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
