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Year 2: LCRS > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

What results in tertiary endocrine gland disease?

A

Disorder of the hypothalamus

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2
Q

What results in secondary endocrine gland disease?

A

Disorder of the anterior pituitary

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3
Q

What results in primary endocrine gland disease?

A

Disorder of the endocrine gland (thyroid, gonads, adrenal cortex)

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4
Q

What is hypopituitarism?

A

A decreased production of all anterior pituitary hormones or the decreased production of specific hormones

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5
Q

What is panhypopituitarism?

A

Decreased production of all anterior pituitary hormones

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6
Q

What causes panhypopituitarism?

A

It is rare.
Caused by congenital defects.
Very rare causes are gene mutations such as the PROP 1 gene.

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7
Q

In adults, in what order is there often progressive loss of pituitary secretion?

A

Progressive loss of pituitary secretion often in the following order:

  • Gonadotrophins (LH and FSH)
  • GH
  • Thyrotrophin
  • Corticotrophin
  • Prolactin deficiency is uncommon
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8
Q

What causes Simmond’s disease?

A 
Panhypopituitarism.
Variety of causes including:- 
- Infiltrative processes (e.g. lymphocytic) 
- Pituitary adeomas
- Craniopharyngiomas
- Cranial injury 
- Following surfery
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9
Q

What are the symptoms of simmond’s disease?

A

Symptoms are usually due to decreased thyroidal, adrenal and gonadal function

Symptoms:

  • Secondary amenorrhoea or oligomenorrhoea (women?
  • Impotence (men)
  • Loss of libido
  • Tiredness
  • Waxy skin
  • Loss of body hair
  • Hypotension
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10
Q

What is sheehan’s syndrome?

A

Panhypopituitarism.
It is specific in women and develops acutely following post-partum haemorrhage. Results in pituitary infarction.
The blood loss causes vasoconstrictor spasm of hypophysial arteries which leads to:
- Ischaemia of pituitary (enlarged during pregnancy), and then
- Necrosis of pituitary

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11
Q

What is pituitary apoplexy?

A
  • A similar intra-pituitary haemorrhage or infarction

- Often presents dramatically in patients with pre-existing pituitary tumours which suddenly infarct

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12
Q

How is hypopituitarism diagnosed?

A
  • Stimulation ( ‘provocation’) test.
  • It can be used as a combined function test with involves rapid IV sequential administration of GHRH, CRH, GnRH and TRH
  • For GH, insulin-induced hypoglycaemia can be used
  • Basal plasma values of pituitary or target endocrine gland hormones are useful if measured after a stimulation test
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13
Q
  • What is hypo-adreno-corticalism?
A

A lack of corticotrophin (ACTH)

loss of glucocorticoids

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14
Q

What is the effect of a lack of somatotrophin in children?

A

Pituitary dwarfism (short stature)

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15
Q

What is the effect of a lack of somatotrophin in adults?

A

Loss of GH though the effects are uncertain

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16
Q

What causes short stature in children?

A
  • Genetic determination
  • Malnutrition
  • Emotional deprivation
  • Endocrine disorders
  • Other causes (various, often unknown)
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17
Q

What are the congenital causes of GH deficiency in children? (rare)

A
  • Deficiency of hypothalamic GHRH
  • Mutations of GH gene (very rare)
  • Developmental abnormalities (e.g. aplasia or hypoplasia of pituitary)
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18
Q

What are the acquired causes of GH deficiency in children? (common)

A
  • Tumours of hypothalamus or pituitary
  • Other intracranial tumours nearby (e.g. optic nerve glioma)
  • Secondary to cranial irradiation
  • Head injury
  • Infection or inflammation
  • Severe psychosocial deprivation
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19
Q

What are examples of GnRH deficiency? (tertiary hypopituitarism)

A

Kallmann’s syndrome

Prader-Willi syndrome

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20
Q

What are the types of GH provocation tests?

A 
GHRH (IV)
Insulin (IV) 
Arginine (IV) 
Glucagon (IM)
Exercise 
Measure GH at specific time points
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21
Q

What is the principle aim when treating pituitary deficiencies?

A

To restore homeostasis by replacing the missing hormones

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22
Q

When ACTH is deficient, what is checked and which hormone is used as a replacement?

A

Check: Serum cortisol
Replacement: Hydrocortisone

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23
Q

When TSH is deficient, what is checked and which hormone is used as a replacement?

A

Check: Serum T3
Replacement: Thyroxine

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24
Q

When LH/FSH is deficient in women, what is checked and which hormone is used as a replacement?

A

Check: Oestrogen deficiency, libido
Replacement: Ethinyloestradiol, Medroxyprogesterone

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25
Q

When LH/FSH is deficient in men, what is checked and which hormone is used as a replacement?

A

Check: Libido, serum testosterone
Replacement: Testosterone undecanoate

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26
Q

When GH is deficient, what is checked and which hormone is used as a replacement?

A

Check: IGF1, growth chart
Replacement: GH

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27
Q

What is seen in growth hormone therapy in children?

A
  • Acceleration of linear growth: decreased body fat
  • The effects are most marked in the first year of treatment
  • Younger children respond better
  • Obese children response better
  • Resistance can develop (antibody formation)
  • If more generalised pituitary deficiency, other hormones need to be given
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28
Q

How is growth hormone therapy prepared and administered?

A

Preparation: Human recombinant GH (Somatototrophin is the approved name)
Administration:
- Subcutaneous or intramuscular injection
- Daily or 4-5 times/week pm
- Adjust dose to size

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29
Q

What is the absorption and distribution of growth hormone therapy?

A

Maximal plasma concentration in 2-6 hours

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30
Q

What is the metabolism of growth hormone therapy?

A

Hepatic or renal

Short half life of 20 minutes

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31
Q

What is the duration of action of growth hormone therapy?

A
  • It last well beyond clearance

- Peak IGF1 levels at approximately 20 hours

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32
Q

What are the adverse affects of growth hormone therapy?

A
  • Lipoatrophy at injection site
  • Intracranial hypertension
  • Headaches
  • Increased incidence of leukaemia
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33
Q

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

A
  • Reduced lean mass, increased adiposity, increased waist:hip ratio
  • Reduced muscle strength and bulk. Reduced exercise performance.
  • Decreased plasma HDL-cholesterol and raised LDL cholesterol
  • Impaired ‘psychological well being’ and reduced quality of life’
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34
Q

Over what age does GH production tend to decrease?

A

60

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35
Q

How is GH deficiency in adults diagnosed?

A
  • Lack of response to GH stimulation test (e.g. to insulin)
  • Low plasma IGF1
  • Low plasma IGF-BP3
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36
Q

What are the potential benefits of GH therapy in adults?

A
  • Improved body composition
  • Improved muscle strength and exercise capacity
  • Normalisation of HDL cholesterol
  • Increased bone mineral content
  • Improved psychological well being and quality of life
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37
Q

What are the potential risks of GH therapy in adults?

A
  • Increase risk of cardiovascular accidents
  • Increased soft tissue growth which could lead to issues such as cardiomegaly
  • Increased susceptibility to cancer
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38
Q

What is hyperpituitarism?

A
  • It is usually due to isolated pituitary tumours but can also be ectopic (non-endocrine tissue) in origin
  • Can often be associated with visual field and other defects
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39
Q

What is bitemporal hemianopia?

A

It occurs when the growth of a suprasellar tumour pressed onto the optic chiasm, causing a lesion which damages the optic nerves.
The temporal visual paths are disrupted: loss of peripheral vision

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40
Q

What can excess corticotropin (ACTH) result in?

A

Cushing’s disease

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41
Q

What can excess thyrotrophin result in?

A

Thyrotoxicosis

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42
Q

What can excess gonadotrophins (LH and FSH) result in?

A

Precocious puberty in children

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43
Q

What can excess prolactin result in?

A

Hyperprolactinaemia

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44
Q

What can excess somatotrophin (GH) result in?

A

In childhood: Gigantism

In adulthood: Acromegaly

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45
Q

What is hyperprolactinaemia?

A

Excess circulating prolactin that is not due to a physiological cause such as pregnancy or breast feeding.
It is usually due to prolactinoma (often microadenomas

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46
Q

What is seen in women with hyperprolactinaemia due to a pituitary adenoma?

A
  • Galactorrhea (milk production)
  • Secondary amenorrhoea (or oligomenorrhoea)
  • Loss of libido
  • Infertility
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47
Q

What is seen in men with hyperprolactinaemia due to a pituitary adenoma?

A
  • Loss of libido
  • Impotence
  • Infertility
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48
Q

Why are untreated gigantism and acromegaly associated with an increased morbidity and mortality?

A

Due to cardiovascular and/or respiratory complications

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49
Q

How can the onset of acromegaly be described?

A

Slow and Insidious

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50
Q

What shows increased growth in acromegaly?

A
  • Periosteal bone
  • Cartilage
  • Fibrous tissue
  • Connective tissue
  • Internal organs (cardiomegaly, splenomegaly, hepatomegaly etc)
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51
Q

What are the metabolic effects of acromegaly?

A
  • Increased plasma insulin response to oral glucose load
  • Increase insulin resistance
  • Impaired glucose tolerance test (50% patients)
  • Diabetes mellitus (10% patients)
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52
Q

What are the common clinical manifestations of acromegaly?

A
  • Enlargement of supraorbital ridges and nose, hands and feet, thickening of lips and general coarseness of features
  • Excessive sweating (hyperhidrosis)
  • Mandible grows, leading to protrusion of lower jaw (prognathism)
  • Carpal tunnel syndrom: joint pain
  • Barrel chest, curvature of spine (kyphosis)
  • Menstrual abnormalities, decreased libido and impotence
  • Galactorrhea in women (uncommon in men)
  • Hypertension
  • Abnormal glucose tolerance, symptoms of diabetes mellitus
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53
Q

What type of tests are used to diagnose pituitary overactivity?

A

Suppression tests

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54
Q

What are the treatment options for acromegaly?

A
  • Surgery (transphenoidal)
  • Radiotherapy
  • Chemotherapy (somatostatin analogues e.g. octreotide and dopamine agonists e.g. bromocriptine)
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55
Q

What are the clinical used of octreotide?

A
  • Short term treatment before pituitary surgery
  • Long term treatment in those not controlled by other means
  • Treatment of other neuroendocrine tumours e.g. carcinoid tumours
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56
Q

How is octreotide administered?

A
  • Subcutaneously or intramuscular 3 times per day
  • Depot preparation once GH levels are under control
  • Adjust dose according to need
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57
Q

How is octreotide distributed?

A

It is retained in the extracellular fluid

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58
Q

What is the metabolism of octreotide?

A

Hepatic or renal

Half life of 2- 4 hours

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59
Q

What are the adverse side effects of octreotide?

A
  • GI tract disturbances
  • Initial reduction in insulin secretion: transient hyperglycaemia
  • Gallstones are rare
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60
Q

Why are dopamine receptor agonists used to treat hyperprolactinaemia?

A
  • Decrease prolactin (and GH) secretion
  • Reduce the size of the tumour
    Examples are bromocriptine and cabergoline
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61
Q

What is bromocriptine?

A

A dopamine receptor agonist.

  • Administered by mouth (1/day)
  • Highly plasma protein bound (93%)
  • Hepatic metabolism
  • Half life= 7 hours
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62
Q

What are the adverse effects of bromocriptine?

A
  • Nausea/vomiting and abdominal cramps
  • Psychomotor excitation
  • Postural hypotension
  • Vasospasm in fingers and toes (caution Raynaud’s disease)
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63
Q

Aside from treating hyperprolactinaemia, what are the other uses of bromocriptine?

A
  • Supression of lactation
  • Cyclical benign breast tumours
  • Acromegaly
  • Parkinson’s disease
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64
Q

What is the mode of action for cabergoline?

A

DA2 receptor agonist

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65
Q

What are the pharmacokinetics of cabergoline?

A

Oral, 1-2 times per week

- Half life: > 45 hours

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66
Q

What are the unwanted effects of cabergoline?

A

Same as bromocriptine but are less pronounced

  • Nausea/vomiting and abdominal cramps
  • Psychomotor excitation
  • Postural hypotension
  • Vasospasm in fingers and toes (caution Raynaud’s disease)
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67
Q

What are the principle actions of vasopressin?

A

Antidiuretic effect.

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68
Q

How does vasopressin act on the renal and cortical medullary collecting ducts?

