Therapeutics & Investigations 2 (Part 2)

Question 1

Describe normal metabolic processes in the body, in relation to acid + bases and water

Answer 1

• Normal metabolic processes in the body make 40-80mmol of hydrogen ions, in 24hrs
• Non-volatile acid
• These are then excreted in the urine
• Imbalances = absorbed by buffers.
• Overall acid formation and removal are balanced in health.

Question 2

What his [H+] a direct measure of

Answer 2

Ø H+ ion concentration is a direct measure of acid base status = this is the direct measure
Ø Other method = pH. Expresses acidity and alkalinity in the reverse way. 1/[H+]
Ø If there is acidosis (too much acid) = pH will drop below 7

Alkalosis = the pH will get higher.

Question 3

How much CO2 is produced during aerobic oxidation

Answer 3

• 15k mmol/24h of CO2.
• Produces carbonic acid (H2CO3)
• Excreted by the lungs - amount of CO2 is equivalent to 15kmmol/24 of hydrogen ion (volatile acid)

Question 4

How is the hydrogen ion concentration [H+] of ECF maintained

Answer 4

• Within narrow limits of the 36-44nmol/l (pH 7.35-7.45)
• The intracellular [H+] = a bit higher but is also tightly controlled
• In disease, imbalances between acid formation + removal might develop and persist, which results in acidosis, or alkalosis

Question 5

Why are the kidneys important in acid-base balance?

Answer 5

• They reabsorb all of the filtered bicarbonate + synthesise additional bicarbonate, to add to blood.
• Produce ammonia - important mechanism for H+ excretion and also use phosphate to excrete H+

Question 6

What happens in the capillary beds with Co2

Answer 6

• Co2 that is made by tissue respiration diffuses into the RBCs. Forms carbonic acid, in the presence of carbonate hydratase
• Carbonic acid dissociates to form H+ and bicarbonate HCO3-.
• H+ are buffered by deoxygenated Hb.
• HCO3- diffuse outside RBCs in exchange for chloride ions (Cl-), which is chloride shift
• Maintains electrochemical neutrality

Question 7

What has to be present for co2 to form carbonic acid

Answer 7

• Carbonate hydratase must be present, for CO2 to be able to form carbonic acid

Question 8

Describe Chloride Shift which occurs in capillary beds

Answer 8

• HCO3- diffuses outside of Red blood cells, in exchange for chloride ions.
• Maintains electrochemical neutrality

Question 9

Where does the reverse of the chloride shift + where does it happen

Answer 9

• Happens in the alveolar capillaries
• The co2 that is produced is excreted into the alveoli

Ask: so would HCO3- diffuse INTO the Red Blood Cells + then chloride ions would come out? would electrochemical neutrality still be maintained?

Question 10

What is H ion homoeostasis dependent on?

Answer 10

• Buffering in the tissues + blood stream. Acid excretion by the kidneys
• Expiration of CO2 through the lungs. The blood hydrogen ion concentration is directly proportional to the partial pressure of CO2 (Pco2)
  Ø The blood [hydrogen ion] = inversely proportional to the concentration of bicarbonate [HCO3]
• Illustrated by the Henderson Hasselbalch equation

Question 11

Describe the process of metabolic (non-respiratory) acidosis

Answer 11

• When there is either increased production / decreased removal of H+ ions (OTHER than those that come from carbonic acid, or CO2)
• Or both - due to excessive loss of bicarbonate from the body = bicarbonate is the buffer that goes through the blood to deal with too much acid.
• TOO MUCH ACID IN THE BODY
  • High H+ ion, and low pH
  The markers for metabolic, non-respiratory acidosis
  
  1. Rise in H+ concentration
  2. Lower pH value
  3. Reduced bicarbonate - ranging between 22-33 millimolar

Question 12

What are the causes of metabolic non respiratory acidosis

Answer 12

1. Increased acid production
2. Decreased H+ secretion
3. Loss of bicarbonate in diarrhoea

Question 13

What happens to the excess H+ in non respiratory acidosis

Answer 13

• Buffered by bicarbonate, to make CO2. This is lost in expired air.
• Minimises the rise in H+ concentration, or pH drop of the plasma @ the expense of a drop in plasma bicarbonate (alkali reserve)
• Low plasma bicarbonate concentration is marker for presence, and a measure of severity of metabolic acidosis

Question 14

What will limit respiratory compensation

Answer 14

• Respiratory compensation is limited if respiratory function is compromised - like in COPD, asthma, heart failure.
• If kidney function is normal, XS H+ can be excreted by the kidney
• But a slower rate as compared to the very rapid respiratory component of compensation

Question 15

What is the clinical presentation of metabolic (non-respiratory) acidosis - Things that are caused by increased [H+]

Answer 15

- Hyperkalaemia with ECG changes 
	• Higher levels of potassium
- Increased adrenaline 
- Decreased myocardial contractility 
- CNS depression
- Hyperventilation = breathing deep and fast because the medulla oblongata, brain stem is triggered.

Question 16

What is the clinical presentation of metabolic (non-respiratory) acidosis - Things that are caused by increased pCO2

Answer 16

• Peripheral vasodilatation
• Headache
• Bounding pulse
• Papilloedema
• Flapping tremors
• Drowsiness + Coma

Question 17

How would you achieve complete correction of metabolic acidosis

Answer 17

• Treating the cause. Like insulin + fluids for diabetes ketoacidosis
• Or removal of ethylene glycol in poisoning
  • In severe conditions with [H+] of 100nmol/l or above - i.v. bicarbonate (1.26%), 150mmol/L is given in small volumes.
  • The effect on arterial H+ regularly checked
  • Careful monitoring of Hyperkalaemia + treatment if necessary using glucose and insulin + dialysis

Question 18

Summary of changes in respiratory compensation?

Answer 18

1. [H+] elevated (RR between 35-46nmol/l)
   Ø pH is just the minus log, of hydrogen ion concentration
2. pH decreased (RR between 7.36 - 7.44)
3. Pco2 decreased (RR between 4.5 - 6 kPa)
   Ø This all means the same thing.
4. [HCO3-] much reduced (RR between 22-30mmol/L)

Question 19

How is respiratory acidosis characterised

Answer 19

1. Increased pCo2
	Ø Expected to be high = acidosis, expect the hydrogen ion concentration to be high
2. Increased [H+]
3. Decrease in pH 
4. Compensatory increase in bicarbonates

Question 20

What are the causes of respiratory acidosis ?

Answer 20

Airway obstruction

Respiratory centre depression

Neuromuscular diseases

Pulmonary diseases

Thoracic wall diseases

Question 21

How can respiratory acidosis be corrected?

Answer 21

• By means that will restore the Pco2 back to normal
• If this elevated pCO2 persists the compensation will occur.
• This compensation occurs through increased renal H+ excretion

Question 22

Give a summary of the acute biochemical changes that occur in respiratory acidosis*

These are important markers to remember!!

Answer 22

1. Acute respiratory acidosis 
	Ø H+ is elevated (RR 35-46nmol/L)
	Ø pH decreased (RR - 7.36-7.44)
	Ø PCO2 increased (RR - 4.5-6Kpa)
	Ø [HCO3-] slightly increased (RR 22-30mmol/L)

2. Chronic respiratory acidosis
   Ø H+ slightly elevated, or high-normal (RR 35-46nmol/L)
   Ø pH slightly decreased, or low (RR - 7.36-7.44)
   Ø PCO2 increased (RR 4.5-6Kpa)
   Ø HCO3- increased (RR 22-30mmol/L)

Question 23

What are the management aims of respiratory acidosis

Answer 23

• Lowering Pco2
• Combatting hypoxaemia, by improving vascular ventilation
• Bronchodilators, antibiotics, physiotherapy, artificial ventilation used
• O2 @ high concentration can be used in acute resp failure
  • Could be dangerous in chronic respiratory failure because the respiratory centre starts to be insensitive to CO2.
  • Hypoxia becomes the main stimulus to respiration

Question 24

Describe metabolic [non respiratory] alkalosis

Answer 24

• Metabolic = bicarbonate will go up
• Increase in extracellular fluid bicarbonate concentration
• With consequent reduction in [H+] - normally, increased plasma bicarbonate = incomplete renal tubular reabsorption of bicarbonate and increased excretion in the urine

Question 25

What are the causes of metabolic alkalosis

Answer 25

1. ECF volume depletion + hypochloraemia Ø As in gastric aspiration; repeated vomiting w/ pyloric stenosis Ø Chloride loss in diarrhoea Ø Loop and thiazide diuretics (but NOT potassium sparing diuretics) Ø Loss of sodium and water = contraction of the ECF volume, which will stimulate the renal sodium retention, through stimulating the renin-angiotensin-aldosterone system + increased excretion of potassium and hydrogen ions Ø Potassium = very low levels in the plasma. Majority of potassium is inside the cells, measure of plasma is a poor indicator. Ø Potassium kept INSIDE and sodium kept outside. Sodium potassium ATPase, will keep pushing sodium out AGAINST the concentration gradient Ø That enzyme / pump alone uses 25% of our energy expenditure every day. 2. Alkali intake as in chronic antacid intake, over treating acidosis 3. Potassium depletion Ø Reduced intake + increased loss Ø Mineralocorticoid excess like in ○ Cushings, Conns, Barrters, Secondary Hyperaldosteronism ○ Drugs like carbenoxolone Ø Potassium depletion and the loss of intracellular shift of H+

Question 26

What does the shift of H+ that is in metabolic

Answer 26

- This shift will cause extracellular alkalosis - Potassium depletion, will cause more Hydrogen ions to get exchanged (lost in urine), for the reabsorbed sodium ions in the distal convoluted tubules - Potassium depletion also stimulates ammonia formation by kidney and thus increases acid secretion

Question 27

What are the biochemical changes in metabolic alkalosis?

Answer 27

Ø Metabolic alkalosis = metabolic condition in which the pH of the tissue is elevated beyond the normal range of 7.35-7.45 Ø This is the result of decreased hydrogen ion concentration Ø This results in increased bicarbonate concentrations. 1. Decreased [H+] (RR 35-46nmol/L) 2. Increased pH (RR - 7.36-7.44) 3. Increased Pco2 (RR 4.5-6Kpa) 4. Much increased [HCO3-] (RR 22-30mmol/L)

Question 28

What is the expected compensatory change in metabolic non respiratory alkalosis

Answer 28

- Increased PCO2 - Would increase the PCO2 / [HCO3-] and thus [H+] = a low arterial blood [H+] will inhibit the respiratory centre - Which will cause hypoventilation + increased PCO2 - This is a self-limiting mechanism, because the increased Co2 stimulates respiration and thus it is mainly useful in acute conditions - In more chronic conditions, the respiratory centre becomes less sensitive to Co2 - If hypoventilation leads to significant hypoxaemia, the low Po2 would be a powerful stimulus of respiration and prevent further compensation

Question 29

What is the management of metabolic non respiratory alkalosis

Answer 29

- 0.9% (w/v) sodium chloride solution (which is isotonic saline) - used to expand the contracted ECF and correct hypochloraemia - The corrected hypovolaemia = improves renal perfusion - And also enhances the excretion of excess bicarbonate - In presence of potassium depletion, correction of the underlying cause + potassium replacement should be initiated.

Question 30

What are the common features of respiratory alkalosis?

Answer 30

- Fall in pCo2 - = reduces ratio of pco2 to bicarbonate concentration, thus reduces H+ Ø This is a disturbance in acid + base balance Ø Due to alveolar hyperventilation Ø Which leads to a decreased partial pressure of arterial carbon dioxide. Main causes of respiratory alkalosis 1. Hypoxia + increased respiratory drive - High altitude, anaemia, pulmonary oedema, pulmonary embolism - Other causes of increased respiratory drive: ○ Cerebral trauma ○ Infection ○ Tumours ○ Respiratory stimulants (salicylates, liver failure, septicaemia, primary or voluntary hyperventilation and mechanical ventilation)

Question 31

What are the biochemical features of acute respiratory alkalosis

Answer 31

1. Decreased [H+] (RR 35-46 nmol/l) 2. Increased pH (RR 7.36-7.44) 3. Decreased pCO2 (RR 4.5-6 kPa) 4. Slight decrease in [HCO3-] (RR 22-30 mmol/l).

Question 32

What are the biochemical features of chronic respiratory alkalosis

Answer 32

1. Slightly decreased or low-normal [H+] (RR 35-46 nmol/l), 2. Slightly increased or high-normal pH (RR 7.36-7.44) 3. Decreased pCO2 (RR 4.5-6 kPa) 4. Decreased [HCO3-] (RR 22-30 mmol/l)

Question 33

What determines water distribution

Answer 33

- The osmotic contents of these different compartments - Kept equal apart from the kidney - Changes in solute content of a compartment will result in water shift - Water shift will restore isotonicity

Question 34

What determines the osmolality of ECF

Answer 34

- Mainly due to sodium (135mmol/L) + its associated anions, chloride and bicarbonate • + with glucose and urea also contributing

Question 35

What determines the osmolality of ICF

Answer 35

- Mainly determined by potassium (110mmol/L) - + its associated anions phosphates, proteins and sulfates Ø The osmotic effect of plasma proteins (the colloid osmotic pressure, or oncotic pressure), is important in determining the water distribution between these compartments Ø Normally, the amount of water that is taken into the body (fluids, water in solid food + metabolic water) - equals that lost in urine, stools, sweat, and through lungs which is about 1500ml/24h, & is really variable

Question 36

What is the minimal urine volume that is needed for excretion of waste

Answer 36

- 500ml/24h - Because of obligatory losses through other routes - the minimus daily water intake to maintain balance, is about 1100ml - This increases with excessive sweating, diarrhoea + diuretic use

Question 37

What do changes in body water content, independent to amount of solute do to the osmolality?

Answer 37

- Changes in body water content, independent of the amount of solute will alter osmolality, which is normally 280-295 mmol/kg of ECF water. - Loss of water, as in water deprivation, • Would increase osmolality and cause water movement from ICF to ECF, thus a slight increase in ECF osmolality occurs. Ø Stimulates thirst centre in hypothalamus, which promotes our desire to drink and stimulate the hypothalamic osmoreceptors Ø Which will cause the release of ADH (anti diuretic hormone, or vasopressin) Ø This peptide hormone is synthesized in the hypothalamus + transported to the posterior pituitary to be secreted into the blood Ø Renders the renal collecting ducts permeable to water - thus permitting water reabsorption and urine concentration.

Question 38

What happens if ECF osmolality falls

Answer 38

- There will be no thirst sensation - Vasopressin secretion will be inhibited + urine will be dilute - This will allow water loss + restoration of normal ECF osmolality

Question 39

What happens in Diabetes Insipidus?

Answer 39

- Either ADH is not produced by the hypothalamus (Cranial DI = no creation of ADH) • There are other that produce the hormone • Tell to reabsorb water and concentrate urine • Failure of the kidney receptors to respond to the ADH = called insipidus - Or the kidney receptors are resistant to its action (Nephrogenic DI) • There are 2 types - Very large volume of dilute urine is produced - this is the end result. Like 15 litres rather than a litre and a half. - This happens at a time when the plasma concentration is expressed as plasma osmolarity

Question 40

Water balance + distribution

Answer 40

- Vasopressin can also be stimulated by a decrease in plasma or blood volume of 8-10%, even if osmolality is decreased - Osmolarity is increased and there is linear increase in ADH - Another factor that influences is the volume of blood - doesn’t have to be blood ; can be loss of fluids (e.g. through a car accident) - If the blood volume decreases, the dotted line is the response to hypovolemia - Hyperbolic rise = very fast elevation of ADH - Even if the plasma is diluted, ADH production is elevated - Nicotine = stimulates ADH - this is why smokers are less likely to go to the toilet.

Question 41

Describe the stimulating factors in the control of vasopressin secretion

Answer 41

1. Increased ECF osmolality 2. Stress, pain, nausea 3. Exercise 4. Severe hypovolemia 5. Drugs: nicotine, morphine, sulphonylureas, carbmezapine, clofibrate, vincristine

Question 42

Describe the inhibiting factors in the control of vasopressin secretion

Answer 42

- Decreased ECF osmolality - Hypervolaemia - Alcohol

Question 43

Describe the sodium distribution in our bodies

Answer 43

- Body of an adult man = 3000mmol of sodium - 70% of this freely exchangeable - 30% is complexed in bone - ECF sodium concentration is 135-145 mmol/L - ICF sodium is 4-10mmol/L - This gradient is maintained by the activity of Na+/K+ ATPase, which uses energy of ATP to pump sodium into the outside of the cells in exchange for potassium = Both against their own concentration gradient! - Western diet = 100-200mmol of sodium in 24h - Obligatory sodium loss via kidney, skin + gut is less than 10mmol/24h - Excess sodium might contribute to hypertension - Is a PUMP called sodium potassium ATPase

Question 44

Describe potassium distribution

Answer 44

- Predominant intracellular cation. - 90% of body potassium = freely exchangeable. Ø The rest is bound in RBCs, bone + brain, and only 2% (50-60mmol) is located in the ECF - Which transports potassium into the cells, in exchange for sodium, against concentration gradient - Potassium tends to diffuse down its concentration gradient from the cells into the ECF - this is efficiently opposed by the pumping actions of Na+/K+ ATPase

Question 45

Sodium + ECF characteristics

Answer 45

- ECF volume depends upon total body sodium content - Since water intake + loss is regulated to maintain a constant ECF osmolality - This in turn will depend mainly on sodium concentration • Facing a variable intake - sodium balance is maintained by the regulation of renal excretion - Normally 70% of filtered sodium gets actively reabsorbed in the proximal convoluted tubules - With further reabsorption in the Loop of Henle - Thus less than 5% of filtered sodium reaches the distal convoluted tubules - Fine control of the distal tubule sodium excretion depends on the activity of aldosterone, secreted by the adrenal cortex in response to activation of the Renin-Angiotensin Aldosterone System

Question 46

Describe the functional anatomy of the renal system

Answer 46

- Kidney is connected to the heart - Nephron = 1 million of those in each kidney, collect in the connecting duct and then spill open - The kidneys filter everything that is smaller in the whole size of the membrane - Water, glucose, amino acids, potassium - all go in as long as they are small enough - Red and white cells are larger so cannot get in. - After that there are secretions - the rest of the tubules fine tunes the rest of the amino acids and glucose - Adjusts water balance by anti-diuretic hormone ○ All proteins and nucleic acids release nitrogen which are secreted in the form of urea

Question 47

Outline kidney function | Ø Describe glomerular filtration

Answer 47

- Fluid that is filtered by the glomerular capillary filtration membrane is similar to the blood plasma - With the exception of proteins, as it is virtually protein free - The hydrostatic pressure that is within the glomerular capillaries is the major force that drives water + solutes out of the blood capillaries and into the Bowmans capsule - It is opposed by oncotic pressure - due to plasma proteins of the capillary blood

Question 48

Outline kidney function | Ø Proximal tubular transport

Answer 48

- In the proximal tubule: • 70% of filtered sodium, chloride and water • As well as > 90% of potassium, glucose, bicarbonate, calcium, phosphate, amino acids, and reabsorbed back to the blood - mostly by active transport - Glucose re-absorption has maximum capacity: called renal threshold Ø If amount of filtered glucose exceeds the renal threshold Ø Because blood glucose if higher than 10mmol/L as occurs in diabetes mellitus - Not all glucose can be reabsorbed back to blood, and glucose will appear in the urine

Question 49

Outline kidney function | Ø Loop of Henle + distal tubular transport

Answer 49

- The loop of Henle + distal and collecting ducts concentrate the urine and conserve water under the influence of ADH - Also finely adjust the composition of urine under the influence of aldosterone - This stimulates further sodium reabsorption in exchange for potassium or hydrogen ions

Question 50

What happens to hydrogen ions (acids) in the kidneys

Answer 50

- Hydrogen ions (acids) are excreted in the distal tubule, which thus contributes to the regulation of acid-base balance

Question 51

What happens to waste products? + what are they [of the kidneys]?

