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MEH Flashcards

1
Q

How much of the consumed alcohol is metabolised by the liver and of the amount that isn’t where does it go?

A

> 90% liver

10% passively in urine and on breath

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2
Q

What enzyme breaks down alcohol?

A

Alcohol dehydrogenase to acetaldehyde

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3
Q

What enzymes breaks down acetaldehyde?

A

Aldehyde dehydrogenase to acetate

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4
Q

What is acetate made into from alcohol?

A

Combines with Acetyl-CoA and used in the TCA cycle or for fatty acid synthesis

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5
Q

What enzymes apart from alcohol dehydrogenase break down alcohol?

A

CYP2E1 liver

Catalase in brain

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6
Q

How much is 1 unit of alcohol?

A

10ml of pure alcohol = 8grams

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7
Q

What is the elimination rate of alcohol?

A

7grams/hours

Constant rate of elimination

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8
Q

Production of what enzymes causes the hangover feeling?

A

Acetaldehyde

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9
Q

Why do people who drink alcohol need to urinate more frequently?

A

Ethanol inhibits ADH release -> increase water loss -> increase urinary frequency

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10
Q

Excess of what 2 substances makes the liver undergo negative changes in alcohol excess?

A

NADH and Acteyl-CoA

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11
Q

What are the 4 main end point of alcohol oxidation?

A

Lactic acidosis
Urate crystals accumulate in tissues -> gout
Hypoglycaemia
Fatty liver

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12
Q

Why do people get lactic acidosis in alcohol metabolism?

A

Decrease NAD+/NADH ratio -> Inadequate NAD+ conversion of lactate to pyruvate -> lactate accumulates in blood -> lactic acidosis

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13
Q

Why do people get Urate crystals accumulate in tissues -> gout?

A

Decrease NAD+/NADH ratio -> Inadequate NAD+ conversion of lactate to pyruvate -> lactate accumulates in blood -> kidneys ability to excrete uric acid reduced -> Urate crystals form -> gout

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14
Q

Why do people get hypoglycaemia in alcohol metabolism?

A

Decrease NAD+/NADH ratio -> (1) inadequate NAD+ for glycerol metabolism -> deficit in gluconeogenesis -> hypoglycaemia
(2) Inadequate NAD+ conversion of lactate to pyruvate -> deficit in gluconeogenesis -> hypoglycaemia

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15
Q

Why do people get a fatty liver when they consume alcohol?

A

(1) Increased acetyl-CoA -> increased synthesis of fatty acids and ketone bodies -> increase synthesis of triacylglycerol -> fatty liver
(2) Decrease NAD+/NADH ratio -> Inadequate NAD+ for fatty acid oxidation -> increased synthesis of triacylglycerol -> fatty liver
(3) Lower lipoprotein synthesis -> fatty liver

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16
Q

What drug could be used in alcohol dependence to help them avoid using it?

A

Disulfiram -> blocks aldehyde dehydrogenase -> build up of acetaldehyde -> hangover symptoms -> unpleasant feeling prevent drinking

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17
Q

What are the two main groups of reactive species that cause oxidative damage?

A

ROS

RNS

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18
Q

What are the reactive oxygen species and how do they form?

A

Oxygen -> O2. [superoxide] -{2H+, e-}-> H2O2 [hydrogen peroxide] -{e-, H+}-> H20 + OH. [hydroxyl radical]
OH. -{H+, e-}-> H2O

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19
Q

What are the reactive nitrogen species and how are they formed?

A

NO. + [superoxide] O2.-> NOOO. [peroxynitrite]

peroxynitrite is not a free radical but powerful oxidant

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20
Q

How do ROS react inside cells to cause damage to DNA?

A

ROS reacts with base -> modified base -> mispairing and mutation
ROS reacts with sugar (ribose/deoxyribose) -> strand break and mutation on repair

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21
Q

How does ROS damage proteins?

A

Back bone affected -> fragmentation -> protein degradation
Side chain affected -> modified amino acids -> change in protein structure -> (1) protein degradation (2) loss of function-> protein degradation (3) gain of function

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22
Q

How do ROS damage lipids?

A

Free radical (OH.) extracts hydrogen from polyunsaturated FA in membrane lipid -> forms lipid radical -> reacts with oxygen -> lipid peroxyl radical -> chain reaction of gaining of hydrogen from neighbouring FA -> hydrophobic layer disrupted and integrity

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23
Q

What are some endogenous sources of biological oxidants?

A

Electron transport chain
Nitric oxide synthases
NADPH oxidases

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24
Q

What are the 3 types of nitric oxide produced due to nitric oxide synthase?

A

iNOS - inducible - produces high [NO] -> phagocytes for direct toxic effect
eNOS- endothelial
nNOS- neuronal

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25
Q

What amino acid is used to produce Nitric oxide and what is the resultant amino acid?

A

Arginine used

Citrulline produced

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26
Q

What is the respiratory burst?

A
  • Rapid release of superoxide (O2.) from phagocytic cells -> H2O2 -{Cl- + myeloperoxidase}-> HOCl (hypochlorite)
  • O2. + NO. -> ONOO.
  • ROS and peroxynitrite destroy invading bacteria
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27
Q

What enzymes are cellular defences to oxygen free radicals?

A

Superoxide dismutase and catalase

Glutathione

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28
Q

How does superoxide dismutase work to reduce free radicals?

A 
Converts superoxide (O2.) to H2O2 and oxygen
Primary defence as superoxide is strong initiator of chain reactions
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29
Q

How does catalase work to reduce free radicals?

A

Converts H2O2 to water and oxygen

Declining levels in hair follicles -> explains grey hair

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30
Q

How does glutathione work against free radicals?

A

Glutathione has a thiol (-SH) group - reduced form
2Glutathione (GSH) + H2O2 -{glutathione peroxide}-> GSSG + 2H20
GSSG - oxidised form
Requires NADPH to donate Hydrogen to Sulphur -> GSSG-{glutathione reductase}-> 2GSH

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31
Q

What is the pentose phosphate pathway?

A

Glucose-6-phosphate -{+NADP + glucose-6-phosphate dehydrogenase}-> {NADPH} + 6-phosphogluconate -{+NADP}-> {NADPH}->Ribulose-5-phosphate + {CO2} -> Ribose-5-phosphate

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32
Q

Why is the pentose phosphate pathway important in oxidative stress?

A

Source of NADPH which is a reducing agent for glutathione

Produces C5-sugar= Nucleotides and DNA/RNA

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33
Q

What function does Vitamin E and C have in oxidate stress?

A

Vit E is a lipid soluble antioxidant that acts against lipid peroxidation
Vit C water soluble -> regeneration of Vit E

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34
Q

What is a potential complication of dietary lactose and an increased activity of aldose reductase?

A

Lactose -> glucose + galactose
Galactose -{NADPH + aldose reductase}-> Galactitol -> osmotic pressure effect in the eye -> cataracts (crystalline protein in lens of eye denatured)

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35
Q

Deficiency in which enzymes can lead to galactosaemia and cataracts?

A

Galactokinase
Uridyl transferase
UDP-galactose epimerase

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36
Q

What is the function of galactokinase in preventing galactosaemia?

A

Galactose -{galactokinase}-> Galactose-1-P -{uridyl transferase}-> Glucose-1P -> Glucose-6P -> glycolysis

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37
Q

What is the function of uridyl transferase in preventing galactosaemia?

A

(1) Galactose -{galactokinase}-> Galactose-1-P
(2) Galactose-1-P -{uridyl transferase}-> Glucose-1P ->
(3) Glu-1-P -{phosphoglucomutase}-> Glucose-6P -> glycolysis

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38
Q

What is the function of UDP-galactose epimerase in preventing galactosaemia?

A

(1) Galactose -> Galactose-1P UDP-galactose UDP-glucose-> glycogenesis
Allows the reaction to move forward to produce glycogen rather than stay as galactose and end up producing galactitol

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39
Q

What are symptoms of galactosaemia?

A 
Hepatomegaly+ cirrhosis 
Renal failure
Vomiting
Seizure + brain damage
Cataracts
Hypoglycaemia
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40
Q

What is a G6PD deficiency and why does it cause problems?

A

Pentose phosphate pathway
Glucose -6-P + NADP -{G6PD}-> 6-Phosphogluconate + NADPH

G6PD deficiency -> process occurs less often
If oxidative stress increases -> NADPH used up to replenish GSSG -> but less G6PD less NADPH -> less NADP -> less GSH -> less ability to fight oxidative damage

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41
Q

What occurs in RBC in G6PD deficiency in case of oxidative stress?

A

Increased oxidative stress -> more O2 free radicals -> Protein damage -> aggregates of cross-linked Hb -> Heinz bodies (precipitated Hb)-> haemolysis

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42
Q

What can precipitate haemolysis in G6PD deficiency patients?

A

Infection
Drugs e.g. anti-malarials
Broad beans

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43
Q

What is the function of acetylcysteine treatment in paracetamol poisoning?

A
  • Paracetamol -> NAPQI (toxic) -> oxidative damage
  • NAPQI levels reduced by glutathione -> significantly reduced oxidative damage
  • Glutathione levels replenished by precursor acetylcysteine -> levels of glutathione raised -> reduced oxidative damage
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44
Q

What are the major nitrogen containing compounds found in the body?

A

Amino acids
Proteins
Purines + pyrimidines (DNA/RNA)

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45
Q

What is nitrogen balance?

A

In equilibrium - intake=output
Positive balance - Intake > output
Negative balance - Intake < output

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46
Q

What states are in a positive nitrogen balance?

A

Normal state in growth
Pregnancy
Adults recovering from malnutrition

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47
Q

What states are in a negative nitrogen balance?

A

Net loss of body protein
Trauma
Infection
Malnutrition

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48
Q

How much nitrogen is required for intake?

A

16grams approx in the form of amino acids/ proteins

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49
Q

How is nitrogen used in the body in simple terms?

A

De novo amino acid synthesis
Glucogenic amino acids and ketogenic amino acids -> gluconeogenesis and ketone bodies -> energy
Amino group -> urea -> urine loss

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50
Q

Name one glucogenic, ketogenic and a combined glucogenic/ketogenic amino acid

A

Glucogenic - Aspartate
Ketogenic - Leucine
Both- tyrosine, threonine

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51
Q

What is the mnemonic for the essential amino acids and what are they

A 
PVT TIM HALL
Phenyalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Alanine
Leucine
Lysine
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52
Q

In what two states would affect protein mobilisation and what hormones are involved?

A

-Insulin + growth hormone - protein synthesis predominantly

Glucocorticoids (cortisol) - protein degradation predominantly

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53
Q

What are the two main pathways of removal of nitrogen from amino acids?

A

Transamination

Deamination

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54
Q

What is the process of transamination?

A
  • Amino acid 1+ keto acid (alpha-ketoglutarate) -> amino acid 2 + keto acid
  • R group of the amino acid 1 moves over to the keto acid
  • Enzymes used - aminotransferases
  • Aspartate aminotransferase uses oxaloacetate as the keto acid to produce aspartate as the amino acid exiting
  • All enzymes require pyridoxal phosphate - derivative of vit B6
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55
Q

What are the ALT and AST enzymes in relation to amino acid conversion?

A 
ALT= alanine aminotransferase - converts alanine to glutamate
AST= aspartate aminotransferase - converts glutamate to aspartate
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56
Q

What is the process of deamination?

A

Liberation of free ammonia
Occurs in liver and kidney
Keto acids used for energy
D-amino acids = metabolised by this method
Ammonia (ammonium ions) toxic and removed by conversion to urea -> urine removal

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57
Q

What is urea and how is it excreted?

A

Water soluble non-toxic source of nitrogen
Bacteria break it down to release NH3
Most excreted via kidneys and performs a useful osmotic role in kidney tubules

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58
Q

What is the urea cycle?

A

Glutamate -> aspartate -> Argininosuccinate -> arginine -> urea
Aspartate produces argininosuccinate by addition of citrulline from mitochondria
Occurs in liver
High protein diet induces enzymes and visa versa

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59
Q

What substance causes the N+V, delirium problems seen in refeeding syndrome?

A

Ammonia toxicity

Avoided by gradual increase in protein ingested - waiting for enzymes to upregulate

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60
Q

What are symptoms of urea toxicity?

A

Vomiting, lethargy, irritability, mental retardation, seizures, coma

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61
Q

How do you manage hyperuraemia in the long term?

A

low protein diet

replace amino acids with keto acids

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62
Q

What two transport mechanisms are there for handling nitrogen from Amino acids?

A

Tissues = Glutamate + ammonia -> glutamine (blood)-> kidneys/liver. Liver-> urea cycle. Kidneys -> urine excretion.

