Endocrinology Flashcards

Question

Explain syndrome of inappropriate ADH (SIADH).

Answer 1

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

Answer 2

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

Answer 3

``` 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.

Answer 4

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 ```

Answer 5

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

Answer 6

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

Answer 7

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.

Answer 8

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

Answer 9

``` 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.

Answer 10

Sensitises beta adrenoceptors to ambient levels of adrenaline and noradrenaline. Thus there is apparent sympathetic activation Tachycardia, palpitations, tremor in hands, lid lag

Answer 11

``` Weight loss despite increased appetite Breathlessness, palpitations, tachycardia Sweating Heat intolerance Diarrhoea Lid lag and other sympathetic features ```

Answer 12

``` 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 ```

Answer 13

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.

Answer 14

``` 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. ```

Answer 15

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

Answer 16

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)

Answer 17

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. ```

Answer 18

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

Answer 19

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

Answer 20

``` Taking too many steroids Endogenous: Pituitary dependent Cushing's disease Ectopic ACTH from lung cancer Adrenal adenoma secreting cortisol ```

Answer 21

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

Answer 22

Depends on cause Pituitary surgery (transsphenoidal hypophysectomy) Bilateral adrenalectomy Unilateral adrenalectomy for adrenal mass Inhibitors of steroid biosynthesis: metyrapone; ketoconazole

Answer 23

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.

Answer 24

``` 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.

Answer 25

Benign adrenal cortical tumour (zona glomerulosa) Aldosterone in excess Hypertension and hypokalaemia Diagnosis Primary hyperaldosteronism Renin - angiotensin system should be suppressed (exclude secondary hyperaldosteronism)

Answer 26

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.

Answer 27

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 ```

Answer 28

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

Answer 29

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)

Answer 30

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

Answer 31

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)

Answer 32

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

Answer 33

Diagram ``` Stimuli for renin production: Hyperkalaemia Hyponatraemia Decreased renal blood flow - vasoconstriction for haemorrhage and H20 reabsorption B1-adrenoceptor stimulation ```

Answer 34

Members of the nuclear receptors ``` Glucocorticoid receptors (GR) Mineralocorticoid receptors (MR) ``` Comparison: GR; MR -wide distribution; discrete distribution (kidney) -selective for glucocorticoids; do not distinguish between aldosterone and cortisol -low affinity for cortisol; high affinity for cortisol Cortisol converted to cortisone (inactive) by 11b-hydroysteroid dehydrogenase 2 (11B-HSD) to prevent from binding to MR. In Cushing’s, too much cortisol and this enzyme not very effective.

Answer 35

Hydrocortisone Glucocorticoid with mineralocorticoid activity at high doses (bind to MR). Prednisolone Glucocorticoid with weak mineralocorticoid activity. Dexamethasone Synthetic glucocorticoid with no mineralocorticoid activity. Fludrocortisone Aldosterone analogue Used as an aldosterone substitute Subtle changes in drug structures to bind to different receptors with different affinities

Answer 36

1) Routes of administration Oral: hydrocortisone, prednisolone, dexamethasone, fludrocortisone Parenteral - large dose delivered quickly - acutely unwell (i.v. Or i.m.): hydrocortisone, dexamethasone 2) Distribution Bind to plasma proteins (cortisol binding globulin, CBG and albumin) as circulating cortisol does - not many are free 3) Duration of action Hydrocortisone - duration - 8h Prednisolone - duration - 12h Dexamethasone - duration - 40h

Answer 37

1) Primary adrenocortical failure Addison’s disease Patients lack cortisol and aldosterone Treat with hydrocortisone and fludrocortisone by mouth 2) Secondary adrenocortical failure (ACTH deficiency) Patients lack cortisol but aldosterone is normal because adrenal cortex is fine and renin-angiotensin system is fine. Treat with hydrocortisone 3) Acute adrenocortical failure - Addisonian crisis I.v. 0.9% sodium chloroform to rehydrate patient (saline) High dose hydrocortisone i.v. Infusion or i.m. Every 6h mineralocorticoid effect at high dose - intervenors hydrocortisone -big dose (overwhelm HB-HSD, therefore also MR and aldosterone effects) 5% dextrose if hypoglycaemic 4) congenital adrenal hyperplasia (CAH) Congenital lack of enzymes needed for adrenal steroid synthesis (primary adrenal cortex failure with enzymes missing) Objectives of therapy: -replace cortisol -suppress ACTH and thus adrenal androgen production -replace aldosterone in salt Main problem is sex steroid production Dexamethasone 1/day, pm or hydrocortisone 2-3/day, high dose Fludrocortisone ``` Monitor/ optimise therapy by measuring: 17 OH progesterone Clinical assessment -Cushingoid - GC dose too high -Hirsutism - GC dose too low (and hence ACTH has risen) ``` Additional measures in subjects with adrenocortical failure: Normal cortisol production - 20mg/ day In stress production - 200-300mg/ day Increase glucocorticoid dosage when patients are vulnerable to stress E.g. in minor illness - 2x normal dose Surgery - hydrocortisone .i.m. With pre-med at 6-8 hour intervals, oral once eating and drinking - general anaesthetic is stress, nil by mouth so i.m. Patients should carry a steroid alert card and wear a MedicAlert bracelet/necklace to let others know in an emergency.

Answer 38

28 days Follicular phase Ovulation Luteal phase If implantation does not occur - endometrium is shed (menstruation) If implantation does occur - pregnancy.

Answer 39

``` The inability to conceive after 1 year of regular unprotected sex. 1:6 couples Caused by abnormalities : -in males (30%) -or females (45%) -or unknown (25%) ``` Causes: 1) Primary gonadal failure (testes and ovaries) Low testosterone/ oestradiol so less negative feedback to hypothalamus giving high GnRH this high LH and FSH from pituitary. 2) Hypo/pituitary disease Low LH and FSH hence low testosterone/ oestradiol.

Answer 40

``` Hypogonadism Clinical features: -loss of libido = sexual interest/ desire -impotence -small testes -decrease muscle bulk -osteoporosis ``` ``` Causes: Hypothalamic-pituitary disease -hypopituitarism -Kallmans syndrome (anosmia -failure of smell, and low GnRH) olfactory nerves migrate with GnRH neurones in embryogenesis Testes originally undescended Stature low-normal -illness/ underweight ``` Primary gonadal disease - congenital: Klinefelters syndrome (XXY) - acquired: testicular torsion, chemotherapy Hyperprolactinaemia - switch off gonadotropin secretion e.g. pituitary tumour Androgen receptor deficiency ``` Investigations: LH, FSH, testosterone -if all low >> MRI pituitary Prolactin Sperm count -Azoospermia = absence of sperm in ejaculate -oligospermia = reduced numbers of sperm in ejaculate Chromosomal analysis (Klinefelters XXY) ``` Treatment Replacement testosterone for all patients For fertility: if hypo/pit disease, subcutaneous gonadotrophins (LH and FSH) mimic using hCG and recombinant FSH respectively Hyperprolactinaemia - dopamine agonist

Answer 41

``` Endogenous sites: Interstitial Leydig cells of the testes Adrenal cortex Ovaries Placenta Tumours ``` ``` Main actions: Development of the male genital tract Maintains fertility in adulthood Control of secondary sexual characteristics Anabolic effects (muscle, bone) ``` Circulating testosterone is 98% protein bound Tissue specific processing: -converted to dihydrotestosterone (DHT) active form which acts via the androgen receptor (AR) -17b-oestrodial (E2) acts via the oestrogen receptor (ER) e.g. brain and adipose tissue (found in men with obesity) Mechanism of action of DHT and E2 via nuclear receptors Clinical uses: Testosterone in adulthood will increase: -lean body mass -muscle size and strength -bone formation and bone mass (in young men) -libido and potency It will not restore fertility which requires treatment with gonadotrophins to restore normal spermatogenesis.