Answer 51

- Creatinine, urea, uric acid, organic acids are excreted through filtration at the glomerulous + secretion by tubules

Question 52

What are the 3 renal function tests?

Answer 52

1. Plasma creatinine + creatinine clearance Ø Keeps falling if there is kidney disease Ø Below certain amount = need dialysis 2. Blood urea nitrogen (RR=3-7) 3. Urine analysis Ø Microscopic functions of the kidney - Water depletion could occur due to increased loss form the kidney, in renal disease - Lost from the skin (e.g. sweating, hyperventilation etc.)

Question 53

Describe the renal function test: | Ø Plasma creatinine + creatinine clearance

Answer 53

- Creatinine = metabolite of skeletal muscle. Is excreted by the kidney. - In renal damage = creatinine concentration in the blood is increased above the upper reference level of 140micromol/L - Elevated creatinine level • Indicates that a decreased GRF (glomerular filtration rate) - Creatinine clearance is calculated from creatinine level in blood and urine + volume of urine, per minute Monitoring creatinine clearance allows monitoring the progress of kidney disease + response to therapy estimating the time at which dialysis or renal transplantation would be needed.

Question 54

Describe the renal function test: | Ø Blood Urea Nitrogen

Answer 54

- Reflects glomerular filtration + urine concentration ability - Its level increases as GFR decreases - It also rises in states of dehydration/hypovolemia as it is reabsorbed back to blood • Weakness, confusion, weight loss. Diabetes insipidus - stays low even when the patient is dehydrated. • Is dangerous and can affect the brain and cause the brain to shrink • Lining of the meninges, vessels get stretched and there are atherosclerotic vessels which can break + haemorrhage - It is also sensitive to protein intake - Normal reference = 3-7mmol/L

Question 55

Describe the renal function test: | Ø Urine analysis

Answer 55

- Urines physical properties like colour, aspect, odour, pH, volume, specific gravity, chemical properties. - The presence of the following: Ø Albumin, glucose, acetone, nitrates Ø + microscopic picture: pus and red cells, crystals, casts, epithelial cells, parasites ova - These are all useful in diagnosis + management of renal diseases

Question 56

Describe the properties of ANP, Atrial Natriuritic Peptide

Answer 56

- Secreted by cardiac atria. In response to atrial stretch - Following a rise in atrial pressure - ANP acts directly, by inhibiting the distal tubular sodium reabsorption - + also through inhibiting the renin-angiotensin-aldosterone system - ANP also antagonises the pressor effects of noradrenaline and angiotensin 2 Ø This will cause vasodilatation

Question 57

How does sodium depletion arise

Answer 57

- Sodium is lost from the body as isotonic, or hypertonic fluid - Thus decreases ECF volume - Both vasopressin + aldosterone secretion are stimulated, to retain water and sodium

Question 58

What is the clinical presentation of sodium depletion?

Answer 58

- Weakness, dizziness, apathy, weight loss, elasticity (skin does not drop again after being pulled out) - Shortness of breath (dyspnoea), peripheral oedema - Venous congestion - Hypertension - Weight gain - Pulmonary oedema Ø These are all due to expansion of ECF volume - Management of this would be to 1. Treat cause 2. Use Diuretics 3. Control Sodium Intake

Question 59

Describe potassium homeostasis of the kidney

Answer 59

- In kidneys, filtered potassium = almost fully reabsorbed in the proximal tubules - Some active secretion occurs in the most distal part of the distal convoluted tubules. - Potassium excretion is mainly a passive process, and togetether with hydrogen ions counterbalance the active sodium reabsorption. - Aldosterone will stimulate potassium excretion directly @ distale tubule - Aldosterone will stimulate potassium excretion indirectly by increasing active sodium reabsorption, in distal tubules + collecting ducts - Aldosterone secretion from the adrenal cortex is stimulated by renin angiontensin system - + by hyperkalaemia

Question 60

What can potassium and hydrogen do to the membrane potential

Answer 60

- Both potassium and hydrogen ions can neutralise the membrane potential that is generated by active sodium reabsorption - In acidosis, a lot of Hydrogen ions compete with potassium. Ø Potassium excretion decreases and its blood level rises (hyperkalaemia) - In alkalosis (which is low hydrogen ion concentration) Ø Potassium excretion increases. Ø Potassium blood level decreases (hypokalaemia) ○ Potassium depletion, causes alkalosis

Question 61

What does potassium depletion cause

Answer 61

- Potassium depletion causes alkalosis

Question 62

Describe potassium homeostasis of the gut

Answer 62

- Potassium gets excreted in the gastric juice. - Much of the gastric juice + also dietary potassium gets reabsorbed in the small intestine - In the colon + rectum, potassium is secreted in exchange for sodium. Ø This is partly under the control of aldosterone. - Considerable amounts of potassium can be lost in the stools Ø (in patients that have: ○ chronic diarrhoea ○ or fistulae ○ or in patients that have persistent vomiting / nasogastric aspiration) - Aggressive insulin treatment, of high blood glucose (as in non ketotic- hyperhlycaemia coma) - might induce hypokalaemia. - Conditions of: Ø Rapid cell death Ø or membrane damage (like in leukaemia, lymphoma or crush accidents) Ø = can cause hyperkalaemia

Question 63

What stimulates the cellular uptake of potassium

Answer 63

- Insulin stimulates the cellular uptake of potassium. | - In exchange for sodium, co transported with glucose

Question 64

Describe what happens in potassium depletion

Answer 64

- Normal dietary intake = 60-200mmol/24hours | - This is prevalent in many foods.

Question 65

What are the causes of hypokalaemia

Answer 65

1. Decreased intake (parenteral or oral) 2. Transcellular movement Ø Alkalosis 3. Increased renal excretion as happens with diuretics 4. Increased extra renal excretion

Question 66

What are the clinical features of hyperkalemia?

Answer 66

- Can kill without warning! Through ventricular fibrillation and cardiac arrest - ECG changes might precede ventricular fibrillation

Question 67

What is the management of hyperkalaemia?

Answer 67

1. Calcium gluconate - 10ml of 10% solution iv over 1 minute and then repeated 2. Iv glucose and insulin 3. Dialysis 4. Restriction of intake 5. Oral ion exchange resin

Question 68

Describe the anatomy of the hypothalamus-pituitary connections

Answer 68

- Pit gland = base of the brain, just underneath the optic chiasm - If there are adenomas here then you will present with visual field defects - Ant. And posterior make it up ○ Posterior = effectively an extension of the brain, has terminals of neurosecretory cells that have their cell bodies in particular parts of the hypothalamus ○ Oxytocin, Vasopressin (ADh) ○ Anterior = not directly neuronally innervated but is under neuronal control. Have neurosecretory cells in the hypothalamus but these do not go into the pituitary but they secrete into the portal circulation ○ Trigger anterior pit cells to stimulate their hormones

Question 69

Describe the regulation of anterior pituitary hormones - GH

Answer 69

Ø GH-RH - stimulatory "growth hormone releasing hormone" Ø Somatostatin - inhibitory, suppresses the anterior pituitary making growth hormone

Question 70

Describe the regulation of anterior pituitary hormones - Prolactin

Answer 70

Ø PIF (dopamine) | • Prolactin inhibitory factor

Question 71

Describe the regulation of anterior pituitary hormones - TSH | Thyroid stimulating hormone. Also known as thyrotropin

Answer 71

Ø TRH

Question 72

Describe the regulation of anterior pituitary hormones - ACTH Ø Adrenocorticotrophic hormone

Answer 72

Ø CRF - corticotrophin releasing factor

Question 73

Describe the regulation of anterior pituitary hormones - LH + FSH

Answer 73

GnRH

Question 74

Regulation of anterior pituitary hormones - anterior pituitary hormones : TSH Target hormone / action (what is made when it is stimulated)

Answer 74

Ø Thyroxine, T3

Question 75

Regulation of anterior pituitary hormones - anterior pituitary hormones : ACTH Target hormone / action (what is made when it is stimulated)

Answer 75

Ø Promotes release of Cortisol, main glucocorticoid

Question 76

Regulation of anterior pituitary hormones - anterior pituitary hormones : LH, FSH Target hormone / action (what is made when it is stimulated)

Answer 76

Ø Gonadal Hormones

Question 77

Regulation of anterior pituitary hormones - anterior pituitary hormones : Growth Hormone Target hormone / action (what is made when it is stimulated)

Answer 77

Ø IGF-1, insulin like growth factor, when in the circulation they exert negative feedback and release production of pituitary hormone and hypothalamic pathway • GHRH --> GH --> liver release of IGF1 --> Suppression of GH.

Question 78

Regulation of anterior pituitary hormones - anterior pituitary hormones : Prolactin Target hormone / action (what is made when it is stimulated)

Answer 78

Ø Breast Development, lactation

Question 79

Describe how you would do an investigation of endocrine disorders

Answer 79

- In endocrine disorders, hormone levels = too high, or too low - so you have to measure if in normal range or not. Ø TOTAL hormone levels (in a radioimmunoassay) ○ = relatively straightforward but depends on protein binding Ø Free hormone levels. Hormones in circulation = bound to certain proteins. Ø Hormone release = usually pulsatile, and or circadian Ø Dynamic function tests ○ This is physiological ability, of endocrine tissue, to stimulate or inhibit hormone release: testing whether it is functionally intact. Do this by inhibiting or stimulating the release of the hormone to see if the system is ok. § e.g. checking the release of cortisol by giving ACTH ○ Dynamic = this is over time

Question 80

Describe the negative regulatory feedback of hormones THYROID HORMONES Ø Released by thryroid gland Ø Then effects rest of the body

Answer 80

- TSH made. Binds to its receptors on the thyroid follicular cells - This then produces T3 and T4, which then exert negative feedback and maintain levels

Question 81

Describe the thyroid hormones functions

Answer 81

- Effect on every single cell in the body. Can be divided into: Ø 1. Normal growth + development in humans and other vertebrates (e.g. metamorphasis in lower animals) 2. Non developmental = essential for maintaining normal metabolism (BMR) - tends to increase the metabolic rate - Made in the thyroid via series of enzyme catalysed reactions • Beginning with the uptake of iodine into gland - Synthesis + release is controlled by TSH - T4 = main hormone secreted by the thyroid [most abundant] - T3 = more biologically active. Mostly formed by the peripheral conversion of T4 into T3, @ cellular level within the target tissues. - These effects are mediated via the activation of nuclear receptor - Made via iodine uptake by the thyroid gland = 1st step of synthesis

Question 82

Describe circulating thyroid hormone

Answer 82

- Both T4/T3 = extensively protein bound, principally to TBG - Free (non- protein bound) fraction physiologically active - taken up, then there is no further release - Changes in protein binding affect total hormone concentrations - Accurate measurement : has to be a measurement of free hormones, is not affected by variation in TBG - & so discriminates more reliably between normal + abnormal thyroid function

Question 83

Describe total and free thyroid hormone concentrations

Answer 83

T4 and T3 in plasma = more than 99% protein bound. The total (all of the T4 or T3 that can be detected) there is a nanomolar concentration. This is a low []. Free one is in the picomolar, very low concentrations of the free form.

Question 84

Describe disorders of Thyroid function - Hypothalamic-Pituitary Thyroid Axis

Answer 84

- Stimulating hormone from the anterior pituitary, TSH | - Could be a disorder anywhere along this axis

Question 85

Describe disorders of Thyroid function - Euthyroid, hypothyroid, hyperthyroid

Answer 85

Ø Primary = problem is with the thyroid gland itself Ø Secondary. Problem is with pituitary regulation. Not enough stimulation or suppression. (this is not direct) Ø Tertiary = more rare Ø Could be issue with TRH, which in turn would affect the THs.

Question 86

Describe hyperthyroidism

Answer 86

- Excessive production of the thyroid hormones (Thyrotoxicosis) - Not same thing. TTC is the condition that results from elevated thyroid levels. - Thyrotoxicosis = associated with hyperthyroidism. Is the clinical result

Question 87

What are the clinical features of hyperthyroidism

Answer 87

Results of thyrotoxicosis - Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves) - In extreme: thyroid storm - this is especially sympathetically related: palpitations, excess heart rate, raised body temperature. Bradycardia to the extend where it would be a cardiovascular emergency. - Presents as a sympathetic overload / excess. Would therefore treat it using Beta Blockers

Question 88

What are the causes of hyperthyroidism

Answer 88

- Graves = most common due to stimulatory TSH-R antibodies(AUTOantibodies) - antibdoies act as agonists at the TSH receptor and stimulate release. - Toxic multinodular goitre - Toxic adenoma Ø Benign tumour that secretes excess hormone Ø All of these are primary - Excess TSH secretion (rare) Ø In this case would be secondary.

Question 89

What are the actions of TSH | goitre

Answer 89

- Increases iodine uptake - Stimulates other reactions that are involved with TH synthesis (e.g. TPO) - Stimulates colloid uptake - Induces the growth of the thyroid gland - which can lead to goitre - Stimulates all of the steps, right through to stimualtion of growth of the thyroid gland - This is why hyperthyroidism can lead to goitre - Graves = hyperthyroidism. Leads to diffuse goitre. This is enlargement of the hyperthryorid gland which is evenly spread - Toxic multinodular goitre = some of the thyroid nodules are hyperactive and grow. Goitre that is more lumpy + uneven

Question 90

Describe hypothyroidism

Answer 90

- Not enough production of thyroid hormones

Question 91

What are the clinical characteristics of hypothyroidism

Answer 91

- The symptoms are things that you would get through a lowering of metabolic rate. - Weight gain, cold intolerance, lack of energy, goitre, - Congenial - developmental abnormalities - Still would get goitre = if the thyroid is not fully making TH, the TSH levels will increase. The stimulatory effects of TSH on thyroid gland, promote growth and the hypothyroidism can be due to something else breaking in the synthesis pathway - TSH is trying to compensate and beef up the thyroid gland and get levels back up to normal, therefore is a compensatory response. - If the hypothyroidism = congenital (from birth), then it will lead to developmental abnormalities, "cretin" = this initially was a description of growth / developmental / learning difficulties that were common in those who lived in low iodine environments - Clearly demonstrating the need of thyroid hormones to support normal need and development

Question 92

What are the causes of hypothyroidism?

Answer 92

1. Autoimmune thyroiditis (Hashimotos) Ø Thyroid peroxidase antibodies (Anti - TPO) - anti thyroid peroxidase] ○ Crucial in making thyroid hormones. Ø DESTRUCTIVE circulating antibodies. Do not act like agonists like with hyper. They are destructive to thyroid function. 2. Iodine deficiency Ø Worldwide = the most common cause. Common cause of goitre. 3. Toxic adenoma 4. Pituitary / hypothalamic - lack of TSH Raised serum TSH would indicated endocrine investigation + thyroid replacement therapy.

Question 93

Treatment + monitoring of thyroid disorders : HYPERTHRYOIDISM TREATMENTS

Answer 93

- Depends on the actual cause, but mostly will treat the symptoms. In graves, would address the immune issues that cause the symptoms but in the absence of that, it has to be managed. - Anti thyroid drugs, like carbimazole, partial - Thyroidectomy - would then need T3 and T4 supplements - Radioactive iodine for partial or complete destruction of the thyroid gland - Ft4 levels fall rapidly, with successful treatment, TSH might remain suppressed for several months - These are not fatal conditions, but they can be in a thyroid storm, but can be awful for the patient

Question 94

Treatment + monitoring of thyroid disorders : HYPO- THRYOIDISM TREATMENTS

Answer 94

- Thyroxine replacement - Ft4 might remain a bit raised - Best monitored by TSH (elevated values indicate under / & suppressed values over replacement), get a stable level of TSH over time = means that there are the right amounts of T4 (thyroxine) involved.