A

Acts on V2 receptors and stimulates the synthesis and insertion of aquaporin 2 into the apical membranes of the principle cells.
Aquaporin 2 increases water transport from the tubular fluid into the general circulation which increases the amount of water that is retained in the body

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69
Q

What is the effect of vasopressin when interacting with V1a receptors?

A

Vasoconstrictor activity

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70
Q

What is the effect of vasopressin when interacting with V1b receptors?

A

Corticotrophin (ACTH) release

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71
Q

What are other effects of vasopressin when interacting with V2 receptors?

A

V2 receptors are involved in the production of Factor VIII and von Willebrand factor.
This means it has an important role in blood clotting

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72
Q

What are the principle actions of oxytocin?

A
  • Constriction of myometrium at parturition
  • Milk ejection reflex
  • Central effects
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73
Q

What is the result of a lack of oxytocin and vasopressin?

A

Lack of oxytocin: parturition and milk ejection effects are induced by other means
Lack of vasopressin: Diabetes insipidus

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74
Q

What are the differences between central diabetes insipidus and nephrogenic diabetes insipidus?

A

Central: absence of lack of circulating vasopressin
Nephrogenic: End-organ (kidneys) resistance to vasopressin

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75
Q

What are the causes of central diabetes insipidus?

A

Damage to the neurohypophysial system: e.g.

  • Injury to the neurohypophysis
  • Surgery
  • Cerebral thrombosis
  • Tumours (intrasellar and suprasellar)
  • Granulomatous infiltrations of median eminence

It can be idiopathic or familial (rare)

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76
Q

What are the causes of nephrogenic diabetes insipidus?

A

1) Familial - rare (e.g. receptor defects)

2) Drugs (e.g. lithium, demethyl chlortetracylcine DMCT)

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77
Q

What are the signs and symptoms of diabetes insipidus?

A
  • Large volumes of urine (polyuria)
  • Urine is very dilute (hypo-osmolar)
  • Thirst and increased drinking (polydipsia)
  • Dehydration (and consequences) if fluid intake not maintained
  • Possible disruption to sleep associated problems
  • Possible electrolyte imbalance
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78
Q

What are the pattern of events seen in diabetes insipidus?

A

1) Lack of vasopressin
2) Polyuria
3) Increase in plasma osmolarity (Na+)
4) Reduction in ECF volume
5) Stimulation of osmoreceptors
6) Thirst centre
7) Polydipsia
8) Replacement of ECF volume ( usually this switches off vasopressin, but as there isn’t any the cycle will repeat)

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79
Q

What is the normal (hydrated) range of plasma osmolality?

A

280 mOsm.kg H2O-1

270-290

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80
Q

What is the range of plasma osmolality in diabetes insipidus?

A

> 290 mOsm.kg H2O-1

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81
Q

What is the range of plasma osmolality in poldypsia?

A
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82
Q

What is psychogenic polydipsia?

A

A central disturbance creates the sensation of third therefore leads to increased drinking (polydipsia). This leads to the expansion of extracellular fluid volume and a decrease in plasma osmolality.
An increase in urine excretion which leads to a reduction of extracellular fluid volume, increasing plasma osmolality.
This combined with the central disturbance increases a sensation of thirst thus causes the cycle of events

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83
Q

What is seen when a fluid deprivation test is done on a healthy person?

A

Fluid deprivation should increase plasma osmolarity. This will increase vasopressin and the urine produced should be more concentrated

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84
Q

What is seen when a fluid deprivation test is done on a patient with psychogenic polydipsia?

A

As there is a normal vasopressin system, the urine can be concentrated though not as well as in a healthy person.
This is due to the kidneys becoming used to driven in such a way that the urea is lost in the kidneys therefore gradually, the concentrating ability is lost

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85
Q

What is seen when a fluid deprivation test is done on a patient with diabetes insipidus?

A

There is no functioning vasopressin system.
Their is no means of concentrating urine which results in extreme dehydration. There is a risk of coma and death if the patient is not rehydrated.

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86
Q

What test differentiates between central and nephrogenic diabetes insipidus?

A

DDAVP administration test.
Central: there is a lack of vasopressin. Replacing the vasopressin will reverse the effects, thus increase urine concentration
Nephrogenic: There is no lack of vasopressin, but a lack of a functioning receptor system so replacing vasopressin with DDAVP will have no effect

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87
Q

What is the stimulation with intravenous hypertonic saline test?

A

A more rapid test which is used to distinguish cranial diabetes insipidus from normal patients, polydipsics or nephrogenics.
An infusion with hypertonic saline causes a rapid increase in plasma osmolarity which initiates the normal vasopressin release.
In central diabetes insipidus, the patient cannot secrete vasopressin therefore there is no response

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88
Q

What is Syndrome of Inappropriate ADH (SIADH)

A

When plasma vasopressin concentration is inappropriate for the existing plasma osmolarity.

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89
Q

How does increased vasopressin lead to SIADH?

A
  • Excess vasopressin leads to increased water reabsorption
  • Decreased plasma osmolality (hyponatraemia)
  • Decreased urine volume
  • Compensatory ‘escape’ phenomenon. The body tries to compensate by making more urine (natriuresis) to restore urine output but this further decreases sodium.
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90
Q

What are the signs of SIADH?

A
  • Raised urine osmolality, decreased volume (initially)

- Decreased p[Na+] (hyponatraemia) mainly due to increased water reabsorption

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91
Q

What are the symptoms of SIADH?

A
  • Can have no symptoms
  • If p[Na+] is less than 120mM there is generalised weakness, poor mental function and nausea
  • If p[Na+] is less than 110 mM, there is confusion leading to coma and ultimately death
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92
Q

What are the causes of SIADH?

A
  • Tumours (ectopic secretion)
  • Neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease)
  • Thoracic disease (e.g. pneumonia)
  • Endocrine disease (e.g. Addison’s disease)
  • Physiological i.e. non-osmotic stimuli (e.g. hypovolaemia, pain, surgery)
  • Drugs, e.g. chlopropamide)
  • Idiopathic
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93
Q

How is SIADH treated?

A
  • Once the cause has been identified (e.g. tumour) then appropriate treatment (e.g. surgery) is applied
  • To reduce immediate concern, (i.e. hyponatraemia)
    1) Immediate: fluid restriction
    2) Longer-term: use drugs which prevent vasopressin action in the kidneys e.g. lithium, di-methyl-chlor-tetracycline (and V2 receptor antagonists)
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94
Q

Where are responses to exogenous vasopressin (argipressin) seen?

A 
- All vasopressin receptors are activated 
V1:
- Vascular smooth muscle 
- Non vascular smooth muscle 
- Anterior pituitary 
- Liver 
- Platelets 
- CNS

V2:

  • Kidney
  • Endothelial cells
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95
Q

What are the the pharmacological actions of argipressin-1?

A

Natriuresis:

  • V2 mediated however the mechanism is unclear
  • Evident only in high doses
  • May contribute to hyponatraemia
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96
Q

What are the pharmacological actions of argipressin-2?

A

Pressor action:

  • V1 mediated
  • effect of vascular smooth muscle
  • Not all beds are equally sensitive
  • Effect on coronary vessel are important (may cause cardiac ischaemia or anginal attacks)
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97
Q

Give example of selective vasopressin receptor peptidiergic agonists

A

V1 receptors: Terlipressin

V2 receptors: Desmopressin (DDAVP)

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98
Q

What are the clinical uses of desmopressin?

A
  • Central diabetes insipidus
  • Nocturnal enuresis
  • Haemophilia
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99
Q

How is desmopressin administered?

A

Nasally and orally

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100
Q

What is the effect of oral desmopressin?

A

Oral desmopressin produces a prompt sustained decrease in urine volume and an increase in urine osmolarity

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101
Q

How is desmopressin distrubited and what is its metabolism?

A

Distrubition: Retained in extraceullar fluid
Metabolsim: hepatic/ renal- half life of about 5 hours

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102
Q

What are the unwanted effects of desmopressin?

A
  • Fluid retention and hyponatraemia
  • Abdominal pain
  • Headaches
  • Nausea
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103
Q

What are the clinical uses of V1 receptor agonists?

A

Terlipressin: Oesophageal varices
Felypressin: To prolong the action of local anaesthetics

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104
Q

How is nephrogenic diabetes insipidus treated?

A
  • Thiazides e.g. bendroflumethiazide
    Possible mechanism:
  • Inhibits Na+/Cl- transport in distal convoluted tubule (leading to diuretic effect)
  • Volume depletion
  • Compensatory increase in Na+ reabsorption from the proximal tubule (plus a small decrease in GFR) etc
  • Increased proximal water reabsorption
  • Decreased fluid reaches collecting duct
  • Reduced urine volume
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105
Q

What are Vaptans?

A

Non- preptide vasopressin analogues use in the treatment of SIADH.
e.g. TOLVAPTAN (V2 receptor antagonist) is used for the treatment of hyponatraemia associated with SIADH
May be useful is treating congestive heart disease and other conditions

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106
Q

How does nicotine affect vasopressin secretion?

A

Increases secretion

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107
Q

What drugs decrease vasopressin secretion?

A

Alcohol

Glucocorticoids

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108
Q

What are the clinical features of hypothyroidism?

A
  • Dry and brittle hair
  • Lethargy, memory impairment and depression
  • Oedema of face and eyes
  • Think tongue, slow speech
  • Deepening voice
  • Cold intolerance, diminished perspiration
  • Cardiomegaly, poor heart sounds, hypertension
  • Weight gain with reduced appetite and ascites
  • Constipation
  • Eventually myoxodema coma
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109
Q

What is Plummer’s disease?

A

Where an adenoma (benign thyroid tumour) secretes thyroxine. It is also called a toxic nodule

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110
Q

What is Graves disease?

A

An autoimmune disease where anti -TSH receptor antibodies cause:

1) Hyperthyroidism
2) Visible goitre
3) Pretibial myoxoedema
4) Exophthalmos

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111
Q

What is a thyroid storm?

A

A medical emergency as is defined as anyone who is thyrotoxic who also has two key features that increase mortality. These are:

1) Pyrexia over 41 degrees celcius
2) A tachycardia over 140 or any arrhythmia
3) Cardiac failure
4) Derilium or psychosis or confusion
5) Jaundice or liver failure

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112
Q

What are the treatment options for Graves disease or hyperthyroidism?

A

1) Surgery
2) Radioiodine
3) Drugs

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113
Q

In hyperthyroid disorders, what activates the sympathetic nervous system?

A

Activated by the fact that thyroxine sensitises the beta adrenoreceptor to adrenaline and noradrenaline, so that minimal activity causes a profound effect
Thyroxine also increases basal metabolic rate

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114
Q

What is tetraiodothyronine (thyroxine T4)?

A

A prohormone which is converted by deiodinase enzyme activity into the more active metabolite tri-iodothyronine (T3)

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115
Q

Where does circulating T3 come from?

A

80%= deiodination of T4
20%= from direct thyroidal secretion
T3 provides almost all the thyroid hormone activity in target cells

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116
Q

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

A

1) Autoimmune primary hypothyroidism
2) Iatrogenic primary hypothyroidism- e.g. post-thyroidectomy, post-radioactive iodine
Oral administration
TSH used as a guidance for thyroxine dose- aim to suppress TSH into the reference range

3) Secondary hypothyroidism e.g. pituitary tumour, post-pituitary surgery or radiotherapy

Oral administration
TSH low due to pituitary failure so can’t use TSH as a guide to dose

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117
Q

What is the clinical use of liothyronine (synthetic trio-iodothyronine)

A

Myxoedema coma- a very rare complication of hypothyroidism

IV initially- as onset of action faster than T4 then oral when possible

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118
Q

What are complications of combined thyroid hormone replacement (T3/T4)?

A

Symptoms of toxicity

  • Palpitations
  • Tremor
  • Anxiety
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119
Q

What are the adverse effects of thyroid over-replacement?

A
  • Usually associated with low/suppressed TSH
  • Skeletal: increased bone turnover, reduction in bone mineral density, risk of osteoporosis
  • Cardiac: tachycardia, risk of dysrhythmia, particular atrial fibrillation
  • Metabolism: increased energy expenditure, weight loss
  • Increased β-adrenergic sensitivity: tremor, nervousness
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120
Q

What are the pharmacokinetics of T4 and T3

A
  • Active orally
    T4 plasma half life: 6 days
    T3 plasma half life: 2-5 days
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121
Q

What percentage of circulating T4 and T3 are bound to plasma proteins. What is the main plasma protein?

