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Medicine Phase 2a > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

What are the hormones released from the anterior pituitary?

A

Thyroid Stimulating Hormone (TSH)
Adrenocorticotropic Hormone (ACTH)
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
Growth Hormone (GH)
Prolactin

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2
Q

What are the hormones released from the posterior pituitary?

A

Oxytocin
Antidiuretic Hormone (ADH)

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3
Q

Explain the Thyroid Axis

A

Hypothalamus - TRH
Ant. Pit - TSH
Thyroid - T3/T4

T3/T4 - negative feedback on Hypothalamus and Ant. Pit

Deiodinases act to convert T4 to T3 by removal of iodine

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4
Q

Explain the Adrenal Axis

A

Hypothalamus - CRH
Ant. Pit - ACTH
Adrenal gland - Cortisol

Cortisol - negative feedback on hypothalamus and Ant. pit

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5
Q

What are the functions of cortisol?

A

Inhibits the immune system
Inhibits bone formation
Raises blood glucose (stimulates glucagon, inhibits insulin)
Increases metabolism
Increases alertness

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6
Q

Explain the Growth hormone Axis

A

Hypothalamus - GHRH
Ant Pit - GH
Liver - IGF-1

Negative feedback

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7
Q

What are the major functions of growth hormone?

A

Stimulates muscle growth
Increases bone density and strength
Stimulates cell regeneration and reproduction
Stimulates growth of internal organs

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8
Q

Explain the parathyroid axis

A

PTH released from Chief cells of the parathyroid gland in response to low serum calcium (hypocalcaemia)

PTH acts to increase serum calcium by:
Indirectly (stimulates Osteoblasts) increase activity/number of osteoclasts - increase bone resorption
Stimulates kidneys to increase calcium reabsorption and Phosphate excretion in DCT
Stimulates kidneys to Convert VitD3 to calcitriol to increase calcium absorption from the gut.

Increased serum Calcium will suppress PTH via negative feedback

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9
Q

Explain the renin - angiotensin - aldosterone system

A

Renin is a hormone secreted by the juxtaglomerular cells that sit in the afferent arterioles in the kidney.
They secrete more renin in response to low blood pressure and secrete less renin in response to high blood pressure.
Renin acts to convert angiotensinogen (released by the liver) into angiotensin I.
Angiotensin I converts to angiotensin II in the lungs by angiotensin-converting enzyme (ACE).
Angiotensin II increases blood pressure (by vasoconstriction) and stimulates aldosterone release

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10
Q

How does aldosterone increase blood pressure

A

Aldosterone is a mineralocorticoid steroid hormone. It acts on the nephrons in the kidneys to:

Increase sodium reabsorption from the distal tubule
Increase potassium secretion from the distal tubule
Increase hydrogen secretion from the collecting ducts

When sodium is reabsorbed in the kidneys water follows it by osmosis. This leads to an increase in intravascular volume and subsequently blood pressure.

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11
Q

What is the Pituitary-Gonadal Axis?

A
  • 1️⃣ Hypothalamus produces GnRH which acts on pituitary
  • 2️⃣ Pituitary produces LH and FSH
  • 3️⃣ LH travels to the gonads and causes;
  • Men
    - LH stimulates interstitial cells of the testes to produce testosterone
    - FSH stimulates spermatogenesis
  • Women
    FSH and LH act to activate the ovaries to produce oestrogen and inhibin; regulate the menstrual and ovarian cycle
  • 4️⃣ Negative feedback for hypothalamus and pituitary
    • Men
      • Testosterone acts on the hypothalamus to inhibit the production of GnRH
    • Women
      • Oestrogen acts on the hypothalamus directly to inhibit the production of GnRH
      • Inhibin acts to inhibit activin, a peripherally produced hormone that positively stimulates GnRH-producing cells
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12
Q

What is the Hypothalamus-Pituitary-Prolactin Axis?

A

1️⃣ TRH, Breast feeding and oestrogen will all stimulate the release of prolactin from the pituitary gland.

2️⃣ Pituitary produces Prolactin

3️⃣ Hypothalamus also produces dopamine (prolactin inhibiting hormone); this acts on the pituitary gland to reduce prolactin secretion

4️⃣ Cortisol acts as negative feedback for pituitary and hypothalamus

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13
Q

How does a pituitary adenoma cause symptoms?
(VERY KEY POINT)

A
  • Exerts pressure on local structures (e.g. optic nerves)
  • Exert pressure on the normal pituitary
  • Behaves as a functioning tumour
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14
Q

What is cushings syndrome?

A

Cushing’s Syndrome is used to refer to the signs and symptoms that develop after prolonged abnormal elevation of cortisol (hypercortisolaemia)

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15
Q

What is Cushing’s Disease?

A

Cushing’s Disease is used to refer to the specific condition where a pituitary adenoma (tumour) secretes excessive ACTH leading to hypercortisolaemia

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16
Q

What is the pathogenesis of cushings syndrome?

A

Constantly high cortisol levels
Therefore CRH and ACTH are inhibited (unless ACTH dependent)

Therefore there is loss of the circadian rhythm release of cortisol

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17
Q

What is pseudo cushings?

A

Mimics cushings syndrome
Due to alcohol excess or severe depression.
Resolves in 1-3 weeks

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18
Q

What are the clinical features of someone with Cushing’s Syndrome?

Symptoms:

Signs (high stress hormone related)

Extra effects:

A

Round in the middle with thin limbs:
Round “moon” face
Central Obesity
Abdominal striae
Buffalo Hump (fat pad on upper back)
Proximal limb muscle wasting

High levels of stress hormone:
Hypertension
Cardiac hypertrophy
Hyperglycaemia (Type 2 Diabetes)
Depression
Insomnia

Extra effects:
Osteoporosis
Easy bruising and poor skin healing

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19
Q

What are the main causes of Cushing’s Syndrome?

A

Exogenous steroids (in patients on long term high dose steroid medications)
Cushing’s Disease (a pituitary adenoma releasing excessive ACTH)
Adrenal Adenoma (a hormone secreting adrenal tumour)
Paraneoplastic Cushing’s

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20
Q

What is paraneoplastic Cushing’s?

A

Paraneoplastic Cushing’s is when excess ACTH is released from a cancer (not of the pituitary) and stimulates excessive cortisol release.

ACTH from somewhere other than the pituitary is called “ectopic ACTH”. Small Cell Lung Cancer is the most common cause of paraneoplastic Cushing’s.

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21
Q

How is Cushing’s Syndrome diagnosed?

A

24 hour Urinary free cortisol: (often measured at 12am)
will diagnose Cushing’s, but not determine the cause

Dexamethasone Suppression Test (DST):
Give patient dexamethasone at 10pm and measure ACTH and cortisol at 9am next morning to see if dexamethasone suppressed the normal morning spike

Low dose (1mg) - determine if patient has Cushings
Dexamethasone (synthetic glucocorticoid) should suppress HPA axis.
If not suppressed in morning then Cushings syndrome

High Dose (8mg) - done after low dose to determine cause:

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22
Q

What results would be seen in the High dose dexamethasone test to determine the cause of Cushing’s?

A

Cushings disease - High Dose will suppress pituitary - ACTH and cortisol is suppressed

Adrenal adenoma - High dose will suppress pituitary (-tve feedback) but not cortisol as it is independently produced by adrenal adenoma

Ectopic ACTH (SCLC) - Neither cortisol or ACTH is suppressed as their production is independent of hypothalamus/pituitary/adrenal glands

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23
Q

What other investigations may be wanted for a diagnosis of Cushing’s Syndrome?

A

FBC - raised white cells
Electrolytes - Low potassium if aldosterone is secreted
MRI brain - pit adenoma
Chest CT - Small cell lung cancer
Abdominal CT - adrenal tumour

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24
Q

What is the treatment of Cushing’s Syndrome?

A

Remove underlying cause

Withdraw exogenous steroids
Trans-sphenoidal removal of Pit. Adenoma
Surgical removal of adrenal adenoma/other cancer

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25
Q

What is the difference between ACTH-dependent and ACTH-independent Cushing’s?

A
  • ACTH-dependent → caused by a pituitary adenoma (or ectopic, ACTH producing tumour)
  • ACTH-independent → caused directly by the adrenal glands
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26
Q

What is adrenal insufficiency?

A

where the adrenal glands do not produce enough steroid hormones, particularly cortisol and aldosterone

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27
Q

What is Addison’s Disease?

A

refers to the specific condition where the adrenal glands have been damaged, resulting in a reduction in the secretion of cortisol and aldosterone. This is also called Primary Adrenal Insufficiency

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28
Q

What is the main cause of Adrenal insufficiency in the Developed and developing world?

A

Developed - Addison’s disease
Developing - TB (+Sarcoidosis)

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29
Q

What is the most common cause of Addison’s Disease?

A

Autoimmune destruction of the adrenal gland

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30
Q

What is secondary adrenal insufficiency?

A

Hypopituitarism
A result of inadequate ACTH stimulating the adrenal glands, resulting in low cortisol release.
This is the result of loss or damage to the pituitary gland.

Most commonly due to long term steroids

Also can be due to surgery to remove a pituitary tumour, infection, loss of blood flow or radiotherapy.

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31
Q

What is Tertiary Adrenal insufficiency?

A

Tertiary Adrenal Insufficiency is the result of inadequate CRH release by the hypothalamus.
This is usually the result of patients being on long term oral steroids (for more than 3 weeks) causing suppression of the hypothalamus and then suddenly stopping the steroids causing the HPA axis to not wake up properly

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32
Q

How can you distinguish Addison’s disease from 2’ adrenal insufficiency?

A

Addison’s disease - High ACTH, Low Adrenal hormones

2’ Cause - HPA suppression - Low ACTH, Low adrenal hormones (no hyperpigmentation)

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33
Q

What are the Symptoms of adrenal insufficiency?

A

Fatigue
Nausea
Cramps
Abdominal pain
Reduced libido

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34
Q

What are the major Signs of adrenal insufficiency?

A

Bronze hyperpigmentation to skin (ACTH stimulates melanocytes to produce melanin)
Hypotension (particularly postural hypotension)

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35
Q

Why does Bronze hyperpigmentation only usually occur in Addison’s disease?

A

This is primary adrenal insufficiency and therefore the Hypothalamus and Ant. pit are still working.

These are releasing CRH and ACTH to increase the levels or cortisol but the adrenals are not responding.

High levels of ACTH are not seen in 2’ or 3’ adrenal insufficiency

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36
Q

What investigations should be done for adrenal insufficiency?

A

Early Morning cortisol (measured at 9am)

ACTH blood test:
1’ - ACTH is High
2’ / 3’ - ACTH is Low

GS - Short Corticotrophin (Synacthen) Test

Hyponatraemia - Low aldosterone
Hyperkalaemia - Low aldosterone

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37
Q

What is the Short Synacthen test?

A

The test involves giving synacthen, which is synthetic ACTH.

The blood cortisol is measured at baseline, 30 and 60 minutes after administration.

Synacthen will stimulate healthy adrenal glands to produce cortisol and the cortisol level should at least double.

A failure of cortisol to rise (less than double the baseline) indicates primary adrenal insufficiency (Addison’s disease).

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38
Q

What autoantibodies may be found in adrenal insufficiency?

A

Adrenal autoantibodies (80% of autoimmune adrenal insufficiency)
21-hydroxylase antibodies
17alpha hydroxylase antibodies

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39
Q

What is the treatment of adrenal insufficiency?

A

Replace steroids titrated to signs.

Hydrocortisone - replace cortisol

Fludrocortisone - replace aldosterone

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40
Q

What is addisonian Crisis?
How do they present?

