Theme 1 - Endocrine System Flashcards
Do the glands in the endocrine system have ducts?
No they are ductless
Do hormones act upon all cells?
No only those with target tissues
Draw or list the endocrine glands
Hypothalamus Pituitary (Anterior/Posterior) Thyroid ParaThyroid Thymus Kidney Adrenal Pancreas Gonad
Draw and label the hypothalamus/pituitary gland.
Hypothalamus
Hypothalamico-hypophyseal vessel
Infindibulum
anterior/posterior
What is the main function of thyroid and parathyroid
Metabolic rate
calcium homeostasis
What hormone does the pancreas secrete
Insulin
Function of Adrenal medulla and cortex
Medulla -Stress response,
Cortex - Stress, Sodium and glucose
Function of gonads
Secondary sexual characteristics
What are the three main types of hormone receptor?
G protein coupled
Steriod
Tyrosine Kinase
Steroid hormone - Mechanism of action
Crosses membrane
binds to receptor in cytoplasm or nucleus
This complex then influences gene transcription
G protein mechanism of action
Binds to receptor
Synthesis of second messenger CAMP
Second messenger phosphorelates to cause …
Tyrosine mechanism of action
Sometimes dimerised
Hormone binds to receptor
recptor then acts as enzye to influence intracellular activity
What are the characteristics of peptide hormones?
Water solvable Not orally active Rapid onset Protease vulnerable Unable to cross cell membrane without carrier protein Short duration and plasma half life
Characteristics of steriod and thyroid hormones
Lipid soluble Orally active Slow onset Must be protein bound in blood But unbound is biologically active Can cross cell membrane Long duration and half life
Is secretion usually controlled by the anterior or posterior pituitary
anterior
TSH stimulates?
Thyroid - Thyroxine
ACTH stimulates?
Adrenal cortex - cortisol
TRH, from/stimulates?
Hypothalamus/ant pit to relaese TSH
CRH from/stimualtes?
Hyopthalamus to ant pit to relaease ACTH
GnRH from/stimulates?
Hypothalamus to ant pit to release FSH
GHRH from stimulates?
Hypothalamus to ant pit to release growth hormone
How is hormone secretion typically regulated, give an example?
Negative feedback.
eg TRH, TSH, Thyroxine
CRH, ACTH, cortisol
GnRH, FSH, oestrodiol
What hormaones are secreted by the posterior pituitary ?
ADH/vasopressin and Oxytocin
What types of hormone are ADH and oxytocin, where are they synthesised?
Peptide
Synthesised in supraoptic and para-ventricular nuclei of the hypothalamus
What influences the secretion of ADH
Plasma osmolarity.
What affect does ADH have upon the kidney?
Stimulates v2 receptors which cause the translocation of aquaporins to membrane of tubule membrane that lead to water re absorption
How does vasopressin/ADH act upon the vascular system?
Stimulates v1 receptors to cause vasoconstriction.
What influences secretion of oxytocin?
Stimulation of genitals and nipples
What does oxytocin act upon?
Acts via IP3 channes to cause contraction of smooth muscle in breast and uterus.
During pregnancy there is an increase in oxytocin, explain why this dies not result in a premature birth?
Increase in oxytocin paralleled by an increase in oxytocinase. Inhibits the contraction of smooth muscle in uterus.
Explain how the childbirth an oxytocin constitutes a positive feedback loop.
oxytocin causes contraction of smooth muscle in uterus. Foetus pushes against cervix. Stimulation of cervix causes further release of oxytocin leading to further contraction of uterus.
What hormones are secreted by the anterior pituitary?
Growth Hormone Prolactin TSH ACTH FSH LH
What’s the difference between where hormones released from the ant and post pituitary gland are synthesised?
Hormones from post pituitary gland are synthesised in the hypothalamus (supraoptic and paraentricular).
Hormones secreted from ant pituitary gland are synthesised in the ant pituitary.
Where are the following hormones synthesised and by what cells? FSH, ACTH, TSH, proactin, growth hormone
In the ant pituitary by: gonadotrophe, corticotrophe, thyrotrophe and lactotrophe, somatotrophe cells respectively
What hormones inhibits/stimulates prolactin synthesis?
Dopamine inhibits. TRH stimulates.
What non hormonal factors can stimulate prolactin secretion?
Mild stress, nipple stimulation, coitus.
What is the role of prolactin?
Development of breast tissue and lactation.
Is prolactin secreted in males?
Yes
What inhibits and stimulates the release of growth hormone?
GHRH from hypothalamus
GHRIH /somatoststin
How do nutritional factors influence the secretion of growth hormone?
