Endocrinology

Question 1

What is the pituitary divided into?

Answer 1

Anterior pituitary

Posterior pituitary

Question 2

What hormones are secreted by the anterior pituitary?

Answer 2

FSH/LH
Prolactin
GH
TSH
ACTH

Question 3

What causes a primary endocrine gland disease?

Answer 3

Disorder in the endocrine gland e.g. thyroid, gonads, adrenal cortex

Question 4

What causes a secondary endocrine gland disease?

Answer 4

Disorder in the anterior pituitary

Question 5

What causes a tertiary endocrine gland disease?

Answer 5

Disorder in the hypothalamus

Question 6

Hypopituitarism

Answer 6

Decreased production of all anterior pituitary hormones (panhypopituitarism) OR specific hormones

Congenital (rare) or aquired

Question 7

What causes congenital panhypopituitarism and what is the main symptoms it causes?

Answer 7

Rare
Usually mutations of transcription factor genes needed for normal pituitary development e.g. PROP1 mutation
Deficient in GH and at least 1 other pituitary hormone

Short stature

Question 8

Congenital panhypopituitarism sufferers will be deficient in …… and at least 1 more pituitary hormone

Answer 8

GH

Question 9

What are the MRI findings for congenital panhypopituitarism?

Answer 9

Hypoplastic anterior pituitary gland on MRI

Question 10

What are possible causes of acquired panhypopituitarism (8)?

Answer 10

Tumours (hypothalamic craniopharyngiomas or pituitary adenomas/metastases/cysts)
Radiation
Infection (e.g. meningitis)
Traumatic brain injury
Infiltrative disease (often involving pit stalk)
Inflammatory (hypophysitis)
Pituitary apoplexy (haemorrhage or infarction)
Peri-partum infarction (Sheehan’s syndrome)

Question 11

How does panhypopituitarism/Simmond’s disease present?

Answer 11

Symptoms due to deficient hormones

FSH/LH= Secondary hypogonadism
Reduced libido
Secondary amenorrhoea
Erectile dysfunction

ACTH= Secondary hypoadrenalism (cortisol deficiency)
Fatigue

TSH= Secondary hypothyroidism
Fatigue
Weight gain

Question 12

What causes Sheehan’s syndrome?

Answer 12

Post-partum hypopituitarism secondary to hypotension

Because of post partum haemorrhage (PPH)-> pituitary infarction

Normally in developing countries

Question 13

What happens to the anterior pituitary in pregnancy?

Answer 13

Enlarges

Lactotroph hyperplasia

Question 14

How does Sheehan’s Syndrome present?

Answer 14

Lethargy, anorexia, weight loss- TSH/ACTH/ GH deficiency
Failure of lactation (PRL deficiency)
Failure to resume menses post-delivery
Posterior pituitary usually not affected

Often diagnosed late because many common symptoms

Question 15

Pituitary apoplexy basis

Answer 15

Intra-pituitary haemorrhage (or less commonly infarction)
May be first presentation of a pituitary adenoma or a presentation of an existing one
Precipitated by anti-coagulants

Question 16

Pituitary apoplexy symptoms

Answer 16

Severe sudden onset headache
Visual field defect- compressed optic chiasm (bitemporal hemianopia)
Cavernous sinus may be involved (diplopia of CN 4 and 6, ptosis of CN 3)

Question 17

How is hypopituitarism diagnosed (2 biochem tests and 1 radiological)?

Answer 17

BIOCHEMICAL

1. Basal plasma concentrations of pit/target endo gland hormones
2. Stimulated ‘dynamic’ pituitary function tests

RADIOLOGICAL
Pituitary MRI

Question 18

How does it work and what are the limitations of the biochemical diagnosis of hypotituitarism? (METHOD 1= BASAL PLASMA CONCS)

Answer 18

BIOCHEMICAL
Basal plasma concentrations of pit/target endo gland hormones

Limitations...
Cortisol fluctuates during the day
T4 (thyroxine) circulating t1/2 6 days (long half life means may start to fall)
FSH/LH depends on menstruation
GH/ACTH pulsatile (stress of blood test)

Question 19

How does biochemical diagnosis of hypotituitarism work? (METHOD 2= STIMULATED ‘DYNAMIC’ PITUITARY FUNCTION TESTS)

Answer 19

ACTH and GH= stress hormones
Hypoglycaemia <2.2mM= stress

Insulin-induced hypoglycaemia stimulates GH release and ACTH release

TRH stimulates TSH release
GnRH stimulates FSH and LH release

Measure TSH, FSH and LH
Should increase but in a person with hypopituitarism will decrease or stay the same

Question 20

What does a radiological diagnosis of hypotituitarism show? (MRI OF PITUITARY)

Answer 20

Pituitary MRI

May reveal specific pituitary pathology e.g. haemorrhage (apoplexy), adenoma

Empty sella- thin rim of pituitary tissue

Question 21

What hormone replacements are used in therapy for hypopituitarism?
Deficient hormone-
Replacement-
Check-

Answer 21

Deficient hormone- ACTH
Replacement- hydrocortisone
Check- serum cortisol

Deficient hormone- TSH
Replacement- thyroxine
Check- serum free T4

Deficient hormone- women LH/FSH
Replacement- HRT (E2 plus progestagen)
Check- symptom improvement, withdrawal bleed

Deficient hormone- men LH/FSH
Replacement- testosterone
Check- symptom improvement serum testosterone

Deficient hormone- GH
Replacement- GH
Check- IGF1, growth chart (children)

Question 22

What happens to children and adults in GH deficiency?

Answer 22

Children- short stature (=2 SDs < mean height for children of that age and sex)

Adults- less clear

• Reduced lean mass, increased waist:hip ratio
• Reduced muscle strength and bulk reduced exercise performance
• Decreased plasma HDL-cholesterol and raised LDL-cholesterol
• Impaired ‘psychological well being’ and reduced quality of life

Question 23

What are the causes of short stature? (7)

Answer 23

Genetic= Down’s, Turner’s, Prader-Willi

Emotional deprivation= stress, absue

Systemic disease= CF, rheumatoid arthritis

Malnutrition

Malabsorption= coeliac

Endocrine disorders= Cushing’s, hypothyroidism, GH deficiency, poorly controlled T1DM

Skeletal dysplasias= achrondroplasia, osteogenesis imperfecta

Question 24

What part of the growth axis is disrupted in Prader-Willi syndrome?

Answer 24

Hypothalamus

Question 25

What part of the growth axis is disrupted in pituitary dwarfism?

Answer 25

Lack of GH

Question 26

What part of the growth axis is disrupted in Laron Dwarfism?

Answer 26

GH receptor defect

Question 27

What causes Prader-Willi syndrome?

Answer 27

Deficient in GH secondary to hypothalamic dysfunction | Floppy when babies, food seeking behaviour and weight problem

Question 28

Achondroplasia

Answer 28

Mutation in fibroblast growth Factor R 3 (FGF3) Abnormality in growth plate chondrocytes-> impaired linear growth in limbs Average size trunk

Question 29

How do the physical features of achondroplasia and pituitary dwarfism differ?

Answer 29

Achondroplasia= average trunk, short limbs Pituitary dwarfism= proportionally normal but short

Question 30

Are the GH receptors working in laron dwarfism?

Answer 30

GH R mutations Hypothalamus and ant pit in tact GH can't act on R

Question 31

How can laron dwarfism be treated?

Answer 31

IGF-1 to increase height

Question 32

How is short stature diagnosed?

Answer 32

Mid parental height = prediction | Then compared to curves of normal growth

Question 33

What causes acquired GH deficiency in adults?

Answer 33

Trauma Pituitary tumour Pituitary surgery Cranial radiotherapy

Question 34

How is GH deficiency diagnosed?

Answer 34

Random GH so little use- pulsatile | Need provocative challenge (i.e. stimulation) = GH PROVOCATION TESTS

Question 35

What are GH provocation tests?

Answer 35

GHRH + ARGININE (iv) Inhibiting the inhibitor GH flat if GH deficient Arginine may stimulate GH release by inhibiting somatostatin release INSULIN (iv) Hypoglycaemia Normal GH should rise but in GH deficiency will stay mostly flat GLUCAGON (im) EXERCISE Then can measure plasma GH at specific time points to check for normal release patterns

Question 36

How is GH therapy administered?

Answer 36

Human recombinant GH (SOMATOTROPIN) Daily, subcutaneous injection Monitor clinical response and adjust dose to IGF-1

Question 37

How long does it take for GH therapy to reach maximal plasma concentration?

Answer 37

2-6h

Question 38

Describe the duration of action of GH therapy

Answer 38

Lasts beyond clearance | Peak IGF1 levels at approx 20h

Question 39

How can GH therapy benefit adults?

Answer 39

Improved body composition Improved muscle strength and exercise capacity More favourable lipid profile e.g. higher HDL-cholesterol, lower LDL-cholesterol Increased bone mineral density Improved psychological well being and quality of life

Question 40

What are the problems with giving GH therapy to adults?

Answer 40

Increased susceptibility to cancer? Expensive (lifelong = £42k for adult)

Question 41

Hyperpituitarism

Answer 41

Symptoms associated with excess production of adenohypophysial hormones Usually due to pituitary tumours or ectopic (non-endocrine) Associated with visual field/CN defects and endocrine symptoms

Question 42

How does a pituitary tumour disrupt the visual field?

Answer 42

Optic chiasm compression by growth of a suprasellar tumour Loss of vision from outer temporal visual fields (because light from here strieks the nasal aspect of the retina) Bitemporal hemianopia

Question 43

How does bitemporal hemianopia manifest?

Answer 43

Bumping into things | People don't realise they've lost their peripheral vision

Question 44

An excess of ACTH (corticotrophin)->

Answer 44

Cushing's disease

Question 45

An excess of TSH (thyrotrophin)->

Answer 45

Thyrotoxicosis

Question 46

An excess of gonadotrophins (LH/FSH) in children->

Answer 46

Precocious puberty

Question 47

An excess of prolactin->

Answer 47

Hyperprolactinaemiaa

Question 48

An excess of GH>

Answer 48

Gigantism | Acromegaly

Question 49

When is hyperprolactinaemia physiological and pathological?

Answer 49

Physiological= high when pregnant/breastfeeding Pathological= prolactinoma (most common functioning pituitary tumour, usually <10mm diameter microadenoma)

Question 50

What is the main other hormone affected when a person has a prolactinoma?

Answer 50

High prolactin suppresses GnRH pulsatility

Question 51

What are the signs and symptoms of hyperprolactinaemia due to pituitary adenoma? (M & F)

Answer 51

``` WOMEN Galactorrhoea Secondary amernorrhoea or oligomenorrhoea Loss of libido Infertility ``` ``` MEN Galactorrhoea uncommon Loss of libido Erectile dysfunction Infertility ```

Question 52

What does an anterior pituitary lactotroph secrete?

Answer 52

Prolactin

Question 53

How does dopamine affect prolactin secretion? (D2 R agonism)

Answer 53

Dopamine from hypothalamic dopaminergic neurones binds to D2 receptors on ant pit lactotroph and stops prolactin production

Question 54

How is hyperprolactinaemia treated>

Answer 54

Medical= D2 (DA R) agonist-> decrease prolatin secretion, reduce tumour size E.g. bromocroptine, cabergoline (oral admin)

Question 55

What are the side effects of DA R agonists?

Answer 55

``` Nausea and vomiting Postural hypotension Dyskinesias Depression Pathological gambling (BNF) ```

Question 56

How does excess GH affect children and adults?

Answer 56

Children- gigantism Adults- acromegaly (can't have increased linear growth because growth plates have fused Usually due to benign growth hormone secreting pituitary adenoma

Question 57

Why is acromegaly often diagnosed late?

Answer 57

Insidious in onset | Signs and symptoms progress gradually (can remain undiagnosed for years)

Question 58

What are common causes of death due to acromegaly?

Answer 58

CV disease 60% Respiratory complications 25% Cancer 15%

Question 59

What parts of the body grow in acromegaly?

Answer 59

``` Periosteal bone Cartilage Fibrous tissue Connective tissue Internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.) ```

Question 60

What are the clinical features of acromegaly?

Answer 60

Excessive sweating (hyperhidrosis) Headache (very prevalent, hard to treat) Enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features Enlarged tongue (macroglossia) Mandible grows causing protrusion of lower jaw (prognathism) Carpal tunnel syndrome (median nerve compression) Barrel chest, kyphosis Spade shaped hands with doughy palms

Question 61

Why is diabetes mellitus a metabolic effect of acromegaly?

Answer 61

Excess GH inhibits insulin signalling - > increased insulin resistance - > impaired glucose tolerance - > diabetes mellitus

Question 62

4 major complications of acromegaly

Answer 62

Obstructive sleep apnoea (bone and soft-tissue changes surrounding upper airway-> narrowing/collapse during sleep) Hypertension (due to GH or IGF1 on vascular tree and GH mediated renal Na reabsorption) Cardiomyopathy (hypertension, DM, direct toxic effects of excess GH on myocardium) Increased cancer risk (need colonoscopy- enlarged bowel)

Question 63

What hormone is commonly secreted with GH in acromegaly?

Answer 63

Prolactin Hyperprolactinaemia causes secondary hypogonadism

Question 64

How is GH secretion regulated?

Answer 64

Stimulated by GHRH | Inhibited by SS

Question 65

What does GH lead to in the liver?

Answer 65

Somatomedin production (mainly IGF1)

Question 66

How does glucose-induced suppression of growth hormone show whether or not a person is acromegalic?

Answer 66

After 75mg oral glucose given: Normal= decrease (trough) in GH in first 2 hours and then increase (overcorrection) in next 2 hours Acromegaly= rise in GH in first 2 hours AND higher start point of GH mU/l

Question 67

Treatment of acromegaly

Answer 67

Surgery (trans-sphenoidal) Medical= somatostatin analogues (SS inhibits GH secretion from ant pit) e.g. octreotide = dopamine agonists (GH secreting pit tumours frequently express D2 Rs) Radiotherapy

Question 68

How can somatostatin analogues be used to treat acromegaly?

Answer 68

Injection (sc) or monthly depot Reduces GH secretion and tumour size Pre-treatment before surgery to make resection easier or Post-operatively

Question 69

What are common side effects of somatostatin analogues as treatment for acromegaly?

Answer 69

GI side effects | Nausea, diarrhoea, gallstones

Question 70

What is the neurohypophysis?

Answer 70

Posterior pituitary

Question 71

What is the adenohypophysis?

Answer 71

Anterior pituitary

Question 72

What does the posterior pituitary look like on an MRI (sagittal section)?

Answer 72

'Bright spot' on pituitary MRI

Question 73

Why is the posterior pituitary call the neurohypophysis and what cells are present?

Answer 73

Collection of axons from neuronal projections | Magnocellular- big cell bodies

Question 74

What hormones are released by the post pit?

Answer 74

Oxytocin | Vasopressin (ADH- anti diuretic hormone)

Question 75

What is diuresis?

Answer 75

Increase in urine production

Question 76

How does ADH reduce diuresis?

Answer 76

Promotes retention from renal cortical and medullary collecting ducts Via vasopressin 2 receptors (V2Rs) Stimulates synthesis of AQP 2 (water channels)

Question 77

What does aquaporin 2 do?

Answer 77

Water channels (to allow water passage through membrane) Bags of AQP2 are inserted into apical membrane of the collecting duct When there is an osmotic gradient across the cell then water flows in through aquaporin (into collecting duct cell) then across to BL membrane through AQP3 and AQP4 into plasma Net effect is reabsorption of water from nephron into the plasma

Question 78

What is the net effect of the actions of ADH in the kidney?

Answer 78

Net effect is reabsorption of water from nephron into the plasma

Question 79

What do osmoreceptors do?

Answer 79

Sense osmolality | Very sensitive to changes in EC osmolality (think of it as conc)

Question 80

Where are osmoreceptors located and why is this area of the brain a different colour?

Answer 80

Organum vasculosum Project to hypothalamic PVN and SON (where there are vasopressinergic nuclei) Different colour because no BBB (so can communicate directly with system circulation)

Question 81

Why does the organum vasculosum region of the brain have no BBB?

Answer 81

Contains osmoreceptors | Can communicate directly with system circulation)

Question 82

How does an osmoreceptor respond to increased EC sodium?

Answer 82

Increased osmolality Osmoreceptor shrinks in response (water moves out) Stimulates osmoreceptor firing-> triggers release of ADH from hyperthalamic neurons in SON and PVN

Question 83

How does an osmoreceptor respond to water deprivation?

Answer 83

Increased serum osmolality (dehydrated) Stimulation of osmoreceptors-> thirst and increased VP release Increased water reabsorption from renal collecting ducts Reduced urine volume, increase in urine osmolality AND Reduced serum osmolality

Question 84

What causes diabetes insipidus?

Answer 84

Absence or lack of circulating ADH (cranial/central) End-organ (kidneys) resistance to ADH (nephrogenic)

Question 85

What is the difference between nephrogenic and cranial DI?

Answer 85

Absence or lack of circulating ADH (cranial/central) End-organ (kidneys) resistance to ADH (nephrogenic)- RARER, harder to manage

Question 86

What causes acquired cranial diabetes insipidus?

Answer 86

Damage to Neurohypophysial system E.g. Traumatic brain injury Pituitary surgery (damage to stalk) Pituitary tumours, craniopharyngioma Metastasis to the pituitary gland e.g. breast Granulomatous infiltration of median eminence eg TB, sarcoidosis

Question 87

Is acquired or congenital cranial DI more common?

Answer 87

Acquired | Congenital is rare

Question 88

What causes congeital nephrogenic diabetes insipidus?

Answer 88

Rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)

Question 89

What causes acquired nephrogenic diabetes insipidus?

Answer 89

Drugs e.g. lithium

Question 90

What are the signs and symptoms of DI?

Answer 90

Large volumes of urine (polyuria) Urine very dilute (hypo-osmolar) Thirst and increased drinking (polydipsia) Dehydration (and consequences) if fluid intake not maintained - can lead to DEATH Possible disruption to sleep with associated problems

Question 91

What is polyuria?

Answer 91

Large volumes of urine

Question 92

What is polydipsia?

Answer 92

Excessive thirst and increased drinking

Question 93

How does diabetes insipidus lead to EC fluid volume expansion?

Answer 93