Answer 42

1) amenhorrhoea 2) polycystic ovarian syndrome (PCOS) 3) hyperprolactinaemia

Answer 43

Absence of periods Primary amenorrhoea = failure to begin spontaneous menstruation by age 16 years. Secondary amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles. Oligomenorrheoa = irregular long cycles ``` Causes - pregnancy/ lactation -ovarian failure: Premature ovarian failure - menopause earlier, apoptosis eggs earlier, POI (primary ovarian insufficiency) Ovariectomy/ chemotherapy Ovarian dysgenesis (Turners 45 XO) - lacking one chromosome - short stature, cubitus valgus (wide carrying angle), gonadal dysgenesis, 1:5000 live F births. - gonadotrophin failure: Hypo/pit disease Kallman’s syndrome (anosmia, low GnRH) Low BMI - leptin, can’t carry baby Post pill amenorrhoea - on pill oestrogen and testosterone exogenous so own axis switches so advised to stop every 4 years -hyperprolactinaemia -androgen excess: gonadal tumours ``` Investigation: Pregnancy test LH, FSH, oestrodial - up and down because cycle differs, if all low then hypothalamic pituitary disease Day 21 progesterone - after ovulation Prolactin, thyroid function tests (hypothyroidism -> amenorrhoea) Androgens (testosterone, androstenedione, DHEAS) Chromosomal analysis (Turners 45 XO) Ultrasound scan ovaries/ uterus Treatment Treat the cause (e.g. low weight) Primary ovarian insufficiency (failure - not called anymore) - infertile, HRT (prevent osteoporosis) Hypothalamic/pituitary disease: -HRT for oestrogen replacement -fertility: gonadotrophins (LH and FSH) - part of IVF treatment

Answer 44

Polycystic ovarian syndrome Incidence: 1 in 12 women of reproductive age Associated with increased cardiovascular risk and insulin resistance (-> diabetes) Polycystic ovaries on ultrasound scan ``` Criteria to diagnose PCOS Need 2 of the following: -polycystic ovaries on ultrasound scan -oligo-/anovulation -clinical/ biochemical androgen excess ``` Clinical features of PCOS Hirsutism Menstrual cycle disturbance Increased BMI Treatment of PCOS - fertility Metformin - insulin sensitivity Clomiphene - a fertility drug for irregular periods Gonadotrophins therapy as part of IVF treatment Clomiphene Anti-oestrogenic in the hypothalamo-pituitary axis Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback, resulting in an increase in the secretion of GnRH and gonadotrophins.

Answer 45

Diagram Causes: Dopamine antagonist drugs -Anti-emetics (metoclopramide) -Anti-psychotics (phenothiazines) Prolactinoma - usually benign Stalk compression due to pituitary adenoma, can be detected by pituitary MRI PCOS Hypothyroidism - increase in TRH, increase in prolactin Oestrogens (OCP), pregnancy, lactation Idiopathic ``` Clinical features Galactorrhoea - breast milk Reduced GnRH secretion/ LH action -> hypogonadism Prolactinoma -headache -visual field defect ``` ``` Treatment Treat the cause - stop drugs Dopamine agonist -bromocriptine -cabergoline ``` Prolactinoma - dopamine agonist therapy - pituitary surgery rarely needed

Answer 46

Permanent cessation of menstruation Loss of ovarian follicular activity Average age 51 (range 45-550 Climacteric: period of transition period ``` Symptoms Hot flushes (head, neck, upper chest) Urogenital atrophy and dyspareunia (painful sex) Sleep disturbance Depression Decreased libido Joint pain - arthralgia Symptoms usually diminish/ disappear with time. ``` Diagram Ovaries release no oestradiol/ inhibit B, reducing negative feedback on hypothalamus so increased GnRH and increased LH and FSH from pituitary. ``` Complications of menopause Osteoporosis -oestrogen deficiency (makes bones) -loss of bone matrix -10-fold increased risk of fracture Cardiovascular disease -protected against CVD before the menopause -have the same risk as men by the age of 70 ```

Answer 47

Control vasomotor symptoms (hot flushes) Oestrogen and progestogen Oestrogen: - endometrial proliferation - risk of endometrial carcinoma Progestogens Progestogen also given to prevent endometrial hyperplasia (If hysterectomy, oestrogen only given because no risk of endometrial cancer) Cyclical: oestrogen given every and progestogen every 12-14 days (later part of cycle) Continuous combined Oestrogen preparations: -oral oestradiol (1 mg) Oral conjugated equine oestrogen (0.625 mg) Transdermal (patch) oestradiol (50 microgravity/ day) Intravaginal Oestradiol is well absorbed Low availability (first pass metabolism) Estrone sulphate (conjugated oestrogen) Ethinyl estradiol - a semi-synthetic oestrogen, the ethinyl group protects the molecule from first pass metabolism, Most oestrogens can also be administered via trasndermal skin patches. ``` Side effects: Breast cancer Coronary heart disease Deep vein thrombosis Stroke Gallstones The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low. ``` HRT and coronary heart disease, mean age 63 years, women <10 years since menopause or 50-59: no excess risk. ``` Effects of oestrogen and progesterone Oestrogen: Beneficial effects on lipid profile and endothelial function Synthetic progestins: Negate these effects of oestrogen Older women (>60): Atherosclerosis Susceptible to prothrombotic and proinflammatory effects of oestrogen. ```

Answer 48

Tibolone Synthetic pro hormone Oestrogenic, progestogenic and weak androgenic actions Reduces fracture risk Increased risk of stroke Might increase risk of beast cancer (unknown) ``` Raloxifene Selective oestrogen receptor modulator Oestrogenic in bone: -reduces risk of vertebral fractures Antioestrogenic in breast and uterus -reduces breast cancer risk Does not reduce vasomotor symptoms - hot flushes Increases risk of VTE and fatal stroke ``` Tamoxifen Anti-oestrogenic on breast tissue Used to treat oestrogen-dependent breast tumours and metastatic breast cancers