Stimulated by: Increased carbs and amino acids
Decreased amino acids.
In some tissues GH needs to act via second messengers, what are these and where are they produced?
INsulin like growth factor 1 &2. Made in the liver
What is the role of GH? Is
Increase linear growth in adolescence (foetal growth independent of this)
Which part of the adrenal/suprerenal gland is essential for life?
The cortex
What types of hormones are secreted from the adrenal cortex?
glutocorticoids
mineralcorticoids
What steriod hormones are synthesised from cholesterol?
Adosterone
Cortisol
Testerone to androsterone
It it significant that the adrenal glands secrete small amounts of male and female sex hormones?
No, this is only significant in adrenal disorders
When does ACTH secretion peak?
Morning (assuming non shift work)
Stress
What is the typical lad time of cortisol levels in relation to ACTH peak and nadir?
2hrs
What percentage of cortisol in the blood is free and what happens to the rest?
10% free the rest is protein bound.
In the plasma what is cortisol bound to?
10% free
15% albumin
75% corticosteroid binding globulin
What influence does pregnancy have on the levels of corticosteriod binding globulin?
CBG increses but cortisol increases to maintain some level of free cortisol.
Where does the metabolism of adrenal steroids take place?
Liver
How does cortisol influence carbohydrate metabolism?
Antagonises the effects of insulin on cellular uptake of glucose
Stimulates glycogenolysis
Stimulates hepatic gluconeogenesis
What influence does cortisol have on lipid metabolism?
Stimulates lipolysis and mobilisation of fatty acids.
In relation to fat synthesis and disposition, what can excessive levels of cortisol cause?
Increased fat synthesis.
fat deposited around face and inter scapula region and trunk.
What effect does cortisol have on amino protein metabolism?
Stimulates amino acid uptake in liver, leading to gluconeogenesis.
Inhibits amino acid uptake in periphery
How does cortisol influence blood pressure?
Enhances vasoconstrictor response to catechloamines, which then increases blood pressure.
What are the psycholgical effects of glutocosteroids ?
Elation and sedation
How do glutocorticoids affect immune response?
They suppress the lymphoid tissue, reduce the antibody production and inhibit the cellular immune system.
• They stabilize leucocyte membranes and reduce the release of proteolytic enzymes.
• They inhibit phospholipase A2 and reduce the synthesis of the inflammatory mediators.
Name 2 mineralocorticoid
Aldosterone and 11-deoxycorticosterone
What is the major controlling factor of aldosterone?
Renin angiotensin system
Other than renin-angiotensin, what other factors influence aldosterone?
Stimulated by: Trauma anxiety Hyperkalemia Hyponaturemia Inhibited by: atrial natriuric peptide
Within the circulation how much aldosterone is protein bound?
50%
Aldosterone mechanism of action?
intracellular receptors which cause expression of ion channels that transport sodium and potassium ions across the cell membrane
Upon what part of the kidey does aldosterone affect reabsorption?
distal tubule
To a lesser extent what tissues does aldersterone affect sodium reabsoption?
Loop of Henle collecting duct proximal tubule colon sweat glands salivary glands
Pharma uses of adrencorticosteroids (hydrocartisone)
Asthma, allergies, arthritis
What type of therapy are mineralocorticoids used for?
replacement therapy
What is used to replace aldersterone and why?
fludricortisol, because aldosteron has a short half life
What are the adverse affects of glucocortioids?
Steroid usage may suppress wound healing and may exacerbate infections due to their immunosuppresant effects.
Long term use in children may cause inhibition of growth, and in adults may result in osteoporosis.
The development of diabetes mellitus and other symptoms of Cushing’s syndrome also often accompanies steroid therapy.
Adverse chronic effect of glucocorticoid and explain this
Chronic administration of exogenous glucocorticoids results in suppression of ACTH secretion leading to atrophy of the adrenal cortex.
Why would it be a bad idea for a pt to suddenly stop long term steriod therapy?
If steroid therapy is then stopped abruptly, the adrenal cortex is unable to secrete endogenous hormones and the patient suffers an Addisonian crisis, which may be fatal. This consequence overcome by the gradual reduction of the dose of the exogenous steroid
Within the thyroid what is the function of the colliods
reserviour for thyroid hormone
Thyroid hormones are especially important for the development of the CNS, what aspect in particular
The mylenation of nerve fibres
By what primary mechanism do thyroid hormones increase metabolic rate?
Increase number and size of mitochondria, increase in metabolic enzymes
Thyroid hormones increase basal metabolic rate, and therefore oxygen consumption, in nearly every organ except?