A

Describes acute presentation of severe Addisons disease where the absence of hormones leads to a life threatening presentation. often occurs from suddenly stopping long term steroids

Present with: (4 Hs)
Reduced consciousness
Hypotension
Hypoglycaemia,
Hyponatraemia
Hyperkalaemia

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41
Q

How would you treat adrenal crisis?

A
  • Immediate parenteral hydrocortisone (100mg IV, IM) then100mg every 6hrs
  • Fluid resuscitation (1L N/saline 1 hour)
  • Correct hypoglycaemia
  • If the patient has primary adrenal insufficiency, give fludocortisone (100-200µg)
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42
Q

What should patients with adrenal insufficiency carry with them?

A

10x 10mg Tablets Hydrocortisone

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43
Q

Why should hydrocortisone be administered without prejudice?

A

Cannot harm the patient and can be life saving

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44
Q

When should prednisolone be administered in glucocorticoid replacement therapy?

A
  • 3-5mg/d orally once or twice a day
  • Patients with reduced compliance to hydrocortisone
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45
Q

What results for TSH, T3 and T4 would you see in hyper and hypothyroidism?

A

Hyperthyroidism:
TSH - Low (except in a pituitary adenoma)
T3/T4 - High

Primary Hypothyroidism:
TSH - High
T3/T4 - Low

Secondary Hypothyroidism:
TSH - Low
T3/T4 - Low

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46
Q

What are the different antibodies related to Thyroid dysfunction and what conditions are they present in?

A

Anti-thyroid Peroxidase antibodies (Anti-TPO) - Graves disease and Hashimoto’s Thyroiditis

Antithyroglobulin antibodies - Graves disease, Hashimoto’s Thyroiditis and thyroid cancer

TSH Receptor antibodies (IgG) - Graves disease

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47
Q

What imaging techniques are useful in diagnosing thyroid conditions?

A

Thyroid Ultrasound for Nodules

Radioisotope Scan with radioactive iodine:
Diffuse high uptake - Graves disease
Focal high uptake - TMG/adenoma
Cold areas (low uptake) - Thyroid cancer

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48
Q

What is Hyperthyroidism?

A

Over production of Thyroid hormone from the thyroid gland

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49
Q

What is Thyrotoxicosis?

A

Abnormal/excessive quantity of thyroid hormone in the body.

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50
Q

What is Graves disease?

A

An autoimmune condition where TSH receptor autoantibodies stimulate the TSH-R leading to increased production of T3/T4.
Most common cause of hyperthyroidism (80-90% primary cause)

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51
Q

What is Toxic Multinodular Goitre (TMG)?

A

Nodules develop in the thyroid gland that act independently of the normal negative feedback system and therefore result in over production of T3/T4

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52
Q

What are the main causes of Hyperthyroidism?

A

Grave’s disease
Toxic multinodular goitre
Benign Adenoma (Solitary toxic thyroid nodule)
Thyroiditis (e.g. De Quervain’s, Hashimoto’s, postpartum and drug-induced thyroiditis)

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53
Q

What Conditions present with a smooth goitre?

A

Graves’ disease
Hashimoto’s disease
Drugs (e.g. lithium, amiodarone)
Iodine deficiency/excess
De Quervain’s thyroiditis (painful)
Infiltration (e.g. sarcoid, haemochromatosis

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54
Q

What conditions present with a nodular goitre?

A

Toxic solitary adenoma
Non-functional thyroid adenoma
Multinodular goitre
Thyroid cyst
Cancer

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55
Q

What are the Universal features of Hyperthyroidism?

A

(EVERYTHING FAST)
Sweating and heat intolerance
Tachycardia
Weight loss
Fatigue
Frequent loose stools
Sexual dysfunction
Anxiety and irritability

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56
Q

What are the unique features of Graves Disease?

A

Diffuse goitre (without nodules)
Graves eye disease
Bilateral exophthalmos
Pretibial myxoedema
Acropachy

All relate to the presence of TSH Receptor antibodies

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57
Q

What is Exopthalmos?

A

bulging of eyeball out of the socket caused by Graves Disease.

This is due to inflammation, swelling and hypertrophy of the tissue behind the eyeball that forces the eyeball forward.

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58
Q

What is Pretibial Myxoedema?

A

Deposits of mucin under the skin on the anterior aspect of the leg (the pre-tibial area).

This gives a discoloured, waxy, oedematous appearance to the skin over this area.

It is specific to Grave’s disease and is a reaction to the TSH receptor antibodies.

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59
Q

What are the unique features of TMG?

A

Goitre with firm nodules
Most patients are aged over 50
Second most common cause of thyrotoxicosis (after Grave’s)

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60
Q

What is Thyroid Storm?

A

A rare presentation of hyperthyroidism. It is also known as “thyrotoxic crisis”.

It is a more severe presentation of hyperthyroidism with pyrexia, tachycardia and delirium.

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61
Q

How is Thyroid storm treated?

A

ABCDE and fluids to correct volume

1st Line: Using Propylthiouracil AND hydrocortisone AND propranolol
GS: Thyroidectomy

Can also give Hydrocortisone

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62
Q

What is Gestational Thyrotoxicosis?

A

Transient form of thyrotoxicosis caused by excessive stimulation of thyroid gland by hCG.
This leads to raise free T4 but low TSH.
Usually limited to the first 12-16 weeks of pregnancy

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63
Q

What is Foetal Thyrotoxicosis?

A

Transplacental transfer of thyroid stimulating autoantibodies from mother to fetus.
These autoantibodies bind to the fetal thyroid stimulating hormone (TSH) receptors and increase the secretion of the thyroid hormones.

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64
Q

What is the first line anti-thyroid drug?

A

Carbimazole:
Prevent thyroid peroxidase enzyme coupling and iodinating tyrosine residues on thyroglobulin → reduce T3 and T4

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65
Q

What is the second line anti-thyroid drug?

A

Propylthiouracil (PTU):
inhibits the conversion of T4 to T3

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66
Q

why would you not prescribe a pregnant women carbimazole?

A

Carbimazole is teratogenic
therefore give PTU

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67
Q

What is a key side effect of carbimazole?

A

Agranulocytosis
Presents as a sore throat

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68
Q

What are the various treatment options for Hyperthyroidism?

A

Carbimazole
Propylthiouracil
Radioactive iodine
Beta-Blockers
Surgery

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69
Q

Why is Carbimazole preferred over PTU?

A

PTU has high risks of severe hepatic reactions

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70
Q

What is the function of Radioactive iodine to treat hyperthyroidism?

A

Drinking a single dose of radioactive iodine.
This is taken up by the thyroid gland and the emitted radiation destroys a proportion of the thyroid cells.
This reduction in functioning cells results in a decrease of thyroid hormone production and thus remission from the hyperthyroidism

Patients are then on Levothyroxine replacement

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71
Q

Who cannot have radioactive iodine?

A

Pregnant women

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72
Q

What is the function of Beta-blockers in hyperthyroidism?

A

Used to block the adrenaline related symptoms
Typically Propranolol (non-selective) would be used

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73
Q

When would Surgery be used in treating Hyperthyroidism?

A

To removed toxic nodules/adenomas

The patient would likely be on Levothyroxine permanently

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74
Q

What are the differences between Graves Disease and Gestational Thyrotoxicosis?

A

Graves Disease symptoms predate pregnancy (and are more prominent during pregnancy)

N&V is greater in Gestational Thyrotoxicosis
Graves disease will present with Goitres
Graves disease ill have TSH-R antibodies

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75
Q

What is De Quervain’s Thyroiditis?

A

Subacute Granulomatous thyroiditis
Self limited inflammation of the thyroid often following viral infection.

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76
Q

What is the pathophysiology of De Quervain’s Thyroiditis?

A

4 Phases:
Phase 1 (3-6 weeks) Hyperthyroidism and painful goitre
Phase 2 (1-3 weeks) Euthyroid - normal function
Phase 3 (weeks-months) Hypothyroidism
Phase 4 Thyroid structure and function return to normal

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77
Q

What is the typical presentation of De Quervain’s Thyroiditis?

A

Neck pain (may radiate to jaw/ears)
Difficulty eating
Tender firm enlarged thyroid + goitre
Fever
Palpitations - often secondary to thyrotoxicosis

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78
Q

What are the diagnostic investigations for De Quervain’s Thyroiditis?

A

All elevated
Total T4, T3, T3 resin uptake
CRP elevated

Often follows viral infection

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79
Q

What is the treatment for De Quervain’s Thyroiditis?

A

Hyperthyroid Phase - NSAIDs and corticosteroids
Hypothyroid Phase - No Tx usually

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80
Q

Who is more likely to get hyperthyroidism?

A

Women

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81
Q

What is Hypothyroidism?

A

Inadequate output of thyroid hormones by the thyroid gland.

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82
Q

What is the most common cause of hypothyroidism in the developed world?

A

Hashimoto’s Thyroiditis

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83
Q

What is Hashimoto’s Thyroiditis?

A

Autoimmune destruction of the thyroid gland associated with anti-TPO antibodies and Anti thyroglobulin antibodies.
It initially causes a goitre when then leads to atrophy of the gland

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84
Q

What are the Transient causes of hypothyroidism?

A

Post partum Thyroiditis
De Quervain’s thyroiditis

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85
Q

What is the most common cause of hypothyroidism in the developing world?

A

Iodine deficiency

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86
Q

What are the main causes of hypothyroidism?

A

Hashimoto’s Thyroiditis (autoimmune)
Iodine deficiency
Secondary to Hyperthyroid treatment
Medications - lithium, Amiodarone

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87
Q

What are the main causes of Secondary Hypothyroidism?

A

Tumours
Infection
Vascular (Sheehan Syndrome)
Radiation

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88
Q

What is secondary hypothyroidism?

A

Where the pituitary gland is failing to produce enough TSH.
This is often associated with a lack of other pituitary hormones such as ACTH. This is called hypopituitarism

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89
Q

What is the presentation of Hypothyroidism?

A

(EVERYTHING SLOW)
Cold Intolerance
Weight gain
Fatigue
Dry skin
Coarse hair and hair loss
Fluid retention (oedema, pleural effusions, ascites)
Heavy or irregular periods
Constipation

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90
Q

What are the investigations to diagnose Hypothyroidism?

A

TSH and Thyroid hormone blood tests

TSH & T3/T4:
Primary Hypothyroidism:
TSH - High
T3/T4 - Low

Secondary Hypothyroidism:
TSH - Low
T3/T4 - Low

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91
Q

What is the management of Hypothyroidism?

A

Replacement of thyroid hormone - Levothyroxine
Dose is titrated until TSH becomes normal

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92
Q

How does Lithium medication cause Hypothyroidism?

A

Inhibits the production of thyroid hormones in the thyroid gland
Can cause a goitre and hypothyroidism

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93
Q

How does amiodarone lead to hypothyroidism?

A

Interferes with thyroid hormone production and metabolism.
Can lead to hypothyroidism.
Can also cause destruction of the thyroid leading to acute release of thyroid hormone and transient thyrotoxicosis

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94
Q

What is a key side effect of carbimazole?

A

Agranulocytosis
Presents as a sore throat

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95
Q

What is the main complication of Hypothyroidism?

A

Myxoedema coma - usually infection precipitated
Rapid loss of T4
Hypothermia, loss of consciousness, heart failure

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96
Q

What is the treatment for Myxoedema coma?

A

Levothyroxine
Hydrocortisone until adrenal insufficiency has been ruled out

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97
Q

What are the different types of Thyroid carcinoma?

A

Papillary - (70%) has Orphan Annie Eyes
Follicular (25%)
Medullary (5%) MEN-2 associated. Secretes Calcitonin
Anaplastic (1%) - worst prognosis

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98
Q

What are the Symptoms of Thyroid carcinoma?

A

Presents as Thyroid Nodules - hard and irregular
May have local compression on the recurrent laryngeal nerve - hoarse voice

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99
Q

What is the diagnosis for thyroid carcinoma?

