Endocrinology

Question 1

Name the two most common causes hyperthyroidism?

Answer 1

• Graves’ Disease
• Nodular Goitre (Plummer’s Disease) -> a benign tumour producing thyroxine

Question 2

What is Graves’ Disease?

Answer 2

• an autoimmune disease that produces antibodies that bind to and stimulate the TSH receptor in the thyroid
• the stimulation leads to the thyroid gland becoming smoothly enlarged (goitre)

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Question 3

How do patients suffering from Graves’ Disease present?

Answer 3

• patients will come complaining of being overactive with weight loss and sweating etc.
• on palpation, the thyroid gland will feel very diffuse and it’ll be smoothly enlarged
• a family history of hyperthyroidism
• exophthalmos - there is another antibody that binds to the growth factor receptors behind the eye -> muscles behind the eye grow and push the eyes forward (worsened by smoking)
• localised pretibial myxoedema (weird growth of soft tissue in the shin) - caused by another antibody

Question 4

On further medical examination, what else would you find in a patient with Graves’ Disease?

Answer 4

• a rapid pulse (raised metabolic rate)
• warm
• imaging the thyroid, by giving the patient some radioactive iodine, will show up on the scintigram, showing that the iodine is going into the thyroid gland and the whole thyroid gland is active

Question 5

What is Plumber’s Disease?

Answer 5

• a toxic nodular goitre, originating from a benign adenoma that is overactively producing thyroxine

Question 6

How do patients suffering from Plumber’s Disease present?

Answer 6

• with generally hypothyroidism symptoms
• distinct symptoms is on palpation and examination there is a lump on one side

Question 7

On further medical examination, what else would you find in a patient with Plumber’s Disease?

Answer 7

• because there is too much thyroxine coming from the tumour the pituitary will stop making TSH -> normal part of the thyroid will slowly shrink and stop making thyroxine
• the iodine thyroid scan you will just see a hot nodule and the rest of the thyroid scan will not be seen because of the negative feedback from the tumour
• sometimes patients may have a multinodular goitre

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Question 8

What are the effects of thyroxine on the sympathetic nervous system?

Answer 8

• SENSITISES beta adrenoceptors to ambient levels of adrenaline and noradrenaline -> normal levels of adrenaline and noradrenaline will have much stronger effects than they should -> patients with hyperthyroidism will also have features of having too much adrenaline e.g. palpitations, tachycardia, tremor, lid lag

Question 9

Name some symptoms of having too much adrenaline?

Answer 9

• palpitations
• tachycardia
• tremor
• lid lag

Question 10

Summarise the symptoms of hyperthyroidism?

Answer 10

• weight loss despite increased appetite
• breathlessness
• palpitations
• tachycardia
• sweating
• heat intolerance
• diarrhoea
• lid lag and other sympathetic features

Question 11

What is a Thyroid Storm (Thyrotoxic Crisis)?

Answer 11

• a rare but severe complication of hyperthyroidism - MEDICAL EMERGENCY (50% mortality if untreated - die of heart failure or arrhythmia)
• features of thyroid storm:

o hyperpyrexia > 41 degress

o tachycardia/arrhythmia – over 170 bpm

o cardiac failure

o delirium/frank psychosis

o hepatocellular dysfunction, jaundice

Question 12

What is the cause of thyroid storm?

Answer 12

• hyperthyroidism that has been left untreated for long enough, two or more features of a thyroid storm = high risk of death

Question 13

How is the diagnosis of a thyroid storm confirmed?

Answer 13

• a blood test

Question 14

What are the treatment options for thyroid storm?

Answer 14

must be prompt and aggressive treatment

• surgery (thyroidectomy)
• radioiodine
• drugs

Question 15

Name the classes of drugs used to treat hyperthyroidism?

Answer 15

· Thionamides (anti-thyroid drugs)

· Potassium iodide

· Radioiodine

· Beta-blockers - others reduce thyroid hormone synthesis, beta blockers simply help symptoms

Question 16

What are the uses of thionamides?

Answer 16

• daily treatment of hyperthyroid conditions -> Graves’ or Plummer’s
• control hyperthyroidism before thyroidectomy -> don’t want to give a general anaesthetic to someone who is tachycardic with a labile heart rate
• following radioactive iodine treatment -> radioactive iodine takes a while to work so something else must control the thyroid hormone level before the radiotherapy starts to take effect

Question 17

Name the 2 main thionamides.

Answer 17

• propylthiouracil
• carbimazole

Question 18

Describe the synthesis of thyroid hormone.

Answer 18

• iodine is taken up into the follicular cells
• under the action of thyroperoxidase with hydrogen peroxide you get iodination of tyrosine residues in the thyroglobulin
• coupling of monoiodotyrosine and diiodotyrosine to form T3 and T4, which is taken up and released by the cells into the circulation

Question 19

What is the mechanism of thionamides

Answer 19

• INHIBIT THYROPEROXIDASE
• hence, they inhibit the iodination of thyroglobulin and the coupling of iodotyrosines therefore there is a net reduction in synthesis and secretion of thyroid hormones
• also suppress antibody production in Graves’ and diodination of T4 to T3 in peripheral tissue

Question 20

How long does it take for thionamides to have an effect?

Answer 20

• the biochemical effects of inhibition with thionamides occurs in hours but it takes weeks before the clinical effects can be seen
• this is because there is a lot of STORED thyroid hormone in the lumen of the thyroid follicles and anti-thyroid hormones only affect the synthesis of thyroid hormones, not stored thyroid hormone
• NO CHANGE FOR 7-10 DAYS

Question 21

What is the clinical consequence of the lag between giving the thyroid drug and the response?

Answer 21

• symptoms have to managed short-term so non-selective beta blockers are given

Question 22

What are the unwanted side effects of thionamides?

Answer 22

• agranulocytosis/granulocytopenia (reduction or absence of granular leukocytes) - rare and reversible on withdrawal of the drug
• rashes (relatively common)
• headaches
• nausea
• jaundice
• joint pain

Question 23

Describe the pharmacokinetics of thionamides.

Answer 23

• orally active
• plasma half-life of 6-15 hours
• crosses the placenta and is secreted in the milk
• metabolised in the liver and excreted in the urine
• carbimazole is a pro-drug which is converted to methimazole (active)

Question 24

What is the significance of thionamides crossing the placenta?

Answer 24

• thyroid disease is common in women around reproductive age so you must consider pregnancy
• patients can conceive on thionamides but ideally on as low a dose as possible -> high doses of thionamides in a pregnant woman could cause foetal hypothyroidism

Question 25

What is the significance of thionamides being secreted in milk?

Answer 25

• thyroid disease is common in women around reproductive age so you must consider pregnancy and neonatal period
• patients can breast-feed on thionamides but ideally on as low a dose as possible -> high doses of thionamides in a pregnant woman could cause foetal hypothyroidism
• propylthiouracil crosses into breast milk LESS than carbimazole -> breast-feeding woman are put on PTU over CBZ

Question 26

How long is it aimed to keep a patient on thionamides?

Answer 26

18 months -> 50:50 chance of relapse after stopping

Question 27

When is iodide treatment used?

Answer 27

o Preparation of hyperthyroid patients for surgery

o Severe thyrotoxic crisis (thyroid storm)

Question 28

What compound is most commonly used in iodide treatment?

Answer 28

• KI

Question 29

What is the mechanism of action of KI?

Answer 29

• Wolff-Chaikoff Effect = the temporary reduction in thyroid hormones following ingestion of large amounts of iodine
• an autoregulatory phenomenon -> the thyroid rejects the ingested iodide, hence prevents the gland from sucking up loads of iodine and making too much thyroid hormone
• KI inhibits the iodination of thyroglobulin and the generation of hydrogen peroxide

Question 30

How long does it take for KI to have an affect?

Answer 30

• very quick, a matter of hours
• maximum effect after 10 days of contiuous administration
• over weeks it reduces the size and vascularity of the thyroid

Question 31

What are the unwanted side effects of KI?

Answer 31

• ALLERGIC REACTION
• rashes
• fever
• angioedema

Question 32

Describe how KI is given?

Answer 32

• given orally or Lugol’s Solution or Aqueous Iodine

Question 33

What is Radioiodine ¹³¹I^- high dose used to treat?

Answer 33

• Graves’
• Plummer’s
• Thyroid Cancer

Question 34

What is Radioiodine mechanism of action?

Answer 34

• permanently switching off the thyroid without surgery
• the method relies on the thyroid gland taking up iodine to make thyroid hormone so thyroid follicular cells take up the radioiodine so, it accumulates in the colloid -> emits beta particles of radiation that destroy the follicular cells

Question 35

What do some patients complain about as a result of radioiodine treatment?

Answer 35

• discomfort in the neck

Question 36

What other drugs must be taken into account when prescribing someone with radioiodine?

Answer 36

• anti-thyroid drugs must have been discontiued 7-10 days prior to radioiodine treatment so that the thyroid gland can rev up and be really active so that it sucks up a lot of radioactive iodine when it is administered to get maximal destruction of the gland

Question 37

Give the dose of radioiodine given to treat Graves’ Disease.

Answer 37

• oral dose of approx. 500 MBq

Question 38

What is the dose of radioiodine given to patients suffering from Thyroid Cancer?

Answer 38

• oral dose of circa 3000 MBq

Question 39

Describe the radioactivity of radioiodine.

Answer 39

o Radioactive half-life = 8 days

o Radioactivity negligible after 2 months (maximum effect 2-3 months)

Question 40

What precautions must be taken after taking radioiodine?

Answer 40

• avoid close contact with small children for several weeks
• contra-indictaed in pregnancy and breast-feeding

Question 41

What are the results of a thyroid uptake scan of Graves’ Disease?

Answer 41

• entire gland is active and smoothly enlarged

Question 42

What are the results of a thyroid uptake scan of a patient with Plummer’s?

Answer 42

• single focus of activity and the rest is supressed

Question 43

What are the results of a thyroid uptake scan of a patient with Thyroiditis?

Answer 43

• inflamed thyroid gland where there is NO activity at all

Question 44

What is Viral Thyroiditis?

Answer 44

• caused by a virusattacking the thyroid gland and it causing a fever
• it damages the thyroid follicles and all the stored thyroxine gets released so patients present with OVERACTIVE thyroid, after a bout a month when all the thyroxine has ran out they will become hypothyroid as the damaged gland will no longer make thyroxine

Question 45

What are the symptoms of viral thyroiditis?

Answer 45

• piainful dysphagia
• hyperthyroidism
• pyrexia
• raised erythrocyte sedimentation rate

Question 46

What is the treatment for viral thyroiditis?

Answer 46

• you have to wait for all the thyroxine to have been used up before giving thyroxine to treat the hypothyroidism
• drugs can be given to help with the symptoms

Question 47

Answer 47

D

• all the others will control thyroid function but the lugol’s iodine, used for 10 days before the operation, will reduce the size and vascularity of the thyroid gland

Question 48

What are the 6 anterior pituitary hormones?

Answer 48

• FSH
• LH
• GH
• TSH
• ACTH
• prolactin

Question 49

Define hypopituitarism.

Answer 49

• decreased production of ALL anterior pituitary hormones (panhypopituitarism) or of specific hormones

Question 50

How common are congeital reason for panhypopituitarism?

Answer 50

• rare

Question 51

Name a gene mutation which leads to panhypopituitarism.

Answer 51

• PROP1 mutation - this is a transcription factor that allows the development of the pituitary gland to take place
• is congenital

Question 52

What are the causes of acquired panhypopituitarism?

Answer 52

o Tumours -> hypothalamic (craniopharyngiomas) or pituitary (denomas, metastases, cysts)

o Radiation -> hypothalamic/pituitary damage (GH most vulnerable, TSH relatively resistant)

o Infection -> meningitis

o Traumatic brain injury

o Infiltrative disease -> often involves pituitary stalk (neurosarcoidosis)

o Inflammatory (hypophysitis)

o Pituitary apoplexy -> haemorrhage (or less commonly infarction)

o Peri-partum infarction (Sheehan’s syndrome)

Question 53

What is the usually loss of secretion of hormones in panhypopituitarism?

Answer 53

o Gonadotrophins (LH and FSH)

o GH

o Thyrotrophin

o Corticotrophin

o Prolactin deficiency is uncommon/unrecognised

Question 54

What are the symptoms of hypopituitarism?

Answer 54

o Secondary Amenorrhoea OR Oligomenorrhoea

o Impotence

o Loss of libido

o Erectile dysfunction

o Tiredness

o Waxy skin

o Loss of body hair

o Hypotension

• no really symptoms for growth hormone in adults

Question 55

What is Sheehan’s Syndrome?

Answer 55

o develops acutely following post-partum haemorrhage resulting in PITUITARY INFARCTION

• blood loss results in vasoconstrictor spasm of hypophysial arteries and this leads to: ischaemia of the pituitary (enlarged during pregnancy due to swelling of prolactin glands) and necrosis of the pituitary
• develops very FAST

o more prevelant in less developed countries as hypotension post-partum is more common

Question 56

What is the presentation of Sheehan’s Syndrome?

Answer 56

• lethargic
• anorexia
• weight loss
• failure of lactation
• failure to resume menses post-delivery

o posterior pituitary usually not affected

Question 57

What is pituitary apoplexy?

Answer 57

• intra-pituitary haemorrhage or, less commonly, infarction
• often dramatic, rapid presentation in patients with pre-existing pituitary tumours (adenomas) -> may be first presentation of a pituitary adenoma
• often causes severe headaches and visual field defects (depression on the optic chiasm)
• can be precipitated by anti-coagulants

Question 58

What differentiates between Sheehan’s Syndrome and pituitary apoplexy?

Answer 58

• pituitary apoplexy isn’t specific to women

Question 59

What might be lead to if the cavermous sinus becomes involved?

Answer 59

• diplopia (IV, VI), ptosis (III)

Question 60

How can hypopituitarism be diagnosed?

Answer 60

o Biochemical

• basal plasma values of pituitary or target endocrine gland hormones
• stimulated (dynamic) pituitary function test

o Radiological

• pituitary MRI

Question 61

What is the problem for testing for basal plasma values of pituitary or target endocrine gland hormones?

Answer 61

• most things released from the hypothalamus are released in pulses -> single measurements are not useful -> low or high results could be physiological

Question 62

What is a stimulated pituitary function test?

Answer 62

• done using a combined function test -> involves the administration of various releasing hormones -> releasing hormones are administered IV
• the same thing can be done with just one releasing hormone if you’re testing for a specific hypothyroidism -> the specific test for GH is the insulin-induced hypoglycaemia test

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Question 63

What can be revealed by a pituitary MRI?

Answer 63

o specific pituitary pathology eg haemorrhage (apoplexy), adenoma

o empty sella – thin rim of pituitary tissue

Question 64

What is the general treatement for hypopituitarism?

Answer 64

• hormone replacement therapy

Question 65

What is the treatment for ACTH deficiency?

Answer 65

• hydrocortisone

Question 66

What is the treatment for TSH deficiency?

Answer 66

• thyroxine

Question 67

What is the treatment for GH deficiency?

Answer 67

• GH

Question 68

What is the treatment for LH/FSH deficiency in women?

Answer 68

• oestrogen
• if the patient has a uterus progesterone must be given with the oestrogen - prevents endometrium hyperplasia

Question 69

What is the GH also known as?