Brain Uterus Testes Spleen Thyroid gland Anterior pituitary gland
What is levothyroxine used to treat and how is it administered?
treat thyroid deficiency. It can be used to suppress TSH secretion in the treatment of some thyroid tumours. It can be given by mouth or by injection.
Where is levothyroxine metabolised and what are the adverse effects associated with it?
Liver
palpitations, arrhythmias, diarrhoea, insomnia, tremor, weight loss
name two anti thyroid drugs
carbimazole
methimazole
potassium perchlorate
How can nuclear medicine be used to reduce thryroid hormaone secretion
Iodine 131 (raduioactive isotope) actively taken up by thyroid. This in turn will damage cells and reduce secretion.
What is carbimazole and its mechanism of action?
anti thyroid drug - used to treat hyperthyroidsim.
Converted into methimazole. Prevents synthesis if T3 and T4.
Adverse effects of carbimazole?
Rashes and pruritus are common which can often be treated with antihistamines. The most serious rare side effect is neutropenia and agranulocytosis. Teratogenic.
What is Propylthiouracil and its mechanism of action?
Used to treat hyperthyroidism. Inhibits thyroid hormone synthesis. can be used in first trimester
Adverse effects of Propythiouracil?
Rashes and pruritus are common which can often be treated with antihistamines. Its notable side effects include a risk of agranulocytosis and risk of serious liver injury, including liver failure and death
Goitre?
Enlargement of thyroid gland
Primary hypothyroidism
problem with thyroid
Secondary hypothyroidism
Problem with pituitary
Hypothyroidism Symptoms
May be none Lethargy Mild weight gain Cold intolerance Constipation Facial puffiness Dry skin Hair loss Hoarseness Heavy menstrual periods
Severe hypothyroidism: signs
Change in appearance eg face puffy and pale Periorbital oedema Dry flaking skin Diffuse hair loss Bradycardia Signs of median nerve compression (carpal tunnel) Effusions, eg ascites, pericardial Delayed relaxation of reflexes Croaky voice Goitre Rarely stupor or coma
Causes of Primary Hypothyroidism
Autoimmune
iatrogenic
Thyroiditis
Drugs (e.g. lithium
treatment for primary hypothyroidism?
Thyroxine
What is Hasimoto’s disease?
Chronic autoimmune thyroisitis
Symptoms of thyrotoxicosis?
Weight loss Lack of energy Heat intolerance Anxiety/irritability Increased sweating Increased appetite Thirst Palpitations Pruritus Weight gain Loose bowels Oligomenorrhoea
Signs of thyrotoxicosis
Tremor Warm, moist skin Tachycardia Brisk reflexes Eye signs Thyroid bruit Muscle weakness Atrial fibrillation
Signs and symptoms of thyroid eye disease
itchy eyes bulging eyes diplopia loss of colour vision inability to close eyes reddening of conjunctiva
what is the most common cause (75%) of hyperthyroidism?
Graves Disease (autoimmune) Autoantibody stimulates the TSH receptor, causing excess thyroid hormone production and thyroid growth (goitre)
Other causes of thyrotoxicosis
Toxic multinodular goitre
Toxic adenoma
Thyroiditis
Drugs (e.g. amiodarone)
what is gestational thyrotoxicosis?
Placental β-human chorionic gonadotrophin is structurally similar to TSH and TSH-like action on the thyroid
likely if hyperemesis / twin pregnancy
Settles after 1st trimester of pregnancy
medical treatment of hyperthyroidism?
Carbimazole or propylthiouracil (PTU)
18 months – 2 years
non medical treatment of hyperthyroidism?
radioactive iodine Sub-total thyroidectomy (“almost total”) Patients must be euthyroid pre-operatively Medical therapy first Risks Anaesthetic Neck scar Hypothyroidism Hypoparathyroidism Vocal cord palsy (recurrent laryngeal nerve damage)
What are the features of thyroid storm/thyrotoxic crisis?
Graves Goitre, thyroid eye disease Hyperpyrexia CNS Agitation, delirium Cardiovascular Tachycardia >140 bpm Atrial dysrhythmias Ventricular dysfunction Heart failure GI Nausea & vomiting Diarrhoea Hepatocellular dysfunction
Who gets thyroid storm?
Usually 2 degree Graves disease.
Unrecognised
Incompletely treated hyperthyroidism
What percentage if cortisol is bound in plasma and what to?