A

Fine needle aspriation biopsy
TFTs
Thyroid ultrasound

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100
Q

Where are common metastasis sites for thyroid carcinoma?

A

LLBB

Lung
Liver
Bone
Brain

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101
Q

What is the treatment for Thyroid carcinoma?

A

Papillary / Follicular - Thyroidectomy / radioiodine
Anaplastic - palliative care

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102
Q

What is the bodies normal blood glucose concentration?

A

between 4.4-6.1 mmol/l

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103
Q

In the fasting state where does glucose come from?

A

Liver - breakdown of glycogen
-gluconeogenesis

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104
Q

In the fasting state, what are the levels of insulin?

A

Low - there is less glucose in the blood so insulin is low because it does not need to stimulate glucose storage

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105
Q

What do muscles use for fuel in the fasting state?

A

Free fatty acids

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106
Q

In the post prandial state what does the increase of glucose from a meal lead to?

A

Inhibition of glucagon secretion
Stimulation of insulin
Glucose is taken up by the liver (40%) and peripheral tissues (60%)

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107
Q

What does a high level of insulin and glucose promote?

A

Inhibition of lipolysis
reduced levels of free fatty acids

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108
Q

What is the site of insulin and glucagon secretion?

A

Islets of langerhans of the pancrease
Alpha cells - glucagon
Beta cells - Insulin

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109
Q

What is the paracrine function of insulin?
What is the effect of DM on this?

A

The release of insulin from beta cells acts on the alpha cells of the pancreas to inhibit further glucagon release.

In diabetes the insulin is lost and therefore you lose the alpha cell inhibition mechanism leading to excess glucagon and increased levels of glucose and free fatty acids in the blood.

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110
Q

Explain the process of insulin secretion?

A

Glucose is taken into the pancreas via GLUT2 transporters
Once in the pancreas glucose is metabolised by glucokinase which forms ATP
ATP then acts on the SUR1 potassium channels to close the K+ channels
This leads to depolarisation of the cell membrane and thus the opening of Ca channels
Calcium influx stimulates exocytosis of insulin secretory granules
Insulin is released

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111
Q

What is the action of insulin on the fat and muscle cells?

A

Stimulates the metabolism of GLUT4 channels to the cell membrane
Allows for the entry of glucose into the cell
increases peripheral uptake

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112
Q

What is the action of insulin?

A

Suppresses hepatic glucose output - Decrease glycogenolysis, Decrease gluconeogenesis.

Increase glucose uptake into insulin sensitive tissues - fat and muscle.

Suppresses lipolysis and muscle breakdown

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113
Q

What is the action of glucagon?

A

Increases hepatic glucose output - increase glycogenolysis, increased gluconeogenesis

Reduces peripheral glucose uptake - keeps glucose in the blood

stimulates peripheral release of gluconeogenic precursors - glycerol and amino acids, lipolysis, muscle glycogenolysis and breakdown.

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114
Q

What is ketogenesis under normal physiological circumstances?

A

Occurs when there is insufficient glucose supply and glycogen stores are exhausted (prolonged fasting)

There is lipolysis, liver converts FFAs to Ketones.

This are normally buffered by HCO3 from the kidneys preventing acidosis.

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115
Q

What happens in T1DM that leads to ketoacidosis?

A

Lack of insulin and therefore no peripheral uptake of glucose into fat and muscle cells
They believe they are starving - therefore undergo lipolysis and proteolysis.
Increased FFAs, and krebs is saturated (due to hyperglycaemia) so ketogenesis occurs.
Extreme hyperglycaemic ketosis occurs and the bicarbonate is used up.
Blood becomes acidic leading to ketoacidosis

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116
Q

What is Diabetes Mellitus?

A

A disorder of carbohydrate metabolism characterised by hyperglycaemia

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117
Q

How does DM cause morbidity and mortality?

A

Acute hyperglycaemia if untreated leads to diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic states (HHS)

Chronic hyperglycaemia leads to tissue complications (macro and microvascular)

Side effects of treatment - hypoglycaemia

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118
Q

What are the different types of diabetes Mellitus?

A

Type 1 DM - Insulin dependent
Type 2 DM - Insulin Independent - Maybe be gestational or medication induced)
MODY
Pancreatic diabetes
Endocrine diabetes - Acromegaly, Cushing’s
Malnutrition related diabetes

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119
Q

What is MODY?

A

Maturity onset diabetes of youth

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120
Q

What is the pathogenesis of T1DM?

A

Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterised by hyperglycaemia due to an absolute deficiency of insulin. This is caused by an autoimmune destruction of beta cells of the pancreas.
May have a genetic component, may be triggered by a certain event.
Type 4 hypersensitivity reaction

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121
Q

What mechanism of autoimmunity is responsible for T1DM?

A

Beta cells express HLA antigens ( HLA DR3 and HLA DR4) on MHC in response to an environmental event
Activates chronic cell mediated immune response leading to chronic insulitis

Islet cell autoantibodies
Glutamic acid decarboxylase
Insulin Autoantibodies
Protein tyrosine phosphatase

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122
Q

What are the Genes associated with T1DM?

A

HLA DR3
HLA DR4

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123
Q

What happens to insulin metabolism in T1DM and what is the consequence of this?

A

Loss of beta cells - Loss of insulin secretion
Leads to:
unrestricted hepatic glucose output:
Continued glycogenolysis in the liver + gluconeogenesis.

Impaired peripheral glucose uptake - cells believe they are starving and so need to obtain energy from:
Unrestricted lipolysis and skeletal muscle breakdown for gluconeogenesis
Increased Ketone Production leading to DKA

Glucose concentration rises lead to excretion of glucose in urine as renal reuptake routes are saturated (glycosuria). This also draws other essential electrolytes into the blood causing polyuria and polydipsia

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124
Q

What are the main consequences of DKA?

A

Ketoacidosis:
Can cause nausea and vomiting due to acidosis

Dehydration:
Hyperglycaemia overwhelms the kidneys - glucose is filtered into urine
Osmotic diuresis draws water into urine
Causes polyuria and polydipsia

Potassium Imbalance:
No insulin so K is not driven into cells. - Low cellular K but high/normal serum K
Total body K is low as there is no K stored in cells.
When insulin treatment is given this causes K influx into cells
Low serum K
Can lead to hypokalaemia and fatal arrhythmias.

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125
Q

What is the function of insulin in relation to Potassium ions?

A

Insulin increases the number of Na/K/ATPases present on cell membranes which leads to K influx into cells and removes K from circulation.

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126
Q

What are the risk factors for DKA?

A

Undiagnosed T1DM (potentially also T2DM)
Inadequate insulin / non-adherence to Insulin therapy

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127
Q

What are the signs/symptoms of DKA?

A

Polyuria
Polydipsia
Nausea and vomiting
Acetone smell to their breath
Kussmaul Respiration - Deep laboured breathing to reverse acidosis
Dehydration and subsequent hypotension
Altered Consciousness
They may have symptoms of an underlying trigger (i.e. sepsis)

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128
Q

How is DKA diagnosed?

A

Hyperglycaemia (i.e. blood glucose > 11 mmol/l)
Ketosis (i.e. blood ketones > 3 mmol/l)
Acidosis on VBG/ABG (i.e. pH < 7.3)

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129
Q

How is DKA Treated?

A

FIG-PICK: ABCs
F – Fluids – IV fluid resuscitation with normal saline
I – Insulin – Add an insulin infusion
G – Glucose – Closely monitor blood glucose and add a dextrose infusion if below a certain level
P – Potassium – Closely monitor serum potassium (e.g. 4 hourly) and correct as required
I – Infection – Treat underlying triggers such as infection
C – Chart fluid balance
K – Ketones – Monitor blood ketones

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130
Q

What is the Epidemiology of T1DM?

A

Younger onset (<30yrs)
Usually lean
North European
Associated with other Autoimmune Disorders

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131
Q

What is the Epidemiology of T2DM?

A

Onset older (>30 years).
Usually overweight.
More common in African/Asian.
More common in general.

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132
Q

What are the symptoms of T1DM?

A

2-6 week history of: (shorter history and more severe symptoms)
Polyuria
Polydipsia
Weight loss

Over longer periods of time may have:
Lethargy
eye problems
Neuropathy - glove/stocking

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133
Q

What are the first line investigations for Type I diabetes?

A

1st Line:
Random Blood Glucose - >11mmol/L
Fasting Blood Glucose - >7 mmol/L

For Borderline cases:
OGTT - >11mmol/L 2 hours after 75g oral glucose load
HbA1c - >48mmol/L

Ix to Consider:
C-peptide
Autoantibodies - Glutamic acid, insulin, islet cell

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134
Q

How is T1DM managed?

A

Patient education is essential:
- Monitoring dietary carbohydrate intake
- Monitoring blood sugar levels on waking, at each meal and before bed
- Monitoring for and managing complications, both short and long term

Insulin is prescribed.

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135
Q

How is insulin prescribed in T1DM?

A

1st Line: Basal-Bolus Regimen
- Log acting Insulin (levemir) + rapid acting insulin before meals (Humalog)
(Short acting insulin - 30mins prior to CHO intake)

Other:
Mixed insulin - Mix of short/rapid + intermediate given 2x daily

Continuous - If Px has disabling hypoglycaemia or persistent hyperglycaemia

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136
Q

What are some Complications of insulin therapy?

A
  • Hypoglycaemia - most common (also caused by SULFONYLUREA - antidiabetic drug)
  • Injection site - lipohypertrophy
  • Insulin resistance - mild and associated with obesity
  • Weight gain - insulin makes people feel hungry
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137
Q

What is lipodystrophy?

A

May occur when a patient injects insulin into the same spot causing the subcutaneous fat to harden.
This can lead to poorer absorption of insulin

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138
Q

What is a short term complication of treating diabetes with insulin?

A

Hypoglycaemia
Patients may inject insulin and become hypoglycaemic which can cause death.

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139
Q

What are the symptoms of hypoglycaemia?

A

PISTD

Pallor
Irritability
Sweating
Tremor
Dizziness

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140
Q

What can severe hypoglycaemia lead to?

A

Reduced consciousness
Coma
Death

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141
Q

Why is DKA less likely in T2DM?
When can it occur in T2DM?

A

Low levels of insulin are still produced
Low levels of insulin enough to prevent muscle catabolism and ketogenesis so muscle breakdown and ketone production rarely excessive

In chronic T2DM the beta cells may be destroyed and very little insulin is produced which can result in DKA.

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142
Q

What is the role of basal insulin in T1DM therapy?

A

Control glucose between meals and at night.
Adjusted to maintain fasting blood glucose between 5-7mmol/L

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143
Q

What is hypoglycaemia?

A

Low plasma glucose causing impaired brain function

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144
Q

What is the glucose value for hypoglycaemia?

A

<3.9 mmol/L

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145
Q

What is significant about the relationship between HbA1c levels and hypoglycaemic episodes?
Why does this mean that hypoglycaemia prevention mechanisms fail in DM?

A

The higher the HbA1c levels, the higher the glucose levels can be when the patient experiences a hypoglycaemic episode

In DM a patient will have higher HbA1c levels and therefore the threshold of the secretion of counter-regulatory hormones is lower

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146
Q

What are the risk factors for severe hypoglycaemia in a patient with T1DM?

A
  • History of severe episodes
    • HbA1c > 48 mmol/l (6.5%)
    • Long duration of diabetes
    • Renal impairment
    • Impaired awareness of hypoglycaemia
    • Extremes of age
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147
Q

What are the risk factors for severe hypoglycaemia in a patient with T2DM?

A
  • Advancing age
  • Cognitive impairment
  • Depression
  • Aggressive treatment of glycaemia
  • Impaired awareness of hypoglycaemia
  • Duration of multi dose insulin therapy
  • Renal impairment and other comorbidities
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148
Q

What normally prevents hypoglycaemia?