``` Inadequate production of/response to ADH Large volumes of dilute (hypotonic) urine Increase in plasma osmolality (and Na) Reduction in EC fluid volume Thirst- polydipsia EC fluid volume expansion ```

Question 94

How does diabetes insipidus with no access to water lead to dehydration and death?

Answer 94

``` Inadequate production of/response to ADH Large volumes of dilute (hypotonic) urine Increase in plasma osmolality (and Na) Reduction in EC fluid volume NO ACCESS TO WATER Dehydration and death ```

Question 95

What is psychogenic polydipsia? What causes it?

Answer 95

Most frequently seen in psychiatric patients – aetiology unclear, may reflect anti-cholinergic effects of medication – ‘dry mouth’ Can be in patients told to ‘drink plenty’ by healthcare professionals Excess fluid intake (polydipsia) and excess urine output (polyuria) – BUT unlike DI, ability to secrete vasopressin in response to osmotic stimuli is preserved

Question 96

How does psychogenic polydipsia occur?

Answer 96

Increased drinking (polydipsia) Expansion of EC fluid volume, reduction in plasma osmolality Less VP secreted by posterior pituitary Large volumes of dilute (hypotonic) urine EC fluid volume returns to normal Increased drinking (polysipsia)... REPEAT

Question 97

How can you tell if someone is normal, has DI or has psychogenic polydipsia?

Answer 97

Numbers in mOsm/kg H2O (plasma osmolality) DI= >290 Normal= Around 270-290 Psychogenic polydipsia= <270

Question 98

What do the water deprivation test show?

Answer 98

Determines whether the patient has diabetes insipidus as opposed to other causes of polydipsia (a condition of excessive thirst that causes an excessive intake of water)

Question 99

How do you test for DI? (incl different types of DI)

Answer 99

Measure urine osmolality of... 1. Normal hydrated 2. Water deprivation (to see DI or other cause of polydipsia) 3. Give synthetic VP (DDAVP) to distinguish between cranial and nephrogenic DI

Question 100

What are the biochemical features of DI?

Answer 100

Hypernatraemia Raised urea Increased plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality

Question 101

What are the biochemical features of pyschogenic polydipsia?

Answer 101

Mild hyponatraemia – excess water intake Low plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality

Question 102

What is terlipressin?

Answer 102

A selective vasopressin receptor peptidergic agonists for V1

Question 103

What is desmopressin (DDAVP)?

Answer 103

A selective vasopressin receptor peptidergic agonists for V2

Question 104

What are the selective vasopressin receptor peptidergic agonists for VI and V2

Answer 104

V1 –terlipressin V2 – desmopressin (DDAVP)

Question 105

How is desmopressin administered?

Answer 105

Nasally (usually spray before bed) Orally SC

Question 106

What effect does desmopressin have on cranial DI?

Answer 106

Reduction in urine volume and concentration in cranial DI CAN'T DRINK AS MUCH AS NORMAL-> risk of hyponatraemia

Question 107

How can nephrogenic diabetes insipidus be treated?

Answer 107

Thiazides e.g. bendroflumethiazide

Question 108

What is the possible mechanism of thiazide to treat nephrogenic diabetes insipidus?

Answer 108

Inhibits Na+/Cl- transport in distal convoluted tubule (-> diuretic effect) Volume depletion Compensatory increase in Na+ reabsorption from the proximal tubule (plus small decrease in GFR, etc.) Increased proximal water reabsorption Decreased fluid reaches collecting duct Reduced urine volume

Question 109

What happens if there is excess ADH?

Answer 109

Syndrome of Inappropriate ADH (SIADH) Make too much ADH Plasma vasopressin concentration is inappropriately high for the existing plasma osmolality

Question 110

How does SIADH lead to euvolaemia and hyponatraemia?

Answer 110

Increased ADH Increased H2O reabsorption from renal collecting ducts Expansion of ECF volume -> Hyponatraemia OR -> Atrial natriuretic peptide (stretch sensitive) from right atrium Natriuresis -> Euvolaemia OR hyponatraemia

Question 111

What is euvolaemia?

Answer 111

Normal circulating volume | Maintained because of collecting ducts and ANP

Question 112

What are the signs of SIADH?

Answer 112

Raised urine osmolality, decreased urine volume (initially) Decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption Feel unwell but can be symptomless

Question 113

What happens if you are hyponatraemic?

Answer 113

Normal plasma conc of Na= 120mM <120mM-> generalised weakness, poor mental function, nausea <110mM-> confusion, coma, death

Question 114

What are the causes of SIADH? (5 groups)

Answer 114

``` CNS= SAH, stroke, tumour, TBI Pulmonary disease= Pneumonia, bronchiectasis Malignancy= Lung (small cell) Drug-related= Carbamazepine, SSRI Idiopathic ```

Question 115

How is SIADH treated?

Answer 115

Surgery for tumour/radiotherapy if there is one If there is severe hyponatraemia - Fluid restriction first - Drugs to prevent VP action in kidneys (to induce nephrogenic DI to reduce renal water reabsorption)

Question 116

What does demeclocycline do?

Answer 116

Induce nephrogenic DI (in a SIADH patient) ie reduce renal water reabsorption

Question 117

What to V2 receptor antagonists (VAPTANS) do?

Answer 117

Inhibit action of ADH Non-competitve V2 R antagonists Inhibit AQP2 synthesis-> promote water loss rather than losing water and sodium

Question 118

What causes primary hypothyroidism (myxoedema)?

Answer 118

Autoimmune damage to thyroid Leads to decline in thyroxine (low T4) levels TSH levels climb

Question 119

What are common symptoms of hyothyroidism?

Answer 119

``` Weight gain Cold intolerance Voice deepens Bradycardia-> hypertension Constipation Depression and tiredness Oedema Dry hair ``` Eventual myxoedema coma

Question 120

What does a healthy adult thyroid gland secrete?

Answer 120

T4 (less active) and T3 (more active metabolite)

Question 121

Why is T4 (thyroxine) a prohormone?

Answer 121

T4 converted by deiodinase enzyme activity into tri-iodothyronine (T3) T3= active metabolite that provides almost all thyroid hormone activity to target cells

Question 122

How much T3 is from deiodination of T4 and how much is from direct thyroidal secretion?

Answer 122

80% from deiodination of T4 | 20% from direct thyroidal secretion

Question 123

What is TRE?

Answer 123

Thyroid response element

Question 124

What happens to T4 and T3 in the target cell?

Answer 124

Enter target cell T4 converted to T3 T3 transported into cell nucleus Binds to heterodimer: T3 binds to thyroid receptor and RXR (retinoid x receptor) and TRE-> alters gene expression

Question 125

What thyroid hormone replacement therapy exists?

Answer 125

Levothyroxine sodium (THYROXINE=T4)= more commonly used Liothyronine sodium (TRIIODOTHYRONINE=T3)= less commonly used

Question 126

What are the clinical uses of levothyroxine sodium (synthetic thyroxine)?

Answer 126

Autoimmune primary hypothyroidism OR Iatrogenic primary hypothyroidism – e.g. post-thyroidectomy, post-radioactive iodine OR Secondary hypothyroidism (problem with pituitary not gland)

Question 127

How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)

Answer 127

Oral administration TSH used as guidance for thyroxine dose - aim to suppress TSH into the reference range

Question 128

What does levothyroxine sodium aim to do?

Answer 128

Negative feedback | Reduce production of TSH (ant pit)

Question 129

How is levothyroxine sodium administered for primary hypothyroidism? (incl. how to guide dose)

Answer 129

Oral administration. TSH low due to anterior pituitary failure, so can’t use TSH as a guide to dose Aim for fT4 middle of reference range

Question 130

When is liothyronine (synthetic trio-iodothyronine) used? How is it administered?

Answer 130

Myxoedema coma - a VERY RARE complication of hypothyroidism iv initially – as onset of action faster than T4 then oral when possible

Question 131

What is combined thyroid hormone replacement?

Answer 131

Combo of T4 and T3= some reported improvement in well-being Not advised because T3 effects so potent e.g. symptoms of ‘toxicity’ (palpitations, tremor, anxiety) Also, often combination treatment suppresses TSH

Question 132

What happens in thyroid hormone over-replacement? (4 groups)

Answer 132

Usually associated with low/suppressed TSH Skeletal- increased bone turnover, reduction in bone mineral density, risk of osteoporosis Cardiac– tachycardia, risk of dysrhythmia, particularly atrial fibrillation Metabolism– increased energy expenditure, weight loss Increased β-adrenergic sensitivite tremor, nervousness

Question 133

What is the half life of levothyroxine (T4) and liothyronine (T3)

Answer 133

Levothyroxine (T4) plasma half life= 6 days Liothyronine (T3) plasma half life= 2.5 days

Question 134

How much circulating T4 and T3 is bound to plasma proteins (mainly TBG)?

Answer 134

Approx 99.97% of circulating T4 Approx 99.7% of circulating T3 Bound to plasma proteins, mainly thyroxine binding globulin (TBG)

Question 135

Is bound thyroid hormone available to tissues?

Answer 135

No Only free (unbound) thyroid hormones are available to tissues

Question 136

What can increase or decrease plasma binding proteins? (I.e. TBG)

Answer 136

Plasma binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines TBG falls with malnutrition, liver disease, certain drug treatments (e.g. co-administered drugs incl. phenytoin/salicylates compete for protein binding sites)

Question 137

How much T4 is there compared to T3 (in the plasma)?

Answer 137

10x more T4

Question 138

How long does it take free and conjugated T3 and T4 to be secreted in the urine?

Answer 138

T3 is cleared in hours | T4 is cleared in about 6 days

Question 139

What drugs are used in treatment of hyperthyroidism? (4 groups)

Answer 139

The thionamides (thiourylenes; anti-thyroid drugs) Potassium Iodide Radioiodine β-blockers

Question 140

Which hyperthyroid drugs are aimed at blocking thyroxine synthesis

Answer 140

The thionamides Potassium Iodide Radioiodine

Question 141

What is the aim of beta blockers in treatment of hyperthyroidism?

Answer 141

Relieves symptoms

Question 142

Give 2 examples of thionamides

Answer 142

Propylthiouracil (PTU) | Carbimazole (CBZ)

Question 143

How can thionamides (PTU and CBZ) be used clinically? (3 ways)

Answer 143

Daily treatment of hyperthyroid conditions e.g. Graves Treatment prior to surgery Reduction of symptoms while waiting for radioactive iodine to act

Question 144

What are hyperthyroid conditions which may require daily treatment with thionamides?

Answer 144

Graves | Toxic thyroid nodule/toxic multinodular goitre

Question 145

How are thyroid hormones synthesised?

Answer 145

Uptake of iodide by active transport Iodination= iodide converted to iodine Condensed onto tyrosine residues along the polypeptide backbone of thyroglobulin Coupling reaction= storage in colloid Endocytosis and secretion

Question 146

What enzymes are used in thyroid hormone synthesis to get thyroid hormone in and out of the cell?

Answer 146

Into cell= peroxidase transaminase Out of cell= thyroperoxidase and H202

Question 147

How do thionamides interfere with thyroid hormone synthesis?

Answer 147

Inhibit thyroperoxidase (and hence T3 and T4 synthesis and secretion)

Question 148

How long does it take biochemically and clinically to have an effect from thionamides?

Answer 148

Biochemical effect= hours | Clinical effect= weeks

Question 149

Why might treatment with thionamides often include proranolol?

Answer 149

Rapidly reduces tremor and tachycardia | -olol= beta blocker

Question 150

How does thionamide lead to improvements in patients with hyperthyroidism? (2 ways)

Answer 150

May suppress antibody production in Graves' disease Reduces conversion of T4 to T3 in peripheral tissues (PTU) Lots of T3 made by iodination but want to try and reduce this manufacture

Question 151

What unwanted actions does thionamide cause?

Answer 151

Agranulocytosis/granulocytopenia reduced/absent granular leukocytes (RARE and reversible on withdrawal of drug) Rashes (relatively common)

Question 152

Outline the pharmacokinetics of thionamides? PTU and CBZ

Answer 152

PTU Orally active Plasma half life 6-15h Crosses placenta and secreted in breastmilk (less than in CBZ) Metabolised in liver and secreted in urine CBZ Orally active Carbimazole= pro-drug (first converted to methimazole) Plasma half life 6-15h Crosses placenta and secreted in breastmilk (more than in PTU) Metabolised in liver and secreted in urine

Question 153

How long is anti-thyroid drug treatment usually for?

Answer 153

18 months | Period reviews including thyroid function tests for remission/relapse

Question 154

What is the role of β blockers in thyrotoxicosis?

Answer 154

Anti-thyroid drugs don't have clinical effects for 2 weeks B blockers lead to reduced tremor, slower heart rate, less anxiety Non-selective (i.e. B1 and B2) B blocker e.g. propanolol are more effective than selective B1 blockers e.g. atenolol for this

Question 155

When is iodide (usually KI) used for hyperthyroidism?

Answer 155

Preparation of hyperthyroid patients for surgery Severe thyrotoxic crisis (thyroid storm) KI doses= 30x average daily requirement

Question 156

How does KI treat hyperthyroidism (2 ways)?

Answer 156

Inhibits iodination of thyroglobulin | Inhibits H202 generation

Question 157

Time taken for: Hyperthyroid symptoms to reduce Vascularity and size of gland to reduce

Answer 157

Hyperthyroid symptoms to reduce= 1-2 days | Vascularity and size of gland to reduce= 10-14 days

Question 158

What is the Wolff-Chaikoff effect?

Answer 158

Reduction in thyroid hormone levels caused by ingestion of a large amount of iodine Presumed autoregulatory (KI hyperthyroidism)

Question 159

What are the unwanted actions of KI treatment of hyperthyroidism?

Answer 159

Allergic reaction e.g. rashes, fever, angio-oedema

Question 160

Pharmacokinetic features of KI treatment of hyperthyroidism?

Answer 160

``` Given orally (Lugol’s solution; aqueous iodine) Maximum effects after 10 days’ continuous administration ```

Question 161

How does high dose radioiodine treat hyperthyroidism (2 ways)?