90% to cortisol binding globulin
Describe cortisol levels in relation to circadian rhythm
rise during the early morning
peak just prior to awakening
fall during the day
are low in the evening
How does 11--HSD-2 relate to cortisol function in the kidney?q
inactivates cortisol, enabling aldosterone to bind the Mineralocorticoid receptor
What syndrome is an excess of cortisol?
Cushings
Signs of Cushings x4
Weight gain Central obesity Hypertension Insulin resistance Neuropsychiatric problems Osteoporosis
Pathogenesis of Cushings? x4
Pituitary adenoma: ACTH-secreting cells (‘Cushing’s disease’)
Adrenal tumour: adenoma (or carcinoma)
‘Ectopic ACTH’: carcinoid, paraneoplastic
Iatrogenic: steroid treatment (‘Cushingoid’)
Clinical features of Cushings in relation to appearance
Central obesity with thin arms & legs
Fat deposition over upper back (‘buffalo hump’)
Rounded ‘moon’ face
Thin skin with easy bruising, pigmented striae
Hirsutism
Disease associated with lack of cortisol?
Addisons disease
Pathogenesis of Addisons disease?
Primary adrenal insufficiency - usually autoimmune
iatrogentic - sudden withdrawl of steriods
Clinical features of Addisons disease?
Malaise, weakness, anorexia, weight loss Increased skin pigmentation: knuckles, palmar creases, around / inside the mouth, pressure areas, scars Hypotension / postural hypotension Hypoglycaemia
Differences between AUTOIMMUNE POLYENDOCRINE SYNDROMES type 1 and 2 in terms of epidemiology?
Rare/More common (still rare)
Infancy/Infancy to adulthood
Differences between AUTOIMMUNE POLYENDOCRINE SYNDROMES type 1 and 2 in terms of genealogy?
AIRE gene/polygenic
Common phenotype of AUTOIMMUNE POLYENDOCRINE SYNDROMES type 1
Addison’s disease
Hypoparathyroidism
Candidiasis
Common phenotype of AUTOIMMUNE POLYENDOCRINE SYNDROMES type 2
Addison’s disease
T1 diabetes
Autoimmue thyroid disease
In terms of AUTOIMMUNE POLYENDOCRINE SYNDROMES, what conditions can occur together?
Type 1 diabetes Autoimmune thyroid disease (hypo- or hyper-) Also gestational / post-partum thyroiditis Coeliac disease Addison’s disease Pernicious anaemia Alopecia Vitiligo Hepatitis Premature ovarian failure Myasthenia gravis
Management of Cushings?
Surgical (depending on the cause)
Transphenoidal adenectomy
Adrenalectomy
Pituitary radiotherapy
Managment of Addisons?
Steroid hormone replacement therapy (‘glucocorticoid’):
Usually hydrocortisone (sometimes prednisolone)
Patients with primary adrenal insufficiency also need mineralocorticoid replacement therapy (fludrocortisone).
Patients with secondary adrenal insufficiency will often be taking other hormone replacement therapy (do not need fludrocortisone).
Considerations for patients on long term steroid replacement therapy?
They may not mount an adequate ‘stress response’.
Their steroid treatment should not be stopped suddenly.
If they need a major procedure / an operation, they require increased steroid cover as described.
They should be given a ‘Steroid Treatment Card’ to remind them (& their doctors) about this.
Key hormone involved in fluid balance
ADH/vasopressin
What stimulates ADH/vasopressin
Changes in plasma osmolality
Osmoreceptors detect changes in plasma osmolality, where are these located?
Anterior wall of third ventricle
How do osmorececeptors influence the fluid balance?
Their volume changes which in turn stimulates synthesis if ADH in the hypothalamus and signals cerebral cortex to generate feeling of thirst.
Where is vasopressin synthesised and released from?
Synthesised in supraoptic and paraventricular nuclei of hypothalamus and secreted from posterior pituitary gland.
What are the features of low plasma osmolality in terms of AVP, urine and thirst?
AVP undetectable
Dilute urine
High urine output
No thirst
What are the features of high plasma osmolality in terms of AVP, urine and thirst?
High AVP secretion Concentrated urine Low urine output Increased thirst sensation Drinking immediately transiently suppresses AVP secretion and thirst Avoids ‘overshoot’
Polydipsia
Excessive thirst
Polyuria
Excessive urination
Other than DM what are the 3 main causes of polydipsia and polyuria?
Cranial DI
Nephrogenic DI
Primary polydipsia
Principle mechanism of cranial DI?
Decreased osmoregulated AVP recretion.
Causes of cranial DI?
Genetic
Idiopathic
Secondary - post surgical/trauma
How does cranial DI relate to polydipsia?