A
  • Counter-regulatory hormones
    • Glucagon
    • Adrenaline
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149
Q

What is the treatment of hypoglycaemia?

A
  1. Recognise symptoms
  2. Confirm the need for treatment with plasma glucose test
  3. Treat with 15g fast-acting carbohydrate to relieve symptoms (lucozade)
  4. Retest in 15 minutes to ensure blood glucose > 4 mmol/l and re-treat if needed
  5. Eat a long-acting carb to prevent recurrence of symptoms (toast, biscuit)
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150
Q

What is the pathophysiology of T2DM?

A

Repeated glucose and insulin exposure leads to cellular resistance to the effects of insulin.
Overtime the pancreas becomes fatigued and damaged from the over production of insulin leading to cell destruction (50% of beta cell loss)
Reduced insulin effects leads to hyperglycaemia

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151
Q

What is a common complication of uncontrolled T2DM?

A

Hyperosmolar Hyperglycaemic State (HHS)

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152
Q

What is HHS?

A

Hyperosmolar Hyperglycaemic State:
Profound Hyperglycaemia and Hyperosmolality in the absence of ketoacidosis

Occurs when the blood glucose levels go really high ( >33.3 mmol/l)
Results in a blood osmolality of >320 mOsm/kg
The hyperosmolar state draws water out of cells and into the blood
This leads to polyuria and severe dehydration

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153
Q

What is the pathogenesis of HSS?

A

Usually triggered by an infection:

  • relative Lack of insulin coupled with a rise in counter regulatory Hormones (Cortisol, GH, glucagon)
  • Leads to profound rise in glucose (but insulin is adequate to prevent DKA)
  • Excessive glucose leads to osmotic diuresis as capacity for renal reabsorption is full. This also draws out other essential electrolytes.
  • As water is lost there is dehydration and reduced circulating volume.
  • Leading to hyperosmolarity with Hyperglycaemia
  • This can cause hypovolaemia and cause AKI. Hyperosmolarity also increases viscosity of blood increase risk of thrombotic events.
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154
Q

What are some symptoms of HHS?

A

Polyuria
Extreme thirst
Dehydration - Can lead to neurological symptoms
Reduced GCS
Poor capillary refill
Hypotension
Tachycardia

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155
Q

What is the diagnosis of HHS?

A

History and physical exam

Blood tests and U&Es:
Severe hyperglycaemia - >30mmol/l
High blood osmolality >320mOsm/kg
Hypotension
No/minimal urinary ketones

ABG - No acidosis

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156
Q

What is the treatment of HHS?

A

ABCs
IV Fluids
Electrolyte Replacement
IV Insulin

VTE prophylaxis

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157
Q

What are the consequences of chronic hyperglycaemia as seen in T1DM and T2DM?

A

Microvascular
Macrovascular
Infection complications.

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158
Q

What are the non-modifiable risk factors for T2DM?

A

Older age
Male
Ethnicity (Black, Chinese, South Asian)
Family history

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159
Q

What are the modifiable risk factors for T2DM?

A

Obesity
Sedentary lifestyles
High carbohydrate (particularly refined carbohydrate) diet

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160
Q

How does T2DM present?

A

Fatigue
Polydipsia and polyuria (thirsty and urinating a lot)
Unintentional weight loss
Opportunistic infections
Slow healing
Glucose in urine (on dipstick)

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161
Q

How is T2DM Diagnosed?

A

1st Line:
Random Blood Glucose - >11mmol/L
Fasting Blood Glucose - >7 mmol/L

For Borderline cases:
OGTT - >11mmol/L 2 hours after 75g oral glucose load
HbA1c - >48mmol/L

Ix to Consider:
Fasting Lipids
U&Es - if suggestive signs of Diabetic Nephropathy

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162
Q

What is the oral Glucose Tolerance Test (OGTT)?

A

performed in the morning prior to having breakfast.
It involves taking a baseline fasting plasma glucose
giving a 75g glucose drink
measuring plasma glucose 2 hours later.
If >11mmol/L then Diabetes
It tests the ability of the body to cope with a carbohydrate meal.

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163
Q

What is pre diabetes?

A

The body struggles to get their blood glucose levels in to normal range, even after a prolonged period without eating carbohydrates.
But glucose levels are not high enough to be diagnosed with DM

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164
Q

What are the results of a pre diabetes diagnosis?

A

HbA1c – 42-47 mmol/mol
Fasting plasma glucose 6.1 – 6.9 mmol/l
OGTT - plasma glucose at 2 hours 7.8 – 11.1 mmol/l on an OGTT

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165
Q

What are the blood results for a diabetes diagnosis?

A

HbA1c > 48 mmol/mol
Random Glucose > 11 mmol/l
Fasting Glucose > 7 mmol/l
OGTT 2 hour result > 11 mmol/l

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166
Q

What is the Lifestyle management of T2DM?

A

Patient education about condition and their lifestyle
Dietary modification
Exercise and weight loss
Smoking Cessation
Monitor for DM complications

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167
Q

What is the first line medication for T2DM treatment?

A

Metformin (biguanide) to keep HbA1C <48mmol/mol
Increases insulin sensitivity and decreases liver production of glucose
Does not alter weight

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168
Q

What is the second line medication for T2DM treatment?

A

If HbA1c rises above 58 mmol/mol Dual therapy of Metformin + one of:
Sulfonylurea
Pioglitazone
DPP4 inhibitor
SGLT2 inhibitor
GLP-1 analogues

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169
Q

What is the third line medication for T2DM treatment?

A

If HbA1c still >58 mmol/mol on dual therapy then:
Triple Therapy - Metformin + 2 of the second line medications
OR
Metformin + insulin

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170
Q

When should SGLT2 and GLP-1 inhibitors be used in T2DM treatment?

A

Preferentially in patients with CVD

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171
Q

What is the mechanism of action of Metformin?

A

Increases insulin sensitivity and decreases liver production of glucose

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172
Q

What are the notable side effects of Metformin?

A

Diarrhoea and abdominal pain - dose dependent
Lactic acidosis
Does NOT typically cause hypoglycaemia

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173
Q

What is the mechanism of action of Pioglitazone?

A

A Thiazolidinedione acts on the PPAR-y receptor to
Increases insulin sensitivity and decreases liver production of glucose

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174
Q

What are the notable side effects of Pioglitazone?

A

Weight gain
Fluid retention
Anaemia
Heart failure
Extended use may increase the risk of bladder cancer
Does NOT typically cause hypoglycaemia

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175
Q

What is the mechanism of action of Sulfonylurea and give an example?

A

Gliclazide
Stimulate insulin release from the pancreas acting on the SUR1 receptor

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176
Q

What are the notable side effects of Sulfonylureas?

A

Weight gain
Hypoglycaemia
Increased risk of cardiovascular disease and myocardial infarction when used as monotherapy

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177
Q

What is an incretin?

A

Hormones produced by the GI Tract (GLP-1 and GIP)
They act in response to large meals and reduce blood sugar.

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178
Q

What are the roles of incretins?

A

Increase insulin secretions
Inhibit glucagon production
Slow absorption by the GI tract

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179
Q

What is the mechanism of action of DPP4 inhibitors and give an example?

A

Sitagliptin
Inhibit the DPP4 which breaks down incretins.
Therefore there is increased activity of GLP-1 and GIP

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180
Q

What are the notable side effects of DPP4 inhibitors?

A

GI tract upset
Symptoms of upper respiratory tract infection
Pancreatitis

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181
Q

What is the mechanism of action of GLP-1 mimetics and give an example?

A

Exenatide/liraglutide
Mimic GLP-1

182
Q

When are GLP-1 mimetics used?

A

In combination with Metformin and a Sulfonylurea in overweight patients

183
Q

What are the notable side effects of GLP-1 mimetics?

A

GI tract upset
Weight loss
Dizziness
Low risk of hypoglycaemia

184
Q

What is the main second line management of T2DM after a weight loss and metformin has failed?

A

Metformin + Sulfonylurea

185
Q

What is the mechanism of action of SGLT2 inhibitors and give examples?

A

Empagliflozin, Canagliflozin, Dapaglifozin
Inhibit SGLT2 from reabsorbing glucose in the PCT in the kidneys.
They cause glucose to be excreted in the urine.

186
Q

What are the notable side effects of SGLT2 inhibitors?

A

Glucosuria
Increased rate of urinary tract infections
Weight loss
Diabetic ketoacidosis, notably with only moderately raised glucose (rare)

187
Q

What are the HbA1c treatment targets for T2DM?

A

48 mmol/mol for new type 2 diabetics
53 mmol/mol for diabetics that have moved beyond metformin alone

188
Q

What is HbA1c?

A

Glycated haemoglobin
This is an average glucose level over the last 3 months (due to lifespan of an RBC)
it is measured every 3-6 months in diabetics.

189
Q

What are the long term complications of diabetes?

A

Macrovascular
Microvascular
Infection related

190
Q

How does chronic hyperglycaemia lead to macro and microvascular complications of diabetes?

A

hyperglycaemia causes damage to the endothelial cells of blood vessels. This leads to leaky, malfunctioning vessels that are unable to regenerate.

High levels of sugar in the blood also causes suppression of the immune system, and provides an optimal environment for infectious organisms to thrive.

191
Q

What are the Macrovascular complications of diabetes?

A

Coronary artery disease
Peripheral ischaemia/peripheral vascular disease - leads to diabetic foot
Stroke
Hypertension

192
Q

What are the Microvascular complications of diabetes?

A

Peripheral neuropathy
Diabetic retinopathy
Peripheral nephropathy - glomerulosclerosis

193
Q

What are the infection related complications of diabetes?

A

UTI
Pneumonia
Skin and soft tissue infections - often feet
Fungal infections - oral/vaginal candidiasis

194
Q

What percentage of diabetes patients experience diabetic neuropathy?

A

30-50%

195
Q

What percentage of patients with diabetes experience foot ulceration?

A

15%

196
Q

Can you name some drugs that can induce diabetes?

A
  • Steroids
  • Tacrolimus
  • Thiazides
  • Protease inhibitors (HIV)
  • Antipsychotics
197
Q

What are the symptoms and signs of diabetic neuropathy?

A

Pain:
Allodynia
Paraesthesia
Burning
Hyperaethesia

Autonomic:
Gastroparesis
Diarrhoea/Constipation
Incontinence
Orthostatic Hypotension - Postural hypotension

Insensitvity:
Foot ulceration
Infection
amputation
Charcot foot

198
Q

What is Paraethesia?

A

Abnormal sensation (normally tingling or pins and needles) due to peripheral nerve damage

199
Q

What is Allodynia?

A

pain response to normally non-painful stimulus

200
Q

What is Charcot Foot?

A

Weakening of the bones of the foot, they are more prone to fractures and the stress of walking leads to deformity of the foot

201
Q

What is the treatment of diabetic neuropathy?

A

Non-reversible condition
Treatment is only symptomatic management

202
Q

Describe the progression of diabetic neuropathy

A
  • gloves and stocking sensory loss
  • Starts in tips of fingers and toes and works its way up
203
Q

What are the risk factors for diabetic neuropathy?

A
  • Hypertension
  • Smoking
  • Poor glycaemic control
  • Diabetic duration
  • BMI
  • Triglycerides
  • Total cholesterol
204
Q

What screening tests are available for diabetic neuropathy?

A
  • Test sensation
  • Vibration perception
  • Ankle Reflexes
205
Q

What is the risk associated with diabetic foot ulceration?

A

Amputation

206
Q

What is the treatment for peripheral vascular disease?

A

Quit smoking
Walk through the pain
Surgical Intervention

207
Q

What is the pathogenesis of diabetic retinopathy?