Answer 161

Accumulates in colloid Emits B particles Destroys follicular cells

Question 162

Pharmacokinetic features of radioiodine treatment of hyperthyroidism?

Answer 162

Discontinue ATDs 7-10 days before radioiodine treatment Administer as a single oral dose Radioactive half life of 8 days Radioactivity negligible after 2 months

Question 163

What are the single oral radioiodine doses administered for Graves and thyroid cancer?

Answer 163

Graves’ disease: approx 500 MBq | Thyroid cancer: circa 3,000 MBq

Question 164

Who can't receive radioiodine to treat hyperthryoidism?

Answer 164

Pregnant women Breast feeding women NB. Avoid close contact with small children for several weeks after receiving radioiodine

Question 165

What is 131^I?

Answer 165

Radioiodine for treatment of hyperthyroidism

Question 166

What is the use of radioiodine (131^I or technetium 99 pertechnetate) in very low, tracer doses?

Answer 166

To test thyroid gland pathology e.g. toxic nodule, thyroiditis vs Graves' Administer IV Negligible cytotoxicity

Question 167

What diseases are caused by hypersecretion of adrenal hormones?

Answer 167

Cushing's syndrome (cortisol) | Conn's syndrome (aldosterone)

Question 168

What inhibits steroid biosynthesis in Cushing's syndrome?

Answer 168

Metyrapone | Ketoconazole

Question 169

What is an MR antagonist in Conn's syndrome?

Answer 169

Spironolactone | Epleronone

Question 170

How does metyrapone act to relieve Cushing's syndrome?

Answer 170

Inhibition of 11β-hydroxylase -> Stops cortisol synthesis = Steroid synth in z. fasc (and z.retic) are arrested at the 11-deoxycortisol stage -> ACTH secretion increased -> Plasma deoxycortisol increases =There is no negative fb effect on the hypothalamus and pituitary gland by 11-deoxycortisol

Question 171

What are the main arms of steroid biosynthetic pathways?

Answer 171

Cholesterol-> Mineralocorticoid arm Glucocorticoid arm Adrenocorticoid arm SEE DIAGRAM

Question 172

What is the principal glucocorticoid in humans?

Answer 172

Cortisol

Question 173

In which layers of the adrenal cortex are the following found? Mineralocorticoid arm Glucocorticoid arm Adrenocorticoid arm

Answer 173

Mineralocorticoid arm= z. glomerulosa Glucocorticoid arm= z. fasciculata Adrenocorticoid arm= z. reticularis

Question 174

How is metyrapone used to treat Cushing's syndrome? (2 times)

Answer 174

Control of Cushing's before surgery Control of Cushing's syndrome after radiotherapy (slow to work)

Question 175

Why does metyrapone help control Cushing's before surgery?

Answer 175

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)

Question 176

Why can metyrapone cause hypertension?

Answer 176

Deoxycorticosterone accumulates in z. glomerulosa Has aldosterone-like (mineralocorticoid) activity, leading to salt retention and hypertension

Question 177

Why can metyrapone cause hirsutism?

Answer 177

Precursors accumulate (may go to different arm) Increased adrenal androgen production hirsutism in women

Question 178

What are the unwanted actions of metyrapone?

Answer 178

Hypertension (on long-term admin) | Hirsutism

Question 179

How was ketoconazole originally intended to be used (before Cushing's)? How did it become off-label treatment for Cushing's?

Answer 179

Antifungal agent Withdrawn due to hepatotoxicity risk Higher conc-> inhibits steroidogenesis (needs careful monitoring but useful for Cushing's)

Question 180

How does ketoconazole help Cushing's syndrome patients?

Answer 180

Block production of glucocorticoids, mineralocorticoid and sex steroids Many steps blocked, stops production of cortisol (amongst other features)

Question 181

How is ketoconazole used?

Answer 181

For Cushing's patients Treatment and control of symptoms prior to surgery Orally active

Question 182

What are the unwanted actions of ketoconazole?

Answer 182

``` Liver damage (possibly fatal) So monitor liver function weekly, clinically and biochemically ```

Question 183

What is spironolactone used for?

Answer 183

Primary hyperaldosteronism (Conn's syndrome)

Question 184

How does spironolactone treat Conn's syndrome?

Answer 184

Converted to several active metabolites including canrenone Canrenone= competitive antagonist of the mineralocorticoid receptor (MR) Blocks Na+ resorption and K+ excretion in the kidney tubules (K sparing diuretic)

Question 185

What is canrenone? What is it converted from?

Answer 185

Converted from spironolactone Canrenone= competitive antagonist of the mineralocorticoid receptor (MR)

Question 186

Pharmacokinetics of canrenone?

Answer 186

Orally active | Highly protein bound and metabolised in the liver

Question 187

What are the unwanted effects of spironolactone? Why do these occur?

Answer 187

``` Menstrual irregularities (+ progesterone receptor) Gynaecomastia (- androgen receptor) ```

Question 188

How does epleronone treat Conn's syndrome?

Answer 188

Mineralocorticoid receptor (MR) antagonist Similar affinity to the MR compared to the MR compared to spironolactone Less binding to androgen and progesterone, better tolerated

Question 189

What is CRH?

Answer 189

Corticotrophin releasing hormone

Question 190

What is ACTH?

Answer 190

Adrenocorticotrophic hormone= corticotrophin

Question 191

How many carbons are in cholesterol?

Answer 191

C27

Question 192

CHOLESTEROL SYNTHESIS. What are the hydroxylase enzymes in the cholesterol synthesis pathway?

Answer 192

CHOLESTEROL SYNTHESIS Learn the numbers from diagram

Question 193

What are the main causes of adrenocortical failure?

Answer 193

Tuberculous Addison's disease (most common worldwide) Autoimmune Addison's disease (commonest UK) Congenital adrenal hyperplasia

Question 194

What happens in congenital adrenal hyperplasia?

Answer 194

Missing 2nd enzyme Adrenal glands are enormous but not functioning properly 95% cases= lack 21-hydroxylase

Question 195

List symptoms of Addison's

Answer 195

``` Tan Buckle pigmentation (teeth, eyes) Pigmented scar Weak- proximal myopathy Losing weight Vitiligo- predisposition to thyroid disease (autoimmune) Hypotensive (postural hypotension) ```

Question 196

What are the consequences of of adrenocortical failure?

Answer 196

Can't make aldosterone Fall in BP Loss of salt in urine-> hypotension Increased plasma potassium (hyperkalaemia) Fall in glucose due to glucocorticoid deficiency High ACTH resulting in increased pigmentation Eventual death due to severe hypotension if not treated

Question 197

Why does high CTH lead to increased pigmentation?

Answer 197

Damage to adrenal gland-> less cortisol so no negative feedback Make more ACTH from the precursor POMC Synthesised in pituitary and broken down to ACTH and MSH (and endorphins, enkephalins, other peptides) MSH-> look tanned

Question 198

What is MSH and why does it cause a tanned appearance?

Answer 198

Melanocyte stimulating hormone | Stimulates melanocytes to make melanin

Question 199

What should the cortisol and ACTH be in an Addison's patient at 9am in a blood test?

Answer 199

``` Cortisol= low ACTH= high ```

Question 200

What specific test is used for Addison's?

Answer 200

Short synacthen test (synACTHen= synthetic ACTH) Give 250ug synacthen IM so should make lots of IM Measure cortisol response Normal person= cortisol goes up Addisons patient= very small/no rise Then imaging studies to find source e.g. adrenal or pituitary tumour

Question 201

What is the most common cause of congenital adrenal hyperplasia?

Answer 201

21-hydroxylase deficiency | Complete or partial

Question 202

What hormones are totally absent or in excess in complete 21-hydroxylase deficiency?

Answer 202

Totally absent= aldosterone and cortisol Excess= sex steroids and testosterone No cortisol production, so ACTH rises (no -ve fb)-> drives further adrenal androgen production

Question 203

When a baby has congenital adrenal hyperplasia, how do they present?

Answer 203

Usually by 1 week old As a neonate with a salt losing Addisonian crisis Some girls may have ambiguous genitalia (virilised by adrenal testosterone) NB. In utero, foetus gets steroids across placenta

Question 204

What hormones are deficient or in excess in partial 21-hydroxylase deficiency?

Answer 204

``` Deficient= cortisol and aldosterone Excess= sex steroids and testosterone ```

Question 205

What age do people with partial 21-hydroxylase deficiency patients present? What is the main problem with the deficiency?

Answer 205

Any age They survive Main problem in later life is hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone

Question 206

How does 11 deoxycorticosterone behave?

Answer 206

Like aldosterone

Question 207

What happens if there is excess 11 deoxycorticosterone?

Answer 207

Hypertension | Hypokalaemia

Question 208

What hormones are deficient or in excess in 11-hydroxylase deficiency?

Answer 208

``` Deficient= cortisol and aldosterone Excess= sex steroids, testosterone and 11-deoxycorticosterone ```

Question 209

What are the problems of 11-hydroxylase deficiency?

Answer 209

Essentially becomes a problem of too much mineralocorticoid | This means virilisation, hypertension and low K

Question 210

What hormones are deficient or in excess in 17-hydroxylase deficiency?

Answer 210

``` Deficient= cortisol and sex steroids Excess= 11-deoxycorticosterone and aldosterone (mineralocorticoids) ```

Question 211

What are the problems of 17-hydroxylase deficiency?

Answer 211

Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low glucose)

Question 212

What are the functions of cortisol, aldosterone and androgens/oestrogens?

Answer 212

``` Cortisol= essential for life Aldosterone= promotes Na+ retention and K+ loss Androgens/oestrogens= different sexual/reproductive functions (from gonads) ```

Question 213

What are the main two types of corticosteroid receptors?

Answer 213

Glucocorticoid receptors | Mineralocorticoid receptors

Question 214

What are the differences between glucocorticoid Rs and mineralocorticoid Rs?

Answer 214

GR Wide distribution Selective for glucocorticoids Low affinity for cortisol MR Discrete distribution (kidney) Don't distinguish between aldosterone and cortisol High affinity for cortisol

Question 215

How does 11B-hydroxysteroid dehydrogenase (11BHSD) protect mineralocorticoid receptors from cortisol?

Answer 215

11BHSD inactivates cortisol-> cortisone (inactive) | Stops aldosterone receptors being overly activated by cortisol

Question 216

What happens in Cushing's syndrome that leads to hypertension?

Answer 216

Cushings-> making too much cortisol but 11BHSD enzyme can't do it all so some cortisol not converted to cortisone (inactive) and instead binds to MR aldosterone receptors Excess cortisol binds to MR-> hypokalamia, hypernatreamia so HYPERTENSIVE

Question 217

``` What kind of corticosteroid receptors do the following drugs act on? Hydrocortisone Prednisolone Fludrocortisone Dexamethasone ```

Answer 217

``` Hydrocortisone= acts on GR/MR Prednisolone= acts on GR/weak MR Fludrocortisone= acts on MR Dexamethasone= acts on GR ```

Question 218

What kind of drug is fludrocortisone?

Answer 218

Aldosterone analogue Used as an aldosterone substitute Corticosteroid drug

Question 219

How are corticosteroids administered?

Answer 219

Oral= hydrocortisone, prednisolone, dxamethasone, fludrocortisone Parental (IV or IM)= hydrocortisone, dexamethasone

Question 220

How are corticosteroids distributed?

Answer 220

Bind to plasma proteins (cortisol binding globulin CBG and albumin) as circulating cortisol does

Question 221

How long do corticosteroids last?

Answer 221

``` Hydrocortisone= duration 8h Prednisolone= duration 12h Dexamethasone= duration 40h ```

Question 222

What hormones do Addison's patients lack?

Answer 222

Cortisol and aldosterone Primary adrenocortical failure

Question 223

What hormones do patients of secondary adrenocortical failure lack?

Answer 223

Cortisol but not aldosterone ACTH deficiency

Question 224

How is secondary adrenocortical failure treated?

Answer 224

Oral hydrocortisone

Question 225

What is an acute adrenocortical failure?

Answer 225

Addisonian crisis (severe hypotension occurs)

Question 226

How is a patient undergoing a Addisonian crisis treated?

Answer 226

IV saline (0.9% sodium chloride) to rehydrate patient High dose hydrocortisone (IV infusion or IM every 6h, mineralocorticoid effect at high dose-11BHSD overwhelmed) 5% dextrose if hypoglycaemia

Question 227

How is congenital adrenal hyperplasia treated?

Answer 227

Dexamethasone 1/day pm OR Hydrocortisone 2-3/day, high dose pm = to replace cortisol Fludrocortisone= to replace aldosterone

Question 228

What are aims for the therapy of congenital adrenal hyperplasia?

Answer 228

Replace cortisol and aldosterone

Question 229

Why is it important to monitor/optimise corticosteroid replacement therapy by measuring?

Answer 229

Measure 17 OH progesterone (precursor) Clinical assessment: - Cushingoid if GC dose too high - Hirsutism if GC dose too low (hence ACTH risen)

Question 230

Why do you increase glucocorticoid dosage when patients are vulnerable to stress?

Answer 230

17 OH progesterone | Cortisol (normally= 20mg/day but in stress 200-300mg/day)

Question 231

When is glucocorticoid dosage increased?

Answer 231

Under stress In minor illness (2x normal dose) In surgery- hydrocortisone IM with pre-med and at 6-8h intervals, oral once eating and drinking

Question 232

Outline the male HPG axis

Answer 232

``` GnRH released from hypothalamus Stimulatory effect on pituitary Leads to release of LH and FSH Stimulatory effect on testis Production of testosterone ``` Inhibin released by sertoli cells With increasing testosterone-> inhibits release of FSH and LH from pit gland and inhibits hypothalamus

Question 233

How many days is the female menstrual cycle? What are the phases?