Answer 49

Menopause occurring before the age of 40. 1% of women Autoimmune Surgery Chemotherapy Radiation

Answer 50

Combined oral contraceptives Oestrogen (ethinyl oestradiol) + progestogen (e.g. levonorgestrel or norethisterone) Suppress ovulation: -oestrogen and progestogen: negative feedback andirons at hypothalamus/ pituitary -progestogen thickens cervical mucus - more difficult for sperm to penetrate Take for 21 says (or 12 weeks), stop for 7 days Progesterone only contraceptive When oestrogens contra-indicated -smoker, > 35 years old, migraine with aura, coronary heart disease risk already high Must be taken at the same time each day -short half-life -short duration of action Long acting preparations may be given via an intra-uterine system Emergency (post-coital) contraception Copper IUD (intrauterine contraceptive device) -exclude pregnancy first -effects sperm viability and function -effectiveness not reduced in overweight/ obese women -5 (up to 7) days after unprotected intercourse Levonorgestrel (within 73 hrs) Ulipristal (up to 120 hrs after intercourse) -anti-progestin activity -delay ovulation by as much as 5 days -impairs implantation

Answer 51

``` Tubular reabsorption (induced by oestrogen from testosterone aroma tase) in testes Nutrients e.g. fructose and glycoproteins (protect sperm from hostile environment) to concentrate and secretion into epididymal fluid (induced by androgens) ``` Spermatozoa travel 100000x its length from Testis to Fallopian tube In semen: -spermatozoa -seminal fluid -leucocytes (potential viruses e.g. hep B, HIV) 1/100 of spermatozoa in ejaculate enter the cervix 1/10000 cervix to ovum Overall 1/million reach ovum ``` Small contribution of seminal fluid from epididymis/testis Mainly from accessory sex glands: -seminal vesicles -prostate -bulbourethral glands ``` Decreased aromatase: - symptoms of increased testosterone .e.g. acne - tall, oestrogen needed for growth plate closure - osteoporosis

Answer 52

Achieve fertilising capability in the female repro tract Loss of glycoprotein coat Change in surface membrane characteristics Develop whiplash movements of tail

Answer 53

Acrosome reaction Sperm binds to ZP3 - zona pellucida = sperm receptor Ca2+ influx into sperm (stimulated by progesterone) from corpus luteum Release of hyaluronidase and proteolytic enzymes (from acrosome) Spermatozoon penetrates the Zone Pellucida Chromosome evenly divide into 23 chromosomes each. Cytoplasm does not evenly divide, end up with small cell with 23 chromosomes - first polar body Fertilisation occurs within the Fallopian tube Triggers cortical reactions Cortical granules release molecules which degrade Zona Pellucida (e.g. ZP2 and 3) therefore prevents further sperm binding as no receptors Haploid -> diploid Development of conceptus (embryo) Continues to divide as it moves down Fallopian tube to uterus (3-4 days) Receives nutrients from uterine secretions This free-living phase can last for 9-10 days Corpus albicans - stops producing progesterone unless pregnancy achieved, if pregnancy hCG maintains corpus luteum and acts on LH receptor.

Answer 54

Attachment phase: outer trophoblast cells (form placenta) contact uterine surface epithelium Then Decidualisation phase: changes in underlying uterine stromal tissue (within a few hours) Requires progesterone domination in the presence of oestrogen. ``` Important factors for implantation: LIF - leukemia inhibiting factor IL11 - trophoblast migration, decidualisation Progesterone Diagram ``` Attachment LIF from endometrial secretory glands and blastocyst? Stimulates adhesion of blastocysts to endometrial cells Interleukin-11 also from endometrial cells is released into uterine fluid, and may be involved Many other molecules involved in process (e.g. HB-EGF) Decidualisation Endometrial changes due to progesterone (provide nutrients and support for possible entry) -glandular epithelial secretion -glycogen accumulation in stromal cell cytoplasm -growth of capillaries -increased vascular permeability (-> oedema) Factors involved: Interleukin-11 (IL11), histamine, certain prostaglandins and TGFb (TGFb promotes angiogenesis)

Answer 55

Hormone hCG - trigger for ovulation in IVF - corpus luteum maintained - source of progesterone and oestrogen - released by placenta Human placental lactogen - involved in metabolism, cause insulin resistance to promote nutrients to bay because mother glucose levels increase Oestrogens (mainly oestriol) Progesterone Progesterone and oestrogen production during pregnancy -first 40 days Produced in corpus luteum (in maternal ovary) stimulated by hCG (produced by trophoblasts) which acts on LH receptors Essential for developing fetoplacental unit Inhibits maternal LH and FSH (-ve feedback) -from day 40 Placenta starts to take over - hCG decreases Maternal and foetal DHEAS are main sources of substrates that’s made into oestrogens. Increase: - ACTH - adrenal steroids - prolactin - lactotroph hyperplasia (side note: cant check prolactin in pregnancy because high anyway so visual fields checked) - IGF1 (stimulated by placenta GH-variant) - Iodothyronines - hCG stimulates thyroids because has common alpha subunit with TSH - PTH related peptides - breast tissue decrease: - gonadotrophins - pituitary GH - TSH because hCG does some of job of TSH

Answer 56

Suckling (stimulus) sends signals through neural pathways to hypothalamus. Neurohypophysis (posterior PG) releases oxytocin and adenohypophysis (anterior PG) releases prolactin. Oxytocin causes milk ejection Prolactin causes milk synthesis (Side note: marathon runners can get low testosterone, females can get galactorrhoea because nipple stimulation can cause high prolactin

Answer 57

Prolactin binds to prolactin receptors on Kisspeptin neurones which secrete Kisspeptin which bind to Kisspeptin receptors on GnRH neurones. GnRH causes LH and FSH release -> testosterone and oestrogen release. High prolactin dowmregulates, low libido in man, amenhorrhoea in women therefore Kisspeptin given to high prolactin patients. Kisspeptin neurones have oestrogen receptors, not GnRH neurones. If patient has anorexia, leptin is low. Kisspeptin have leptin receptors, low leptin means low Kisspeptin.

Answer 58

Parathyroid hormone from parathyroid glands= increase serum Ca2+ after sensing low serum calcium - acts of bone, increases reabsorption of Ca2+ - action on kidney, increases absorption of Ca2+ (increases calcitriol formation, decreases excretion of calcium) - regulates production of active vitamin D (calcitriol) from liver, increase Ca2+ reabsorption by gut (small intestine)

Answer 59

Na+/PO43- enters proximal convoluted tubule cell from urine through Na+/PO43- co-transporter 3 wats decrease PO43- reabsorption: PTH inhibits transporter therefore PO43- loss in urine, decrease reabsorption of PO43- by gut. FGF23 also inhibits transporter and calcitriol is formed and enters blood. (FGF23 - fibroblast growth factor 23 from osteocytes) calcitriol also reduces reabsorption of PO43- from gut.

Answer 60

Parathyroid cells have Ca2+ sensing receptor. When there’s high ECF Ca2+, Ca2+ binds to receptor, receptor activation leads to inhibition of PTH secretion When there’s low ECF Ca2+, Ca2+ not bound to receptor so no inhibition and PTH is secreted. PTH action in body leads to increased ECF Ca2+.

Answer 61

7-dehydrocholesterol (precursor) found in skin converted to vitamin D3 (cholecalciferol) by UVB light -> 25OH-D3 in liver (not active, hydroxylated once) -> renal 1a-hydroxylase stimulated by PTH causes increased renal Ca2+ reabsorption forming calcitriol 1,25(OH)2D3. Calcitriol causes Ca2+ absorption in gut, Ca2+ maintenance in bone, negative feedback on PTH

Answer 62

Lack of sunlight (UVB light) Gi malabsorption e.g. coeliac disease, inflammatory bowel disease Dietary insufficiency Renal failure, liver failure Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment) Re-emerging as problem in UK due mainly to inadequate diet and lack of sunlight. Definition: lack of mineralisation in bone, Results in ‘softening’ of bone, bone deformities, bone pain; sever proximal myopathy. In children = rickets In adults = osteomalacia

Answer 63