Excess solute free urine. So thirst stimulated to maintain plasma osmolality
5 Symptoms of hypothalmic syndrome
Disordered thirst and DI Disordered appetite (hyperphagia) Disordered temperature regulation Disordered sleep rhythm Hypopituitarism
Mechanism of nephrogenic DI?
Renal tubules resistant to AVP
causes of nephrogenic DI?
Idiopathic Genetic Metabolic - High Ca/low K Chronic Kidney Disease Drugs - Lithium
Wis primary polydipsia and how dies it relate to polyurea?
Psychogenic. Increased fluid intake leads to low plasma osmolality which in turn increases AVS secretion causing polyuria.
What is the water deprivation test?
Period of dehydration Measure plasma and urine osmolalities & weight Injection of synthetic vasopressin Desmopressin (DDAVP) Measure plasma and urine osmolalities
Following a water deprivation test what would the responses be for; normal, cranial DI and nephrogenic DI?
Normal response to dehydration
Normal plasma osmolality, high urine osmolality
Cranial diabetes insipidus
Poor urine concentration after dehydration
Rise in urine osmolality after desmopressin
Nephrogenic diabetes insipidus
Poor urine concentration after dehydration
No rise in urine osmolality after desmopressin
Treatment for cranial DI?
DDAVP (desmopressin)
Over-treatment can cause hyponatraemia
treatment for nephrogenic DI?
Correction of cause (metabolic / drug cause)
Thiazide diuretics / NSAIDs
treatment for primary polydipsia?
Explanation, persuasion
Psychological therapy
Definition and symptoms of hyponatraemia?
[Sodium] <135 mmol/L Severe [Na] <125 mmol/L May be asymptomatic Depends on rate of fall as well as absolute value Brain adapts (chronic) Non-specific Headache, nausea, mood change, cramps, lethargy Severe / sudden Confusion, drowsiness, seizures, coma
In terms of hyponatraemia, what factors need to be excluded?
Drug causes - thiazide
High glucose protein concentrations
How is hyponatraemia classified?
Classify by extracellular fluid volume status
Hypovolaemia
Renal loss, non-renal loss (D&V, burns, sweating)
Normovolaemia (euvolaemia)
Hypoadrenalism, hypothyroidism
Syndrome of inappropriate ADH secretion (SIADH)
Hypervolaemia
Renal failure, cardiac failure, cirrhosis, excess IV dextrose
What is SIADH?
syndrome of inappropriate ADH secretion
Signs of SIADH?
Clinically euvolaemic patient
Low plasma sodium and low plasma osmolality
Inappropriately high urine sodium concentration and high urine osmolality
treatment of SIADH
Identify and treat the underlying cause Fluid restriction (<1000 ml daily) Induce negative fluid balance 500 ml Aim ‘low normal’ sodium Demeclocycline Drug that induces mild nephrogenic DI Vasopressin (V2 receptor) antagonists “Vaptans” – induce a water diuresis Expensive, variable responses, some attenuation Lack of clinically significant outcome data
Risks of correcting hyponatraermi too rapidly?
oligodendrocyte degeneration and CNS myelinolysis (osmotic demyelination)
Severe neurological sequelae, may be permanent
Alcoholics & malnourished particularly at risk
normal BMI range and calculation
18.5 - 24.9 kg/m2
Ways of measuring body mass/obesity?
BMI Waist circumference skin fold thickness Bioelectrical impedance analysis Ethnicity specific cut-offs
8 Medical problems associated with obesity?
Metabolic syndrome / type 2 diabetes Cardiovascular disease Respiratory disease Liver disease Cancer Reproductive dysfunction Joint problems Psychological morbidity
What is metabolic syndrome?
Constellation of closely associated CV risk factors’
Visceral obesity
Dyslipidaemia
Hyperglycaemia
Hypertension
INSULIN RESISTANCE is the underlying pathophysiological mechanism
What is metabolic syndrom assocciated with in terms of BMI and body fat distribution?
central fat distribution and BMI above 30
What is CV disease?
Metabolic syndrome’ PLUS blood volume and blood viscosity vascular resistance hypertension left ventricular hypertrophy coronary artery disease stroke
What respiratory related disorders are associated with obesity?
Obstructive sleep apnoea Hypoxia / hypercapnia Pulmonary hypertension Right heart failure Accidents Daytime somnolence
What GI/liver disorders are associated with obesity?
Non-alcoholic fatty liver
Non-alcoholic steatohepatitis
May progress to cirrhosis, portal hypertension, hepatocellular cancer
Gallstones
Reflux
Cancers associated with obesity?