Answer 233

28 | Follicular phase, ovulation, luteal phase

Question 234

Outline the female HPG axis (not in ovulation)

Answer 234

``` GnRH released from hypothalamus Stimulatory effect on pituitary Leads to release of LH and FSH Stimulatory effect on ovary Production of oestradiol and progesterone ``` Inhibin released With increasing testosterone-> inhibits release of FSH and LH from pit gland and inhibits hypothalamus

Question 235

Outline the female HPG axis (in ovulation)

Answer 235

``` GnRH released from hypothalamus Stimulatory effect on pituitary Leads to release of LH and FSH Stimulatory effect on ovary Production of oestradiol ``` Positive feedback leads to increased GnRH and LH/FSH surge which triggers ovulation

Question 236

What happens if implantation doesn't occur in the luteal phase?

Answer 236

Endometrium is shed (menstruation)

Question 237

Define: infertility

Answer 237

Inability to conceive after 1 year of regular unprotected sex 1:6 couples

Question 238

What percentage of infertility is caused by abnormalities of M and F?

Answer 238

Males- 30% Females- 45% Unknown- 25%

Question 239

How is the HPG axis affected in primary gonadal failure?

Answer 239

GnRH released from hypothalamus (HIGH) LARGE stimulatory effect on pituitary Leads to HIGH release of LH and FSH But problem in testes/ovary-> LOW testosterone/oestradiol LOW inhibin so not appropriate -ve feedback .... high GnRH etc.

Question 240

How is the HPG axis affected in hypothalamic/pituitary disease

Answer 240

Low LH/FSH Low testosterone/oestradiol Low inhibin

Question 241

What are the clinical features of male hypogonadism?

Answer 241

``` Loss of libido = sexual interest / desire Impotence Small testes Decrease muscle bulk Osteoporosis ```

Question 242

What are the causes of male hypogonadism?

Answer 242

Hypothalamic-pituitary disease (pituitary not working, low testosterone) Primary gonadal disease Hyperprolactinaemia Androgen receptor deficiency

Question 243

What are the symptoms of Kallmans syndrome?

Answer 243

Anosmia Low GnRH Testes orignally undesecended Stature low-normal

Question 244

What are examples of hypothalamic-pituitary disease that cause male hypogonadism?

Answer 244

Hypopituitarism Kallmans syndrome Illness/underweight

Question 245

What are examples of primary gonadal disease that cause male hypogonadism?

Answer 245

Congenital: Klinefelters syndrome (XXY) Acquired: Testicular torsion, chemotherapy

Question 246

How can you investigate male hypogonadism?

Answer 246

LH, FSH, testosterone (if all low-> MRI pituitary) Prolactin Sperm count Chromosomal analysis (Klinefelters XXY)

Question 247

Define: azospermia

Answer 247

Absence of sperm in ejaculate

Question 248

Define: oligospermia

Answer 248

Reduced numbers of sperm in ejaculate

Question 249

How is male hypogonadism treated?

Answer 249

Replacement testosterone for all patients For fertility: if hypo/pit disease subcutaenous gonadotrophins (LH/FSH) Hyperprolactinaemia- DA agonist

Question 250

What are the endogenous sites of production of androgens?

Answer 250

Interstitial Leydig cells of the testes Adrenal cortex (males and females) Ovaries Placenta Tumours

Question 251

What are the 4 main actions of testosterone?

Answer 251

``` Development of the male genital tract Maintains fertility in adulthood Control of secondary sexual characteristics Anabolic effects (muscle, bone) ```

Question 252

How much testosterone is bound to protein?

Answer 252

98%

Question 253

What can testosterone be converted in to? What enzymes does this involve?

Answer 253

Tissue specific processing Dihydrotestosterone (DHT) acts via the androgen receptor (AR) Converted with 5a-reductase ``` 17β-Oestradiol (E2) acts via the oestrogen receptor (ER) e.g. brain and adipose tissue Converted with aromatase ```

Question 254

What receptors do the actions of DHT/E2 depend on?

Answer 254

Nuclear receptors

Question 255

What are the clinical uses of testosterone?

Answer 255

``` Testosterone in adulthood will increase: Lean body mass Muscle size and strength Bone formation and bone mass (in young men) Libido and potency ```

Question 256

Can testosterone restore fertility?

Answer 256

Will not restore fertility alone | Requires treatment with gonadotrophins to restore normal spermatogenesis

Question 257

What are gonadal disorders in the female?

Answer 257

Amenorrhoea Polycystic ovarian syndrome (PCOS) Hyperprolactinaemia

Question 258

What is amenorrhoea? Primary? Secondary?

Answer 258

Amenorrhoea= absence of periods 1 amenorrhoea= failure to being spontaneous menstruation by age 16 years 2 amenorrhoea= absence of menstruation for 3 months in a woman who has previously had cycles

Question 259

What is oligomenorrhoea?

Answer 259

Irregular long cycles

Question 260

What causes amenorrhoea?

Answer 260

Pregnancy Lactation Ovarian failure (premature ovarian failure, ovariectomy/chemo, ovarian dysgenesis) Gonadtrophin failure Hyperprolactinaemia Androgen excess: gonadal tumour

Question 261

What is ovarian dysgenesis?

Answer 261

``` In Turners (45 XO) Lacking one chromosome ```

Question 262

What are common features of Turners syndrome?

Answer 262

Short stature Cubitus valgus (wide carrying angle) Gonadal dysgenesis 1:5000 live births

Question 263

What can cause a gonadotrophin failure in women?

Answer 263

Hypo/pit disease Kallmann's syndrome Low BMI Post pill amernorrhoea

Question 264

What investigations would be carried out on a patient with amernorrhoea? (7)

Answer 264

``` Pregnancy test LH, FSH, oestradiol Day 21 progesterone Prolactin, thyroid function tests Androgens (testosterone, androstenedione, DHEAS) Chromosomal analysis (Turners 45 XO) Ultrasound scan ovaries / uterus ```

Question 265

How is amenorrhoea treated?

Answer 265

Treat the cause e.g. low weight Primary ovarian failure- infertile, HRT Hypothalamic/pit disease (HRT for oestrogen replacement and gonadotrophins in IVF)

Question 266

What is PCOS?

Answer 266

Polycystic ovarian syndrome Incidence: 1 in 12 women of reproductive age Associated with increased cardiovascular risk and insulin resistance (>diabetes)

Question 267

How is PCOS diagnosed?

Answer 267

2 of: Polycystic ovaries on US Oligoovulation/anovulation Clinical/biochemical androgen excess

Question 268

What are the clinical features of PCOS?

Answer 268

Hirsuitism Menstrual cycle disturbance Increased BMI

Question 269

What fertility drugs are given to treat PCOS?

Answer 269

Metformin Clomiphene Gonadotrophic therapy as part of IVF

Question 270

What is clomiphene? How does it work?

Answer 270

Fertility drug Anti-oestrogenic in the hypothalamo-pituitary axis Bind to oestrogen Rs in hypothalamus-> blocks normal negative feedback-> increased secretion of GnRH and gonadotrophins

Question 271

Outline prolactin secretion control

Answer 271

Hypothalamus releases TRH (+) and DA (-) which act on pituitary Leads to release of prolactin Prolactin-> lactation AND Prolactin-> inhibits LH actions on ovary/testis and inhibits GnRH pulsatility

Question 272

What causes hyperprolactinaemia? (7)

Answer 272

DA antagonists (e.g. anti-emetics like metoclopramide and anti-psychotics like phenothiazines) Prolactinoma Stalk compression due to pituitary adenoma PCOS Hypothyroidism (TSH stimulates PL) Oestrogens (OCP), pregnancy, lactation Idiopathic

Question 273

How does stalk compression cause hyperprolactinaemia?

Answer 273

Stops/reduces affect of DA and TRH on pituitary Imbalance in - and + Increased prolactin secretion

Question 274

What are the clinical features of hyperprolactinaemia?

Answer 274

Galactorrhoea Reduced GnRH secretion/LH action-> hypogonadism Prolactinoma-> headache, visual field defect

Question 275

What are the treatments for hyperprolactinaemia?

Answer 275

Treat cause e.g. stop anti-emetics DA agonist (e.g. bromocriptine, cabergoline) Prolactinoma rarely needs pituitary surgery

Question 276

A male presents to endocrine clinic who has had bilateral orchidectomy (removal of testes). What would you expect his blood results to show: 1. Low LH, Low FSH, Low Testosterone 2. Low LH, high FSH, Low Testosterone 3. high LH, high FSH, Low Testosterone 4. high LH, high FSH, high Testosterone

Answer 276

3. high LH, high FSH, Low Testosterone

Question 277

A young woman presents to endocrine clinic who complains of secondary amenorrhea and galactorrhea. Her GP measured her prolactin at 4500 (high). What would you expect her blood results to show: 1. Low LH, Low FSH, Low oestradiol 2. Low LH, high FSH, Low oestradiol 3. high LH, high FSH, Low oestradiol 4. high LH, high FSH, high oestradiol

Answer 277

1. Low LH, Low FSH, Low oestradiol

Question 278

What is dyspareunia?

Answer 278

Painful sex

Question 279

``` Which of the following is a common symptom of menopause? Sleep disturbance Headache Chest pain Leg swelling ```

Answer 279

Sleep disturbance

Question 280

Why may menopause affect the bones?

Answer 280

Low oestrogen-> osteoporosis and fracture

Question 281

What risks are related to HRT?

Answer 281

``` Blood clots Strokes Breast cancer Heart attacks Gallstones ``` Absolute risk of complications for healthy symptomatic postmenopausal woman in their 50s taking HRT for 5 years is very low

Question 282

What is menopause?

Answer 282

Permanent cessation of menstruation Loss of ovarian follicular activity Climacteric (period of transition period)

Question 283

What's the average age of menopause?

Answer 283

Average age 51 (range 45-55)

Question 284

What are the symptoms of menopause?

Answer 284

``` Hot flushes (head, neck, upper chest) Urogenital atrophy and dyspareunia Sleep disturbance Depression Decreased libido Joint pain ``` Symptoms usually diminish/disappear with time

Question 285

How do the hormonal changes during menopause affect the HPG axis?

Answer 285

Hypothalamus releases GnRH Causes increased LH and FSH (either or both) Ovaries are not producing oestradiol or inhibin B No negative feedback Increases LH and FSH further

Question 286

Why does menopause lead to osteoporosis?

Answer 286

Oestrogen deficiency Loss of bone matrix 10-fold increased risk of fracture

Question 287

Why does menopause lead to cardiovascular disease?

Answer 287

Protected against CVD because the menopause | Have the same risk as men by the age of 70

Question 288

What is the main purpose of HRT?

Answer 288

Control vasomotor symptoms (hot flushes)

Question 289

What drug is prescribed as HRT?

Answer 289

HRT= E (oestrogen) and P (progesterone) to prevent endometrial hyperplasia If a woman has had a hysterectomy- E only (don't need to worry about endometrial proliferation)

Question 290

Why isn't oestrogen usually used in HRT alone in patients without a hysterectomy?

Answer 290

Risk of endometrial carcinoma

Question 291

What are HRT formulations?

Answer 291

Cyclical (oestrogen every day and progesterone for the last 12 days) Continuous combined Oestrogen preparations

Question 292

What are the different oestrogen preparations in HRT?

Answer 292

Oral estradiol (1mg) Oral conjugated equine oestrogen (0.625mg) Transdermal (patch) oestradiol (50ug/day) Intravaginal

Question 293

What are the different kinds of oestrogen?

Answer 293

``` Estradiol Estrone sulphate (conjugated) Ethinyl estradiol (semi-synthetic) ```

Question 294

Why is estradiol not that useful in HRT?

Answer 294

``` Well absorbed Low bioavailability (first pass metabolism) ```

Question 295

Why is ethinyl estradiol useful in HRT?

Answer 295

Ethinyl group protects the molecule from first pass metabolism

Question 296

What does it mean that 'timing of exposure' is importnant in HRT when considering CHD risk?

Answer 296

No excess risk in younger menopausal women (50-59) or women <10 years since menopause

Question 297

What is tibolone?

Answer 297

Synthetic prohormone Oestrogenic, progestogenic and weak androgenic actions Rarely used

Question 298

What affect does tibolone have on risks related to HRT?

Answer 298

Reduces fracture risk Increased risk of stroke Unknown risk of breast cancer

Question 299

What is Raloxifene?

Answer 299

Selective oestrogen receptor modulator | SERM

Question 300

What affect does raloxifene have on risks related to HRT?

Answer 300

Ostrogenic in bone- reduces risk of vertebral fractures Anti-oestrogenic in breast and uterus- reduces breast cancer risk Increases risk of VTE and fatal stroke

Question 301

What is premature ovarian insufficiency?

Answer 301

Menopause occurring before age 40 | 1% of women

Question 302

What causes premature ovarian insufficiency?

Answer 302

Autoimmune Surgery Chemotherapy Radiation

Question 303

What is in combined oral contraceptives?

Answer 303

Oestrogen (ethinyl oestradiol) and progestogen (e.g. levonorgestrel or norethisterone)

Question 304

How do combined oral contraceptives work?

Answer 304

Suppress ovulation - E and P-> -ve fb actions at hypothalamus/pit - P thickens cervical mucus Taken 21 days, stop for 7

Question 305

What is the progesterone only contraceptive? When is it used?

Answer 305

P only | When oestrogens contra-indicated e.g. patient ?35 with migraines

Question 306

When must progesterone only contraceptives be taken? Why?

Answer 306

Same time every day Short duration of action Short half-life NB. Long acting preparations may be given via an intra-uterine

Question 307

What are the available types of emergency (post-coital) contraception? When can they be used?

Answer 307

Copper IUD Levonorgestrel (within 72hrs) Ulipristal (up to 120h after intercourse)

Question 308

What is a copper IUD? How does it work?

Answer 308

Intrauterine contraceptive device | Affects sperm viability and function

Question 309

What is ulipristal?

Answer 309

Emergency contraception Anti-progestin activity Delay ovulation by as much as 5 days Impairs implantation

Question 310

Describe the male reproductive organ

Answer 310

Testis- with seminiferous tubules (spermatozoa surrounded by sertoli cells, in interstitia have leydig cells) Prostate Seminal Efferent ductis (from testis to epididymus)

Question 311

What does oestrogen control in the male reproductive organ?

Answer 311

Tubular fluid reabsorption

Question 312

What does androgen control in the male reproductive organ?

Answer 312

Nutrients and glycoprotein secretion into epididymal fluid

Question 313

How far does spermatozoan travel from testic to oviduct?

Answer 313

100,000 x its length

Question 314

What proportion of sparmatozoa reach the ovum?

Answer 314

<1/10^6

Question 315

What is ejaculate comprised of?