A 
T4= 99.97%
T3&= 99.7%

protein: thyroxine binding globuline (TBG)

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122
Q

In which situations will plasma proteins which bind to T3 and T4 increase in number?

A

In pregnancy

On prolonged treatment with oestrogens and phenothiazines

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123
Q

What causes thyroxine binding globulin to fall?

A

Malnutrition
Liver disease
Certain drug treatments

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124
Q

How much more T4 is in the plasma than T3?

A

10x more T4 than T3

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125
Q

How long does it take for T3 and T4 to be cleared?

A

The free and conjugated hormone is secreted in the bile and urine

T3: cleared in hours
T4: cleared in about 6 days

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126
Q

What is pretibial myxoedema?

A
  • The swelling (non-pitting) that occurs on the shins of patients with Grave’s disease: growth of soft tissue
  • Not to be confused with myoedema= hypothyrodism
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127
Q

What are the clinical features of hyperthyroidism?

A
  • Weight loss despite increased appetite
  • Breathlessness
  • Palpitations, tachycardia
  • Sweating
  • Heart intolerance
  • Diarrhoea
  • Lid lag and other sympathetic features
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128
Q

What are the features of Viral (de Quervain’s) thyroiditis?

A
  • Painful dysphagia
  • Hyperthyroidism
  • Pyrexia
  • Raised erythrocyte sedimentation rate
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129
Q

What is the natural history of viral thyroiditis?

A
  • Virus attacks thyroid gland which causes pain and tenderness
  • Thyroid stops making thyroxine and makes viruses instead
  • Therefore there is no iodine uptake
  • Radioiodine uptake is zero
  • Stores thyroxine is released
  • This is toxic with zero uptake
  • Four weeks later, stored thyroxine is exhausted, so hypothyroid
  • After a further month, resolution occurs
  • Patient then becomes euthyroid again
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130
Q

What are the classes of drugs used in the treatment of hyperthyroidism?

A

1) Thionamides (thiourylenes; anti-thyroid drugs)
- propylthiouracil (PTU)
- carbimazole (CBZ)
2) Potassium iodide
3) Radioiodine
4. β-blockers

The first three drugs are aimed at blocking thyroxine synthesis whereas beta blockers help the symptoms

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131
Q

What are the clinical uses of thionamides?

A

1) Daily treatment of hyperthyroid conditions (Graves)
2) Treatment prior to surgery
3) Reduction of symptoms while waiting for radioactive iodine to act

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132
Q

How do thionamides result in the reduction in synthesis and secretion of thyroid hormones?

A

The mechanism is based on inhibiting thyroid peroxidase. This leads to the inhibition of iodination of thyroglobulin. This inhibits the coupling of iodotyrosines which decreases the synthesis and secretion of T3 and T4

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133
Q

What are the effects of thionamides?

A

1) Effects on synthesis and secretion of T3 and T4
2) Possible immunosuppressive effects which might suppress antibody production in Graves disease
3) Reduces the conversion of T4 and T3 in peripheral tissues

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134
Q

What are the unwanted actions of thionamides?

A

1) Agranulocytosis/granulocytopenia (reduction or absence of granular leukocytes - rare and reversible on withdrawal of the drug
2) Rashes (relatively common)
3) Headaches
4) Nausea
5) Jaundice
6) Joint pain

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135
Q

What are the pharmacokinetics of thionamides?

A

1) Orally active
2) Carbimazole is a pro-drug which first has to be converted into methimazole
3) Plasma half life = 6-15 hours
4) Crosses placenta and is secreted in milk
5) Metabolised in the liver and is secreted in the urine

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136
Q

How are patients on thionamides followed up?

A
  • Usually the aim is to stop anti-thyroid drug treatment after 18 months
  • Review the patient periodically including thyroid function tests for remission/relapse
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137
Q

What is the role of beta blockers in thyrotoxicosis?

A
  • It takes several weeks for anti-thryoid drugs to have clinical effects such as reduced tumour, slower heart rate and less anxiety.
  • A non selective beta blocker (propanolol) achieves these effects in the interim
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138
Q

What are the uses of iodide (usually KI) in hyperthyroidism?

A

Used in combination with other drugs.

  • Preparation of hyperthyroid patients for surgery
  • Severe thyrotoxic crisis (thyroid storm)
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139
Q

What is the Wolff-Chaikoff effect?

A

The temporary reduction in thyroid hormones following ingestion of large amounts of iodine.
Inhibition of organification (thyroglobulin iodination)
Auto-regulatory phenomenon; thyroid rejects ingested iodide and hence prevents synthesis of large quantities of thyroid hormone..

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140
Q

How does iodine act in hyperthyroidism?

A

1) Inhibiting secretion of thyroid hormones, particularly in thyrotoxic patients
2) Reducing hyperthyroid symptoms
3) Reducing vascularity and size of the thyroid gland

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141
Q

What are the unwanted actions of iodine?

A

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

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142
Q

What are the pharmacokinetics of iodine?

A 
Given orally (Lugol's solution, aqueous iodine) 
Maximum effects after 10 days continuous administration
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143
Q

What is radioiodine used to treat?

A

Hyperthyroidism (usually Graves disease) and thyroid cancer

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144
Q

What is the mode of action of radioiodine?

A

The isotope becomes incorporated into thyroglobulin and therefore concentrates in the thyroid gland, emitting beta particles which have a very short range.
Thyroid function is ablated as local tissue damage occurs

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145
Q

What are the pharmacokinetics of radioiodine?

A

1) Discontinue anti-thyroid drugs 7-10 days prior to radioiodine treatment
2) Administer as a single oral dose
3) Radioactive half life = 8 days
4) Radioactivity negligible after 2 months. Maximum effect 2- 3 months

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146
Q

What cautions are in place when using radioiodine?

A
  • Avoid close contact with small children for several week after receiving radioiodine
  • Contra-indicated in pregnancy and breast feeding
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147
Q

What are the four common histologies of thyroid cancers?

A

1) Papillary thyroid cancer- takes up radioiodine. Good prognosis.
2) Follicular thyroid cancer- takes up radioiodine. Good prognosis
3) Anaplastic- poor prognosis
4) Medullary thyroid cancer- from C cells of the thyroid and secretes calcitonin

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148
Q

What are the clinical features of Cushing’s?

A
  • Too much cortisol
  • Centripetal obesity
  • Moon face and buffalo lump
  • Proximal myopathy
  • Hypertension and hypokalaemia
  • Red striae, thin skin and bruising
  • Osteoporosis, diabetes
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149
Q

What are the causes of Cushing’s?

A
  • Taking too many steroids
  • Pituitary dependent Cushing’s disease
  • Ectopic ACTH from lung cancer
  • Adrenal adenoma secreting cortisol
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150
Q

What investigations are used to determine the cause of Cushing’s syndrome?

A
  • 24 hour urine collection for urinary free cortisol
  • Blood diurinal cortisol levels
  • Low dose dexamethasone suppression test
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151
Q

When is cortisol usually highest and lowest

A

Cortisol is usually highest at 9am and lowest at midnight if asleep

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152
Q

What is the low dose dexamethasone suppression test?

A

Used to determine the cause of Cushing’s syndrome

  • 0.5 mg 6 hourly for 48 hours
  • Dexamethasone is an artificial steroid
  • Normals will suppress cortisol to zero
  • Any cause of Cushing’s will fail to suppress
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153
Q

How is Cushing’s treated?

A
  • Dependant on the cause
  • Pituitary surgery (transsphenoidal hypophysectomy)
  • Bilateral adrenalectomy
  • Unilateral adrenalectomy for adrenal mass
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154
Q

What is Conn’s syndrome?

A
  • A benign adrenal cortical tumour
  • Aldosterone in excess
  • Results in hypertension and hypokalaemia
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155
Q

How is Conn’s syndrome diagnosed?

A
  • Primary hyperaldosteronism

- Renin-angiotensin system should be suppressed

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156
Q

How is Conn’s syndrome treated?

A
  • Aldosterone receptor antagonist: spironolactone
  • Surgery: image and remove the adenoma
  • If bilateral adrenal hyperplasia, can stay on spironolactone
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157
Q

What are phaeochromocytomas?

A
  • Tumours of the adrenal medulla which secrete catecholamines
    (adrenaline and nor-adrenaline)
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158
Q

What are the clinical features of a patient with a phaeochromocytoma?

A
  • Hypertension in young people
  • Episodic severe hypertension (after abdominal palpation)
  • More common in certain inherited conditions
  • Severe hypertension can cause myocardial infarction or a stroke
  • High adrenaline can cause ventricular fibrillation and death
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159
Q

How is phaeochromocytoma managed?

A
  • Eventually will need surgery. The patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis
  • Alpha blockade is first therapeutic step
  • Patients may need IV fluid as alpha blockade commences
  • To prevent tachycardia, a beta blockade is added
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160
Q

Which drugs are inhibitors of steroid biosynthesis?

A

Metraprone
Ketaconazole

(used for treatment of Cushing’s Syndrome)

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161
Q

What is the mechanism of action of metyrapone

A

Inhibits the enzyme 11β-hydroxylase which causes the inhibition of the production of corticosterone and cortisol.
Steroid synthesis in the zona fasciculata (and reticularis) is arrested at the 11-deoxycortisol stage
11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland which results in ACTH secretion increasing and plasma deoxycortisol levels increasing.

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162
Q

What are the uses of metyrpone?

A

1) Control of Cushing’s syndrome prior to surgery
- Adjust dose (oral) according to cortisol production (aim for mean serum cortisol 150-300 nmol/L)
2) Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)

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163
Q

What are the unwanted action of metyrapone?

A
  • Nausea, vomiting, dizziness
  • Sedation, hypoadrenalism
  • Hypertension on long term administration
  • Hirsutism
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164
Q

What is the mechanism of action of ketoconazole?

A

Mainly used as an anti-fungal agent
At higher concentrations, it inhibits steroidogenesis due to non-specific inhibition of cytochrome P450 enzymes. It blocks the production of glucocorticoids, mineralcorticoids and sex steroids

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165
Q

What are the uses of ketoconazole?

A

Similar to metryapone
Cushing’s syndrome: treatment and control of symptoms prior to surgery
- Orally active

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166
Q

What are the unwanted action of ketoconazole?

A
  • Nausea, vomiting, abdominal pain,
  • Alopecia
  • Gynaecomastia, oligospermia, impotence, decreased libido
  • Ventricular tachycardias
  • Liver damage, possibly fatal therefore need to monitor liver function weekly, clinically and biochemically
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167
Q

What is spironolactone used for?

A

Primary hyperaldosteronism (Conn’s syndrome)

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168
Q

What is the mechanism of action for spironolactone?

A
  • It is a prodrug which is rapidly converted into canrenone: a competitive antagonist of the mineraolcorticoid receptor.
  • It blocks Na+ reabsorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
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169
Q

What are the pharmacokinetics of spironolactone?

A
  • Orally active
  • Given daily in single or divided doses
  • Highly protein bound and metabolised in the liver
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170
Q

What are the unwanted action of spironolactone?

A
  • Menstrual irregularities (+ progesterone receptor)
  • Gynaecomastia (androgen receptor binding)
  • Gi tract irritation

Caution- renal and hepatic disease

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171
Q

What is epleronone?

A
  • A mineralocorticoid receptor antagonist
  • Similar affinity to the mineralocorticoid receptor compared to spironolactone
  • Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated
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172
Q

What are the causes of adrenocorticol failure?

A
  • Adrenal glands destroyed
  • Enzymes in the steroid synthetic pathway not working
  • Tuberculous Addison’s disease (commonest worldwide)
  • Autoimmune Addison’s disease (commonest in UK)
  • Congenital adrenal hyperplasia
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173
Q

What are the consequences of adrenocortical failure?

A
  • Fall in blood pressure
  • Loss of salt in the urine
  • Increased plasma potassium
  • Fall in glucose due to glucocorticoid deficiency
  • High ACTH resulting in increased pigmentation
  • Eventual death due to severe hypotension
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174
Q

Where is POMC (pro-opio melanocortin) synthesised and what is it broken down into?

A

Synthesised: Pituitary

Broken down to ACTH and MSH and endorphins and enkephalins and other peptides

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175
Q

What are the tests for Addison’s?