Question 95

Adrenal steroids characteristics

Answer 95

- The adrenal cortex has 3 zones - Steroids all come from cholesterols in a series of enzymatic reactions Characteristics of the 3 adrenal steroids Ø Aldosterone = main mineralocorticoid that is made in the outer zona glomerulosa ○ Not under control of the HPA. Mostly controlled by the RAAS system. XS ACTH can also lead to aldosterone secretion Ø Cortisol = principal glucocorticoid that is produced by the zona fasciculata Ø Glucocorticoids + adrenal androgens are made in the zona fasciculata & zona reticularis

Question 96

What are the 3 adrenal steroids

Answer 96

1. Cortisol 2. Aldosterone 3. Glucocorticoids

Question 97

Describe the biosynthesis of the adrenal steroid hormones

Answer 97

- Particular enzymes for these reactions are specific for the zones that the blood flows through - Outer = cholesterol can be carried further to the middle zones - Intermediate products that flow rather than going to further reactions then encounter a different set of reactions that go through more and make cortisol - Depends on the presence of the certain enzyme for certain stages, localised to certain zones

Question 98

``` Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Cortisol "stress hormone" ```

Answer 98

Ø Controlled by ACTH Ø NOT only present in stress, essential to life: CVS function, metabolism, protective against hypoglycaemia and promotes increases in insulin Ø Antagonises the effects of insulin, by enhancing gluconeogenesis Ø Promotes the central deposition of fat Ø Increases catabolism of proteins (protein breakdown, feeding them into gluconeogenesis) Ø Weak mineralocorticoid effects Ø Anti-inflammatory

Question 99

``` Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Aldosterone ```

Answer 99

Ø Increases sodium reabsorption in the renal DCT Ø Controlled by the RAAS. ACTH additionally has the effect of stimulating adrenal androgen synthesis, especially at higher levels.

Question 100

``` Describe the biological effects of adrenal steroids: CORTISOL ALDOSTERONE ANDROGENS - Androgens ```

Answer 100

Ø Virilising effects when secreted in excess

Question 101

Describe the control of adrenal steroid secretion?

Answer 101

- The synthesis of cortisol is regulated, by the Hypothalamic-Pituitary Adrenal Axis - Aldosterone synthesis is controlled by the Renin-Angiotensin System - Adrenal Androgen Synthesis is regulated by ACTH, not gonadotrophins - Cortisol can also stimulate aldosterone secretion

Question 102

Hyperfunction of the adrenal cortex - Ø Can cause CONNS, or CUSHINGS syndrome describe CONNS

Answer 102

- Excess secretion of aldosterone because of a tumour or hyperplasia of adrenal - sodium retention + other volume problems.

Question 103

Hyperfunction of the adrenal cortex - Ø Can cause CONNS, or CUSHINGS syndrome describe Cushing's syndrome {more common}

Answer 103

- Excess cortisol secretion. This will cause: Ø Pituitary Tumour (Cushings disease) that results in excess ACTH secretion. This is secondary because it is the pituitary making the ACTH Ø Ectopic ACTH production ○ Production of ACTH that is other than where it usually happens, i.e. the pituitary. Small cell lung carcinomas have neuroendocrine origins and can start to produce cortisol Ø Adrenal Tumour ○ Resulted in hyperproduction of cortisol ○ This would be primary Ø Exogenous administration of steroids

Question 104

What are the characteristics of Cushings syndrome?

Answer 104

Ø Raise glucose, promote lipogenesis, also promoting proteolysis in muscles as part of its gluconeogenic action as well as its immune functions. Might get raised blood glucose but also: • Muscle weakness • Menstrual disturbances+ psychiatric disturbances • Moon face (rounding of the face due to fat deposition) + truncal obesity • Striae, Bruising • Hirsuitsm (ACTH stimulates the adrenal cortex and the secretion of cortisol, and also adrenal androgens which suggests that it is due to ACTH and not definitve factors), • Acne, hypertension, • Glucose intolerance (due to raising blood glucose), osteoporosis Ø Excessive cortisol production by the adrenals.

Question 105

What are the diagnostic steps of Cushings syndrome

Answer 105

1. Demonstration of excessive cortisol production | 2. Elucidation of cause

Question 106

Describe the dynamic tests of endocrine function

Answer 106

Test of endocrine function type 1 Ø Stimulatory test Test of endocrine function type 2 Ø Suppression test Ø Investigating endocrine gland hypofunction Ø Investigation of the suspected hyperfunction

Question 107

Dexamethasone characteristics

Answer 107

Dexamethasone characteristics Ø Synthetic glucocorticoid (analogue) Ø Will not show up in cortisol assay but will stimulate cortisol receptors centrally. Ø Binds to GC receptors in the pituitary to suppress ACTH release + cortisol secretion from the adrenal If given to a normal patient

Question 108

Describe the low dose dexamethasone suppression test

Answer 108

1. 1mg of dexamethasone given @ night. Serum cortisol looked @ 9AM the next morning 2. Normal subject = cortisol

Question 109

What would you see in dex suppression test in a normal person

Answer 109

- Decreased cortisol because of the negative feedback.

Question 110

Describe the high dose dexamethasone suppression test

Answer 110

1. 2mg dexamethasone, 6 hourly for 2 days | 2. To determine the cause of Cushing's syndrome

Question 111

Differential diagnosis of Cushings syndrome

Answer 111

Ø There is a low dose and a high dose version. If the cause is XS ACTH, if you then give the low dose test there might be some suppression of cortisol then ACTH turned up anyway so might not get degree of separation as in a normal person. Ø If then, in this same person if it IS due to excess ACTH then enough dexamethasone WILL result in suppression. Can suppress pituitary production of ACTH as much as you want if this is not from the pituitary.

Question 112

What are the causes of adrenocortical insufficiency

Answer 112

- Primary adrenocortical failure - Addison's disease, is rare, but the most common cause of adrenal insufficiency. It is due to Ø Autoimmune disease Ø TB Ø Less common: metastases, haemochromatosis, haemorrhage - Secondary to impaired ACTH release Ø Tumour, head trauma, surgery, rapid withdrawal of steroids - Can have adrenal failure due to lack of cortisol or aldosterone.

Question 113

Clinical features of adrenocortical insufficiency

Answer 113

Ø Fatigue, weakness, hypoglycaemia, hypotension

Question 114

Dynamic tests that can be carried out - SHORT synacthen tests

Answer 114

- Certain criteria by which cortisol can arise. Rise of greater than 200 nanmoles from a given peak level, for e.g. - Assess ability of adrenal to produce cortisol in response to ACTH - Serum cortisol measured, after giving synacthen (synthetic ACTH ) - (normal response – cortisol increases by >200nmol/L over basal level with peak of >550nmol/L). If the adrenal gland is failing to produce cortisol = recovers from lack of production by producing ACTH If the failure is 2ndary it is failing because the pituitary is not producing enough ACTH.

Question 115

Dynamic tests that can be carried out - LONG synacthen tests

Answer 115

- 3 day stimulation with 1mg depot synacthen im daily | - In secondary adrenal hypofunction, serum cortisol levels increase to atleast 200nmol/L over baseline values

Question 116

Other tests of adrenal insufficiences

Answer 116

- ACTH assay • Increase in primary disease • Decrease in secondary failure

Question 117

What is the name for synthetic ACTH

Answer 117

- Synacthen

Question 118

Congenital adrenal hyperplasia characteristics

Answer 118

- Group of inherited metabolic disorders of the adrenal steroid hormone biosynthesis - Clinical features depend on the position of the enzyme defect in the metabolic pathway - 21 hydroxylase deficiency >90% cases, prevalence 1:5000-12k - Leads to impaired production of cortisol + aldosterone - Raised ACTH will stimulate production of adrenal androgens

Question 119

Neonatal manifestation of Congenital adrenal hyperplasia

Answer 119

- There is virilisation of female infants - Salt wasting + dehydration occurs in first 4 weeks of life Ø Serum Na 2 days after birth - Needs glucocorticoid + mineralocorticoid replacement - Treatment monitored by measurement of plasma 17a hydroxyprogesterone or androstenedione

Question 120

Describe the combined pituitary function test

Answer 120

Ø Destructive lesions of pituitary tend to present with pituitary hypofunction Ø Thus stimulatory tests are used to assess ability of gland to secrete hormones Ø When assessing patients with suspected anterior pituitary dysfunction, it is often convenient to test the capacity of the gland, to secrete GH, ACTH, TSH, and the gonadotrophins in a single procedure • This is the combined pituitary function test Ø This involves measurement of the anterior pituitary hormones following the administration of: • TRH, GnRH, insulin

Question 121

Summary of investigating endocrine disorders

Answer 121

- Hormones of the anterior pituitary, and the target endocrine glands might be measured by immunoassay in order to investigate disorders of endocrine function - And to distinguish between primary and secondary disease - Dynamic function tests have greater utility in detecting impaired pituitary function, than measuring the basal hormone concentrations

Question 122

What are the characteristics of Alkaptonuria?

Answer 122

- Autosomal recessive (AR) - Urine turns black on standing (homogensitic acid - shown in the container of urine) • & alkinisation - Black onchrontic pigmentation of cartilage + collagenous tissue - Arthritis - Homogentisic acid oxidase deficiency - Alkapotonuria = ears going black • If a baby has it, liquid will stay in the Terry nappies - when you try and bleach it, will go extremely black.

Question 123

What are the characteristics of Cystinuria?

Answer 123

- Autosomal recessive. - There is defective transport of cysteine + dibasic amino acias through the epithelial cells of renal tubule and intestinal tract - Cysteine = has low solubility, formation of calculi in the renal tract = children will get kidney stones - COLA or COAL are the patterns of amino acids ○ Cysteine - Mutations of the SLC3A1 aa transporter gene: ○ (Chr 2p) ○ SLC7A9 (Chromosome 19)

Question 124

What are the characteristics of Albinism?

Answer 124

- Need to produce melanin, to have pigmentation | - Children with albinism have pink eyes (+ white rabbits with pink eyes)

Question 125

What are the characteristics of Pentosuria?

Answer 125

- Excrete 1-4 grams of pentose sugar L-XYLULOSE daily (reducing sugar) - Benign & is almost exclusively Ashkenazi Jews, of Polish Russian Extraction

Question 126

Describe the one gene - one enzyme concept

Answer 126

- Substrate A going to product B, if there is a defect in the enzyme that takes A to B then the substrate will increase and the product will decrease • Goes into a secondary metabolic pathway • And this will start to produce C, which is toxic. • This is where inborn errors of metabolism arise - That all biochemical processes in organisms = under genetic control - That these biochemical processes are resolvable into series of stepwise reactions - Each biochemical reaction is under the ultimate control of a different single gene - Mutation of a single gene results in an alteration in the ability of a cell to carry out a single primary chemical reaction

Question 127

Describe the molecular disease concept

Answer 127

- Work on Hb in SCD. Found direct evidence that human gene mutations: Ø Actually produce an alteration in the primary structure of proteins Ø Inborn errors of metabolism are caused by mutations in genes which then will produce abnormal proteins, whose functional activities are altered

Question 128

What are the 5 mechanisms of inheritance?

Answer 128

1. Autosomal recessive 2. Autosomal dominant 3. X linked 4. Co dominant 5. Mitochondrial

Question 129

Describe autosomal recessive inheritance? Ø 1:4 risk

Answer 129

- Both parents = carry mutations that affect same gene - 1:4 risk each pregnancy - Consanguity increases risk of autosomal recessive conditions (e.g. marrying a cousin.) Ø Cystic Fibrosis Ø Sickle cell disease Gene from both parents

Question 130

Describe autosomal dominant inheritance?

Answer 130

- Rare in IEMs - Dominant condition which is fatal = less likely to survive - Someone who is heterozygote for AD condition will develop disease - Might not develop until it is actually reproduced Ø Huntingtons ○ Neurological conditions ○ Happens in 40s so have already passed on to offspring Ø Marfans ○ Long limbs Ø Familial hypercholesterolaemia ○ Buildup in their cholesterol ○ Really early myocardial infarctions

Question 131

Describe X linked inheritance?

Answer 131

- Characterised by carrier females, passing on the condition to affected sons, there is NO male to male transmission whatsoever - Female carriers might manifest condition. This is LYONISATION Ø Random Inactivation of one of the X chromosomes Ø Common in things like urea cycle defect with OTC. Ø When female carriers have a baby, involution of the uterus post-delivery = massive protein load and THIS can be the first sighting of this defect; and cause death.

Question 132

What happens when females get X linked conditions

Answer 132

- Lyonisation | - There is random inactivation of one of the X chromosomes

Question 133

X linked dominant?

Answer 133

- There is a fragile X

Question 134

X linked recessive?

Answer 134

- Haemophilia - Fabrys disease • Has cardiac involvement

Question 135

Describe codominant inheritance

Answer 135

- 2 different versions (alleles) of the gene expressed - Each version makes a slightly different protein - Both alleles will influence the genetic trait or determine the characteristics of genetic conditions Ø ABO blood group Ø (alpha)1AT deficiency (alpha 1 anti-trypsin) - Father has allele for A and O - Mother allele for B and O - Variation of what the children can get is shown in the cartoon

Question 136

Describe mitochondrial influence - this is NOT the same as an X linked disease

Answer 136

- Mitochondrial DNA • 21 genes that are coded for in the mitochondria - Inherited exclusively from mother • Only the egg will contribute mitochondria to the developing embryo ○ Sperm does NOT contain mitochondria. • Only females can pass on their mitochondrial mutations to children = but this is different to X linked although they are both female to male transmission (affects both female and male offspring) • Fathers do not pass these disorders to their children

Question 137

Describe mitochondrial DNA replication

Answer 137

- Heteroplasmy = separation of wild type and normal mitochondria - End up with cell that contains ALL normal, ALL wiltype, ALL mutant or a mix - Presentation depends on the load of affected mitochondria - Any inheritance can affect any tissue - Mix of things occur.

Question 138

How do inborn errors of metabolism present - Neonatal presentation is often acute

Answer 138

Neonatal presentation is often acute Ø Things that you do not screen for Ø Maple syrup urine disease Ø Tyrosinaemia Ø OTC (urea cycle defect) - Often caused by defects in energy metabolism • Amino acid, organic acid, carbohydrate metabolism • Urea cycle defects • Respiratory chain defects

Question 139

Biochemical abnormalities in IEM

Answer 139

- Hypoglycaemia, hyperammonaemia - Unexplained metabolic ketoacidosis - Lactic acidosis

Question 140

Clinical abnormalities in IEM

Answer 140

- Cognitive decline - Epileptic encephalopathy - Floppy baby - Exercise intolerant • Glycogen storage diseases affecting the muscle • Issues with fatty acid metabolism - Cardiomyopathy - Dysmorphic features • Mucopolysaccoridosis • Gargolyism = ears are set @ different angle and eyes are set far apart - SUDI • Sudden unexplained death in infancy • Do not know why - if a baby dies quickly, need to get skin biopsy really quickly - Fetal hydrops

Question 141

Lab investigations of IEM?

Answer 141

Ø General screening | Ø Specific tests to get the diagnosis

Question 142

1st line lab investigations for IEM

Answer 142

- Blood gas analysis • Acid base status of the baby (acidotic or alkalotic) - Blood glucose • Hyperglcaemia or no - Plasma ammonia • Elevated? • Urea cycle defect - Liver function test • Things like bilirubin, alanin transaminase gamma GT • True test = liver failure, if they can actually clot their blood - this is a true test of if they have synthetic capacity in the blood - Urinary ketones - Urine reducing substances • Putting out a lot of galactose or fructose

Question 143

2nd line investigations for IEM

Answer 143

- Plasma + urine amino acids - Urinary organic acids - Urinary orotic acids - Blood acyl carnites - Blood lactate and pyruvate - Urinary glucosaminoglycans - Plasma very long chain fatty acids

Question 144

What are the confirmatory investigations of IEM

Answer 144

``` - Enzymology • Red cell galactose 1 phosphate uridyl transferase • Lysosomal enzyme screening - Biopsy, (muscle and liver) - Fibroblast studies - Complementation studies - Mutation analysis ```

Question 145

Describe thin layer chromatography urine reducing sugars

Answer 145

- Pattern that you get on urine chromatography - Galactose = overloaded and then diluted out. - Found all the galactose in the urine; very toxic = want to remove lactose from the diet because it is metabolised into the glucose

Question 146

What are the possible metabolic causes for acute liver disease in neonate

Answer 146

Classical galactosaemia Hereditary fructose intolerance Ø Newborn = unlikely because you have to give them fructose in their diet Ø If getting just fructose from the milk = present with fructosaemia An organic acidaemia Tyrosinaemia type 1 = diagnosis Ø High tyrosine and methionine Ø Found high levels of succicyl acetate. Do not find them in other forms of liver disease Ø Increased tyrosine Ø Ended up with all of the substrates increasing Ø This also goes with the liver disease

Question 147

Describe TYPE 1 Tyrosinaemia

Answer 147

- Issues with breaking down tyrosine amino acid from the food that they eat - If not treated = severe liver problems - Cause the enzymes to stop working properly

Question 148

Diagnostic test - liver biopsy

Answer 148

Ø Liver enzymology Ø Ornithine transcarbamlyase 1.00 (ref range 11.8 - 44.7) Ø Carbamylphosphate synthase 0.98 (ref range 0.73 - 3.19)

Question 149

Blood supply to the liver 2

Answer 149

Ø Branches of the hepatic artery and the hepatic vein pull together Ø Nuclei of the hepatocytes = black Ø Lipoproteins can be secreted from the liver Ø Across the "front door" of the liver cells which are call the sinusoid membrane Ø There is a space (green spot) which is called the canaliculi membrane - a small canal which is called the bile canaliculi Ø If you were to keep going along this = go from this small canal and it gets larger until you get to the right or left hepatic duct Ø Which join to form the common bile duct

Question 150

Describe the biliary passages & the pancreatic duct

Answer 150

- Makes it more alkaline = more appropriate to its function by neutralising the acid that comes from the stomach - This is important for fat emulsification - Enzymes are proteins& water soluble. - Enzymes digest fats @ the interface between water and fats - Fat digestion is efficient, then absorption is efficient - Bile acids are not free in the body - they are present as bile salts. [like detergents]

Question 151

What are the major functions of the liver?