Answer 69

• somatotrophin

Question 70

What are the effects of a lack of somatotrophin?

Answer 70

o children -> pituitary dwarfism

o adults -> effects are unclear

Question 71

Name the causes of short stature in children?

Answer 71

o Lack of GH

o Genetic -> Down’s syndrome, Turner’s syndrome, Prader Willi syndrome

o Malnutrition

o Emotional deprivation (potentially due stress response effecting the growth axis)

o Endocrine disorders -> Cushing’s syndrome, Hypothyroidism, GH deficiency, poorly controlled T1DM

o Systemic disease -> Cystic Fibrosis, Rheumatoid arthritis

o Malabsorption -> Coeliac disease

o Skeletal dysplasia -> Achondroplasia, osteogenesis imperfecta

Question 72

Describe the growth axis.

Answer 72

• GHRH is released from the hypothalamus and truggers the anterior pituitary to release GH
• GH caues growth in target tissue as well as stimulating the production of IGF I and IGF II in the liver-> IGF I mediates growth
• GH is controlled in the hypothalamus by GHRH and GH

Question 73

What is Laron Dwarfism?

Answer 73

• a form of dwarfism caused by a GH receptor defect -> results in low IGF I levels because GH isn’t having an effect

Question 74

What is the cause of teritary hypopituitarism?

Answer 74

• specific hypothalamic hormone defects

Question 75

Give an example of tertiary hypopituitarism.

Answer 75

• GnRH deficiency

Question 76

Name some GnRH deficiencies.

Answer 76

• Kallmann’s Syndrome
• Prader-Willi-Syndrome

Question 77

Describe Kallmann’s Syndrome.

Answer 77

• caused by a genetic defect where the neurones in the embryo that will go on to produce GnRH are unable to migrate to the hypothalamus -> hypothalamus LACKS GnRH neurones
• the defect also prevents the migration of the neurones that are going to develop a sense of smell resulting in various degrees of anosmia
• hypogonadism -> untreated suffers never go through puberty

Question 78

How is a diagnosis of short stature made in a child?

Answer 78

• if they fall below their percentile on the charts within their red book

Question 79

What are the likely causes of acquired GH deficiency in adults?

Answer 79

• trauma
• pituitary tumour
• pituitary surgery
• cranial radiotherapy

Question 80

How is GH deficiency diagnosed?

Answer 80

o GH provocation tests in which plasma GH is measured at specific points before and aftwerwards

• GHRH + ARGININE (IV) - (in combination more effective than each alone)
• INSULIN (IV) – via hypoglycaemia
• GLUCAGON (IM)
• EXERCISE (e.g. 10 min step climbing; when appropriate)

Question 81

What is the NICE cut-off for GH deficiency in response to hypoglycaemia?

Answer 81

• 3mcg/L

Question 82

What is the treatment for GH deficiency?

Answer 82

o hormone replacement therapy

• human recombinant GH
• daily, subcutaneous injection

Question 83

What are the signs and symptoms of GH deficiency in adults?

Answer 83

o impaired ‘psychological well being’ and reduced quality of life -> only proved symptom

• reduced lean mass
• increased adiposity
• increased waist:hip ratio
• reduced muscle strength & bulk à reduced exercise performance
• decreased plasma HDL-cholesterol & raised LDL-cholesterol

Question 84

State the potential benefits of GH therapy in adults.

Answer 84

o improved psychological well being and quality of life

• improved body composition -> decreased waist circumference, less visceral fat
• improved muscle strength and exercise capacity
• more favourable lipid profile - higher HDL-cholesterol, lower LDL-cholesterol
• increased bone mineral density

Question 85

What are the potential Risks of GH Therapy in Adults?

Answer 85

o increased risk of cardiovascular accidents -> due to its growth promoting effects, an excess of GH can cause cardiomegaly

o increased soft tissue growth, leading to e.g. cardiomegaly

o expensive

o increased susceptibility to cancer was thought but proved wrong

Question 86

Describe Hyperpituitarism.

Answer 86

o symptoms associated with excess production of adenohypophysial hormones

• can be due to isolated tumours but can be ectopic in origin (eg vasopressin in lung tumours)

Question 87

What is hyperpituitatarism associated with?

Answer 87

• visuial field defects
• often accompanied with other defects particularly cranial nerve defects

Question 88

Exactly, what crosses at the optic chiasm?

Answer 88

• fibres from the inner (nasal) part of the retinae cross

Question 89

What kind of visual impairment is caused by an enlarged pituitary gland?

Answer 89

o bitemporal heminaopia

• you lose the temporal/peripheral vision

Question 90

How are bitemporal hemianopia assessed?

Answer 90

o perimetry

• press button when the patient can see the flashing light which builds up a visual field

Question 91

What is the difference between Cushing’s Disease and Cushing’s Syndrome?

Answer 91

• the syndrome is simply to much ACTH whereas the disease is due to a pituitary adenoma

Question 92

Give two physiological and one pathological reason for hyperprolactinaemia.

Answer 92

o physiological = pregnancy and breastfeeding

o pathological = prolactinoma (often microadenomas<10nm diameter)

Question 93

In terms of the gonadal axis, what does high prolactin do?

Answer 93

• it suppresses GnRH pulsatility
• can cause secondary hypogonadism

Question 94

What are the presenting complaints/problems with hyperprolactinaemia in women?

Answer 94

• galactorrhoea (milk production when not breastfeeding)
• secondary amenorrhoea or oligomenorrhoea
• loss of libido
• infertility

Question 95

What are the presenting complaints/problems with hyperprolactinaemia in men?

Answer 95

• loss of libido
• erectile dusfunction
• infertility
• galactorrhoea can occur but is very uncommon

Question 96

What supresses prolactin release?

Answer 96

• dopamine binding to D2 receptors

Question 97

How is hyperprolactinamia treated?

Answer 97

• 1st line = dopamine receptor agonists therefore inhibiting prolactin and reduce the tumours size
• include bromocriptine and cabergoline via oral administration

o unusual that it is medical and not surgical treatment

Question 98

What are the side effects of dopamine receptor agonists?

Answer 98

• nausea and vomiting
• postural hypotension
• dskinesias
• depression
• pathological gambling

Question 99

What does excess GH causes?

Answer 99

o in children = gigantism

o in adults = acromegaly

• in adults, the growth plates of the long bones have fused so there is no longer a possibility of an increase in height but you still get other effects

Question 100

What is the major cause of excess GH?

Answer 100

• usually benign growth hormone secreting pituitary adenoma
• maybe benign but can be deadly due to pressure it can provide on cranium

Question 101

Describe the signs and symptoms of acromegaly. Go onto state the issues that arise if acromegaly is left untreated.

Answer 101

• incidious onset -> gradual changes over many years

o increased morbidity and mortality

• > death: CVD = 60%
• > respiratory complications = 25%
• > cancer = 15%

Question 102

What grows in acromegaly?

Answer 102

o periosteal bone

o cartilage

o fibrous tissue

o connective tissue

o internal organs (cardiomegaly, splenomegaly, hepatomegaly etc.)

o prognathism

o enlarged supraorbital ridges

o enlarged soft tissues

Question 103

State the clinical features of acromegaly.

Answer 103

• EXCESSIVE SWEATING (HYPERHIDROSIS)
• HEADACHES
• enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features
• enlarged tongue (macroglossia)
• mandible grows causing protrusion of lower jaw (prognathism)
• carpal tunnel syndrome (median nerve compression)
• barrel chest
• kyphosis

Question 104

What are the metabolic effects of acromegaly?

Answer 104

excess GH -> increased endogenous glucose production and decreased muscle uptake -> increased insulin production -> increased insulin resisitance -> impaired glucose tolerance (50% of patients) -> diabetes mellitus

Question 105

State 4 major clinical complications linked to acromegaly.

Answer 105

o obstructive sleep apnoea -> bone and soft-tissue changes surrounding the upper airway lead to narrowing and subsequent collapse during sleep

o hypertension

o cardiomyopathy -> hypertension, DM, direct toxic effects of excess GH on myocardium

o increased risk of cancer -> colonic polyps, regular screening with colonoscopy

Question 106

What other hormone if often high in acromegaly?

Answer 106

• prolactin

Question 107

State and explain the ‘gold standard’ test for acromegaly.

Answer 107

• oral glucose tolerance

o paradoxical rise of GH following oral gluscose load

Question 108

What is the treatment for acromegaly.

Answer 108

o SURGERY is the main treatment - transphenoidal hypophysectomy

o Radiotherapy - problem is that over a long period of time the patient ends up hypopituitary as a result

o Chemotherapy/Drugs -> somatostatin analogues or dopamine Agonists

Question 109

Name a somatostatin analogue.

Answer 109

• octreotide

Question 110

Name two dopamine agonsits.

Answer 110

• bromocriptine
• cabergoline

Question 111

What is the clincal use of octreotide?

Answer 111

• short-term treatment before pituitary surgery -> reduces the size of the tumour to make surgery easier
• treatment of other neuroendocrine tumours e.g. carcinoid tumours

Question 112

How are somatostain analogues administed?

Answer 112

• subcutaneous or intramuscular

Question 113

What are the side effecst of somatostatin analogues?

Answer 113

o GI tract disturbances (somatostatin is produced by the small intestine) -> gallstones

o initial reduction in insulin secretion - transient hyperglycaemia -> inhibits the production of insulin by beta cells leading to transient hyperglycaemia

Question 114

What does the posterior pituitary look like on MRI?

Answer 114

• is the bright spot at the back of pituitray gland

Question 115

What two hormones are produced in the neurohypophysis/posterior pituitary?

Answer 115

• vasopressin (ADH)
• oxytocin

Question 116

What is the role of oxytocin?

Answer 116

• constriction of myometrium at parturition
• milk ejection reflex

Question 117

How is vasopressin regulated?

Answer 117

• osmoreceptors in the organum vasculosum

Question 118

What are the two types of diabetes insipidus?

Answer 118

o central/cranial -> absense or lack of circulating vasopressin

o nephrogenic -> end-organ (kindeys) resistence to vasopressin

Question 119

What are the causes of cranial diabetes insipidus?

Answer 119

o acquired (more common) -> damage to neurohypophysial system

• traumatic brain injury
• pituitary surgery
• pituitary tumours, craniopharyngioma
• metastasis to the pituitary gland - e.g. breast
• granulomatous infiltration of median eminence - e.g. TB, sarcoidosis

o Congenital – rare

• usually receptor gene mutations

Question 120

What are the causes of nephrogenic diabetes insipidus?

Answer 120

• familial (rare)
• drugs -> LITHIUM (used to treat bi-polar disorder), dimethyl chlortetracycline (DMCT)

Question 121

What are the signs and symptoms of diabetes insipidus?

Answer 121

• polyuria
• very dilute urine (hypo-osmolar)
• thirst and increased drinking (polydipsia)
• dehydration (and consequences) if fluid intake is not maintained
• possible disruption of sleep with associated problems
• possible electrolyte imbalance

Question 122

What is the cycle of diabetes insipidus?

Answer 122

Question 123

What happens to the usual cycle of diabetes insipidus if the patient doesnt have access to water?

Answer 123

Question 124

Name a disease which presents with similar symptoms to DI?

Answer 124

• psychogenic polydipsia

Question 125

What is the cycle of patients suffering from psychogenic polydipsia?

Answer 125

Question 126

How can DI and psychogenic polydipsia be distinguished between?

Answer 126

o normal person has a tightly maintained osmolality (270-290 mOsm/kg H₂O)

o diabetes insipidus = high osmolality

o psychogenic polydipsia = low osmolality

Question 127

What is the ‘gold standard’ test to diagnose diabetes insipidus?

Answer 127

o fluid deprivation test

Question 128

What are the biochemical features of DI?

Answer 128

• hypernatraemia
• raised urea
• increased plasma osmolality
• dilute (hypo-osmolar) urine - ie low urine osmolality

Question 129

State the biochemical features of psychogenic polydipsia.

Answer 129

• mild hyponatraemia -> excess water intake
• low plasma osmolality
• dilute (hypo-osmolar) urine -> ie low urine osmolality

Question 130

What is the treatment for cranial DI?

Answer 130

• V2 receptor agonists -> desmopressin (DDAVP)

Question 131

What is the clinical use of terlipressin?

Answer 131

• is V1 receptor agonist -> used to treat GI bleeds

Question 132

How is desmopressin administrated?

Answer 132

• nasally or orally
• produces a prompt sustained decrease in urine volume and increase in urine osmolarity -> has a very long effect so you don’t need to take desmopressin too often

Question 133

Apart from cranial DI, what else can desmopressin be used to treat?

Answer 133

• nocturnal eneuresis (bedwetting)
• haemophilia - you need V2 receptor stimulation

Question 134

What are the side effects of desmopressin?

Answer 134

• fluid retention and hyponatraemia
• abdominal pain
• headaches
• nausea

Question 135

What is the treatemnt for nephrogenic diabetes insipidus?

Answer 135

• thiazide diuretic

Question 136

Define SIADH.

Answer 136

• plasma vasopressin concentration is INAPPROPRIATE for the existing plasma osmolarity -> too much ADH for current osmolarity

Question 137

Show the pathway of SIADH.

Answer 137

Question 138

What are the signs and symptoms of SIADH?

Answer 138

o Signs of SIADH:

• raised urine osmolarity
• decreased urine volume (initially)
• hyponatraemia - decrease in plasma sodium concentration due to increased water reabsorption

o Symptoms of SIADH:

• often asymptomatic
• when Na⁺ concentration falls < 120mM = generalised weakness, nausea and poor mental function
• when Na⁺ conc. falls <110mM = confusion, coma and death

Question 139

What are the causes of SIADH?

Answer 139

• tumours (ectopic secretion)
• neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease)
• pulmonary disease (e.g. pneumonia)
• malignancy (in particular small cell lung cancer)
• endocrine disease (e.g. Addison’s disease)
• physiological - it can happen under quite normal circumstances where AVP release is stimulated by non-osmotic stimuli (e.g. hypovolaemia, pain, surgery)
• drugs (e.g. chlorpropamide)
• idiopathic

Question 140

What is the treatment of SIADH?

Answer 140

• treat the cause (e.g. tumour)
• if someone is already hyponatraemic, you need to deal with that as quickly as possible: -> immediate = fluid restriction and longer-term = drugs that prevent vasopressin action in the kidneys (e.g. lithium, dimethyl chlortetracycline (DMCT), V2 receptor antagonists)

Question 141

What are Vaptans?

Answer 141

• non-peptide vasopressin analogues
• tolvaptan - V2 receptor antagonist

o can be used for SIADH but are very expensive so are rarely used

Question 142

What is another disease (not SIADH) that vaptans could be used for)

Answer 142

• congestive heart failure

Question 143

What drugs affect ADH secretion?

Answer 143

• increase = nicotine
• decrease = alcohol and glucocorticoids

Question 144

What are the symptoms of primary hypothyroidism?

Answer 144

o Tongue gets thick

o Speech slows down

o Deepening of the voice

o Basal Metabolic Rate falls

o Bradycardia

o General weakness

o Depression

o Cold intolerance

o Weight gain and reduced appetite

o Constipation

• Eventual myzoedema coma

Question 145

What happens to TSH in primary hypothyroidism?

Answer 145

• it goes up to try and stimulate the thyroid

Question 146

What enzyme converts T4 to T3?

