
Where in the adrenal gland is aldosterone made?
- zona glomerulosa
What is Conn’s Syndrome?
- too much aldosterone
- due to a benign adrenal cortical tumour in the zona glomerulosa
What are the features of Conn’s Syndrome?
- hypertension and hypokalaemia (low potassium)
How is Conn’s Syndrome (aka primary hyperaldosteronism) diagnosed?
- high aldosterone and low renin
What is spironolactones mechanism of action?
- is converted into several metabolites including canrenone which competitively antagonises MRs -> blocks the action of aldosterone (sodium reabsorption and potassium secretion in the kidney tubules)
When is spironolactone used?
- prior to surgery to make the patient a better candidate
- people who have bilateral adrenal hyperplasia -> can’t take both adrenals out as not enough cortisol or aldosterone would be produced
Name the side effects of spironolactone.
o spironolactone is a very non-specific drug so there are lots of side-effects
- a progesterone receptor agonist so causes menstrual irregularities
- an androgen receptor antagonist so it can cause gynaecomastia in men -> clinically can’t be used in men for this reason (must use much more commonly used epleronone)
- GI tract irritation
- renal and hepatic disease
What makes epleronone a better drug than spironolactone?
- has the same mechanism with same affinity for MRs while being more specific so doesn’t interfere with progesterone or androgen receptors so has less side effects
- FAR MORE COMMONLY USED
What is Phaeochromocytoma?
- tumours of the adrenal MEDULLA which secrete catecholamines (adrenaline and noradrenaline)
What are the effects of phaeochromocytoma?
- adrenaline has a rapid effect -> from time to time (more likely after trauma) the tumour will release a lot of adrenaline -> massive rise in bp (e.g. 300/150) -> to the sort of level that cause sudden strokes or MIs - MAIN EFFECT
- is a sudden onset of panic, you feel anxious, tachycardia and severe hypertension
What are the clinical features of phaeochromocytoma?
- hypertension in a young person
- episodic severe hypertension (after abdominal exam - press on adrenal causing release of NA and A)
- more common in certain inherited conditions
What makes the diagnoses of phaeochromocytoma a medical emergency?
- severe hypertension -> MI or Stroke
- high adrenaline -> Ventricular Fibrillation (VF) -> Sudden Cardiac Death
What is the treatment/management of phaeochromocytoma?
- first is alpha blockade - patients may need intravenous fluid as alpha blockade commences
- second is beta blockade added to prevent tachycardia
- once adrenalines effects have been nullified surgery to remove the gland
State some key statistics about the positioning and status of phaeochromocytoma tumours.
- 10% extra-adrenal (sympathetic chain) and 90% inside the adrenal
- 10% are malignant
- 10%are bilateral making 90% are curable by operation
- phaeochromocytoma is EXTREMELY RARE
What hormones are present in the hypothalamo-pituitary-adrenal axis?
- CRH = corticotrophin releasing hormone
- ACTH = adrenocorticotrophic hormone (corticotrophin)
- aldosternone, cortisol, adrenaline and noradrenaline
Where does all steroid comes from?
- cholesterol
What is made in the zona glomerulosa?
- aldosterone
What is made in the zona fasciculata?
- cortisol
What is produced in the adrenal medulla?
- adrenaline and noradrenaline
Describe the pathway that leads to aldosterone and cortisol production?
- after each number adding hyrdoxylase gives you the enzyme
Globally, what is the most common cause of adrenal failure?
- TB Addison’s Disease
In the UK, what is the most common cause of adrenocortical failure?
- Autoimmune Addison’s Disease
Barring Addison’s Disease, name a cause for adrenocortical failure?
- congenital adrenal hyperplasia -> caused by enzyme deficiency so hormones aren’t made properly
What are the consequences/symptoms of adrenal failure?
- fall in blood pressure -> no aldosterone
- loss of salt in urine -> unable to retain salt because of the lack of aldosterone -> salt loss in urine and potassium plasma
- fall in glucose -> due to glucocorticoid deficiency
- high ACTH (no -ve feedback) resulting in increased pigmentation with some vitilgo-> ACTH is cleaved from POMC -> the remaining part is MSH (melanocyte stimulating hormone)
o eventual death due to severe hypotension -> if this happens suddenly it is called an Addisonian Crisis
What tests can be done to diagnose Addison’s?
- low 9am cortisol and high ACTH at any time in blood tests
- unresponsive/reduced amount of cortisol produced to a big dose of synthetic ACTH (synacthen)
What is the results of a typical Addison’s patient to tests for Addison’s?
- 9am cortisol = 100 (normal = 270-900)
- 9.30, post IM injection of synacthen = 150 (normal = >600)
What is the commonest cause of congenital adrenal hyperplasia?
- 21-hydroxylase deficiency
How long will a baby with complete 21-hydroxylase deficiency survive without treatment?
- less than 24 hours
What happens to the hormone balance in someone with complete 21-hydroxylase deficiency?