Answer 315

Spermatozoa= 15-120 x 10^6/ ml Seminal fluid= 2-5ml Leucocytes NB. Potentially viruses e.g. hep V, HIV

Question 316

What percent of the spermatozoa in ejaculate enter the cervix?

Answer 316

1%

Question 317

Where is seminal fluid from?

Answer 317

Small contribution from epididymis/testis Mainly from accessory sex glands - Seminal vesicle - Prostate - Bulbourethral glands

Question 318

What needs to happen for a sperm to achieve fertilizing capability in the female reproductive tract?

Answer 318

Maturation/capacitation

Question 319

Outline maturation/capacitation of sperm

Answer 319

1. Loss of glycoprotein coat 2. Change in surface membrane characteristics 3. Whiplash movements of tail

Question 320

What does capacitation of sperm depend on?

Answer 320

Oestrogen-dependent Takes place in ionic and proteolytic environment of the Fallopian tube Ca dependent

Question 321

What is the acrosome reaction?

Answer 321

RELEASE ENZYMES FROM ACROSOME TO ALLOW SPERM TO ENTER THE OVUM Proteolytic digestive enzymes in capacitated sperm bind to ZP3 (R) glycoprotein coating on zona pellucida of ovum Ca influx into sperm stimulated by progesterone Release of hyaluronidase and proteolytic enzymes Spermatozoon penetrates the zona pellucida

Question 322

What hormone is involved in Ca influx into sperm in the acrosome reaction?

Answer 322

Progesterone

Question 323

Where does fertilisation occur?

Answer 323

Within the fallopian tubes

Question 324

What does fertilization trigger?

Answer 324

Triggers cortical reaction

Question 325

What is the cortical reaction triggered by fertilization? What does this do?

Answer 325

Cortical granules release molecules which degrade zona pellucida Prevent binding of another sperm Diploidy is achieved (2 sets of chromosomes= 1 from ovum, 1 from sperm)

Question 326

What are polar bodies (relate to fertilization)?

Answer 326

Unequal division of cytoplasm Leaves polar bodies

Question 327

What happens to the fertilised egg as it moves down the Fallopian tube?

Answer 327

Moves to uterus and continues to divide (3-4 days) Receives nutrients from uterine secretions Free-living phase can last for 9-10 days

Question 328

How does the fertilised egg become a blastocyst?

Answer 328

Fertilised egg 2-cell conceptus 4-cell conceptus 8-cell conceptus COMPACTION Morula Blastocyst

Question 329

What can be found in a blastocyst?

Answer 329

Blastocoelic cavity Inner cell mass Trophoblast cells

Question 330

What are the phases of implantation? What do they require?

Answer 330

Attachment phase Decidualization Requires progesterone domination in the presence of oestrogen

Question 331

What happens in the attachment phase of implantation?

Answer 331

Outer trophoblast cells contact uterine surface epithelium

Question 332

What happens in decidualization of implantation?

Answer 332

Decidualization of underlying uterine stromal tissue (within a few hours)

Question 333

What is released from secretory glands in endometrial lining in implantation? What do they do?

Answer 333

ADHESION Leukaemia-inhibitory factor and IL11 promote attachment of trophoblast cells (of inner cell mass) to endometrial lining Many other molecules involved in process (e.g. HB-EGF) Blastocyst attachment by adhesion DECIDUALISATION IL11 also leads to trophoblast migration, decidualisation

Question 334

What is LIF?

Answer 334

Leukaemia inhibitory factor from endometrial secretory glands Stimulates adhesion of blastocyst to endometrial cells

Question 335

What does IL11 do in implantation?

Answer 335

Interleukin-11 from endometrial cells | Released into uterine fluid

Question 336

What is decidualisation?

Answer 336

Endometrial changes due to progesterone

Question 337

What happens in decidualisation?

Answer 337

Endometrium changes due to progesterone Glandular eipthelial secretion Glycogen accumulation in stromal cell cytoplasm Growth of capillaries Increased vascular permeability (oedema)

Question 338

What factors are involved in decidualisation?

Answer 338

IL11 Histamine Certain prostaglandins TGF beta (which promotes angiogenesis)

Question 339

What are the main hormonal changes during pregnancy?

Answer 339

First 10 weeks= Peak HCG (produced by placenta) which gradually falls Oestrogen and progesterone increase Human placental lactogen increases Very low LH and low FSH

Question 340

What is hCG?

Answer 340

Human chorionic gonadotrophin Produced by developing implanting blastocysts (syncytiotrophoblast)

Question 341

How do the oestrogens of pregnancy change?

Answer 341

5-6 weeks - Maternal ovaries (corpus luteum) - Rising circulating progesterone and oestradiol - Essential for developing fetoplacental unit - Inhibit maternal LH and FSH (-ve feedback) Then taken over by hCG - Produced by developing implanting blastocyst - Later takes over stimulatory role of gonadotrophins on corpus luteum From day 40 - Fetoplacental unit takes over

Question 342

How does the placenta make oestradiol/oestrone?

Answer 342

Mother produces cholesterol, DHEA and pregnenolone (which -> progesterone that acts on fetal adrenals) Fetus produces DHEAS (in adrenals) Cholesterol from mother acts in placenta to convert DHEAS to oestradiol and oestrone Also cholesterol-> pregnenolone SEE DIAGRAM IN NOTES

Question 343

What maternal hormones increase and decreases in pregnancy?

Answer 343

``` INCREASE ACTH Prolactin Iodothyronines Adrenal steroids PTHrp (lactation) ``` DECREASE Gonadotrophins TSH hCH (decreases as the placental hCH variant increases)

Question 344

Where is PTHrp secreted from?

Answer 344

Breast | Important for lactation

Question 345

What happens endocrinologically in parturition?

Answer 345

Oxytocin Raised calcium Contraction Fetal hypothalamus makes CRH Pituitary makes corticotrophin Adrenals make cortisol

Question 346

What happens endocrinologically in lactation?

Answer 346

Suckling (stimulus)-> neural pathways stimulate hyopathlamus-> pituitary Neurohypophysis-> oxytocin-> milk ejection Adenohypophysis-> prolactin-> milk synthesis

Question 347

What percentage of the body's calcium is stored in bone?

Answer 347

>95%

Question 348

What are the main components of bone? What percentage of bone mass is it?

Answer 348

Inorganic mineral component (65%) - Calcium hydroxyapatite crystals fill the space between collagen fibrils ``` Organic components (osteoid- unmineralised bone) (35%) - Type 1 collagen fibres (95%) ```

Question 349

Why is bone remodelling called a dynamic process?

Answer 349

Osteoblasts= bone deposition | Osteoclasts=bone resorption

Question 350

What do osteoblasts do?

Answer 350

Synthesise osteoid and participate in mineralisation/ calcification of osteoid BONE DEPOSITION

Question 351

What do osteoclasts do?

Answer 351

Release lysosomal enzymes which break down bone BONE RESORPTION

Question 352

What do osteocytes do?

Answer 352

Make type 1 collage and other EC matrix components

Question 353

Outline osteoclast differentiation

Answer 353

RANKL expressed on osteoblast surface RANKL binds to RANK-R on osteoclast precursor to stimulate osteoclast formation and activity -> Activated osteoclast Can be inhibited by OPG (decoy receptor for RANKL)

Question 354

What does RANKL do?

Answer 354

Activates osteoclast differentiation

Question 355

What does osteoprotegerin (OPG) do?

Answer 355

Inhibits osteoclast differentiation

Question 356

How is bone remodelling regulated?

Answer 356

Osteoblasts synthesis new bone | Express Rs for PTH and calcitriol

Question 357

What are PTH and calcitriol the key hormones for?

Answer 357

Regulating bone remodelling and calcium balance

Question 358

What is the active form of vitamin D?

Answer 358

Calcitriol 1, 25 (OH2D) 1, 25 dihydroxy vitamin D

Question 359

What is the inactive form of vitamin D?

Answer 359

Calcidiol Inactive, stored 25 hydroxyide vitamin D

Question 360

What regulates the production of the active form of vitamin D?

Answer 360

PTH

Question 361

How do changes in EC Ca affect nerve and skeletal muscle excitability?

Answer 361

Na influx across cell membrane required for generating AP in nerves/skeletal muscle High EC Ca (hypercalcaemia)= Ca blocks Na influx, less membrane excitability Low EC Ca (hypocalcaemia)= greater Na influx allowed, more membrane excitability

Question 362

What are the signs and symptoms of hypocalcaemia?

Answer 362

PACT (or CATs go numb) Parasthesia (hands, mouth, feet, lips) Arrhythmias Convulsions Tetany Because excitable tissues are sensitised

Question 363

What is Chvostek's sign?

Answer 363

Tap facial nerve just below zygomatic arch Positive response = twitching of facial muscles Indicates neuromuscular irritability due to hypocalcaemia Important after surgery which may have affected parathyroid glands (PTH may have been affected)

Question 364

What is Trousseau's sign?

Answer 364

Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia Spasm is painful, like tetany (can’t relax) so don’t repeat too often

Question 365

What can cause hypocalcaemia?

Answer 365

Vit D deficiency Low PTH levels= hypoparathyroidism (surgical or auto-immune) PTH resistance e.g. pseudohypoparathyroidism Renal failure

Question 366

Why does renal failure lead to hypocalcaemia?

Answer 366

Impaired 1α hydroxylation -> decreased production of 1,25(OH)2D3 If you’re not making that enzyme, then you’re not doing second hydroxylation step which is very important

Question 367

What is the normal range for calcium?

Answer 367

2.2-2.6 mmol/L

Question 368

What are the signs and symptoms of hypercalcaemia?

Answer 368

Reduced neuronal excitability-> atonal muscles ‘Stones RENAL, abdominal GI moans and psychic CNS groans’ RENAL EFFECTS Polyuria and thirst Nephrocalcinosis (can cause stones), renal colic, chronic renal failure (if prolonged exposure, rare) GI EFFECTS Anorexia, nausea, dyspepsia, constipation, pancreatitis CNS EFFECTS Fatigue, depression, impaired concentration, altered mentation, coma (usually >3mmol/L)

Question 369

What causes hypercalcaemia?

Answer 369

Primary hyperparathyroidism Malignancy- tumours/metastases often secrete a PTH-like peptide Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone- immobilised patient) Vitamin D excess (rare)

Question 370

How are Ca and PTH release related normally?

Answer 370

PTH released in response to falling serum calcium | Then-> negative feedback

Question 371

What happens in primary hyperparathyroidism?

Answer 371

RAISED CALCIUM RAISED (UNSUPPRESSED) PTH NO negative feedback Autonomous PTH secretion DESPITE hypercalcaemia

Question 372

What regulates the production of the active form of vitamin D?

Answer 372

PTH

Question 373

How do changes in EC Ca affect nerve and skeletal muscle excitability?

Answer 373

Na influx across cell membrane required for generating AP in nerves/skeletal muscle High EC Ca (hypercalcaemia)= Ca blocks Na influx, less membrane excitability Low EC Ca (hypocalcaemia)= greater Na influx allowed, more membrane excitability

Question 374

What are the effects of the bioactive form of vitamin D?

Answer 374

Bioactive form= 1,25 (OH2)D3, calcitriol Stimulate intestinal absorption of Ca2+ (and Mg2+) and PO4^3- -> provides ions necessary for normal bone mineralisation Regulates osteoblast differentiation Has renal effects (increased Ca2+ reabsorption, decreased PO4^3- reabsorption via FGF23)

Question 375

What is Chvostek's sign?

Answer 375

Tap facial nerve just below zygomatic arch Positive response = twitching of facial muscles Indicates neuromuscular irritability due to hypocalcaemia Important after surgery which may have affected parathyroid glands (PTH may have been affected)

Question 376

What is Trousseau's sign?

Answer 376

Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia Spasm is painful, like tetany (can’t relax) so don’t repeat too often

Question 377

What can cause hypocalcaemia?

Answer 377

Vit D deficiency Low PTH levels= hypoparathyroidism (surgical or auto-immune) PTH resistance e.g. pseudohypoparathyroidism Renal failure

Question 378

Why does renal failure lead to hypocalcaemia?

Answer 378

Impaired 1α hydroxylation -> decreased production of 1,25(OH)2D3 If you’re not making that enzyme, then you’re not doing second hydroxylation step which is very important

Question 379

What is the normal range for calcium?

Answer 379

2.2-2.6 mmol/L

Question 380

What can cause vitamin D deficiency?

Answer 380

No sunlight (e.g. elderly/ overprotected child/ non-Caucasian) Malabsorption or dietary insufficiency (GI e.g. coeliac disease, IBD) Liver disease Renal disease Receptor defects (N.B. very rare)

Question 381

What causes hypercalcaemia?

Answer 381

Primary hyperparathyroidism Malignancy- tumours/metastases often secrete a PTH-like peptide Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone- immobilised patient) Vitamin D excess (rare)

Question 382

How are Ca and PTH release related normally?

Answer 382

PTH released in response to falling serum calcium | Then-> negative feedback

Question 383

What happens in primary hyperparathyroidism?

Answer 383

RAISED CALCIUM RAISED (UNSUPPRESSED) PTH NO negative feedback Autonomous PTH secretion DESPITE hypercalcaemia

Question 384

What happens in hypercalcaemia of malignancy?

Answer 384

RAISED CALCIUM SUPPRESSED PTH Not an abnormal parathyroid gland Caused by metastatic cancer deposits in bone There is still negative feedback (PTH turned off by increasing Ca)

Question 385

How is vitamin D deficiency treated in patients with normal renal function?

Answer 385

Give 25 hydroxy vit D (25 (OH) D) Patient can convert this to 1,25 dihydroxy vit D via 1a hydroxlyase in kidney ``` Ergocalciferol= 25 hydroxy vitamin D2 Cholecalciferol= 25 hydroxy vitamin D3 ```

Question 386

What is FGF23?

Answer 386

Hormone produced by bone which increases urine PO4^3- excretion

Question 387

What happens if there is a lack of vitamin d?

Answer 387

Lack of mineralisation in bone-> 'softening' of bone, bone deformities, bone pain, severe proximal myopathy ``` Children= rickets Adults= osteomalacia ```

Question 388

Where does vitamin D come from?

Answer 388

UVB light (reacts with skin 7-dehydrocholesterol (precursor))- vitamin D3 Vitamin D2 from diet

Question 389

What is osteoporosis?

Answer 389

Condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma Bone mineral density (BMD) 2.5 SDs below the average value from young healthy adults (T-score of -2.5 or lower)

Question 390

What does calcitriol do?

Answer 390

Ca absorption in gut Ca maintenance in bone renal effects Negative feedback on PTH

Question 391

What happens in secondary hyperparathyroidism?

Answer 391

PTH increases to try to normalise serum calcium (which has fallen from vitamin D deficiency)

Question 392

How do you diagnose vitamin D deficiency?

Answer 392

Low inactive vit D (calcidiol)- NB don't measure active because assay difficult Low plasma Ca conc (may be normal if secondary hyperparathyroidism has developed) Low plasma phosphate conc High PTH (secondary hyperparathyroidism) Radiological findings e.g. widened osteroid seams

Question 393

How does renal dysfunction lead to bone disease?

Answer 393

Decreased renal function 1a) -> Decreased calcitriol Decreased Ca absorption Hypocalcaemia AND/OR 1b) -> Decreased phosphate excretion Increased plasma phosphate Hypocalcaemia ----- 2a) Decreased bone mineralization Osteitis fibrosa cystica AND/OR 2b) Increased PTH concentration Increased bone resorption Osteitis fibrosa cystica ---- NB. Increased phosphate-> extra-skeletal calcification

Question 394

What are brown tumours?

Answer 394

Radiolucent bone lesions (not actually tumours) | Reflect excessive osteoclastic bone resorption secondary to high PTH

Question 395

How is vitamin D deficiency treated in patients with renal failure?

Answer 395

Inadequate 1α hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations Give active form which is quite potent (has to be prescribed) Alfacalcidol= 1α hydroxycholecalciferol

Question 396

What happens if someone has excess vitamin D (intoxication)?

Answer 396

Can lead to hypercalaemia and hypercalciuria due to increased intestinal absorption of calcium Can occur as a result of: - Excessive treatment with active metabolites of vit D - Granulomatous diseases

Question 397

What granulomatous diseases can lead to vitamin D excess? Why do they do this?

Answer 397

Sarcoidosis Leprosy TB Macrophages in the granuloma produce 1a hydroxylase to convert from inactive to active vit D

Question 398

Why do women with an intact uterus need additional progestogen with HRT oestrogen?

Answer 398

Prevent endometrial hyperplasia/cancer Will give withdrawal bleed- patients not pleased as they had stopped periods

Question 399

What conditions pre-dispose patients for osteoporosis?

Answer 399

``` Postmenopausal oestrogen deficiency Age-related deficiency in bone homeostasis Hypogonadism in young women and in men Endocrine conditions Iatrogenic ```

Question 400

How does postmenopausal oestrogen deficiency predispose a patient to osteoporosis?