A
  • Hyperglycaemia induces apoptosis of perictyes (which causes micro-aneurysms) and endothelial cells (which increases permeability of capillaries, proteins leak into retina)
  • It does this by increasing blood flow to the retinal capillaries and inducing abnormal metabolism
  • Loss of pericytes cause endothelial cells to respond by increasing turnover, which cause thickening of the capillary wall and cause ischaemia
  • Vascular growth factors are released in response to ischaemia, which cause the growth of new, fragile blood vessels which are prone to bursting
208
Q

How does diabetic retinopathy get graded?

A
  • R0 - None detected
  • R1 - Background changes; screened once a year
  • R2 - Pre-proliferative; early changes screened 6-monthly
  • R3 - Proliferative; called into eye clinic to look at interventions to protect vision
  • M - Maculopathy; changes that happen close to the fovea
  • P - Photocoagulation; laser treatment has been done
  • U - Unclassifiable
209
Q

What’s the treatment for diabetic retinopathy?

A
  • Laser therapy
  • Aim is to stabilise the changes
  • Target abnormal blood vessels to stop them bleeding
  • Does not improve sight
210
Q

What is the hallmark of diabetic nephropathy?

A

Proteinuria

211
Q

What is nephropathy a major risk for?

A

CVD

212
Q

What are the risk factors of Diabetic retinopathy?

A

Poor blood pressure and blood glucose control

213
Q

What is the pathophysiology of diabetic nephropathy?

A
  • Hyperglycaemia leads to RBCs becomming sticky and can cause occlusion of the efferent arteriole.
  • Efferent arteriole is blocked leading to a build up of pressure and Hyperfiltration.
  • The hyperfiltration damages the filtration barrier and stimulates mesangial cells to secrete extracellular matrix
  • This leads to sclerosis and scarring (glomerulosclerosis) and subsequent nephropathy
214
Q

When does diabetic nephropathy develop in type 1 and type 2 diabetes?

A

T1DM - Around 10 years after diagnosis
T2DM - Can be present at diagnosis

215
Q

What is Acromegaly?

A

Clinical manifestation of excessive growth hormone (GH).
Growth hormone is produced by the anterior pituitary gland.

This drives increased bone and muscle growth, increased protein synthesis

216
Q

What is the most common cause of acromegaly?

A

Pituitary Adenoma secreting excess GH
Account for >90% of causes

217
Q

Acromegaly and Gigantism are caused by the excessive production of which hormone?

A

Growth hormone

218
Q

What is the difference between Acromegaly and Gigantism?

A

Acromegaly occurs in adults - after growth plates are fused.

Gigantism occurs in children - prior to epiphyseal fusion

caused by a pituitary tumour causing increased GH release however the tumour also presses on the pituitary so you get hypopituitarism which means the other hormones do not work and therefore they don’t go through puberty as no testosterone is being produced

219
Q

What is the mean age of diagnosis for Acromegaly?

A

44 years old; mean duration of symptoms is 8 years

220
Q

What are rarer causes of Acromegaly?

A

excess secretion of GH from an ectopic source:
e.g. lung/adrenal tumours that produce GHRH or GH

Hypothalamic dysfunction e.g. hypothalamic tumours

221
Q

How does Acromegaly present?

Space occupying lesions?

Overgrowth of tissues?

Organ dysfunction?

A

Slow gradual changes:

Space Occupying Lesion:
Headaches
Visual field defect (“bitemporal hemianopia”)

Overgrowth of tissues:
Prominent forehead and brow (“frontal bossing”)
Large nose
Large tongue (“macroglossia”)
Large hands and feet
Large protruding jaw (”prognathism”)
Arthritis from imbalanced growth of joints

GH can cause organ dysfunction:
Hypertrophic heart
Hypertension
Type 2 diabetes
Colorectal cancer

Symptoms suggesting active raised growth hormone:
Development of new skin tags
Profuse sweating

222
Q

What visual defect is common in acromegaly patients/patients with pituitary adenomas?
Why?

A

Bitemporal hemianopia:
A pituitary tumour of sufficient size will start to press on the optic chiasm that lies just above.
Pressure on the optic chiasm will lead to a stereotypical “bitemporal hemianopia” visual field defect.
This describes loss of vision on the outer half of both eyes.

223
Q

What investigations should be done for someone with suspected acromegaly?

A

Insulin-like Growth Factor 1 (IGF-1) is the initial screening test (raised)

Oral glucose tolerance test whilst measuring growth hormone (high glucose normally suppresses growth hormone)

MRI brain for the pituitary tumour
Refer to ophthalmology for formal visual field testing

224
Q

What are some common Acromegaly Co-morbidities?

A

Hypertension and heart disease
Diabetes
Cerebrovascular events and headache
Arthritis
Insulin resistant Diabetes
Sleep Apnoea

225
Q

What is the first line treatment for acromegaly?

A

Often caused by pituitary adenoma:
Therefore Trans-sphenoidal surgery is first line treatment

If ectopic GH is the cause then surgical removal of these cancers is also treatment.

226
Q

What medications can be used to treat acromegaly?

A

2nd Line: Somatostatin analogues - Block GH release (Ocreotide)

3rd Line: Pegvisomant - GH antagonist
OR
Dopamine agonists - Block GH release (Bromocriptine/Cabergoline)

1st line Tx = transsphenoidal surgery

227
Q

What is Pegvisomant?

A

GH Antagonist used to treat acromegaly

228
Q

What is Ocreotide?

A

Somatostatin analogue used to treat acromegaly as this blocks the Growth Hormone axis

229
Q

What is Bromocriptine/Cabergoline?

A

A dopamine agonist used to treat acromegaly as this blocks the growth Hormone axis

230
Q

What is the biggest risk of radiotherapy when treating acromegaly?

A

The development hypopituitarism; therefore, it is generally avoided in those of reproductive age.

231
Q

What are the causes of Hypercalcaemia?

A

CHIMPANZEES:
Calcium supplementation
Hyperparathyroidism
Iatrogenic immobilisation
Multiple Myeloma
Parathyroid Hyperplasia (3’ Hyperparathyroidism)
Alcohol
Neoplasms
Zollinger-ellison syndrome
Excessive Vitamin D
Excessive Vitamin A
Sarcoidosis

232
Q

What are the symptoms of Hypercalcaemia?

A

Renal STONES
Painful BONES
Abdominal GROANS - Constipation, nausea, vomiting
Psychiatric MOANS - Fatigue, depression, psychosis
THRONES - Polyuria, Polydipsia

233
Q

What ECG abnormality may suggest hypercalcaemia?

A

Short QT interval
Shortening of the ST segment - faster ventricular repolarisation as a result of increased calcium entering the cell through L type calcium channels

234
Q

What are the main causes of Hypercalcaemia?

A

90% of the time caused;
- Malignancies
- Hyperparathyroidism - primary and tertiary

235
Q

What are the common malignancies that may cause hypercalcaemia?

A

Myeloma
Bone metastases
Lymphoma
PTH related tumour.

236
Q

What are the investigations for Hypercalcaemia?

A

Fasting Serum Calcium
Serum PTH
Ultrasound for Primary Parathyroidism
24hr urinary calcium

237
Q

What is the treatment for Hypercalcaemia?

A

Rehydration with normal saline
Bisphosphonates
Loop Diuretics (furosemide)

238
Q

What is Primary Hyperparathyroidism?

A

Uncontrolled parathyroid hormone produced directly by a tumour of the parathyroid glands.
This leads hypercalcaemia: an abnormally high level of calcium in the blood.
This is treated by surgically removing the tumour.

239
Q

What is Secondary Hyperparathyroidism?

A

This is where insufficient vitamin D or chronic renal failure leads to low absorption of calcium from the intestines, kidneys and bones.
This causes hypocalcaemia: a low level of calcium in the blood.

The parathyroid will react to the chronically low serum Ca and secrete excessive PTH.

240
Q

What are the blood levels of PTH and Ca in secondary hyperparathyroidism?

A

Parathyroid undergoes hyperplasia due to overactivation from chronic hypocalcaemia.

This results in serum calcium being low/normal but PTH being high

241
Q

What is Tertiary Hyperparathyroidism?

A

When 2’ hyperparathyroidism continues for a long time it leads to hyperplasia of the gland and the baseline PTH increases drastically.
If the 2’ Hyperparathyroid cause is treated then there is high PTH in the absence of pathology leading to hypercalcaemia

242
Q

How is Primary, Secondary and Tertiary Hyperparathyroidism treated?

A

Primary:
Surgical removal of adenoma. Potentially bisphosphonates.

Secondary:
Calcium correction. Treat underlying condition

Tertiary:
Calcium mimetic (Cinacalcet), total or subtotal parathyroidectomy

243
Q

How is Primary, Secondary and Tertiary Hyperparathyroidism treated?

A

Primary:
Surgical removal of adenoma. Potentially bisphosphonates.

Secondary:
Calcium correction. Treat underlying condition

Tertiary:
Calcium mimetic (Cinacalcet), total or subtotal parathyroidectomy

244
Q

What are the blood levels of PTH and Ca in Tertiary hyperparathyroidism?

A

High PTH due to hyperplasia and increased baseline levels
High serum calcium due to high PTH in the absence of pathology.

245
Q

Fill out this chart:

Hyperparathyroidism:
Primary:
Cause -
PTH -
Calcium -

Secondary:
Cause -
PTH -
Calcium -

Tertiary:
Cause -
PTH -
Calcium -

A

Primary:
Cause - Tumour
PTH - High
Calcium - High
Phosphate - Low

Secondary:
Cause - Low Vitamin D / CKD
PTH - High
Calcium - Low/Normal
Phosphate - High

Tertiary:
Cause - Hyperplasia
PTH - High
Calcium - High
Phosphate - High

246
Q

Why can PTH be normal in Primary Hyperparathyroidism?

A

Occasionally PTH can be normal if the calcium suppresses the PTH production.
This is an inappropriate suppression

247
Q

What is the blood concentration of Calcium:

Mild/moderate Hypocalcaemia
Sever Hypocalcaemia

Normal Serum level

Mild Hypercalcaemia
Moderate Hypercalcaemia
Severe Hypercalcaemia

A

Mild/moderate Hypocalcaemia: 1.9-2.2 mmol/l
Sever Hypocalcaemia: <1.9 mmol/l

Normal Serum level: 2.2-2.6 mmol/l

Mild Hypercalcaemia: 2.7 - 2.9 mmol/l
Moderate Hypercalcaemia: 3.0-3.4 mmol/l
Severe Hypercalcaemia: >3.4 mmol/l

248
Q

What are the clinical features of Hypocalcaemia?

A

CATS go Numb

Convulsions
Arrhythmias
Tetany
Spasm
Numbness

249
Q

What clinical signs are suggestive of Hypocalcaemia?

A

Chvostek:
Facial nerve spasm when tapped

Trousseau:
Carpopedal

250
Q

What ECG abnormality may suggest hypocalcaemia?

A

QT prolongation
Prolongation of the ST segment due to slower ventricular repolarisation as there is less calcium entering myocardial cells.

251
Q

What are some causes of Hypocalcaemia?

A

Vit D Deficiency
CKD
Hyperphosphatemia
Diuretics
Hypoparathyroidism
Pseudohypoparathyroidism
Critical illness - sepsis

252
Q

What are possible causes of hypoparathyroidism?

A

Primary:
gland failure - autoimmune destruction
Congenital - Di George Syndrome

Secondary
Surgery/radiation therapy

253
Q

How does Hypoparathyroidism lead to Hypocalcaemia?

A

PTH stimulates the activation of vitamin D, which facilitates intestinal calcium absorption, renal reabsorption of calcium as well as calcium release from bone. Phosphate reabsorption is inhibited by PTH.

In Hypoparathyroidism, these processes do not occur as PTH is not produced

254
Q

What are the features of Hypoparathyroidism?