Tissues = Glutamate (transamination process) + pyruvate -> alanine (blood) -> liver -> transamination -> pyruvate -> glucose -> blood/ krebs

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63
Q

What is phenylketonuria?

A

Deficiency in phenylalanine hydroxylase
Accumulation of phenylalanine in tissue, plasma, urine
Phenylketones in urine - musty smell
Avoid artificial sweeteners, high protein foods, strict avoidance, enriched food with tyrosine

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64
Q

What is homocystinuria?

A

Problem breaking down methionine -> homocysteine -{this step}> cystathionine.
Excess homocysteine excreted in urine
Defect in cystathionine beta-synthase
Avoid methionine, high protein diet but supplement with B12,B6, cysteine, folate, betaine

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65
Q

What 4 tissues have an absolute requirement for glucose?

A

RBC
Neutrophils
Innermost cells of kidney medulla
Lens of the eye

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66
Q

At what blood glucose level would be enough to cause brain damage and death?

A

<0.6mmol/L

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67
Q

At what blood glucose level would be enough to cause confusion?

A

2.8mmol/L

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68
Q

What enzyme is responsible for converting glucose to glycogen?

A

Glycogen synthase

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69
Q

What is the difference between the storage of glycogen in muscles compared to liver?

A

Muscle - between intra and intermyofibrillar glycogen is stored
Hepatocyte - glycogen granules

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70
Q

What are the two types of bonds between glucose molecules that hold it in place within glycogen?

A

1-4, and 1,6 glycosidic bonds

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71
Q

What is the glycogenesis process?

A

(1) Glucose + ATP -{hexokinase}-> Glucose-6-phosphate + ADP
(2) Glucose-6-phosphate Glucose-1-phosphate
(3) Glucose-1-phosphate + UTP + H2O -{G1P uridyltransferase}-> UDP-glucose + Pyrophosphate
(4) Glycogen + UDP-glucose -{glycogen synthase or branching enzyme}-> Glycogen + UDP

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72
Q

What are the steps of glycogenolysis?

A

Glycogen + Pi -{glycogen phosphorylase or de-branching enzyme}-> G1P + glycogen

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73
Q

What is the difference between the stores of glycogen in muscles and the liver, in terms of amount and why?

A

Liver - 100grams stored, for blood glucose levels, has glucose-6-phosphatase
Muscle - 300grams - for muscle cells use only - lacks glucose-6-phosphatase which would allow it to release glucose to the blood but instead sends it to go into glycolysis

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74
Q

What effect does insulin have on the enzymes that convert glucose to glucose-6-phosphate?

A

Insulin induces glucokinase but not hexokinase
Glucokinase found in liver only
Hexokinase found in most cells
Hexokinase inhibited by G-6-P but not glucokinase

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75
Q

Do muscles have a glucagon receptor and why?

A

No
Glucagon is a signal to release glucose into the blood stream. Muscles only have glycogen stored in them for their own use and not to maintain plasma levels hence no need for a glucagon receptor

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76
Q

What benefit would it be to have AMP an allosteric activator of muscle glycogen phosphorylase?

A

AMP - low energy signal ->activate glycogen phosphorylase -> glycogenolysis -> glucose released into cells -> glycolysis -> ATP production

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77
Q

What affect does glucagon have on the glycogen enzymes that maintain blood glucose?

A

Glycogen synthase - inhibited by phosphorylation

Glycogen phosphorylase - activated - inhibited by phosphorylation

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78
Q

What affect does insulin have on the glycogen enzymes that maintain blood glucose?

A

Glycogen synthase - activated - dephosphorylation

Glycogen phorphorylase - inhibited - dephosphorylation

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79
Q

What is a glycogen storage disease?

A

Deficiency or dysfunction of enzymes of glycogen metabolism
Liver and/muscle affected
Excess glycogen storage can lead to tissue damage
Diminished glycogen stores can lead to hypoglycaemia and poor exercise tolerance

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80
Q

Name 2 glycogen storage diseases and what enzyme is affected

A

von Gierke’s disease - glucose-6-phosphatase deficiency - G6P conversion to glucose deficient
McArdle disease - muscle glycogen phosphorylase deficiency - Glycogen conversion to glucose-1-phosphate
Both lead to less glucose being produced

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81
Q

Where does gluconeogenesis occur?

A

Liver

Lesser extent in kidney cortex

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82
Q

What are 3 main precursors to gluconeogenesis?

A

Lactate
Glycerol
Amino acids

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83
Q

What is the Cori Cycle?

A

Lactate produced in the muscles -> blood -> liver -> 2xlactate -> glucose -> blood -> muscles

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84
Q

What are the 3 control enzymes in gluconeogenesis from pyruvate?

A

1 - phosphoenolpyruvate carboxykinase
2 - fructose 1,6,-bisphosphatase (opposite of phosphofructokinase)
3 - glucose-6-phosphatase (opposite of hexokinase)

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85
Q

Is gluconeogenesis just a reversal of glycolysis/ Krebs?

A

No

The pathway goes backwards but from pyruvate-> oxaloacetate in Krebs -> phosphoenolpyruvate -> back to glucose

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86
Q

What activities release hormones that regulate the enzymes for gluconeogenesis?

A

Starvation - glucagon
Prolonged exercise - insulin
Stress - cortisol

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87
Q

What 2 enzymes of gluconeogenesis are regulated by hormones in response to starvation?

A

fructose 1,6-bisphophatase

Phosphoenolpyruvate carboxykinase

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88
Q

What happens to fructose 1,6-bisphophatase and

phosphoenolpyruvate carboxykinase when glucagon and cortisol are released?

A

fructose 1,6-bisphophatase - increased amount and activity

Phosphoenolpyruvate carboxykinase - increased amount

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89
Q

What happens to fructose 1,6-bisphophatase and

phosphoenolpyruvate carboxykinase when insulin is released?

A

fructose 1,6-bisphophatase - decreased amount and activity

phosphoenolpyruvate carboxykinase - decreased amount

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90
Q

How many hours after consuming a meal does glycogenolysis and gluconeogenesis occur?

A

Glycogenolysis - from 2 hours after eating till 8-10 hours after eating.
Gluconeogenesis - from 8-10 hours onwards

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91
Q

During which processes are lipids/ triacylglycerol used?

A

Prolonged exercise, stress, starvation, during pregnancy

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92
Q

Where does lipogenesis occur mainly in the body?

A

Liver

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93
Q

How is glucose converted to fatty acids?

A

Glucose -> pyruvate -> mitochondrion -> acetyl-CoA + oxaloacetate (OAA) -> citrate -> cytoplasm -> Acetyl-CoA + OAA -> acetyl-CoA carboxylase produces malonyl-CoA -> FA synthase complex + malonyl-CoA -> FA

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94
Q

Where in the cell does FA oxidation and FA synthesis occur?

A

FA oxidation = mitochondria

FA synthesis = cytoplasm

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95
Q

How does insulin and glucagon and adrenaline affect FA oxidation and synthesis?

A

Insulin - FA synthesis = stimulation, FA oxidation = inhibits
Glucagon/ adrenaline - FA synthesis =inhibits, FA oxidation = stimulates

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96
Q

What is the enzyme that is activated by glucagon and adrenaline that leads to the break down of TAG?

A

Hormone sensitive lipase

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97
Q

What tissues can not use fatty acids?

A

RBC
Brain
CNS

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98
Q

What is the main enzyme regulator of glycolysis?

A

Phosphofructokinase

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99
Q

What glucose transporter does insulin promote the translocation of?

A

GLUT4

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100
Q

How are lipids transported around the body?

A

~2% bound to albumin

~98% lipoprotein particles

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101
Q

What are the 2 apolipoprotein groups?

A

Integral - e.g. ApoA and ApoB

Peripheral - e.g. ApoC and ApoE

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102
Q

What are the 5 distinct classes of lipoproteins?

A 
Chylomicrons
VLDL
IDL
LDL
HDL
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103
Q

Of the lipoprotein classes which carry fats and which carry cholesterol esters?

A

Chylomicrons and VLDL - fats

IDL,LDL,HDL - cholesterol esters

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104
Q

How many hours after a meal are chylomicrons still be found in blood?

A

4-6hours

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105
Q

How many classes of apolipoproteins are there and which ones are they?

A

6 classes

A,B,C,D,E and H

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106
Q

What lipoproteins are apoB associated with?

A

VLDL, IDL, LDL

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107
Q

What lipoproteins are apoA1 associated with?

A

HDL

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108
Q

What are the functions of apolipoproteins?

A

Structural - packaging water insoluble lipid

Functional - co-factor for enzymes, ligands for cell surface receptors

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109
Q

What apolipoprotein is added to chylomicrons before entering lymphatic system?

A

ApoB-48

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110
Q

What apoliproproteins are added to chylomicrons when they are in the blood from the thoracic duct into left subclavian?

A

apoC and poE

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111
Q

What is the function of apoC on the chylomicrons?

A

ApoC binds lipoprotein lipase on adipocytes and muscle

Releases FA depleting chylomicron of its FAT content

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112
Q

When does apoC dissociate from a chylomicron?

A

When triglyceride reduced to 20%, apoC dissociates and chylomicron becomes a chylomicron remnant

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113
Q

What happens to a chylomicron remnant?

A

Returns to liver
LDL receptor on hepatocytes binds poE and chylomicron remnant take up by receptor mediated endocytosis
Lysosymes release remaining contents for use in metabolism

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114
Q

What is the purpose of a VLDL?

A

VLDL made in liver for transporting TAG to other tissues

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115
Q

How do you remember what apoC and apoE are for?

A

ApoC- Cleaves = binding to LPL to release FA

ApoE - hepatic Emptying = release to the liver

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116
Q

What apolipoprotein is added to VLDL’s during formation in the hepatocyte?

A

ApoB100

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117
Q

What apolipoproteins are added to VLDL’s during their transit in the blood?

A

From HDL’s

Obtain ApoC and ApoE

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118
Q

How are IDL and LDL formed?

A

VLDL-> IDL->LDL
[TAG] in VLDL reduces -> VLDL particles dissociate from LPL enzyme complex -> go to liver
VLDL depletes to 30% -> short lived IDL -> taken up by liver or rebind with LPL to further deplete TAG
Upon depletion to 10% IDL loses apoC and apoE -> LDL particle (high cholesterol content)

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119
Q

What is the primary function of LDL?

A

Provide cholesterol from liver to peripheral tissues

Peripheral LDL receptors take up LDL as receptor mediated endocytosis

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120
Q

Why are LDL’s in the blood for a long period of time?

A

They lack apoC and apoE which is used by the liver to remove the particles from the circulation therefore aren’t removed from the circulation

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121
Q

How are LDL’s and oxidative stress connected?

A

LDL’s have a long half life -> more likely to get oxidative damage
Oxidised LDL taken up by macrophages -> foam cells -> atherosclerotic plaques formed

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122
Q

What is the function of apoB-100 and what is the result of the interaction?

A

cells requiring cholesterol express LDL receptor
ApoB-100 on LDL is a ligand
Receptor/LDL taken up by receptor mediated endocytosis into endoscopes
Fuse with lysosomes for digestion to release cholesterol and fatty acids
LDL-R expression controlled by cholesterol conc in cells

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123
Q

What are 3 methods by which HDL’s are synthesised?

A

(1) (Empty) Nascent-HDL formed by liver and intestines (low TAG levels)
(2) HDL particles bud off from chylomicrons and VLDL during digestion
(3) Free apoA-I - acquire cholesterol and phospholipid from other apolipoproteins and cell membranes to form nascent-like HDL

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124
Q

How are HDL’s matured?

A

Nascent-HDL accumulates phospholipids and cholesterol from cells lining blood vessels
Hollow core fills
Transfer of lipids to HDL doesn’t require enzyme activity

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125
Q

How are HDL’s able to remove cholesterol from the periphery?

A

ABCA1 protein within cholesterol laden cell facilitates transfer of cholesterol to HDL to return to liver
Cholesterol then converted to cholesterol ester by LCAT enzyme

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126
Q

Once a HDL has acquired its cholesterol what does it do with it?

A

Taken up by liver
Cells requiring cholesterol can also express scavenger receptor (SR-B1) to obtain it from HDL
HDL can also exchange cholesterol ester for TAG with VLDL via cholesterol exchange transfer protein

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127
Q

What are the consequences of hyperlipoproteinaemia?

A

Defective LPL - chylomicrons in fasting plasma
LDL receptor deficiency - CHD
Defective apoE - raised IDL, chylomicron remnants - CHD
Raised chylomicrons + VLDL in fasting plasma - CHD

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128
Q

What are 3 main signs of hypercholesterolaemia?

A

Xanthelasma
Corneal arcus
Tendon xanthoma

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129
Q

What are the treatments of hyperlipoproteinaemias?