Answer 146

• deiodinase

Question 147

What percentage of hormones are made in the thyroid?

Answer 147

• 80% is deiodination of T4
• 20% is direct thyroidal secretion of T3

Question 148

Describe the mechanism of thyroid hormones.

Answer 148

• thyroxine enters the target cell and is converted to T3 by deiodinase (can also be T3 that enters directly)
• T3 moves to the nucleus and binds to the thyroid hormone receptor and then heterodimerises with a Retinoid X Receptor
• this complex then binds to the Thyroid Response Element that causes a change in gene expression

Question 149

What is used in thyroid hormone replacement therapy?

Answer 149

• the usual thyroxine replacement is levothyroxine sodium or direct thyroxine (T4)
• rarely liothyroxine sodium is used as a T3 replacement

Question 150

What is levothyroxine sodium used to treat?

Answer 150

• primary hypothyroidism - autoimmune or iatrogenic (post-thyroidectomy or post-radioactive iodine)
• secondary hypothyridsim (pituitary tumour, post-pituitary surgery/radiotherapy)

Question 151

What is used as reference to thyroxine dose in primary hypothyroidism?

Answer 151

• TSH levels

Question 152

What is used as a reference for thyroxine dose in secondary hypothyroidism?

Answer 152

• isn’t any TSH (or is very low) so middle of T4 reference range is used

Question 153

What is the clincal use of liothyronine?

Answer 153

• to treat MYXOEDEMA COMA - a very rare complication of hypothyroidism
• IV liothyronine (T3) is given in this situation because the onset of action is faster than T4
• then when the patient has recovered from the coma oral thyroxine replacement is given

Question 154

As well as being expensive, name another reason why T3 hormone replacement therapy is not favoured.

Answer 154

• T3 is very potent -> very difficult to get the dose right
• high T3 switches off TSH and patients show thyrotoxicosis symptoms = palpatations, tremors and anxiety
• combined thyroid hormone replacement does exsist but again isn’t favoured

Question 155

How does T3 and T4 circulate in the blood plasma?

Answer 155

• 99.97% of T4 and 99.7% of T3 are bound to thyroxine binding globulin (TBG) (not to be confused with thyroglobulin in the colloid of follicular cells)

Question 156

What factors affect plasma protein production?

Answer 156

• increase in pregnancy and with prolonged treatment with oestrogens and phenothiazides

decreased with liver disease or if you are severely malnourished

Question 157

Name two drug classes that can compete for binding sites of TBG.

Answer 157

• phenytoin
• salicylates (e.g. aspirin)

Question 158

What is the most common cause of hypothyroidism?

Answer 158

• autoimmune -> 5% of people suffer from this in their life

Question 159

What are the adverse effects of thyroid hormone over-replacement?

Answer 159

o usually associated with a low/suppressed TSH

o Skeletal -> increased bone turnover, reduction in bone mineral density therefore risk of osteoporosis

o Cardiac -> tachycardia, risk of Dysrrhythmia (particularly atrial fibrilation)

o Metabolism - increased energy expenditure, weight loss

o Increase b-adrenergic sensitivity -> tremors, nervousness

ARE ALL SYMPTOMS OF THYROTOXICOSIS

Question 160

Answer 160

• D

Question 161

Answer 161

• D

Question 162

What is Cushing’s Syndrome?

Answer 162

• too much cortisol

Question 163

What are the clinical features of Cushing’s Syndrome?

Answer 163

• centripetal obesity
• moon face
• buffalo hump
• proximal myopathy
• hypertension
• hypokalaemia
• red striae
• thin skin and bruising
• osteoporosis
• diabetes

Question 164

What are the causes of Cushing’s Syndrome?

Answer 164

o exogenous

• taking too many steroids

o endogenous

• pituitary dependent cushing’s disease (pituitary produces too much ACTH causing adrenal growth therefore too much cortisol)
• ectopic ACTH from lung cancer
• adrenal adenoma secreting cortisol

Question 165

What is the pattern of cortisol release?

Answer 165

• diurnal rhythm

Question 166

Compare the release of cortisol throughout the day between a normal person and someone with Cushing’s Syndrome.

Answer 166

Question 167

What are the methods of diagnosing Cushing’s Syndrome?

Answer 167

• 24h urine collection for urinary free cortisol
• blood diurnal cortisol levels
• low dose dexamethasone suppression test

Question 168

Describe the low dose dexamethasone suppression test.

Answer 168

• 0.5mg of dexamethasone (artificial steroid) every 6hrs for 48hrs
• normally this suppress cortisol to 0
• in any cause of Cushing’s Syndrome this will fail to suppress it to 0

o GOLD STANDARD

Question 169

Barring surgery, what treatments are available for Cushing’s Syndrome?

Answer 169

• inhibitors of sterid biosynthesis -> metyrapne, ketoconazole

Question 170

Barring surgery, what treatments are available for Conn’s Syndrome?

Answer 170

• mineralocorticoid receptor (MR) antagonists -> spironolactone, epleronone

Question 171

What is the mechanism of metyrapone?

Answer 171

• inhibition of 11beta-hydroxylase therefore blocking steroid synthesis in the zona fasciculata
• causes ACTH to rise as no cortisol is made so no negative feedback

Question 172

What are the clinical scenarios in which metyrapone is used?

Answer 172

o Control of Cushing’s syndrome prior to surgery

• cushing’s patients are not good surgical candidates because they are predisposed to infection and have very thin skin
• metyrapone is used to improve the patient’s symptoms and promotes better post-op recovery (better wound healing, less infection)
• oral metyrapone is dosed according to cortisol production (aim for mean serum cholesterol of 150-300 nmol/L)

o Control of Cushing’s symptoms after radiotherapy

• radiotherapy is usually quite slow to work so you would give metyrapone after radiotherapy until the effects of the radiotherapy start to come about

Question 173

State two biological/mechanical negative aspects about metyrapone.

Answer 173

o accumulation of 11-deoxycorticosterone which has mineralcorticoid properties -> sodium retention and potassium secretion -> salt retention -> hypertension

o all precursors are channeled towards sex steroid synthesis -> increase in adrenal androgens -> hirsutism and acne (more unpleasant for women is general)

Question 174

What are the side effects of metyrapone?

Answer 174

• nausea, vomiting, dizziness
• sedation
• hypoadrenalism
• hypertension on long-term administration
• hirsuitism

Question 175

How does ketoconazole function?

Answer 175

• inhibits Cytochrome P450 side chain cleavage enzymes meaning that glucocorticoid, mineralocorticoid and sex steroid production is blocked

Question 176

What are the uses of ketoconazole?

Answer 176

• treatment and control of symptoms prior to surgery
• an anti-fungal (not licensed anymore due to its reduction on cortisol)

Question 177

What are the side effects of ketoconazole?

Answer 177

• nausea, vomiting
• abdominal pain
• alopecia
• gynaecomastia, oligospermia, impotence, decreased libido -> due to reduction of sex steroid production
• ventricular tachycardias
• hepatotoxicity -> can be fatal - patients are monitored with regular liver function tests

Question 178

Where in the adrenal gland is aldosterone made?

Answer 178

• zona glomerulosa

Question 179

What is Conn’s Syndrome?

Answer 179

• too much aldosterone
• due to a benign adrenal cortical tumour in the zona glomerulosa

Question 180

What are the features of Conn’s Syndrome?

Answer 180

• hypertension and hypokalaemia (low potassium)

Question 181

How is Conn’s Syndrome (aka primary hyperaldosteronism) diagnosed?

Answer 181

• high aldosterone and low renin

Question 182

What is spironolactones mechanism of action?

Answer 182

• is converted into several metabolites including canrenone which competitively antagonises MRs -> blocks the action of aldosterone (sodium reabsorption and potassium secretion in the kidney tubules)

Question 183

When is spironolactone used?

Answer 183

• prior to surgery to make the patient a better candidate
• people who have bilateral adrenal hyperplasia -> can’t take both adrenals out as not enough cortisol or aldosterone would be produced

Question 184

Name the side effects of spironolactone.

Answer 184

o spironolactone is a very non-specific drug so there are lots of side-effects

• a progesterone receptor agonist so causes menstrual irregularities
• an androgen receptor antagonist so it can cause gynaecomastia in men -> clinically can’t be used in men for this reason (must use much more commonly used epleronone)
• GI tract irritation
• renal and hepatic disease

Question 185

What makes epleronone a better drug than spironolactone?

Answer 185

• has the same mechanism with same affinity for MRs while being more specific so doesn’t interfere with progesterone or androgen receptors so has less side effects
• FAR MORE COMMONLY USED

Question 186

What is Phaeochromocytoma?

Answer 186

• tumours of the adrenal MEDULLA which secrete catecholamines (adrenaline and noradrenaline)

Question 187

What are the effects of phaeochromocytoma?

Answer 187

• adrenaline has a rapid effect -> from time to time (more likely after trauma) the tumour will release a lot of adrenaline -> massive rise in bp (e.g. 300/150) -> to the sort of level that cause sudden strokes or MIs - MAIN EFFECT
• is a sudden onset of panic, you feel anxious, tachycardia and severe hypertension

Question 188

What are the clinical features of phaeochromocytoma?

Answer 188

• hypertension in a young person
• episodic severe hypertension (after abdominal exam - press on adrenal causing release of NA and A)
• more common in certain inherited conditions

Question 189

What makes the diagnoses of phaeochromocytoma a medical emergency?

Answer 189

• severe hypertension -> MI or Stroke
• high adrenaline -> Ventricular Fibrillation (VF) -> Sudden Cardiac Death

Question 190

What is the treatment/management of phaeochromocytoma?

Answer 190

• first is alpha blockade - patients may need intravenous fluid as alpha blockade commences
• second is beta blockade added to prevent tachycardia
• once adrenalines effects have been nullified surgery to remove the gland

Question 191

State some key statistics about the positioning and status of phaeochromocytoma tumours.

Answer 191

• 10% extra-adrenal (sympathetic chain) and 90% inside the adrenal
• 10% are malignant
• 10%are bilateral making 90% are curable by operation
• phaeochromocytoma is EXTREMELY RARE

Question 192

What hormones are present in the hypothalamo-pituitary-adrenal axis?

Answer 192

• CRH = corticotrophin releasing hormone
• ACTH = adrenocorticotrophic hormone (corticotrophin)
• aldosternone, cortisol, adrenaline and noradrenaline

Question 193

Where does all steroid comes from?

Answer 193

• cholesterol

Question 194

What is made in the zona glomerulosa?

Answer 194

• aldosterone

Question 195

What is made in the zona fasciculata?

Answer 195

• cortisol

Question 196

What is produced in the adrenal medulla?

Answer 196

• adrenaline and noradrenaline

Question 197

Describe the pathway that leads to aldosterone and cortisol production?

Answer 197

• after each number adding hyrdoxylase gives you the enzyme

Question 198

Globally, what is the most common cause of adrenal failure?

Answer 198

• TB Addison’s Disease

Question 199

In the UK, what is the most common cause of adrenocortical failure?

Answer 199

• Autoimmune Addison’s Disease

Question 200

Barring Addison’s Disease, name a cause for adrenocortical failure?

Answer 200

• congenital adrenal hyperplasia -> caused by enzyme deficiency so hormones aren’t made properly

Question 201

What are the consequences/symptoms of adrenal failure?

Answer 201

• fall in blood pressure -> no aldosterone
• loss of salt in urine -> unable to retain salt because of the lack of aldosterone -> salt loss in urine and potassium plasma
• fall in glucose -> due to glucocorticoid deficiency
• high ACTH (no -ve feedback) resulting in increased pigmentation with some vitilgo-> ACTH is cleaved from POMC -> the remaining part is MSH (melanocyte stimulating hormone)

o eventual death due to severe hypotension -> if this happens suddenly it is called an Addisonian Crisis

Question 202

What tests can be done to diagnose Addison’s?

Answer 202

• low 9am cortisol and high ACTH at any time in blood tests
• unresponsive/reduced amount of cortisol produced to a big dose of synthetic ACTH (synacthen)

Question 203

What is the results of a typical Addison’s patient to tests for Addison’s?

Answer 203

• 9am cortisol = 100 (normal = 270-900)
• 9.30, post IM injection of synacthen = 150 (normal = >600)

Question 204

What is the commonest cause of congenital adrenal hyperplasia?

Answer 204

• 21-hydroxylase deficiency

Question 205

How long will a baby with complete 21-hydroxylase deficiency survive without treatment?

Answer 205

• less than 24 hours

Question 206

What happens to the hormone balance in someone with complete 21-hydroxylase deficiency?

Answer 206

• no aldosterone and cortisol
• lots of sex steroids, particularly testosterone, because all pro-hormones are channelled down that pathway

Question 207

What is the age of presentation of congenital adrenal hyperplasia?

Answer 207

• as a neonate with salt losing Addisonian crisis - floppy baby
• before birth if a previous child had suffers from CAH

Question 208

What is an important feature to notice immediately after birth due to congenital adrenal hyperplasia?

Answer 208

• ambiguous genitalia in girls due to the excess testosterone -> virilisation - fusion of labia into a scrotum like structure
• if this is noticed they are keep in hospital to prevent arrest
• can be prevented by giving the mother some steroid in pregnancy if there is a known risk of 21-hydroxylase deficiency

Question 209

What occurs in partial 21-hydrxylase deficiency?

Answer 209

• low levels of cortisol and aldosterone but crucial enough to survive so they present at any age
• excess sex steroid -> often misdiagnosed as PCOS or other similar disease

Question 210

What are the main problems with partial 21-hydroxylase deficiency?

Answer 210

• boys = precocious/early false puberty
• girls = hirsutism, virilisation and acne

Question 211

What are the consequences of 11-beta-hydroxylase deficiency?

Answer 211

• acts as an aldosterone receptor agonist so behaves as if there is too much aldosterone -> hypertension and hypokalaemia
• sex hormones are also in excess so virilisation, hirsutism etc
• lack of cortisol and aldosterone -> aldosterone issues dont present due to reasons above

Question 212

What happens to the hormone balance in 17-hydroxylase deficiency?

Answer 212

• low cortisol and sex steroids
• 11-deoxycorticosterone and aldosterone are high

Question 213

What are the presentations of 17-hydroxylase deficiency?

Answer 213

• never go through puberty -> usually present around pubertal age
• hypertension without addisonian crisis because they have aldosterone
• borderline hypoglycaemia
• lots of infections because you need cortisol to cope with the stress of infection

Question 214

What is made in the zona reticularis?

Answer 214

• androgens and oestrogens

Question 215

Which adrenal hormone is not under ACTH control? State what controls its release.

Answer 215

• aldosterone -> release is stimulated by renin in the renin-angiotensin system
• hyperkalaemia, hyponatraemia, drop in renal blood flow and beta-1 adrenoceptor stimulation

Question 216

Compare glucocorticoid and minerocorticoid receptors?

Answer 216

• GR = wide distribution, selective for glucocorticoids, low affinity for cortisol
• MR = descrete distribution to the kidney, don’t destingiush between aldosterone and cortisol, high affinity to cortisol

Question 217

How come cortisol doesn’t usually activate MR receptors despite being able to do so?

Answer 217

• 11b-hydroxysteroid dehydrogenase deactivates cortiol into cortisone

Question 218

Why is hypokalaemia seen in Cushing’s Syndrome?