To generate an AP in nerves/ skeletal muscle requires Na+ influx across cell membrane High extracellular calcium (hypercalcaemia) = Ca2+ blocks Na+ influx so less membrane excitability Low extracellular calcium (hypocalcaemia) = enables greater Na+ influx, so more membrane excitability (not much competition) Normal range series Ca2+ (2.2-2.6 mol/L) ``` Hypocalcaemia Signs and symptoms: Parasthesia (hands, mouths, feet, lips) Convulsions (seizures) Arrhythmias -heart contraction Tetany - muscles contract but can’t relax (CATs go numb) Sensitises excitable tissues, muscle cramps/ tetany, tingling ``` Chvostek’s sign Tap facial nerve just below zygomatic arch Positive response = twitching of facial muscles Indicates neuromuscular irritability due to hypocalcaemia. Trousseau’s sign Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia. Causes of hypocalcaemia: Vitamin D deficiency Low PTH levels = hypoparathyroidism -surgical - neck surgery -auto-immune -magnesium deficiency - needed to make PTH PTH resistance e.g. pseudohypoparathyroidism - make PTH but can’t use it, resistance Renal failure Impaired 1a hydroxylation -> decreased production of 1,25(OH)2D3 Hypercalcaemia Signs and symptoms ‘Stones, abdominal moans and psychic groans’ Stones - renal effects -polyuria and thirst -nephrocalcinosis calcium stone formation in kidneys) renal colic (try to pass kidneys - painful) , chronic renal failure (kidneys keep filtering Ca2+) Abdominal moans - GI effects -anorexia, nausea, dyspepsia (indigestion), constipation, pancreatitis Psychic groans - CNS effects -fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L) Reduced neuronal excitability, atonal muscles Causes: - primary hyperparathyroidism - malignancy - tumours/metastases often secrete a PTH-like peptide; calcium deposits in bone mean lots of Ca2+ released - conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone - immobilised patient) - vitamin D excess (rare)

Answer 64

If low Ca2+ more PTH made If high Ca2+, low PTH - negative feedback Primary hyperparathyroidism = high Ca2+, high PTH; no negative feedback, autonomous PTH secretion despite hypercalcaemia -raised calcium -low phosphate, more lost in urine -raised (unsuppressed) PTH Hypercalcaemia of malignancy Raised calcium and suppressed PTH, metastatic bone deposits damaging bone therefore releasing Ca2+, appropriate negative feedback

Answer 65

PTH increases to try to normalise serum calcium | Vitamin D deficiency

Answer 66

Plasma [25(OH)D3] usually low (we don’t measure 1,25 dihydroxy vitamin D to assess body vitamin D stores) Plasma [Ca2+] low (may be normal if secondary hyperparathyroidism has developed) Plasma [PO43-] low (reduced gut absorption) [PTH] high (2o hyperparathyroidism) ``` Treatment In patients with normal renal function: -give 2 hydroxy vitamin D (25(OH)D) -patient converts this to 1,25 dihydroxy vitamin D (1,25(OH)2D) via 1a hydroxylase Ergocalciferol 25 hydroxy vitamin D2 Cholecalciferol 25 hydroxy vitamin D3 ``` In patients with renal failure: Inadequate 1a hydroxylation, so cant activate 25 hydroxyl vitamin D preparations Give alfacalcidol - 1a hydroxycholecalciferol (active) Vitamin D excess: Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium Can occur as a result of: -excessive treatment with active metabolites of vitamin D .e.g. alfacalcidol -granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH)D to the active metabolite 1,25(OH)2D. Treatment for hyperparathyrodism is parathyroidectomy.

Answer 67

Organic components Osteoid - unmineralised bone, 35% bone mass Type 1 collagen fibres Inorganic mineral component 65% bone mass Calcium hydroxyapatite crystals fill the space between collagen fibrils Cells Osteoblasts - synthesis osteoid and participate in mineralisation/ calcification of osteoid (bone formation) Osteoclasts - release lysosomal enzymes which break down bone (bone resorption) Osteoclast differentiation RANKL (ligand) expressed on osteoblast surface RANKL binds to RANK-R to stimulate osteoclast formation and activity; activated osteoclast causes bone resorption Osteoblasts express receptors for PTH and calcitriol - regulate balance between bone formation and resorption. Cortical (hard) bone Trabecular (spongy) bone Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong Woven bone - disorganised collagen fibrils, weaker Bone remodelling is a dynamic process

Answer 68

Vitamin D deficiency: -inadequate mineralisation of newly formed bone matrix (osteoid) -children - rickets Affects cartilage of epiphysial growth plates and bone Skeletal abnormalities and pain, growth retardation, increased fracture risk -adults - osteomalacia After epiphyte all clsoure, affects bone Skeletal pain, increased fracture risk, prox myopathy No bowing Stress fractures from weight of skeleton Normal stresses on abnormal bone cause insufficiency fractures - looser zones Waddling gait - typical Hyperparathyroidism 1) Adenoma Primary hyperparathyroidism Parathyroids - high PTH and high Ca2+ (no negative feedback, autonomous PTH) 2) Low plasma [Ca2+] e.g. renal failure, Vit D deficiency Secondary hyperparathyroidism Parathyroids - low/ normal Ca2+ so increase PTH 3) Chronic low plasma [Ca2+] Tertiary hyperparathyroidism Parathyroids (autonomous) high Ca2+ and PTH, 1 vs 3 - 1 is normal kidney and 3 is chronic kidney failure.

Answer 69

Decreased renal function -> decrease calcitriol -> decrease Ca2+ absorption -> hypocalcaemia -> decrease bone mineralization -> osteitis fibrosa cystica Decreased renal function -> decrease PO43- excretion -> increase plasma [PO43-] -> hypocalcaemia -> increases PTH -> increases bone resorption -> osteitis fibrosa cystica (Can get tertiary parathyroidism) Increase plasma [PO43-] which binds to Ca2+ in plasma -> vascular calcification Osteitis fibrosa cystica (hyperparathyroid bone disease) - rare = excess osteoclastic bone resorption 2o to high PTH ‘Bone tumours’ = radiolucent bone lesions Treatment of osteitis fibrosa cystica (hyperparathyroid bone disease) -hyperphosphataemia Low phosphate diet Phosphate binders - reduce GI phosphate absorption -alphacalcidol - i.e. calcitriol analogues -parathyroidectomy in 3o hyperparathyroidism Indicated for hypercalcaemia and/or hyperparathyroid bone disease

Answer 70

Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after mineral trauma. Bone mineral density (BMD) > or equal to 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower) BMD predicts future fracture risk -1 to -2.5 = osteopenia Measuring BMD Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine Mineral (calcium) content of bone measured, the more mineral the greater the bone density (bone mass) - strength Osteoporosis vs osteomalacia Both predispose to fracture Osteomalacia -vitamin D deficiency (adults) causing inadequately mineralised bone -serum biochemistry abdnormal (low 25(OH) Vit D, low/ low N Ca2+, high PTH (2o hyperparathyroidism) -abnormal biochemistry issue so can diagnose using blood test Osteoporosis -Bone resorption exceeds formation -Decreased bone mass -Serum biochemistry normal - can’t diagnose with blood test -Diagnosis via DEXA scan Pre-disposing conditions for oesteoporosis: -Postmenopausal oestrogen deficiency Oestrogen deficiency leads to a loss of bone matrix Subsequent increased risk of fracture -Age-related deficiency in bone homeostasis (men and women) .e.g. osteoblast sensescence -hypogonadism in young women and in men (pituitary gland) -endocrine conditions Cushing’s syndrome Hyperthyroidism Primary hyperparathyroidism -iatrogenic Prolonged use of glucocorticoids -steroids Heparin

Answer 71

1) Oestrogen (HRT)/ Selective oestrogen receptor modulators: Treatment of post-menopausal women with pharmacological doses of oestrogen -anti-resorptive effects on the skeleton -prevents bone loss Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/ cancer Use limited largely due to concerns: -increased risk of breast cancer -venous thromboembolism May not be good for long term 2) Bisphosphonates - bind avidly to hydroxyapatite crystals and ingested by oestoclasts - impair ability of osteoclasts to reabsorption bone - decrease osteoclast progenitor development and recruitment - promote osteoclast apoptosis (programmed cell death) - net result = reduced bone turnover ``` Uses of bisphosphates -osteoporosis - first line treatment -malignancy Associated hypercalcaemia Reduce bone pain from metastases -paget’s disease - reduce bony pain -severe hypercalcaemic emergency - i.v. Initially (re-hydration first) ``` Pharmacokinetics - Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally) - Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years Unwanted actions of bisphosphonates -oesophagitis May require switch from oral to iv preparation -osteonecrosis of the jaw Greatest risk in cancer patients receiving iv bisphosphates -atypical fractures May reflect over-suppression of bone remodelling in prolonged bisphosphate use 3)Denosumab - inhibits switching on of osteoclasts Human monoclonal antibody Binds RANKL, inhibiting osteoclast formation and activity Hence inhibits osteoclast-mediated bone resorption SC injection 2nd line bisphosphonates 3) Teriparatide Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH Increases bone formation and bone resorption, but formation outweighs resorption 3rd line treatment for oestoporosis Daily s.c. injection £££

Answer 72