A

Can be tested for if 9am cortisol is low and ACTH is high.
synACTH test test- 250 ug synacthen intramuscularly
Measure cortisol response

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176
Q

What is the comment cause of congenital adrenal hyperplasia

A

21- hydroxylase deficiency

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177
Q

In complete 21-hydroxylase deficiency, which hormones are totally absent, which are in excess and how long can one survive?

A

Absent: Aldosterone and cortisol
Excess: Sex steroids and testosterone
Survival: Less than 24 hours

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178
Q

What is the name given when congenital adrenal hyperplasia presents as a neonate?

A

Addisonian crisis

- Girls might have ambiguous genitalia

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179
Q

Which hormones are deficient and in excess in partial 21-hydroxylase deficiency?

A

Deficient: cortisol and aldosterone
Excess: sex steroids and testosterone

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180
Q

What problems are associated with partial 21 hydroxylase deficiency?

A

In later life, hirsutism and virilisation in girls.

Precocious puberty in boys due to adrenal tesosterone

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181
Q

What can 11 deoxycorticosterone cause in excess?

A

Hypertension and hypokalaemia
Virilisation
11 deoxycorticosterone behaves like aldosterone

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182
Q

In 11-hydroxylase deficiency, which hormones are deficient and which are in excess?

A

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

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183
Q

What hormones are deficient and which are in excess in 17-hydroxylase deficiency?

A

Deficient: Cortisol and sex steroids
Excess: 11-deoxycorticosterone and aldosterone (mineralocorticoids)

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184
Q

What are the problems associated with 17-hyroxylase deficiency?

A
  • Hypertension
  • Low K+
  • Sex steroid deficiency
  • Glucocorticoid deficiency (low glucose)
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185
Q

What are the main differences between glucocorticoid receptors and mineralocorticoid receptors?

A

Glucocorticoid receptors:

  • Wide distribution
  • Selective for glucocorticoids
  • Low affinity for cortisol

Mineralocorticoid receptors:

  • Discrete distribution
  • Do NOT distinguish between aldosterone and cortisol
  • High affinity for cortisol
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186
Q

What is cortisol (hydrocortisone)?

A

Glucocorticoid with mineralocorticoid activity at high doses

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187
Q

What is prednisolone?

A

Glucocorticoid with weak mineralocorticoid activity

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188
Q

What is dexamethasone?

A

Synthetic glucocorticoid with no mineralocorticoid activity

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189
Q

What is fludrocortisone?

A
  • Aldosterone analogue

- Used as an aldosterone substitute

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190
Q

Which corticosteroids are administered orally?

A

Hydrocortisone
Prednisolone
Dexamethasone
Fludrocortisone

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191
Q

Which corticosteroids are administered parenterally (IV or IM)?

A

Hydrocortisone
Prednisolone
Dexamethasone

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192
Q

How are corticosteroids distributed?

A 
- Binding to plasma proteins (CBG and albumin) 
Hydrocortisone (90-95% bound) 
> Prednisolone 
>Dexamethasone 
> Fludrocortisone (only albumin)
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193
Q

How are corticosteroids metabolised and excreted?

A

Hepatic

  • Reduction of A ring and other modifications
  • Conjugation
  • Excretion via bile and urine
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194
Q

What is the duration of corticosteroids?

A 
Hydrocortisone and fludrocortisone: 
Half life= 1 hour 
Duration= 8 hours
Prednisolone: Duration= 12 hours 
Dexamethasone: Duration= 40 hours
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195
Q

What is primary adrenocortical failure?

A

Cortical adrenal insufficiency/ Addison’s disease

- Patients lack cortisol and aldosterone

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196
Q

How is primary adrenocortical failure treated?

A

Treat with hydrocortisone and fludrocortisone by mouth

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197
Q

What is secondary adrenocortical failure?

A

ACTH deficiency

Patients lack cortisol bu aldosterone is normal

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198
Q

How is secondary adrenocortical failure treated?

A

Treat with hydrocortisone

- Titrate dose

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199
Q

What is acute adrenocortical failure?

A

Addisonian crisis

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200
Q

How is acute adrenocortical failure treated?

A
  • Saline to rehydrate the patient
  • High dose hydrocortisone (IV infusion or IM ever 6 hours, mineralocorticoid effect at high dose)
  • 5% dextrose if hypoglycaemic
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201
Q

What is congenital adrenal hyperplasia (CAH)?

A

Congenital lack of steroid synthetic enzymes

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202
Q

What are the objectives of corticosteroid replacement therapy for congenital adrenal hyperplasia?

A
  • Replace cortisol
  • Suppress ACTH and thus adrenal androgen production
  • Replace aldosterone in salt wasting forms
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203
Q

What is normal cortisol production?

A

20mg/day

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204
Q

What is cortisol production in stress?

A

200-300 mg/day

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205
Q

In patients with adrenocorticol failure, what should be done if patients are vulnerable to stress?

A

Increase dosage of corticosteroid replacement therapy

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206
Q

What is iatrogenic adrenocorticol failure?

A
  • Patients are on long-term, high dose corticosteriod treatment
  • They have a suppressed HPA axis
  • Require protection with additional steroids e.g. surgery, acute illness
  • Should carry a steroid alert card
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207
Q

What are the clinical uses of glucocorticoids?

A
  • Replacement in adrenocortical insufficiency
  • Replacement and suppression of ACTH in congenital adrenal hyperplasia
  • Differential diagnosis of Cushing’s syndrome
  • Inflammatory disease
  • Hypersensitivity
  • Autoimmune disorders
  • Prevention of tissue rejection
  • Neoplastic disease
  • Preterm birth
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208
Q

How can inflammation be both helpful and harmful?

A

Helpful: powerful defence against pathogens
Harmful: When the response is inappropriate
- Hypersensitivity reactions e.g. anaphylaxis
- Chronic disease e.g. rheumatoid arthritis

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209
Q

What are the characteristics of inflamed tissue?

A

Red- vasodilation
Hot- increased blood flow
Swollen- local oedema
Painful- activation of sensory afferents

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210
Q

What are the characteristics of chronic inflammatory responses?

A
  • Tissue damage e.g. cell death, ulceration
  • Local repaire: proliferation of local cells, fibrous connective tissue and blood vessels
  • Scarring
  • Impaired tissue function:
    e.g. restricted joint movement in RA
    bronchospasm in asthma
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211
Q

What is the innate (non-immunological) mechanism of inflammation?

A
  • Comprises of vascular and cellular events
  • Triggered by pro-inflammatory mediators which are derived from plasma (e.g. complement factors) and local and invading cells (e.g. histamine, eicosanoids, nitric oxide and cytokines)
  • Modulated by anti-inflammatory substances
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212
Q

What is the acquired (specific) mechanism of inflammation?

A

Acquired immunological responses are initiated by

  • Antigenic products of invading micro-organisms
  • Hypersensitivity reactions to exogenous substances
  • Hypersensitivity reactions to endogenous proteins that are normally innocuous i.e. autoimmunity
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213
Q

Describe the induction and effector phases of lymphocyte activation

A

1) The antigen is present by APC to naive CD4+ T-helper cells
2) CD4+-T helper cells recognise the antigen and binds which activates the CD4+ T-helper cell
3) Activation leads to the release of IL-2 and expression of IL-2 receptors
4) IL-2 causes proliferation of the CD4+ T helper cell into a clone of activated T cells
5) Activated T cells differentiate into Th1 or Th2 cells
6) CD8+ T-cells effect cell mediated reactions whereas B cells are involved in antibody-mediated reactions

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214
Q

What drugs are used to treat inflammation?

A
  • Non-steroidal anti-inflammatory drugs (e.g. aspirin)

- Steroidal anti-inflammatory drugs i.e. glucocorticoids

215
Q

What effects do glucocorticoids have on vascular events?

A
  • Inhibit the vasodilator response

- Reduce fluid exudation

216
Q

What effects do glucocorticoids have of cellular events?

A
  • Reduce influx and activity of polymorphonuclear leukocytes
  • Inhibit recruitment and activity of mononuclear cells
  • Inhibit angiogenesis
  • Block clonal proliferation of T-cell, therefore reduce T-cell dependent immunity
  • Inhibit fibroblast function
217
Q

The production of which pro-inglammatory mediators are inhibited with the use of glucocorticoids?

A
  • Histamine
  • Eicosanoids (prostanoids, leukotrienes and PAF)
  • Cytokines which drive immune responses
  • Complement components
  • Nitric oxide
218
Q

Which anti-inflammatory protein does the use of glucocorticoids increase the production of?

A

Annexin-1

219
Q

Why is extracellular matrix formation suppressed by glucocorticoids?

A
  • Matrix protein production is reduced e.g. collagen, glycosaminoglycans
  • Enhancing production of degrading enzymes e.g. collagenase
220
Q

What is the molecular bases of glucocorticoid action?

A
  • Blockade of eicosanoid production

- Inhibition of cell mediated immune responses

221
Q

What are the uses of glucocorticoids as anti-inflammatory/immunosuppressive therapy?

A
  • Asthma
  • Inflammatory conditions of the skin, nasal mucosa, ear, eye, joints
  • Autoimmune/inflammatory disease e.g. rheumatoid arthritis
  • Other autoimmune disease, e.g. myasthenia gravis
  • To prevent rejection following organ or bone marrow transplants
222
Q

What are the uses of glucocorticoids in neoplastic disease?

A
  • In combination with cytotoxic drugs in specific malignancies e.g. acute lymphocytic leukaemia
  • To reduce cerebral oedema in patients with brain tumours
  • As a component of anti-emetic treatment with chemotherapy
  • To elevate mood in terminally ill subjects
223
Q

What is the clinical use of glucocorticoids in pregnancy?

A

To mature the foetal lung for pre-term birth

224
Q

How can the unwanted effects of corticosteroids be minimised?

A
  • Administer locally where possible
  • Use minimum effective dose
  • Use a GR- selective steroid
  • Use alternate day therapy or intermittent therapy
  • Recommend patients carry a steroid card
  • Withdraw steroids slowly
225
Q

What is a result of prolonged glucocorticoid excess?

A

Iatrogenic Cushing’s syndrome

226
Q

What is the definition of menopause?

A

The permanent cessation of menstruation resulting from the loss of ovarian follicular activity. Average age 51 (range 45-55)

227
Q

What is the definition of climacteric?

A

The period of transition from predictable ovarian function though the postmenopausal years

228
Q

What is premature ovarian insufficiency?

A

Menopause occurring before the age of 40 and occurs in 1% of women.
May be autoimmune or secondary to surgery, chemotherapy or radiation

229
Q

What are the symptoms of menopause?

A

1) Hot flushes (head, neck and upper chest)
2) Sleep disturbance
3) Depression
4) Urogenital atrophy
5) Decreased libido
6) Joint pain

230
Q

How can menopause cause osteoporosis?

A

Oestrogen deficiency leads to a loss of bone matrix.

Postmenopausal women may lose 1-3% of bone mass per year and have a 10-fold increased risk or fracture

231
Q

Why is cardiovascular disease a complication of menopause?

A

Women are relatively protected against CV disease before menopause but have the same risk as men by the age of 70.

232
Q

When should oestrogen only hormone replacement therapy be used?

A

Only in women who have had a hysterectomy

233
Q

What is the purpose of hormone replacement therapy in treating menopause?

A

Controls the vasomotor symptoms (hot flushes)

234
Q

What does combined hormone replacement therapy consist of?

A

Oestrogen and Progestagen to prevent endometrial hyperplasia.
Oestrogen promotes endometrial proliferation and increases the risk of endometrial carcinoma
Progestogens reduce the risk of endometrial cancer

235
Q

How is hormone replacement therapy formulated?

A

Cyclical: Oestrogen everyday and progestagen (12-14 days) Continuous combined
Oestrogen preparations:
- Oral estradiol (1mg)
- Oral conjugated equine oestrogen (0.625mg)
- Transdermal (patch) oestradiol (50 microgram/day)
- Intravaginal

236
Q

What are the characteristics of oestogens?

A 
Estradiol is well absorbed 
Low bioavailability (first pass metabolism)
237
Q

What is estrone sulphate?

A

A ‘conjugated oestrogen’

238
Q

What is ethinyl estradiol?

A

A semi synthetic oestrogen. The ethinyl group on position 17 of oestradiol protect the molecule from first pass metabolsim

239
Q

What are the side effects of hormone replacement therapy?