Answer 218

• the 11b-hydroxysteroid dehydrogenase system becomes overwhelmed so potassium is excreted due to activation of MRs
• the same mechanism cause hypertension by absorbing sodiuma nd water

Question 219

Describe the structure of hydrocortisone.

Answer 219

• cortisol and hydrocortisone have the same structure, it’s just that cortisol is endogenous and hydrocortisone is synthetic - can be used to treat Addison’s disease/crisis
• at high doses it can cause MR activation because it overwhelms the 11b-hydroxysteroid dehydrogenase system just like cortisol

Question 220

Describe prednisolone.

Answer 220

• a glucocortcoid with weak mineralocortioid activity
• tends to be used as an immunosuprressive

Question 221

Describe dexamethasone.

Answer 221

• very POTENT glucocorticoid -> used clinically for things like brain metastases where there is a lot of oedema -> used as an acute anti-oedema agent
• NO mineralocorticoid effect

Question 222

Describe fludrocortisone.

Answer 222

• an aldosterone analogue -> used as an aldosterone substitute in Addison’s disease
• NOT a glucocorticoid

-

Question 223

What is the method of administration for corticosteroids?

Answer 223

• all can be given orally
• in acute situations they are given parenterally (IV or IM)

Question 224

Compare the biological activity of the corticosteroids.

Answer 224

• binding to plasma proteins (corticosteroid binding globulin and albumin)
• hydrocortisone is about 90-95% bound
• prednisolone is less bound and dexamethasone and fludrocortisone are even less bound
• fludrocortisone is only bound to albumin

Question 225

State and explain the difference in treatment between patients with primary and secondary adrenocortical failure.

Answer 225

• primary = hydrocortisone and fludrocortisone
• secondary = hydrocortisone -> is a porblem with the pituitary and not adrenal so aldosterone isn’t affect as renin-angiotensin system is fine

Question 226

What is the treatment for Addisonian crisis?

Answer 226

• FIRSTLY = 0.9% NaCl for rehydration
• then high dose of hydrocortisone (IV or IM)
• 5% dextrose if hypoglycaemic

Question 227

How is congenital adrenal hyperplasia treated?

Answer 227

• cortisol replacement -> hydrocortisone or dexamethasone
• replace aldosterone -> fludrocortisone
• suppress ACTH -> reduced adrenal androgen production

Question 228

How is therapy for CAH monitored?

Answer 228

o17a-hydroxyprogesterone levels

o clinical assessments of patients complaintst:

• cushingoid - glucocorticoid dose too HIGH
• hirsuitism/acne - glucocorticoid dose too LOW (so ACTH is high)

Question 229

Name some times in which hydrocortisone/cortisol mimicing drugs dosage should be increased.

Answer 229

• when the patient is vunerable to stress
• minor illness = x2 normal dose
• surgery = IV or Im hydrocortisone in the build up to the generla anaesthetic

Question 230

Answer 230

• C

Question 231

Describe the hypothalamo-pituitary-testes axis.

Answer 231

Question 232

What are the 3 phases of the menstrual cycle?

Answer 232

• Follicular Phase
• Ovulation
• Luteal Phase

Question 233

Describe the hypothalamo-pituitary-ovarian axis in the follicular phase.

Answer 233

• LH stimulates production of oestradiol and progesterone in the ovaries
• FSH stimulates follicular development and inhibin
• by around day 10, the leading follicle develops into a Graffian Follicle
• oestrogen initially has negatively inhibits LH and FSH secretion
• so in the follicular phase their HPG axis is basically the same as men

Question 234

Describe the hypothalamo-pituitary-ovarian axis in the luteal phase.

Answer 234

• once the oestrogen levels reach a certain point, it switches from negative feedback to positive feedback
• it increases GnRH release and increases LH sensitivity to GnRH -> leads to a mid-cycle LH surge -> triggers ovulation from the leading follicle
• if implantation does NOT occur, the endometrium is shed (menstruation), but if implantation does occur you have pregnancy

Question 235

Define infertility in the clinical environment.

Answer 235

• inability to conceive after 1 year of regular uprotected sex

Question 236

How common is infertility and in what percentage of causes are the abnormalities in males and females?

Answer 236

• 1/6 couples are affected
• males = 30% - females = 45% - unknown = 25%

Question 237

What happens to the hormone balance in someone with primary gonadal failure?

Answer 237

• high GnRH
• high LH and FSH
• low testosterone/oestradiol

Question 238

What happens to the hormone balance in someone with secondary gonadal failure?

Answer 238

• low FSH and LH
• low testosterone/oestradiol
• could also be a low GnRH if it hypothalamic

Question 239

State 5 clinical features of male hypogonadism.

Answer 239

· Loss of libido

· Impotence

· Small testes

· Decreased muscle bulk

· Osteoporosis (testosterone has an anabolic action in the bone)

Question 240

What are the causes of male hypogonadism?

Answer 240

• hypothalamic-pituitary disease
• primary gonadal disease
• hyperprolactinaemia
• adrogen receptor deficiency

Question 241

Name some hypothalamic-pituitary diseases which lead to infertility.

Answer 241

• Hypopituitarism -> pituitary is not working properly -> secondary gonadal failure
• Kallman’s Syndrome (anosmia (lack of smell) and low GnRH) -> GnRH neurones migrate forwards with olfactory neurones hence link
• Illness/underweight -> due to low levels of leptin -> body knows you’re underweight -> it’s not an appropriate time to reproduce)

Question 242

State some causes of primary gonadal disease.

Answer 242

• congenital: Klinefelter’s syndrome
• acquired: testicular torsion, chemotherapy

Question 243

What tests can be ran to investigate male hypogonadism?

Answer 243

• LH, FSH and testosterone blood tests -> if all low then pituitary (look at an MRI)
• prolactin -> check for hyperprolactinaemia
• sperm count and motility
• chromosomal analysis -> Klinefelter’s (XXY)

Question 244

Compare the terms azoospermia and oligospermia.

Answer 244

• Azoospermia = absence of sperm in ejaculate
• Oligospermia = reduced numbers of sperm in ejaculate

Question 245

What treatments are available for male hypogonadism?

Answer 245

o replacement testosterone for all patients -> increase their muscle bulk and protect against osteoporosis

o for fertility (if hypothalamic/pituitary disease) -> subcutaneous gonadotrophins (LH and FSH) to stimulate testosterone release (don’t want to switch off pituitary functions so can’t give straight testosterone because that will have negative feedback) -> induces spermatogenesis

o dopamine agonist for hyperprolactinaemia -> main hypothalamic influence over prolactin release and it has a negative effect on prolactin release

Question 246

What are the endogenous sites of androgen production?

Answer 246

· Interstitial Leydig cells of the testes

· Adrenal cortex (males and females)

· Ovaries

· Placenta

· Tumours

Question 247

What are the main actions of testosterone?

Answer 247

· Development of the male genital tract

· Maintains fertility in adulthood

· Control of secondary sexual characteristics

· Anabolic effects (muscle, bone)

Question 248

How does testosterone circulate in the body?

Answer 248

o 98% is protein bound

Question 249

What happens to testosterone in certain tissues?

Answer 249

o in different tissues you get testosterone being converted to other things

• 5 a-reductase converts testosterone to dihydrotestosterone (DHT), in muscle and bone, which then acts on androgen receptors (AR)
• aromatase, found in brain and adipose tissue, can convert testosterone to 17b-Oestradiol (E2) which acts via the oestrogen receptors (ER) -> mechanism which may explain obesity causing infertility
• DHT and E2 receptors act via nuclear receptors -> are intracellular -> have to go into the nucleus to have an effect

Question 250

Name 4 clinical uses of testosterone.

Answer 250

o testosterone in adulthood will increase:

• lean body mass
• muscle size and strength
• bone formation and bone mass (in young men)
• libido and potency

o it will NOT restore fertility -> requires treatment with gonadotrophins to restore normal spermatogenesis

Question 251

What are the 3 categories of infertility in women?

Answer 251

· Amenorrhoea

· Polycystic Ovarian Syndrome (PCOS)

· Hyperprolactinaemia

Question 252

Define primary amenorrhoea.

Answer 252

• failure to develop spontaneous menstruation by the age of 16 years -> likely to be an abnormal puberty -> could be congenital

Question 253

Define secondary amenorrhoea.

Answer 253

• absence of menstruation for 3 months in a woman who has previously had cycles

Question 254

Define oligomenorrhoea.

Answer 254

• irregularly long cycles

Question 255

What are the main causes of amenorrhoea?

Answer 255

o PREGNANCY

o Lactation -> progesterone suppresses menstration

o Ovarian Failure:

• premature ovarian insufficiency (early menopause)
• ovariectomy
• chemotherapy
• ovarian dysgenesis (Turner’s Syndrome (45 X)) - lacking an X chromosome

Question 256

What are the features of Turner’s Syndrome?

Answer 256

• thick neck tissue with further swelling (cystic hygroma)
• heart and kidney issues
• short stature
• cubitus valgus (where the forearm is angled away from the body to a greater degree than normal when fully extended)
• gonadal dysgenesis (defective development)

Question 257

Name some of the rarer causes of amenorrhoea.

Answer 257

o Hypothalamic/pituitary disease

o Kallmann’s syndrome

o Low BMI

o Post-pill amenorrhoea (downregulates the hypothalamus and pituitary) -> if you use the pill for a long time then periods don’t come back for around 12 months after cessation of use -> why it is advised that you stop using the pill every 4 years

o Hyperprolactinaemia

o Androgen excess: gonadal tumour

Question 258

What tests can be conducted to diagnose/find the cause of amenorrhoea?

Answer 258

• Pregnancy Test
• LH, FSH and Oestradiol -> hard due to changes in natural cycle
• Day 21 Progesterone -> in the second half of the menstrual cycle the progesterone rises over a prolonged period of time -> there should be a rise in progesterone around this time to show that they are ovulating
• Prolactin -> hyperprolactinaemia
• Thyroid function test -> hyper- and hypothyroidism can cause problems with periods
• Androgen blood test (testosterone, androstenedione, DHEAS)
• Chromosomal Analysis (Turner’s)
• Ultrasound Scan Ovaries/Uterus

Question 259

Describe the treatment for amenorrhoea.

Answer 259

• Treat the cause (e.g. low weight)
• Primary Ovarian Failure = Hormone Replacement Therapy
• Hypothalamic/pituitary disease -> HRT for oestrogen replacement but for FERTILITY = gonadotrophins (LH and FSH) -> part of IVF treatment

Question 260

What female infertility is associated with an increased risk of CVD and diabetes?

Answer 260

• PCOS

Question 261

What is the criteria for PCOS diagnosis?

Answer 261

o Need TWO of the following:

• polycystic ovaries on the ultrasound scan
• oligoovulation/anovulation
• clinical/biochemical androgen excess

Question 262

What are the clinical features of PCOS?

Answer 262

· Hirsutism – male pattern hair growth

· Menstrual cycle disturbance

· Increased BMI makes the symptoms worse

Question 263

What is the treatment for PCOS?

Answer 263

• Metformin -> insulin sensitiser used in type II diabetes
• Clomiphene -> anti-oestrogenic effect in the hypothalamo-pituitary axis -> binds to oestrogen receptors in the hypothalamus thereby blocking the negative feedback -> results in an increase in GnRH and gonadotrophin secretion -> kick-starts the HPG axis for short periods for fertility
• Gonadotrophin therapy as part of IVF treatment

Question 264

Describe the control of prolactin secretion.

Answer 264

• dopamine has a negative effect on prolactin release, is the main hypothalamic hormone controlling prolactin release
• TRH has a mild stimulatory effect
• prolactin stimulates the production of milk in lactating women
• if it becomes dysregulated it will switch off gonadal function via LH actions on the ovaries and testes -> natural contraceptive just after birth
• also reduces GnRH pulsatility so that it is released basally all the time rather than in regular pulses

Question 265

What are the cause of hyperprolactinaemia, highlight the main ones?

Answer 265

• DOPAMINE ANTAGONISTS -> anti-emetics (metoclopramide) or anti-psychotics (phenothiazines) **
• PROLACTINOMA **
• COMPRESSION ON THE STALK DUE TO A PITUITARY ADENOMA **
• hypothyroidism
• PCOS
• eestrogens (oral contraceptive pill), pregnancy, lactation
• idiopathic

Question 266

What are the clinical features of hyperprolactinaemia?

Answer 266

• galactorrhoea (discharge unrelated to breastfeeding)
• reduced GnRH secretion?LH action leads to hypogonadism
• if its due to prolactinoma -> headaches and visual field defects

Question 267

Describe the treatment for hyperprolactinaemia.

Answer 267

o Treat the cause - e.g. stop the drugs if that’s what’s causing it if it is possible (e.g. anti-psychotics can’t always be stopped, it’s a balancing act)

o Dopamine Agonists -> bromocriptine or cabergoline -> also causes a decrease in the size of the tumour if it is being caused by a prolactinoma

o Pituitary surgery but is rarely needed (because drugs usually work)

Question 268

Answer 268

• 3

Question 269

Answer 269

• 1 -> prolactin switches off GnRH pulsitivity so FSH and LH would be low as well as oestradiol

Question 270

Define menopause.

Answer 270

• permanent cessation of menstraution due to a lack of ovarian follicular activity

Question 271

Define climacteric.

Answer 271

• the periiod of transition in which menstraution become irregular

Question 272

What is the average age of menopause?

Answer 272

• 51 -> (45-55)
• before 40 is deemed to be premature

Question 273

State the symptoms of the menopause.

Answer 273

• hot flushes
• urogenital atrophy and dyspareunia (difficult or painful sexual intercourse) -> due to vaginal atrophy
• sleep disturbance
• depression
• decreased libido
• joint pain

o symptoms usually diminish/disappear with time

Question 274

What are the hormonal chages that occur during meopause?

Answer 274

• levels of oestradiol and inhibin B fall due to follicular atresia -> less negative feedback so gonadotrophin levels rise
• a 55-year old women is expected to have high LH and FSH

Question 275

What are the two major complication of the menopause?

Answer 275

o osteoporosis - caused by oestrogen deficiency -> oestrogen is an anabolic hormone -> in osteoporosis there is less matrix and that predisposes these patients with oestrogen deficiency to osteoporotic fractures

• 10-fold increase in the risk of fracture in a post-menopausal woman

o Cardiovascular Disease - oestrogen is protective against CVD before menopause

• women have the same risk as men after the age of 70

Question 276

What is given as HRT therapy?

Answer 276

• usually oestrogen + progesterone -> can’t just give oestrogen as is increases the risk of endometrial carcinoma (progesterone inhibits the proliferation)
• if the patient has had a hysterectomy then oestrogen only can be given

Question 277

How can oestrogen be prepared?

Answer 277

o Oral oestradiol

o Oral conjugated equine oestrogen

o Transdermal (patch) oestradiol

o Intravaginal

Question 278

How often is HRT given?

Answer 278

• Cyclical -> oestradiol every day and for the last 12-14 days you take some progesterone
• Continuous Combined -> a little bit of oestrogen and a little bit of progesterone every day

Question 279

When is HRT prescribed?

Answer 279

• for disabling hot flushes

Question 280

How well is oestrogen absorbed?

Answer 280

• very well absorbed but it has a low bioavailabitility due to extensive first pass metabolism

Question 281

How is the issue of oestrogens low bioavailability overcome?