A

Diet, lifestyle modifications
Statins - HMG-CoA reductase inhibitor
Bile acid sequestrates - cholestyramine

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130
Q

What areas of the body in adults does haemopoiesis occur?

A

Pelvis, sternum, skull, ribs, vertebrae

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131
Q

What hormone causes platelets to be produced?

A

Thrombopoietin

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132
Q

What hormone causes basophils and neutrophils to be produced?

A

G-CSF

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133
Q

What hormone causes lymphocytes to be produced?

A

Interleukins and TNF’s

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134
Q

What hormone causes RBC’s to be produced?

A

Erythropoietin

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135
Q

What phagocytic cells are found in the reticuloendothelial system?

A

Monocytes, macrophages, Kupffer cells, Tissue histiocytes, Microglial cells in CNS

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136
Q

What organs are part of the reticuloendothelial system?

A

Spleen and liver

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137
Q

What are the main parts of the spleen?

A

Red pulp- sinuses lined by endothelial macrophages and cords

White pulp - similar structure to lymphoid follicles

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138
Q

What type of cells pass through the red pulp and white pulp?

A

Red pulp - RBC’s preferentially pass through it

White pulp - WBC and plasma pass through it

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139
Q

What are the 4 functions of the spleen in adults?

A

1 - sequestration and phagocytosis - old/abnormal red cells removed by macrophages
2 - blood pooling - platelets and RBC’s can be rapidly mobilised during bleeding
3 - extra medullary haemopoiesis - pluripotent stem cells proliferate during haematological stress or if marrow fails
4 - Immunological function - 25% of T cells and B cells are present in the spleen

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140
Q

Why would the spleen grow?

A

1 - back pressure - portal HTN
2 - over working red pulp
3 - over working white pulp
4 - reverting to what it used to do - extra medullary haemopoiesis
5 - expanding as infiltrated by cells which shouldn’t be there - cancer cells of blood origin
6 - expanding as infiltrated by other material - Gauchers disease, sarcoidosis

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141
Q

Define hyposplenism

A

Lack of adequately functioning splenic tissue

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142
Q

What are 3 causes of hyposplenism?

A

Splenectomy
Sickle cell disease
Coeliac disease

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143
Q

On blood film what is seen in patients with hyposplenism?

A

Howell Jolly Bodies

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144
Q

What encapsulated organisms are patients who are hyposplenic at risk of getting?

A

Pneumococcus
Haemophilus influenzae
Meningococcus

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145
Q

What protein is the cytoskeleton?

A

Spectrin and ankyrin

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146
Q

What is the process that occurs if a patient becomes anaemic due to poor RBC production?

A

Anaemia -> reduced O2 detected in interstitial peritubular cells in kidney -> inc production of EPO by kidney -> epo stimulates maturation and release of RBC -> inc RBC + inc Hb -> more O2 delivered -> feedback loop EPO reduces

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147
Q

What is the term that describes a reduction in the number of blood cells?

A

Cytopenia

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148
Q

What cells are included in pancytopenia?

A

RBC’s, WBC’s, and platelets

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149
Q

What suffixes are used to describe increased number of blood cells?

A

-cytosis or -philia

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150
Q

What type of immune system is the neutrophil part of?

A

Innate immune system

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151
Q

From which pre-cursor is a neutrophil from?

A

Myeloblast

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152
Q

What are the biggest causes of neutrophilia?

A

98% mostly Infection related

Tissue damage, acute inflammation, cancer, acute haemorrhage

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153
Q

A neutrophil count of what number counts as neutropenia?

A

<1.5x10^9/L

Severe if <0.5x10^9/L

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154
Q

What are normal causes of neutropenia?

A

Benign ethnic neutropenia

Cyclic neutropenia

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155
Q

What is aplastic anaemia in terms of causing neutropenia?

A

Empty bone marrow, no precursors

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156
Q

What are consequences of neutropenia?

A

Severe life threatening bacterial and fungal infections
Mucosal ulceration
Neutropenia itself predisposes to infections occurring but doesn’t always lead to neutropenic sepsis

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157
Q

What are 4 causes of monocytosis?

A

Chronic inflammatory conditions
Chronic infection
Carcinoma
Myeloproliferative disorders/ leukaemias

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158
Q

What are some causes of eosinophilia?

A

Allergic disease, drug hypersensitivity
Parasitic infections
Hodgkin lymphoma, acute myeloid leukaemia, eosinophilic leukaemia

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159
Q

What are some causes of basophilia?

A

Immediate hypersensitivity reactions
Ulcerative colitis
Rheumatoid arthritis
CML

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160
Q

What are the subgroups of lymphocytes?

A

B cells
T cells
NK cells

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161
Q

What are some causes of lymphocytosis?

A 
Viral infections
Bacterial infections
Stress related MI/cardiac arrest
Post splenectomy
Smoking
Malignant - chronic lymphocytic leukaemia, lymphoma
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162
Q

What is the purpose of K-EDTA in a blood test tube?

A

Chelates calcium ions which stops blood coagulation

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163
Q

Which gender has a higher haematocrit and red cell count?

A

Males

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164
Q

What is serum?

A

Plasma minus clotting factors

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165
Q

What is plasma?

A

Water, proteins, nutrients, hormones etc

The clear layer above the white buffy coat when blood is centrifuged

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166
Q

What is packed cell volume?

A

Same as haematocrit - the portion of blood made up of RBC’s

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167
Q

What condition would lead to a raised haematocrit?

A

polycythaemia

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168
Q

What can cause a low haemoglobin reading on a blood test?

A

Acute bleed, haemolysis, bone marrow disorders

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169
Q

What can cause a high haemoglobin reading on a blood test?

A

Dehydration, diuretics, burns

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170
Q

What is the difference between polycythaemia and erythrocytosis?

A

Polycythaemia - actual physical increase in RBC’s

Erythrocytosis - a measured raised RBC mass

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171
Q

What happens to red cell count in microcytic anaemia?

A

Reduced in iron deficiency anaemia

Increased in thalassaemia trait

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172
Q

If suspecting erythrocytosis what would red cell count show if this was a true diagnosis?

A

A raised red cell count - polycythaemia

A non-raised red cell count would be indicative that it was not true polycythaemia

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173
Q

What can cause a raised mean cell volume?

A 
Megaloblastic anaemia (B12, folate deficiency)
Liver disease
Alcoholism
Haemolytic anaemia
Hypothyroidism
Drugs
Myelodysplasia
Myeloma
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174
Q

What can cause a reduced mean cell volume?

A

Iron deficiency anaemia
Thalassaemia
Anaemia of chronic disease
Lead poisoning

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175
Q

What would a raised red cell distribution width mean?

A

Anisocytosis - RBC’s of unequal size

Post blood transfusion

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176
Q

What happens to red cell distribution width in the short and long term stages of iron deficient anaemia?

A

Increased acutely in iron deficient anaemia as there are more larger cells being produced but then as those cells are removed from the circulation the RDW decreases as all the cells become microcytic

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177
Q

What would a decreased red cell distribution width mean?

A

Iron deficiency anaemia - chronic

Normal in thalassaemia

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178
Q

When is mean cell haemoglobin usually reduced or increased?

A

Reduced - iron deficiency

Raised - macrocytic anaemia

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179
Q

What would cause a raised reticulocyte count?

A 
Haemolytic anaemia
Recent blood loss
Response to iron, Vit B12, folate replacement
Response to EPO
Recovery from bone marrow suppression
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180
Q

What would cause a reduced reticulocyte count?

A 
Haematinic deficiency (B12, folate, iron)
Bone marrow failure
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181
Q

What causes schistiocytes?

A

RBC broken up in the circulation

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182
Q

What are inclusions in erythrocytes and describe them?

A

Howell-Jolly bodies = DNA/nuclear fragments
Basophilic stippling = RNA inclusions
Pappenheimer bodes = Iron inclusions in cells
Heinz bodies = denatured Hb
Haemoglobin H inclusions= Golf-ball cells,

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183
Q

How would you describe cellular colour in iron deficient anaemia?

A

Hypochromic microcytic

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184
Q

What is anaemia?

A

Hb below the reference range for the normal population of that country
The ref range varies depending on the location of that population i.e. UK, Africa

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185
Q

What are signs and symptoms of anaemia?

A

Symptoms: SOB, Tiredness, Cardiac failure, Palpitations, Headache
Signs: Pallor, Tachycardia, Tachypnoea, Hypotension

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186
Q

What is a specific sign of iron deficiency?

A

(1) Koilonychia - spoon nails
(2) Oesophageal webs (Plummer vinson syndrome) - thin webs that grow across the inside of the upper part of the oesophagus and may cause dysphasia
(3) Angular stomatitis
Hypochromic anaemia

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187
Q

What is a specific sign of fit B12 deficiency?

A

Glossitis - enlarged shiny tongue

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188
Q

What is a specific sign of thalassaemia?

A

Abnormal facial bone development

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189
Q

What are 2 methods of causing reduced erythropoiesis?

A

1 - empty bone marrow - unable to respond to stimulus from EPO e.g. after chemotherapy or toxic insult such as parvovirus infection of in aplastic anaemia
2 - marrow infiltrated by cancer cells or fibrous tissue

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190
Q

What is dyserythropoiesis and what is the result?

A

(A) Anaemia of inflammation or anaemia of chronic disease
1 - iron is not released for use in bone marrow
2 - reduced lifespan of RBC
3 - marrows shows lack of response to EPO
(B) Myelodysplastic syndromes- acquired genetic mutations

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191
Q

What causes iron not being released for use in bone marrow in dyserythropoiesis?

A

Cytokines during inflammation reduce life span of RBC’s

Macrophages will be prevented from releasing the iron once they have been destroyed

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192
Q

What are defects in Hb synthesis?

A

Deficiencies in essential nutrients:
(1) - Lack of iron - deficiency in Haem synthesis:
Iron deficiency, anaemia of chronic disease (functional lack of iron)
(2) Lack of B12/Folate: deficiency in the building blocks for DNA synthesis
Mutations in the proteins encoding the globing chains: Thalassaemia or Sickle cell disease

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193
Q

What are the 3 main inherited RBC structure defects?

A

Hereditary spherocytosis - mutations in a number of genes that allow RBC to change shape
Hereditary eliptocytosis - genetic condition - haemolytic anaemia - hence some elliptical shaped
Hereditary pyropoikilocytosis - genetic mutation that makes RBC sensitive to heat deformity

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194
Q

What are 3 areas of acquired defects in RBC membrane structure?

A
  • Mechanical damage - heart valves, vasculitis, microangiopathies, DIC
  • Heat damage - Burns
  • Osmotic change - Drowning
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195
Q

What are defects in RBC metabolism?

A

G6PD deficiency

Pyruvate kinase deficiency

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196
Q

Why does splenomegaly cause anaemia?

A

The spleen carries a large amount of RBC’s and so if it is big then it would have more RBC’s inside it which would mean less RBC’s in the circulation

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197
Q

What 2 areas are RBC’s damaged?

A

Intravascular

Extravascular - reticuloendothelial system

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198
Q

What is the result of autoimmune haemolytic anaemia and why?

A

Anaemia result

Autoantibodies attack the RBC’s - cells in the RES recognise the Ab and remove the RBC from circulation

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199
Q

How do you treat autoimmune haemolytic anaemia?

A

Steroids, folic acid, rituximab, IVIG

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200
Q

What is the result of myelofibrosis of RBC’s?

A

Fibrotic marrow has little space for haemopoiesis
Result is decreased erythropoiesis and increased pooling in the spleen which takes over erythropoiesis.
RBC look like tear drops as they are squeezed out of the marrow

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201
Q

What are the 3 stages of development of the RBC to become an erythrocyte?

A

1 - ribosome synthesis
2 - Hb accumulation
3 - ejection of nucleus (reticulocyte)
-> Erythrocyte

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202
Q

What is the mechanism for causing reticulocytosis in anaemia?

A

Bone marrow compensates for reduced O2 carrying capacity by releasing more immature RBC’s

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203
Q

When would anaemia with reticulocytosis occur?

A

Acute blood loss
Splenic sequestration
Haemolysis - immune, non-immune, haemoglobinopathies etc

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204
Q

What is the mnemonic used to help remember the causes of anaemia in low reticulocyte counts?

A 
MICRO TAILS - micro= microcytic TAILS = causes
T- thalassaemia trait
A - anaemia of chronic disease
I - iron deficiency
L - Lead poisoning
S - sideroblastic anaemia
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205
Q

What MCV is seen in anaemia with low reticulocyte count?

A 
High MCV (macrocytic)
Vit B12 deficiency, Folate deficiency, MDS, Liver disease, Hypothyroidism, Alcohol
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206
Q

What causes anaemia with low reticulocyte count but also is normocytic/ normal MCV?