A
  • Breast cancer
  • Venous thromboembolism (VTE)
  • Stroke
  • Gallstones
  • The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for 5 years is very low
240
Q

What is Tibolone? (used in the treatment of menopause)

A
  • A synthetic prohormone
  • Oestrogenic, progestogenic and weak androgenic actions
  • Reduces fracture risk
  • Increased risk of stroke, possible increase risk of breast cancer
241
Q

Give examples of two selective oestrogen receptor modulators (SERMs)

A

Raloxifene

Tamoxifen

242
Q

What is raloxifene use for?

A

The treatment and prevention of postmenopausal osteoporosis

243
Q

What is the mechanism of raloxifene?

A
  • Tissue selective

- Oestrogenic in bone, anti-oestrogenic in breast and uterus

244
Q

What sees a reduced and increased risk upon use of raloxifene?

A
  • Reduces risk of vertebral fractures and breast cancer
  • Increases risk of fatal stroke and venous thromboembolism
  • Does not reduce vasomotor symptoms
245
Q

What is tamoxifen?

A

An SERM and an anti-cancer drug

  • Anti-oestrogenic on breast tissue
  • Used to treat oestrogen-dependent breast tumours and metastatic breast cancers
246
Q

How can most oestrogens be administered?

A

Via transdermal skin patches

247
Q

What are the characteristics of progestogens?

A

Poorly absorbed

Rapidly metabolised in the liver

248
Q

How can progesterone be administered?

A

Intramuscular injections as a depot preparation

249
Q

What do combined oral contraceptives consist of?

A

Oestrogen (ethinyl oestradiol) and progestogen (eg levonorgestrel and norethisterone). These components provide synergistic pharmacology to suppress ovulation via multiple mechanisms

250
Q

By which mechanisms do combined oral contraceptives suppress ovulation?

A
  • Feedback actions of oestrogen and progestogen at hypothalamus and pituitary
  • Progestogen thickens cervical mucus
  • Oestrogen upregulates progestogen receptrs
  • Oestrogen counteracts the androgenic effects of synthetic progestogen
  • Take for 21 days (or 12 weeks) stop for 7 days
251
Q

When are progesterone-only contraceptives used?

A

When oestrogens are contra-indicated e.g. CVS problems, history of thrombosis, prior to major surgery, during lactation

252
Q

What is emergency contraception?

A

Consists of combined oestrogen and progestogen
or progestogen only (levonorgestrel)- within 72 hours
- Ulipristal (up to 120 hours after intercourse)
- Anti-progestin activity
- Delay ovulation by as much as 5 days
- Impairs implantation
- May cause nausea and vomiting

253
Q

During the luteal phase of the menstrual cycles, what happens to the endometrium if implantation does not occur?

A

It sheds

254
Q

What is infertility?

A

Inability to conceive after 1 year of regular unprotected sex. Occurs in 1:10 couples. Caused by abnormalities in males (30%) or females (45%) or unknown (25%)

255
Q

What are the clinical features of male hypogonadism?

A
  • Loss of libido
  • Impotence
  • Small testes
  • Decrease muscle bulk
  • Osteoporosis
256
Q

What are the causes of male hypogonadism

A 
- Hypothalamic-pituityary disease
(hypopituitarism, Kallman's syndrome, illness/underweight) 
- Primary gonadal disease
- Hyperprolactinaemia 
- Androgen receptor deficiency
257
Q

What are the congenital and acquired causes of primary gonadal disease?

A

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

258
Q

What are investigations are used for male hypogonadism?

A
  • LH, FSH, testosterone > if all are low then MRI pituitary
  • Prolactin
  • Sperm count
  • Chromosomal analysis (Klinefelters XXY)
259
Q

What is azoospermia?

A

Absence of sperm in ejaculate

260
Q

What is oligospermia?

A

Reduced numbers of sperm in ejaculate

261
Q

What is the treatment for male hypogonadism?

A
  • Replacement testosterone for all patients
  • For fertility: if hypothalamus/pituitary disease
  • Hyperprolactinaemia- dopamine agonist
262
Q

Where are the endogenous sites of production of androgens?

A

1) Interstitial Leydig cells of the testes
2) Adrenal cortex (males and females)
3) Ovaries
4) Placenta
5) Tumours

263
Q

What are the main actions of testosterone?

A

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

264
Q

How much of circulating testosterone is protein bound?

A

98%

265
Q

What are the clinical uses of testosterone?

A

In adulthood, testosterone will increase:

  • Lead body mass
  • Muscle size and strength
  • Bone formation and bone mass (in young men)
  • Libido and potency

Does not restore fertility

266
Q

What is amenorrhoea?

A

Absence of periods

267
Q

What is primary amenorrhoea?

A

Failure to begin spontaneous menstruation by the age of 16

268
Q

What is secondary amenorrhoea?

A

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

269
Q

What is oligomenorrhoea?

A

Irregular long cycles

270
Q

What are the causes of amenorrhoea?

A
  • Pregnancy/lactation
  • Ovarian failure
  • Gonadotrophin failure
  • Hyperprolactinaemia
  • Androgen excess: gonadal tumour
271
Q

What is used to investigate amenorrhoea?

A
  • Pregnancy test
  • LH, FSH, oestradiol
  • Day 21 progesterone
  • Prolactin, thyroid function tests
  • Androgens (testosterone, androstenedione, DHEAS)
  • Chromosomal analysis (Turners 45 XO)
  • Ultrasound scan ovaries/ uterus
272
Q

How is amenorrhoea treated?

A
  • Treat the cause (eg low weight)
  • Primary ovarian failure - infertile, HRT
  • Hypothalamic/pituitary disease:
    HRT for oestrogen replacement
    Fertility: gonadotrophins (LH and FSH) part of IVF treatment
273
Q

What is the incidence of polycystic ovarian syndrome (PCOS)?

A

1 in 12 women of reproductive age

- Associated with increased cardiovascular risk and insulin resistance

274
Q

What is the criteria to diagnose polycystic ovarian syndrome?

A

Need 2 of the following:

  • Polycystic ovaries on USS
  • Oligo-/anovulation
  • Clinical/biochemical androgen excess
275
Q

What are the clinical features of polycystic ovarian syndrome?

A
  • Hirsuitism
  • Menstrual cycle disturbance
  • Increased BMI
276
Q

What is used in the treatment of polycystic ovarian syndrome?

A

Metformin
Clomiphene
Gonadotrophin therapy as part of IVF treatment

277
Q

What is clomiphene?

A

A fertility drug

  • Is anti-oestrogenic in the hypothalamo-pituitary axis
  • Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback, resulting in an increase in the secretion of GnRH and gonadotrophins
278
Q

What are the causes of hyperprolactinaemia?

A

1) Dopamine antagonist drugs
- Anti-emetics (metoclopramide)
- Anti-psychotics (phenothiazines)
2) Prolactinoma
3) Stalk compression due to pituitary adenoma
4) Polycystic ovarian syndrome
5) Hypothyroidism
6) Oestrogens (OCP), pregnancy, lactation
7) Idiopathic

279
Q

What are the clinical features of hyperprolactinaemia?

A
  • Galactorrhoea
  • Reduced GnRH secretion/ LH action > hypogonadism
  • Prolactinoma (headache, visual field defect)
280
Q

How is hyperprolactinaemia treated?

A
  • Treat the cause - stop drugs
  • Dopamine agonist: bromocriptine, cabergoline
  • Prolactinoma: dopamine agonist therapy, pituitary surgery rarely needed
281
Q

What are the investigations used to diagnose hyperprolactinaemia?

A

1) Drug history
2) Serum prolactin
3) Pregnancy test
4) Thyroid function tests
5) Anterior pituitary function
6) MRI pituitary
7) Visual fields

282
Q

What controls the reabsorption of most tubular fluid reabsorbed within rete testes and early epididymis?

A

Oestrogen

283
Q

What controls the secretion of nutrients and other molecules within the male reproductive tract?

A

Androgen in order to :

  • provide energy for impending possible journey
  • coat the surface of the spermatozoa
284
Q

What does semen consist of?

A
  • Spermatazoa (15-120x106/ml)
  • Seminal fluid (2-5ml)
  • Leukocytes
  • Potential viruses eg. heptatitis B, HIV
285
Q

Where is semen ejaculated into?

A

The female tract, usually vagina but sometimes into the cervical canal

286
Q

What is contributed to the seminal fluid from the epididymis/testis?

A 
The contribution is small
Consists of:-
Inositol
Carnitine 
Glycerolphosphorylcholine
287
Q

What is contributed to the seminal fluid from the accessory sex glands?

A

Seminal vesicle contributes approx 2/3 vol, including:
- fructose
fibrinogen
Prostate contributes approx 1/3 volume, including
- citric acid (Ca2+ chelator)
- acid phosphatase
- fibrinogenase (& fibrinolytic enzyme)
The ampulla and bulbourethral glands are also accessory organs

288
Q

What is the form of spermatozoa from the seminiferous tubule?

A

Quiescent and incapable of fertilising ovum

289
Q

What is the form of spermatozoa from the vas deferens?

A

Capable of limited movement (whiplash activity) and have only limited capability for fertilising the ovum. This is activation

290
Q

What is capacitation?

A

Only occurs within the female reproductive tract, it isis where full activity and fertilising capability of the spermatozoa is achieved

291
Q

What are the steps involved in capacitation of the sperm?

A

1) Loss of glycoprotein coat
2) Change in surface membrane characteristics leading to the acrosome reaction when in close proximity to an ovum
3) Further whiplash movements of the tail

292
Q

What percentage of spermatozoa in ejaculate enter the cervix?

A

1%

293
Q

Where does capacitation of the sperm take place?

A

In the ionic and proteolytic environment of the oviduct- it is oestrogen dependent
The components of capacitation are Ca++ dependent

294
Q

What is the acrosome reactions?

A

There is a ZP3 glycoprotein containing binding site on the ovum to which the capacitated sperm binds.
Following the binding, progesterone stimulates Ca++ influx into the sperm. This results in the Ca- dependent acrosome reaction.
This results in an exposed spermatozoon recognition site to bind to a second glycoprotein (ZP2). This leads to the speratozoon penetrating the zona pellucida.

295
Q

During the acrosome reaction, how does the spermatozoon penetrate the zona pellucida?

A

By releasing hyaluronidase and other proteolytic enzymes

296
Q

What is fertilisation?

A
  • Normally occurs within the fallopian tube
  • It results in the expulsion of a second polar body which leads to the zonal reaction.
  • One diploidy is established, the zygote starts dividing to form the initial 2-cell conceptus
297
Q

What is the zonal reaction?

A

Cortical granules release molecules which degrade the zona pellucida (including ZP2 and ZP3) to prevent further binding of other sperm (Ca++ dependent)

298
Q

How does the conceptus develop?

A
  • The conceptus continues to divide as it moves down the fallopian tube to the uterus (3-4 days)
  • The conceptus first compacts to 8-16 cell morula, then into a blastocyst
  • The transfer to the uterus is facilitated by increasing the progesterone: oestrogen ratio (luteal phase)
  • It estabilishes physical and nutritional contact with maternal tissues
299
Q

Until implantation, from where does the developing conceptus receive its nutrients?

A

Uterine secretions

300
Q

How long can the free-living phase last during the development of the conceptus?

A

9-10 days

301
Q

What do the layers of a blastocyst develop into?

A

Inner cell mass- becomes the embryo

Outer trophoblast- becomes the chorion

302
Q

Describe implantation

A
  • It is invasive in humans
  • Involved initial attachment phase (other trophoblast cells contact uterine surface epithelium)
  • Within a few hours, decidualisation of underlying uterine stromal tissue
  • Requires progesterone domination in the presence of oestrogen
303
Q

What stimulates the adhesion of the blastocyst to the endometrial cells?

A
  • Leukaemia inhibitory factor (LIF) from the endometrial secretory glands (and blastocyst)
  • Interleukin-11 (IL11) from the endometrial cells released into the uterine fluid may be involved
  • Other molecules involved includes HB-EGF
304
Q

What is the decidualisation reaction?

A
  • Involves invasion of the underlying uterine stromal tissue by the trophoblast cells of the blastocyst
  • Within hours there is increase vascular permeability in the invasion region associated with oedema of tissues. There is also localised changes in the intracellular composition and progressive sprouting and growth of capillaries.
305
Q

What factors are involved in the decidualisation reaction?