Answer 151

``` Ø Carbohydrate metabolism Ø Lipid metabolism Ø Protein metabolism Ø Bilirubin metabolism Ø Hormones Ø Xenobiotic Metabolism Ø Storage ```

Question 152

Carbohydrate metabolism function of liver?

Answer 152

- Gluconeogenesis • Production of glucose from non-carbohydrate sources • This is important in fasting - Glycogen synthesis and degradation

Question 153

Lipid metabolism function of liver? - Fatty acid synthesis

Answer 153

- Cholesterol synthesis & degradation | • Liver = only organ that can get rid of cholesterol outside the body.

Question 154

Lipid metabolism function of liver? - LIPOPROTEIN

Answer 154

- Ketogenesis - VLDLs and the LDL, which are made outside. - All depends on the clearance of chylomicrons etc.

Question 155

Lipid metabolism function of liver? - Vitamin D 25-OH

Answer 155

- Vitamin D activation | - Bile acid synthesis + excretion

Question 156

Protein metabolism function of liver?

Answer 156

- Plasma protein production. Albumin can only be produced in the liver. Oncotic pressure of the plasma - start to have fluid in our stomachs if we have low albumin. - Normal albumin, between 30-50grams - Ammonia detoxification happens in liver. Liver takes ammonia in the portal vein, runs it in urea cycle. Ammonia = toxic, and in normal health the liver will detoxify it by changing it into urea which is less toxic- stops ammonia from going into the brain - Normal urea = 3-7millimolar. Choleaemia = liver failure

Question 157

Hormone functions of liver?

Answer 157

1. Conjugation of steroid hormones Ø Sex hormones also Ø Can cause female hormones to accumulate in men with liver disease ○ Gynaecomastia, balding, feminisation, voice changes etc. accumulation of female sex hormones! 2. Degradation of peptide hormones

Question 158

Describe the metabolism of bilirubin

Answer 158

- Bilirubin - bile pigments - Bile pigments and bile salts are really diff. - Salts = detergents that work for emulsification. - Comes from senescent red cells - everything can be recycled apart from porphyrin. - When the body is left with a porphyrin will break it open into biliverdin, => broken down to be yellow, which is bilrubin • This is hydrophic. Need a carrier (albumin)

Question 159

LIVER FUNCTION TESTS: Why are albumin and bilirubin insensitive indicators of disease.

Answer 159

- Liver = has considerable function reserve - Therefore simple liver function tests, like: Ø Bilirubin concentrations Ø Albumin concentrations ○ Has a half-life of 21 days - Are insensitive indicators of disease - As the cells die they release their contents into the plasma.

Question 160

What liver function test are more sensitive

Answer 160

- Tests that actually reflect liver cell damage | - Like hepatic enzymes in plasma

Question 161

What are the true tests of liver functions

Answer 161

- Brom sulphophtalein (BSP) • See how much time the liver has taken to capture radioactivity • Enters the different stages of liver circulation • And then look @ secretion of bile in the intestine - Indocyanin Green - Caffeine clearance - Radiolabelled bile acid uptake + clearance tests

Question 162

Describe the biochemical tests of liver functioning

Answer 162

- Reflect basic pathological processes that are common to lots of conditions - Rarely provide precise diagnosis: are cheap, non-invasive, can direct other investigations Ø e.g. liver biopsy and imaging Ø Useful in detecting presence of liver disease + monitoring process

Question 163

What are the objectives doing routine liver function tests?

Answer 163

- Aid to establish liver disease, by showing abnormal values - Inform or help specific diagnosis, by showing different patterns - Establish the severity of liver damage & provide prognostic insight - Monitor disease progression - Assess the response to therapy

Question 164

Describe the characteristics of Bilirubin and Urobilinogen (the bile pigments)

Answer 164

Ø Derived from the breakdown of HAEM of senescent RBCs Ø Derived from (to lesser extent) from myoglobin, cytochromes and some enzymes Ø WATER INSOLUBLE. Transported to the plasma, to the liver by albumin • At this stage, bilirubin = unconjugated + cannot pass in the urine, even if it is present at a high level Ø Conjugated bilirubin = direct. Ø Uncongjugated bilirubin gets taken up by the liver cells, to get conjugated/ link with glucoronic acid • by the enzyme UDP-glucoronyl transferase, ○ Binds glurononic acid to bilirubin. ○ to produce bilirubin diglucoronide • Bilirubin glucoronide= water soluble. Is called conjugated bilirubin => secreted into bile. • Reaches the intestine. Most of it is oxidised by bacteria --> urobilinogen + stercobolin • Small amount of urobilinogen & bilirubin = reabsorbed through entero-hepatic circulation to be secreted in urine.

Question 165

Where are bilirubin and urolbilinogen derived from

Answer 165

Ø Derived from the breakdown of HAEM of senescent RBCs | Ø Derived from (to lesser extent) from myoglobin, cytochromes and some enzymes

Question 166

What happens to uncongjugated bilirubin

Answer 166

- Taken up by the liver cells - To be conjugated with glucoronic acid - By the enzyme UDP-glucoronyl transferase - This produces bilirubin digluoronide, which is water soluble & is called conjugated bilirubin

Question 167

Describe what happens to conjugated bilirubin

Answer 167

- Also known as bilirubin diglucoronide, (is water soluble) - Secreted into the bile - Eventually gets to the intestine where most it is oxidised, by bacterio - To make 1. urobilinogen and 2. Stercobilin - Then a small amount of urobilinogen + bilirubin are reabsorbed through the enterohepatic circulation to be secreted in the liver

Question 168

What is bilirubin reference range

Answer 168

3-17micromoles/L

Question 169

What is total bilirubin reference range/ changes

Answer 169

- Plasma bilirubin will rise when there is significant liver damage - Causes yellowish discolouration of skin + mucous membranes (Jaundice) - This can be clinically detected, at bilirubin level of 50micromolar/L - Leave bilirubin to go inside brain = will damage brain centres permanently.

Question 170

When can jaundice be detected

Answer 170

- At a bilirubin level of 50 micromolar/L

Question 171

What is motoring bilirubin used to do

Answer 171

1. Investigate liver diseases + investigated subclinical hyperbilirubinaemia 2. Determines need for exchange transfusion in neonatal jaundice 3. Assesses surgical treatment of bile duct striature Ø Duct can be narrow and surgically dilated Ø Set the liver @ particular rate and if this has not happened then the stricture is not working properly 4. Determines the correct doses of drugs, e.g. cytotoxic therapy

Question 172

What is the RR of ALP (alkaline phosphatase)

Answer 172

- 30 to 130 U/I = the RR of ALP (alkaline phosphatase) • Removes phosphate • (Group of enzymes that will hydrolyse phosphate esters) • ALP is also present in the bone and the placenta.

Question 173

Generally, when will plasma ALP increase

Answer 173

- In presence of obstruction to biliary passages, or cholestasis - The block could be intrahepatic, as in PBC - Or block could be due to a stone in the bile duct - Or pressure by a tumour, e.g. head of pancreas or lymph nodes - Liver disease = mainly damaging liver cells = AST and ALP will go up.

Question 174

In which diseases will plasma ALP increase

Answer 174

- Increases in liver + bone disease - Pregnancy, growing children - To enhance specificity, ALP isoenzymes can be measured by using electrophoresis - Or by using different thermal stablities of isoenzymes - As liver isoenzyme activity drops by 40% after 15 minutes incubation @ 56 degrees - Bone isoenzyme activity decreases only by 15% of yGT is used

Question 175

When does liver isoenzyme activity drop

Answer 175

- Liver isoenzyme activity drops by 40% after 15 minutes incubation @ 56 degrees

Question 176

When does bone isoenzyme activity drop

Answer 176

- Decreases only by 15% of yGT is used

Question 177

Describe the characteristics of: Ø Alanaine aminotransferase (ALT) Ø Asparate aminotransferase (AST)

Answer 177

- Can get thermal inactivation = enzymes work in narrow range of temperatures. - RR is 0-40U/I for both - Also called transaminases. Because they transfer an amino group, from an amino acid --> keto acid - Increase in the plasma in the presence of liver cell damage. - These are both markers of liver cell damage. - Wide tissue distribution. - When patients condition improves = levels of these will go down in the blood.

Question 178

Where is AST present

Answer 178

- Wide tissue distribution • Not only present in the liver: no longer used to look @ myocardial infarction. - Liver, heart, skeletal muscle, kidney, brain, erythrocytes, lung

Question 179

Where is ALT present

Answer 179

- Similar wide tissue distribution to AST (Liver, heart, skeletal muscle, kidney, brain, erythrocytes, lung) - More specific for liver disease - but we still mostly measure AST not ALT. - CK for muscle + troponins for heart - Greater the ratio between the 2 = the more likely that it was due to inflammed liver cells

Question 180

Aminotransferase activity is above 10 times the upper limit of RR?

Answer 180

- Most often due to hepatocellular damage • Like viral, or drug induced hepatitis • Or autoimmune hepatitis

Question 181

Aminotransferase below 10 times the upper limit of RR?

Answer 181

- But higher than upper limit of RR are less specific - But could occur in chronic liver diseases - Aminotranferase activities within the RR do not excluse liver diseases that could be assessed by histological examination of biopsy specimen

Question 182

What happens the higher the AST/ALP ration

Answer 182

- The more likely the underlying condition to be a form of hepatitis - The lower the ratio, the more indicative of cholestatic disorder

Question 183

What does an AST/ALT ratio of more than 2 mean

Answer 183

- In a patient who clinically appears to have hepatitis | - Strongly suggests that alcohol is involved when the AST/ALT ratio is more than 2.

Question 184

What is mitochondrial AST

Answer 184

- Accounts for 80% of total AST in the liver cells - And the ratio of m AST/ Total AST is a good marker for chronic alcohol consumption - This is very sensitive but very non specific - Anything at all wrong with the liver = will be picked up

Question 185

What are the characteristics of y-Glutamyl Transferase

Answer 185

- A microsomal enzyme, that transfers glutamyl groups between peptides & amino acids • And is involved in the transport of peptides, across plasma membranes - Plasma activity = mostly derived from the liver - Despite its wide distribution - And it has a poor specificity & high sensitivity for liver disease - Its measurement helps in linking elevated ALP to the liver - Is elevated with chronic alcohol consumption & is more elevated in the presence of chronic liver disease, with alcohol consumption

Question 186

Describe the characteristics of albumin

Answer 186

- RR = 30-50g/L - Made exclusively by the liver + its plasma half-life is 21 days - Maintains plasma oncotic pressure - Binds: Ø Calcium, fatty acids, bilirubin, some hormones + drugs - Its level tends to fall with progress of chronic liver disease - & therefore plays a major prognostic role - It also will fall with inadequate protein intake - Not an enzyme, but a plasma protein - Need some time for albumin to start to be affected. Transport of calcium by bilirubin, hormones and drugs

Question 187

Describe characteristics of Prothrombin Time (PT)

Answer 187

- Looks @ production and function of blood clotting factors that are produced by the liver. - Measures the rate @ which prothrombin - Is converted to thrombin in the presence of: Ø Thromboplastin Ø Calcium Ø Fibrinogen Ø Coagulation factors V, VII, X - If control takes a certain amount of clot and patient's blood takes another time. You do patients clotting time / control material clotting time, control material standardised clotting time across the world.

Question 188

What is INR (International normalised rate (INR))

Answer 188

- The ratio of PT of the patient, to that obtained, using a control preparation - Normal individuals have INR

Question 189

What happens in the presence of severe acute chronic liver damage

Answer 189

- Synthesis of clotting proteins by the liver is impaired - Prothrombin half life is 6 hours - Therefore a prolonged INR which can only be improved by fresh plasma transfusion or providing the deficient clotting factors - Is a good indicator of severe liver damage, e.g. acute liver failure

Question 190

Describe the characteristics of Vitamin K

Answer 190

- Fat soluble vitamin - Needs bile salts for absorption - Is also needed for the synthesis of clotting factors by the liver

Question 191

What happens to vitamin K in cholestasis

Answer 191

- Vitamin K absorption is defective - Synthesis of clotting factors is impaired. - This causes an increased INR which can be corrected within 24hours by an injection of vitamin K

Question 192

Describe hepatocellular carcinoma

Answer 192

- Environmental factors rather than genetic/racial predisposition, play key role in pathogenesis - Rising in the West because of improved treatment of alcoholic + other cirrhosis - e.g. after hepatitis B/C and more prolonged survival - More common in men, M:F ratio 4/1 to 8/1

Question 193

Clinical presentation of hepatocellular carcinoma

Answer 193

- Tumour usually presents in a patient known to have had cirrhosis, or haemochromatosis for some time - High incidence = appears in individuals who were apparently healthy - However majority of affected patients are found to have cirrhosis in non-tumour part of liver

Question 194

What are the symptoms of hepatocellular carcinoma

Answer 194

- Usually runs a silent course until it is advanced. Once advanced, prevents with: Ø Upper abdo pain, in the right hypochrondrium or epigastrium. Radiating to the right sub scapular region or shoulder Ø Weight loss + weakness Ø Fullness feeling in upper abdomen after meals / anorexia Ø Abdo swelling due to ascites Ø N&V, constipation Ø Peritoneal haemorrhage - acute abdo due to tumour rupture Ø Bone pain because of skeletal metastasis

Question 195

Early signs of hepatocellular carcinoma

Answer 195

- Usually runs a silent course until it is advanced. Once advanced, prevents with: Ø Upper abdo pain, in the right hypochrondrium or epigastrium. Radiating to the right sub scapular region or shoulder Ø Weight loss + weakness Ø Fullness feeling in upper abdomen after meals / anorexia Ø Abdo swelling due to ascites Ø N&V, constipation Ø Peritoneal haemorrhage - acute abdo due to tumour rupture Ø Bone pain because of skeletal metastasis

Question 196

Diagnosis of hepatocellular carcinoma

Answer 196

- Determination of alpha-fetoprotein: markedly elevated - Biochemistry: Ø Similar to cirrhosis Ø Markedly elevated by Alkaline Phosphatase with normal or slightly elevated bilirubin + transaminases Ø Low albumin + elevated IgG and IgM

Question 197

Radiological investigations for hepatocellular carcinoma

Answer 197

1. Isotope liver scanning 2. Hepatic angiography 3. Ultrasonography (solid vs. cysts) 4. CT scans

Question 198

Percutaneous transhepatic cholangiography characteristics

Answer 198

Ø Percutaneous, transhepatic cholangiograpphy (PTC) Ø To delineate bile passages using radio opaque dye Ø Arrow = @ a blocked segment of biliary passages due to cholangio carcinoma (bile duct cancer) Ø Above which the bile passages were dilated Ø Cancer of the bile ducts. Dye (that appears white) is injected inside the ducts. Dilated above and below

Question 199

Barretts oesophagus

Answer 199

- There are islands of squamous epithelium - With suspicious area in close up, on the right side - Get reflux symptoms - Looks like geographical maps - the pink background is the normal oesophagus. - Need a specialist to do this.

Question 200

Describe the characteristics of Helicobacter Pylori Infection

Answer 200

- H Pylori infection = main cause of duodenal or gastric ulcers - Plays important role in gastric cancer - Can be diagnosed by microscopical examincation of biopsy specimens • These biopsies can be tested for presence of urease • Urease is specific for H. Pylori in the presence of indicator that changes colour with release of ammonia, when there are positive bipsies • Antibodies for H. Pylori can also be checked but C13/C14 urea breath test or PCR preferred

Question 201

Describe the exocrine pancreatic functions

Answer 201

- Alkaline secretion - Enzymes • Amylase, lipase, trypsin, chymotrypsin, carboxypeptidases, elastase, esterases, phospholipases - Bile salts + lipases are essential for fat digestion + absorption and adsorption of fat soluble vitamins ADEK

Question 202

Describe the endocrine pancreatic functions

Answer 202

Ø Insulin Ø Glucagon Ø Somatostatin

Question 203

Describe the symptoms of acute pancreatitis

Answer 203

- Upper abdominal pain => radiates to the back | - Enzymes marked elevation of amylase + lipase in blood & urine

Question 204

What causes acute pancreatitis

Answer 204

- Alcohol - Gallstones - Post operative hyperlipidaemia - Traumatic carcinoma - Drugs: Steroids, Azathioprine, Diuretics

Question 205

Investigations of acute pancreatitis: biochemistry

Answer 205

- Serum / urine amylase or lipase (high) - Serum calcium (low) - Falling arterial O2 tension - Coagulopathy

Question 206

Investigations of acute pancreatitis: radiology & imaging

Answer 206

- Plain radiography - Ultrasonography - Computerised tomography (CT) - ERCP - PTC

Question 207

Describe the characteristics of gallstones | - Cholesterol stones

Answer 207

Cholesterol stones ``` Ø >70% cholesterole Ø Mucoprotein + calcium Ø Supersaturation Ø Nucleation Ø GB motor dysfunction ```

Question 208

Describe the characteristics of gallstones | - Pigment stones

Answer 208

``` Ø Calcium bilirubinate Ø Cholesterol Ø Calcium soaps Ø Mucoprotein matrix Ø Bacterial Beta glucoronidase ```