Breast, endometrial, oesophagus,
colon, gall bladder, renal, thyroid
Reproductive disorders associated with obesity
Polycystic ovarian syndrome Oligomenorrhoea, hirsutism, acne Subfertility Endometrial hyperplasia Insulin resistance
Male hypogonadism
Adverse pregnancy outcomes
What is the 1 licenced pharmacological treatment for obesity?
Orlistat
Orlistat mechanism of action?
Binds & inhibits lipases in the lumen of the gut
Prevents the hydrolysis of dietary fat into absorbable free fatty acids / glycerol
Excrete ~ 1/3rd dietary fat
Adverse affects of orlistat?
Flatulence
Oily faecal leakage
decreased absorptive of fat soluble vitamins
2 surgical treatments for obesity?
Laparoscopic adjustable banding
Roux-en-Y gastric bypass
Differences between Laparoscopic adjustable banding
Roux-en-Y gastric bypass
Restrictive
Malabsorptive
Alterations in gut hormones and bile acid flow contribute to weight loss
banding adjustable.
Adverse affects of Roux-en-Y
Micronutrient deficiencies
Supplement with iron, B12, folate, calcium, vitamin D
Dumping syndrome
GI & vasomotor symptoms
Advantages of surgical treatment for obesity?
Weight loss 25-30%
Resolve or improve co-morbidities
Brings cost savings
Disadvantages of surgical treatment for obesity
Perioperative mortality / morbidity Depends on procedure and experience of surgeon Long-term follow-up Micronutrient deficiencies Some weight re-gain Patients will still be obese Expense
NICE guidelines for bariatric surgery
Recent onset T2DM:
Expedite bariatric surgery if BMI > 35
Consider surgery if BMI > 30
Must have been obese for at least 5 years
Must engage with non-surgical weight-loss programme for 12-24 months first
Oestrogen, FSH and LH levels in pre and post menopausal women
Oestrogen levels
Pre-menopausal: cycling
Post-menopausal: very low constant levels
↓E2, ↑LH / FSH
Age of menopause
50 +/-2
Symptoms of menopause and median length of symptoms
Hot flushes and night sweats
7 years
Morbidities associated with menopause
osteoporosis, CHD, sexual dysfunction
Benefits of Hormone Replacement Therapy
Rx menopausal Sx
↓ osteoporosis / fracture risk
for duration Rx
Adverse affects of Hormone Replacement Therapy?
↑ venous thrombo-embolism ↑ breast Ca (small) esp > 5 years ↑ endometrial Ca if use unopposed E2
What are the effects of starvation/ anorexia nervosa upon hormones?
↓ LH, ↓ FSH, ↓ oestrogen / testosterone ↓ fertility, amenorrhoea ‘hypothalamic amenorrhoea’ makes ‘evolutionary sense’ in times of famine Osteoporosis Rx HRT / COCP
Explain in terms of hyperglycaemia, how insulin deficiency can lead to CV collapse
Hyperglycaemia leads to hyper osmolality and glycusuria whcih in turn lead to severe dehyration, electrolyte loss, renal failure and CV collapse.
Explain in terms of lypolysis, how insulin deficiency can lead to CV collapse
Increased rate of lypolysis and free fatty acids/ketone porduction. If supply is greater than demand from brain and muscle tissue ruslting affect will be acidosis that then causes CV collapse.
How will the body ususally try to manage acidosis?
Intracellualr buffering via K/H ion pump
increased ventilation to breath off CO2 and lower pH
Incresed renal excretion of H+ ions
In terms of electrolyte disturbances, what can the bodies managene t of ketoacidosis result in?
K+ depletion (possibly over 250mmol)
Sodium deplation
dehydration
What pt group is most succeptable to diabetic ketoacidosis?
young T1DM
name some precipitation factors of diabetic ketoacidisis x6
Infections – pneumonia, urinary tract, viral illnesses, gastroenteritis Error/ missed insulin administration Myocardial infarction Previously undiagnosed Type 1 diabetes Drugs: steroids Unidentified
Symptoms of diabetic ketoacidosis caused by hypergycaemia and dehydration
Thirst and polyuria
Weakness and malaise
Drowsiness, confusion
symptoms of diabetic ketoacidosis caused by acidosis
Nausea and vomiting
Abdominal pain
Breathlessness
signs of diabetic ketoacidosis caused by hypergycaemia and dehydration
Dry mouth, Sunken eyes
Postural or supine hypotension
Hypothermia & Coma
signs of diabetic ketoacidosis caused by acidosis
Facial flush
Hyperventilation
Smell of ketones on breath and ketonuria
Clinical management of diabetic ketoacidosis 5 steps
Confirm diagnosis and check for precipitating causes
Rehydrate & monitor fluid balance
Iv fluids - saline with added potassium
Consider urinary catheter
Lower glucose
Intravenous insulin – fixed rate 0.1Unit/kg/hr
Monitor electrolytes
Potassium (and sodium)
Prevent clots
Prophylactic low molecular weight heparin
What is most likely age group for Hyperosmolar Hyperglycaemic State?