Accelerated, localised but disorganised bone remodelling Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) in a non-organised way. New bone formed = WOVEN bone -structurally disorganised -mechanically weaker than normal adult lamellar bone Bone frailty Bone hypertrophy and deformity Often positive family history - ?genetic cause ?evidence for viral origin (e.g. measles virus) Prevalence -highest in UK, N America, Australia and NZ -lowest in Asian and Scandinavia Men and women affected equally Disease usually not apparent under age 50 yrs Most patients are asymptomatic Characterised by abnormal, large osteoclasts - excessive in number Clinical features: Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected Arthritis Fracture Pain Bone deformity Increased vascularity (warmth over affected bone) - too much activity because remodelling Deafness -cochlear involvement Radiculopathy - due to nerve compression Diagnosis: Plasma [Ca2+] normal Plasma [alkaline phosphatase] (bone enzyme) usually increased Plain x-rays = lytic lesions (early), thickened, enlarged, deformed bones (later) Radionuclide bone scan demonstrates extent of skeletal involvement Treatment: Bisphosphonates - very helpful for reducing bony pain and disease activity Simple analgesia

Answer 73

Diagram Ghrelin, PYY and other gut hormones, neural input from the periphery and other brain regions, leptin -> hypothalamus -> food intake/ energy expenditure

Answer 74

Arcuate nucleus in rhodents, infundibular nucleus in humans Key brain area involved in the regulation of food intake Incomplete blood brain barrier, allows access to peripheral hormones Integrates peripheral and central feeding signals Two neuronal populations: -stimulatory (NPY/ Agrp neurone) - increase appetite -Inhibitory (POMC neurone) - alpha MSH, different enzymes to ACTH - decrease appetite Both sets of neurones extend to other hypothalamic regions

Answer 75

No NPY or Agrp mutations associated with appetite discovered in humans. POMC deficiency and MC4-R (regulate food intake) mutations cause morbid obesity. Mutations not responsible for the prevalence of obesity - but useful to explain signalling

Answer 76

Recessive mutation in ob gene Profoundly obese Diabetic Infertile Stunted linear growth Decreased body temperature Decreased energy expenditure - don’t want to waste, want to conserve Decreased immune function - may turn off immune system to save energy Similar abnormalities to starved animals - on mouse thinks its starving to death therefore eats a lot Leptin Codes for 167 amino acid hormone Missing in the ob/ob mouse A way in which fat tissue can tell brain not starving to death Low when low body fat High when high body fat - the more fat you have, the more leptin you have - leptin coded in adipose tissue Central or peripheral administration decreases food intake and increases thermogenesis Activates POMC and inhibits NPY/AgRP neurones. Leptin resistance Leptin circulates in plasma in concentrations proportional to fat mass Most fat humans have high leptin Obesity due to leptin resistance - hormone is present but doesn’t signal effectively Leptin is ineffective as a weight control drug Absence of leptin has profound effects, including hyperphagia, lowered energy expenditure, sterility. However, leptin is an anti-starvation hormone rather than anti-obesity hormone. Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning-but high leptin has little effect. Insulin circulates at levels proportional to body fat - high fat can get insulin resistance like leptin Receptors in hypothalamus Central administration reduces food intake Insulin and leptin signal to regulate long term food intake. The GI tract signals to regulate short-term food intake. Specific neuronal circuits in the hypothalamus and other brain regions regulate food intake.

Answer 77

The GI tract is the body’s largest endocrine organ. Releases more than 20 different regulatory peptide hormones. Influence processes including gut motility, secretion of other hormones, appetite Release regulated by gut nutrient content ``` From duodenum: Cholecystokinin -gall bladder contraction -gastrointestinal motility -pancreatic exocrine secretion Secretin -pancreatic exocrine secretion GIP -Incretin activity Motilin -gastrointestinal motility ``` ``` From stomach: Ghrelin -hunger -growth hormone release Gastrin -acid secretion ``` ``` From pancreas: Insulin and glucagon -glucose homeostasis Pancreatic polypeptide -gastric motility -satiation Amylin -glucose homeostasis -gastric motility ``` ``` From colon: GLP-1 -incretin activity -satiation GLP-2 -gastrointestinal motility and growth Oxyntomodulin -satiation -acid secretion PYY3-36 -satiation ``` Hormones released from basal side of epithelial cells in gut wall Paracrine effects - affect cells nearby Modulation of neuronal function - enteric nervous system; vagus nerve Endocrine effects - pancreas ``` L cells (flask shape) secrete PYY and GLP-1 If something from lumen enters (signal), secretory granules released Open endocrine cells, contact with lumen of gut ``` Peptide YY - 36aa Post-prandial (lunch/dinner) secretion of PYY - the more calories you eat, the more PYY is released PPY3-36 directly modulates neurones in the arcuate nucleus: -inhibits NPY release -stimulates POMC neurones -decreases appetite Brain tricked that you’ve just had a meal, PYY3-36 reduces food intake

Answer 78

28aa gastric hormone Ghrelin O-acyltransferase - attach fatty acids to it, fatty acid chain binds to receptor/ proteins in circulation Ghrelin directly modulates neurones in the arcuate nucleus - stimulates NPY/ Agrp neurones - inhibits POMC neurones - increases appetite Ghrelin increases food intake in humans Glucagon-like peptide-1 Gut hormone coded for by the preproglucagon gene (same gene that codes for glucagon) and released post-prandially Processing of pro-glucagon in intestinal L cells GLP-1 to agonist (active) by prohormone convertase 1 then inactive by DP-IV. Well characterised incretin role (decrees glucose) in stimulating glucose-stimulated insulin release and also reduces food intake. Saxenda Long -acting glucagon-like peptide-1 receptor agonist (liraglutide) Double the dose used for T2DM Used for weight loss Only small part of it effective, short half-life Side effect = nausea so build up dosage Dietary manipulation? Synthetic nutrients to stimulate nutrient receptors Delivering nutrients to specific regions of the gut

Answer 79

1)post-prandial Reduces food intake following a meal 2) chronic Gut disease - chronic elevation suppresses appetite to allow gut to recover 3) acute nausea Toxin ingestion - acutely very high levels

Answer 80

Obesity is associated with comorbidities - depression - stroke - sleep apnoea - diabetes - hypertension Thrifty gene hypothesis Specific genes selected for to increase metabolic efficiency and fat storage. In the context of plentiful food and little exercise these genes predispose their carriers to obesity and diabetes. Evolutionarily sensible to put on weight. Thin humans didn’t survive famines, so didn’t pass their genes on to modern humans. Evidence? Populations historically prone to starvation become most obese when exposed to Western diet and sedentary lifestyle e.g. Pacific Islanders Weakness: not everyone is fat Adaptive drift (drifty gene) hypothesis Normal distribution of body weight: the fat are eaten, the thin starve 10-20000 years ago, humans learned to defend against predators Thus obesity not selected against Putting on body fat then a neutral change (genetic drift). (Though unlikely to put on much weight) In current context, the inheritors of these genes became obese Example of genetic effect within a specific environment - obesity driven by the effects of environment on genetic background

Answer 81

Autoimmune ‘type 1’ diabetes leading to insulin deficiency can present > decades of life = latent autoimmune diabetes in adults (LADA) -antibodies against pancreas, now type 1 T2DM may present in childhood, increasing because of obesity epidemic Diabetic ketoacidosis is a feature of T2DM Monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (e.g. MODY, mitochondrial diabetes) -strong genetic family history Diabetes may present following pancreatic damage or other endocrine disease - pheochromocytoma (tumour of adrenal gland), Cushing’s syndrome increase glucose

Answer 82

Type 1 Environmental trigger and genetics -> autoimmune destruction of islet cells -> insulin deficiency -> hyperglycaemia Type 2 Genetics and obesity -> insulin resistance -> B cell failure -> hyperglycaemia

Answer 83

- Increased prevalence of other autoimmune disease .e.g coeliac disease, Addison’s - Risk of autoimmunity in relatives - More complete destruction of B-cells - Auto antibodies can be useful clinically - Immune modulation offers the possibility of novel treatments - still in reasearch Genetic susceptibility - different HLA-DR alleles on chromosome 6 Environment - bacterial/viral conditions increase type 1 prevalence? Markers - islet cell antibodies (ICA) - group O human pancreas - insulin antibodies (IAA) - glutamic acid decarboxylase (GADA) - widespread neurotransmitter - insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family

Answer 84

Symptoms - polyuria - nocturia - polydipsia - blurring of vision - ‘thrush’ - yeast growth - weight loss - fatigue Signs - dehydration - cachexia - hyperventilation - Kussmaul breaking, metabolic acidosis therefore more CO2 - smell of ketones - glycosuria - ketonuria

Answer 85