Answer 400

Oestrogen deficiency leads to a loss of bone matrix | Subsequent increased risk of fracture

Question 401

How does age increasing predispose a patient to osteoporosis?

Answer 401

Ostoblast senescence

Question 402

Why are bisphosphonates used to treat osteoporosis?

Answer 402

Bind avidly to hydroxyapatite and ingested by osteoclasts-> impair ability of osteoclasts to reabsorb bone Decrease osteoclast progenitor development and recruitment Promote osteoclast apoptosis (programmed cell death) Net result = reduced bone turnover

Question 403

What can bisphosponates be used to treat?

Answer 403

Net result= reduced bone turnover Osteoporosis (first line treatment) Malignancy (associated hypercalcaemia and reduced bone pain from metastases) Paget's disease (reduce bony pain) Severe hypercalcaemic emergency (IV, after rehydration to dilute Ca)

Question 404

What are the treatment options of osteoporosis?

Answer 404

Oestrogen/Selective Oestrogen Receptor Modulators (SERM) Bisphosphonates Denosumab Teriparatide

Question 405

How does HRT (oestrogen) treat osteoporosis? Why is it limited?

Answer 405

Given to post-menopausal women (pharmacological doses of oestrogen) Prevents bone loss and has anti-resorptive effects on the skeleton Women with intact uterus need progestogen too LIMITED Increased risk of breast cancer Venous thromboembolism

Question 406

What is denosumab?

Answer 406

Human monoclonal antibody Binds RANKL-> inhibits osteoclast formation and activity -> Inhibits osteoclast-mediated bone resorption Given as SC injection every 6 months 2nd line to bisphosphonates

Question 407

What is teriparatide?

Answer 407

Recombinant PTH fragment (amino-terminal 34 AAs of native PTH) Increases bone formation and bone resorption but formation outweighs resorption 3rd line treatment for osteoporosis Daily SC injection

Question 408

What is Paget's disease of bone?

Answer 408

Accelerated, localised but disorganised bone remodelling Excessive bone resorption (ostoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) Leads to formation of woven bone (structurally disorganised) which is weaker than normal adult lamellar bone -> bone frailty and bone hypertrophy/ deformity CHARACTERISED BY abnormal, large osteoclasts- excessive in number

Question 409

How do tissue selective ER agonists work and how is this useful in osteoporosis?

Answer 409

Oestrogenic activity in bone Anti-oestrogenic at breast and uterus Risks include venous thromboembolism, stroke NB. Raloxfene has been further developed for its selectivity on bone

Question 410

What are the pharmacokinetics of bisphosphonates?

Answer 410

Orally active but poorly absorbed (take on empty stomach, not with milk which reduces drug absorption) Accumulates at site of bone mineralisation and remains part of bone until it's resorbed

Question 411

What are the clinical features of Paget's disease?

Answer 411

``` Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected Arthritis Fracture Pain Bone deformity Increased vascularity (warmth over affected bone) Deafness- cochlear involvement Radiculopathy- due to nerve compression ```

Question 412

How do you diagnose Paget/s disease?

Answer 412

Normal plasma Ca conc Increased plasma alkaline phosphatase Plain X-rays (lytic lesions= early THEN deformed, enlarged, thickened bones= later) Radionuclide bone scan demonstrates extent and locations of skeletal involvement

Question 413

What causes Paget's disease?

Answer 413

Possibly genetic (family history) Viral origin? Men and women equal Usually >50y Prevalence - Highest in UK, N America, Australia and NZ - Lowest in Asian and Scandinavia

Question 414

How is body weight homeostasis regulated by the hypothalamus?

Answer 414

INPUTS TO HYPOTHALAMUS Ghrelin, PYY and other gut hormones Leptin Neural input from the periphery and other bran regions INTEGRATED IN HYPOTHALAMUS HYPOTHALMUS THEN DETERMINES.... Food intake Energy expenditure

Question 415

What are the hypothalamus subregions determined by?

Answer 415

Nuclei differentiated by anatomy/function Paraventricular nucleus Lateral hypo Ventromedial hypo Arcuate nucleus

Question 416

What is the arcuate nucleus?

Answer 416

Key brain area involved in food intake regulation Incomplete BBB so has access to peripheral hormones (can integrate peripheral and central feeding signals) Has stimulatory neuronal populations (NPY/Agrp neurons) and inhibitory neuronal populations (POMC neurons) These neurons extend to other hypothalamic and extra-hypothalamic regions

Question 417

What do NPY/Agrp neurons in the arcuate nucleus do?

Answer 417

Increase appetite

Question 418

What do POMC neurons in the arcuate nucleus do?

Answer 418

Decrease appetite

Question 419

How do POMC and Agrp from the arcuate nucleus affect the paraventricular nucleus MC4R?

Answer 419

POMC-> a-MSH-> activates MC4R-> suppresses food intake Agrp-> Agrp-> inhibits MC4R-> increases food intake

Question 420

Why haven't NPY or Agrp mutations associated with appetite been identified?

Answer 420

Maybe brain rewires | Maybe just don’t study thin people

Question 421

What do POMC deficiency and MC4R mutations cause?

Answer 421

Morbid obesity | Useful to explain signalling

Question 422

What are the features of the ob/ob mouse?

Answer 422

MISSING LEPTIN ``` Recessive mutation Profoundly obese Diabetic Infertile Stunted linear growth Decreased body temperature Decreased energy expenditure Decreased immune function Similar abnormalities to starved animals ```

Question 423

What is leptin?

Answer 423

Anti-starvation hormone (rather than anti-obesity hormone) Codes for 167 AA hormone Missing in ob/ob mouse Low when low body fat (high when high) Central or peripheral admin-> decreased food intake and increased thermogenesis Activates POMC and inhibits NPY/Agrp neurones

Question 424

What can leptin resistance cause?

Answer 424

Obesity due to leptin resistance- hormone is present but doesn’t signal effectively Don't realise how much leptin you have

Question 425

What happens in the absence of leptin?

Answer 425

Profound effects e.g. hyperphagia, lowered energy expenditure, sterility Presence of leptin tells the brain that one has sufficient fat reserves for normal functioning- but high leptin has little effect

Question 426

Why can leptin be used for children?

Answer 426

Suppresses food intake-> brings body weight down They haven't been exposed to it in the past Reproductive process can be restored (kids don't go through puberty- body switches off fertility)

Question 427

Why can leptin be used in women with amenorrhea?

Answer 427

If they have low body fat leptin can fool their brain that they have fat reserves Restores LH pulsatility Preferable to put on some weight

Question 428

How does insulin affect food intake?

Answer 428

Insulin also circulates at levels proportional to body fat Receptors in the hypothalamus Central administration reduces food intake May co-ordinate glucose and energy homeostasis-> regulates blood glucose and body adiposity

Question 429

What are gut hormones important for?

Answer 429

GI tract= >20 different regulatory peptide hormones Influence processes including gut motility, secretion of other hormones, appetite

Question 430

What regulates gut hormones?

Answer 430

Gut nutrient content

Question 431

What are the major GI hormones?

Answer 431

``` Cholecystokinin Secretin GIP Motilin Ghrelin Gastrin Insulin Glucagon Pancreatic polypeptide Amylin GLP-1 GLP-1 Oxymtomodulin PYY3-36 ```

Question 432

What is cholecystokinin involved in?

Answer 432

Gall bladder contraction GI motility Pancreatic exocrine secretion

Question 433

What is secretin involved in?

Answer 433

Pancreatic exocrine secretion

Question 434

What is GIP involved in?

Answer 434

Incretin activity

Question 435

What is motilin involved in?

Answer 435

GI motility

Question 436

What is ghrelin involved in? how?

Answer 436

Hunger Growth hormone release Directly modulates neurones in the arcuate nucleus - > stimulates NPY/Agrp neurones - > inhibits POMC neurons - > increases appetite

Question 437

What is gastrin involved in?

Answer 437

28AA gastrin hormone Acid secretion

Question 438

What are insulin and glucagon involved in?

Answer 438

Glucose homeostasis

Question 439

What is pancreatic polypeptide involved in?

Answer 439

Gastric motility | Satiation

Question 440

What is amylin involved in?

Answer 440

Glucose homeostasis | Gastric motility

Question 441

What is GLP-1 (glucagon- like peptide 1) involved in? What codes for it?

Answer 441

``` Incretin activity (involved in stimulating glucose-stimulated insulin release) Satiation-> reduced food intake ``` Coded for by the preproglucagon gene and released post-prandially

Question 442

What is GLP-2 involved in?

Answer 442

GI motility and growth

Question 443

What is oxymtomodulin involved in?

Answer 443

Satiation | Acid secretion

Question 444

What is PYY3-36 involved in? How?

Answer 444

Satiation Secreted post-prandially Directly modulates neurons in the arcuate nucleus - > inhibits NPY release - > stimulates POMC neurones - > decreases appetite

Question 445

What happens if peripheral GLP-1 is given to rodents/humans?

Answer 445

Inhibits food intake GLP-1 agonists have been FDA approved (and DPP-4 inhibitors)

Question 446

What happens to pro-glucagon in intestinal L-cells after a meal?

Answer 446

Processing of pro-glucagon Prohormone convertase 1-> active agonist Very short half life (regulated by inactivation)

Question 447

What is Saxenda?

Answer 447

Long-acting GLP-1 R agonist (liraglutide) Used originally for T2DM but people using it released they'd lost weight-> FDA approval for weight loss (EMEA soon)

Question 448

Why is PYY3-36 limited as a drug target?

Answer 448

Narrow therapeutic window (effective area) ``` ABOVE= nausea BELOW= no effect ```

Question 449

What comorbidies are associated with obesity?

Answer 449

``` Depression Stroke Sleep apnoea Myocardial infarction Hypertension Diabetes Bowel cancer Osteoarthritis Peripheral vascular disease Gout ```

Question 450

How do twin studies show genetic involvement of obesity?

Answer 450

Monozygotic twins= 0.66 correlation Dizygotic twins= 0.26 correlation

Question 451

Outline the thrifty gene hypothesis

Answer 451

Specific genes selected for to increase metabolic efficiency and fat storage Now we have plentiful food and do little exercise these genes predispose their carriers to obesity and diabetes Evolutionarily sensible to put on weight Supported because the most likely to be come obese are those exposed to Western diet and sedentary life-style after being historically prone to starvation (e.g. Pima Indians, Pacific Islanders)

Question 452

Outline the adaptive drift (drifty gene) hypothesis

Answer 452

Normal distribution of body weight: the fat are eaten, the thin starve Humans defend against predators Obesity not selected against Body fat then became neutral change

Question 453

What is the main difference between T1DM and T2DM?

Answer 453

``` T1= lacking insulin T2= insulin resistance ```

Question 454

What are the ambiguous features of diabetes T1/T2?

Answer 454

Autoimmune T1 diabetes= leading to insulin deficiency can present in later decades (LADA= Latent autoimmune Diabetes in Adults) T2DM may present in childhood Diabetic ketoacidosis can occur in T2DM (particularly afro-caribbean patients) Monogenic diabetes can be type 1 or type 2 (MODY= mitochondrial diabetes)

Question 455

What is LADA?

Answer 455

Latent autoimmune Diabetes in Adults Autoimmune T1 diabetes= leading to insulin deficiency can present in later decades

Question 456

What is MODY?

Answer 456

Monogenic diabetes can be type 1 or type 2 Mitochondrial diabetes Treat with sulfonylureas not insulin

Question 457

Approximate number of people with T2DM and T1DM in UK?

Answer 457

T1= 0.5 mil T2= 6% population, going up

Question 458

What causes hyperglycaemia in T1DM?

Answer 458

Environmental trigger and genetics Autoimmune destruction of islet cells Insulin deficiency Hyperglycaemia

Question 459

What causes hyperglycaemia in T2DM?

Answer 459

Obesity and genetics Insulin resistance Pancreas will start to fail when it’s making too much insulin over long time-> leads to B cell failure Hyperglycaemia

Question 460

Outline the pathogenesis of type 1 diabetes

Answer 460

PREDIABETES (decrease in B cell mass) - Interactions between genes imparting susceptibility and resistance - Variable insulitis B-cell sensitivity to injury OVERT Very low B cell mass Glucose intolerance develops C peptide below detection Depending on type of immune insult, can happen quickly or over years

Question 461

What is the honeymoon phase in T1DM?

Answer 461

When pancreas produces last of insulin and then suddenly beta cells fail Could be due to imbalance of T cells Because T1DM is relapsing-remitting disease

Question 462

Why is the immune basis of T1DM important?

Answer 462

Increased prevalence of other autoimmune disease Risk of autoimmunity in relatives (e.g. family could have pernicious anaemia with B12 deficiency) More complete destruction of B cells Auto antibodies can be used clinically Immune modulation offers the possibility of novel treatments

Question 463

What happens to beta cells in the pancreas when there is an increased amount of inflammatory cells?

Answer 463

In T1DM, beta cells destroyed

Question 464

What has a larger genetic basis, T1 or T2DM?

Answer 464

Type 2

Question 465

What are the HLA-DR alleles that cause a significant risk of T1DM?

Answer 465

DR3 and D4

Question 466

What seasonal, environmental factors have been identified in T1DM?

Answer 466

Environmental influence > genetic influence T1DM patients normally present in winter/autumn (maybe an infectious process)

Question 467

When are markers (antibodies) used for diabetic patients?

Answer 467

Measure antibodies in blood stream to see T1DM when unsure if patient T1 or T2 Not needed for most patients

Question 468

What markers are used for differentiating between T1DM and T2DM?

Answer 468

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

Question 469

What are the symptoms and signs in T1DM?

Answer 469

``` SYMPTOMS Polyuria Nocturia Polydipsia Blurring of vision Thrush Weight loss ``` ``` SIGNS Dehydration Cachexia Hyperventilation Sme;l of ketones Glycosuria Ketonuria ```

Question 470

Why does metabolic acidosis lead to hyperventilation?