Question 209

Signs of carcinoma of the pancreas

Answer 209

``` Ø Jaundice Ø Hepatomegaly Ø Palpable gallbladder Ø Epigastric tenderness Ø Ascities Ø Enlarged lymph nodes ```

Question 210

Treatment of pancreatic carcinoma?

Answer 210

- Preoperative biliary drainage - Palliative surgery - Resection : prognosis + complications - Chemotherapy: Ø 5-Fluoroacil Ø Cyclophosphamide Ø Methotrexate Ø Vincristine - Radiotherapy

Question 211

Describe the classification of laboratory tests in cardiac disease

Answer 211

- Markers of risk for development of coronary artery disease (cholesterol, HDL + LDL) - Genetic analysis for candidate genes of risk factors - Markers of cardiac tissue damage - Markers of myocardial function / overload: when the heart is working too hard and exerting too much force.

Question 212

What are cardiac markers

Answer 212

Ø Located in the myocardium Ø Released in response to cardiac overload (when heart is working too hard) Ø Released in response to cardiac injury Ø Release in response to cardiac failure Ø Can be easily measured in blood samples - this is particularly useful about them.

Question 213

The biochemical markers of cardiac dysfunction / damage can contribute to:

Answer 213

- Rule in / out an acute MI - Confirm an old MI - Help to define therapy - Monitor the success of therapy - Diagnosis of heart failure - Risk stratification of death - Heart failure = when

Question 214

What are the analytical characteristics of the ideal cardiac marker

Answer 214

- No marker fulfils all of these criteria - Things that are important about a blood test: - Measurable by cost-effective method - Simple to perform - Rapid turnaround time - if someone has had an MI we want to know quickly + easily if the person has had an MI or not - Sufficient precision and accuracy - good degree of specificity and selectivity in the disease. - Reasonable cost

Question 215

What are the clinical characteristics of the ideal cardiac marker

Answer 215

- Early detection of disease - Sensitivity vs. specificity - Validation decision limits - Selection of therapy - Risk stratification - Prognostic value - Ability to improve patient outcome

Question 216

Describe coronary heart disease (ischaemic heart disease)

Answer 216

- Reduced blood flow to certain sections of the heart because of a thrombus - Blocked blood flow = o2 and nutrients to a certain area of the heart. Get necrosis (dead tissue) as this happens for a prolonged time period

Question 217

Describe the process of development of atheromatous plaques

Answer 217

- Streaks of initial fat deposits are happening from about 18+ - Buildup of plaques over time, later on see patients presenting with blocked arteries/ lesions that have burst through and formed a blood clot - Patients present with chest pain • Acute =

Question 218

What are the chronic and acute coronary syndromes

Answer 218

- Acute: Ø in acute there is unstable angina: plaque could be breaking off and causing vessel blockage Ø Patients with severe chest pain Chronic = different levels of vessel occlusion, therefore they have a stable condition

Question 219

Describe how plaque rupture can lead to myocardial infarction

Answer 219

- Blood flow still going in angina - Cap ruptures = plaque is covered by a cap which can rupture and forms a blood clot; so there is complete occlusion of the artery - Then you will see cell death in this region of the heart - Acute MI = need treatment fast.

Question 220

Why is it important to define the type of IHD

Answer 220

- For treatment, prognosis & management | - Stable angina vs. acute myocardial infarction

Question 221

Describe how ECG + biomarkers can define type of acute coronary syndrome

Answer 221

- ST elevation MI = caused by complete obstruction of coronary artery Ø Causes damage that involves full thickness of heart muscle Ø Have classes PQRST wave and within this ST segment. Ø When presenting with MI there will be elevation of this particular segment Ø Changes in the curve because there is damage to full thickness of the heart muscle + complete obstruction of the coronary artery, that causes damage to the full thickness. - Non-ST elevation MI is caused by partial obstruction of a coronary artery Ø Causes damage that does not involve the full thickness of the heart wall - These are both acute = important to diagnose from angina

Question 222

What is the criteria for acute myocardial infarction. DEFINITION OF MI

Answer 222

- Evidence of myocardial necrosis in a clinical setting, with ischaemia. - That is consistent with acute myocardial ischaemia - Under these conditions the following criteria will meet the diagnosis for MI Ø Ischaemia symptoms Ø New / presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch block (LBBB) Ø Development of pathological Q waves in the ECG Ø Imaging evidence of new loss of viable myocardium, or new regional wall motion abnormality Ø Identification of intracoronary thrombus by angiography or autopsy - One of the biomarkers is important marker of MI - cardiac tropnins need to rise and fall, and together with the above > symptoms.

Question 223

Describe myocardial injury?

Answer 223

- Do not have enough oxygen supply, will lead to Irreversible injury, = takes 30 minutes of ischaemia - High risk that 80% cardiac cells die within 3 hours (significant death) - Almost 100% die by 6 hours, if they have not got enough o2 within this time period - Cellular content leak out thorough the membrane, dependent on size + solubility within this time frame. - Concentration gradient from inside to outside is important • High gradient will help improve the detection of early damage

Question 224

Describe the release kinetics of myocardial cell constituents ?

Answer 224

- Myocardial cell constituents - Ions get detected sooner: Ø Because they are smaller Ø Smaller ions + metabolites are detected first - Larger macromolecules Ø Start to see @ about 6 hrs Ø Do not peak until about 18hrs - Do not see until after the onset of the chest pain

Question 225

Describe the markers of myocardial damage

Answer 225

Markers that are used for MI - 7-36h peak, after MI start being able to detect these markers in the blood. - Heart muscle specific markers troponin-T and troponin-I - Creatinine kinase (increase 90% MI s, but less specific as also released from skeletal muscle) - Heart specific isoforms of creatinine phosphokinase (CPK-MB) - Myoglobin raised early, but less specific for heart damage Creatine kinase = elevated in 90% Mis but is not specific to myocardial tissue. CPK Mb, Creatine phosphokinase = heart specific isoform of creatine kinase Myoglobin = less specific for heart damage Troponins = specific to heart. (I and M) and they are elevated.

Question 226

Describe the protein elevations in serum after MI

Answer 226

- Elevations in serum occur after MI - These show the 3 different parameters - If you went to A&E with chest pain, these might be useful. - Takes 4-6hrs for creatinine kinase levels, or troponin to change - Have to see a rise and fall in troponin - Myoglobin = useful to see that there is damage going on (levels will go up) - but not sufficient to measure this alone - This is why you have to measure these parameters over time

Question 227

What are the characteristics of Troponins

Answer 227

- The troponin complex, is a component of the thin filaments in striated muscle complexed to actin. - They are quite structurally different to other troponins There are 3 types of troponins: - Complexed to actin 1. Troponin T (tropomyosin binding) 2. Troponin I (inhibits actomyosin ATPase) 3. Troponin C (calcium binding) - The troponins are 2 different proteins - They are structurally unrelated with each other - Cardiac troponin T & I differ significantly from Troponin T & I found in skeletal muscle

Question 228

Troponin T?

Answer 228

- Tropomyosin biding

Question 229

Troponin I?

Answer 229

- Inhibits actomyosin ATPase

Question 230

Troponin C?

Answer 230

- Calcium binding

Question 231

Describe Troponin release after myocardial infarction

Answer 231

Advantages of cardiac troponin Ø Index of cardiac damage Ø Blood levels related to severity of cardiac damage Ø Predicts major adverse cardiac events, such as myocardial infarction Ø Acute/ significant damage to the muscles = in the top ones the troponins are significant elevated, way above the normal reference range Ø Middle = lesser amount of troponin released so less severe. Ø Bottom (myocarditis) - infections you may not see elevations of troponiin

Question 232

Describe the differential diagnosis of high sensitive cardiac troponin

Answer 232

- Highly dependent on the absolute level - Have to be done rapidly - Have to differentiate between whether person had a SMALL AMI vs micro, or very large. - Can differentiate between conditions

Question 233

Signs + symptoms of congestive heart failure

Answer 233

``` Ø Breath shortness Ø Swelling of feet and legs (classic of heart failure but can also be linked to other conditions ) Ø Chronic lack of energy Ø Hard to sleep @ night because of breathing problems Ø Swollen / tender abdomen Ø Cough w/ frothy sputum Ø Increased night time urination Ø Confusion and or impaired memory ```

Question 234

Describe the clinical utilisation of cardiac biomarker testing in heart failure

Answer 234

- Manifestation of the above signs + symptoms - parameters + proteins called: Natriuretic peptide - Natriuretic peptides as markers of cardiac damage / overload - When the ventricles are pumping too hard = stretched. This will release the Natriuretic peptide; which can actually be useful for the heart failure. - An A,B,C of natriuretic peptides - Initial evaluation of heart failure - Screening for cardiac dysfunction - Guiding management of heart failure - Assessment of prognosis + survival

Question 235

ANP, BNP, CNP Natriuretic peptides

Answer 235

- Most released in high molecular weight precursor form - Main effect = natriuretic. This means that sodium is released through the urine - Trying to expel water / remove fluid accumulation. - Therefore the main function of these peptides is response to overload of the heart - Vasodilation effect inhibit the renin angiotensin system - Released naturally in response to over load of the heart - Stimulus = stretch + dilation. - Can be used to our advantage in diagnosis of heart failure

Question 236

Measurement of plasma natriuretic peptides

Answer 236

- Assays = available for active peptides and the N-terminal precursors forms ANP & BNP - Can measure them in the blood - Before it gets cleaved to the active form = long terminus is present in the blood - Can measure both of them. - Advantages of measuring the N terminal forms = longer half life - More sensitive to fluctations with the shorter ones

Question 237

What are the advantages of N terminal precursor forms over ANP / BNP

Answer 237

- Longer half life - Higher plasma concentrations - Less sensitive to rapid fluctuations

Question 238

When are plasma levels of ANP/BNP markedly raised

Answer 238

- Congestive heart failure - Aortic stenosis - Dilated cardiomyopathy - Hypertrophic cardiomyopathy - enlarged hearts that have a lot of stretch occurring. - Myocardial infarction - Chronic renal failure : useful when the heart is overworked.

Question 239

Possible causes for raised plasma natriuretic peptides in heart disease

Answer 239

Haemodynamic structural events that occur Ø LVH Ø Ventricular dilatation Ø Damage + remodelling after myocardial infarction Ø Hypoxia / Necrosis

Question 240

Some conditions investigated for possible use of plasma ANP/BNP

Answer 240

- Assessment of severity of congestive heart failure - Screening for mild heart failure also. - Monitor response to treatment in congestive heart failure - Prognostic outcome/risk stratification

Question 241

Cardiac biomarkers for early detection of myocardial damage

Answer 241

- Other markers that have been looked at Disease progression Ø Initial pathophysiology is because of increased inflammation Ø So could have markers looking @ different points of the disease process Ø And determine if the person is @ risk of disease - Ischaemia modified albumin (IMA)? Low specificity ○ Issue with troponins = see them first @ 6 hours ○ Want markers that can tell us earlier the degree of disease in terms of how much iscaemia is occurring. ○ This also has low specificity :(

Question 242

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Inflammation

Answer 242

- C reactive protein - Tumour necrosis factor 6 - Interleukins 1,6, 10, 18

Question 243

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Oxidative stress

Answer 243

- Important pathophysiological event - Oxidised LDL - Myeloperoxidase

Question 244

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Extracellular-Matrix Remodelling Ø Enzymes that are involved in this process

Answer 244

- MMP2 - MMP3 - MMP9 - TIMP1 - Collagen propeptides - Galectin-3

Question 245

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Neurohormones

Answer 245

- Angiotensin 2 - Aldosterone - Arginine Vasopressin - Endothelin-1 • Vasoconstrictor - useful as a target in diseases like pumonary hypertension. Has not proved to be useful as a biomarker yet.