``` Reduce early mortality Avoid acute metabolic decompensation Prevent long term complications -retinopathy - micro -nephropathy - micro -neuropathy - micro -vascular disease - macro ```

Answer 86

Needs exogenous insulin to preserve life. Ketones define insulin deficiency. Diet - reduce calories as fat - reduce calories as refined carbohydrate - increase calories as complex carbohydrate - increase soluble fibre - balanced distribution of food over course of day with regular meals and snacks Insulin given during meals and also as background insulin. With meals -short acting -human insulin -insulin analogue (lispro, aspart, glulisine) Background - long acting - non-c bound to zinc or protamine - insulin analogue (Glargine, determir, degludec) Genetic engineering to alter absorption, distribution, metabolism and excretion Insulin pump (in abdomen) Continuous insulin delivery Preprogrammed basal rates and bolus for meals Does NOT measure glucose, no completion of feedback loop Islet cell transplants Immunosuppressants

Answer 87

Capillary monitoring Continuous glucose monitoring Measure capillary glucose levels Capillary glucose not as accurate as venous glucose. HbA1c red cells react with glucose as it does with all proteins. Irreversible, non-covalent depends on: -lifespan of red cell, about 120 days e.g. thalassemia, sickle cell have short life span therefore test not as reflective -rate of glycation, faster in some individuals -Hb opathy, renal failure .etc. -level of glucose -forms ideal measure of long term glycemic control and has been shown to be related to risk of complications -furthermore lowering HbA1c associated lower risk of complication particularly microvascular complication <42 mmol = normal > 48 mmol = diabetic 42-48 mmol = prediabetic