Answer 470

Excess CO2 exhalation Heavy breathing Hyperventilation to expel excess CO2

Question 471

What happens in T1DM (when there is no insulin)?

Answer 471

Fats broken down in adipocytes and lipolysis Increased HGO and glucose in liver Decreased glucose uptake into muscles and destruction of muscle tissues Increased proteolysis Fatty acids converted to ketone bodies in liver -> ketone bodies in the blood and in urine

Question 472

What are the aims of treatment in T1DM?

Answer 472

Reduce early mortality Avoid acute metabolic decompensation T1DM need exogenous insulin to preserve life Prevent long term complications= retinopathy, nephropathy, neuropathy, vascular disease

Question 473

What is the recommended diet in type 1 diabetes?

Answer 473

Reduces calories as fat Reduce calories as refined carbs Increase calories as complex carbs Increase soluble fibre Balanced distribution of food over course of day with regular meals and snacks

Question 474

How was insulin discovered?

Answer 474

If you took out pancreas of dogs, they’d develop T1DM and die eventually But you could make dog survive by giving dog without a pancreas an injection of pancreatic cells (including insulin) from another dog Now have insulin analogues

Question 475

What kinds of insulin treatment are there?

Answer 475

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)

Question 476

How were insulin analogues developed?

Answer 476

Genetic engineering to alter absorption, distribution, metabolism and excretion

Question 477

What is b.d. insulin?

Answer 477

Twice a day

Question 478

What is t.b.s. insulin?

Answer 478

3x a day insulin | With every meal

Question 479

If someone eats erratic amounts, how is their dose of insulin affected?

Answer 479

Need to give different doses throughout the day

Question 480

What is an insulin pump?

Answer 480

Continuous insulin delivery (attached to lower abdomen) Preprogrammed basal rates and bolus for meals Doesn't measure glucose- no completion of feedback loop

Question 481

How does an islet cell transplant work? What are the advantages and limitations?

Answer 481

Islet cells from patients who have just died Inject these into another individual Then cells travel through portal system and start producing insulin ADVANTAGES Glucose control better than with injections/insulin pump LIMITATIONS Only for patients who struggle with control because limited number of cells available Will need immunosuppressive agents

Question 482

How can you monitor blood glucose?

Answer 482

CAPILLARY MONITORING Patients prick finger Check blood on meter (tell you glucose level) ABDOMEN MONITORING Monitor on abdomen-> continuous reading (last up to 2 weeks)- not as sensitive as capillary sugars but give an indicate of patients control without them pricking

Question 483

What is the benefit of the capillary monitoring over time?

Answer 483

Can ask retrospectively what they were doing then | Tailor insulin and dietary regime to resolve

Question 484

When is HbA1c false?

Answer 484

In patient has something affecting RBCs = hamoglobinopathy (e.g. SCA, thal) Also rate of glycation is faster in some individuals

Question 485

What kind of binding is glucose to HbA1c?

Answer 485

Irreversible, non-covalent

Question 486

What happens if you lower HbA1c?

Answer 486

Lower risk of complication particularly microvascular complication

Question 487

What is ketoacidosis?

Answer 487

Rapid decompensation of type 1 diabetes Hyperglycaemia= reduced tissue glucose utilisation AND increased HGO Metabolic acidosis= circulating acetoacetate and hydroxybutyrate AND osmotic dehydration and poor tissue perfusion

Question 488

What kind of diabetes has diabetic ketoacidosis?

Answer 488

Normally type 1 | But can be type 2

Question 489

What happens when a patient has a 'hypo'?

Answer 489

Hypoglycaemic episode Plasma glucose of < 3.6 mmol / l (Severe hypoglycaemia - any hypo requiring help of another person to treat) Occasional hypos Inevitable as a result of treating diabetes major cause of anxiety in patients and families Source of major misconceptions in media

Question 490

At what mmol/l are impaired mental processes and consciousness/death likely?

Answer 490

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 (-> cognitive impairment) Recurrent hypos result in loss of warnings ‘Hypoglycaemia unawareness’

Question 491

Who is most at risk of hypos?

Answer 491

Main risk factor is quality of glycaemic control | More frequent in patients with low HbA1c

Question 492

When can hypos commonly occur?

Answer 492

Can occur at anytime but often a clear pattern Pre-lunch hypos common Nocturnal hypos very common and often not recognised ``` WHY? Unaccustomed exercise Missed meals Inadequate snacks alcohol Inappropriate insulin regime ```

Question 493

What are the symptoms and signs of hypoglycaemia?

Answer 493

``` DUE TO INCREASED AUTONOMIC ACITIVATION Palpitations (tachycardia) Tremor Sweating Pallor/cold extremities Anxiety ``` ``` DUE TO IMPAIRED CNS FUNCTION Drowsiness Confusion Altered behaviour Focal neurology Coma ```

Question 494

How can you treat hypoglycaemia?

Answer 494

``` ORAL= feed the patient Glucose (rapidly absorbed as solution or tablets) Complex CHO (to maintain blood glucose after initial treatment) ``` PARENTERAL= give if consciousness impaired IV dextrose e.g. 10% glucose infusion 1mg glucagon IM Avoid concentration solutions if poss (e.g. 50% glucose)

Question 495

What is diabetes mellitus?

Answer 495

State of chronic hyperglycaemia sufficient to cause long term damage to specific tissues (especially retina, kidney, nerves and arteries)

Question 496

What are key features of T2DM?

Answer 496

Not ketosis prone Not mild Often involves weight, lipids and blood pressure

Question 497

What does a fasting glucose <6 mean?

Answer 497

Normal

Question 498

What does a fasting glucose 6 -7mean?

Answer 498

Impaired fasting glucose

Question 499

What does a fasting glucose >7 mean?

Answer 499

Diabetes

Question 500

What does a 2 hour glucose <7.8 mean?

Answer 500

Normal

Question 501

What does a 2 hour glucose 7.8-11.1 mean?

Answer 501

Impaired glucose tolerance

Question 502

What does a 2 hour glucose >11.1 mean?

Answer 502

Diabetes

Question 503

What does a random glucose <11.1 mean?

Answer 503

Normal

Question 504

What does a random glucose >11.1 mean?

Answer 504

Diabetes

Question 505

Outline the epidemiology of T2DM

Answer 505

Diabetes is prevalent Mostly T2DM Increasing age, but now in children (moving younger but typically from middle ages) Increasing prevalence Greatest in ethnic groups that move from rural to urban lifestyle

Question 506

Outline the pathophysiology of T2DM

Answer 506

Genes and intrauterine environment (low birth weight-> T2DM predisposition) combine with adult environment Inulin resistance and insulin secretion defects Fatty acids important (Can be MODY- monogenic, mitochrondrial)

Question 507

What causes maturity onset diabetes of the young (MODY)?

Answer 507

GENETIC MUTATIONS- monogenic Several hereditary forms (1-8) Autosomal dominant Ineffective pancreatic B cell insulin production Mutations of transcription factor genes, glucokinase gene Positive FH, no obesity

Question 508

How do genes lead to macrovascular and microvascular complications?

Answer 508

1) Genes-> IUGR 2) Genes-> Obesity/FA-> insulin resistance and adipocytokines a)-> mitogenic-> MACROVASCULAR B) -> metabolic dyslipidaemia-> MACROVASCULAR 3) Genes-> B cell failure a) -> insulin requirement b) -> hyperglycaemia-> MICROVASCULAR c) -> metabolic dyslipidaemia-> MACROVASCULAR

Question 509

What is the correlation in identical and non-identical twins for T1DM and T2DM?

Answer 509

T1 Identical= 35% Nonidentical= 10% T2 Identical= 70% Nonidentical= 40%

Question 510

How does insulin resistance relate to B cells?

Answer 510

Decreasing B cell reserve with increasing insulin resistance

Question 511

How do people with T2DM usually present?

Answer 511

``` Obesity Hyperglycaemia and dyslipidaemia Actue and chronic complications Osmotic symptoms Infections With a complication (acute= hyperosmolar coma AND chronic= ischaemic heart disease adn retinopathy) ``` Insulin resistance and insulin secretion deficit

Question 512

What does a hyperglycaemic clamp show?

Answer 512

Starts with intravenous bolus, followed by glucose infusion to maintain steady blood glucose levels Look at plasma glucose and plasma insulin Quantifies insulin resistance and secretion

Question 513

What factors contribute to increased fasting plasma glucose in T2DM?

Answer 513

Impaired glucose disposal (e.g. from diminished ability to store glucose) Increased hepatic glucose production Inadequate insulin action Inappropriate glucagon secretion induces continued glucose production by stimulating glycogenolysis (release of glucose from glycogen) and gluconeogenesis (glucose synthesis)

Question 514

Where does glycogen->glucose (gluconeogenesis)?

Answer 514

Liver

Question 515

Where does glucose->glycogen?

Answer 515

Muscle

Question 516

Where are TG->glycerol and NEFA (lipolysis)?

Answer 516

Adipocytes Particularly from omental fat NB. fat cells are profoundly important endocrine tissue (not just a store)

Question 517

How is obesity involved in T2DM?

Answer 517

``` More than a precipitant Fatty acids and adipocytokines important Central and omental obesity= worse 80% T2DM are obese Weight reduction useful signs ```

Question 518

How do gut microbiota contribute to T2DM?

Answer 518

Host and inflammation signaling Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids Most studies show correlation between microbiota and T2DM

Question 519

What diabetes treatments lead to weight gain?

Answer 519

TZDs especially SUs Meglitinides NB. Metformin doesn't so combo treatment help

Question 520

What are the major complications of T2DM?

Answer 520

MICROVASCULAR Retinopathy Nephropathy Neuropathy ``` MACROVASCULAR Ischaemia heart disease Cerebrovascular Renal artery stenosis PVD ``` METABOLIC Lactic acidosis DKA Hyperosmolar TREATMENT Hypoglycaemia

Question 521

What is the basis of management of T2DM?

Answer 521

Education Diet Pharmacological treatment Complication screening MONITOR- weight, glycaemia, blood pressure, dyslipidaemia

Question 522

Why should T2DM be treated?

Answer 522

Symptoms Reduce chance of acute metabolic complications Reduce chance of long term complications Education

Question 523

What is the recommended diet for T2DM?

Answer 523

Control total calories/increase exercise (weight) Reduce refined carbohydrate (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)

Question 524

What are the main drugs for T2DM?

Answer 524

LIVER Metformin ABDOMEN and MUSCLES Thiazolidinediones INTESTINES a glucosidase inhibitor PANCREAS Sulphonylureas and metaglinidies Glucagon like peptide DPP4 inhibitor

Question 525

How does metformin work? When is it used/not used? SEs?

Answer 525

Biguanide, insulin sensitiser Reduces insulin resistance Reduces hepatic glucose output Increases peripheral glucose disposal USED FOR Overweight patient with T2DM where diet alone has not succeeded NOT USED If severe liver, severe cardiac or mild renal failure SEs GI

Question 526

How does sulphonylurea work? When is it used/not used? SEs?

Answer 526

Used in T2DM Glibenclamide, insulin secretagogue Act by increasing insulin release from the beta cells in the pancreas USED FOR Lean patients with type 2 diabetes where diet alone has not succeeded SEs Hypoglycaemia, weight gain

Question 527

How does acarbose work? SEs?

Answer 527

Used in T2DM Alpha glucosidase inhibitor Prolongs absorption of oligosaccharides Allows insulin secretion to cope, following defective first phase insulin As effective as metformin SEs Flatus

Question 528

What is flatus?

Answer 528

Gas in or from the stomach or intestines, produced by swallowing air or by bacterial fermentation

Question 529

How do thiazolidinediones work? SEs?

Answer 529

Peroxisome proliferator-activated receptor agonists (PPAR-γ) E.g. Pioglitazone Insulin sensitizer, mainly peripheral Adipocyte differentiation modified, weight gain but peripheral not central Improvement in glycaemia and lipids Important for vascular system SEs Older types hepatitis Heart failure

Question 530

What increases secretion of incretins? What do these do?

Answer 530

Increased in response to presence of food in GI tract Incretins are additional factors which stimulates insulin secretion after oral glucose ingestion

Question 531

What is GLP-1?

Answer 531

Glucagon ike peptide-1 Used in T2DM 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 degredation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)

Question 532

What does GLP-1 do?

Answer 532

Used in T2DM ``` E.g. Exenatide, liraglutide Injectable Long acting GLP-1 agonist Decrease glucagon conc Decrease glucose conc Weight loss ```

Question 533

What are gliptins?

Answer 533

DPPG-4 inhibitor (used in T2DM) ``` Increase half life of exogenous GLP-1 Increase GLP-1 conc Decrease glucagon conc Decrease glucose conc Neutral on weight ```

Question 534

What is empagliflozin?

Answer 534

For T2DM Inhibits Na-Glu transported, increases glycosuria Lowers mortality especially CV mortality e.g. from heart failure

Question 535

What happens to the B cell function with intervention in T2DM?

Answer 535

B-cell function continues to decline regardless of intervention in T2DM

Question 536

As well as hyperglycaemia, what is important to control in T2DM?

Answer 536

Blood pressure Diabetic dyslipidaemia (increased LDL, decreased LDL)

Question 537

Outline the prevalence of T1DM and T2DM

Answer 537

Type 1= 0.25% | Type 2= 4-7%

Question 538

Outline the geography of T1DM and T2DM

Answer 538

Type 1= Europids | Type 2= Less europids

Question 539

Outline the typical age of T1DM and T2DM

Answer 539

Type 1= Child, adolescent | Type 2= Middle-age +

Question 540

Outline the onset of T1DM and T2DM

Answer 540

Type 1= Acute | Type 2= Gradual

Question 541

Outline the habitus of T1DM and T2DM

Answer 541

Type 1= Lean | Type 2= Obese

Question 542

Outline the family history T1DM and T2DM

Answer 542

Type 1= Uncommon | Type 2= Common

Question 543

Outline the weight loss in T1DM and T2DM

Answer 543

Type 1= Usual | Type 2= Uncommon

Question 544

Outline the ketosis in T1DM and T2DM

Answer 544

Type 1= Yes | Type 2= No

Question 545

Outline the serum insulin in T1DM and T2DM

Answer 545

Type 1= Low/absent | Type 2= Variable

Question 546

Outline the HLA association in T1DM and T2DM

Answer 546

Type 1= DR3, DR4 | Type 2= None

Question 547

Outline the islet B cells in T1DM and T2DM

Answer 547

Type 1= Destroyed | Type 2= Function

Question 548

Outline the islet cells antibodies in T1DM and T2DM

Answer 548

Type 1= Present | Type 2= Absent

Question 549

Why does diabetes lead to micro and macrovascular complications?

Answer 549

Diabetes damages blood vessels

Question 550

Where are the main sites of microvascular complications?