A

Primary bone marrow failure -aplastic anaemia, red cell aplasia
Secondary bone marrow failure - anaemia of chronic disease, combined haematinic deficiency, uraemia, endocrine abnormalities, HIV infection

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207
Q

What type of anaemia is caused by B12 deficiency?

A

Macrocytic anaemia MCV >100fL

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208
Q

How is B12 absorbed into the body?

A

Haptocorrin released from salivary glands -> Intrinsic factor release in the stomach -> pancreatic proteases break B12-haptocorrin complex -> B12 then binds to intrinsic factor -> B12-IF complex binds to receptors in terminal ileum -> absorption of B12 and destruction of IF

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209
Q

How long do normal B12 stores last?

A

3-6 years

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210
Q

What are common causes of B12 deficiency?

A

Vegan diet, poor diet
Pernicious anaemia (autoimmune condition affecting parietal cells), gastrectomy
Crohn’s disease, ideal resection
Lack of trans cobalamin - congenital deficiency

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211
Q

How long does 5mg of folate store for?

A

3-4 months

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212
Q

What are 4 causes of deficiency of folate?

A

Dietary deficiency
Increased use - pregnancy, increased erythropoiesis, severe skin disease, haemolytic anaemia
Disease of duodenum/ jejunum - coeliac disuse, crohns disease
Lack of methylTHF - drugs with inhibit dihydrofolate reductase enzyme (MTX)

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213
Q

What is the function of B12 and B9 (folate) together?

A

B12 reactivates B9 (folic acid) back into tetrahydrofolate.

B12 deficiency causes a functional folate deficiency

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214
Q

Why does B12 and folate deficiency cause megaloblastic anaemia?

A

Deficiencies in both lead to thymidylate deficiency
Absence of thymine, uracil is incorporated into DNA instead
DNA repair mechanisms detect the error and DNA strands are destroyed

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215
Q

What is a B12 deficiency associated with?

A

Neurological disease

Focal demyelination affecting the spinal cord, peripheral nerves and optic nerves

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216
Q

How do you treat a B12/ Folate deficiency?

A

B9 - oral folic acid

B12 - IM hydroxocobalamine

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217
Q

After how many months of B12/ folate treatment should blood counts be fully back to normal?

A

3-6months

2 months there should be resolution of anaemia

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218
Q

What is the difference between ferric and ferrous iron?

A 
Ferrous = Fe2+
Ferric = Fe3+
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219
Q

What is the difference between haem iron and non-haem iron?

A

Dietary iron = haem iron = Fe2+

Non - haem iron = Mixture of Fe2+ and Fe3+

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220
Q

What charge of iron can only be absorbed by the body?

A

Fe2+

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221
Q

How does an acidic environment help with absorbing iron?

A

Acidic environment helps convert Fe3+ + e- =Fe2+

Fe2+ is the absorbed iron

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222
Q

How much maintenance iron is needed per day?

A

10-15mg/day

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223
Q

Where does haem iron and non-haem iron get absorbed?

A

Duodenum/ Jejunum

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224
Q

How much of ingested iron is absorbed/ day?

A

5-15%

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225
Q

What is the process of iron absorption from ingestion?

A

1 - Fe2+ in GI
2 - Transported into enterocytes through DMT1 (divalent metal transporter 1)
3 - Fe2+ <=> Fe3+ - Ferritin complex storage in enterocyte
4 - Ferroportin in basolateral side of enterocyte transports Fe2+ into the blood
5 - Fe2+ enters blood and converted to Fe3+ by hephaestin
6 - Fe3+ attaches to transferrin which carries 2xFe3+ ions per molecule around the body

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226
Q

What controls the absorption of iron from the basolateral surface of the enterocytes?

A

Hepcidin - negative regulator
Regulates ferroportin
Function of ferroportin - allows Fe2+ to pass from the enterocytes into the blood and from the blood into the macrophage).
Hepcidin signals for ferroportin destruction and as a result less Fe2+ will be absorbed

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227
Q

What could high transferrin levels indicate?

A

Iron deficiency anaemia

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228
Q

What do low levels of transferrin levels indicate?

A

Liver disease / haemolytic anaemia

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229
Q

What function does Vitamin C play in iron absorption?

A

Anti-oxidant therefore prevents iron being turned into Fe3+ which can’t be absorbed

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230
Q

What negative factors affect absorption of non-haem iron from food?

A

Tannins (tea)
Phytates (chapattis, pulses)
Fibre
Antacids

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231
Q

What positive factors affect absorption of non-haem iron from food?

A

Vitamin C and citrate

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232
Q

What is the total iron stored in the body and how much of it is functional and stored?

A

Total iron = 3350mg
Functional: Hb = 2000mg, Myoglobin = 300mg, Enzymes = 50mg, Transported iron in transferring = 3mg
Stored: 1000mg - Ferritin (soluble) and haemosiderin (insoluble)

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233
Q

Where does haemosidderin accumulate?

A

Liver, spleen, bone marrow

234
Q

How do cells take up iron?

A

(1) Fe3+ bound to transferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis
(2) Fe3+ within endoscope released by acidic environment and reduced to Fe2+
(3) Fe2+ transported to the cytosol via DMT1
(4) Fe2+ stored in ferritin, exported by ferroportin

235
Q

How is iron recycled?

A

Old RBC’s phagocytosed by macrophages
Macrophages catabolise haem -> released from RBC
Amino acids reused and iron exported to blood by transferrin or returned to storage pool as ferritin

236
Q

What regulates iron absorption?

A
  • Regulation of transporters: ferroportin
  • Regulation of receptors: transferrin and HFE protein (interacts with transferring protein)
  • Hepcidin and cytokines
  • Crosstalk between epithelial cells and other cells like macrophages
237
Q

What is the function of ferroportin?

A

Function of ferroportin - allows Fe2+ to pass from the enterocytes into the blood and from the blood into the macrophage).
Hepcidin signals for ferroportin destruction and as a result less Fe2+ will be absorbed

238
Q

How does chronic disease cause anaemia of chronic disease?

A

Cytokines (e.g. IL-6)from immune cells -> (1) increase hepcidin production (2) Inhibition of erythropoietin release from kidneys (3) Inhibit erythropoietin in bone marrow.
Inc hepcidin = inhibition of ferroportin = dec iron release from RES and dec iron absorption from GIT

239
Q

What are non specific signs and symptoms of iron deficiency?

A

Tiredness, pallor, reduced exercise tolerance (SOB), Cardiac, Inc resp rate, headache, dizziness, light-headedness
Pica (unusual cravings for non-nutritive substances)
Cold extremeties
Epithelial changes

240
Q

On a peripheral blood smear what type of RBC’s would be seen on iron deficiency anaemia?

A

RBC’s are microcytic and hypochromic
Anisopoikilocytosis = change in size and shape
Sometimes pencil cells and target cells

241
Q

What blood tests would be done to diagnose anaemia?

A

Plasma ferritin - indirect marker of total iron status
Reduced plasma ferritin definitively indicates iron deficiency
BUT normal or increased ferritin doesn’t exclude iron deficiency
CHr (reticulocyte Hb content) - functional iron deficiency - CHr remains low during inflammatory responses

242
Q

What conditions can cause ferritin to be raised and would give a false negative of iron deficiency?

A 
Cancer
Infection
Inflammation
Liver disease
Alcoholism
Iron deficiency anaemia
243
Q

How do you treat iron deficiency anaemia?

A

Dietary advice
Oral iron supplementation
IM, IV iron
Blood transfusion

244
Q

What type of response would be suitable for iron replacement in anaemia?

A

20g/L rise in Hb in 3 weeks

245
Q

Why is iron excess dangerous?

A

Excess iron can exceed binding capacity of transferrin ->

iron deposited in end organs as haemosiderin -> iron promotes free radical formation and organ damage

246
Q

What 2 conditions are caused by iron excess?

A

Transfusion associated haemosiderosis

Hereditary haemochromotosis

247
Q

How much iron is found in 1 unit of blood?

A

200mg

248
Q

What are the end organ effects of iron accumulation?

A 
Liver cirrhosis
Diabetes mellitus
Hypgonadism
Cardiomyopathy
Arthropathy
Inc skin pigmentation
249
Q

What drug can be given to patients with excess iron?

A

Desferrioxamine

250
Q

What is hereditary haemochromatosis?

A

Autosomal recessive - HFE gene mutation
HFE normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
Mutated HFE can’t bind to transferrin so negative influence on iron uptake is lost
Too much iron enters cells
Iron accumulates in end organs causing damage

251
Q

How do you treat hereditary haemochromatosis?

A

Venesection

252
Q

What is a myeloproliferative disorder?

A

Myeloproliferative neoplasms - dysregulation at the multipoint haematopoietic stem cell level

253
Q

What are the 4 need to know myeloproliferative disorders?

A

Essential thrombocythaemia
Polycythaemia vera
Myelofibrosis
Chronic myeloid leukaemia

254
Q

Describe what the bone marrow would look like in a myeloproliferative disorder?

A

Hypercellular bone marrow / marrow fibrosis

255
Q

Where would haemopoiesis occur in myeloproliferative disorders?

A

Extramedullary - liver or spleen

256
Q

What is the potential for myeloproliferative disorders to become?

A

Acute leukaemia

257
Q

What specific mutation is found in many myeloproliferative disorders?

A

JAK2 = janus kinase 2 gene

Causes increased proliferation and survival of haematopoietic precursors

258
Q

What is polycytheamia Vera?

A

Too many RBC
Haematocrit is raised >0.52 in men, >0.48 in women or raised red cell mass
JAK2 mutation present
Some patients also have high platelets and neutrophils

259
Q

What are symptoms and signs of polycythaemia vera?

A 
Arterial thrombosis
Venous thrombosis
Haemorrhaging in skin, GIT
Pruritis
Splenic discomfort, splenomegaly
Gout
260
Q

How is polycythaemia vera managed?

A

Venesection
Aspirin
Manage CVS risk factors

261
Q

Define polycythaemia

A

Increase in circulating red cell concentration typified by a persistently raised haematocrit

262
Q

What are the subtypes of polycythaemia?

A 
Primary = polycythaemia vera
Secondary = EPO driven production
263
Q

What are the methods of producing ectopic EPO?

A

Central hypoxia - chronic lung disease, R->L shunts, training at altitude, CO poisoning
Renal hypoxia - Renal artery stenosis, polycystic disease
Hepatocellular carcinoma
Renal cell carcinoma
Uterine tumours
Phaeochromocytoma

264
Q

What is essential thrombocythaemia?

A

Excess platelets in blood

Large and excess megakaryocytic in bone marrow

265
Q

How is essential thrombocythaemia managed?

A

Aspirin

CV risk factors managed

266
Q

What are reactive causes for a high platelet count?

A 
Infection
Inflammation
Tissue injury
Haemorrhage
Cancer
Redistribution of platelets
267
Q

What is a complication of myelofibrosis?

A
  • Massive splenomegaly +/- hepatomegaly due to extra medullary haematopoiesis
  • Progresses to pancytopenia
268
Q

What is myelofibrosis?

A

Fibrotic marrow with little space for haemopoiesis

Clonal haemopoietic stem cell proliferation causes it

269
Q

What are clinical features of myelofibrosis?

A

Fatigue, sweats, weight loss
Consequences of massive splenomegaly - pain, early satiety, splenic infarction
Progressive marrow failure - requiring transfusions of blood products
Early death

270
Q

What is chronic myeloid leukaemia?

A

Very high WCC - maybe an incidental finding
Present - symptomatic splenomegaly, blood hyperviscosity or bone pain
Mature and immature myeloid cells
Blood film and marrow will show excess of all myeloid series from blast through to fully mature neutrophils

271
Q

What are the myeloid cells?

A 
Neutrophils
Macrophages
Basophils
Eosinophils
Thombocytes
Erythrocytes
272
Q

What are the lymphoid cells?

A

B lymphocyte

T lymphocyte

273
Q

What is the genetic problem with CML?

A

BCR-abl fusion
Chromosomes 9 and 22 have rearranged
Switches on a receptor tyrosine kinase which drives proliferation

274
Q

Define pancytopenia

A

Reduction in white cells, red cells and platelets

NOT neutrophils

275
Q

What are the 2 areas which would cause pancytopenia?

A 
Reduced production (most common)
Increased removal of cells - immune destruction, splenic pooling
276
Q

What are causes of reduced production in pancytopenia?

A 
B12/ folate deficiency
Drugs - chemo, anticonvulsants etc
Viruses - EBV, HIV, CMV
Bone marrow infiltration by malignancy
Marrow fibrosis
Radiation
Idiopathic aplastic anaemia
Congenital bone marrow failure
277
Q

What is aplastic anaemia?

A

Pancytopenia with a hypo cellular bone marrow in the absence of an abnormal infiltrate with no increase in fibrosis
Mortality is high as Tx is hard - immune treatments and bone marrow transplantation

278
Q

What are causes of thrombocytopenia?