Question 246

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Myocyte Injury + Apoptosis

Answer 246

``` - Troponins I & T • Good in terms of Necrosis in MI - Myosin light chain kinase I - Heart type fatty-acid binding protein - Creatinine kinase MB fraction ```

Question 247

What are the candidate biomarkers in heart failure? Ø Used clinically Being investigated in research lab - Myocyte Stress

Answer 247

- BNP - NT-proBNP - MR-proANP

Question 248

Explain the things that calcium ions effect

Answer 248

Ø Calcium in the body = 1-2kg, 99% mineralised in the bone • ~1% intracellular • Mineral content = hydroxyapatite • Calcium balance depends on metabolic regulation of the tiny extracellular fraction of Ca2+ • [] gradient for calcium across the membrane is from inside to outside- but there is more intracellular because the IC calcium is very bound to stores. The actual free calcium is very low. ○ This is because calcium is such an important signalling molecule ○ Intracellular secondary signalling Ø Continually involved in bone remodelling Ø Neuronal + neuromuscular activity Ø Membrane permeability Ø Activity of many enzymes [calcium] in ECF is normally kept within closely defined limit

Question 249

How is calcium kept within closely defined limits? | via PTH and its characteristics

Answer 249

Ø Parathyroid hormone • (PTH) • 84aa peptide • Secreted by the chief cells of the parathyroid gland • [ca2+] levels monitored by chief cell membrane Ca receptor (GPCR) Target organs

Question 250

how the KIDNEY keeps calcium within its limits?

Answer 250

Ø Increases calcium reabsorption • Especially in the distal convoluted tubule. Ø Decreases phosphate reabsorption Ø Increases synthesis of calcitiol (active vitamin D)

Question 251

how the BONE keeps calcium within its limits?

Answer 251

- Affects calcium homeostasis - Increases bone resorption by increasing osteoclast activity / increases the rate of bone remodelling - "Dissolving" bone => releasing Ca from mineralised bone - Indirectly increases calcium absorption from the gut • Indirect action via vitamin D

Question 252

Describe calcium distribution in the body - Dietary intake

Answer 252

- 400-1200mg /day • Of which about 200mg is absorbed • Increased need during pregnancy, lactation and growth

Question 253

Describe calcium distribution in the body - Intestinal absorption

Answer 253

- In the duodenum | - Stimulated by vitamin D

Question 254

Describe calcium distribution in the body - Calcium exchange in the bone

Answer 254

~ 99% of body calcium is in the bone | ~5g is in readily exchangeable form

Question 255

Describe calcium distribution in the body - Renal excretion

Answer 255

~ 6mmol/day when renal function is normal | PTH will increase reabsorption

Question 256

Describe calcium distribution in the body - Plasma

Answer 256

~ 50% protein bound (mainly to albumin), ~50% ionised (active form ~1mmol/L)

Question 257

Characteristics of vitamin D

Answer 257

- Steroid hormone, not a vitamin - Fat soluble "vitamin" that is made in the skin in response to exposure to UV (the sunshine vitamin) - (Cholecaliferol)

Question 258

What steps is vitamin D activated by

Answer 258

1. 25 hydroxylation in liver to form 25OH D, major circulating metabolite - measurements of vitamin D involve measurements of 25OHD (reliable guide to vitamin D status) 2. 1alpha hydroxylation of 25OHD in the kidney, produced calcitriol (1α,25(OH)2D3), active hormonal metabolite (1 alpha hydroxylation) Ø Calcitriol increases intestinal absorption of dietary calcium

Question 259

Characteristics of calcitonin

Answer 259

Ø Hormone that is secreted by the thyroid gland itself. Ø 32 amino acid peptide • Secreted by the C cells of the thyroid • Stimulus for secretion = high Ca2+ Ø Target organs Kidney = decreases calcium and phosphate reabsorption Bone = decreases bone resorption by inhibiting osteoclast activity Synthetic calcitonin is used in treatment of Pagets disease of the bone

Question 260

Major causes of hypercalcaemia

Answer 260

Ø Cancer associated - due to bone metastases Ø Primary hyperparathyroidism (ambulatory patients) Ø Malignancy = most common cause in hospitalised patients: secretions from a tumour or metastases.

Question 261

Less common causes of hypercalcaemia

Answer 261

Ø Secondary to hyperthyroidism | Ø Excessive intake of vitamin D

Question 262

Describe the clinical features of hypercalcaemia in the kidney

Answer 262

- Renal calcifications and stones - Excess calcium being excreted by the kidneys - Increased urine volume - Neuromuscular + neurological effects • Abdo pain, constipation • Anorexia, N&V, mental changes

Question 263

Describe the clinical features of hypercalcaemia in Neuromuscular and neurological effects

Answer 263

- Abdominal pain + constipation | - Anorexia, N&V, mental changes

Question 264

Describe the clinical features of hypercalcaemia in Heart

Answer 264

- Cardiac arrhytmias, cardiac arrest

Question 265

Describe primary hyperparathyroidism

Answer 265

- This is the most common cause in non-hospitalised patients - Usually due to a benign adenoma - Most common in post-menopausal women - Often does not lead to overt symptoms, but will be detected on screening when calcium is measured - ~10% of patients present with clinical evidence of bone disease - 10-20% patients present with kidney stones

Question 266

Serum biochemistry

Answer 266

• Serum calcium - modest to marked increase • Serum phosphate - low or low normal • Serum alkaline phosphatase raised in ~ 20% of cases Ø Marker of bone remodelling Ø Raised levels = indicate an increase of osteoblast + osteoclast activity Ø Associated with bone disease • Serum creatinine may be elevated in longstanding disease (kidney damage) Ø Kidney disease = creatinine levels would be increased also! • Serum PTH concentration should be interpreted in relation to calcium Ø Would expect effect on serum calcium Ø Very marked increase. Calcium + phosphate handling by the kidney are reciprocal

Question 267

Bone resorbing agent involved in Humoral hypercalcaemia | Ø Lung, renal carcinoma

Answer 267

PTHrp (being ectopically secreted) - usually in the case of a tumour, will be PTHrp rather than just PTH • Do not have to do tests to distinguish between ectopic source or primary hyperparathyroidism. • Tumour that is doing something similar to releasing ectopic source of hormone

Question 268

Bone resorbing agent involved in Metastatic hypercalcaemia | Ø Solid tumours with bone mets, like breast carcinoma

Answer 268

Prostaglandins, TGFs • Tumour can metastasise to the bone • Regulation of the delicate balance of osteoclasts + blasts = complex and there are many diff. signalling molecules involved => tipping of this balance to favour osteoclasts => bone breakdown => hypercalcaemia because there is more free calcium.

Question 269

Bone resorbing agent involved in Haematological malignancies Ø Multiple myeloma lymphoma

Answer 269

IL-1, TNFalpha | cytokines, calcitriol

Question 270

Management of hypercalcaemia of malignancy

Answer 270

* Vitamin D deficiency and disordered vitamin D metabolism (e.g. renal failure) * Hypoparathyroidism (failure of parathyroid gland to secrete enough parathyroidism) * / pseudohypoparathyroidism (PTH is secreted but the problem is with the PTH receptor.) * Magnesium deficiency (Mg required for PTH secretion and action on target tissues) * Acute pancreatitis ? Formation of insoluble calcium salts of fatty acids * Spurious - blood collected into EDTA tube

Question 271

What are the clinical features of hypocalcaemia

Answer 271

* Numbness * Muscle cramps and spasms * Convulsions * ECG changes * Prolonged hypocalcaemia * Cataracts * Mental disturbances

Question 272

What are the characteristics of rickets and osteomalacia

Answer 272

* Bone diseases associated with vitamin D deficiency * Rickets - in children, failure of bone mineralisation and disordered cartilage formation * Osteomalacia - in adults, impaired bone mineralisation (like rickets).

Question 273

How can sunlight act as a source of Vit. D

Answer 273

* Adequate supplies of vitamin D3 can be synthesized with sufficient exposure to solar ultraviolet B radiation * Depends on latitude and season * Summer sunlight in Cape Town = 2500 IU vitamin D3 daily * Melanin, clothing or sunscreens that absorb UVB will reduce cutaneous production of vitamin D3 => darker skin, need more vitamin D

Question 274

Describe the metabolism of Vit. D

Answer 274

Ø Synthesised in the skin Ø Needs further reactions for this to proceed Ø Fall in skin vitamin D = excessive sun block. Ø The sources can be synthesis from a precursor in the skin, or from the diet Ø If you do not make enough in the skin it is fine as long as there is enough in the diet that can be metabolised by these pathways Ø Then metabolised by the liver to make intermediate (25OHD) which undergoes final processing stage of cells in the kidney tubules; where calcitriol is produced and released into the circulation by the tubule cells.

Question 275

What are the causes of vitamin D deficiency

Answer 275

* Deficient synthesis and supply of vitamin D * Inadequate intake * Limited sunlight exposure * Impaired absorption of vitamin D * Malabsorption syndromes (e.g. coeliac disease)

Question 276

Describe rickets due to nutritional deficiency | those at risk

Answer 276

* Those at risk include: * Babies who are bottle fed on non-vitamin supplemented feeds. * Children who have little sunlight exposure * Breast fed babies of mothers with marginal vitamin D status

Question 277

How does rickets manifest?

Answer 277

* Muscle weakness * Bowing deformity of long bones = this is the main sign of rickets. Due to the fact that vitamin D is needed for the mineralisation of bone, which needs calcium. Bones are basically "soft" osteoid is made but the defect is in mineralisation. * Prominence of the costochondral junction (rachitic rosary) * On X-ray, generalized demineralization of bone

Question 278

What are the features of osteomalacia?

Answer 278

Softening of the bone. Bones are demineralised and soft. • Stress fractures might show up on X-Rays. Has normal proteins + Protein osteoid matrix, but without the actual mineralisation. • Diffuse bone pain • Waddling gait, muscle weakness • On X-ray, stress fractures

Question 279

Test results that you would expect to see with osteomalacia

Answer 279

• Serum biochemistry: • Low/normal calcium • Hypophosphataemia • Raised alkaline phosphatase ○ This is a sign of bone turnover • Secondary hyperparathyroidism ○ This means that there are high levels of PTH ○ In this case 2ndary = if the high levels of PTH are secondary to lower calcium. § [primary would due to the parathyroid itself, hypersecretion is secondary to the fact that calcium has not gone up (stays low, or @ the lower end of normal)]

Question 280

Privational osteomalacia characteristics?

Answer 280

- Neither vitamin D via the diet or from the sun would be enough. Diet vs. sunlight as a source of vitamin D • Limited exposure to UV light leads to vitamin D deficiency • Limited UV exposure is necessary but insufficient in itself to induce the biochemical, radiological and clinical expression of privational osteomalacia • If you don’t do either of them = then result will be vitamin D deficiency. • In the presence of limited UV exposure, dietary factors are the major determinants of privational osteomalacia • Major dietary risk factors are low or absent meat intake and high intake of wholemeal cereals

Question 281

Describe acquired/inherited abnormalities in vitamin D metabolism

Answer 281

• Failure of 25 hydroxylation of vitamin D • Chronic liver disease • Anticonvulsant therapy • Failure of 1 hydroxylation of 25 OH-vitamin D • Chronic renal failure • Vitamin D dependent rickets type I • Others • Vitamin D resistant rickets ○ Issue/mutation with the actual vitamin D receptor, which is a nuclear receptor • Vitamin D dependent rickets type II ○ Absence of the kidney enzymes, could be corrected by vitamin D supplement

Question 282

Describe renal osteodystrophy

Answer 282

- As renal function fails, the cells that are generating calcitriol will fail so that the production of calcitriol will go down - Absorption of calcium from the gut falls - Plasma calcium will fall - PTH will rise - That will favour bone erosion + osteoclast activity - In addition as renal function goes down the acid base regulatory function of the kidney will be impaired + the tendency for metabolic acidosis - Acidosis in itself = can tip the complex balance in favour of osteoclasts. (vs osteoblasts) - Environment favours the solubility of calcium salts.

Question 283

Describe how you get hypoparathyroidism

Answer 283

* Primary = May be congenital or acquired (e.g. following thyroid surgery, autoimmune disease). Most common acquired form is after thyroid surgery. PTH glands are individually variable and embedded in the thyroid itself. * Serum biochemistry * Calcium decreased, phosphate increased, low PTH, alkaline phosphatase normal * May be treated with vitamin D (or an analogue) with or without calcium supplements * If there is no PTH= lower calcium. * Primary hypothyroidism = know that it would be a problem in the parathyroid gland itself * Low calcium levels => PTH high. [negative feedback relationship] * Drop in both implies impairment in the secretion of PTH. * There are rare inherited inactivated mutations in the receptor, in the gene for the calcium sensing. (CSAR) * If there is a mutation that INACTIVATES this receptor, then you would expect there to be a RISE * No calcium to the PTH gland * High PTH levels

Question 284

What is hypophosphataemia

Answer 284

* Causes * Primary hyperparathyroidism * Vitamin D deficiency * Persistent hypophosphataemia may be observed during intravenous nutrition * Severe hypophosphataemia (0.2 - 0.3mmol/L) may cause neuromuscular irritability, confusion and hyperventilation

Question 285

What are the disorders associated with normal serum calcium concentration

Answer 285

* Paget’s disease of bone (generalised increase in bone turnover) * Osteoporosis * Medullary carcinoma of the thyroid (increased circulating concentrations of calcitonin)

Question 286

What are the causes of osteoporosis

Answer 286

* Ageing, especially post-menopausal * Endocrine * Premature ovarian failure/hypogonadism * Thyrotoxicosis, Cushing’s, diabetes mellitus * Drugs * Glucocorticoids, alcoholism, prolonged heparin treatment * Others * Immobilization, malabsorption of calcium, weightlessness (Piezoelectricity)

Question 287

What is primary immunodeficiency

Answer 287

Ø Defect in the immune system components. | Ø The most likely consequence of this => infections

Question 288

What is secondary immunodeficiency

Answer 288

Ø Caused by non-immune disease (due to another disease that the patient has) - nothing primarily wrong with the immune cells themselves

Question 289

Clinical features of immunodeficiency

Answer 289

1. Recurrent infections Ø Happen more often, patients keep getting it Ø These infections tend to be more severe 2. Severe infections + unusual pathogens (Aspergillus, Pneumocystis) Ø In other people these 2 pathogens would not cause a disease Unusual sites = liver abscess, osteomyelitis

Question 290

Describe primary immunodeficiencies

Answer 290

- Usually genetic- in the genes that code for various componnts of the immune system. Due to defect that is located in the cells immune system. - Infrequent but can be life threatening - Adaptive immune system can be affected = T & B lymphocyte cells - Innate immune system = phagocytes, complement system Ø 50% of the primary immunodeficiencies are because of insufficient production of antibodies Ø 30% are due to problems with the T lymphocyte cells 18% phagocytes Ø 2% complement system defects

Question 291

Primary immunodeficiencies - major B lymphocyte disorders

Answer 291

These all involve the B cells - X linked agammaglobulinaemia (Brutons diease) - Common variable immunodeficiency (CVID) - Selective IgA production deficiency - IgG2 subclass deficiency

Question 292

Describe X-Linked Agammaglobulinaemia Primary immunodeficiencies - major B lymphocyte disorders

Answer 292

- Brutons disease - Defect in BTK gene (X chromosome) - Defect in Brutons Tyrosine Kinase - the gene for this tyrosin kinase is located on the X chromosome - Encodes Brutons tyrosine kinase • Tyrosine Kinases are usually involved in siganlling pathways and phosphorylate other proteins that are part of this pathway • When this is defective and the kinase is not present, then the B cell development is blocked => do not develop normally => insufficient antibodies => these infections start to become visible in the second half of the first year of life. • For the 1st year of life children are protected from this because some classes of antibodies (like IgG) can come through the placenta, plus they gain IgA from breastfeeding. - Block in B cell development (stop @ Pre B cells) - Recurrent severe bacterial infections

Question 293

Investigations for X-Linked Agammaglobulinaemia

Answer 293

Ø All Igs absent / very low • If you look at the full blood count you would see that this is low Ø B cells absent / low

Question 294

What is the treatment for X-Linked Agammaglobulinaemia

Answer 294

- Replace the Abs and give the patient the chance to fight off the infection. - IVIg: 200-600mg/kg/month @ 2-3 week intervals - Or subcutaneous Ig weekly - Prompt antibiotic therapy (URI/LRI)

Question 295

Describe common variable immuno deficiency

Answer 295

- The most frequent that is symptomatic. Commonest symptomatic Ab deficiency - Presentation: any age at all. Peak: early childhood / early adulthood - Recurrent bacterial infections (chest + sinus) until they have been diagnosed, because the presentation is not as clear and it affects such different ages. - Autoimmune problems (in addition to the immune deficiency) - these can lead to chronic inflammation and destruction - Usually missed due to: Ø Exclusion diagnosis => late diagnosis => complications => structural lung/sinus damage

Question 296

Describe common variable immuno deficiency

Answer 296

- B cell levels are normal, or low - 1+ Igs are missing. - T cells = normal. In some patients CD4+ T cells can also be low. - Treatment: IVIg; antibiotic prophylaxis

Question 297

What is a selective IgA deficiency?

Answer 297

- Selectively affects the production of immunoglobulin A. mucosa of the GI or respiratory tract. - Most common = 1:400-1:800 - Most cases are asymptomatic, some have respiratory infections + diarrhoea - this means that it can go undiagnosed. - Not as severe, but is the most frequent.

Question 298

Specific Ab deficiency with normal Igs

Answer 298

- Hep B vaccination, 5% do not respond - some people who get the Ab fail to mount suffient titres against the Ag. May have defect that makes them fail to mount Ab against this antigen. Might have infections slightly more often than the average person. - Recurrent bacterial infections (URI/LRI)

Question 299

Primary immuno-deficiencies: combined immuno-deficiences

Answer 299

- Severe combined immunodeficiency (SCID) - they affect both T and B lymphocytes.

Question 300

Primary immuno-deficiencies: predominant T cell disorders

Answer 300

- DiGeorge syndrome - Wiskott Aldrickh syndrome - Ataxia-Telagiectasia

Question 301

What is SCID (Severe combined immunodeficiency)

Answer 301

- Involves both T & B cells - 50% X linked (on the X chromosome) - Well/normal @ birth. Problems >1st month, which is quite early. - Diarrhoea, weight loss, persistent candida albicans - this does not usually happen unless you have a bad infection that leavves you immunosuppressed. - Severe bacterial / viral infections - Failure to clear vaccines • When given a live pathogen vaccine they will develop the disease rather than producing antibodies against it. - Unusual infectinos

Question 302

What are the causes of SCID (Severe combined immunodeficiency)

Answer 302

Components that can stop the normal production of T & B lymphocytes 1. RAG-1/RAG-2 defect => no T & B cells - RAG, recombination activation genes - If rearrangements of the T and B cells do not happen = then they will not be made, will only be present in low numbers, - If the numbers of the B cells are affected = T cells are affected - Of there is a low number of T cells = improper functioning. Will not be able to do this in vivo in patients 2. Common cytokine receptor, y chain defect (IL2R) - Common gamma chain of cytokines - Part of the IL2 receptor which is critical because it allows the T cells to respond to their most important growth factor which is Interleukin 2. 3. ADA (adenosine deaminase deficiency) - Enzyme that helps cells stay alive when the adenosines increase a lot 4. Bare lymphocyte syndrome (MHC1 or MHCII) - Major histocompatability complexes - Not able to express these on the surface of lymphocytes - If this happens then T cells will not be able to see antigens anymore.

Question 303

Investigations that you would do for SCID (Severe combined immunodeficiency)

Answer 303

1. Lymphocyte subsets/ Ø T, B, NK (% & numbers) Ø Low total lymphocyte count = SCID sign 2. Pattern = very low/absent T; normal/absent B 3. Igs low 4. T cell function decreases (proliferation, cyotkines)

Question 304

What is the treatment for SCID

Answer 304

- Isolation. Prevents further infections : characteristic child = "bubble boy/girl" - Do not give live vaccines because patients will not react well to them - Blood products from CMV-negative donors • As they devlop infections with cytomegalo virus - IVIg replacement - Treat infections promptly - Bone marrow / stem cell transplant • Their immune system needs to just be replaced with a functional system

Question 305

Treatment outcomes of SCID

Answer 305

- Depends on how prompt the diagnosis was = SCID is very severe. - Survival = >80% (early diagnosis, good donor match, no infections pre bone marrow transplant) - Survival = >40% (late diagnosis, chronic infections, badly matched donors) - survival will halve. - Regular monitoring post Bone Marrow Transplant => engraftment

Question 306

Primary immunodeficiencies | Ø DiGEORGES SYNDROME

Answer 306

Ø Defective development of the THYMUS => affects T cell production Ø Defect is mainly in the T cell compartment, but does not involve only immunoodeficiencies = there are defects in the actual genes. Ø Pateint has a number of defects in their development Ø 22q11 deletion Ø Complex array of developmental defects Ø Dysmorphic face : characteristic look • Cleft palate, low set ears, fish shaped mouth • Hypocalcaemia, cardiac abnormalities Ø Variable immunodeficiency • Absent / reduced thymus • Affects T cell development ○ Once generated in the bone marrow the T cells go to the thymus = if the thymus is not tthere / there is only a remnant then the production of T cells will suffer

Question 307

Primary immunodeficiencies | Ø WISKOTT ALDRICH SYDROME (WAS)

Answer 307

Ø X linked Ø Defect in WASP (Wiskott Aldrich Syndrome Protein) • WASP is a protein that is involved in actin polymerisation => defect in signalling ○ Proper cytoskeleton remodelling is important for lots of pathways of the cells ○ If the WASP protein does not allow actin to polymerise then the signalling is also affected • Thrombocytopaenia, eczema (hypersensitivety), infections • Progressive immunodeficiency Ø Progressive fall in T cells and T cell proliferation/cytokine production • These are dependent on optimal signalling from the T cell

Question 308

Primary immunodeficiencies | Ø ATAXIA-TELANGIECTASIA (AT)

Answer 308

Ø Defects in the T lymphocytes Ø Defect in the genes that control the cell cycle checkpoint => cells are very sensitive to ionising radiation - cells that often proliferate very rapidly like T ymphocytes are very sensitive. Ø Progressive cerebellar ataxia • Cannot maintain a stable gait Ø Typical telangiectasia (ear lobes, conjunctivae) • Other characteristic sign = these dilatations of the capillaries in these area.

Question 309

Primary immunodeficiencies | Ø PHAGOCYTE DEFECTS

Answer 309

``` Ø Due to defects in PHAGOCYTES Ø Quantitative. Fall in number of the phagocytes: may be insufficient, or good number but they just do not function correctly Ø Qualitative Ø Chronic granulomatous disease Ø Chediak Higashi syndrome Ø Leucocyte adhesion defects (LADs) ```

Question 310

Chronic granulamatous disease characteristics

Answer 310

There is defective oxidative killing of phagocytosed microbes, mutation in NADPH component (cytochrome b558) - Phagocytes = neutrophils, macrophages. These are the cells that will be affected - In the step of the phagocytosis pathway when the bacteria is taken up by the phagosome. The digestion / killing of the microbe in the phagolysosome will not happen very well = gets recurrent infection. - NADPH oxidase component is defective • Does not allow oxygen to be involved in making the superoxide anion.

Question 311

Phagocyte defects - CDG. Diagnosis (Chronic granulamatous disease)

Answer 311

- Defects in phagocytosis => have to look at NADPH oxidase - NBT test (nitroblue tetrzolium reduction) - Flow cytometry assay dihydrorhodamine

Question 312

Describe the NBT reduction test

Answer 312

- Take blood from patient and control, can isolate neutrophils and then culture them with nitroblue tetrzolium and bacteria that you know should produce a response

Question 313

Describe the dihydrohodamine assay

Answer 313

- Take blood, stain Abs that help identify neutrophils - Microbial compounds that help find the oxiddase - Label with dihydrohodamine - Will be cleaved => flourescent - If it becomes fluorescentt => produces fluoroescent light - Allows us to compare between ccells of patients who are suspsected to have the granulomatous disease.

Question 314

Phagocyte defects | Ø Chediak-Higashi syndrome

Answer 314

- Rare genetic disease - Defect in LYST gene (which regulates lysosome trafficking inside cells in general) • If lysosomes cannot traffick correctly they will fuse together and form giant lysosomes • Therefore patients cannot get rid of the bacteria that they have taken in. - Neutrophils have defective phagocytosis - Repetitive + severe infections - Defect phagosome-lysosome fusion => defective killing of the phagocytosed microbes => recurrent infections

Question 315

What is the diagnosis of Chediak-Higashi syndrome

Answer 315

1. Decreased number of neutrophils 2. Neutrophils will have giant granules / lyosomes - Control = can hardly see granules - CHS = can see the giant lysosomes.

Question 316

What is Leukocyte Adhesion Deficiency (LAD)

Answer 316

- This does not involve destruction of the bacteria once they have been phagocytosed. - Defect in beta2 chain integrins (LFA-1, MAC-1) - cannot migrate properly, there are improper chemotacic cues. - Delayed umbilical cord separation => diagnosis - Skin infections, intestinal + perianal ulcers - Decrease in neutrophil chemotaxis. Can quantify their ability to chase microbial compounds. Due to low levels of the beta 2 chains of integrins. - Decrease in integrin on phagocytes (flow cytometry)

Question 317

Schematic of LADLeukocyte Adhesion Deficiency

Answer 317

- To get other infection site neutrophils and monocytes use stepwise process that allows them to roll, mediated by selectins to adhere to the sides - Then they can transmigrate from the vessel into the tissue - Beta chain of the integrin is missing => cell cannot adhere to the integrin at the site of adhesion.