Answer 550

``` Retinal arteries Glomerular arterioles (kidney) Vasa nervorum (tiny blood vessels that supply nerves) ```

Question 551

What are the main microvascular complications?

Answer 551

``` Severity of hyperglycaemia Hypertension Genetic Hyperglycaemic memory Tissue damage through originally reversible and later irreversible alterations in proteins ```

Question 552

What is the challenge of hyperglycaemic memory?

Answer 552

Have epigenetic 'reminiscence' of altered metabolic state Challenge= lots of patients carry on with normal lifestyle Then wait for complication and then consider changing lifestyle but TOO LATE

Question 553

How does severity of hyperglycaemia relate to microvascular complication?

Answer 553

Complications are reduced if HbA1c is low (i.e. not severe)

Question 554

How does hypertension relate to microvascular complications?

Answer 554

Vessels that control BP can be affected | Higher bP-> more likely to get systolic disease

Question 555

What are the mechanisms of glucose damage?

Answer 555

Hyperglycaemic and hyperlipidaemia - > AGE-RAGE (advanced glycation end-product), oxidative stress, hypoxia - > inflammatory signaling cascades - > local activation of pro-inflammatory cytokine - > inflammation - > nephropathy, retinopathy, neuropathy

Question 556

What is diabetic retinopathy?

Answer 556

Complication of diabetes, caused by high blood sugar levels damaging the back of the eye (retina) Main cause of visual loss in people with diabetes and the main cause of blindness in people of working age

Question 557

What is background diabetic retinopathy? 3 common features

Answer 557

Happens to majority of patients 3 common features: Hard exudates (cheese colour, lipid) Microaneurysms (“dots”) Blot haemorrhages

Question 558

What is pre-proliferative diabetic retinopathy?

Answer 558

Progression from background diabetic retinopathy (if untreated) Cotton wool spots also called soft exudates (fluffy) Represent retinal ischaemia-. various parts become ischaemic

Question 559

What is proliferative retinopathy?

Answer 559

Visible new vessels on disk or elsewhere in retina

Question 560

What is maculopathy?

Answer 560

Hard exudates near the macula Same disease as background but happens to be near macula Can threaten direct vision May also have cotton wool spots

Question 561

What is the progression of retinopathy?

Answer 561

Background Pre-proliferative Proliferative NB. Could have maculopathy

Question 562

How is diabetic retinopathy managed?

Answer 562

Need to improve control of blood glucose (warn patient that warning signs are present) Pan retinal photocoagulation for pre-proliferative and proliferative (Round circles where eye laser beam fired into eye-> prevents new ischaemic patches forming) Treat maculopathy with GRID of photocoagulation (GRID laser therapy) NOT PAN RETINAL because problem only around macula

Question 563

Which of the following statement is true regarding diabetic retinopathy? Progression is unrelated to glycaemic control Cotton wool spots are a feature of background retinopathy Hard exudates are always treated with pan retinal photocoagulation Maculopathy can threaten direct vision Proliferative changes are best left untreated

Answer 563

Maculopathy can threaten direct vision

Question 564

What is the pathophysiology of diabetic nephropathy?

Answer 564

Hypertension Progressively increasing proteinuria Progressively deteriorating kidney function Classic histological features

Question 565

Why is it important to understanding kidney disease with diabetes?

Answer 565

Diabetes and kidney disease-> increased risk of CHF (chronic heart failure), AMI (acute MI), CVA/TIA (stroke), PVD (periph vasc disease) , death -> ASSOCIATED MORBIDITY AND MORTALITY Health care burden

Question 566

What are the histological features of diabetic nephropathy?

Answer 566

GLOMEULAR Mesangial expansion Basement membrane thickening Glomerulosclerosis VASCULAR TUBULOINTERSTITIAL Essentially in diabetic nephropathy, metabolic and haemodynamic factors-> over production of matrix leading to mesangial expansion and to basement membrane thickening As this progresses you get sclerosis of the glomerulus and secondary effects in the tubulointerstitium

Question 567

What is the epidemiology of diabetic nephropathy?

Answer 567

Type 1 DM= 20-40% after 30-40 years Type 2 DM= Probably equivalent but compounding factors

Question 568

What factors can affect the epidemiology of nephropathy in T2DM?

Answer 568

``` Age at development of disease Racial factors Age at presentation May have been asymptomatic but still glucose unregulated Loss due to cardiovascular morbidity ```

Question 569

What are the clinical features of diabetic nephropathy?

Answer 569

Progressive proteinuria Increased BP Deranged renal function

Question 570

What are the ranges for proteinuria?

Answer 570

See degree of protein being expelled Normal range <30mg/24hrs Microalbuminuric range 20-200mg/24hrs Asymptomatic range 300-3000mg/24hrs Nephrotic range >3000mg/24hr

Question 571

What are the strategies for intervention of diabetic nephropathy?

Answer 571

Diabetic control (decreasing HbA1c-> reduced microvascular complications) Inhibition of activity of RAS system Blood pressure control (e.g. ACE inhibitors) Stopping smoking

Question 572

What drugs affect angiotensin 2?

Answer 572

ACE inhibitors

Question 573

What effects does angiotensin 2 have?

Answer 573

``` Vasoactive effects Mediation of glomerular hyperfiltration Increased tubular uptake of proteins Induction of pro fibrotic cytokines Stimulation of glomerular and tubular growth Podocyte effects Induction of pro inflammatory cytokines Generation of ROS and NF-kB Stimulates fibroblast proliferation Up regulation of adhesion molecules on endothelial cells Up regulation of lipoprotein receptors ```

Question 574

Which microvascular complication of diabetes do ACE inhibitors prevent?

Answer 574

Diabetic nephropathy

Question 575

Which of the following are features of diabetic nephropathy? Affects all patients with diabetes over time Associated with decreased blood pressure Progressively increasing proteinuria Unrelated to glycaemic control Associated with a low risk of cardiovascular events

Answer 575

Progressively increasing proteinuria

Question 576

What is diabetic neuropathy?

Answer 576

Diabetic neuropathies are a family of nerve disorders caused by diabetes Blocking of small vessels supplying nerves (vasa nervorum) Some people with nerve damage have no symptoms Others may have symptoms such as pain, tingling or numbness in the hands, arms, feet, and legs

Question 577

What kinds of diabetic neuropathy are there?

Answer 577

``` Peripheral polyneuropathy Mononeuropathy Mononeuritis multiplex Radiculopathy Autonomic neuropathy Diabetic amyotrophy Sensory and motor ```

Question 578

How does diabetic neuropathy progress?

Answer 578

Initiating event (genetics and inflammation contribute)- from insult or chronic disorders Glycation Epigenetic Function and progressive pathological changes

Question 579

What is peripheral neuropathy?

Answer 579

Longest nerves supply feet Loss of sensation, ankle jerks, vibration sense (tuning fork) Danger is that patients will not sense an injury to the foot (e.g. stepping on nail) May repeatedly injure but not notice-> multiple fractures on foot X-ray (Charcot's joint)

Question 580

Who is peripheral neuropathy most likely to occur in?

Answer 580

Who is it most likely to occur in?

Question 581

What is a monofilament exam?

Answer 581

``` Test for peripheral neuropathy Metal object (nylon filament) has predefined pressure (when it bends = 10g of pressure applied to skin) Ask patient to say when they can feel the pressure point on their foot ``` Predicts neuropathy and ulceration

Question 582

What is mononeuropathy?

Answer 582

Usually sudden motor loss Wrist drop, foot drop Cranial nerve palsy (double vision due to 3rd nerve palsy)

Question 583

What is pupil sparing third nerve palsy?

Answer 583

Eye is usually down and out 6th nerve pulls eye out and 4th nerve pulls it down Pupil does respond to light (because parasympathetic fibres on outside don't easily lose blood supply in diabetes)

Question 584

How can an aneurysm cause third nerve palsy?

Answer 584

Press on parasympathetic fibres first causing fixed dilated pupil Pupil not spared (so can tell it's not diabetic)

Question 585

What is mononeuritis multiplex?

Answer 585

Random combo of peripheral nerve lesions Can occur in different ways E.g. optic nerve and radial nerve can be affected despite not being linked

Question 586

What is radiculopathy?

Answer 586

Pain over spinal nerves, usually affecting a dermatome on the abdomen or chest wall Nerves that are connected

Question 587

What is the difference between mononeuritis multiplex and radiculopathy?

Answer 587

``` Mononeuritis= random combo of peripheral nerve lesions Radiculopathy= nerves that are connected ```

Question 588

What is autonomic neuropathy?

Answer 588

Loss of sympathetic and parasympathetic nerves to GI tract, bladder, cardiovascular system

Question 589

How does autonomic neuropathy affect the GI tract?

Answer 589

Difficulty swallowing Delayed gastric emptying Constipation/ nocturnal diarrhoea

Question 590

How does autonomic neuropathy affect the postural hypotension?

Answer 590

Can be disabling e.g. collapsing on standing

Question 591

How can you measure cardiac autonomic supply in diabetic autonomic neuropathy?

Answer 591

Measure changes in heart rate in response to Valsalva manoevre (blow into syringe-> pressure-> affect HR, patients with autonomic neuropathy may not do as well) Normally there is a change in heart rate Look at ECG and compare R-R intervals

Question 592

What are the main types of macrovascular disease in diabetes?

Answer 592

Early widespread atherosclerosis Ischaemic heart disease Cerebrovascular disease Peripheral vascular disease

Question 593

How are atheromas formed? (Macrovascular disease and the metabolic syndrome_

Answer 593

SILENT CLINICALLY Initial lesion (grows with IR lipid BP) Fatty streak (IR lipid BP) Intermediate (IR lipid BP) OVERT CLINICALLY Atheroma (smooth muscle IR) Fibroatheroma Complicated (thrombosis) *IR= insulin resistance

Question 594

What risk factors contribute to atheromas?

Answer 594

Atheroma= macrovascular complication of diabetes Fasting glucose (>6mmol/l) HDL (<1 for men or <1.3 women) Hypertension (BP >135/80) Insulin resistance, inflammation, adipocytokines, urine microalbumin Waist circumference (>102 in men and >88 in women)

Question 595

How is life expectancy affected by hyperglycaemia?

Answer 595

Hyperglycaemia is associated with significantly reduced life expectancy

Question 596

True or false: macrovascular conditions occur in people with diabetes only

Answer 596

FALSE | Occurs in people with or without diabetes

Question 597

How do microvascular and macrovascular diseases affect morbidity and mortality?

Answer 597

Microvascular disease causes morbidity | Macrovascular disease causes morbidity and mortality

Question 598

How does diabetes mortality change with known CVD?

Answer 598

Mortality increased in MI if you have diabetes Mortality similar if someone has diabetes and no MI AND someone who has no diabetes but has had MI Harder to treat patients with co-morbidities

Question 599

How does macrovascular disease affect ischaemic heart disease, cardiovascular disease, peripheral vascular disease and renal artery stenosis?

Answer 599

IHD The major cause of morbidity and mortality in diabetes The mechanisms are similar with and without diabetes CVD Earlier than without diabetes More widespread PVD Contributes to diabetic foot problems with neuropathy RAS May contribute to hypertension and renal failure

Question 600

Is controlling blood sugar more important for microvascular or macrovascular conditions of diabetes?

Answer 600

Microvascular

Question 601

What is adiponectin?

Answer 601

Mechanism possibly responsible to T2DM Normally decreases insulin resistance

Question 602

How should macrovascular diseases be managed?

Answer 602

Aggressive management of multiple risk factors (modifiable and non-modifiable) Intensive therapy over conventional

Question 603

What are the risk factors for macrovascular disease?

Answer 603

``` NON-MODIFIABLE Age Sex Birth weight FH/Genes ``` ``` MODIFIABLE Dyslipidaemia High blood pressure Smoking Diabetes ```

Question 604

What are the treatment goals in T2DM?

Answer 604

Lower blood glucose Treat BP Manage blood lipids

Question 605

What complications of diabetes predispose the patient to foot disease?

Answer 605

Neuropathy- sensory, motor and autonomic Peripheral vascular disease

Question 606

What is the prevalence of current or past foot ulceration in diabetes?

Answer 606

5-7% Risk of amputation 60x in diabetes

Question 607

What is the pathway to foot ulceration?

Answer 607

``` Sensory/motor/autonomic neuropathy Limited joint mobility Peripheral vascular disease Trauma Reduced resistance to infection Diabetic complications e.g. retinopathy (can't see things-> stub toe) ```

Question 608

What happens in sensory neuropathy that leads to foot ulceration?

Answer 608

Loss of touch (don't notice stone in shoe/sore feet) Loss of vibration Loss of temp sensation (hot bath)

Question 609

What happens in motor neuropathy that leads to foot ulceration?

Answer 609

Clawing of toes and flattening of arch of foot | -> abnormal neuropathy

Question 610

What happens in autonomic neuropathy that leads to foot ulceration?

Answer 610

Lack of sweating

Question 611

How does limited joint mobility lead to foot ulceration?

Answer 611

Abnormal pressure on parts of feet

Question 612

How does reduced resistance to infection lead to foot ulceration?

Answer 612

White cells don't work as well in hyperglycaemia

Question 613

What will a magnetic resonance angiography for peripheral vessel disease show?

Answer 613

Major stenoses (e.g. at the origin of left external iliac artery) and occlusion (e.g. in proximal segment of the right superficial femoral artery)

Question 614

What are the features of the neuropathic foot, ischaemic foot and neuro-ischaemic foot?

Answer 614

NEUROPATHIC FOOT= numb, warm, dry, palpable foot pulses, ulcers at points of high pressure loading. ISCHAEMIC FOOT= cold, pulseless, ulcers at the foot margins. NEURO-ISCHAEMIC FOOT= numb, cold, dry, pulseless, ulcers at points of high pressure loading and at foot margins

Question 615

Why may someone with a diabetic ulcer have a black toe?

Answer 615

Peripheral vascular disease | End artery has occluded-> gangrene of toe

Question 616

Where are common sites for foot ulcers?

Answer 616

Dorsum of toes | Ball of foot

Question 617

What should be considered when you assess the foot of a diabetic patient?

Answer 617

Appearance= deformity? callus? Feel= hot? cold? dry? Foot pulses= dorsalis pedis? posterior tibial pulse? Neuropathy= vibration sensation, temp, ankle jerk reflex, fine touch sensation

Question 618

How can you prevent foot ulcers?

Answer 618

``` PREVENTATIVE 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 ``` ``` DIABETES CONTROL Hyperglycaemia Hypertension Dyslipidaemia Stop smoking Education ```

Question 619

How are diabetic foot ulcers managed?

Answer 619

``` Relief of pressure bed rest (risk of DVT, heel ulceration, redistribution of pressure/total contact cast) ``` Antibiotics, possibly long term Debridement Revascularization (angioplasty, arterial bypass surgery) Amputation

Question 620

What features of diabetic feet may lead to osteomyelitis?

Answer 620

Patient with Charcot neuro-osteoarthropathy and a rocker-bottom foot Will have osteomyelitis on cuboid bone

Question 621

How can you differentiate between osteomyelitis and active charcot?

Answer 621

OSTEOMYELITIS Hot red foot with ulcer X ray= normal first weeks MRI= marrow oedema in forefoot and hindfoot near ulcer ``` ACTIVE CHARCOT Hot red foot, no ulcer Midfood subarticular X ray= normal first weeks MRI= marrow oedema in midfoot subcondral ```