A

Acquired - Decreased production, increased consumption, inc destruction
Inherited - rare syndromes

279
Q

What are consequences of severe thrombocytopenia?

A 
Patients not symptomatic until platelet count <30
Easy bruising
Petechiae, purport
Mucosal bleeding
Severe bleeding after trauma
Intracranial haemorrhage
280
Q

What is immune platelet destruction?

A

Immune thrombocytopenic purport
Autoantibodies against Glycoprotein 2b/3a and 1b/1x
Secondary to autoimmune conditions
Tx - steroids
Platelet transfusions dont work as they get destroyed too

281
Q

What are hereditary disorders of platelet function?

A

Bernard Soulier syndrome

Glandmann’s thrombasthenia

282
Q

What are acquired disorders of platelet functions?

A

Aspirin, NSAIDs

Uraemia

283
Q

What is thalassaemia?

A

Normal alpha or beta globin chains - the alpha and beta thalassaemias

284
Q

What is the problem caused in thalassaemia?

A

Low level of intracellular Hb = hypochromic microcytic RBC
Excess of globin chains - e.g. in beta-thal get insoluble aggregates of alpha chains. Chains aggregate and get oxidised and damage RBC membrane
Leads to haemolytic anaemia

285
Q

What is a alpha-thalassaemia trait?

A

Deletion of 2 alpha-globin genes
Minimal or no anaemia and no physical signs
Findings are identical to those of beta-thalassaemia minor

286
Q

What is haemoglobin H disease?

A

Deletion of 3 alpha-globin genes
Tetramers of beta-globin, called HbH are formed
Moderately severe anaemia, resembling beta-thalassaemia intermedia

287
Q

What cells would be in anaemia with haemoglobin H disease?

A

Microcytic, hypochromic anaemia with target cells and Heinz bodies in the blood film

288
Q

What is hydrops foetalis?

A

Deletion of all 4 alpha-globin genes
In the foetus, excess gamma-globin chains form tetramers (Hb Bart) that are unable to deliver the oxygen to tissues.
Usually intrauterine death

289
Q

What is beta-thalassaemia?

A

Gene mutations rather than deletions
Beta-0 = total absence of production
Beta+ = reduction of globin production

290
Q

What is beta thalassaemia major?

A

Severe transfusion dependent anaemia that first becomes manifest 6-9months after birth as synthesis switches from HbF to HbA
Either Beta-0/Beta-0 or Beta+/Beta+

291
Q

What is beta thalassaemia minor?

A

Usually asymptomatic with mild anaemia (very microcytic and hypochromic)
Heterozygous
One normal gene (Beta-0/Beta or Beta+/Beta)

292
Q

What is beta thalassaemia intermedia?

A

Severe anaemia, but not enough so to require regular blood transfusions
Genetically heterozygous
Mild variants of homozygous beta-thalasaemia
Severe

293
Q

What are the variants of beta thalassaemia intermedia?

A

Mild - variants of homozygous beta-thalassaemia
Severe - Beta-0/Beta or Beta/Beta
Double heterozygosity Beta-0/Beta

294
Q

What are the consequences of thalassaemia?

A

Extramedullary haemopoiesis - compensatory mechanism resulting in splenomegaly, hepatomegaly, expansion of haemopoiesis into the bone cortex - stunted growth
Iron overload - premature death - excessive absorption of dietary iron, repeated blood transfusions to treat anaemia

295
Q

What is the treatment for thalassaemia?

A 
Transfusions -2 weekly
Iron chelation
Folic acid
Immunisation
Stem cell transplant
Pre-conception counselling
296
Q

What is sickle cell?

A

Point mutation causes substitution of valine for glutamic acid in position 6 in beta chain
Confers protection against malaria hence found more in western african people

297
Q

What are symptoms of sickle cell disease?

A

Anaemia
HbS readily give up oxygen in comparison to HbA
Low oxygen states the deoxygenated HbS forms polymers and RBC form a sickle shape
Irreversibly sickeld cells - less deformable - occlusion occurs more frequently

298
Q

What are the 3 sickle cell crises?

A

1 - vaso-occlusive - painful bone crises
2 - Aplastic - triggered by parvovirus
3 - Haemolytic

299
Q

What are the treatments for sickle cell patients?

A 
Folic acid
Penicillin prophylactically
Splenectomy
Hydroxycarbamide - increases HbF levels
Red cell exchange
300
Q

What are long term consequences of sickle cell?

A

Stroke
Cognitive and neurological problems
Kidney failure
Priapism

301
Q

What does haemolytic anaemia result in?

A

Anaemia symptoms
Accumulation of bilirubin -> jaundice
Splenomegaly
Massive sudden haemolysis - cardiac arrest - lack of O2 delivery to tissues and hyperkalaemia

302
Q

What are the 4 inherited haemolytic anaemia causes?

A

Glycolysis defect - pyruvate kinase deficiency
Pentose-p-pathway - G6PDHH deficiency
Membrane protein - hereditary spherocytosis
Haemoglobin defect - sickle cell

303
Q

What are the categories of autoimmune haemolytic anaemia?

A

Warm - IgG - maximally active at 37 degrees

Cold - IgM - maximally active at 4 degrees

304
Q

What can cause autoimmune haemolytic anaemia?

A

Infections

Cancers of lymphoid system

305
Q

What happens to core body temperature when a person sleeps?

A

Temperature decreases as sleep progresses but rises as sleep comes to an end

306
Q

What happens to cortisol levels during sleep?

A

Initially decreases till mid way through sleep but then increases rapidly before waking

307
Q

What happens to melatonin during sleep?

A

Initially rises till the mid point of sleep then drops rapidly to pre sleep levels

308
Q

Where in the brain is the biological clock?

A

Suprachiasmatic nucleus

309
Q

From where in the pituitary does ADH get released from?

A

Posterior pituitary

310
Q

From which part of the brain controls the release of ADH?

A

Osmoreceptors in the hypothalamus

311
Q

What is autocrine communication?

A

Hormone signal acts back on the cell of origin

312
Q

What is paracrine communication?

A

Hormone signal carried to adjacent cells over a short distance via interstitial fluid

313
Q

What is endocrine communication?

A

Hormone signal released into blood stream and carried to distant target cells

314
Q

What is neurocrine communication?

A

Hormone originates in neurone and after transport down axon released into bloodstream and carried to distant target cells

315
Q

What are the 4 classes of hormones?

A

Peptide
Amino acid derivative
Glycoproteins
Steroids

316
Q

From which precursor molecule are steroid hormones synthesised from?

A

Cholesterol

317
Q

What is the role of carrier proteins in hormone transport?

A

Increase solubility of hormone in plasma
Increase half life
Readily accessible reserve

318
Q

What is the difference in lipid soluble and water soluble hormones in their receptor area of activity?

A

Lipid soluble - intracellular receptors

Water soluble - extracellular/ cell surface receptors

319
Q

Where is the control for appetite control?

A

Satiety centre in the hypothalamus - arcuate nucleus

320
Q

What are the two types of primary neurone in the arcuate nucleus?

A

Stimulatory - contain neuropeptide Y (NPY) and Agouti-related peptide. These promote hunger
Inhibitory - contain pro-opiomelanocortin (POMC) which yields several neurotransmitters including alpha-MSH and beta-endorphin. These promote satiety.

321
Q

What hormone is released that causes excitation of the excitatory primary neurones arcuate nucleus?

A

Ghrelin

322
Q

What is the function of ghrelin?

A

Stimulates appetite

323
Q

What is the function of peptide tyrosine tyrosine (PYY)?

A

Inhibits excitatory primary neurones of the arcuate nucleus and stimulates the inhibitory neurones. Effect is therefore to suppress appetite.

324
Q

What is the clinical correlation of peptide tyrosine tyrosine?

A

PYY is released when eating a protein rich meal and suppresses appetite
It is related to obesity as a blunted response to it can cause obesity

325
Q

What 3 hormones are responsible for suppressing appetite that act on the hypothalamus?

A

Leptin, Insulin, Amylin

326
Q

What releases leptin?

A

Adiopocytes

327
Q

Where does leptin have its effects on the brain?

A

Arcuate nucleus:
1 - stimulates the inhibitory POMC neurones
2 - inhibits the excitatory (AgRP/NPY) neurones

328
Q

What is the over effect of leptin?

A

Suppress appetite

329
Q

How does insulin have its effects of appetite suppression on the brain?

A

Arcuate nucleus:

Stimulates the inhibitory POMC neurones

330
Q

What is the effect of amylin?

A

Secreted by beta cells in pancreas
Suppresses appetite
Decrease glucagon secretion and slow gastric emptying

331
Q

Which organ secretes PYY?

A

Small intestine

332
Q

What is the disease process of anaemia of chronic renal failure?

A

(1) Reduced EPO production due to damage to kidneys
(2) Often associated with raised cytokines
(3) Reduced clearance of hepcidin
(4) Increased hepcidin production due to inflammatory cytokines
(5) Dialysis - damage to RBC and loss due to bleeding
(6) Reduced lifespan of RBC as a direct effect of uraemia

333
Q

How does uraemia affect lifespan of RBC and why?

A

It suppresses the bone marrow due to uraemic toxins

334
Q

What is the treatment for anaemia of chronic renal failure?

A

Use reticulocyte haemoglobin content (CHr) to assess for functional iron deficiency
Given iron if ferritin <200micrograms/L or CHr low
Give IV iron if hepcidin is raised or inflammatory condition present

335
Q

What would cause low neutrophils in renal disease?

A

Immunosuppression due to post transplant drugs

Marrow infiltration e.g. in myeloma

336
Q

What would cause raised neutrophils in renal disease?

A

Inflammation
Connective tissue disease
Infection
Drugs: steroids cause neutrophilia

337
Q

What would cause low platelets in renal disease?

A

Direct effect of uraemia on platelet production
Drugs
Haemolytic ureamic syndrome

338
Q

What would cause raised platelets in renal disease?

A

Reactive
Bleeding
Iron deficiency

339
Q

What is Felty’s syndrome?

A

Triad of:
Splenomegaly
Neutropenia
Rheumatoid arthritis

340
Q

What is the potential cause of neutropenia in Felty’s syndrome in rheumatoid arthritis?

A

Secondary to splenomegaly, peripheral destruction of neutrophils, failure of bone marrow to produce neutrophils
High levels of G-CSF, insensitivity of myeloid cells to cytokines

341
Q

What is the haematological consequence of portal hypertension?

A

Splenomegaly -> splenic sequestration of cells, overactive removal of cells

342
Q

What are the haematological features of liver disease?

A 
Blood loss
Deficiencies in clotting factors
Endothelial dysfunction
Thrombocytopenia
Defective platelet function
343
Q

What type of RBC’s will be seen in liver disease?

A

Target cells
Spurr cells - found in end stage alcoholic liver disease
Accumulation of excess membrane cholesterol

344
Q

Why is thrombocytopenia seen in alcoholic liver disease?

A

Thombopoietin is made in the liver - if liver damaged no hormone made

345
Q

Why would low levels of neutrophils be seen in post op period?

A

Reactive changes - severe sepsis

346
Q

Why would low levels of platelets be seen in the post op period

A

Medications - heparin

Sepsis - DIC

347
Q

What is the difference in the lymphocyte changes in amount depending on bacterial or viral infections?

A

Bacterial infections - neutrophils

Viral infections - lymphocytosis

348
Q

Why would there be leucoerythroblasts seen on a blood film?

A 
Granulocyte precursors
Bone marrow infiltration by carcinoma or haematological malignancy
Causes severe megaloblastic anaemia
Primary myelofibrosis
AML/MDS
Storage diseases
349
Q

What is diabetes?

A

Blood glucose is too high (hyperglycaemia) and over years leads to damage of the small and large blood vessels causing premature death from cardiovascular diseases

350
Q

What are the 2 main types of diabetes?

A

Type 1 and Type 2

Different aetiologies BUT similar complications

351
Q

What are the biggest problems with diabetes?

A 
Blindness - retinopathy
ESRD - nephropathy
Amputation - peripheral vascular disease
15% life time risk of amputation
70% death from CVD and stroke
352
Q

What is the pathophysiology of diabetes?

A

(1) inability to produce insulin due to beta cell failure

(2) insulin production adequate but insulin resistance prevents insulin working effectively

353
Q

What is type 1 diabetes?

A

Auto-immune beta cell destruction
Beta cells - secrete insulin
Autoantibodies made are directed against beta cells
Mostly a genetic pre-disposition

354
Q

How does T2DM present?

A

Typical symptoms: Polyuria, polydipsia, blurring of vision, urogenital infections- thrush
Symptoms of poor energy utilisation: tiredness, weakness, lethargy, weight loss

355
Q

How is diabetes diagnosed?