A

Mainly interleukin-11 (IL11), histamine, certain prostaglandins and and TGFb which promotes angiogenesis

306
Q

What hormones are involved in the first 5-6 weeks of pregnancy?

A

The maternal ovaries release gonadal steroids that are essential for the developing fetoplacental unit.

  • Circulating progesterone and oestadriol concentrations are high during this period. Release of maternal LH and FSH are inhibited via negative feedback.
  • The stimulatory role of gonadotrophins on the corpus luteum are taken over by human chorionic gonadotrophin (hCG) which are produced by the developing implanting blastocyst (syncytiotrophoblast)
307
Q

What are the roles of hormones during pregnancy from day 40 onwards?

A
  • Ovariectomy has no effect on pregnancy

- Role of the corpus luteum is taken over by the fetoplacental unit

308
Q

During pregnancy, which maternal hormones increase?

A 
Thyrotrophin 
Corticotrophin 
Prolactin 
Growth hormone 
Iodothyronines 
Adrenal steroids 
PTH
309
Q

During pregnancy, which maternal hormones decrease?

A

Gonadotrophins

hCH decreases as the placental hGH- Variant increases towards term

310
Q

What is the purpose of 1,25(OH)2D3 (Calcitrol)?

A

Crucial in regulating the absorption of calcium.
Its principle effect is to stimulate intestinal absorption of Ca++, which provides the necessary ions for normal bone mineralisation.
- Stimulates osteoclast formation from precursors in the bone and stimulates their activity and stimulates osteoblasts- OAFs, matrix protein synthesis or repressin.
- Has renal effects

311
Q

What is the definition of vitamin D deficiency?

A

Lack of mineralisation in bone

312
Q

What is the result of vitamin D deficiency?

A

Results in softening of bone
Bone deformities
Bone pain
Severe proximal myopathy

313
Q

What does vitamin D deficiency cause in children and adults?

A

Children- rickets

Adults- osteomalacia

314
Q

What are the causes of vitamin D deficiency?

A
  • Diet
  • Lack of sunlight
  • Gastrointestinal malabsorptive states
  • Renal failure
  • Receptor defects (autosomal recessive)
315
Q

Why is vitamin D deficiency re-emerging as a problem in the UK?

A

Inadequate diet and lack of sunlight

316
Q

How can vitamin D deficiency be diagnosed?

A
  • Plasma [25(OH)D3] usually low
  • Plasma [Ca++] low unless secondary hyperparathyroidism has been induced when it may appear normal
  • [PTH] high
  • Plasma [PO43-] low
  • Radiological findings (variable); e.g. widened osteoid seams
317
Q

What two main effects of decreased renal function lead to hypocalcaemia?

A
  • Decrease calcitrol- causes decreased calcium absorption

- Decreased phosphate excretion- increased plasma phosphate which leads to extra- skeletal calcification

318
Q

What are the main effects of hypocalcaemia which results from renal failure?

A
  • Decreased bone mineralisation- osteitis fibrosa cystica (softening and deformities of bone
  • Increase PTH secretion- increased bone resorption- osteitis fibrosa cystica
319
Q

What are the results of vitamin D excess (intoxication)?

A

Hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium

320
Q

What can cause vitamin D excess?

A
  • Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure
  • In granulomatous diseases such as sarcoidosis, leprosy and tuberculosis, where the granulomatous tissues can convert 25(OH)D to the active metabolite 1,25 (OH)2 D.
321
Q

What is the definition of Paget’s disease?

A

Very active (increase) localised but disorganised bone metabolism. Usually slowly progressive

322
Q

What characterises Paget’s disease?

A

Abnormal, large osteoclasts

323
Q

What percentage of Paget disease cases are autosomal dominant?

A

30%

324
Q

What are the symptoms of Paget’s disease?

A
  • Increased vascularity (warmth over affected bone)
  • Increased osteoclast/osteoblast activity; initially osteoclast activity ( increased deformity and fracture risk), followed by osteoblast activity (thickening of deformed bone)
  • Pelvis, femur, spine, skull (associated with hearing loss) and tibia most commonly affected
  • Fractures
  • Bone pain (nerve entrapment, joint involvement)
325
Q

How is Paget’s disease diagnosed?

A
  • Plasma [Ca++] normal
  • Plasma [alkaline phosphatase usually increased
  • Radiology demonstrating variable features including loss of trabecular bone, increased density and deformity
  • Radioisotope (Technetium) scanning of bone indicating areas of involvement)
326
Q

What are the signs and symptoms of hypocalcaemia?

A 
PACT 
1) Parasthesia (hands, mouth, feet, lips) 
2) Arrhythmias 
3) Convulsions 
4) Tetany 
[CATS go numb]
327
Q

What is Chvostek’s sign?

A

Tap the facial nerve just below the zygomatic arch.
Postive response= twitching of facial muscles
- Indicates neuromuscular irritability due to hypocalcaemia

328
Q

What is Trousseau’s sign?

A

Inflation of BP cuff for several minutes induces carpopedal spasm
= Neuromuscular irritability due to hypocalcaemia

329
Q

What are the causes of hypocalcaemia?

A
  • Vitamin D deficiency
  • Low PTH levels= hypoparathyroidism (surgical- neck surgery, auto-immune)
  • PTH resistance eg. pseudohypoparathyroidism
  • Renal failure (impaired 1-aplha hydroxylation leads to decreased production of 1,25(OH)2 D3
330
Q

What is the normal range for serum Ca++?

A

2.2- 2.6 mmol/L

331
Q

What are the signs and symptoms of hypercalcaemia?

A

‘Stones, abdominal moans and psychic groans)

1) Stones- renal effects
- Polyuria and thirst
- Nephrocalcinosis, renal colic, chronic renal failure
2) Abdominal moans- GI effects
- Anorexia, nausea, dyspepsia, constipation, pancreatitis
3) Psychic groans- CNS effects
- Fatigue, depression, impaires concentration, altered mentation, coma (usually >3mmol/L)

332
Q

What are the causes of hypercalcaemia?

A
  • Primary hperparathyroidism
  • Malignancy- tumours/metastases often secrete a PTH- like peptide
  • Conditons with high bone turnover (hyperthyroidism, Paget’s disease of bone, immobilised patient)
  • Vitamin D excess (rare)
333
Q

What causes 90% of hypercalcaemia cases?

A

Primary hyperparathyroidism and malignancies

334
Q

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

A
  • Give 25 hydroxy vitamin D (25(OH)D)
  • Patient converts this to 1,25 dihydroxy vitamin D (1,25 (OH)2 D) via 1a hydroxylase
  • Supplements are in the form of
    Ergocalciferol 25 hydroxy vitamin D2
    Cholecalciferol 25 hydroxy vitamin D3
335
Q

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

A

Inadequate 1a hydroxylation so can’t activate 25 hydroxyl vitmain D preparations
- Give Alfacalcidol- 1a hydroxycholecalciferol

336
Q

What are the functions of osteoblasts?

A

Synthesise new bone

Synthesise osteoid and participate in mineralisation/calcification of osteoid (bone deposition)

337
Q

What are the functions of osteoclasts?

A

Resorb bone

Release lysosomal enzymes which break down bone (bone resorption)

338
Q

What are functions of osteocytes?

A

Make type I collagen and other EC matrix components

339
Q

What is the function of RANKL?

A
  • Stimulates maturation of osteoclasts from osteoclast precursors
  • This stimulates bone resorption
340
Q

How much of the body’s Ca++ is stores by the bone?

A

> 95%

341
Q

What are the components of bone?

A

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

342
Q

What is osteoporosis?

A

A condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma

343
Q

What is the definition of osteoporosis in terms of BMD?

A

Defined as having a bone mineral density (BMD( that is 2.5 standard deviations (SD) or more below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower

344
Q

How is bone mineral density measured?

A

Dual Energy X-ray Absorpitometry DEXA

345
Q

Why does postmenopausal oestrogen deficiency pre-dispose to osteoporosis?

A
  • Oestrogen deficiency leads to a loss of bone matrix

- Subsequent increased risk of fracture

346
Q

What are conditions pre-dispose to osteoporosis?

A
  • Postmenopausal oestrogen deficiency
  • Age related deficiency in bon homeostasis (men and women) e.g. osteoblast senescence
  • Hypogonadism in young women and in men
  • Endocrine conditions (Cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism)
  • Iatrogenic (Prolonged use of glucocorticoids, heparin)
347
Q

What are the treatment options for osteoporosis?

A
  • Oestrogen/selective oestrogen receptor modulators
  • Bisphosphonates
  • Denosumab
  • Teriparatide
  • Strontium ranelate
348
Q

What effect does treatment of post-menopausal women with pharmacological doses of oestrogen have?

A
  • Anti-resorptive effects on the skeleton

- Prevention of bone loss

349
Q

Why do women with an intact uterus need additional progesterone during oestrogen hormone replacement therapy?

A

To prevent endometrial hyperplasia/cancer?

350
Q

Why is oestrogen hormone replacement therapy use limited?

A

Due to concerns of increased risk of breast cancer and venous thromboembolism

351
Q

What are the effects of tissue selective ER antagonists/anti-oestrogens?

A

Is a selective oestrogen receptor modulator.
Antagonises oestrogen receptors in the breast but has oestrogenic activity in the bone
Oestrogenic effects on endometrium limit its use in osteoporosis management

352
Q

Give an example of a tissue selective ER antagonist/anti-oestrogen?

A

Tamoxifen

353
Q

What are the effect of tissue selective ER agonists?

A

Is a selective oestrogen receptor modulator.
Oestrogenic activity in the bone. Anti-oestrogenic at breast and uterus
Risks include venous thromboembolism and stroke

354
Q

Give an example of tissue selective ER agonist

A

Raloxifene

355
Q

What are bisphosponates?

A

Analogues of pyrophosphate?

356
Q

What is the mechanism of bisphosponates?

A
  • Bind avidly to hydroxyapatite and ingested by osteoclasts which impairs the ability of osteoclasts to reabsorb bone
  • Decrease osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis
  • The result is reduced bone turnover
357
Q

Give examples of bisphosponates

A

Alendronate

Sodium etidronate

358
Q

What are the uses of bisphosponates?

A

1) Osteoporosis- first line treatment
2) Malignancy (associated hypercalcaemia, reduce bone pain from metastases)
3) Paget’s disease (reduce bony pain)
4) Severe hypercalcaemic emergency- IV initially

359
Q

What are the pharmacokinetics of bisphosponates?

A
  • Orally active but poor absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)
  • Accumulates at site of bone mineralisation and remains part of bone until it is resorbed- months, years
360
Q

What are the unwanted actions of bisphosponates?

A

1) Oestophagitis- may require switch from oral to IV preparation
2) Flu-like symptoms (IV preparation- often limited to first dose
3) Osteonecrosis of the jaw- greatest risk in cancer patients recieving IV bisphonponates
4) Atypical fractures- may reflect over-suppression of bone remodelling in prolonged bisphosponate use

361
Q

What is Denosumab?

A
  • Human monoclonal antibody
  • Binds RANKL which inhibits osteoclast formation and activity
  • Therefore osteoclast-mediated bone resorption is inhibits
  • 2nd lind to bisphosponates
362
Q

What is Teriparatide?

A

A recombinant fragment of PTH

  • Increases bone formation and bone resorption but formation outweighs resorption
  • 3rd line treatment for osteoporosis
  • Daily subcutaneous injection
  • Is expensive
363
Q

What is strontium ranelate?

A
  • Accumulates in bone, especially areas of active remodelling
  • Stimulates bone formation, reduced bone resorption
  • Use limited by increase risk of thromboembolism and myocardial infarction
364
Q

Why does the arcuate nucleus have an incomplete brain barrier?

A

Allows access to peripheral hormones therefore peripheral and central feeding signals can be integrated

365
Q

What are the two neuronal populations of the arcuate nucleus?

A

Stimulatory- NPY/Agrp neuron (increase appetite)

Inhibitory - POMC neuron (decrease appetite

366
Q

Where do the two populations in the arcuate nucleus extend?

A

To other hypothalamic and extra-hypothalamic regions

367
Q

What human CNS mutations can cause morbid obesity?

A

POMC deficiency

MC4-R mutations

368
Q

What does leptin activate and inhibit?

A

Activates- POMC neurons

Inhibits- NPY/AgRP neurons

369
Q

What is the effects of central or peripheral administration of leptin?

A

Decreased food intake and increased thermogenesis

370
Q

In what concentrations does leptin circulate in plasma?