- no aldosterone and cortisol
- lots of sex steroids, particularly testosterone, because all pro-hormones are channelled down that pathway
What is the age of presentation of congenital adrenal hyperplasia?
- as a neonate with salt losing Addisonian crisis - floppy baby
- before birth if a previous child had suffers from CAH
What is an important feature to notice immediately after birth due to congenital adrenal hyperplasia?
- ambiguous genitalia in girls due to the excess testosterone -> virilisation - fusion of labia into a scrotum like structure
- if this is noticed they are keep in hospital to prevent arrest
- can be prevented by giving the mother some steroid in pregnancy if there is a known risk of 21-hydroxylase deficiency
What occurs in partial 21-hydrxylase deficiency?
- low levels of cortisol and aldosterone but crucial enough to survive so they present at any age
- excess sex steroid -> often misdiagnosed as PCOS or other similar disease
What are the main problems with partial 21-hydroxylase deficiency?
- boys = precocious/early false puberty
- girls = hirsutism, virilisation and acne
What are the consequences of 11-beta-hydroxylase deficiency?
- acts as an aldosterone receptor agonist so behaves as if there is too much aldosterone -> hypertension and hypokalaemia
- sex hormones are also in excess so virilisation, hirsutism etc
- lack of cortisol and aldosterone -> aldosterone issues dont present due to reasons above
What happens to the hormone balance in 17-hydroxylase deficiency?
- low cortisol and sex steroids
- 11-deoxycorticosterone and aldosterone are high
What are the presentations of 17-hydroxylase deficiency?
- never go through puberty -> usually present around pubertal age
- hypertension without addisonian crisis because they have aldosterone
- borderline hypoglycaemia
- lots of infections because you need cortisol to cope with the stress of infection
What is made in the zona reticularis?
- androgens and oestrogens
Which adrenal hormone is not under ACTH control? State what controls its release.
- aldosterone -> release is stimulated by renin in the renin-angiotensin system
- hyperkalaemia, hyponatraemia, drop in renal blood flow and beta-1 adrenoceptor stimulation
Compare glucocorticoid and minerocorticoid receptors?
- GR = wide distribution, selective for glucocorticoids, low affinity for cortisol
- MR = descrete distribution to the kidney, don’t destingiush between aldosterone and cortisol, high affinity to cortisol
How come cortisol doesn’t usually activate MR receptors despite being able to do so?
- 11b-hydroxysteroid dehydrogenase deactivates cortiol into cortisone
Why is hypokalaemia seen in Cushing’s Syndrome?
- the 11b-hydroxysteroid dehydrogenase system becomes overwhelmed so potassium is excreted due to activation of MRs
- the same mechanism cause hypertension by absorbing sodiuma nd water
Describe the structure of hydrocortisone.
- cortisol and hydrocortisone have the same structure, it’s just that cortisol is endogenous and hydrocortisone is synthetic - can be used to treat Addison’s disease/crisis
- at high doses it can cause MR activation because it overwhelms the 11b-hydroxysteroid dehydrogenase system just like cortisol
Describe prednisolone.
- a glucocortcoid with weak mineralocortioid activity
- tends to be used as an immunosuprressive
Describe dexamethasone.
- very POTENT glucocorticoid -> used clinically for things like brain metastases where there is a lot of oedema -> used as an acute anti-oedema agent
- NO mineralocorticoid effect
Describe fludrocortisone.
- an aldosterone analogue -> used as an aldosterone substitute in Addison’s disease
- NOT a glucocorticoid
-
What is the method of administration for corticosteroids?
- all can be given orally
- in acute situations they are given parenterally (IV or IM)
Compare the biological activity of the corticosteroids.
- binding to plasma proteins (corticosteroid binding globulin and albumin)
- hydrocortisone is about 90-95% bound
- prednisolone is less bound and dexamethasone and fludrocortisone are even less bound
- fludrocortisone is only bound to albumin
State and explain the difference in treatment between patients with primary and secondary adrenocortical failure.
- primary = hydrocortisone and fludrocortisone
- secondary = hydrocortisone -> is a porblem with the pituitary and not adrenal so aldosterone isn’t affect as renin-angiotensin system is fine
What is the treatment for Addisonian crisis?
- FIRSTLY = 0.9% NaCl for rehydration
- then high dose of hydrocortisone (IV or IM)
- 5% dextrose if hypoglycaemic
How is congenital adrenal hyperplasia treated?
- cortisol replacement -> hydrocortisone or dexamethasone
- replace aldosterone -> fludrocortisone
- suppress ACTH -> reduced adrenal androgen production
How is therapy for CAH monitored?
o17a-hydroxyprogesterone levels
o clinical assessments of patients complaintst:
- cushingoid - glucocorticoid dose too HIGH
- hirsuitism/acne - glucocorticoid dose too LOW (so ACTH is high)
Name some times in which hydrocortisone/cortisol mimicing drugs dosage should be increased.
- when the patient is vunerable to stress
- minor illness = x2 normal dose
- surgery = IV or Im hydrocortisone in the build up to the generla anaesthetic
- C
Describe the hypothalamo-pituitary-testes axis.