Answer 281

• oestrone sulphate (conjugated oestrogen)
• ethinyl oestradiol: semi-synthetic oestrogen -> form that’s used in oral contraceptives

o provides protection from first pass metabolism

Question 282

What are the side effects of HRT?

Answer 282

• Breast Cancer
• Venous Thromboembolism (VTE)
• Stroke
• Gallstones

o absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low but there is a relative risk

o MUST consider the circumstance of the patient e.g. family history of breast cancer

Question 283

Explain the link between HRT and coronary heart disease.

Answer 283

• there is an increased risk of CHD with HRT
• younger women had no problem, they had no increased risk but those who were in their 60s and started HRT, had an increased risk of CHD
• it is about the timing of exposure -> older patients who are started on HRT have a higher risk of CHD due to baseline disease

Back

Question 284

What are the benefits of oestrogen and how does it change with HRT?

Answer 284

• lipid profile and endothelial function however, synthetic progestins negates these beneficial effects

Question 285

Describe Tibolone.

Answer 285

• synthetic prohormone which has oestrogenic, progestogenic and weak androgenic effects
• reduces the risk of fracture
• increase the risk of STROKE (RR: 2.2) and possibly breast cancer

Question 286

Describe Raloxifene.

Answer 286

o Selective Oestrogen Receptor Modulator (SERM)

o it is tissue selective:

• bone - it has oestrogenic effects = reduces the risk of fracture
• breast and uterus - it has anti-oestrogenic effects = this reduces the risk of breast cancer

o however, raloxifene is associated with an increased risk of fatal stroke and VTE

o HRT used to be prescribed to women as a first line treatment of osteoporosis but it is NOT any more because you have other treatments like oral bisphosphonates which are not associated with a risk of breast cancer -> however, if someone has menopausal symptoms then HRT is the treatment of choice

Question 287

Describe Tamoxifen.

Answer 287

• anti-oestrogenic on breast tissue

• used to treat oestrogen-dependent breast tumours and metastatic breast cancers

Question 288

What are the causes of premature ovarian insufficiency (early menopause)?

Answer 288

• occurs to 1% of women

o Autoimmune

o Surgery

o Chemotherapy

o Radiation

Question 289

Describe the combined oral contraceptive pill?

Answer 289

• oestrogen in the oral contraceptive is often ethinyl oestradiol
• progestogen in the pill is levonorgestrel or norethisterone
• take it for 21 days and stop for 7 days

Question 290

What is the mechanism of the combined oral contraceptive

Answer 290

• suppresses the hypothalamus and pituitary (both E and P do this)
• progesterone also thickens cervical mucous (this makes it more difficult for the sperm to pass through)

Question 291

When is progesterone only contraception given?

Answer 291

• when oestrogens are contra-indicated - this is if there is a risk of THROMBOSIS -> oestrogen has pro-coagulant effects so progesterone is used instead
• less effective than the combined contraceptive but if there are contra-indications (such as in a smoker) then the progesterone only contraceptive is the best option

Question 292

What is very important about administration of progesterone only contraception?

Answer 292

• must be taken at the same time every day due to a short half-life

Question 293

What is a long acting progesterone only contraception?

Answer 293

• mirena coil

Question 294

Name 3 emergency contraceptives.

Answer 294

• copper IUD
• levonorgestrel
• ulipristal

Question 295

What is the mechanism of the copper IUD?

Answer 295

• affects sperm viability and function -> inhibits fetilisation

Question 296

When is copper IUD the prefferred option?

Answer 296

• in the overweight as its effectiveness isn’t compromised

Question 297

What is levonorgestrel?

Answer 297

• a high progesterone dose

Question 298

How does ulipristal function?

Answer 298

o Anti-progestin activity

o Delay ovulation by as much as 5 days

o Impairs implantation

Question 299

How long after coiteus can emergency contraception be taken?

Answer 299

• copper IUD = 5-7 days
• levonorgestrel = 72 hours
• ulipristal = 5 days

Question 300

How many sperm reach the ovum?

Answer 300

• 1 in a million manages the journey of 100,000 times the length of a sperm

Question 301

How is oestrogen made in men?

Answer 301

• testosterone is converted to oestrogen by aromatase

Question 302

How is most tubular fluid reabsorbed?

Answer 302

• within the rete testis and early epididymis under control of oestrogen

Question 303

What elements of the epididymal fluid is under the influence of androgens?

Answer 303

• energy for the journey
• coating of the surface of the spermatozoon

Question 304

Which location within the male reproductive tract has the highest concentration of spermatoza?

Answer 304

• vas deferens concentration of spermatozoa is higher than later on in the reproductive tract once other fluids have been added

Question 305

Where is cut when performing a vasectomy?

Answer 305

• vas deferens towards the bottom end

Question 306

How many spermatoza are in the average ejaculate?

Answer 306

• 15-120x10⁶/ml (average has 2-5 ml of seminal fluid

Question 307

What are the elements of ejaculate?

Answer 307

• spermatoza
• seminal fluid
• leucocyte
• potentially viruses -> hepatitis B, HIV etc

Question 308

Where does seminal fluid come from?

Answer 308

• mainly = accessory sex glands = prostate, bulbourethral gland and the seminiferous tubules

Question 309

Where does capacitation of sperm occur?

Answer 309

• achieving fertilisation capacity takes place in the ionic and proteolytic environment of the fallopian tube

Question 310

What changes occur in the capacitation of sperm?

Answer 310

• loss of glycoprotein coat
• change in surface membrane characteristics
• develop whiplash movement of tail

Question 311

What is the capacitation of sperm dependent on?

Answer 311

• oestrogen
• calcium

Question 312

Describe the acrosome reaction.

Answer 312

• spermatozoon binds to the ZP3 glycoprotein on the zona pellucida -> once bound to ZP3, progesterone stimulates calcium influx into the spermatozoon
• results in the calcium-dependent acrosome reaction
• enables an exposed spermatozoon recognition site to bind to a second glycoprotein (ZP2) -> once ZP2 has bound, the acrosome releases its enzymes allowing penetration of the zona pellucida so that the head of the spermatozoon can enter the ovum

Back

Question 313

Where does fertilisation occur?

Answer 313

• fallopian tube

Question 314

What are the results of fertilisation?

Answer 314

o leads immediately into zonal reaction

• cortical granules release molecules which degrade the zona pellucida (including ZP2 and ZP3) -> prevents further binding of other sperm
• also calcium dependent

o explusion of the second polar body

Question 315

Describe the development of a conceptus?

Answer 315

• conceptus continues to divide as it moves down the fallopian tube to the uterus (3-4 days)
• until implantation, the developing conceptus receives its nutrients from uterine secretions
• cell division continues you will have a ball of cells with the outside cells receiving the nutrients but the inner cells will be receiving less and less nutrients
• the free-living phase will last about 9-10 days

Question 316

In what stage of the menstraul cycle does development of the conceptus occur?

Answer 316

• luteal phase -> oestrogen and progesterone will be high

Question 317

What follows the formation of a conceptus?

Answer 317

• compactation into 8-16 cell morula
• followed by blastocyst formation

Question 318

What does a blastocyst become?

Answer 318

o Inner cell mass - becomes the embryo

o Trophectoderm - becomes the chorion (which becomes the placenta)

Question 319

What assists the transfer of the blastocyst into the uterus ?

Answer 319

• increasing progesterone : oestrogen ratio in luteal phase

Question 320

What are the two stages of implantation?

Answer 320

• attachment phase -> outer trophoblast cells make contact with the uterine surface epithelium -> establises a system for getting the nutrients from the mother to all the cells within the embryo
• decidualisation phase -> deeper implantation into the underlying uterine stromal tissue occuring within a few hours

Question 321

What is the process of implantation dependent on?

Answer 321

• progesterone domination in the presence of oestrogen

Question 322

What two molecules are particularly important in the attachment phase?

Answer 322

o Leukaemia Inhibitory Factor (LIF) - from endometrial secretory glands -> stimulates attachment of blastocyst to the endometrial cells

o Interleukin-11 (IL-11) - from endometrial cells -> released into the uterine fluid

Question 323

Describe what changes occur due to decidualisation.

Answer 323

o endometrial changes due to progesterone

• glandular epithelial secretion
• glycogen accumulation in stromal cell cytoplasm
• growth of capillaries
• increased vascular permeability

Question 324

What factors are required for decidualisation?

Answer 324

• mainly IL-11
• histamine
• certain prostaglandins
• TGFb - promotes angiogenesis

Question 325

What hormonal changes occur during pregnancy?

Answer 325

• hCG (produced in the placenta) is vital for the first 6 weeks at least as its purpose is to replace LH which will be low due to high oestrogen and progesterone -> in a normal menstrual cycle, the oestrogen and progesterone levels will eventually fall and you’ll get menstruation
• to maintain the stimulation of oestrogen and progesterone, hCG is being produced by the trophoblast cells -> hCG binds to LH receptors on the corpus luteum hence replacing the effects of LH
• after about 5 weeks or so, the placenta will have taken over the production of hormones so the ovaries are no longer necessary
• oestrogen and progesterone levels increase throughout pregnancy and right until the end, progesterone remains the DOMINANT influence

Question 326

Describe oestrogen production in pregnancy.

Answer 326

• mother provides the precursors which tends to be pregnenolone which leads to progesterone -> progesterone is then going to lead to steroid production by the foetus (in the foetal adrenals)
• maternal AND foetal adrenals produce a precursor (which is an androgen) - dehydroepiandrosterone sulfate (DHEAS)
• 16a-hydroxy-DHEAS is then taken up by the placenta to produce OESTRIOL
• DHEAS is also used by the placenta to produce small amounts of oestrone and oestradiol

Question 327

What is the main oestrogen in pregnancy?

Answer 327

• oestriol
• molecule for molecule, weaker than oestradiol but it is produced in large amounts during pregnancy
• source of oestriol is placenta

Question 328

Describe a hormonal test that can be done to check the general health of a feotus.

Answer 328

• looking at the ratio of oestriol : oestradiol and oestrone or the ratio of oestriol : total oestrogens and you see a change

Question 329

What changes in maternal hormones occur during pregnancy?

Answer 329

• hGH (human growth hormone) decreases as the placental hGH-variant increases towards term
• kiss peptin also increases 1000s of times to act as a natural contraception by down regulating the axis

Question 330

Describe the endocrine control of lactation.

Answer 330

• suckling stimulates neural pathways to the hypothalamus and on to the pituitary
• the neurohypophysis secretes oxytocin and the adenohypophysis secretes prolactin
• prolactin = promotion of milk synthesis
• oxytocin = promotoin of milk ejection

Question 331

Describe the hormonal control of parturition.

Answer 331

• parturition is all about contraction of actin and myosin filaments which requires CALCIUM -> to initiate contraction you need to increase the intracellular calcium concentration
• oestrogen stimulates production of prostaglandins by the endometrial cells -> prostaglandins stimulates the production and release of calcium into the cytoplasm from intracellular stores

o Main Point: OESTROGEN tends to INCREASE the chance of contraction

• progesterone has the OPPOSITE EFFECT TO OESTROGEN -> inhibits prostaglandin synthesis and oestrogen receptors -> keeps the effects of oestrogen under control
• once the foetus reaches a certain size, the production of steroids is switched from the production of progesterone to the production of oestrogen (oestrogen dominates)
• at parturition, oxytocin will be released which will bind to its receptor and open calcium channels allowing calcium ions to move in from outside

Back

Question 332

Summarise calcium homeostasis.

Answer 332

o interactive system between PTH and vitamin D

o as serum calcium falls, you get an increase in PTH (parathyroid hormone)

• PTH mobilises calcium from bone to increase plasma calcium
• direct effect on the kidneys to increase reabsorption of calcium in the kidneys
• stimulates an increase in plasma calcium indirectly via the activation of vitamin D (calcidiol from liver to calcitriol/active vitamin D)

o calcitriol then has two main effects to increase serum calcium:

• increased calcium absorption in the intestines
• increased calcium mobilisation in bone

Question 333

What is the mechanism of action of calcitriol?

Answer 333

• act on oesteoblasts to cause them to release RANKL -> RANKL activates osteoclasts

Question 334

Name two hormones that inhibit Na⁺ and PO₄^3- reabsorption in the kidneys.

Answer 334

• PTH
• FGF23

Question 335

What are the actions of FGF23?

Answer 335

• inhibit Na⁺ and PO₄^3- transporter in the kidneys
• negative feedback on calcitriol -> less PO₄^3- reabsorption from the gut

Question 336

Which enzyme activates 25 OH-D₃ into calcitriol (1,25 (OH)₂D₃)?

Answer 336

• renal 1 alpha-hydroxylase
• stimualted by PTH

Question 337

What are the actions of calcitriol?

Answer 337

• Ca²⁺ absorption in the gut
• Ca²⁺ maintenance in the bone
• increased renal Ca²⁺ reasbsorption
• ve feedback on PTH

Question 338

Name some causes of Vitamin D deficiency.

Answer 338

• diet
• lack of sunlight
• gastrointestinal malabsorptive states -> liver disease, coeliac, IBD
• renal failure
• receptor defects (autosomal recessive)

Question 339

What are the resulting symptoms of Vitamin D deficiency?

Answer 339

o Softening of bone - you are unable to bear the weight of the rest of the body so you get the characteristic bowing of the legs

o Bone deformities

o Bone pain

o Severe proximal myopathy

Question 340

What are the signs and symptoms of hypocalcaemia?

Answer 340

• convulsions
• arrhythmias
• tetany
• parasthesia (hands, mouth, feet, lips)

o CATs go Numb

Question 341

What is the general trend caused by hypocalcaemia?

Answer 341

• sensitises excitable tissues -> muscle cramps/tetany, tingling

Question 342

What two signs are checked for if hypocalcaemia is suspected?

Answer 342

• Chvostek’s
• Trousseau’s

Question 343

What is Chvostek’s sign?

Answer 343

• tap the facial nerve just below the zygomatic arch
• POSITIVE response = twitching of the facial muscles
• indicates neuromuscular irritability due to hypocalcaemia

Question 344

What is Trousseau’s sign?

Answer 344

• inflation of the blood pressure cuff for several minutes induces carpopedal spasm (aka neuromuscular irritability due to hypocalcaemia)
• very painful so isn’t done for long

Question 345

Name some causes of hypocalcaemia.

Answer 345

• Vitamin D deficiency
• hypoparathyroidism (low PTH) -> surgical, auto-immune, magnesium deficiency
• PTH resistance (e.g. pseudohypoparathyroidism)
• renal failure -> impaired 1a-hydroxylase -> decreased production of calcitriol

Question 346

What are the signs and symptoms of hypercalcaemia?

Answer 346

• stones - renal effects -> polyuria + thirst can go onto cause nephrocalcinosis (deposition of calcium in the kidneys), renal colic, chronic renal failure
• abdominal moans - GI effects -> anorexia, nausea, dyspepsia, constipation, pancreatitis
• psychic groans - CNS effects -> fatigue, depression, impaired concentration, altered mentation, coma (the last three only tend to occur when calcium concentration is > 3 mmol/L)

o Stones, Moans and Groans

Question 347

State some causes of hypercalcaemia.