A

Hypocalcaemia
Hyperphosphatemia

255
Q

What is the treatment for hypoparathyroidism?

A

Acute: IV calcium gluconate
Persistent: Vitamin D analogue/supplementation

256
Q

How does CKD lead to hypocalcaemia?

A

CKD
Increased phosphate
Microprecipitation of calcium phosphate in tissues
Low serum level of calcium.

CKD
Inadequate production of active vitamin D.

257
Q

What is Conn’s Syndrome?

A

An adrenal adenoma secreting Aldosterone leading to hyperaldosteronism independent of the RAAS

258
Q

What is Primary Hyperaldosteronism?

A

When the adrenal glands are directly responsible for producing too much aldosterone
Serum renin will be low as it is suppressed by the high blood pressure

259
Q

What are the various causes for Primary Hyperaldosteronism/

A

Bilateral adrenal hyperplasia (most common)
An adrenal adenoma secreting aldosterone (known as Conn’s Syndrome)
Familial hyperaldosteronism type 1 and type 2 (rare)
Adrenal carcinoma (rare)

260
Q

What is Secondary Hyperaldosteronism?

A

Where excessive renin stimulates the adrenal glands to produce more aldosterone
Serum renin will be high

261
Q

What are the causes of Secondary Hyperaldosteronism?

A

Renal artery stenosis
Renal artery obstruction
Renin secreting tumours
Heart failure

262
Q

What 1st line and GS Investigations are done in suspected hyperaldosteronism?

A

1st Line: FBC/U&E

Check Renin : Aldosterone ratio:
High aldosterone and low renin indicates primary hyperaldosteronism
High aldosterone and high renin indicates secondary hyperaldosteronism

GS- Selective adrenal venous sampling

CT / MRI to look for an adrenal tumour
Renal doppler ultrasound, CT angiogram or MRA for renal artery stenosis or obstruction

263
Q

What are the symptoms of Conn’s Syndrome?

A

Resistant HTN (unfixable with ACEi / Bb)
Hypokalaemia
Muscle weakness
Paraesthesia
Polydipsia
Polyuria and nocturia
Mood Disturbance

264
Q

What are some physiological effects of hyperaldosteronism?

A

Hypertension (most common cause of secondary hypertension)
Hypokalaemia
Hypernatraemia
Alkalosis

265
Q

What are the goals of Conn’s Syndrome management?

A

Lower BP
Decrease Aldosterone
Resolve electrolyte imbalance

266
Q

What is the management of Hyperaldosteronism?

A

Aldosterone antagonists:
Spironolactone/Eplerenone

Treat underlying cause:
Surgical removal of tumour
Renal artery angioplasty

267
Q

What is the most common cause of secondary hypertension?

A

Hyperaldosteronism

268
Q

What is Syndrome of Inappropriate ADH (SIADH)?

A

Where there is inappropriately large amounts of ADH release

269
Q

What are the causes of SIADH?

A

Idiopathic
CNS disorders
Head Injury
Tumours - Pituitary or Ectopic ADH production
pneumonia
Respiratory causes
Drugs

270
Q

What Tumours can cause SIADH?

A

Small cell lung cancer
Prostate
Thymus
Lymphomas

271
Q

What is the pathogenesis of SIADH?

A

Excess ADH secreted
Excessive water reabsorption in CD of nephron
Water dilutes Na in the blood so low serum Na concentration (hyponatraemia)
Water reabsorption does not normally cause fluid overload so euvolemia
Euvolemic Hyponatraemia
Urine is more concentrated - less water is excreted
SIADH patients high High urine osmolality and High urine Sodium

272
Q

What are the Symptoms of SIADH?

A

Non-specific

Headache
Fatigue
Muscle aches/cramps
Confusion
Severe Hyponatraemia - can cause seizures and reduced consciousness

273
Q

How is SIADH diagnosed?

A

In a way, SIADH is a diagnosis of exclusion as we do not have a reliable test to directly measure ADH activity.

Clinical examination will show euvolaemia.
U+Es will show a hyponatraemia.
Urine sodium and osmolality will be high.

274
Q

What causes of Hyponatraemia are exlcuded to give a diagnosis of SIADH?

A

Negative short synacthen test to exclude adrenal insufficiency
No history of diuretic use
No diarrhoea, vomiting, burns, fistula or excessive sweating
No excessive water intake
No chronic kidney disease or acute kidney injury

275
Q

How is SIADH managed?

A

Establish and treat the cause
Correct sodium levels - must be done slowly to prevent CPM
Fluid restriction
Tolvaptan - ADH receptor blockers (V2 receptors)
Demeclocycline - tetracycline antibiotic that inhibits ADH

276
Q

What is CPM?

A

Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)
Usually caused by treating severe hyponatraemia too quickly

277
Q

What is an important defining factor when determining if the hyponatraemia is caused by SIADH or fluid overload/dehydration?

A

SIADH will release more ADH
Will increase water retention but have compensatory Na excretion to maintain euvolemia
Therefore SIADH presents as Euvolemia and Hyponatraemia

Other Hyponatraemia causes can be fluid overload (Liver failure) or dehydration

278
Q

What is Diabetes Insipidus being renamed to?

A

Arginine Vasopressin Deficiency (AVP Deficiency) - Cranial Diabetes Insipidus
Arginine Vasopressin Resistance (AVP Resistance) - Nephrogenic Diabetes Insipidus

279
Q

What is diabetes insipidus (AVP deficiency/resistance)

A

A lack of ADH or a lack of response to ADH.
This prevents the kidneys from being able to concentrate the urine leading to polyuria and polydipsia.

280
Q

What is AVP Deficiency (cranial Diabetes insipidus)?

A

A lack of ADH production

281
Q

What is AVP Resistance (Nephrogenic Diabetes Insipidus)?

A

Although ADH is produced, it is not able to bind to receptors to induce a response and hence ADH does not function.

282
Q

What is Primary Polydipsia?

A

When the patient has normally functioning ADH system but they are drinking excessive quantities of water leading to excessive urine production.

283
Q

What can cause AVP resistance?

A

Drugs, particularly lithium used in bipolar affective disorder
Mutations in the AVPR2 gene on the X chromosome that codes for the ADH receptor
Intrinsic kidney disease
Electrolyte disturbance (hypokalaemia and hypercalcaemia)

284
Q

What can cause ADVP deficiency?

A

Can be idiopathic - no clear cause
Brain tumours
Head injury
Brain malformations
Brain infections (meningitis, encephalitis and tuberculosis)
Brain surgery or radiotherapy

285
Q

How does Diabetes insipidus (AVP D/R) present?

A

Polyuria (excessive urine production)
Polydipsia (excessive thirst)
Dehydration
Postural hypotension
Hypernatraemia
No Glycosuria

286
Q

What investigations are required to diagnose Diabetes insipidus?

A

Low urine osmolality
High serum osmolality
Water deprivation test

Desmopressin suppression test

287
Q

What is the water deprivation test?

A

Also known as desmopressin stimulation test:

Initially the patient should avoid taking in any fluids for 8 hours (This is referred to as fluid deprivation)
Then, urine osmolality is measured and synthetic ADH (desmopressin) is administered.
8 hours later urine osmolality is measured again.

288
Q

How do you interpret the results for the water deprivation test?

A

AVP Deficiency (Cranial DI):
After Deprivation - Urine osmolality is Low
After ADH (desmopressin) - Urine osmolality is High

AVP Resistance (Nephrogenic DI):
After Deprivation - Urine osmolality is Low
After ADH (desmopressin) - Urine osmolality is Low

Primary Polydipsia:
After Deprivation - Urine osmolality is High
After ADH (desmopressin) - Urine osmolality is High

289
Q

What is the management for AVP deficiency (Cranial DI)?

A

Desmopressin - Synthetic ADH to replace normal ADH

290
Q

What is the management for AVP Resistance (Nephrogenic DI)?

A

Adequate fluid intake to match output and insensible losses

Thiazide Diuretics - increase sodium excretion to reduce blood osmolality and therefore reduce stimulation of thirst centres in the hypothalamus

291
Q

What is the normal range for sodium?

A

135-145mmol/l

292
Q

What is the sodium levels in Hyponatraemia?

Mild?
Moderate?
Severe?

A
  • Mild130-135mmol/l
  • Moderate 125-129mmol/L
  • Severe <125mmol/l
293
Q

What are the signs and symptoms of Hyponatraemia?

A
  • Headache
  • Lethargy
  • Anorexia and abdominal pain
  • Weakness
  • Confusion/hallucinations
  • Agitation
  • Decreased consciousness level
  • Fitting
  • Coma
294
Q

What is the difference between acute and chronic hyponatraemia and how does this affect its management?

A
  • Acute - 48 hours
    • Rapid correction safer and may be necessary
  • Chronic - CNS adapts
    • Correction must be slow
    • <8mmol/24hr
295
Q

How does CPM/Osmotic Demyelination Syndrome occur?

A

Severe Hyponatraemia
Water moves by osmosis across BBB into the cells of the brain (from low solute conc to high solute conc)
Causes the brain to swell.
Brain adapts by reducing solutes in brain cells so water is balanced across BBB preventing oedema.
This process is protective and takes a few days to adapt
Therefore in chronic hyponatraemia, brain cells will also have low osmolality (after adaptation)

If Hyponatraemia treated too quickly:
Serum Na levels rise
Water rapidly shifts out of brain cells into blood
leads to demyelination of neurones

296
Q

What is Phaeochromocytoma?

A

A tumour of the chromaffin cells in the adrenal medulla that secrete unregulated amounts of adrenaline.
This leads to episodic activation of the sympathetic nervous system

297
Q

What are the causes of Phaeochromocytoma?

A

25% are familial associated with Multiple Endocrine Neoplasia Type 2 (MEN2)

10% rule for patterns of tumour:
10% bilateral
10% malignant
10% outside of adrenal gland

298
Q

How does a patient with phaeochromocytoma present?

A

Signs and symptoms fluctuate with peaks and troughs relating to when the tumour is secreting adrenaline.

Anxiety
Sweating
Headache
Hypertension
Palpitations, tachycardia and paroxysmal atrial fibrillation

299
Q

How is Phaeochromocytoma diagnosed?

A

24 hour urine Catecholamines
Plasma free Metanephrines

300
Q

Why are metanephrines used to diagnose phaeochromocytoma?

A

They are the breakdown product of adrenaline which have a much longer half life
Therefore they are less prone to dramatic fluctuations like adrenaline is

301
Q

What is the management of phaeochromocytoma?

A

Alpha blockers - Phenoxybenazmine
Beta-blockers - Once established on alpha blockers
Adrenalectomy to remove the tumour - definitive management.

302
Q

What is a complication of phaeochromocytoma?

A

Hypertenstion crisis (>180/120 BP)
Treatment is Phentolamine

303
Q

What is a Prolactinoma?

A

Benign adenoma of the pituitary gland secreted Prolactin

304
Q

What are the clinical features associated with a Prolactinoma?

A

Females:
Amenorrhoea/oligorrhoea
Low Libido
Galactorrhoea
Infertility.

Men:
Low testosterone
ED
Reduced facial hair
Low Libido

305
Q

How are Prolactinomas treated?

A

Dopamine agonist (e.g. Cabergoline or Bromocriptine) - produces prolactin-reducing feedback
Surgery possibly

306
Q

Prolactinoma is a tumour of what cell type?

A

Lactotroph

307
Q

What else can cause hyperprolactinemia?

A
  • Hypothalamic-pituitary stalk damage
  • Drug induced e.g. anti-psychotics which block dopamine
  • Pregnancy and lactation
  • Systemic disorders e.g. CKD or cirrhosis
308
Q

How can we diagnose prolactinomas?