Question 318

Primary immunodeficiencies | Ø Complement deficiencies

Answer 318

- Different symptoms depending on which area is affected. - Recurrent infections (Neisseria - terminal complex) C5,C6,C7,C8, C9 deficiency • Aka the membrane attached complex - C3 components = pyogenic. This is at the centre of the affects of the complement - SLE like syndrome (C1q, C2, C4 deficiency) • Classical components • This will mimic SLE. - Hereditary angioneurotic oedema • They have defects in the inhibitor factor / complement factor 1 • Failure to inactivate complement (deficiency in C1 inhibitor) • Intermittent acute oedema skin/mucosa (oral cavity or airways) • Have bouts of acute inflammation • Vomiting, diarrhoea, airway obstruction

Question 319

Investigations that you could do into complement deficiencies

Answer 319

Ø Try to quantify all of the above (numbers and function) 1. Complement function (CH50) - haemolysis 2. Measure the individual components

Question 320

Primary immunodeficiencies (PID) treatment

Answer 320

- The aims are to: 1. Minimise + control infection 2. Replace the defective / absent component of IS Ø Igs, T cells and B cells replaced if missing. - So need to treat promptly - Prevention of infection • Isolation • Antibiotic prophylaxis • Vaccination (but not live vaccines) • nutrition

Question 321

Secondary immunodeficiency

Answer 321

- These are diseases that can lead to immunodeficiencies. - Infections, viral, bacterial Ø All lead organisms to become immunodeficient. - Malignancy, extremes of age, nutrition, chronic renal disease, splenectomy

Question 322

Secondary immunodeficiency: malignancy

Answer 322

Ø Myeloma | Ø Lymphoma (Hodgkin's + non Hodgkin's )

Question 323

Secondary immunodeficiency: chronic renal disease

Answer 323

- Uraemia - Dialysis will be needed - Nephrotic syndrome

Question 324

Secondary immunodeficiency: other

Answer 324

- Burns - Toxins : smoking + alcohol - Drugs : immunosuppressives - Transplant - Trauma + surgery

Question 325

What happens in bone marrow transplantation

Answer 325

Ø Reconstituion of full haematopoietic system / components of it Ø By transfer of pluripotent stem cells from the donor and into the system of the recipient. Ø Used to replace defective, absent, or malignant cells