40 plus
What are the precipitation causes dor HHS?
previously undiagnosed,
steroids,
diuretics,
sugar
Clinical managemt of HSS
Correct the profound dehydration
4 Autonomic Symptoms of Hypoglycaemia
Sweating, feeling hot
Trembling or shakiness
Anxiety
palpitations
Define hypoclycaemia
Hypoglycaemia is a biochemical term and exists when blood sugar < 4mmol/l but is often used to describe a clinical state. The clinical syndrome associated with hypoglycaemia develops as the nervous system becomes glucose deficient or ‘neuroglycopaenic’
What are the 4 classifications of hypogycaemia?
Asymptomatic (Awake/sleeping)
Mild symptomatic (patient can treat himself)
Severe symptomatic (help needed by third party)
Coma and convulsions
6 neuroglycopenic symptoms of hypoglycaemia
Dizziness, light-headedness Tiredness Hunger, nausea Headache Inability to concentrate, confusion, difficulty speaking, poor coordination, behavioural change, automatism Coma and convulsions, hemiplegia
Causes of hypoglycaemia
Insulin
Inappropriately excessive doses
Not eating, or insufficient carbohydrate
Sulfonylureas
What factors help to counter regulate hypoglycaemia and how do they do this?
Glucagon stimulates glycogenolysis and gluconeogenesis ,
adrenaline increases glycogenolysis
cortisol and GH limit glucose disposal in peripheral tissues, but this effect takes several hours
Treatment of hypoglycaemia (mild)
Minor episodes
20g carbohydrate as sugary drink, fruit juice, glucose tablets, glucose gels followed by something ‘starchy’ to eat
Glucose gels
treatment of hypoglycaemic coma
im or iv Glucagon 1mg
iv dextrose 25g (150ml 10% glucose)
What are the long term microvascular and macrovascular compliactions of diabeties mellitus?
Retinopathy
Neuropathy
Nephropathy
IHD
CVD
PVD
What cells are related to the microvascular compliaction of DM?
Retinal endothelial cells
Mesangial cells of glomerulus
Schwann cells and peripheral nerve cells
When are microvascular complications typically likely to presnt themselves in T1 and T2 DM?
May take years to develop so rare before 5 years of T1 DM and may be detected at presentation of T2 DM
Why does DM affect the retina so acutely?
Low density of capillaries
Little functional reserve
Flow needs to respond to local needs
What are the 4 Pathological Findings of Diabetic Retinopathy?
Loss of pericytes
Basement membrane thickening
Capillary closure
Ischaemia
What are the 3 Clinical Stages of Retinopathy?
Non-proliferative
Proliferative
Macular Oedema
What are the ways of managing and treating diabetic retinopathy?
Diabetic control important Blood pressure control important Laser treatment (Pan retinal, Focal) Intra-vitreal anti VEGF Ab
What are the 3 types of neuropathy?
Peripheral neuropathy
Mononeuropathy
Autonomic neuropathy
What 3 signs are indicative of peripheral neuropathy?
Muscle wasting in knuckles
Neuropathic ulcers on feet
Callus
Charcot foot
5 signs of autonomic neuropathy?
Gastroparesis Postural hypotension Erectile dysfunction Gustatory sweating Diarrhoea
4 Pathological Findings of Diabetic Nephropathy?
Basement membrane thickening (Loss of negative charge )
Podocyte loss (Loss of integrity of filtration barrier)
Glomerular sclerosis
Mesangial expansion
Management and treatment of diabetic nephropathy
Blood pressure control important
Blockers of RAS system preferred
Glucose control important but less so once overt proteinuria
Associated with increased CVD risk
Ultimately renal replacement / transplantation
In plasma what % of testeron is bound and what to?
around 50% to albumin
44% sex hormone binding globulin
2% free
What ate the two anatomical units within the testes?