A
  • MRI scan
  • Prolactin levels in the blood
309
Q

What is Adrenal Hyperplasia?

A

Defective enzymes mediating the production of adrenal cortex products

310
Q

What are the symptoms of adrenal Hyperplasia?

A

In severe forms; salt loss.
Female: Ambiguous genitalia with common urogenital sinus.
Male: no signs at birth, bar subtle hyperpigmentation and possible penile enlargement.

311
Q

What are the resulting adrenal hormones in patients with adrenal hyperplasia?

A

Low cortisol, maybe low aldosterone, high androgen

312
Q

What is the pathogenesis of adrenal hyperplasia?

A

Defective 21-hydroxylase -> disruption of cortisol biosynthesis. This causes cortisol deficiency, with or without aldosterone deficiency and androgen excess. In severe forms, aldosterone deficiency -> salt loss

313
Q

What is the cause of adrenal hyperplasia?

A

Genetic 21-hydroxylase deficiency is the cause of about 95% of cases.

314
Q

What investigations are used to diagnose adrenal hyperplasia?

A

Serum 17-hydroxyprogesterone (precursor to cortisol) levels: high

315
Q

How is adrenal hyperplasia managed?

A

Glucocorticoids: Hydrocortisone
Mineralocorticoids: Fludrocortisone
Control electrolytes
If salt loss: Sodium chloride supplement

316
Q

What is Hyperkalaemia?

A

Excess potassium in the blood more than 5.5mmol/L

317
Q

What are the causes of Hyperkalaemia?

A

Impaired excretion:
- CKD/AKI.
- Potassium Sparing Diuretics
- Adrenal Insufficiency/Addisonian Crisis

Increased Intake - dietary/IV

Shift to extracellular - rhabdomyolysis

318
Q

What are the symptoms of Hyperkalaemia?

A

Impaired muscular transmission:
Fatigue
Generalised weakness
Chest pain
cramps
diarrhoea
dyspnoea
Palpitations

Signs:
hyperreflexia
Arrythmias
Reduced power

Can cause MI

319
Q

What ECG abnormality is suggestive of Hyperkalaemia?

A

Tall tented T Waves

Reduced/small P wave
Prolonged PR
Widened QRS

320
Q

What is the main complication of Hyperkalaemia?

A

Myocardial Infarction
Leads to Death

321
Q

How is Hyperkalaemia treated?

A
  • Myocardial protection - IV Calcium gluconate
  • Drive K intracellularly - insulin w/dextrose AND Nebulised salbutamol
  • Dietary potassium restriction and loop diuretic
322
Q

What is Hypokalaemia?

A

Low serum Potassium < 3.5mmol/L

323
Q

What are the symptoms of Hypokalaemia?

A

Usually asymptomatic,

Hypotonia
Hyporeflexia
Muscle cramps and pain
possibly muscle weakness.
Increased risk of cardiac arrhythmias.
Tetany
Palpitations

324
Q

What ECG abnormalities would be suggestive of Hypokalaemia?

A

T wave Inversion or Flat T waves
ST Depression
Prolonged PR
Prominent U waves

325
Q

What is the pathogenesis of Hypokalaemia in the GI tract?

A

Excessive loss of potassium through the kidneys in response to aldosterone or diuretic therapy.

GI fluid loss -> less chloride -> increase in aldosterone -> Decreased potassium reabsorption

326
Q

What is the cause of hypokalaemia?

A

Hypokalaemia w/ alkalosis:
Vomiting, thiazides, loop diuretics, cushings, Conns

Hypokalaemia w/ Acidosis:
Diarrhoea, Rental tubular acidosis, acetazolamide, DKA partially treated

327
Q

What is the treatment for Hypokalaemia?

A

Mild/ASx (3-3.4mmol/l)
Oral replacement/IV

Severe (<2.5mmol/l)
IV replacement 40mmol KCL in 1L 0.9 NaCl

328
Q

What are the main complications of Hypokalaemia?

A

Cardiac Arrythmias
Sudden death

329
Q

What is Puberty?

A

Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms

330
Q

What are the definitive signs of puberty for males and females?

A
  • Girls - menarche
    • First menstrual bleed
  • Boys - first ejaculation
    • Often nocturnal
331
Q

What controls the development of secondary sexual characteristics?

A
  • Girls
    • Ovarian oestrogens
      • Growth of breasts and female genitalia
    • Ovarian and adrenal androgens
      • Control pubic and axillary hair
  • Boys
    • Testicular androgens
      • External genitalia and pubic hair growth
      • Enlargement of larynx and laryngeal muscles
        • Deepening of the voice
332
Q

What are Tanner Stages?

A

Scale of physical development through puberty

333
Q

What is used to measure testicular volume in ml?

A

Orchidometer

334
Q

What are indications for delayed puberty investigation?

A

Girls:
Lack of breast development by 13yrs
More than 5yrs between breast development and menarche
Lack of pubic hair by age 14yrs
Absent menarche by 15-16yrs

Boys:
Lack of testicular enlargement by age 14yrs
Lack of pubic hair by age 15yrs
More than 5 years to complete genital enlargement

335
Q

What are some functional causes of delayed puberty?

A

Chronic Renal disease / Chronic lung disease
Chronic GI disease/malnutrition
Sickle cell disease
Anorexia nervosa/Bulimia
Psychosocial stress
Extreme exercise
Drugs
Poorly controlled T1DM
Hypothyroidism
Cushing’s Syndrome
Hyperprolactinaemia

336
Q

What is primary hypogonadism?

A
  • Issue with the gonads
  • Also known as hypergonadotropic hypogonadism
337
Q

What would the blood test results be for Primary Hypogonadism?

A
  • Gonads not responding to stimulus so hypothalamus and pituitary more stimulated
  • FHS/LH will both be high
  • Sex hormones will be low
338
Q

What is secondary and tertiary Hypogonadism?

A

Also known as Hypogonadotrophic Hypogonadism

Secondary - Issue with Pituitary
Tertiary - Issue with Hypothalamus

339
Q

What are the causes of hypogonadotropic hypogonadism?

A

CNS disorders - tumours
Kallmanns’ Syndrome - Gonadotrophin deficiency
Prader willi syndrome
sickle cell
CF
AIDS

340
Q

Who is mainly affected by Kallmann Syndrome?

A

Mainly Males
4:1 M:F

341
Q

What are the symptoms associated with Kallmanns Syndrome?

A

Anosmia
delayed puberty

342
Q

What causes Kallmann Syndrome?

A

Hypogonadotrophic hypogonadism
- Failure of migration of GNRH neurones from hypothalamus to pituitary
- X-linked, autosomal recessive or dominant

343
Q

What are the main Conditions which fall under the hypergonadotropic hypogonadism?

A

Klinefelters - Males
Turners Syndrome - Females

344
Q

What is Turners Syndrome?

A

45 XO
Loss of an X chromosome

345
Q

What are signs and symptoms of Turners Syndrome?

A

Primary Hypogonadism
Webbing of neck
Short stature
recurrent Otitis media
Small mandible

346
Q

What is Klinefelters Syndrome?

A

47 XXY
Primary hypogonadism

347
Q

What are the signs and Symptoms of Klinefleters Syndrome?

A
  • Azoospermia
  • Gynaecomastia
  • Reduced secondary sexual hair
  • Osteoporisis
  • Tall stature
  • Reduced IQ
348
Q

What risks are associated with Kleinfelter Syndrome?

A

20-fold increased risk of breast cancer

349
Q

What fertility treatments can be done for patients with Hypogonadotropic Hypogonadism?

A
  • GnRH therapy
    • Pituitary must be intact
  • Parenteral combination of gonadotropin therapy
    • LH/hCG and FSH
350
Q

What is thelarche and what initiates it?

A
  • Breast development
  • Oestrogen
351
Q

How long does thelarche take to complete?

A

3 years

352
Q

What other hormones are involved in breast development?

A
  • Prolactin
  • Glucocorticoids
  • Insulin
353
Q

What is adrenarche?

A
  • Maturation process of the adrenal gland
  • Specialised subset of cells arises forming the androgen producing zona reticularis
354
Q

When does adrenarche occur?

A
  • Peri-puberty
  • Premature or exaggerated adrenarche can occur up to 2 years prior to puberty, especially in obese children
355
Q

What happens physiologically during adrenarche?

A
  • Mild advance in bone age
  • Axillary hair growth
  • Mild acne
  • Body odor
356
Q

What is precocious puberty?

A

Early puberty

357
Q

Which population of patients are more likely to have ‘true’ precocious puberty and what is the significance of this?

A
  • Up to 80% female
  • If male patients present with precocious puberty, differentials should be ruled out before a diagnosis of idiopathic puberty is given
    • Brain tumour may be highly likely or some other significant pathology
358
Q

What is precocious pseudopuberty?

A

Resembles puberty, but not from normal hypothalamus activation

359
Q

What can cause precocious pseudopuberty?

A
  • Adrenal sex hormones excess
    • Congenital adrenal hyperplasia
  • hCG Secreting Tumours
    • Gonads
    • Brain
    • Liver
    • Retroperiteneum
    • Mediastinum
360
Q

What is the treatment for precocious puberty?

A
  • Use of GnRH super-agonist suppresses pulsatility of normal physiology
  • Stops the process
361
Q

What is the main cause of delayed puberty?

A
  • IdiopathicHypogonadotropic Or hypergonadotropic hypogonadism
362
Q

Which sex is most affected by idiopathic delays in puberty?

A

Males

363
Q

What are indications for delayed puberty investigation?

A

Girls:
Lack of breast development by 13yrs
More than 5yrs between breast development and menarche
Lack of pubic hair by age 14yrs
Absent menarche by 15-16yrs

Boys:
Lack of testicular enlargement by age 14yrs
Lack of pubic hair by age 15yrs
More than 5 years to complete genital enlargement

364
Q

Give the differences between water and fat soluble hormones:
Transport
Cell interaction
Half life
Clearance

A

Transport: Water - unbound Fat - Protein bound
Cell interaction: Water - Bind to surface receptor Fat - diffuse into cell
Half life: Water - short Fat - long
Clearance: Water - Fast Fat - Long

365
Q

What classes of hormones are water soluble hormones?

A

Peptide hormones
Monoamines

366
Q

What classes of hormones are fat soluble hormones?

A

Thyroid hormones
Steroid Hormones

367
Q

Where are water soluble hormones stored?

A

In vesicles

368
Q

Where are fat soluble hormones stored?

A

Typically not stored
They are synthesised on demand

369
Q

Define Endocrine secretion?

A

Secretions go directly into the bloodstream/lymph to act at distant sites

370
Q

Define exocrine secretions?

A

Glandular secretions poured into a duct to the site of action
Typically will act locally

371
Q

Define paracrine secretions?

A

Cellular secretions/signals that act on adjacent cells

372
Q

Define autocrine secretions?

A

Cellular secretions/signals that feedback on the same cell that secreted the hormone.

373
Q

What is a negative feedback arch?

A
  • Initial stimulus causes response
  • Response feedback to stimulus to reduce
  • Response loop shuts off
374
Q

What is a positive feedback arch?

A
  • Initial stimulus causes response
  • Response causes stimulus to increase
  • Response continues to increase
  • Outside factor required to shut off feedback cycle
375
Q

Give some basic details about peptide hormones?

A
  • Hydrophilic and water soluble
  • Usually stored in secretory granules; released in bursts or as part of a rhythmic cycle
376
Q

Give an example of a peptide hormone?

A

Insulin

377
Q

How does insulin act to reduce blood glucose?

A
  • Translocation of Glut-4 transporter to the plasma membrane and influx of glucose
  • Glycogen synthesis (liver)
  • Glycolysis
  • Fatty acid synthesis (live and adipose tissue)
378
Q

What are the classes of amine hormones?