Answer 88

Ketoacidosis - rapid decompensation (deteriorating functional system) of type 1 diabetes - hyperglycaemia - reduced tissue glucose utilisation; increased hepatic glucose production - metabolic acidosis - circulating acetoacetate and hydroxybutyrate osmotic dehydration and poor tissue perfusion (pH decreases, bicarbonate decreases) Hypoglycaemia - occasional hypos inevitable as a result of treating diabetes - major cause of anxiety in patients and families - source of major misconceptions in media e.g. coma Definitions: Hypoglycaemia - plasma glucose of <3.6 mmol/l Severe hypoglycaemia - any hypo requiring help of another person to treat - most mental processes impaired at <3 mmol/l - consciousness impaired at <2 mmol/l - severe hypoglycaemia may contribute to arrhythmia and sudden death - may have long term-effects on the brain .e.g. cerebral cortex - recurrent hypos result in loss of warnings - hypoglycaemic unawareness

Answer 89

Who - Main risk factor is quality of glycaemic control - More frequent in patients with low HbA1c When - can occur at anytime but often a clear pattern - pre-lunch hypos common - nocturnal hypos very common and often not recognised - increase adrenaline when hypoglycaemic at night therefore high glucose in morning Why - Unaccustomed exercise - Missed meals - inadequate snacks - alcohol - inappropriate insulin regime ``` Symptoms and signs Due to increased autonomic innervation: -palpitations (tachycardia) -tremor -sweating -pallor/ cold extremities -anxiety ``` Due to impaired CNS function: - drowsiness - confusion - altered behaviour - focal neurology - coma Treatment Oral (feed the patient): -glucose - rapidly absorbed as solution or tablets -complex CHO - to maintain blood glucose after initial treatment Parenteral (give it consciousness impaired) - IV dextrose e.g. 10% glucose infusion - 1 mg glucagon IM - if fasting, glucose reserves low therefore may not work so if cachexic give i.v. - avoid concentrated solutions if possible (e.g. 50% glucose)

Answer 90

Diabetes mellitus is the state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves and arteries. Impaired fasting glucose: 6-7 mmol Impaired glucose tolerance: 7.8 -1 mmol

Answer 91

Several hereditary forms (1-8) - single gene defects Autosomal dominant Ineffective pancreatic B cell insulin production Mutations of transcription factor genes, glucokinase gene - mechanism by which B cell recognises a particular glucose conc. Positive family history, no obesity Specific treatment for type

Answer 92

``` Heterogenous Obesity Insulin resistance and insulin secretion deficit Hyperglycaemia and dyslipidaemia Acute and chronic complications ``` Insulin secretion deteriorates with progressive impairment of glucose tolerance - less able to make first phase insulin Diagram Adipocytes are a major endocrine organ as they make lots of hormones. These hormones are important in the mechanism of diabetes, not the cause of diabetes Enough insulin to switch off ketone production but not enough to switch off hepatic glucose output.

Answer 93

Central or omental obesity Insulin resistance Fatty acids released by bacteria into omental circulation can alter liver metabolism

Answer 94

Osmotic symptoms - polyuria, polydipsia Infections - high sugar for organisms to feed on Screening test - try to do earlier but often at time of complication so too late At presentation of complication - acute: hyperosmolar coma -chronic: ischaemic heart disease, retinopathy ``` Complications Microvascular -retinopathy -nephropathy -neuropathy ``` Microvascular - ischaemic heart disease - cerebrovascular - renal artery stenosis - PVD Metabolic - lactic acidosis - hyperosmolar Treatment -hypoglycaemia

Answer 95

1) education 2) diet 3) pharmacological treatment 4) complication screening

Answer 96

Education - know symptoms - reduce chance of acute metabolic complications - reduce change of long term complications Diet - control total calories/ increase exercise (weight) - reduce refined carbohydrates (less sugar) - increase complex carbohydrate (more rice etc) - reduce fat as proportion of calories (less IR) - increase unsaturated fat as proportion of fat (IHD) - increase soluble fibre (longer to absorb CHO) - address salt (BP risk)

Answer 97

``` Metformin -Biguanide, insulin sensitiser -overweight patient with T2DM where diet alone has not succeeded -reduces insulin resistance Reduced hepatic glucose output Increases peripheral glucose disposal -GI side effects -do not use if severe liver, severe cardiac or mild renal failure ``` Acarbose - alpha glucosidase inhibitor - prolongs absorption of oligosaccharides - allows insulin secretion to cope, following defective first phase insulin - as effective as metformin - side effects flatus - fermentation of sugars in large bowel causes flatus Thiazolidinediones - peroxisome proliferator-activated receptor agonists (PPAR-gamma) - pioglitazone - insulin sensitiser, mainly peripheral - adipocyte differentiation modified, weight gain but peripheral not central - improvement in glycaemia and lipids - Side effects of older types - hepatitis, heart failure Sulfonylureas - e.g. glibenclamide - block K+ channel causing Ca2+ to enter so insulin increases - side effect = weight gain ``` Glucagon like peptide-1 (GLP-1) -secreted in response to nutrients in gut -transcription product of proglucagon gene, mostly from L cell -stimulates insulin, suppresses glucagon -increases satiety -restores B cell glucose sensitivity -short half life, rapid degradation from enzyme dipeptidyl peptides-4 (DPPG-4 inhibitor) Two types: GLP-1 agonist -exenatide, liraglutide -injectable -long acting GLP-1 agonist -decrease glucagon -decrease glucose -weight loss Gliptins (DPPG-4 inhibitor) -increase half life of exogenous GLP-1 -increase GLP-1 -decrease glucagon -decrease glucose -neutral on weight ``` Empaglifozin - inhibits Na-Glu transporter, increases glycosuria - HbA1c lower - can lower risk of heart failure - affect on Na+ transport in heart

Answer 98

Blood pressure Diabetic dyslipidaemia -cholesterol high -triglyceride high HDL-cholesterol low

Answer 99

Problem? Mortality, morbidity, cost Diagnosis? Glucose, fasted or stimulated? High risk? Screen? Specifics of program unclear, which test how often in who? Treatment? All aspects of control

Answer 100

- severity of hyperglycaemia - glucose can damage through protein kinase C, AGEs, hexosamine, Polyol pathway - hypertension - genetic - hyperglycamic memory- those with better control of their diabetes for longer have better outcomes - tissue damage through originally reversible and later irreversible alterations in proteins

Answer 101

- retinal arteries - retinopathy - glomerular arterioles (kidney) - nephropathy - vasa nervorum (tiny blood vessels that supply nerves) - neuropathy