A

Lab testing
Fasting glucose
HbA1c
Symptoms and 1 abnormal test

356
Q

How does T1DM present?

A 
Rapid onset weight loss,
Polyuria
Polydipsia
Late presentation - DKA
Young age
Hyperglycaemia
Ketones present
357
Q

How is T1DM treated?

A

Exogenous insulin - S/C injection

358
Q

What is the theory why T2DM occurs?

A

Obesity

359
Q

What can cause insulin resistance?

A 
Obesity - central more specifically
Muscle and liver fat deposition
Elevated circulating free fatty acids
Physical inactivity
Genetic influences
360
Q

How is a low calorie diet connected to diabetes?

A

600-800 calorie diet - T2DM almost disappears after 7 days

361
Q

How is bariatric surgery related to diabetes?

A

Fasting plasma glucose drops considerably post surgery

Almost full response for T2DM - normalisation of B cell function + decreased pancreatic and liver TAG

362
Q

What is the best treatment for T2DM?

A

Weight loss

363
Q

In general how do we currently treat T2DM?

A 
Lifestyle factors
Non-insulin therapies
Insulin
Control other CV risk factors - hypercholesterolaemia, HTN, smoking, exercise, diet
Surveillance for chronic complications
364
Q

What are acute complications for diabetes?

A

Massive metabolic decompensation =
DKA
Hyperosmolar non-ketotic syndrome in T2DM - hyperosmolar hyperglycaemic syndrome
Coma

365
Q

What are chronic complications for diabetes?

A

Macrovascular complications - cerebrovascular, cardiovascular, peripheral vascular diseases, stroke, MI, intermittent claudication, gangrene
Microvascular - retinopathy, nephropathy, painful peripheral neuropathy, erectile dysfunction, foot ulceration, diarrhoea, constipation

366
Q

What is metabolic syndrome?

A

Cluster of the most dangerous risk factors associated with cardiovascular disease: diabetes, raised fasting plasma glucose, abdominal obesity, high cholesterol and BP

367
Q

what causes metabolic syndrome?

A 
Insulin resistance
Central obesity
Genetics
Physical inactivity
Ageing
368
Q

What are the 4 anatomical areas of the pancreas?

A

Head, neck, body, tail

369
Q

What is the name of the ducts that release pancreatic juices into the GI?

A

Pancreatic duct and accessory pancreatic duct

370
Q

What part of the GIT is the pancreas part of?

A

Embryologically outgrowth of the foregut

371
Q

How much of the pancreas is exocrine and endocrine?

A

Exocrine - 99%

Endocrine - 1%

372
Q

What are the known hormones secreted from the endocrine functioning of the pancreas?

A 
Insulin
Glucagon
Somatostatin
Pancreatic polypeptide
Ghrelin
Gastrin
Vasoactive intestinal peptide
373
Q

What cells in the pancreas produce insulin?

A

Beta cells

374
Q

What cells in the pancreas produce Glucagon?

A

Alpha cells

375
Q

What cells in the pancreas produce Somatostatin?

A

Delta cells

376
Q

What cells in the pancreas produce pancreatic polypeptide?

A

PP cells

377
Q

What cells in the pancreas produce Ghrelin?

A

Epsilon cells

378
Q

What cells in the pancreas produce Gastrin?

A

G cells

379
Q

In a pancreatic islet where can alpha and beta cells generally be found?

A

Alpha - outer area/ periphery

Beta - Inner area/ central

380
Q

What is the renal plasma glucose threshold?

A

10mmol/L

The amount of glucose in the blood that the kidneys can’t reabsorb above and it gets excreted

381
Q

What is the half life of insulin and glucagon?

A

5 mins

382
Q

Where is the insulin receptor found?

A

Cell surface

383
Q

What is the difference between active and inactive insulin?

A

Inactive = structure that has all 3 alpha helices= A-chain, B- chain + C-peptide

384
Q

What is the function of the C-peptide on the insulin structure?

A

Prevents peripheral damage of effects of insulin

385
Q

What test could be used to tell if a patient has been given synthetic or natural insulin?

A

Synthetic doesn’t have C-peptide whereas the natural insulin does

386
Q

What is the synthesis process of insulin?

A

1 - pre-proinsulin made in the endoplasmic reticulum
2 - proinsulin transported to golgi
3 - proinsulin cleaved to produce insulin and C-peptide
4 - insulin packaged into secretory granule
5 - insulin exocytosed when a rise in glucose is detected by the cell

387
Q

How is insulin released from the beta-islet cell?

A

1 - Glucose enters the cell through GLUT2
2- glucose-> glycolysis-> ATP production
3 - ATP rises in cell (ATP/ADP ratio inc)
4 - Inhibits ATP-dependent potassium channels on cell surface that prevents potassium entering the cell
5 - depolarisation of the cell membrane causes VDC-channels to open
6 - influx of calcium into the cell
7 - causes insulin containing secretory channels to release the contents into the surrounding area + blood

388
Q

What receptor attaches to the insulin receptor to promote insulin release?

A

Sulfonylurea receptor (SUR1)

389
Q

What glucose channel does insulin cause to be translocated onto cell surfaces?

A

GLUT4 channels - glucose dependent

390
Q

What receptor does glucagon activate?

A

GPCR

Gs receptor -> Adenlyate cyclase -> cAMP -> PKA -> glycogenolysis, gluconeogenesis -> hyperglycaemia

391
Q

What organ does glucagon mainly affect?

A

Liver - organ controlling blood glucose hence would act on it to maintain plasma glucose levels

392
Q

What is margination and exocytosis of granules in the pancreatic islet cells?

A

Margination - granules move to the cell surface

Exocytosis - fusion of vesicle with plasma membrane -> release of contents

393
Q

Does glucagon cause glucose to be made from fatty acids?

A

No - just cause increased plasma fatty acids

Gluconeogenesis is from amino acids

394
Q

What glucose metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?

A

Fastest -> Slowest

Glucose uptake into muscle and adipose tissue -> Glycolysis -> Glycogenesis

395
Q

What glucose metabolism processes are the fastest and the slowest in producing glucose in response to hypoglycaemia?

A

Fastest -> slowest

Gluconeogenesis -> glycogenolysis

396
Q

What lipid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?

A

Fastest -> slowest

Lipogenesis

397
Q

What lipid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?

A

F->S

Lipolysis -> ketogenesis

398
Q

What amino acid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?

A

Amino acid uptake -> protein synthesis

399
Q

With glucagon what other hormones are released?

A

Adrenaline and noradrenaline

400
Q

What glucose levels would be enough to class someone as diabetic?

A

Fasting >7mmol/L

Random >11mmol/L

401
Q

What is the difference between absolute and relative insulin deficiency?

A

Absolute - Pancreatic beta cells destroyed
Relative - secretory response of beta-cells is abnormally slow or small (insulin deficiency - failure to secrete adequate amounts of insulin from beta-cells)

402
Q

Would a gain of function mutation in the insulin channel cause a patient to become hyper or hypoglycaemic?

A

Gain of function
Less sensitive to the affects of ATP on the channel and so regardless of the increase in ATP the channel would continue to pump out potassium and so would be less likely to depolarise and allow the release of insulin

403
Q

In T2DM what are the subtypes of pathophysiology?

A

Peripheral Insulin resistance:
- Defective insulin receptor mechanism - change in no and/or affinity
- Defective post-receptor events - insulin resistance - tissue become insensitive to insulin
OR
Excessive or inappropriate glucagon secretion

404
Q

What occurs in young people and insulin resistance - leading to the obesity epidemic?

A

Insulin resistance present before 12 years old - onset of hyperglycaemia and development of overt T2DM
Initially: Beta cells compensate by increasing insulin production to compensate for lack of effect
Eventually: Beta cells unable to maintain increased insulin production - impaired glucose tolerance
Finally: Beta-cell dysfunction leads to relative insulin deficiency - overt T2DM

405
Q

How many hormones does the hypothalamus produce?

A

8

406
Q

How many hormones does the pituitary produce in response to the hypothalamus?

A

anterior - 6

posterior - 2

407
Q

What bone does the pituitary sit in?

A

Sphenoid bone

408
Q

What 8 processes does the hypothalamus modulate?

A 
Body growth - GH
Reproduction / Puberty - LH/FSH
Adrenal gland - Cortisol
Water homeostasis - ADH
Milk secretion - oxytocin
Lactation - prolactin
Thyroid gland - thyroid hormones
409
Q

What is the embryological origin of the anterior pituitary?

A

Rathke’s pouch
Primitive gut tissue
Oral ectoderm

410
Q

What is the embryological origin of the posterior pituitary?

A

Neuroectoderm

Primitive brain tissue

411
Q

What is the stalk that connects the hypothalamus and the pituitary called?

A

Infundibulum

412
Q

What nuclei produce oxytocin?

A

Supraoptic

413
Q

What nuclei produce ADH?

A

paraventricular

414
Q

Where are the hormones synthesised in the adenohypophysis?

A

Hypothalamus

415
Q

What are the hormones of the hypothalamus?

A

Thyrotropin releasing hormone
Prolactin releasing hormone (TRH minor positive control on prolactin)
Prolactin-release-inhibiting hormone (dopamine)
Corticotropin releasing hormone
Gonadotropin release hormone
Growth hormone releasing hormone
Growth hormone-inhibiting hormone (somatostatin)

416
Q

What are the hormones release by the anterior pituitary?

A 
TSH
ACTH
LH
FSH
PRL
GH
417
Q

What is the primary effect of growth hormone??

A

Acts on liver and skeletal muscle -> releases insulin-like growth factors - somatomedins

418
Q

What hormone antagonises growth hormone release?

A

Somatostatin

Growth-hormone inhibiting hormone

419
Q

What is the effect of GH on bone and bone growth in childhood and teenage years?

A

Stimulate long bone growth -> length and width prior to epiphyseal closure - width after epiphyseal closure
IGF’s stimulate both bone and cartilage growth

420
Q

What is the effect of GH/ IGFs in adults?

A

Maintain muscle and bone mass
Promote healing and tissue repair
Modulate metabolism and body composition

421
Q

What CNS effects regulate GH secretion?

A

Surge in GH secretion after onset of deep sleep

REM sleep decreases GH secretion

422
Q

How does stress affect GH secretion?

A

Increases GH secretion

423
Q

How does exercise affect GH secretion?

A

Increases GH secretion

424
Q

How does food alter GH secretion?

A

Decrease in glucose or fatty acids leads to increase in GH secretion
Increase in glucose or fatty acids leads to a decrease in GH secretion
Fasting increase GH secretion

425
Q

How does obesity and fasting affect GH secretion?

A

Obesity - dec GH secretion

Fasting - inc GH secretion

426
Q

What are the feedback loops of GH secretion?

A

Long loop -ve feedback:
Mediated by IGFs-
Inhibit release of GHRH + stimulates release of somatostatin from hypothalamus -> inhibit release of GH from ant pituitary
Short loop -ve feedback:
Mediated by GH itself
Stimulation of somatostatin release from hypothalamus

427
Q

What is the childhood result of GH deficiency?

A

Pituitary dwarfism
Proportionate type of dwarfism
Complete or partial deficiency
Height below 3rd percentile on standard growth charts
Growth rate slower than expected for age
Delayed or no sexual development during teen years

428
Q

What is the condition called when there is growth hormone excess in childhood?

A

Gigantism - rare condition in general

429
Q

What is a common cause of growth hormone excess?

A

Rare - often cause is pituitary adenomas

430
Q

What is the condition called when there is growth hormone excess in adulthood?

A

Acromegaly

431
Q

How does GH exert its effects on cells?

A

GH receptor is a Janus Kinase receptor - Tyrosine kinase receptor
Cross-phosporylation of JAK -> phosphorylation of GH receptor -> transcription factor activation and IGF production

432
Q

What are the types of IGF and what do they do?

A

IGF1 - major growth factor in adults

IG2- mainly involved in foetal growth

433
Q

Apart from endocrine functions does IGF have any other function?

A

Paracrine and autocrine function

Muscle repair and growt

434
Q

What are the functions of IGFs?

A

Hypertrophy, hyperplasia,

inc rate of: protein synthesis, lipolysis

435
Q

How can IGFs have metabolic effects and insulin have mitogenic effects?

A

The receptors of insulin and IGF can dimerise together rather than just by its own receptors
This causes cross reactivity
Insulin receptor chain (alpha and beta subunits) + IGF chain (alpha and beta subunits)

436
Q

Apart from insulin and IGF what other hormones influence growth?

A

Thyroid hormones - promote CNS development and enhance GH secretion
Androgens - accelerate pubertal growth spurt, inc muscle mass, promote closure of epiphyseal plates
Oestrogens - decrease somatic growth, promote closure of epiphyseal plates
Glucocorticoids - inhibit somatic growth

437
Q

What’s a common clinical presentation of pituitary tumours?