A

Tryptophan derived amines
Tyrosine Derived amines

379
Q

Give an example of a Tryptophan derived amine hormone?

A

Melatonin

380
Q

Give an example of a Tyrosine Derived amine hormone?

A

Catecholamines - Dopamine, noradrenaline, adrenaline
Thyroid Hormones - T3 and T4

381
Q

Where are the catecholamines secreted from?

A

Adrenaline and noradrenaline from the adrenal medulla

Dopamine from the hypothalamus

382
Q

How does the effect of adrenaline and noradrenaline differ?

A

Both play a role in the body’s sympathetic nervous system;

  • Adrenaline has slightly more of an effect on the heart
  • Noradrenaline has slightly more of an effect on blood vessels
383
Q

Are iodothyronines hydrophobic or Hydrophilic?

A

Hydrophobic

384
Q

What are the iodothyronines?

A

Triiodothyronine (T3)
Thyroxine (T4)

385
Q

Where are T3 and T4 produced?

A

T4 produced by the thyroid gland - more abundant
T3 is produced by the conversion of T4 to T3 in the periphery - more active

386
Q

Explain the synthesis of T3 and T4?

A
  1. Thyroglobulin (T4 precursor) is synthesised in cells of thyroid gland and discharged into follicle lumen
  2. Iodide is actively transported inside the follicular cell
  3. Iodide is oxidised to iodine.
  4. Iodine is attached to tyrosine in colloid, forming Diiodotyrosine (DIT) and Monoiodotyrosine (MIT).
  5. DIT and MIT join together to form T3 and T4;
    - MIT + DIT = T3
    - DIT + DIT = T4
  6. T3 and T4 are stored in follicular cell
  7. lysosomal enzymes cleave T4 and T3 from thyroglobulin and hormones diffuse into bloodstream
387
Q

What enzyme converts T4 into T3 in the peripheral circulation?

A

Iodothyronine deiodinase

388
Q

What are the 2 classes of steroid hormones?

A

Corticosteroids (Adrenocorticoids)
sex steroids (Gonadal)

389
Q

Why are the steroid hormones split into 2 classes?

A

It is based upon the receptor that they bind to!

390
Q

What class do glucocorticoid and mineralocorticoid fit into?

A

Corticosteroids

391
Q

What class do androgens, oestrogens and progestogens fit into?

A

Sex steroids

392
Q

What are steroid hormones synthesised from?

A

Cholesterol

393
Q

What is the pathway of synthesis of the steroid hormones?

A
  • Cholesterol is converted to Pregnenolone
  • Pregnenolone converted to Progesterone
  • In adrenal glands, progesterone changed to Cortisol
  • In ovaries or testes, progesterone converted to Androstenedione which is converted to Testosterone
  • Testosterone converted to Estradiol in the ovaries
394
Q

Are steroid hormones water or lipid soluble?

A

Lipid soluble

395
Q

What are some factors that stimulate the release of steroid hormones?

A
  • Humoral stimulus; released as result of change in environment (e.g. low calcium causes release of PTH)
  • Neural stimulus; sympathetic nervous system stimulates adrenal gland to release adrenaline
  • Hormone stimulus; hypothalamus releases hormone which stimulates pituitary gland which releases further hormones to stimulate other glands.
396
Q

What are the major endocrine organs?

A

Pituitary gland
Thyroid Gland
Parathyroid Gland
Adrenal Gland
Pancreas
Gonads - Ovary / Testes

397
Q

What are the different sections of the Adrenal glands and what do they secrete?

A

Adrenal Cortex:
Zona Glomerulosa - Mineralocorticoids - Aldosterone
Zona Fasciculata - Glucocorticoids - Cortisol/cortisone
Zona Reticularis - Androgens - Oestrogen / Testosterone

Adrenal Medulla:
Catecholamines - Adrenaline, Noradrenaline

398
Q

Define Appetite?

A

The desire to eat food

399
Q

Define Satiety?

A

The feeling of fullness
Disappearance of appetite after a meal

400
Q

Define Anorexia?

A

Lack of Appetite

401
Q

Define Hunger?

A

The need to eat

402
Q

How do you work out BMI?

A

Weight (kg) / Height (m^2)

403
Q

What are the categories of BMI?

A

<18.5 underweight

18.5-24.9 normal

25-29.9 overweight

30-39.9 obese

> 40 morbidly obese

404
Q

What are the 2 drives of the satiety cascade?

A

Internal Physiological drive - a feeling that prompts the thought of food and motivates food consumption

External Psychological drive - Explains why we eat in the absence of hunger (eg. at a buffet)

405
Q

What parts of the brain have key roles in appetite regulation?

A

The Hypothalamus

Lateral Hypothalamus - Hunger centre
Ventromedial Hypothalamic Nucleus - Satiety centre

406
Q

Where is the hunger centre in the brain?

A

Lateral Hypothalamus

407
Q

Where is the satiety centre in the brain?

A

Ventromedial Hypothalamic Nucleus

408
Q

What factors will increase your appetite?

A

NPY - Neuropeptide Y
MCH - Melanin concentrating Hormone
AgRP - Agouti related peptide
Orexin
Endocannabinoid

409
Q

What factors will decrease your appetite?

A
  • α-MSH: alpha melanocyte stimulating hormone from POMC
  • CART: cocaine and amphetamine regulated transcript
  • GLP-1: glucagon like peptide 1
  • Serotonin
  • Peptide YY (PYY)
  • CCK
410
Q

What appetite factors are released by the brain?

A

NPY
POMC - α-MSH

411
Q

What is POMC?

A

Proopiomelanocortins
Precursor polypeptides that are cleaved into 3 main hormones
ATCH
MSH
Endorphins

412
Q

What is the role of α-MSH

A

Induces satiety by binding to the MCR3 and MCR4 receptors in the brain

413
Q

What is the role of Leptin?

A

Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetie factors (POMC; CART) and inhibits the release of pro-apeptite factors (NPY; AgRP).

414
Q

Where is leptin expressed?

A

In adipose tissue

415
Q

How can decreased leptin levels lead to obesity?

A

Through leptin gene deficiency
Through Leptin receptor mutation

416
Q

What is the role of Leptin?

A

Expressed in adipose tissue
Switches off appetite and is immunostimulatory
Leptin is sensed by the arcuate nucleus of the hypothalamus where it stimulates the release of anti-appetite factors (POMC; CART) and inhibits the release of pro-appetite factors (NPY; AgRP).

417
Q

What appetite factors are released by the gut?

A

Ghrelin
PYY
GLP-1
CCK

418
Q

What is the role of Ghrelin?

A

Stimulates GH release
Stimulates appetite (orexigenic)

419
Q

Where is ghrelin secreted from?

A

The stomach

420
Q

What is PYY?

A

Peptide YY
Structurally similar to NPY - binds to NPY receptors

421
Q

What is the role of PYY?

A

Inhibits gastric motility
Reduces appetite

422
Q

Where is PYY secreted from?

A

Neuroendocrine cells in the ileum, pancreas, colon in response to food

423
Q

What is the role of CCK in appetite?

A

Cholecystokinin
Delays gastric emptying time
gallbladder contraction
Insulin release
Acts on the vagus nerve to stimulate satiety

424
Q

What appetite factors are released by adipose tissue?

A

Leptin

425
Q

What appetite factors are released by the pancreas?

A

Insulin

426
Q

How does insulin act in appetite regulation?

A

In a similar way to Leptin
It inhibits NPY/AgRP release
It stimulates POMC/CART release
Acts to decrease appetite

427
Q

Give an overview of Appetite control

A

Leptin and Insulin:
Stimulate POMC/CART neurones - increase CART and alpha-MSH levels
Inhibit NPY/AgRP neurones - Decrease NYP/AgRP
Overall will increase satiety and decrease appetite.

Ghrelin:
Stimulates NPY/AgRP neurone - their levels increase
Increase appetite

PYY:
Binds to an inhibitory receptor on NPY/AgRP neurones - decrease their levels
Decrease appetite

428
Q

What does ADH bind to to act?

A

GPCR:
V1a - in vasculature (similar to adrenoceptors)
V2 - in collecting tubules of nephron - water reabsorption
V1b - In pituitary in the brain

429
Q

What controlls the release of ADH?

A
  • Osmoreceptors in hypothalamus
    • Routine
  • Baroreceptors in brain stem and great vessels
    • Emergency
430
Q

Define osmolality?

A

Concentration of a solute per KG of solution
mOsmol/Kg

431
Q

What drives osmolality?

A

The number of molecules (concentration)

432
Q

What affect does size of particles have on osmolality?

A
  • Size is irrelevant - a molecule of sodium has the same effect as a molecule of albumin
    It is the number of particles (concentration) that makes a difference to the osmolality
433
Q

What molecules are present at a high enough concentration to affect osmolality?

A
  • Sodium
  • Potassium
  • Chloride
  • Bicarbonate
  • Urea
  • Glucose
434
Q

What exogenous molecules can affect osmolality?

A
  • Alcohol
  • Methanol
  • Polyethylene glycol
  • Manitol
435
Q

What is the normal osmolality range?

A

282-295 mOsmol/kg

436
Q

How is osmolality calculated?

A

2x[Na] mmol/L + [Glucose] mmol/L + [urea] mmol/L

437
Q

Why is sodium doubled in the osmolality calculation?

A

To account for the anion gap

438
Q

What is the mechanism of action of vasopressin in the kidney?

A
  • Acts on V2 receptors
  • Stimulates an intracellular cascade
  • Aquaporin-2 proteins are synthesised and inserted into the apical membrane
  • Permeability to water is increased
  • Increased reabsorption of water
  • Concentration of Urine
439
Q

What is a NFPA?

A

Non functioning pituitary adenoma
A benign growth in the pituitary gland that does not produce excessive hormones into the blood

440
Q

What is a craniopharyngioma?

A

Rare type of brain tumour derived from pituitary gland embryonic tissue.

441
Q

Where does a Craniopharyngioma arise from?

A

Squamous epithelial remnants of Rathke’s pouch

442
Q

What are the two clinical subtypes of Craniopharyngioma?

A
  • Adamantinous (classical)
  • Papillary
443
Q

Are Adamantious Craniopharyngioma more common in adults or children?

A

Children!

444
Q

What is a Meningioma?

A

Tumour forming from the three membranous layers of the meninges

445
Q

When do you get peaks of cortisol?

A
  • On waking up
  • Lunchtime
  • Dinnertime
446
Q

What are the long term side effects to steroids?

A

CORTICOSTEROIDS:
Cushing’s Syndrome
Osteoporosis
Reduced Growth
Thin Skin
Immunosuppression
Cataracts
Oedema
Suppressed HPA axis
Teratogenic
Emotional/Mood Disturbances
Rise in blood pressure
Obesity
Increased hair growth
Diabetes + hyperglycaemia
Striae

447
Q

What is Carcinoid Syndrome?
What are the main causes?

A

Neuroendocrine tumour that mainly arises from GI tract, lungs, liver or ovaries.

Secretes serotonin (5-hyroxytryptamine/ 5-HT) into systemic circulation.

448
Q

What is the Presentation of Carcinoid syndrome?

What are the main Symptoms when Symptomatic?

A

If from GI tumour - ASx - serotonin is metabolised by liver and prevents Sx

Other causes - Flushing, palpitations, diarrhoea (main three), cramps, abdo pain, bronchospasm,

449
Q

What is the 1st line investigation, GS and treatment for carcinoid syndrome?

A

Ix:
1st: Urinary 5-HT acid test.
GS: Chromagranin-A + Octreoscan
Then CXR/CAP MRI for tumours.

Tx: Surgery is only cure. Ocreotide can help

450
Q

Give 3 DDx of weight gain, fatigue and headache

A

Hypothyroidism
Cushing’s
Acromegaly

Medicine Phase 2a (20 decks)

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