Describe the hypothalamo-pituitary-ovarian axis in the follicular phase.
- LH stimulates production of oestradiol and progesterone in the ovaries
- FSH stimulates follicular development and inhibin
- by around day 10, the leading follicle develops into a Graffian Follicle
- oestrogen initially has negatively inhibits LH and FSH secretion
- so in the follicular phase their HPG axis is basically the same as men
Describe the hypothalamo-pituitary-ovarian axis in the luteal phase.
- once the oestrogen levels reach a certain point, it switches from negative feedback to positive feedback
- it increases GnRH release and increases LH sensitivity to GnRH -> leads to a mid-cycle LH surge -> triggers ovulation from the leading follicle
- if implantation does NOT occur, the endometrium is shed (menstruation), but if implantation does occur you have pregnancy
Describe the control of prolactin secretion.
- dopamine has a negative effect on prolactin release, is the main hypothalamic hormone controlling prolactin release
- TRH has a mild stimulatory effect
- prolactin stimulates the production of milk in lactating women
- if it becomes dysregulated it will switch off gonadal function via LH actions on the ovaries and testes -> natural contraceptive just after birth
- also reduces GnRH pulsatility so that it is released basally all the time rather than in regular pulses
- 3
- 1 -> prolactin switches off GnRH pulsitivity so FSH and LH would be low as well as oestradiol
What changes in maternal hormones occur during pregnancy?
- hGH (human growth hormone) decreases as the placental hGH-variant increases towards term
- kiss peptin also increases 1000s of times to act as a natural contraception by down regulating the axis
What is the mechanism of RANKL?
- RANKL expressed on osteoblast surface
- RANKL binds to RANK-R to stimulate osteoclast formation and activity
- osteoblasts express receptors for PTH and calcitriol -> regulate balance between bone formation & resorption
Describe bone structure.
- cortical (hard) bone -> outer area
- trabecular (spongy or trabecular) bone -> inner area
o both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
What are the effects of renal failure on bone disease?
- decreased renal function = decrease in the production of calcitriol and phosphate excretion so plasma phosphate increases
- the decrease in calcitriol production will cause a decrease in calcium absorption from the intestines while phosphate plasma concentration rises both leading to hypocalcaemia
- hypocalcaemia will stimulate PTH release -> PTH will break down bone matrix in order to try and restore the blood calcium concentration to the normal level -> hypocalcaemia decreases bone mineralisation
- combination of the increased bone resorption and decreased bone mineralisation will lead to osteitis fibrosa cystica
- imbalance between calcium and phosphate you can get some of it forming the main salts which can be deposited in extra-skeletal tissue causing vascular calcification
Define osteoporosis - include the clinical cut off point?
- a condition of reduced bone mass (fewer trabeculae) and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma
- clinically having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average value for young healthy adults
What are the clinical features of Paget’s disease?
- bone pain
- increased vascularity -> warmth over affected bones
- deafness -> cochlear involvement
- radiculopathy -> due to nerve compression
- multiple fractures
- increased bone width
Describe the melanocortin system.
- under normal conditions, the POMC, from arcuate nucleus, will be broken down to a-MSH which is an endogenous agonist of the MC4R (paraventricular nucleus) -> the reason why you aren’t hungry all the time is because of this a-MSH tone
- you trigger hunger by the release of Agrp from the arcuate nucleus which is an endogenous antagonist of MC4R
- when you need to eat, you increase Agrp activity, block the inhibitory signal of a-MSH and stimulates food intake
Describe the ob/ob mouse.
Name some co-morbidities associated with obesity.
What is the thrifty gene hypothesis?
What is the current classification of diabetes?
What is the mechanism of glucose damage to the microvascular?
What does a normal retina look like?
- optic disc at the nasal part of the eye and the macula more laterally (involved in colour vision and acuity)
- various vessels that come out into the back of the retina and they usually have a very regular arrangement
What are the features of background diabetic retinopathy?
- hard exudates -> appear as cheesy, yellow space in the retina -> due to leakage of lipid content
- microaneurysms -> can rupture and cause blot haemorrhages
What are the features of pre-proliferative diabetic retinopathy?
- cotton wool spots - aka soft exudates -> show retinal ischaemia
- show severall haemorrhages
Describe proliferative retinopathy.
- involves the formation of new vessels in response to retinal ischaemia
- if the vessels form in the region of the macula they cause problems with acuity and colour vision
- the newly formed vessels are generally more fragile -> can bleed at anytime
Describe maculopathy.
- hard exudates near the macula -> same disease a background diabetic retinopathy barring the location of the hard exudates
- can threaten direct vision
What are the risk factors for macrovascular disease?
- low birth weight increases the chance of macrovascular disease
What is the pathway to foot ulceration?
What is this?
- a Charcot’s Foot
How is it possible to distinguish betwen osteomyelitis (infection of the bone) and Charcot’s foot?
- MRI