Question 326

Bone marrow transplantation: clinical indications in PID

Answer 326

``` - SCID • Severe combined immunodeficiency. - Combined Id (WAS, DiGeorge) - Phagocyte defects - Lymphomas, leukaemias, myeloma ```

Question 327

Types of Bone marrow transplantation (by DONOR source) - Allogenic

Answer 327

Ø Genotypically matched individuals Ø Siblings, or matched unrelated donor (MUD) Ø Donor can also be the recipients (by purging out the bad cells with cytostatic) Ø There needs to be a match => MHC needs to match otherwise will reject

Question 328

Types of Bone marrow transplantation (by DONOR source) - Autologous

Answer 328

Ø The patient is the source

Question 329

Complications of bone marrow transplantation

Answer 329

- Infection (CMV, EBV, adenovirus) - patients will essentially lack an immune system for a certain period of time =>immunodeficient until the transplant starts working - Graft failure (increases with poor matching) - Graft vs. host disease (GvHD) (this is not really encountered anymore) - this could even have beneficial effects be ause the t cells crom the donor could eliminate the malignant monocytes in the patient,

Question 330

GvHD characteristics

Answer 330

- Transplanted immunocompetent T cells of donor respond against recipient - Acute (rare now => improved matching) - Chronic (main cause of death in BMT - Graft vs. tumour (leukaemia) - Prevention : • T cell depletion • Immunosuppressive drugs

Question 331

Immunodeficiency - gene therapy

Answer 331

- This is the transfer of defective genes into cells - Used in: Ø Used in patients that have ADA-SCID Ø X linked SCID => suspended: acute leukaemia in some patients because of insertion of retroviral vector into known oncogenes. Ø Development of self-inactivating lentiviral vectors, to reduce the risk of insertional mutagenesis (some success for ADA-SCID)

Question 332

Organ specific autoimmune diseases

Answer 332

- Graves disease • There is an immune response against the TSH receptors in thyroid, and the body makes antibody against TSH receptor • This antibody that is produced against the receptor will cause firing of the receptor • = Which leads to overproduction of thyroid hormones • Fibroblasts in the eye = low levels of the TSH receptor + cause inflammatory response in the eye - Graves opthalmopathy - Fibroblasts in the eye might express TSH which leads to inflammation Or T cell mediated disease - Type 1 diabetes • Antibodies are produced against the Insulin producing cells of the pancreas • T cells = kill the pancreatic beta cells

Question 333

HLA-B27 associated spondyloarthropathies

Answer 333

- HLA B27 = Molecule which is involved in the presentation of antibodies to T cells of the immune system, particularly cytotoxic cells - Ankylosing spondylitis in particular - which causes progressive curvature of the spine - Undifferentiated spondyloarthropathy - Reactive arthritis which can develop as a consequence of the infection - leading to swollen up legs - Psoriatic arthritis - Urethritis + Iritis - Spectrum of severity + HLA B27 association - Associated with bowel inflammation

Question 334

SLE - systemic autoimmune pathologies - systemic lupus erythematousus

Answer 334

- Multi system disease - does not just affect one organ - Characterised by autoantibodies to nuclear antigens, e.g. double stranded DNA - Relapse and remission : affects various cellular components - Lupus = wolf - Can get anti-nuclear antibodies as well

Question 335

What does SLE stand for?

Answer 335

- Systemic Lupus Erythematosus

Question 336

What is autoimmunity

Answer 336

- Body immune system targeting self proteins - Immune system has regulatory controls = prevent it from attacking self-proteins and cells - but this can fail - Failure of these controls result in immune attack of host components. Recognition of what is a threat and what can stay - Known as autoimmunity

Question 337

Definition of immune tolerance

Answer 337

- Immune system does not attack self- proteins or cells - it is tolerant to them.

Question 338

What is central tolerance?

Answer 338

- Deleting certain cell before they can even get in | - Destroy self-reactive T or B cells before they enter the circulation

Question 339

What is peripheral tolerance?

Answer 339

- Destroy or control any self reactive T or B cells, which do enter the circulation

Question 340

Describe the central tolerance of B cells

Answer 340

When an immature B cell is joint to a stromal cell ==> apoptosis Tregs are involved in both central and peripheral tolerance, because they can be generated from self, or foreign reactive T cells in the thymus during T cell differentiation Ø Can also exert immune suppression in the periphery on other self, or foreign reactive T cells

Question 341

T cells central tolerance

Answer 341

- Thymus = organ that T cells have to go through - More sophisticated than what the b cell does but a bit more specific - Recognises part of the protein or peptide, recognises it in the context of MHC molecule - MHC class 1 presents to CD8+ cells - T cells recognise antigens that are presented to them by MHC proteins - Groove in the circled molecule. Sees in the context of this groove.

Question 342

T cells recognition of foreign peptides

Answer 342

- TCRs are a complex of integral membrane proteins. Participate in the activation of T cells in response to an antigen Ø TCRs get triggered by MHC (major histocompatability complex) molecules, on the cells that are on the antigen. ○ Activated by various co-stimulatory receptors ○ CD28 for example provides costimulatory signal during T cell activation = augments production of Interleukin. Ø Engagement of the TCR will initiate positive / negative cascades = cellular proliferation, differentiation, cytokine production etc. - The T cells need to be able to recognise foreign peptides that are bound to self MHC - Recognition system in place - T cell receptor is stuck on the surface of the CD8 t cell and will bind the peptide - Is also bound to the MHC itself TCR = T cell receptor CD4+ molecule - CD4 binds to the side of the MHC molecule - = how T cell recognises antigens

Question 343

T Cell Receptor (TCR) & MHC binding

Answer 343

- T Cells Receptors (TCRs) ==> will recognise foreign antigens, and then they will convey this meesage to the nucleus ==> invoke a response. • Body makes lots of T cells • Each of these T cells will have specific TCRs on surface, and recombination of genes that encode these receptors before it has encountered complementary antigens - Need to be able to recognise the MHC molecule, but not too much • If binding is too strong then the T cell receptor will not need a peptide, which is how it becomes dangerous - Need to select for T cell receptors, which are going to be capable of binding self MHC - BUT - If binding to self MHC is not strong enough = may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove - If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove

Question 344

T cell selection in the thymus

Answer 344

- Is T cell selection in the thymus useless? - (is that T cell receptor useless) • Does not bind to any self MHC at all - if it doesn’t bind = Death by neglect (apoptosis) - Is T cell selection in the thymus dangerous? • Binds self MGC too strongly = dangerous, there is no need for a peptide in there • Apoptosis is triggered - negative selection - Is T cell selection in the thymus useful? • Binds to self MHC weakly • Signal to survive - positive selection

Question 345

Thymus T cells encountering peptides..

Answer 345

- Can engineer the TCR so that it binds really strongly to an antigen - But you will find that there are certain tissues that are expressing the antigen at a low level - which would not usually cause a problem but if it is binding at high affinity will then cause a problem - Have to therefore be cautious with altering T cell receptors How can a T cell that is developing in the thymus encounter MHC bearing peptides that are expressed in other parts of the body? Ø T cells have to be trained to do so Ø This can occur because a specialised transcription factor, allows thymic expression of the genes that are expressed in peripheral tissues ○ Thymus can express everypeptide that the body is liikely to express ○ This is calld the autoimmune regulator (AIRE )

Question 346

AIRE - Auto Immune Regulator (AIRE)

Answer 346

- Designed to protect against autoimmunity - This will promote self tolerance by allowing the thymic expression of genes from other tissues - Mutations in AIRE result in multi organ autoimmunity • (autoimmune Polyendocrinopathy Syndrome type 1) - Many of these different diseases can manifest if you get rid of this immune system

Question 347

describe The need for costimulatory signals

Answer 347

- TCR = transmembrane heterodimer which is composed of a and b chains - not enough on its own to produce a signal (because of the short cytoplasmic tails) - Antigen binding does not always mount immune response - TCR binds to self antigens at times and this elicits and immune tolerance - T cells have to get a second signal from an antigen presenting cell in the form of costimulatory molecule

Question 348

Peripheral tolerance

Answer 348

Body had processes in place to "tolerise" these things exiting the thymus - Anergy - Ignorance - Regulation

Question 349

describe Ignorance within peripheral tolerance

Answer 349

- Not getting to threshold of T cell activation - Antigen might be present in too low a concentration to reach the threshold for T cell receptor triggering - Immunologically privileged sites, e.g. the eye and the brain

Question 350

describe Anergy in peripheral tolerance

Answer 350

- This is the 2nd route. - T cells need lots of antigens to stimulate a response - need a very particular sequence to become activated - Naiive T cells need costimulatory signals, in order to become activated - Most cells lack costimulatory proteins and MHC class 2 - If a naiive T cell sees its MHC/Peptide ligand without appropriate costimulatory protein, it will become anergic • I.e. less likely to be stimulated in the future, even if costimulation is then present APC - e.g. macrophage etc - Once this has happened, get signals which will activate T cells - Without additional costimulatory signals = will become anergic and will remain inactive. - When there is innappropriate activation the cells will become annergic -

Question 351

Regulation of peripheral tolerance

Answer 351

- This is immunological tolerance that is developed after autoreactive T and B cells get more mature and enter the periphery • Suppression of the autoreactive cells, by regulatory T cells + the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the costimulatory signals that accompany inflammation / in the presence of co inhibitory signals - A subset of helper T cells, which are known as Treg (T regulatory cells) - Inhibit other T cells - Defective Treg have been observed in multiple sclerosis - T reg needs to be able to interact at this stage when just starting to get activated - In MS the Treg compartment does not work. - Peripheral tolerance is key to preventing over reactivity of the immune system to various environmental entities - therefore it is deficits in the peripheral or central tolerance which can cause autoimmune disease.

Question 352

Treg express transcription factor FOXP3

Answer 352

- Tregs express FOXP3 • FOX P3 = forkhead box P3 aka scurfin • Protein that is involved in immune responses • Acts as a master regulator, of the regulatory pathway in the actual development and the function of regulatory T cells ○ Regulatory T cells (Tregs), generally turn immune system down - Which is just a protein type - so can be mutated - Mutations in the FOXP3, leads to severe and fatal autoimmune disorder - Immune dysregulation • Polyendorcrinopathy • Enteropathy X linked (IPEX) syndrome - When mimicked in a mouse model = shows what happens when it is completely removed

Question 353

What happens with the T regulatory cells in cancer

Answer 353

- They can turn the immune system down - In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying the cancer cells - In autoimmune disease, not having enough T regulatory cells can allow other autoimmune cells to attack the bodys own tissues

Question 354

Central tolerance and peripheral T cell tolerance - Anergy

Answer 354

- Immunologic tolerance - this is failure to mount a full immune response against a target - Exposure to antigen - Without appropriate costimulatory signals

Question 355

Central tolerance and peripheral T cell tolerance - Ignorance

Answer 355

- State of unresponsiveness of the immune system, to substances/ tissue that have the capacity to produce an immune response - Immune privilege - Sequestered antigen

Question 356

Genetic + environmental factors - the major histocompatibility complex

Answer 356

- There are 3 MHC + 1, and 3 MHC +2 - 6 altogether and then potentially doubled because you get one from each parent, and they are highly polymorphic. - Each copy of chromosome 6 carried 3 different MHC class 1 and 3 different MHC class 2 genes - High levels of genetic variation (polymorphism) - MHC is associated with more disease than any other region of the genome

Question 357

MHC associations and autoimmunity

Answer 357

- Risk factors for certain autoimmune diseases - B27 + = 150XX more likely to get AS than a control - Certain HLA allotype lead immune diseases or not = the different molecules can present different peptides - There are grooves and then peptides in the middle - different types of MHC molecules have differing affinities depending on the peptides

Question 358

The genetics of autoimmunity - other genes

Answer 358

- There are different genes that are associated with diabetes that are not influenced by MHC.

Question 359

Environmental factors in autoimmunity

Answer 359

- SLE = 10x more common in females than males. MS is approximately 10X more common in females than males - Diabetes is equally common in females and males - Ankylosing spondylitis is approximately 3 times more common in males than females

Question 360

Examples of the immune mechanisms - what might trigger a breakdown of self-tolerance

Answer 360

- Loss of, or a problem with regulatory cells - Release of sequestered antigen - Modification of self - Molecular mimicry

Question 361

Modification of self - occurs with Citrullination

Answer 361

- Citrullin = amino acid, not coded for by DNA - Arginine can be converted to citrulline as post translational modification by peptidyarginine deiminase (PAID) enzymes Ø Citrulline appears to be increased in areas where there is inflammation - Citrullination = alteration of a changed protein. - Autoantibodies to citrullinated proteins seen in rheumatoid arthritis - Now used for clinical diagnosis - The enzyme PAD converts positively charged arginine residues to ==> neutral citrulline residues - Loss of surface charges, will make the protein more susceptible to proteotelytic degradation - Peptides with citrulline amino acid residues are presented by HLA class 2 to CD4 T cells Ø Patients that have rheumatoid arthritis often will have detectable antibodies against proteins that contain citrulline

Question 362

What is citrulin and what increases citrullination

Answer 362

- Citrullin = amino acid, not coded for by DNA - Arginine can be converted to citrulline as post translational modification by peptidyarginine deiminase (PAID) enzymes - Citrullination may be increased by inflammation

Question 363

Molecular mimicry - rheumatic fever

Answer 363

1. The streptococcal cell wall will stimulate Ab response 2. Some Abs will cross react with heart tissues, = this will cause rheumatic fever, because the antibodies that are in the blood will go into the heart. - Disease is triggered by infection with streptococcus pyogenes - Antibodies to strep cell wall antigens might cross react with cardiac muscle • Therefore cause damage to the heart

Question 364

Antibodies in autoimmune pathology example (1)- Graves Diseases

Answer 364

- Auto antibodies bind thyroid stimulating hormone (TSH) receptor, and stimulate it which results in hyperthyroidism - Disease which can be transferred with IgG antibodies

Question 365

Antibodies in autoimmune pathology - myastenia gravis

Answer 365

- Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind - Also lead to receptor internalisation and degradation - There are acetylcholine receptors which get internalised in myastenia gravis Ø This means that there will be no Na+ influx Ø Therefore no muscle contraction = muscle weakness - TSH receptor activating antibodies, which will then cross react with the human TSH receptor (this is called antigenic mimicry)

Question 366

What is antigenic mimicry?

Answer 366

- TSH receptor activating antibodies; will then cross react with human TSH receptor • Antigenic mimicry

Question 367

Antibodies in autoimmune pathology (3) - immune complexes in SLE and vasculitis

Answer 367

- Autoantibodies to soluble antigens form immune complexes - Deposited in tissue e.g. blood vessels, joints, renal glomerulus - Can lead to the activation of complement and phagocytic cells which will cause damage - Immune complexes depositing in kidney can lead to renal failure

Question 368

Autoimmune diseases mediated by IgG can be transferred across the placenta

Answer 368

- Mediated by antibodies therefore can go across the placenta => cause graves in the infant ○ Child might not have the same HLA haplotype. - Patient that has Graves - so will make anti TSHR antibodies There is then the transfer of antibodies across placenta into the fetus - Newborn infant will also suffer from Graves - Plasmapheresis will remove maternal anti TSHR antibodies and cures the disease

Question 369

T cells in autoimmune pathology

Answer 369

- T cells = killers of target cells. Activation of compartment degranulation of target tissues - There is direct killing by CD8+ CTL - Self destruction induced by cytokines, such as TNF alpha - Recruitment and activation of macrophages leading to bystander tissue destruction - Multiple sclerosis, and Insulin dependent diabetes mellitus

Question 370

Characteristics of TH17 cells

Answer 370

- TH17 cells, are helper T cells that produce Cytokine IL-17; which is very inflammatory - Implicated in autoimmune diseases, including: Ø Spondyloarthropathy Ø MS Ø Diabetes - Highly inflammatory - Produce cytokines which are involved in Ø Recruitment, migration and activation of immune cells

Question 371

Key points about autoimmune diseases

Answer 371

- There are different mechanisms of "tolerising" the immune system: Ø Central + peripheral tolerance mechanisms eliminate and control autoreactive T cells - Autoimmune diseases may be systemic or organ specific - The major histocompatibility complex is the most important genetic factor in autoimmune disease - Autoimmune mechanisms can act through Ø Antibody responses Ø T cell responses Ø (Or a combination of both)

Question 372

Immune response actions to the host

Answer 372

- Immune responses can cause harm to the host, when directed at non pathogenic antigens - There are 4 different types of hypersensitivity reactions + there are inflammatory mediators involved - Allergen specific IgE produced

Question 373

What is hypersensitivity

Answer 373

- Innappropriate immune response to non infectious antigens that results in tissue damage and disease

Question 374

What are the 4 types of hypersensitivity

Answer 374

1. Immediate hypersensitivity 2. Cytotoxic hypersensitivity (There is also a 5th type that goes within type 2) 3. Serum sickness + Arthus reaction 4. Delayed type hypersensitivity, contact dermatitis

Question 375

Describe the characteristics of Type 1 hypersensitivty - allergy

Answer 375

- Needs presence of immune reactant, like IgE, which will recognise soluble antigen - These will it on high affinity receptors - If receptors are cross linked = activation of the cell = degranulation and things released that will induce the allergic response - Effector mechanism = mast cell activation and also degranulation

Question 376

Describe what happens in immediate hypersensitity reaction

Answer 376

Ø Prick or inject into the skin - local inflammatory result and there is local oedema because of the exudation of fluid into the intracellularspaces Ø Inducing the response in a sensitised individual Ø Intradermal injection of antigen Ø Then immediate hypersensitivity reaction

Question 377

Examples of disease that are associated with Type 1 Hypersensitivity

Answer 377

Skin prick test = if you have white are (wheal) with flare around it = allergen in that area - Also infant eczema - Seasonal pollens = hypersensitivty in the upper mucosa which causes hayfever

Question 378

Characteristics of systemic anaphylaxis

Answer 378

- Activation of mast cells in the tissues - When this becomes systemic this can be life threatening = need to carry epipen around which is adrenaline inejection which can be immediately administered

Question 379

Describe how type 2 hypersensitivity reactions respond to altered components of human cells Cytotoxic hypersensitivity Ø Due to surface antigens Ø Which become subjects to immune response Ø This leads to killing of the red cells and haemolytic anaemia

Answer 379

Penicillin modified proteins on human erythrocytes to create foreign epitopes Cytotoxic hypersensitivity Ø Due to surface antigens Ø Which become subjects to immune response Ø This leads to killing of the red cells and haemolytic anaemia

Question 380

Type 2 - cytotoxic hypersensitivity characteristics

Answer 380

Special case of a type 2 response Ø Involves IgG antibodies, which are directed at cell surface receptors Ø These antibodies will disrupt the normal functions of the receptor by: 1. Uncontrollable activation 2. Blocking receptor function - People will mount immune response against penicillin, eg on the surface of red cell or a platelet. - Clearing of those drugs - if you have something like haemolytic anaemia or thrombocytopenia - Type 5 = 5 antibody mediated ○ Ab regnoised receptor either inhibiting or stimulating the receptor

Question 381

Examples of Type 2 hypersensitivity

Answer 381

1. Graves disease 2. Myasthenia gravis 3. Hemolytic disease of the newborn

Question 382

Graves Disease characteristics

Answer 382

- Relating to production of autoimmune antibody - Antibody stimulates receptor for thyroxine - Mimics TSH - Uncontrolled stimulation of the receptor

Question 383

Myasthenia gravis characteristics

Answer 383

- Production of Abs against own tissues Block receptor to which Ach binds, in the NMJ (post synaptic membrane) - causing paralysis

Question 384

Describe the characteristics of haemolytic disease of the newborn

Answer 384

1. During birth, there are Rh+ fetal erythrocytes that leak into maternal blood Ø After breakage of the embryonic chorion Ø Which normally isolates the fetal + maternal blood 2. Maternal B cells are activated by the Rh antigen and produce large amounts of anti-Rh antibodies 3. Rh antibody titer in mothers blood is elevated after 1st exposure 4. Rh antibodies are small enough to be able to cross the embryonic chorion Ø Able to attack the fetal erythrocytes - mopping up of these antigens is required RESUS ANTIGEN POSITIVE - They haevv D antigen on their red cells - If mothers have resus positive baby = mount immune response and get antigen

Question 385

Type 3 - serum sickness + arthrus reaction

Answer 385

- Specific IgG, binds to soluble antigen - IgG and soluble antigen form immune complexes - Immune complexes are cleared by phagocytes + complement - Lots of antigen injected into the body = or high levels of titres - Excess of one or the other = excess of immune complexes, lead to activation of complement and the macrophage system

Question 386

Describe Arthrus reaction following diptheria / tetanus vaccination

Answer 386

- High titres of antibodies against disease - When injecting the booster = strong reaction - Immune complexes that are deposited in the skin lead to activation

Question 387

Arthus reaction can be caused by a number of cells: describe its actions

Answer 387

- Activate mast cells in order to release inflammatory mediators - Inflammatory cells invade the site and blood vessel permeability and blood flow are increased - Platelets will also accumulate ○ This will lead to occlusion of the small blood vessels, haemorrhage, and the appearance of purpura - Antibodies can bind to mast cells = leading to local inflammation

Question 388

Serum sickness causes and characteristics

Answer 388

- This is caused by large intravenous doses of soluble antigens, e.g. drugs - IgG antibodies are produced from small immune complexes with the antigen in excess - Immune complexes are deposited in the tissues, e.g. blood vessel walls - Tissue damage is caused by complement activation and the subsequent inflammatory response - Inject large amounts of immunoglobulin into the circulation - develop immune complex diseases. At the second injection can develop cell response

Question 389

Describe serum sickness following antivenom

Answer 389

- Inject horse protein after snake bite = leading to local vasculitis

Question 390

Describe farmers lung

Answer 390

- Hay or grain dust in lung = farmers lung | - Development of immune complexes = internstitial luminitis

Question 391

What are the characteristics of hypersensitivity pneumonitis

Answer 391

- Dusts, bacteria and fungi - Farmers lung ==> thermophilic actinomycosis • Thermoophilic, likes heat so therefore can develop well in the airways - Pigeon breeders lungs ==> proteins derived from birds - Interstitial pneumonitis - Non caseating granulomas in 2/3rds of patients will occur in the lung - Interstitial fibrosis, honey combing & obliterative bronchiolitis - Intra alveloar infiltrate

Question 392

Describe the effects of antigen dose and route

Answer 392

- Antigen dose and route of delivery determine the pathology observed in type 3 hypersensitivity reactions - Arthus = local swelling - Inhaled = damage to the capillarty interface and alveolar

Question 393

Type 4 reactions - delayed type hypersensitivity characteristics

Answer 393

- Th1 immunity which are related to cytokines. If you have T helper cells that are trying to produced tuberculin = produce many of the above cytokines

Question 394

Type 4 reactions - delayed type hypersensitivity characteristics = Tuberculin reaction

Answer 394

- Ag specific, Th1 - Macrophage activation • IFN y • Chemokines, cytokines, cytotoxins - = tuberculin reaction

Question 395

Type 4 reactions - delayed type hypersensitivity characteristics = Allergic contact dermatitis

Answer 395

- Ag specific - Soluble antigen - IL-4, IL-5, Eotaxin - Eosinophil activation - Basic proteins, enzymes and cytokines - = allergic contact dermatitis

Question 396

Describe the time course of delayed (Type 4) hypersensitivity

Answer 396

1. Antigen is injected into the subcutaenous tissue and then processed by local antigen presenting cells 2. A TH1 effector cell will recognise antigen and release cytokines that act on vascular endothelium 3. Recruitment of phagocytes and plasma to the site of antigen injection will cause visible lesion - Time course = after injecting the antigen into the skin; present them to TH1 cells and there is a tuberculin reaction

Question 397

Mantoux test - describe

Answer 397

- Intra dermal injection of tuber culin and then after a2-3 days will measure the size of the reaction

Question 398

Example - characteristics of contact dermatitis

Answer 398

- Exposure to something allergic to on shoes or watch = leading to this local delayed response, which could be either TH1 or TH2 - Lepsory = hyperpigmented centre

Question 399

Example of type 4 Hypersensitivity = poison ivy

Answer 399

- Eversion = exposure to poison ivy - Leads to sensitisation if exposed - Related to cytolytic action of T cells - Killing cells in tissues

Question 400

Production of allergen specific IgE : in Type 1, allergy

Answer 400

- This is defined as disease, following a response by the immune system to an otherwise innocuous antigen - About 40% population in Europe have allergies to 1+ common environmental allergens

Question 401

What are the characteristics of IgE

Answer 401

- First line of defence against "worms" - Binds FcεR1 receptor on mast cells - Pre-arms the mast cells to react when in the presence of an antigen - Ig will bind to this high affinity receptor (FcεR1 ) - This leads to production of the cytokines which is important when inducing B cells

Question 402

Allergen specifc IgE production - the simple model

Answer 402

Ø Exposure to allergen = immune response Ø Prime B cells produce IgE First exposure to pollen ==> IL4 drives B cells to produce IgE in response to pollen antigens ==> pollen specific IgE binds to mast cell

Question 403

Describe the process of allergen specific IgE production

Answer 403

- What causes allergic sensitisation - Exposure to the allergen is critical; which includes: Ø Nature of allergen - Ø Dosage of allergen (high or low) Ø Timing Ø Location of priming - Role of pro allergic dendritic cells + cytokines - induce allergic response - Genetic predisposition to allergy

Question 404

Allergy and environment - being exposed to dirt

Answer 404

- Could potentially be good to be exposed to lots of dirt : which is why it may be so much more prevalent in "cleaner" countries

Question 405

What is the hygiene hypothesis

Answer 405

- Effect of birth order and sibship size on hay fever and atopy • Older siblings bringing back infection and bacteria home = more mature immune response which makes someone less susceptible to getting diseases - Reduced prevalence of atopy asthma and hay fever among children living on farms • Protection due to exposure to a wide variety of microbes • Makes immune response more regulatory

Question 406

Characteristics of filaggrin and atopic dermatitis

Answer 406

- Filaggrin links skin integrity with allergy - When it is defective, atopic dermatitis is greater - This is due to the access for allergens - Key for keeping normal skin barrier function

Question 407

What happens when fillagrin is defective

Answer 407

- When it is defective, atoptic dermatitis is greater | - This is due to the access for allergens

Question 408

What makes dendritic cell pro-allergic

Answer 408

- Not known. But one candidate protein is TSLP - This might switch DC to a pro allergic state - What presents the antigen to the T cell = key - The damage to the barrier like the skin allergens can get through and picked up by cells in the skin - In presence of TSLP, may make those dendritic cells more likely to prime for an allergic response Ø Injury of normal skill will induce cytokine production Ø It is the keratinocytes what will produces cytokines Ø Maturation and migration of the Langerhans and dendritic cells to lymph node • Antigen presentation results in Th2 dominanted immune response

Question 409

What does TSLP stand for

Answer 409

Thymic Stromal Lypho Poietin

Question 410

Effector mechanisms of the allergic immune response

Answer 410

- Primed for allergic response when exposed to an allergen like pollen - TH2 cytokines 1. 1st exposure to pollen 2. IL4 will drive the B cells to produce IgE, in response to pollen antigens 3. Pollen specific IgE binds to mast cells 4. Pollen specific IgE binds to the mast cell 5. On second exposure to pollen 6. There is acute release of mast cell contents; which will cause allergic rhinitis (hay fever)

Question 411

Describe the process of mast cell activation

Answer 411

- Bound IgE is allergen specific - Specific allergen crosslinks IgE Ø The resting mast cell contains granules containing histamine and other inflammatory mediators Ø Multivalent antigen will cross link the bound IgE antibody, which causes release of granule contents Ø Specific = ONLY that allergen can cause cross linking

Question 412

Describe what happens in the immune response to allergens

Answer 412

1. Primary allergen response Ø Allergen presented by APC, like dendritic cells Ø Secondary exposure = high allergic response. Late phase response when secondary

Question 413

Acute allergic reaction

Answer 413

- Wheezing - Urticaria - Sneezing + rhinorrhea - Conjunctivitis

Question 414

Chronic allergic reaction

Answer 414

- Further wheezing - Sustained blockage of the nose - Eczema

Question 415

Effector mediators produced by the mast cells - Histamine role

Answer 415

- Increase vascular permeability | - Can cause smooth muscle contraction

Question 416

Effector mediators produced by the mast cells - Leukotriene role

Answer 416

- Increase vascular permeability - Cause smooth muscle contraction - Stimulates mucus secretion

Question 417

Effector mediators produced by the mast cells - Prostaglandin role

Answer 417

- Chemoattractant for • T cells • Eosinophils • Basophils

Question 418

Describe the process of mast cell activation

Answer 418

- Mast cell activation can cause different effects on different tissues - GI tract = increased peristalsis and fluid secretion ( Evolutonary = expelling intestinal worm infections etc. )

Question 419

Characteristics of eosinophils

Answer 419

- Located in the tissues - Recruited into the sites of allergic reactions - Express FceRI upon activation ==> leads to cascade of recruitment of other types - Attracted to the sites of allergic inflammation

Question 420

What are the 2 effector functions of eosinophils

Answer 420

1. Release of highly toxic granule proteins | 2. Synthesise and release of prostaglandins

Question 421

Effector function of eosinophil 1. Release of highly toxic granule proteins

Answer 421

Ø And also free radicals Ø Upon activation, to kill microorganisms / parasites Ø And cause tissue damage in allergic reaction

Question 422

Effector function of eosinophil 2. Synthesise and release of prostaglandins

Answer 422

Ø Also leukotrienes and cytokines Ø In order to amplify the inflammatory response Ø By activation of epithelial cells and recruiting leukocytes

Question 423

Describe the late phase of the IgE mediated allergic response

Answer 423

- Late phase reaction is dependent on the allergen dose - Continued synthesis and release of inflammatory mediators - Chronic allergic inflammation caused by the Th2 cells • i.e. Type IV hypersensitivity reaction

Question 424

CD4 T Cells

Answer 424

- The 2nd phase of allergic responses are T cell mediated - Mostly consisting of allergen specific Th2 cells - These cells recruit other cells by cytokine release - Potentiate further responses - Allergen specific TH2 cells = amplifies response • Late allergic response • Further wheezing, sustained nasal blockage, eczema

Question 425

Summary of how allergy develops

Answer 425

- There is a key difference between sensitisation to an allergen, and an actual reaction to an allergen - Individuals must be sensitised to an allergen before they are able to react - Sensitisation requires the presentation of allergen to T cells by DC, and the priming of Cognate B cells to produce IgE - The reaction to allergen will occur when the individual is re exposed to allergen and it binds preformed to IgE on mast cells

Question 426

Characteristics of allergic asthma : what is asthma

Answer 426

- A state of irreversible bronchial hyper reactivity - Resulting from a persistent inflammatory process in response to a number of stimuli, in a genetically susceptible individual - Atopic and non atopic • Non atopic causes: occupational, exercise induced, nocturnal asthma, post bronchiolitic wheeze (e.g. expsure to rhinovirus = major cause of worsening asthma in children )

Question 427

What happens in an episode of allergic asthma

Answer 427

- Episodes of wheezy breathing + also narrowing of the airways - Rapid changes in airway obstruction - (reaction times and severity vary) ○ Slight wheeziness to asthma attack

Question 428

What are the common allergens that cause asthma

Answer 428

- Pollen, HDM, Plants, Some foods (e.g. peanuts)

Question 429

Acute response in allergic asthma

Answer 429

- Acute response - This will occur within seconds of allergen exposure - Results in the airways being obstructed and difficulties breathing - Caused by allergen induced mast cell degranulation in the submucosa of the airways - Inflammatory mediators will cause increased mucus secretion and smooth muscle contraction - This leads to airway obstruction - There is then recruitment of cells from the circulation

Question 430

Describe the chronic response to allergic asthma

Answer 430

- Chronic response is produced by cytokines, and also eosinophil products - Chronic inflammation of the airways - Caused by activation of eosinophils, neutrophils, T cells and other leukocytes - Mediators that are released by these cells will cause airway remodelling, permanent narrowing of the airways, and further tissue damage

Question 431

Airway obstruction in chronic asthma

Answer 431

- Smooth muscle contracts, there is also excess mucus, and the lumen will therefore have a reduced diameter

Question 432

Allergic asthma characteristics

Answer 432

- Chronic inflammation in airways of asthmatic patient 1. The bronchus in which the airway is completely obstructed by mucus 2. Bronchial wall injury, with dense inflammatory cell infiltrate

Question 433

Describe treatment of allergy in the clinic

Answer 433

Ø Blockage of effector pathways 1. Inhibits the effects of mediators on specific receptors Ø Anti histamine, which blocks the histamine H1receptors = this is quite traditonal 2. Inhibits mast cell degranulation Ø Non steroidal, anti inflammatory (e.g. chromoglycate) 3. Inhibits synthesis of specific mediators Ø Lipoxygenase inhibitors and also prostaglandings

Question 434

Steroid action = most effective treatment for asthma.

Answer 434

- Act directly on DNA - To increase the transcription of anti inflammatory mediators such as (IL-10) - And decrease transcription of pro inflammatory mediators - Bronchodilators = open up the airways

Question 435

Action of bronchodilators

Answer 435

- Reverse the acute effect of allergy on airways

Question 436

Action of immunotherapy

Answer 436

- Reverses the sensitisation to allergen by means of tolerising exposure

Question 437

Summary of allergy

Answer 437

- Allergy = inappropriate response to an otherwise benign antigen - There are 2 important phases 1. Sensitisation Ø This is when the allergen is presented by DC to TH2 CD4 T cell and B cells 2. Reaction Ø IgE on mast cells cross linked Ø By cognate antigen Ø This leads to inflammation - Simple model that it is a Th2 disease