A

Proportional to fat mass

fat humans have high leptin

371
Q

What are the effects of absence of leptin?

A

Hyperphagia
Lowered energy expenditure
Sterility

372
Q

What does the presence of leptin indicate to the brain?

A

Indicates that a person has sufficient fat reserved for normal functioning

373
Q

Where are insulin receptors?

A

Hypothalamus

374
Q

At what levels does insulin circulate?

A

Proportional to body fat

375
Q

What is the effect of central administration of insulin?

A

Reduced food intake

376
Q

How does insulin lower blood glucose concentration?

A

Suppresses its production by the liver and promoting its uptake into ‘insulin-sensitive’ tissues such as muscle and fat.
Insulin crosses the blood-brain barrier to enter the CNS where it reduces food intake and consequently reduces absorption of glucose and other nutrients into the body

377
Q

How does insulin regulate body adiposity?

A

Glucose-induced insulin secretion from the pancreas increases in proportion to body adiposity

378
Q

What is the body’s largest endocrine organ?

A

The gastrointestinal tract

379
Q

What regulates the release of gut hormones?

A

Gut nutrient content

380
Q

How long is the gastric hormone Ghrelin?

A

28 amino acids

381
Q

How does Ghrelin affect neurons in the arcuate nucleus?

A
  • Stimulates NPY/Agrp neurones
  • Inhibits POMC neurons
    Therefore increases appetite
382
Q

What hormones are secreted by L cells?

A

PYY

GLP-1

383
Q

How does PYY affect neurons in the arcuate nucleus?

A
  • Inhibits NPY release
  • Stiulates POMC neurons
    Decreases appetite
384
Q

What gene codes for GLP-1?

A

Preproglucagon gene

Release post-prandially

385
Q

What is the role of GLP-1?

A
  • Stimulates glucose-stimulated insulin release

- Reduces food intake

386
Q

What is saxenda?

A

A long acting GLP-1 receptor agonist

387
Q

What comorbidities are associated with obesity?

A
  • Depression
  • Stroke
  • Sleep apnoea
  • Myocardial infarction
  • Hypertension
  • Diabetes
  • Peripheral vascular disease
  • Gout
  • Osteoarthritis
  • Bowel cancer
388
Q

What are the symptoms of someone who presents with diabetes?

A
  • Polyuria
  • Nocturia
  • Polydipsia
  • Blurring of vision
  • ‘Thrush’
  • Weight loss
  • Fatigue
389
Q

What are the sign of someone who presents with diabetes?

A
  • Dehydration
  • Cachexia
  • Hyperventilation
  • Smell of ketones
  • Glycosuria
  • Ketonuria
390
Q

How is type 1 diabetes classified based on aetiology?

A

Genetics and an environmental trigger will lead to the autoimmune destruction of islet cells. This coupled with insulin deficiency will lead to hyperglycaemia

391
Q

How is type 2 diabetes classified based on aetiology?

A

Obesity and genetics lead to insulin resistance. Coupled with B-cell failure this will lead to hyperglycaemia

392
Q

What is the risk level for diabetes with the DR2 HLA-DR allele?

A

Protective

393
Q

What is the risk level for diabetes with the DR6 HLA-DR allele?

A

Neutral/protective

394
Q

What is the risk level for diabetes with the DR7 HLA-DR allele?

A

Protective. Risk in African descent.

395
Q

What is the risk level for diabetes with the DR8 HLA-DR allele?

A

Neutral/slight risk?

396
Q

What is the risk level for diabetes with the DR9 HLA-DR allele?

A

Risk in Chinese, Japanese, Korean descent

397
Q

What is the risk level for diabetes with the DR1 HLA-DR allele?

A

Slight risk

398
Q

What is the risk level for diabetes with the DR3 HLA-DR allele?

A

Significant risk

399
Q

What is the risk level for diabetes with the DR4 HLA-DR allele?

A

Significant risk

400
Q

What is the risk level for diabetes with the DR5 HLA-DR allele?

A

Slight risk

401
Q

What are the markers for type 1 diabetes?

A
  • Islet cell antibodies- grp O human pancreas
  • Insulin antibodies
  • Glutamic acid decarboxylase (GADA) - widespread neurotransmitter
  • Insulinomia-associated-2-autoantibodies (IA-2A)- receptor like family
402
Q

What are the aims of treatment in type 1 diabetes?

A
  • Reduce early mortality
  • Avoid acute metabolic decompensation
  • Prevent long term complications (retinopathy, nephropathy, neuropathy, vascular disease)
403
Q

What is the diet required for someone with type 1 diabetes?

A
  • Reduce calories as fat
  • Reduced calories as refined carbohydrate
  • Increase calories as complex carbohydrate
  • Increase soluble fibre
  • Balance distribution of food over course of day with regular meal and snacks
404
Q

What are the characteristics of an insulin pump?

A
  • Continuous insulin deliver
  • Preprogrammed basal rates and bolus for meals
  • Does not measure glucose, no completion of feedback loop
405
Q

What are the characteristics of insulin treatment without meals?

A
  • Long acting
  • Non-c bound to zinc or protamine
  • Insulin analogue (gargine, determir, degludec)
406
Q

What are the characteristics of insulin treatment with meals?

A
  • Short acting
  • Human insulin
  • Insulin analogue (lispro, aspart, gulisine)
407
Q

Why is insulin treatment genetically engineered?

A

To alter absorption, distribution, metabolism and excretion

408
Q

What are the condition for HcA1c red cells reacting irreversibly and non-covalently with glucose?

A
  • Lifespan of red cell, approx 120 days
  • Rate of glycation, which is faster in some individuals
  • Level of glucose
409
Q

Why are HbA1c red cells an ideal measure of long term glycaemic control?

A

Its binding with glucose depends on the level of glucose and has been shown to be related to risk of complications.
Lowering HcA1c is associated with lower risk of complication, especially microvascular complication

410
Q

What is seen when rapid decompensation of type 1 diabetes results in ketoacidosis?

A

Hyperglycaemia:
- Reduced tissue glucose utilisation
- Increased hepatic glucose production
Metabolic acidosis:
- Circulating acetoacetate and hydroxybutyrate
- Osmotic dehydration and poor tissue perfusion

411
Q

What can cause ketoacidosis in type 1 diabetes?

A
  • New presentation
  • Insulin omission
  • Infection/other ilnesses
412
Q

What is hypoglycaemia?

A

Plasma glucose of

413
Q

What is severe hypoglycaemia

A

Any hypoglycaemia that requires the requires the help of another person to treat

414
Q

At which point are most mental processes impaired due to hypoglycaemia?

A
415
Q

At which point is consciousness impaired due to hypoglycaemia?

A
416
Q

Who is most at risk of hypoglycaemia?

A
  • Main risk factor is quality of glycaemic control

- More frequent in patients with low HbA1c

417
Q

When does hypoglycaemia usually occur?

A
  • Can occur at any time but there is often a pattern
  • Pe-lunch is common
  • Nocturnal hypoglycaemia is very common though not often recognised
418
Q

What can cause hypoglycaemia?

A
  • Unaccustomed exercise
  • Missed meals
  • Inadequate snacks
  • Alcohol
  • Inappropriate insulin regime
419
Q

What are the signs and symptoms of hypoglycaemia due to increased autonomic activation?

A
  • Palpitations (tachycardia)
  • Tremor
  • Sweating
  • Pallor/cold extremities
  • Anxiety
420
Q

What are the signs and symptoms of hypoglycaemia due to impaired CNS function?

A
  • Drowsiness
  • Confusion
  • Altered behaviour
  • Focal neurology
  • Coma
421
Q

How is hypoglycaemia treated orally?

A
  • Feed the patient
  • Glucose: rapidly absorbed as solution or tablets
  • Complex CHO: to maintain blood glucose after initial treatment
422
Q

How is hypoglycaemia treated parenterally?

A

Give if consciousness impaired

  • IV dextrose e.g. 10% glucose infusion
  • 1mg glucagon IM
  • Avoid concentrated solutions if possible such as 50% glucose
423
Q

What are general characteristics of Type 1 diabetes?

A
  • Ketosis prone diabetes
  • B cell loss
  • All intermediary metabolism deranged
  • Insulin should be regarded as physiological treatment with pharmacological agents
  • Hypoglycaemia is almost inevitable
  • Organ specific autoimmune disease which leaves patients with an absolute insulin deficiency
424
Q

What is the definition of diabetes?

A

A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves and arteries

425
Q

Is type 2 diabetes ketosis prone?

A

No

426
Q

What is the epidemiology of type 2 diabetes?

A
  • Most diabetes is type 2
  • Increasing age, but now in children
  • Increasing prevalence
  • Occurring and being diagnosed young
  • Greatest in ethnic groups that move from rural to urban lifestyle
427
Q

What is the pathophysiology of type 2 diabetes?

A
  • Genes and intrauterine environment and adult environment
  • Insulin resistance and insulin secretion defects
  • Fatty acids are important in pathogenesis and complications
  • Gut microbiota and adipocytokines have a role
428
Q

What is the pattern of inheritance of MODY?

A

Autosomal dominant

429
Q

How is treatment success assessed for type 1 diabetes using capillary monitoring?

A

Monitor blood glucose levels.

  • Patients can self monitor using a pin prick test
  • There are continuous monitors which monitor glucose more regularly
430
Q

How is type 2 diabetes usually diagnosed?

A

75g glucose is administered orally in a glucose tolerance test.
- Below 6, fasted glucose is normal .

431
Q

According to the glucose tolerance test, between what levels will a patient have impaired fasting glucose?

A

Between 6.0 and 7.0

432
Q

According to the glucose tolerance test, above which level does a patient have diabetes?

A

Above 7.0

433
Q

What causes MODY?

A

Mutations of transcription factor genes and the glucokinase gene

434
Q

What is MODY

A

Maturity onset diabetes of the young
The condition means there is ineffective pancreatic beta cell insulin production. The B cells do not serve to sense glucose levels correctly

435
Q

What is the metabolism type 2 diabetes?

A
  • Heterogenous
436
Q

How does type 2 diabetes present?

A
  • Obesity
  • Insulin resistance and insulin secretion deficit
  • Hyperglycaemia and dyslipidaemia
  • Acute and chronic complications (blindness, renal failure, heart attack, stroke)
437
Q

Why does blood sugar become so high in type 2 diabetes?

A
  • Insulin secretion deteriorates with progressive impairment of glucose tolerance
  • decreased glucose disposal and increased hepatic glucose production contribute to increased plasma glucose
  • Pancreatic islet dysfunction will lead to hyperglycaemia.
438
Q

What effect does type 2 diabetes have on intermediary metabolism.

A

Triglycerides are the main energy store of glucose. Insulin usually prevents lipolysis- breakdown of triglycerides.

  • Lipolysis takes place when there is insufficient insulin. There is associated glycerol and non-fatty acid release.
  • The products go to the liver. Glycerol is used to synthesise new glucose and non-esterified fatty acids form VLDLs
  • Glucose is released from the liver into the bloodstream
439
Q

What percentage of type 2 diabetics are obese?

A

80%

440
Q

What can waist circumference be used to predict?

A

Diabetes

Ischaemic heart disease

441
Q

What waist circumference measurements for men and women increases the risk of diabetes?

A

Woman- Above 35 inches

Man- Above 40 inches

442
Q

What are the ideal values for cholesterol, triglycerides and HDL’s for a diabetic?

A

Cholesterol- under 4
Triglyceride- 2
HDL- Above 1

443
Q

What acute or chronic complications can show someone is presenting with type 2 diabetes?

A 
Acute= hyperosmolar coma 
Chronic= ischaemic heart disease, retinopathy
444
Q

What microvascular complications are associated with type 2 diabetes?

A

Retinopathy
Nephropathy
Neuropathy

445
Q

What macrovascular complications are associated with type 2 diabetes?

A

Ischaemic heart disease
Cerebrovascular disease (stroke)
Renal artery stenosis
Peripheral vascular disease

446
Q

What metabolic complications are associated with type 2 diabetes?

A

Lactic acidosis

Hyperosmolar

447
Q

What iatrogenic complications are associated with type 2 diabetes?

A

Hypoglycaemia

448
Q

What should someone with type 2 diabetes be advised to eat?

A
  • Control total calories/ increase exercise
  • Reduce refined carbohydrates
  • Increased complex carbohydrates
  • Reduce fat as proportion of calories
  • Increase unsaturated fat as proportion of fat
  • Increase soluble fibre
449
Q

What are the 4 main aspects of type 2 diabetes that need to be treated and monitored?