A

Mass effect of tumour on local structures causes visual loss and headaches
Abnormal in pituitary function -> hyper/hypo secretion -> effects of those

438
Q

What visual field loss would be seen in a pituitary adenoma?

A

bitemporal hemianopia - tunnel vision

439
Q

What symptoms would be seen in a lateral displacement of the pituitary tumour?

A

Pain and double vision

Cranial nerve palsy

440
Q

What are signs/symptoms of TSH deficiency?

A

Low thyroid hormone, Low T4 and non-elevated TSH (secondary hypothyroidism)
Cold, weight gain, tiredness, slow pulse

441
Q

What are the signs and symptoms of ACTH deficiency?

A 
Low cortisol
Tiredness, dizziness
Low BP
Low sodium
Can be life threatening
Cortisol effects: increase GFR, inc phosphate excretion, inc Na and H2O retention, inc K+ excretion
442
Q

What type of test would be done to diagnose a suspected hormone excess in the adrenal axis?

A

Suppression test
Suppress ACTH axis with steroids -> should theoretically decrease ACTH. IF ACTH isn’t reduced then there is an atopic supply of ACTH

443
Q

What type of test would be done to diagnose a suspected hormone deficiency in the adrenal axis?

A

Direct stimulation of adrenals by ACTH (synACTHen)
Response to hypoglycaemic stress test (insulin stress test)
Addisons disease - excess ACTH & deficiency in cortisol

444
Q

What type of test would be done to diagnose a suspected hormone excess in the GH axis?

A

Suppress GH axis with glucose load (glucose tolerance test)

445
Q

What type of test would be done to diagnose a suspected hormone deficiency in the GH axis?

A

Response to hypoglycaemic stress (insulin stress test)

446
Q

How are prolactinoma’s classed in terms of size?

A

Large tumour - macro-adenoma >1cm

Small tumour - micro-adenoma <1cm

447
Q

How are prolactinoma’s treated?

A

Dopamine agonists - D2 receptor
Cabergoline or bromocriptine
Anti-sickness and anti-psychotic drugs have dopamine antagonist and agonist affects respectively therefore contraindicated
Make sure patient isn’t pregnant

448
Q

How does protecting affect LH levels?

A

Prolactin acts on the ovary/ testes to inhibit LH effects and its secretion on the hypothalamus.
Hyperprolactinaemia’s can cause reduced testosterone/ oestrogen production

449
Q

What are symptoms of hyperprolactinaemia in women?

A

Menstrual disturbances
Fertility problems
Galactorrhoea

450
Q

What are symptoms of hyperprolactinaemia in men?

A

Man present later than women - therefore larger tumours
Symptoms of low testosterone are non-specific
May present with mass symptoms - visual disturbances

451
Q

What would be the effect of anything blocking the infundibulum connecting the hypothalamus and the pituitary on prolactin levels?

A

Prolactin constitutively produced -> no inhibition -> production will be remain constant

452
Q

What are long term complications of untreated acromegaly?

A

Premature cardiovascular death
Increased risk of colonic tumours
Probably increased risk of thyroid cancers
Disfiguring body changes that may be irreversible
HTN, DM

453
Q

What biochemical tests would be done to confirm acromegaly?

A

Oral glucose tolerance test
Failure to suppress GH
Elevated IGF-1 level (age related ref range)
Growth hormone day curve - elevated mean GH

454
Q

What is the treatment of acromegaly?

A

(1) Surgical removal of tumour = Trans-sphenoidal hypophysectomy
(2) Radiotherapy -
(3) Reduce GH secretion =
Dopamine agonists - cabergoline and bromocriptine
Somatostatin analogues - octreotide, lanreotide
(4) Block GH receptor = pegvisomant

455
Q

What is cushings disease?

A

Excess cortisol production usually due to ACTH secreting pituitary tumour

456
Q

What are the 6 classical changes in appearance in Cushings disease?

A 
Round pink face with round abdomen - central obesity
Skinny and weak arms and legs
Thin skin and easy bruising
Red stretch marks (striae) on abdomen
High blood pressure
Hyperglycaemia -> DM
Oestoporosis
Buffalo hump on neck
457
Q

What is the difference between Cushings disease and Cushings syndrome?

A

Disease - pituitary tumour

Syndrome - Adrenal tumour, ectopic ACTH, steroid medication

458
Q

What is diabetes insipidus?

A

Large quantities of pale urine + extreme thirst due to fluid loss
ADH production is not occurring - similar to alcohol - reduced aquaporin translocation onto apical surface therefore reduced water reabsorption -> increase urine production

459
Q

What are the 2 subtypes of Diabetes Insipidus?

A

Cranial

Nephrogenic

460
Q

What is the difference between cranial diabetes insipidus and nephrogenic diabetes insipidus?

A

Cranial DI is vasopressin deficiency - pituitary disease

Nephrogenic DI is vasopressin resistance - kidney disease

461
Q

What are the consequences of untreated DI?

A

Severe dehydration
Severe hypernatraemia
Reduced consciousness, coma and death

462
Q

What is the treatment for cranial DI?

A

synthetic vasopressin

Desmopressin nasal spray, tablets or injection

463
Q

What is pituitary apoplexy?

A

apoplexy = stroke
Sudden vascular event in the pituitary tumour
Infarction or haemorrhage

464
Q

What is a clinical presentation of pituitary apoplexy?

A 
Sudden onset headache
Double vision
Visual field loss
Cranial nerve palsy
Hypopituitarism - cortisol deficiency most dangerous
465
Q

What autoantibodies can be detected in T1DM?

A

Islet cells auto-antibodies
Insulin auto-antibodies
IA2 - islet secretory protein
GAD - Glutamic acid decarboxylase

466
Q

What the difference between glycosylation and glycation?

A

Glycosylation - post-translational modification - not associated with disease
Glycation - random non-enzymatic reaction - associated with disease

467
Q

What are the layers of the adrenal glands?

A

Cortex (out to in)
Zona glomerulosa -> Zona fasciculata -> Zona reticularis
Medulla:
Chromaffin cells - adrenaline/ noradrenaline

468
Q

What hormones are produced in the adrenal glands and at what layers?

A

Cortex
Zona glomerulosa - mineralocorticoids
Zona fasciculata - glucocorticoids
Zona reticularis - glucocorticoids and small amounts of androgens
Medulla:
Chromaffin cells - adrenaline/ noradrenaline

469
Q

What are the 2 subtypes of hyperaldosteronism?

A

Primary and secondary

470
Q

What is primary hyperaldosteronism?

A

Defect in adrenal cortex

(1) Bilateral idiopathic adrenal hyperplasia
(2) Aldosterone secreting adrenal adenoma (Conn’s syndrome)
(3) Low renin levels (High aldosterone:renin ratio)

471
Q

What is secondary hyperaldosteronism?

A

(1) Renin producing tumour (juxtaglomerular tumour)
(2) Renal artery stenosis
(3) High renin levels (low aldosterone:renin ratio)

472
Q

What are signs of hyperaldosteronism?

A 
HTN
Left ventricular hypertrophy
Stroke
Hypernatraemia
Hypokalaemia
473
Q

What is the treatment of hyperaldosteronism?

A

Depends on type
Aldosterone producing adenomas - surgical resection
Spironolactone/ eplerenone (mineralocorticoid receptor antagonist)

474
Q

What is the plasma protein carrier for cortisol?

A

Transcortin

475
Q

What are the 6 effects of cortisol?

A

(1) Inc proteolysis
(2) Inc lipolysis
(3) inc Gluconeogenesis
(4) Resistance to stress (inc supply of glucose, inc BP, inc blood vessel sensitivity to vasoconstrictors)
(5) anti-inflammatory effects - inhibits macrophage activity and mast cell degranulation
(6) Depression of immune response

476
Q

What are the effects of glucocorticoids on metabolism specifically in the liver?

A

Inc glycogen storage

Inc gluconeogenesis by inc amount and activity of enzymes

477
Q

What are the effects of glucocorticoids on metabolism specifically in the adipocytes?

A

Dec glucose utilisation
Dec sensitivity to insulin
Inc lipolysis

478
Q

What are the effects of glucocorticoids on metabolism specifically in the muscle?

A

Inc protein degradation
Dec protein synthesis
Dec glucose utilisation
Dec sensitivity to insulin - cortisol inhibits insulin-induced GLUT4 translocation in muscle (prevents glucose uptake)

479
Q

How do the skeletal muscles and adipocytes feedback onto the liver during glucocorticoid release?

A

Skeletal muscle - supplies amino acids for gluconeogenesis

Adipocytes - supplies glycerol for glycogenesis

480
Q

What are the effects of chronically high levels of cortisol?

A 
Redistribution of fat to:
Abdomen
Supraclavicular fat pads
Dorso-cervical fat pad (Buffalo hump)
Moon face (moon face)
481
Q

What is addisons disease and most common cause?

A

Reduced cortisol production
Destructive atrophy from autoimmune response
Women>Men

482
Q

What are signs and symptoms of addisons disease?

A

Postural hypotension
Lethargy, Weight loss, Anorexia
Inc skin pigmentation, vitiligo, dizziness
Hypoglycaemia

483
Q

Why do patients get skin hyperpigmentation in Addisons disease?

A

Dec cortisol -> Negative feedback on pituitary -> More POMC required to synthesise ACTH -> ACTH + MSH produced
MSH - melanocyte stimulating hormone
ACTH will also activate melanocortin receptors on melanocytes -> hyperpigmentation

484
Q

What is an Addisonian crisis?

A

Life threatening emergency due to adrenal insufficiency

485
Q

What precipitates an Addisonian crisis?

A

Precipitated by: Severe stress, salt depravation, infection, trauma, cold exposure, over exertion, abrupt steroid drug withdrawal

486
Q

What are symptoms of Addisonian crisis?

A

N+V
Pyrexia
Hypotension
Vascular collapse

487
Q

What is the treatment for Addisonian crisis?

A

Fluid replacement

Cortisol - dexamethasone

488
Q

Why does the adrenal medulla secrete 80% adrenaline and 20% noradrenaline?

A

20% of the cells lack N-methyl transferase which is used to convert noradrenaline to adrenaline

489
Q

What affects does cAMP and PKA have on the pacemaker current in the heart?

A

cAMP increases the slope of the upstroke during depolarisation
PKA decreases the time it takes for depolarisation to occur

490
Q

What is phaeochromocytoma?

A

Rare - catecholamine secreting tumour mainly noradrenaline

May precipitate life-threatening hypertension

491
Q

What are the signs/symptoms of phaeochromocytoma?

A 
Severe HTN
Headaches
Palpitations
Diaphoresis (excess sweating)
Anxiety
Weight loss
Elevated blood glucose
492
Q

What are the signs/ symptoms of mineralocorticoid deficiency?

A

Dizziness
Low Na
High K

493
Q

What are the signs/ symptoms of androgen deficiency?

A

Loss of body hair in women

Low libido

494
Q

What are the signs/ symptoms of excessive catecholamine secretion?

A

Acute episodes
Sweating, anxiety, palpitations, high or low BP, collapse
-> sudden death

495
Q

How would you do a biochemical assessment of the adrenal medulla?

A

24hour urine catecholamines - adrenaline, NA, dopamine, 3-methoxy-tyramine
24hour urine metanephrines - metabolites of adrenaline and noradrenaline
Plasma metanephrines

496
Q

What are causes of primary adrenal failure?

A 
auto-immune
infection- tb, fungal
Infiltration - amyloid, haemochromatosis
Malignancy - lung, breast, kidney
Genetic - Congenital Adrenal Hyperplasia, adrenal-leukodystrophy
Vascular - haemorrhage/ infarction
Iatrogenic - adrenalectomy, drugs
497
Q

What is the treatment for addisons?

A

Glucocorticoid - hydrocortisone, prednisolone

Mineralocorticoid - fludrocortisone

498
Q

What is adrenal cushings syndrome?

A

ACTH is suppressed - ACTH independent

Excess cortisol production usually due to tumour on adrenals

499
Q

How would adrenal cushings syndrome present?

A

Adrogenic symptoms - hirsutism, acne, greasy skin

Virilising features - androgenic alopecia, deep voice, clitoromegaly

500
Q

What is the adrenal cushings syndrome treatment?

A

Surgical intervention - adrenalectomy

Risk of hypoadrenalism due to contra-lateral adrenal suppression

501
Q

What is congenital adrenal hyperplasia?

A

Rare inherited disorder - autosomal recessive
Adrenal crisis and ambiguous genitalia - block in adrenal cortex pathway - presentation depends on enzyme defect
21-hydroxylase deficiency -> can’t produce glucocorticoid/ mineralocorticoids BUT still make androgens

502
Q

What is a paraganglioma?