Answer 347

The first two causes are responsible for 90% of cases of hypercalcaemia

• PRIMARY HYPERPARATHYROIDISM -> e.g. due to a parathyroid adenoma which becomes too busy and produces excessive amounts of PTH
• MALIGNANCY - TUMOURS/METASTASES -> bone metastases where increased bone turnover causes an increase in serum calcium plus tumours can also produce PTH-related peptide
• conditions with a high bone turnover -> hyperthyroidism, Paget’s Disease
• Vitamin D excess (rare)

Question 348

What is the diagnostic approach to hypercalcaemia?

Answer 348

• normally, there is negative feedback on PTH by calcium so if serum calcium rises, PTH will decrease
• in primary hyperparathyroidism a parathyroid adenoma secretes PTH autonomously and is not responding to negative feedback

o Calcium - HIGH

o PTH - HIGH (unsuppressed)

• malignancy is a nother major cause but serum results show low PTH with high calcium -> check for bony metastases

Question 349

What is Vitamin D deficiency reffered to as?

Answer 349

o In children = Rickets

o In adults = Osteomalacia

Question 350

What diagnostic results would be found in the serum of a patient with Vitamin D deficiency?

Answer 350

• plasma 25-hydroxycholecalciferol = usually LOW
• plasma calcium = LOW
• PTH = HIGH -> secondary hyperparathyroidism that can make plasma calcium appear normal
• plasma phosphate = LOW

Question 351

What is the treatment for Vitamin D deficiency?

Answer 351

o In patients with normal renal function -> 25-hydroxy vitamin D (inactive) - either as ergocalciferol (D2) or cholecalciferol (D3)

• patient can convert this to calcitriol via 1a hydroxylase

o In patients with renal failure -> active Vitamin D (alpacalcidol)

• don’t have their own 1a hydroxylase activity, so they can’t activate 25-hydroxy vitamin D preparations

Question 352

What are causes of Vitamin D excess?

Answer 352

o excessive treatment with active metabolites of vitamin D -> only due to the potency of alfacalidol -> lots and lots of Vitamin D is required to be intoxicating

o Granulomatous Disease - e.g. sarcoidosis, leprosy and tuberculosis

• macrophages in the granuloma tissue can convert 25-hydroxycholecalciferol to the active metabolite 1,25-dihydroxycholecalciferol

Question 353

Define oesteoblast.

Answer 353

• synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)

Question 354

Define osteoclast.

Answer 354

• release lysosomal enzymes which breakdown bone (bone resorption)

Question 355

What is RANK ligand?

Answer 355

• an important molecule that activates osteoclasts from precursor form -> more mature osteoclasts = more bone resorption

Question 356

What is the mechanism of RANKL?

Answer 356

• RANKL expressed on osteoblast surface
• RANKL binds to RANK-R to stimulate osteoclast formation and activity
• osteoblasts express receptors for PTH and calcitriol -> regulate balance between bone formation & resorption

Question 357

Describe bone structure.

Answer 357

• cortical (hard) bone -> outer area
• trabecular (spongy or trabecular) bone -> inner area

o both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong

Question 358

What is meant by woven bone?

Answer 358

• bone with disorganised collagen fibrils -> far weaker than healthy bone

Question 359

What is the general problem on bones caused by Vitamin D deficiency?

Answer 359

• inadequate mineralisation of newly formed bone matrix (osteoid) -> bone remains newly formed and therefore soft

Question 360

How does rickets affect bones?

Answer 360

• CHILDREN

o affects cartilage of epiphysial growth plates and bone

o skeletal abnormalities (bowed legs) and pain, growth retardation, increased fracture risk

Question 361

How does osteomalacia affect bones?

Answer 361

• ADULTS

o after epiphyseal closure

o skeletal pain, increased fracture risk, proximal myopathy

Question 362

Describe the kind of fractures that patients who are Vitamin D deficient suffer from.

Answer 362

• stress fractures -> normal stresses on abnormal bone cause insufficiency fractures, particularly in Looser Zones -> these include the pelvis and tibia which leads to a Wide Waddling gait

Question 363

What are the effects of renal failure on bone disease?

Answer 363

• decreased renal function = decrease in the production of calcitriol and phosphate excretion so plasma phosphate increases
• the decrease in calcitriol production will cause a decrease in calcium absorption from the intestines while phosphate plasma concentration rises both leading to hypocalcaemia
• hypocalcaemia will stimulate PTH release -> PTH will break down bone matrix in order to try and restore the blood calcium concentration to the normal level -> hypocalcaemia decreases bone mineralisation
• combination of the increased bone resorption and decreased bone mineralisation will lead to osteitis fibrosa cystica
• imbalance between calcium and phosphate you can get some of it forming the main salts which can be deposited in extra-skeletal tissue causing vascular calcification

Question 364

What are Brown Tumours?

Answer 364

• radiolucent bone lesions due to osteoclastic bone resorption due to high PTH -> very suspectible to fractures
• feature of osteitis fibrosa cystica

Question 365

What is the treatment for osteitis fibrosa cystica?

Answer 365

• hyperphosphataemia -> low phosphate diet and phosphate binders to reduce GI phosphate absorption
• alphacalcidol -> e.g. calcitriol analogues
• parathyroidectomy in tertiary hyperparathyroidism

Question 366

Define osteoporosis - include the clinical cut off point?

Answer 366

• a condition of reduced bone mass (fewer trabeculae) and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma
• clinically having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average value for young healthy adults

Question 367

How is bone mineral density measured?

Answer 367

• in a DEXA -> dual energy x-ray absorptiometry
• measures in femoral neck and lumbar spine

Question 368

Name some conditions that predispose you to osteoporosis.

Answer 368

o Post-menopausal Oestrogen Deficiency

o Age-related deficiency in bone homeostasis (men and women)

o Hypogonadism in young men and women

o Endocrine conditions -> cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism

o Iatrogenic -> prolonged use of glucocorticoids, heparin

Question 369

What treatment options are available to patients suffering form osteoporosis?

Answer 369

• Oestrogen (HRT)/Selective Oestrogen Receptor Modulators
• Bisphosphonates
• Denusomab
• Teriparatide

Question 370

How does oestrogen work to treat osteoporosis in post-menopausal women?

Answer 370

• anti-resoptive effect on bone -> prevents bone loss

Question 371

Why is everyone post-menopausal women not given HRT as a preventative measure against osteoporosis?

Answer 371

o increased risk of breast cancer

o venous thromboembolism

o women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer

Question 372

Why can selective oestrogen receptor modulators?

Answer 372

o tissue-selective ER ANTAGONISTS/anti-oestrogens -> e.g. TAMOXIFEN

• has oestrogenic activity in the bone -> however, it has oestrogenic effects on the endometrium which limits its use in osteoporosis
• tissue-selective ER AGONISTS -> e.g. RALOXIFENE
• has selectivity oestrogenic activity in bone and anti-oestrogenic activity in breast and uterus
• isn’t as widely used due to risk of venous thromboembolism and stroke

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Question 373

What is the main first-line treatment for osteoporosis?

Answer 373

• bisphosphonates

Question 374

What is the mechanism of bisphosphonates in osteoporosis treatment?

Answer 374

• binds avidly to hydroxyapatite and is ingested by osteoclasts -> impairs the ability of osteoclasts to resorb bone and decreases maturation of osteoclasts from their precursors
• possibly promotes osteoclast apoptosis

o NET RESULT = REDUCED BONE TURNOVER

Question 375

What are the clinical uses of bisphosphonates?

Answer 375

o osteoporosis - first line treatment

o malignancy -> particularly helpful when associated to hypercalcaemia or to reduced bone pain from metastases

o paget’s disease -> reduces bony pain

o severe hypercalcaemic emergency -> after IV saline to REHYDRATE

Question 376

What are the side effects of bisphophonates?

Answer 376

• oesphagitis if given orally -> may require switch from oral to IV preparations
• flu-like symptoms -> often this is limited to the first dose
• osteonecrosis of the jaw -> greatest risk in cancer patients receiving IV bisphosphonates
• atypical fractures -> might reflect over-suppression of bone remodelling in prolonged bisphosphonate use

Question 377

What is the mechanism of denosumab?

Answer 377

• is a human monoclonal antibody
• binds to RANKL and inhibits osteoclast formation and activity -> inhibits osteoclast-mediated bone resorption

Question 378

How is denosumab administrated?

Answer 378

• subcutaneously every 6 or 12 months

Question 379

What is second-line treatment for osteoporosis?

Answer 379

• denosumab

Question 380

How does teriparatide work as an osteoporosis treatment?

Answer 380

• is a recombinant PTH (of 34 AA)
• increases bone formation and resorption but FORMATION OUTWEIGHS RESORPTION

Question 381

Define Paget’s Disease.

Answer 381

• very active (increased), localised but disorganised bone metabolism - usually slowly progressive

Question 382

Describe what occurs in Paget’s Disease.

Answer 382

• excessive bone resorption occurs due to osteoclastic overactivity -> this is followed by compensatory increase in bone formation (osteoblasts)
• causes new bone formation = WOVEN bone -> structurally disorganised and mechanically weaker than normal adult lamellar bone -> leads to bone frailty, hypertrophy and deformity

Question 383

What characterises Paget’s disease?

Answer 383

• abnormal, large osteoclasts in excessive numbers
• a disease of the elderlt -> only appears after 50-60
• men and women are affected equally
• common in the UK -> maybe genetic

Question 384

What bones are most commonly affected in Paget’s disease?

Answer 384

· Pelvis

· Femur

· Spine

· Skull (associated with hearing loss)

· Tibia

Question 385

What are the clinical features of Paget’s disease?

Answer 385

• bone pain
• increased vascularity -> warmth over affected bones
• deafness -> cochlear involvement
• radiculopathy -> due to nerve compression
• multiple fractures
• increased bone width

Question 386

How is Paget’s disease diagnosed?

Answer 386

o High Plasma Alkaline Phosphatase (ALP) - calcium is normal

o Radiology demonstrating variable features -> loss of trabecular (spongy/cancellous) bone, increased density, deformity

o Radioisotope (Technetium) scanning can be performed to indicate the areas of involvement

Question 387

State what treatments are available for Paget’s disease.

Answer 387

• bisphosphonates – very helpful for reducing bony pain and disease activity
• simple analgesia

Question 388

What is the arcuate nucleus?

Answer 388

• key area of the brain (within the hypothalamus) involved in food intake regulation
• is a circumventricular organ - meaning that it has an incomplete blood-brain barrier thus allowing access to peripheral hormones -> allows the arcuate nucleus to integrate peripheral and central feeding inputs

Question 389

What are the two neuronal populations of the arcuate nucleus?

Answer 389

o Stimulatory -> NPY + Agrp neurons

o Inhibitory -> POMC neurons

Question 390

What are the two key hypothalamic nuclei in appetite regulation?

Answer 390

• arcuate nucleus
• paraventricular nucleus

Question 391

Describe the melanocortin system.

Answer 391

• under normal conditions, the POMC, from arcuate nucleus, will be broken down to a-MSH which is an endogenous agonist of the MC4R (paraventricular nucleus) -> the reason why you aren’t hungry all the time is because of this a-MSH tone
• you trigger hunger by the release of Agrp from the arcuate nucleus which is an endogenous antagonist of MC4R
• when you need to eat, you increase Agrp activity, block the inhibitory signal of a-MSH and stimulates food intake

Question 392

What CNS mutation occur in humans that affects appetite?

Answer 392

• POMC and MC4 receptor
• NO NPY or Agrp

Question 393

Describe the ob/ob mouse.

Answer 393

Question 394

What is missing in the ob/ob mouse?

Answer 394

• Ob genes codes for leptin

Question 395

Where is leptin released from?

Answer 395

• white adipose tissue -> tells brain how much fat storage there is and therefore regulates eating

Question 396

Name diseases caused by mutations which lead to obesity.

Answer 396

• leptin deficiency
• Prader-Willi Syndrome

Question 397

What happens if leptin is administrated to a patient who suffers from leptin deficiency?

Answer 397

• decreased food intake
• increased thermogenesis/energy expenditure

Question 398

What is the mechanism of leptin?

Answer 398

• activates POMC and inhibits NPY/Agrp neurons

Question 399

Why can’t leptin be used as a weight control drug?

Answer 399

• most fat people have high leptin but a lot are leptin resistant

Question 400

What is proportional to insulin levels?

Answer 400

• body fat

Question 401

What are the different effects of insulin?

Answer 401

o Chronically - reduce body fat

o Acutely - if you have a big glucose load, you should suppress having more sugar

Question 402

What is the largest endocrine gland/organ in humans?

Answer 402

• the GI tract
• releases over 20 hormones

Question 403

What does CCK do?

Answer 403

• causes contraction of the gall bladder

Question 404

What is ghrelin also known as?

Answer 404

• the hunger hormone

Question 405

Where is ghrelin released from?

Answer 405

• the stomach

Question 406

Describe the structure of ghrelin.

Answer 406

• 28 amino acids long
• fatty acid is found on the 3rd amino acid

Question 407

What enzyme converts ghrelin into its active form?

Answer 407

• ghrelin O-acyltransferase (GOAT)

Question 408

How does ghrelin affect appetite?

Answer 408

• increases appetite -> stimulates Agrp/NPY neurones and inhibits POMC neurones

Question 409

Where is PYY secreted from?

Answer 409

• L-cells in the distal small intestine

Question 410

How does PYY 3-36 affect appetite?

Answer 410

• PYY 3-36 is released post-prandially and is dependent on the size of the meal -> decreases appetite -> inhibits NPY release and stimulates POMC
• has the opposie effect of ghrelin

Question 411

Where is GLP-1 secreted from?

Answer 411

• L-cells in the distal small intestine

Question 412

What is GLP-1?

Answer 412

• a gut hormone (from L-cells) coded for by the pre-propglucagon gene releazed post-prandially
• has incretin effects -> increases insulin levels
• reduces food intake

Question 413

What are the clinical uses of GLP-1 based drugs?

Answer 413

• GLP-1 based drug is important in the treatment of diabetes mellitus
• GLP-1 only stimulates glucose-induced insulin release which is good because it means that it only stimulates insulin release when it’s needed -> isn’t going to cause hypoglycaemia

Question 414

How long is GLP-1 active for?

Answer 414

• a very short amount of time -> quickly deactivated by DP-4
• drugs have to be altered so they have a longer half-life

Question 415

What can saxenda be used to treat?

Answer 415

• licensed by FDA and EMEA as a diabetes and obesity treatment

Question 416

Describe how saxenda works.

Answer 416

• long-acting GLP-1 receptor agonist (liraglutide) with a tweak structure -> it is more resistant to degradation which also stops it from being cleared from the circulation giving it a much longer half-life

Question 417

Name some co-morbidities associated with obesity.

Answer 417

Question 418

What is the thrifty gene hypothesis?

Answer 418

Question 419

What is the adaptive drift hypothesis?

Answer 419

• there used to be a normal distribution of body weight
• ones that were too light will die/not be able to reproduce
• ones that were too heavy would get eaten
• eventually, we got better at defending against predators and so excess bodyweight became a neutral change

Question 420

State some ambiguity that occurs when diagnosing diabetes.

Answer 420

• autoimmune (Type I) diabetes leading to insulin deficiency can present after decades of life -> this is Latent Autoimmune Diabetes in Adults (LADA)
• T2DM can present in childhood (linked to an increasing prevalence of childhood obesity)
• people with T2DM can present with diabetic ketoacidosis (though this is more common in T1DM)
• monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (e.g. MODY, mitochondrial diabetes)
• diabetes can present if someone has a problem with the pancreas -> e.g. pancreatitis
• diabetes can also present in endocrine diseases

Question 421

Name the three endocrine diseases which are particularly linked to diabetes?