A

1) Weight
2) Glycaemia
3) Blood pressure
4) Dyslipidaemia

450
Q

When is metformin used in type 2 diabetes?

A

In overweight patient with type 2 diabetes where diet alone has not succeeded

451
Q

What is metformin?

A

Biguanide insulin sensitiser

452
Q

How does metformin reduce insulin resistance?

A
  • Reduces hepatic glucose output

- Increasing peripheral glucose disposal by increasing the ability of glucose to get into muscle

453
Q

What is the basis of type 2 diabetes management?

A
  • Education
  • Diet
  • Pharmacological treatment
  • Complication screening
454
Q

Does Metformin have side effects?

A

Some GI side effects but does not cause hypose

455
Q

When should Metformin not be used?

A

If severe liver, severe cardiac or mild renal failure

456
Q

When is suplhonylurea used in type 2 diabetes?

A

In lean patients with type 2 diabetes where diet alone has not succeeded

457
Q

What are the side effects of sulphonurea?

A

Hypoglycaemia

Weight gain

458
Q

What is acarbose?

A

Alpga glucosidase inhibitor

459
Q

How does acarbose work?

A
  • Prolongs the absorption of oligosaccharides
  • Allows insulin secretion to cope following first phase insulin
  • Is as effective as metformin
460
Q

What are the side effects of acarbose?

A

Flatus

461
Q

What are thiazolidinediones?

A

Peroxisome proliferator-activated receptor agonistst

462
Q

Give an example of a thiazolidinedione

A

Plioglitiazine

463
Q

How do thiazolidinediones work?

A

It is an insulin sensitiser with mainly peripheral action.

  • Causes adipocyte differentiation leading to peripheral weight gain and central weight loss
  • Results in improvement in glycaemia and lipids which improve macrovascular outcomes
464
Q

What are the side effects of thiazolidinediones?

A

Hepatitis

Heart failure

465
Q

What is glucagon like peptide-1 secreted in response to?

A

Nutrients in the gut

466
Q

What does GLP-1 stimulate and suppress?

A

Stimulates insulin
Suppresses glucagon
Increases satiety

467
Q

What restores B cell glucose sensitivity?

A

GLP-1

468
Q

Why does GLP-1 have a short half life?

A

Rapidly degraded by enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)

469
Q

What is diabetic dyslipidaemia?

A

Where cholesterol and triglycerides are high and HDLs are low

470
Q

How is the onset for type 1 and type 2 diabetes described?

A

Type 1= Acute

Type 2= Gradual

471
Q

Is a family history common in type 1 and type 2 diabetes?

A

Type 1= Uncommon

Type 2= Common

472
Q

In which type diabetes are islet B cells destroyed?

A

Type 1

473
Q

Which type diabetes are islet cell antibodies present?

A

Type 1= present

Type 2= absent

474
Q

At which sites can microvascular complications develop?

A
  • Retinal arteries
  • Glomerular arterioles (kidneys)
  • Vasa nervorum (tiny blood vessels that supply nerves)
475
Q

What causes microvascular complications?

A
  • Severity of hyperglycaemia
  • Hypertension
  • Genetic
  • Hyperglycaemic memory
476
Q

What are the mechanisms that result in glucose damage?

A

Hyperglycaemia and hyperlipidemia leads to oxidative stress, hypoxia. These factors lead to inflammatory signalling cascades which in turn results in local activation of pro-inflammatory cytokines.
This results in inflammation leading to nephropathy, retinpathy and neuropathy

477
Q

What pathways result in glucose damage?

A
  • Polyol pathway
  • AGEs
  • Protein kinase C
  • Hexosamine
478
Q

How can diabetic retinopathy be checked?

A

Look at the back of the eyes with a fundoscope

479
Q

What is used to view the retinal arteries?

A

Ophthalmoscope

480
Q

What are the signs of background diabetic retinopathy?

A

Hard exudates
Micro-aneurysms
Blot haemorrhages

481
Q

What are the signs of pre-proliferative diabetic retinopathy?

A

Cotton wool spots

Represent retinal ischaemia

482
Q

What are the signs of proliferative retinopathy?

A

Visible new vessels on disk or elsewhere in the retina

483
Q

What are the signs of maculopathy?

A

Hard exudates near the macula

  • It is the same disease as background diabetic retinopathy but happens to be near the macula
  • Can threaten direct vision
484
Q

How is background diabetic retinopathy managed?

A
  • Control of blood glucose needs to be improved

- Warn patient of the presence of warning signs

485
Q

How is pre-proliferative diabetic retinopathy managed?

A

Suggest general ischaemia.

  • New vessels will grow if left alone
  • Needs pan retinal photocoagulation
486
Q

How is proliferative diabetic retinopathy managed?

A
  • Visible new vessels

- Needs pan retinal photocoagulation

487
Q

How is maculopathy managed

A

The problem is around the macula.

- Only needs a GRID of photocoagulation, NOT pan retinal photocoagulation

488
Q

What is diabetic nephropathy?

A

The term used to describe the expression of diabetic microvascular complications with the kidneys

489
Q

What is the major cause of death in patients with diabetic nephropathy?

A

Cardiovascular disease

490
Q

What are the histological features of diabetic nephropathy?

A

1) Glomerular changes
- Mesangial expansion
- Basement membrane thickening
- Glomerulosclerosis
2) Vascular changes
3) Tubulointerstitial changes

491
Q

When does diabetic nephropathy occur in type 1 diabetics?

A

Occurs in 30-40%

After 30 to 40 years of diabetes

492
Q

How is clinical diabetic nephropathy defined?

A

By the presence of

1) Progressive proteinuria
2) Increased BP
3) Deranged renal function

493
Q

What range of protein in the urine is normal?

A
494
Q

What range of protein in the urine is microalbuminuric?

A

30-300mg/24hrs

495
Q

What range of protein in the urine is assymptomatic?

A

300-3000mg/24hrs

496
Q

What range of protein in the urine is nephrotic?

A

> 3000mg/24hr

497
Q

What are the different interventions for diabetic nephropathy?

A

1) Diabetic control
2) Blood pressure control
3) Inhibition of renin-angiotensin system
4) Stopping smoking

498
Q

What causes diabetic neuropathy?

A

Caused by poor perfusion of the neurones due to damage to small vessels supplying the nerve (vasa nerorum)

499
Q

What are the types of diabetic neuropathy?

A

1) Peripheral polyneuropathy
2) Mononeuropathy
3) Mononeuritis multiplex
4) Radiculopathy
5) Authonomic neuropathy
6) Diabetic amyotrophy

500
Q

How is sorbitol a mechanism for vascular damage leading to neuropathy?

A

Sorbitol is thought to be produced in excess in individuals with high plasma glucose as glucose is reduced to sorbitol by the enzyme aldol reductase

501
Q

Other than sorbitol, what is a mechanism that leads to neuropathy?

A

The production of advanced glycation end products (AGE)

502
Q

What is glycation?

A

The term used for nonenzymatic addition of hexoses to protein

503
Q

What is glycolisation?

A

The term used for the enzymatic addition of hexoses to protein

504
Q

What are the characteristics of peripheral polyneuropathy?

A
  • Usually bilateral and symmetrical
  • Loss of sensation is common
  • Occurs more commonly in tall people with poor glucose control
  • Can be painful
  • Danger is that patients will not sense an injury to the food
505
Q

What are the signs of peripheral polyneuropathy?

A
  • Loss of ankle jerks
  • Loss of vibration sense (using tuning fork)
  • X -ray may show multiple fractures and Charcot’s joint
506
Q

What are the characteristics of mononeuropathy?

A
  • Single nerve loss
  • Usually noted motor loss since a single nerve with sensory loss is rare symptomatic
  • 3rd, 4th, 6th nerve palsy
  • Wrist drop, foot drop
  • Double vision due to 3rd nerve palsy
507
Q

What are the signs of pupil sparing third nerve palsy?

A
  • Eye is usually ‘down and out’
    (6th nerve pulls eye out and 4th pulls it down)
  • Pupil does respond to light
508
Q

In pupil sparing third nerve palsy, why do the parasympathetic fibres not easily lose blood supply in diabetes?

A

The parasympathetic fibres are on the outside

509
Q

What are the signs of a space occupying lesion that causes a third nerve palsy?

A

It will press on parasympathetic fibres first causing fixed dilated pupil

510
Q

What is mononeuritis multiplex?

A

A random combination of peripheral nerve lesions

511
Q

What is radiculopathy?

A

Pain over spinal nerves, usually affecting a dermotome on the abdomen or chest wall

512
Q

What is autonomic neuropathy?

A

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

513
Q

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

A
  • Difficulty swallowing
  • Delayed gastric emptying
  • Constipation/nocturnal diarrhoea
  • Bladder dysfunction
514
Q

What are the other affects of autonomic neuropathy, other than the GI tract?

A
  • Postural hypotension

- Cardiac autonomic supply (case reports of sudden cardiac death)

515
Q

How can autonomic neuropathy be tested?

A
  • Measure changes in heart rate in response to Valsalva manoevre
  • Normally there is a change in heart rate
  • Look at ECG and compare R-R intervals
516
Q

How are microvascular and macrovascular diseases associated with morbidity and mortality?

A

Microvascular disease causes morbidity

Macrovascular disease causes morbidity and mortality

517
Q

Where is macrovascular disease commonly present?

A

In multiple arterial beds

518
Q

What is ischaemic heart disease a major cause of in diabetes?

A

Morbidity and mortality

519
Q

What can renal artery stenosis contribute to?

A

Hypertension and renal failure

520
Q

Above which waist circumference is the risk of macrovascular disease increased?

A

Men > 102 cm

Women > 88cm

521
Q

Below which HDL level is the risk of macrovascular disease increased?

A

Men

522
Q

Above which fasting glucose range is the risk of macrovascular disease increased?

A

> 6.0 mmol/l

523
Q

What factors increase the risk of macrovascular disease?

A

Insulin resistance
Inflammation
Adipocytokines
Urine microalbumin

524
Q

What are the non-modifiable risk factors for macrovascular disease?

A
  • Age
  • Sex
  • Birth weight
  • Family history/ Genes
525
Q

What are the modifiable risk factors for macrovascular disease?

A
  • Dyslipidaemia
  • High blood pressure
  • Smoking
  • Diabetes
526
Q

What complications of diabetes predispose to foot disease?

A

1) Neuropathy; sensory, motor and autonomic

2) Peripheral vascular disease

527
Q

What is the pathway to foot ulceration?

A

1) Sensory neuropathy
2) Motor neuropathy
3) Limited joint mobility
4) Autonomic neuropathy
5) Peripheral vascular disease
6) Trauma- repeated minor/discrete episode
7) Reduced resistance to infection
8) Other diabetic complications eg. retinopathy

528
Q

What are the characteristics of the neuropathic foot?

A
  • Numb, warm, dry
  • Palpable foot pulses
  • Ulcers at points of high pressure loading
529
Q

What are the characteristics of the ischaemic foot?

A
  • Cold
  • Pulseless
  • Ulcers at foot margins
530
Q

What are the characteristics of the neuro-ischaemic foot?

A
  • Numb
  • Cold
  • Dry
  • Pulseless
  • Ulcers at points of high pressure loading and at foot margins
531
Q

How should the foot of a diabetic patient be assessed?

A

1) Appearance?
- Deformity
- Callous
2) Feel?
- Hot/cold
- Dry
3) Foot pulses?
- Dorsalis pedis/ posterior tibial pulse
4) Neuropathy
- Vibration sensation
- Temperature
- Ankle jerk
- Reflex
- Fine touch sensation

532
Q

How can foot ulceration be prevented?

A

1) Control diabetes
2) Inspect feed daily
3) Have feet measured when buying shoes
4) Buy shoes with laces and square toe box
5) Inspect inside of shoes for foreign objects and attend chiropodist
6) Cut nails straight across
7) Care with heart
8) Never walk barefoot

533
Q

In what ways can foot ulceration be managed?

A

1) Relief of pressure
- bed rest (risk of DVT, heel ulceration)
- redistribution of pressure/total contact cast
2) Antibiotics, possibly long term
3) Debridement
4) Revascularisation
- angioplasty
- arterial bypass surgery
5) Amputation

Year 2: LCRS (8 decks)

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