Answer 102

Diabetic retinopathy is the main cause of visual loss in people with diabetes and the main cause of blindness in people of working age. E.g. hyperglycaemia -> PKC activation -> vascular endothelial dysfunction -> vascular permeability -> retinal neovascularisation Background diabetic retinopathy: Hard exudates (cheese colour, lipid) Microaneurysms (“dots”) Blot haemorrhages Pre-proliferative diabetic retinopathy (if you don’t treat background retinopathy): Cotton wool spots also called soft exudates Represent retinal ischaemic - vessels become more ischaemic Proliferation retinopathy (next stage): Visible new vessels On disk or elsewhere in retina Maculopathy: Hard exudates near the macula Same disease as background, but happens to be near macula This can threaten direct vision Management of diabetic retinopathy Background: Improve control of blood glucose Warn patient that warning signs are present Pre-proliferative: Suggests general ischaemia If left alone, new vessels will grow Needs: pan retinal photocoagulation (laser beams fired at back of retina to prevent new vessels from forming) Proliferation: Also needs pan retinal photocoagulation Maculopathy: Only have problem around macula Needs only a GRID of photocoagulation (not pan retinal photocoagulation)

Answer 103

Hypertension Progressively increasing proteinuria Progressively deteriorating kidney function Classic histological features ``` Histological features Glomerular Mesangial expansion Basement membrane thickening - cells become very rigid Glomerulosclerosis ``` Vascular Tubulointerstitial ``` Epidemiology Age at development of disease Racial factors Age at presentation Loss due to cardiovascular morbidity ``` Clinical features: Progressive proteinuria Increased blood pressure Deranged renal function Normal GFR >90 40-90 = chronic kidney disease ``` Strategies for intervention: Diabetic control Blood pressure control Inhibition of the activity of RAS system Stopping smoking ```

Answer 104

Angiotensin 2 - vasoactive effects - mediation of glomerular hyperfiltration - increased tubular uptake of proteins - podocyte effects - induction of pro inflammatory cytokines Diagram

Answer 105

Diabetes is the most common cause of neuropathy and therefore lower limb amputation. Small vessels supplying nerves are called vasa nervorum. Neuropathy results when these get blocked. Diabetic neuropathy: - peripheral polyneuropathy - most common - mononeuropathy - mononeuritis multiplex - radiculopathy - autonomic neuropathy - diabetic amyotrophy ``` 1) peripheral neuropathy Longest nerves supply feet Loss of sensation More common in tall people Danger is that patients will not sense an injury to foot e.g. stepping on a nail More likely to occur in: -tall patients -patients with poor glucose control Loss of ankle jerks Loss of vibration sense (using tuning fork) Multiple fractures on foot x-ray (Charcot’s joint = tender red areas of inflammation) - step on one part of foot more than another = fracture Monofilament examination used ``` ``` 2) mononeuropathy Usually sudden motor loss Wrist drop, foot drop Cranial nerve palsy Double vision due to 3rd nerve palsy ``` 3) mononeuritis multiplex A random combination of peripheral nerve lesions 4) radiculopathy Pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall. 5) autonomic neuropathy Loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system - gastroparesis, incontinence, arrhythmia GI tract: -difficulty swallowing -delayed gastric emptying -constipation/ nocturnal diarrhoea -bladder dysfunction Postural hypotension - can be disabling: collapsing on standing Cardiac autonomic supply - sudden cardiac death Measure changes in HR in response to Valsalva manoeuvre - blow into syringe, build up of pressure, measure HR Normally thee is a change in HR Look at ECG and compare R-R intervals

Answer 106

Pupil sparing third nerve palsy: Eye is usually “down and out” 6th nerve pulls eye out and 4th nerve pulls it down Pupil does respond to light Parasympathetic fibres on outside thus they do not easily lose blood supply in diabetes. Aneurysm causing third nerve palsy Space occupying lesion Will press on parasympathetic fibres first causing fixed dilated pupil

Answer 107

Ischaemic heart disease - the major cause of morbidity and mortality in diabetes Cerebrovascular disease - earlier than without diabetes, more widespread (stroke) Renal artery stenosis - May contribute to hypertension and renal failure Peripheral vascular disease - contributes to diabetic foot problems and neuropathy (narrowing of armies to leg - emboli/ ischaemic)

Answer 108

Hyperlgycaemia is associated with significantly reduced life expenctancy Microvascular disease causes morbidity; macrovascular disease causes morbidity and mortality Macrovascular disease is a systemic disease and is commonly present in multiple arterial beds Treatment targeted to hyperglycaemia alone has minor effect on increased risk of cardiovascular disease ``` Prevention of macrovascular disease requires aggressive management of multiple risk factors Insulin resistance before hyperglycaemia itself contributes Risk factors: Non modifiable -age -sex -birth weight -FH/ genes ``` Modifiable - dyslipidaemia - high blood pressure - smoking - diabetes (sugar)

Answer 109

Neuropathy; sensory, motor and autonomic Peripheral vascular disease

Answer 110

1) sensory neuropathy 2) motor neuropathy - imbalance between long extensors to foot and short flexors, clawing of foot, knuckles of toes scratch against shoe, metatarsal head of big toe have lots of pressure - hard to balance weight of foot 3) limited join mobility - glycosylation of collagen, can’t bend feet properly 4) autonomic neuropathy - dry - sweat glands grease and moisture lost 5) peripheral vascular disease - loss of arteries, not enough blood supply to leg, can surgically bypass 6) trauma - repeated minor/ discrete episode 7) reduced resistance to infection - Candida fungal infection 8) other diabetic complications e.g. retinopathy

Answer 111

The neuropathic foot = numb, warm, dry, palpable foot pulses, ulcers at points of high pressure loading The ischaemic foot = cold, pulseless, ulcers at the food margins- extremities e.g. toes The neuro-ischaemic foot = numb, cold, dry, pulseless, ulcers at points of high pressure loading and at foot margins.

Answer 112

Appearance - deformity, callus - bears weight incorrectly -> ulcerated -> ulcerates -> dry and thick skin around prevent healing Feel - hold/cold, dry Foot pulses - dorsalis pedis/ posterior tibial pulse Neuropathy - vibration sensation, temperature, ankle jerk reflex, fine touch sensation

Answer 113

Hyperglycaemia Hypertension Dyslipidaemia Tackled by stopping smoking, education .etc. Preventative management - control diabetes - inspect feet daily - have feet measured when buying shoes - buy shoes with laces and square toe box - inspect inside of shoes for foreign objects attend chiropodist - cut nails straight across - care with heat - never walk barefoot Management of foot ulceration: Relief of pressure - bed rest (risk of DVT, heel ulceration) - redistribution of pressure/ total contact case Antibiotics, possibly long term (can cause resistance) e.g. for osteomyelitis Debridement - dead tissue needs to be removed ``` MTD Diabetes nurse Diabetologist Chiropodist Vascular surgeon Orthopaedic surgery ``` Revascularisation -angioplasty -arterial bypass surgery Amputation

Answer 114

Charcot foot is a condition causing weakening of the bones in the foot that can occur in people who have significant nerve damage (neuropathy). The bones are weakened enough to fracture, and with continued walking (not painful because neuropathic), the foot eventually changes shape. (Also ulceration and inflammation)