Answer 421

o Phaeochromocytoma

o Cushing’s Syndrome

o Acromegaly

• all of these cause hyperglycaemia

Question 422

What is the current classification of diabetes?

Answer 422

Question 423

What is the pathogenesis of T1DM?

Answer 423

• various environmental and genetic triggers and regulators which come into play and lead to destruction of beta cells
• eventually, auto-antibodies are produced against beta cells -> patients will then go on to lose their first phase insulin

Question 424

What is measured as a marker for insulin?

Answer 424

• C peptide

Question 425

What does the relapsing-remitting theory of T1DM suggest?

Answer 425

• over time the beta cells reduce, then stabilise then reduce again -> a theory suggests that this is due to an imbalance between effector T cells and T-regulatory cells
• as time passes the effector T cells increase in number and the T-regulatory cells decrease
• much like the mechanism of MS

Question 426

What is the importance to T1DM autoimmune basis?

Answer 426

• increased prevalence of other autoimmune disease -> most commonly B12 deficiency and coeliac disease as well as others e.g. rheumatoid arthritis, thyroid disease, fertility problems
• risk of autoimmunity in relatives

Question 427

How can the autoimmune basis of T1DM be useful clinically?

Answer 427

• auto-antibodies can be clinically useful (check the progress of the disease and to confirm the autoimmune basis of the diabetes)
• immune modulation offers the possibility of novel treatments

Question 428

What allele has a susceptibility to T1DM?

Answer 428

• HLA-DR on chromosome 6
• various DR alleles -> particularly DR3 and DR4
• DR2 has a protective effect

Question 429

What markers can be measured to clinically define someone as having T1DM?

Answer 429

o two most significant markers

• islet cell antibodies (ICA) - group O human pancreas
• glutamic acid decarboxylase antibodies (GADA)

o other two antibodies:

• insulin antibodies (IAA)
• insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family

Question 430

What are the symptoms of T1DM?

Answer 430

• polyuria
• nocturia -> passing lots of urine at night
• polydipsia
• blurring of vision
• thrush -> due to increased risk of infections
• weight loss
• fatigue

Question 431

What are the signs of T1DM?

Answer 431

• dehydration
• cachexia
• hyperventilation -> due to metabolic acidosis -> try to blow off CO₂ -> is called Kussmaul breathing
• smell of ketones
• glycosuria
• ketonuria

Question 432

What does insulin do?

Answer 432

o insulin has a negative effect on:

• hepatic glucose output
• protein breakdown in the muscle
• glycerol being taken out from the fatty tissue into the periphery

o insulin has a positive effect on:

• glucose being taken up by the muscle

Question 433

What is the general trend in patients who are insulin deficient?

Answer 433

• lots of glucose goes into the circulation and isn’t utilised/taken up by tissues

Question 434

Name some hormones that increase hepatic glucose output.

Answer 434

• catecholamines
• cortisol
• glucagon
• growth hormone

Question 435

What is the mechanism of diabetic ketoacidosis?

Answer 435

• glucose isn’t taken up into cells, due to insulin deficiency, and utilised so a lot of our energy comes from fatty acids -> lipids in the adipocytes is broken down
• normally, you get glycerol coming out of the adipocytes and going to the liver but in the case of insulin deficiency, you get FATTY ACIDS coming out of the adipocytes into the circulation -> fatty acids then go to the liver where they are converted to ketones (this process is normally inhibited by insulin)

o Key Point: as you are deficient in insulin, you get a lot more ketone bodies being produced by the liver

Question 436

What does a large amount of ketones in the body define?

Answer 436

• insulin deficiency - T1DM

Question 437

What are the aims of treatment of T1DM?

Answer 437

• reduce early mortality
• avoid acute metabolic decompensation
• prevent long-term complications

o TYPE 1 DIABETICS REQUIRE EXOGENOUS INSULIN TO PRESERVE LIFE

Question 438

State some long-term complications of T1DM.

Answer 438

o Retinopathy

o Nephropathy

o Neuropathy

o Vascular Disease

Question 439

What diet recommendations are suggested to patients with T1DM?

Answer 439

• reduce calories as FAT
• reduce calories as REFINED CARBOHYDRATES
• increase calories as COMPLEX CARBOHYDRATES
• increase SOLUBLE FIBRE
• balance distribution of food over the course of a day with regular meals and snacks

Question 440

Describe insulin treatment for those who are insulin deficient.

Answer 440

o With Meals

• short acting insulin
• human insulin
• insulin analogues

o Background Insulin - 50% of insulin requirement is a basal form

• long acting
• non-C bound to zinc or protamine
• insulin analogues

Question 441

Describe insulin pumps.

Answer 441

• provides continuous insulin delivery as well as allowing patients to give dose after eating food (replaces subcutaneous method -> pre-programmed basal rates and a bolus for meals
• does NOT measure blood glucose, so it can’t form a feedback loop and completely replace the beta cell function

Question 442

For patients that insulin replacement that fails to control severe hypoglycaemic attacks, what other treatment are available?

Answer 442

o Islet Cell Transplants

• islet cells are harvested, isolated and injected into the liver
• a high risk of rejection, so patients must be on immunosuppressants for life

Question 443

How can treatment of T1DM be monitored?

Answer 443

• capillary monitoring
• HbA1c

Question 444

Describe capillary monitoring.

Answer 444

• capillary glucose levels can be measured by pricking the finger tips -> is reflective of venous blood glucose but isn’t as accurate
• patients can titrate their insulin does based on the capillary glucose reading

Question 445

Describe HbA1c.

Answer 445

• used for long-term blood glucose control is monitored by measuring HbA1c
• more glucose that is present in the blood, the more the haemoglobin is glycosylated -> there is a good correlation between plasma glucose over a reasonably long period of time and HbA1c

Question 446

For how long does HbA1c show a marker for?

Answer 446

• 3 months -> RBC lifespan is 120 days

Question 447

What is the target HbA1c for T1DM patients?

Answer 447

• <7%

Question 448

What is linked to lower HbA1c?

Answer 448

• lower risk of complications -> particularly microvascular complications

Question 449

When does HbA1c not work?

Answer 449

• the measurement relies on haemoglobin -> anything causing an increased turnover of haemoglobin (e.g. haemolytic anaemia or haemoglobinopathy) means the HbA1c may not be accurate

Question 450

What are the acute complications of T1DM?

Answer 450

o Main Consequence = HYPERGLYCAEMIA

• reduced tissue glucose utilisation
• increased hepatic glucose production

o METABOLIC ACIDOSIS

• circulating acetoacetate and hydroxybutyrate -> results from increased ketone body production in the liver
• osmotic dehydration and poor tissue perfusion -> hypotension

Question 451

Are hypos completely avoidable in T1DM?

Answer 451

• no -> they are inevitable as a result of treating T1DM
• is a major source of anxiety in patients and relative

Question 452

Define hypoglycaemia.

Answer 452

• a plasma glucose <3.6mmol/L

Question 453

Define severe hypoglycaemia.

Answer 453

• any hypoglycaemic event that requires another person to treat it

Question 454

At what glucose level are mental processes impaired?

Answer 454

• <3mmol/L

Question 455

At what glucose level does consciousness become impaired?

Answer 455

• <2mmol/L

Question 456

What are the consequences of severe hypoglycaemia?

Answer 456

• arrhythmia and sudden death
• possible long-term effects on the brain

Question 457

What are the dangers of recurrent hypos?

Answer 457

• loss of warning signs -> hypoglycaemia unawareness -> associated with poorly controlled diabetes

Question 458

Why do diabetic patients become hypoglycaemic?

Answer 458

o Unaccustomed exercise

o Missed meals

o Inadequate snacks

o Alcohol (if they have too much then they can become unaware of the hypoglycaemia)

o Inappropriate insulin regime

Question 459

What are the signs and symptoms of hypoglycaemia?

Answer 459

o due to increased autonomic activation

• palpitations/tachycardia
• tremor
• sweating
• pallor/cold extremities
• anxiety

o due to imparied CNS function

• drowsiness
• confusion
• altered behaviour
• focal neurology
• coma

Question 460

How is hypoglycaemia treated?

Answer 460

o if the patient is conscious -> feed the patient

• glucose -> rapidly absorbed as solution or tablet
• after some recovery complex carbs -> maintains blood glucose after initial treatment

o if unconsciousnessly impaired -> parenternal

• IV dextrose
• 1mg glucagon IM
• avoid concentrated solutions if possible

Question 461

What defines diabetes?

Answer 461

• a fasting blood glucose > 7 mmol/L

Question 462

What is impaired fasting glucose?

Answer 462

• between 6 and 7 mmol/L -> between normal and diabetes
• has some complications but not those to microvascular

Question 463

What factors influence the pathophysiology of T2DM?

Answer 463

• genetics
• intra-uterine environment
• adult environment

Question 464

What is the genetics behind maturity onset diabetes of the young (MODY)?

Answer 464

• autosomal dominant
• several hereditary forms
• strong family history

Question 465

Is MODY associated with obesity?

Answer 465

• no

Question 466

What are some possible mechanisms of MODY?

Answer 466

• ineffective pancreatic beta cell insulin production
• mutations of transcription factor genes and glucokinase genes

Question 467

What is the treatment of MODY?

Answer 467

• specfic to the the type of MODY -> solve that problem and therefore help the MODY

Question 468

Name some risk factors to T2DM.

Answer 468

• genetics - studies show its almost autosomal dominant
• obesity
• intra-uterine growth restriction

Question 469

When is microvascular disease found?

Answer 469

• diabetes with hyperglycaemia

Question 470

What does insulin resistance cause?

Answer 470

• dyslipidaemia and stimulation of the mitogenic pathway -> causes smooth muscle hypertrophy and hypertension -> macrovascular disease

Question 471

What is the relationship between age and insulin resistance and secretion?

Answer 471

o we all make less and less insulin as we grow older

o at the same time, we become more and more insulin resistant

o insulin resistance and insulin secretion lines will intersect -> beyond this point we won’t be able to make enough insulin for our insulin resistance

• in caucasians, this intersection normally occurs around 110 years of age, however in other ethnic groups it intersects much sooner

Question 472

What occurs in the stages of insulin secretion?

Answer 472

• 1st phase -> stored insulin is released immediately
• 2nd phase -> over time more insulin is produced and released

Question 473

Describe the deteriotation of insulin secretion with progression of diabetes.

Answer 473

• patients developing diabetes will still have some insulin production but they will lose their 1st phase insulin response -> they can make insulin eventually but it takes a longer time for them to do it -> can be got around by eating complex carbs which release the glucose more slowly thus reducing the need for a first phase insulin response
• over time insulin will stop being made and both 1st and 2nd phase will be lost -> insulin deficiency sets in

Question 474

How is insulin serum levels maintained after a period of not eating?

Answer 474

• hepatic glucose output maintains blood glucose at 4 mmol/L

Question 475

How does insulin effects hepatic glucose output?

Answer 475

o reduces hepatic glucose output

• after eating, insulin stops HGO because you don’t need this output from the liver once you’ve just eaten while driving the glucose into muscle and adipose tissue

o both of these effects are absent in T2DM -> there is insufficient insulin to inhibit hepatic glucose output and insufficient insulin to move glucose into muscle and fat

Question 476

Describe the effects of insulin resistance on metabolism.

Answer 476

• adipocytes are full of triglycerides which can be broken down to glycerol and non-esterified fatty acids (NEFA)
• insulin would stop this breakdown of triglycerides because there is no need to break down fat stores after you’ve had a meal -> glycerol and NEFA travel to the liver
• in the liver, glycerol can be used to make glucose - gluconeogenesis and can also be released from the liver via glycogenolysis -> insulin resistance means that there is increased hepatic glucose output and decreased glucose uptake into tissues
• the fatty acids go to the liver, are chopped up into 2-carbon segments and CANNOT be used to make glucose -> instead used to make very low density lipoprotein triglycerides which are ATHEROGENIC -> contributes to the atherogenic profile of insulin resistant subjects -> patients can have atheroma years before high blood glucose

Question 477

What is waist circumference a predictive marker for and why?

Answer 477

o ischaemic heart disease

• breakdown of triglycerides are a particular markers for omental adipocytes

Question 478

What is the link betwen diabetes and obesity?

Answer 478

• more than a percipitant -> fatty acids and adipocytokines are important -> OBESITY APPEARS TO BE PART OF THE MECHANISM OF T2DM
• adipocytokines modulate the insulin resistance
• central or omental obesity are the biggest problems
• losing wight is a beneficial treatment

Question 479

How is the gut microbiome linked to obesity, insulin resistance and T2DM?

Answer 479

• may be important through signalling to the host -> various lipopolysaccharides are fermented by the gut bacteria to short chain fatty acids -> can enter the circulation and modulate bile acids and therefore modulate host metabolsim
• also appear to be important in inflammation and are involved in adipocytokine pathways
• microbiota transplants are being investigated as a treatment for obesity

Question 480

What is the most common side effect of diabetes treatment?

Answer 480

• weight gain

Question 481

Which is the only diabetes treatment that causes weight reduction?

Answer 481

• metformin

Question 482

What are the presentations of T2DM?

Answer 482

• osmotic symptoms
• infections
• screening test
• upon presentation of a complication -> acute such as hyperosmolar coma or chronic such as IHD and retinopathy

Question 483

What is the basic management of T2DM?

Answer 483

• education
• diet
• pharmacological treatment
• complication screening

Question 484

Why treat T2DM?

Answer 484

• can help the symptoms of T2DM
• reduces the chance of acute metabolic complications - though these are unlikely in T2DM
• reduce the chance of long-term complications; good evidence base
• education -> people generally only treat things if they have symptoms so it’s important to educate them about the consequences of poor treatment

Question 485

What diet should take place in patients with T2DM?

Answer 485

• 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)
• address salt (BP risk)

Question 486

What is monitored in T2DM treatment?

Answer 486

• weight
• glycaemia
• blood pressure
• dyslipidaemia

Question 487

What pharmalogically treatments are available for T2DM?

Answer 487

• metformin -> used to treat insulin resistance in the liver
• orlistat -> pancreatic lipase inhibitor -> stops the break down of fat thus restricting fat absorption in the gut
• sulphonylureas -> makes the existing pancreas secrete more insulin
• alpha glucosidase inhibitor -> delays glucose absorption
• thiazolidinediones -> acts on the adipocytes and addresses insulin resistance peripherally in fat and muscle
• SGLT2 inhibitors -> increases glucose excretion by the kidneys

Question 488

What is metformin?

Answer 488

• a biguanide (class of drugs used as oral anti-hyperglycaemic drugs) -> an insulin sensitiser
• used in more or less everyone with T2DM, in particular, overweight patients with T2DM where diet alone has not succeeded

Question 489

What are the effects of metformin?

Answer 489

o reduces insulin resistance

• reduces hepatic glucose output
• increase peripheral glucose disposal

o side effects are uncommon but are GI related

Question 490

When can metformin not be used?

Answer 490

• in patients with -> severe liver failure, severe cardiac failure, mild or worse renal failure

Question 491

What is the mechanism of sulphonylureas in diabetes treatment?