Seminiferous tubules
Interstitium
What do the seminiferour tubules produce?
inhibin B and anti-Müllerian hormone are synthesized by Sertoli cells and sperm
What does the interstitium produce?
containing Leydig cells that produce androgens and peritubular myoid cells
Describe/draw the The hypothalamic-pituitary-testicular axis
Pulsatile secretion of GnRH
Secretion of LH and FSH
LH and FSH are composed of two glycoprotein chains.
LH is involved in release of Testosterone
FSH is involved in spermatogenesis and Inhibin B secretion
Describe testerone mechanism of action?
Steriod so passes through cell membrane where Androgen target cells generally convert testosterone to 5 α-dihydrotestosterone before it binds to the androgen receptor
Give 5 functions of testerone?
Regulation of gonadotropin secretion by the hypothalamic-pituitary system
Initiation and maintenance of spermatogenesis
Formation of the male phenotype during embryogenesis
Promotion of sexual maturation at puberty and its maintenance thereafter
Increase in lean body mass and decrease in fat mass
In terms of blood serum levels define primany and secondary hypoganadism
Primary hypogonadism: Testosterone below normal and the serum LHand/orFSH are above normal.
Secondary hypogonadism: Testosterone below normal and the serum LHand/orFSH are normal or low.
7 causes of primary hypognoadism
Klinefelter syndrome Cryptorchidism Infection-mump Radiation Trauma Torsion Idiopathic
8 causes of secondary hypognoadism
Congenital GnRH deficiency Hyperprolactinemia GnRH analog Androgen Opioids Illness Anorexia nervosa Pituitary disorder
Gestationl features of hypogonadism
First trimester – female genitalia to ambiguous genitalia to partial virilization
Third trimester – micropenis
Symptoms/Signs of hypogonadism up tp 10
Incomplete sexual development, eunuchoidism
Sexual desire & activity
Spontaneous erections
Breast discomfort, gynecomastia
Body hair (axillary & pubic), shaving
Very small or shrinking testes (esp < 5 ml)
Inability to father children, low/zero sperm counts
Height, low-trauma fracture, low BMD
Muscle bulk & strength
Hot flushes, sweats
Conditions with a High Prevalence of hypogonadism (Screening Suggested) up to 8.
Sellar mass, radiation to sella, other sellar disease
On meds that affect T production or metabolism
Glucocorticoids, ketoconazole, opioids
HIV-associated weight loss
ESRD and maintenance hemodialysis
Moderate to severe COPD
Osteoporosis or low trauma fracture (esp if young)
Type 2 diabetes mellitus
Infertility
What signs should you look for upon examining someone with suspected hypogonadism?
Amount of body hair Breast exam for enlargement/tenderness Size and consistency of testicles Size of the penis Signs of severe & prolonged hypogonadism Loss of body hair Reduced muscle bulk and strength Osteoporosis Smaller testicles Arm span
what investigations would you carry out for suspected hypogonadism?
Serum testosterone LH/FSH SHBG LFT Semen analysis Karoyotyping Pituitary function testing MRI DEXA scan
What factors can lower SHBG?
Moderate obesity Nephrotic syndrome Hypothyroidism Use of Glucocorticoids Progestins Androgenic steroids
What can raise levels of SHBG?
Aging Hepatic cirrhosis Hyperthyroidism Anticonvulsants Estrogens HIV infection
Treatment for hypoganaism and how can this be administered?
Testosterone
Gel
Injection
Buccal/Patch/Pellet
WHat are the contraindiactions to testerone therapy?
Breast or prostate cancer Lump/hardness on prostate exam by DRE PSA >3 ng/ml that has not been evaluated for prostate cancer Severe untreated BPH (AUA/IPSS >19) Erythrocytosis (hematocrit >50%) Hyperviscosity Untreated obstructive sleep apnea Severe heart failure (class III or IV)
Who does Gynecomastia affect?
Imbalance between androgen and estrogen
60% of boys during puberty – transient
30-70% in adult men
Define Gynecomastia
Gynecomastia, a benign proliferation of the glandular tissue of the male breast
It may be unilateral or bilateral
diagnosed on exam as a palpable mass of tissue at least 0.5 cm in diameter (usually underlying the nipple).
What can cause Gynecomastia?
Persistent pubertal gynecomastia Drugs Idiopathic Cirrhosis or malnutrition Hypogonadism Testicular tumour Hyperthyroidism Chronic renal insufficiency –Leydig cell dysfunction
Investigations for gynaecomatia?
Testosterone LH/FSH Prolactin LFT/U&Es B-hCG TFT Estrogen U/S-Mamogram
Treatmet options for gynaecomatia
Conservative –Reassurance
Treatment of cause
Tamoxifen
Surgery