Answer 491

• block the ATP sensitive potassium channel and cause the influx of calcium which leads to INSULIN SECRETION

Question 492

What is glibenclamide?

Answer 492

• is a sulphonylurea and insulin secretagogue

Question 493

What are the side effects of glibenclamide?

Answer 493

• hypoglycaemia
• weight gain -> therefore preferred in lean suffers of T2DM

Question 494

What is acarbose?

Answer 494

• an alpha glucosidase inhibitor

Question 495

What is the mechanism of alpha glucosidase inhibitors?

Answer 495

• prolongs the absorption of oligosaccharides -> allows insulin secretion to cope following the loss of the first phase insulin response
• as effective as metformin in early diabetes

Question 496

What is the major side effect of acarbose/alpha glucosidase inhibitors?

Answer 496

• flatulence -> sugar reaches the large intestine where it is fermented

Question 497

What is the thiazolidinedione that is available to be prescribed?

Answer 497

• pioglitazone

Question 498

How do thiazolidinediones work as treatment for T2DM?

Answer 498

• peroxisome proliferator-activated receptor (PPAR-g) agonists -> are insulin sensitiser - mainly peripheral -> improvement in glycaemia and lipids

Question 499

What are the side effects of thiazolidinedione?

Answer 499

• peripheral weight gain -> modification to adipocyte differentiation
• older types -> hepatitis and heart failure

Question 500

What is the incretin effect?

Answer 500

• the modulation of insulin secretion by L-cells in the gut -> produces products, such as GLP-1, that increases insulin secretion

Question 501

What hormone can be utilised as a treatment for T2DM?

Answer 501

• GLP-1
• gut hormone produced by L-cells that stimulates insulin secretion (incretin effect) and suppresses glucagon
• increases satiety -> helps with obesity

Question 502

What is the issue with GLP-1 and how is this overcome?

Answer 502

• it has a short half-life due to degeneration from dipeptidyl peptidase-4 (DPP-4)
• gliptins are DPP-4 inhibitors so increase the half-life of GLP-1

Question 503

What other aspects, excluding blood sugar, should be controlled in T2DM?

Answer 503

• weight
• blood pressure -> 90% of T2DM patients -> clear benefits
• diabetic dyslipidaemia (high cholesterol, triglycerides, HDL-cholesterol) -> clear benefits to treatment

Question 504

What is the most affective treatment at prevent the progression of diabetes?

Answer 504

• intensive lifestyle with good diet and exercise

Question 505

What are the sites of microvascular diabetic complications?

Answer 505

• retinala rteris -> diabetic retinopathy
• glomerular arterioles -> nephropathy
• vaso vasorum - tiny arteries that supply nerves neuropathy

Question 506

State some factors that increase the risk of microvascular complications.

Answer 506

• severity of hyperglycaemia
• hypertension
• genetics
• hyperglucaemic memory -> poorly controlled diabetes, even for a short-time, before good controll increase the risk
• tissue damage through originally reversible and later irreversible alterations in proteins

Question 507

What is the mechanism of glucose damage to the microvascular?

Answer 507

Question 508

What is the main cause of blindness in people of working age, in the UK?

Answer 508

• diabetic retinopathy

Question 509

What does a normal retina look like?

Answer 509

• optic disc at the nasal part of the eye and the macula more laterally (involved in colour vision and acuity)
• various vessels that come out into the back of the retina and they usually have a very regular arrangement

Question 510

What are the 4 retinopathies?

Answer 510

• Background Diabetic Retinopathy
• Pre-proliferative Retinopathy
• Proliferative Retinopathy
• Maculopathy

Question 511

What are the features of background diabetic retinopathy?

Answer 511

• hard exudates -> appear as cheesy, yellow space in the retina -> due to leakage of lipid content
• microaneurysms -> can rupture and cause blot haemorrhages

Question 512

What are the features of pre-proliferative diabetic retinopathy?

Answer 512

• cotton wool spots - aka soft exudates -> show retinal ischaemia
• show severall haemorrhages

Question 513

Describe proliferative retinopathy.

Answer 513

• involves the formation of new vessels in response to retinal ischaemia
• if the vessels form in the region of the macula they cause problems with acuity and colour vision
• the newly formed vessels are generally more fragile -> can bleed at anytime

Question 514

Describe maculopathy.

Answer 514

• hard exudates near the macula -> same disease a background diabetic retinopathy barring the location of the hard exudates
• can threaten direct vision

Question 515

What is the management of background diabetic retinopathy?

Answer 515

• improve control of blood glucose
• warn the patient taht the warning signs are present

Question 516

What is the treatment for pre-proliferative diabetic retinopathy?

Answer 516

• pan-retinal photocoagulation -> laser the retina and therefore stop the vessels bleeding

Question 517

What is the treatment for proliferative diabetic retinopathy?

Answer 517

• pan-retinal photocoagulation -> laser the retina and stop the vessels from bleeding

Question 518

What is the treatment for maculopathy?

Answer 518

• GRID of photocoagulation -> no need for pan-retinal photocoagulation, can be more targetted

Question 519

What are the features of diabetic nephropathy?

Answer 519

• hypertension
• progessively increasing proteinuria
• progressively deteriorating kidney function
• classic histological features

Question 520

What events likelihood of occuring increases with diabetes and chronic kidney disease?

Answer 520

• cardiovascular events

Question 521

What are the features of nephropathy?

Answer 521

• mesangial expansion
• basement membrane thickening
• glomerulosclerosis (hardening of the capillaries) -> becomes less flexible and harder -> absorption of nutrients changes -> more pressure going through the kidneys -> changes in blood pressure control

o essentially, in diabetic nephropathy there is overproduction of matrix leading to mesangial expansion and to basement membrane thickening

• as it progresses, you get sclerosis of the glomerulus and secondary effects on the tubulointerstitium -> several stimuli for these processes including the effects of prolonged exposure to high glucose or glycosylated proteins in at risk patients
• rise in the pressure within the glomerular capillaries can stimulate expansion of the matrix -> angiotensin stimulates pathways that result in overproduction of matrix -> angiotensin can also cause the constriction of the efferent arterioles, thus increasing transglomerular capillary pressure

Question 522

How is nephropathy diagnosed?

Answer 522

• albumin in the urine

Question 523

What factor affect the chance of diabetic nephropathy in T2DM?

Answer 523

• age at development of disease will affect the epidemiology
• racial factors
• age at presentation
• death due to cardiovascular morbidity/macrovascular disease -> kills them before development of nephropathy

Question 524

What are the clinical features of diabetic nephropathy?

Answer 524

• progressive proteinuria
• increased blood pressure
• deranged renal function

Question 525

How is proteinuria measured?

Answer 525

• urine dipsticks

Question 526

What are the normal and nephropathy ranges of protein in urine?

Answer 526

• normal = <30mg/24hrs
• nephrotic = >3,000mg/24hrs

Question 527

What are the strategies in diabetic nephropathy intervention?

Answer 527

• diabetic control
• blood pressure control -> slows down the deterioration in kidney function -> usually use ACE inhibitors -> reduce the rate of decline of creatinine thus reducing the rate of deterioration of kidney function
• stopping smoking

Question 528

What is the most common cause of neuropathy?

Answer 528

• diabetes -> therefore it is the most common cause of amputation

Question 529

What does neuropathy result from?

Answer 529

• blockade of the vasa vasorum - small blood vessels which supply the nerves

Question 530

What types of neuropathy are associated with diabetes?

Answer 530

o Peripheral polyneuropathy

o Mononeuropathy

o Mononeuritis multiplex

o Radiculopathy

o Autonomic neuropathy

o Diabetic amyotrophy

• at Parties, Marilyn Manson Regularly Abuses Drugs

Question 531

What are the clinical features of peripheral neuropathy?

Answer 531

• loss of sensation
• loss of ankle jerks
• loss of vibrational sense
• multiple fractures in the feet -> can’t feel in correct walking -> can lead to Charcot’s joints and permenant damage

Question 532

Which areas are most commonly effected in peripheral neuropathy?

Answer 532

• hands and feet -> longest nerves supply the feet and then the hands

Question 533

Peipheral neuropathy is most common in which groups of patients?

Answer 533

• tall patients
• patients with poorly controlled glucose

Question 534

How can you test for peripherla neuropathy?

Answer 534

• monofilament examination

Question 535

What are the features of mononeuropathy?

Answer 535

• usually a sudden motor loss - usually in the longest nerves -> wrist or foot drop
• can cause cranial nerve palsy -> double vision as a consequence

Question 536

What is third nerve palsy?

Answer 536

• the loss of motor function in an eye -> the eye is usually down and out because of the unopposed action of lateral rectus and superior oblique

Question 537

What are the two different 3rd nerve palsy, which one occurs in diabetes and explain why it occurs in diabetes?

Answer 537

o pupil sparing third nerve palsy -> diabetes

• pupil responds to light as parasympathetic fibres are on the outside so don’t lose blood supply

o third nervy palsy caused by aneurysm

• pupil is fixed dilated as the aneurysm presses on the parasympathetic fibres first

Question 538

What is mononeuritis multiplex?

Answer 538

• a random combination of peripheral nerve lesions

Question 539

What is radiculopathy?

Answer 539

• pain over spinal nerves -> usually affects the dermatomes on the abdomen and/or chest wall

Question 540

Which diabetic neuropathy is the hardest to treat?

Answer 540

• autonomic

Question 541

What is autonomic neuropathy?

Answer 541

• loss of sympathetic and parasympathetic nerves to the GI tract, bladder and cardiovascular system

Question 542

What are the effects of autonomic neuropathy on the GI tract?

Answer 542

o difficulty swallowing

o delayed gastric emptying

o constipation/nocturnal diarrhoea

Question 543

What systems are affected by autonomic neuropathy?

Answer 543

• GI
• urinary system
• CVS

Question 544

What are the effects of autonomic neuropathy on the urinary system?

Answer 544

• bladder dysfunction

Question 545

What are the effects of autonomic neuropathy on the CVS?

Answer 545

• postural hypotension
• cardiac autonomic supply -> cause of sudden death in diabetes patients

Question 546

How can you check for autnomic neuropathy?

Answer 546

o measure changes in heart rate in response to the Valsalva manouevre -> patients blows into a tube -> this normally causes a change in heart rate but it doesn’t in diabetics

Question 547

What is the biggest danger in peripheral neuropathy?

Answer 547

• a suffers steps on something like a rusty nail and doesnt know it is there for days

Question 548

Describe the development of atheroma.

Answer 548

• small accumulations of extracellular lipid will lead to atheroma which then leads to fibroatheroma -> could lead to a complicated lesion which can ulcerate, exposing the fat underneath and this can either thrombose entirely or send emboli further down the circulation
• initially, this process begins with accumulation of lipid but progresses to involve smooth muscle -> this can lead to smooth muscle hypertrophy, fibrosis and calcification

Question 549

What are the macrovascular complications of diabetes?

Answer 549

• ischaemic heart disease
• cerebrovascular
• renal artery stenosis
• peripheral vascular disease

Question 550

What is the link to insulin resistance and life expectancy, explaining the link?

Answer 550

o the more insulin resistant you are, the shorter the lifespan

Question 551

What is the likelihood that someone with diabetes, who hasn’t had a MI, will have a MI?

Answer 551

• the same as those who don’t have diabetes but have had a MI

Question 552

What is the Framingham risk score?

Answer 552

• a gender-specific algorithm used to estimate the 10-year cardiovascular risk of an individual

Question 553

What is the main cause of morbidity and mortality in diabetes?

Answer 553

• ischaemic heart disease -> same mechanism as without diabetes

Question 554

What are the difference between diabetic and non-diabetic when it comes to cerebrovascular disease?

Answer 554

• earlier with diabetes
• more widespread -> lots of small strokes as well as larger ones

Question 555

What is the major problem with peripheral vascular disease?

Answer 555

• contributes to diabetic foot problems with neuropathy

Question 556

Does treating blood glucose offset the increased risk of CVD?

Answer 556

• intensive glucose control does improve coronary heart disease risk but not significantly -> does not translate to much of a change in mortality

Question 557

Which race has an increased risk of CHD?

Answer 557

• for a given cholesterol, South Asians have an increased risk of CHD mortality

Question 558

What are the risk factors for macrovascular disease?

Answer 558

• low birth weight increases the chance of macrovascular disease

Question 559

What two complications predispose diabetic to foot disease?

Answer 559

• neuropathy
• peripheral vascular disease

Question 560

Describe the monofilament test.

Answer 560

• the filament bends you have applied 10g of pressure
• a normal foot will be able to feel the 10g
• normally, the ball of the foot is checked because that is the most common site at which ulcers are found -> 50% of new foot disease starts at the ball of the foot

Question 561

What is the pathway to foot ulceration?

Answer 561

Question 562

What is th consequence of motor neuropathy to the feet?

Answer 562

• motor neuropathy can cause an imbalance between the extensors and the long plantar flexors causing an abnormal shape in the foot -> means that increased pressure is being applied on the ball of the foot and the knuckles of the toes

Question 563

Name a problem that could occur withd iabetes that can make tendons less flexible?

Answer 563

• sugar binding to haemoglobin (HbA1c)

Question 564

What are the consequences of autonomic neuropathy to the foot?

Answer 564

• abnormal blood flow in the foot -> could cause an increased blood flow at the wrong time so that there is an increase in pulse pressure in the foot
• reduced sweating/oil release in the foot which normally protects it from minor disease

Question 565

What are the symptoms of neuropathic foot?

Answer 565

• numb
• warm and dry
• palpable foot pulses
• ulcers at points of high pressure -> ball of the foot

Question 566

What are the symptoms of ischaemic foot?

Answer 566

• cold
• pulseless
• ulcers at the foots margins -> toes and heel

Question 567

What are the symptoms of neuro-ischaemic foot?

Answer 567

• numb
• cold and dry
• pulseless
• ulcers at the points of high pressure and the margins of the foot

Question 568

What group of patients are most at risk to neuro-ischaemic foot?

Answer 568

• diabetics who smoke

Question 569

Nme some strategies of managing/preventing diabetic foot ulceration?

Answer 569

• prevent hyperglycaemia
• prevent hypertension
• prevent dyslipidaemia
• stop smoking
• education
• control diabetes
• inspect feet daily
• have feet measured when buying shoes
• buy shoes with laces and square toe box
• inspect inside of shoes for foreign objects attend chiropodist
• cut nails straight across
• care with heat
• never walk barefoot

Question 570

What are the treatment of foot ulceration

Answer 570

o relief of pressure -> bed rest (increases risk of risk of DVT, heel ulceration) so may choose to redistribe the pressurevia a total contact cast

o antibiotics -> possibly long term if it has affected bone

o debridement

o revascularization -> angioplasty, arterial bypass surgery

o amputation if it is severly infected -> could be toe, foot or below the knee

Question 571

What is this?

Answer 571

• a Charcot’s Foot

Question 572

Describe Charcot’s Foot.

Answer 572

• bones in the feet don’t have their normal articulations due to loss of joint position in diabetes -> are articulated in such a way that it would be excruciatingly painful in a normal person but in diabetics it is totally painless
• abnormal shape of the foot means that there is extreme risk of ulceration

Question 573

How is it possible to distinguish betwen osteomyelitis (infection of the bone) and Charcot’s foot?

Answer 573

• MRI