A

Extra-adrenal tumour

Chromaffin tissue origin

503
Q

What neuroendocrine markers can be used to diagnose phaeochromocytoma and paraganglioma?

A

Chromogranin A

504
Q

How do you manage phaeochromocytoma and paraganglioma?

A

Alpha-blockade = phenoxybenzamine
Beta-blocker = bisoprolol
Surgical excision
Unopposed alpha-stimulation can cause a hypertensive crisis therefore give both a + b - blockade

505
Q

What is the cervical spinal level of the middle of the thyroid?

A

C7

506
Q

During embryological development what does the thyroid gland descend through?

A

Thyroglossal duct

507
Q

What is the histology of the thyroid tissue?

A

Follicular cells arranged in spheres called thyroid follicles
Follicles filled with colloid, a deposit of thyroglobulin - thyroid hormone is made
Colloid is extracellular even though it is inside the follicle

508
Q

What do parafollicular cells release in the thyroid?

A

Calcitonin

509
Q

How are the thyroid and parathyroid glands distinct?

A

Parathyroid gland - principal cells also called chief cells produce parathyroid hormone
Thyroid gland - thyroid follicular cells produce thyroid hormone, parafollicular cells produce calcitonin

510
Q

What cells in the parathyroid gland produce PTH?

A

Principal cells - chief cells

511
Q

Describe the molecule of the thyroid hormones?

A

2 tyrosine linked together with iodine at three or four positions on the aromatic rings
Monoiodotyrosine + diiodotyrosine = triiodothyronine
Diiodotyrosine + diiodotyrosine = tetraiodothyronine

512
Q

What is the method of producing thyroid hormones?

A

Thyroglobulin acts as a scaffold on which thyroid hormones are formed.
Follicular cells produce thyroglobulin protein intracellularly + iodide transported into colloid -> released into the colloid -> iodinated to make the T1/T2 -> coupling -> T3/T4 -> pinocytosis into cell into lysosome -> phagolysosome -> release of T3/T3 into the interstitium

513
Q

What is the function of thyroid peroxidase?

A

Membrane bound enzyme that regulates 3 separate reactions involving iodide

(1) Oxidation of iodide to iodine - requires the presence of H2O2
(2) Addition of iodine to tyrosine acceptor residues on the protein thyroglobulin
(3) Coupling of MIT or DIT to generate thyroid hormones within the thyroglobulin protein

514
Q

What in the body is iodine used for?

A

Thyroid hormones and precursors are the only molecules in the human body that contain iodine
90-95% of iodine in the body is contained in thyroid gland

515
Q

How is iodine absorbed into the thyroid gland?

A

Iodide (I-) is taken up from blood by thyroid epithelial cells which has a sodium-iodide symporter or “iodine trap”

516
Q

How much of the T4 is produced and converted into T3?

A

90% of thyroid hormone secreted is T4
T4 - longer half life than T3
80% T3 derived from T4

517
Q

What is the difference between T3 and T4 apart from the iodine amount?

A

Biological activity of T3 is 4 times that of T4
T4 has a longer half life than T3
Most T4 converted to T3 in liver and kidneys

518
Q

How is T3/T4 transported in the blood?

A

Thyroxine-binding globulin

519
Q

What is the function of thyroid hormone?

A

Metabolism - stimulaiton of metabolic pathways -> lipid metabolism and carbohydrate metabolism

Growth and development - In most tissues thyroid hormones stimulate the metabolic rate by: inc number and size of mitochondria, stimulating the synthesis of enzymes in the respiratory chain

Sympathomimetic effects - increase target cell response to catecholamines - inc receptor no on target cells

520
Q

What are the similarities of TSH/ FSH/ LH?

A

They all have alpha subunits

The beta subunits provide unique biological activity of each of them

521
Q

What is the type of the TSH receptor and how it works?

A

TSH receptors -> Gs -> ATP -> cAMP -> PKA -> Protein P -> causes pinocytosis of thyroid hormone (T3/T4)
Gq ->PLC -> DAG, IP3 -> Ca2+ release via IP3 receptor and PKC activation -> thyroid hormone release

522
Q

On what organs do thyroid hormone not stimulate the metabolic rate?

A

Brain
Spleen
Testis

523
Q

What is the cardiac response to thyroid hormone?

A

Increases heart’s response to catecholamines
Inc cardiac output - +vely chronotropic and inotropic
Inc peripheral vasodilation

524
Q

What is the nervous system response to thyroid hormone?

A

Essential for both development and adult function

Inc myelination of nerves and development of neurones

525
Q

What receptor does thyroid hormone work on?

A

Thyroid hormone receptor - pre-bound to specific DNA sequences on DNA called a hormone response elements in promoter region of thyroid hormone regulated genes

526
Q

What are some examples of thyroid hormone activated genes?

A 
Phosphoenolpyruvate carboxylate kinase (PEPCK)
Ca/ATPase
Na/K ATPase
Cytochrome oxidase
6 - phosphogluconate dehydrogenase
527
Q

What is the release profile of TSH?

A

Diurnal variation

528
Q

What is a goitre?

A

Enlargement of the thyroid gland
May accompany either hypo or hyperthyroidism
Develops when the thyroid gland is overstimulated

529
Q

What are causes of hypothyroidism?

A
  • Failure of thyroid gland
  • TSH/TRH deficiency
  • Inadequate dietary supply of iodine
  • radioactive iodine
  • autoimmunity
  • post surgery
  • congenital
  • anti-thyroid drugs
530
Q

What are general symptoms of hypothyroidism?

A

Obesity, Lethargy, Intolerance to cold, Bradycardia, Dry skin, Alopecia, Hoarse voice, Constipation, Slow reflexes

531
Q

What are the effects of hypothyroidism in infants and adults?

A

Infants - cretinism = Dwarfed stature, Mental deficiency, Poor bone development, Slow pulse, Muscle weakness, GI disturbances
Adults - myxoedema = Thick puffy skin, muscle weakness, slow speech, mental deterioration, intolerance to cold

532
Q

What is Hashimoto’s disease?

A

Autoimmune disease resulting in destruction of thyroid follicles -> hypothyroidism
5x w>m
Plasma: low T3/T4 + high TSH

533
Q

How do you treat Hashimoto’s disease?

A

Oral thyroid hormone - T4 long half life

534
Q

What are the causes of hyperthyroidism?

A 
Autoimmune Grave's disease
Toxic multi nodular goitre
Thyroiditis
Excessive T4/T3 therapy
Drugs - amiodarone
Ectopic thyroid tissue
535
Q

What are symptoms of hyperthyroidism?

A

Weight loss, irritability, heat intolerance, sweating warm vasodilator hands, tachycardia, fatigue, weakness, increased bowel movements, possible tremor, hyper-reflexia, breathlessness, loss of libido

536
Q

What is Grave’s disease?

A

Autoimmune condition causing hyperthyroidism
Cause by production of thyroid stimulating immunoglobulin -> continuously stimulates thyroid hormone secretion outside normal negative feedback control

537
Q

What is an uncommon condition caused by Grave’s disease?

A

Bulging eyes- not in every case

TSI affect fibroblasts - CD20 receptor in eyes and extra-ocular muscles

538
Q

What imaging technique would be used for thyroid function?

A

Technetium-99m - detection by gamma camera
1 day biological half life
Also used for: bone scan, MI perfusion, Brain imaging

539
Q

What are antithyroid drugs - treatment for hyperthyroidism?

A

Carbimazole most commonly used
Prevents thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin - block formation of thyroid hormone
Propylthiouracil
Radioactive iodine

540
Q

How long does hypothyroidism take to respond once treatment has started?

A

6-8 weeks

541
Q

What is a potential serious problem with thyroid hormone deficiency?

A

Myxoedema coma
Severe hypothyroidism
Hypothermia and fluid overload in heart pericardial effusion

542
Q

What is borderline or sub-clinical hypothyroidism?

A

Low normal fT4 and high TSH very common

543
Q

What are the causes of thyroiditis?

A 
Inflammation of thyroid
Release of thyroxine into circulation
Viral infection - de quervain's thyroiditis
After childbirth - post-partum
Medication - amiodarone
544
Q

What is a thyroid storm?

A

Rare condition - excess thyroid hormone

Hyperpyrexia, tachycardia, cardiac failure, liver dysfunction

545
Q

What is the problem with pregnancy and Graves disease?

A

Graves disease autoantibodies can cross placenta - baby can be born with hyperthyroidism

546
Q

What are the 4 subcategories of types of goitre?

A

Diffuse goitre
Nodular goitre
Fibrotic goitre
Iodine deficiency

547
Q

How is most of the calcium in the body kept?

A

In hydroxyapatite crystals in the bone - 99%

548
Q

How much calcium is exchanged between the bone and the ECF/ day?

A

300-600mg

549
Q

What are the 3 interconvertible fractions of calcium storage in the body?

A

Ionised
Protein bound
Complexed in with phosphate or citrate

550
Q

What 3 hormones regulate calcium and phosphate?

A

Parathyroid hormone - response to hypocalcaemia
Calcitonin - response to hypercalcaemia
Vit D - absorption of calcium

551
Q

What cells produce calcitonin?

A

C cells in the thyroid

552
Q

How many parathyroid glands do we have?

A

4

2 on each lobe

553
Q

How is PTH synthesised and transported around the body?

A

Transported - free in the serum - unbound
Synthesis - regulated by transcription and post-transcription levels = Low serum Ca upregulated gene, high serum Ca down regulates gene, low serum Ca prolongs survival of mRNA

554
Q

What is important about the synthesis of PTH and the storage?

A

Synthesis is constitutively
T1/2 is 4 mins
released PTH cleaved in liver - active form
PTH not stored

555
Q

How is PTH removed from circulation?

A

Chief cells degrade the hormone

Cleavage of PTH in chief cells accelerated by high serum Ca levels

556
Q

What type of receptor is a Calcium receptor and how does it function when it comes to Ca homeostasis?

A

GPCR - Gs
PIP2 -> DAG, IP3 -> IP3 releases calcium intracellularly -> PLA2 -> AA inhibits PTH secretion + increases VDR expression -> reduces PTH synthesis.

557
Q

What are the PTH target organs and their effects?

A

Bone - increased resorption - increase activity of osteoclasts + decreased activity of osteoblasts
Intestines - activates Vit D - inc uptake from GIT
Kidney - decrease loss to urine by inc re-uptake, loss of phosphate so kidney stones doesn’t become a problem

558
Q

Where are calcium, phosphate and magnesium resorbed the most in the kidneys?

A

PCT - Ca2+ and PO4-

DCT - Mg2+ + thick ascending limb of loop of Henle

559
Q

What is the process of Vit D synthesis?

A

Cholesterol in skin converted to Vit D3 by sun -> Liver converts to 25-dihydroxyvitamin D3 -> kidney converts to 1,25-dihydroxyvitamin D3

560
Q

What two mechanisms does Vit D prevent bone resorption?

A

Inhibits the function of osteoclasts indirectly by action on osteoblasts which produce cytokines that prevent osteoclasts working.
Also - inhibit haematopoietic stem cells producing osteoclasts

561
Q

What is a problem with chronic hypercalcaemia?

A 
Stones, Moans, Groans, Bones
Renal calculi
Kidney damage due to impaired sodium and water retention and renal calculi
Constipation, peptic ulcer, pancreatitis
Dehydration
Tiredness
Depression
562
Q

What is the problem with hypocalcaemia?

A 
Hyper-excitability of NMJ
Pins and needles, - paraesthesia
Tetany
Paralysis
Convulsions
563
Q

What bone problem does prostate cancer mets cause?

A

Oestoblastic mets - no hypercalcaemia

564
Q

What bone problems do most of the cancers that metastasise into the bone cause?

A

Hypercalcaemia
Osteolytic usually
Multiple myeloma commonly

565
Q

What is primary hyperparathyroidism?

A

One of 4 parathyroid glands develops into an adenoma and secretes excessive PTH
Inc serum Ca and dec serum PO4-

566
Q

What is secondary hyperparathyroidism?

A

All 4 parathyroid glands becomes hyper plastic
Seen in Vit D deficiency
Chronic renal failure when can’t convert 25-hydroxyvit D into 1,25 hydroxyvit D

567
Q

How does calcium cause changes in neuronal activity?

A

Hypocalcaemia -> raises threshold for depolarisation -> easy to depolarise -> easy for action potential
Hypercalcaemia -> suppression of neuronal activity - lethargy, confusion, coma

568
Q

What is an iatrogenic cause of symptomatic hypocalcaemia?

A

Post total-thyroidectomy - inadvertent removal/ ischaemia of parathyroid glands

569
Q

When does most of the foetal growth occur during pregnanct?

A

last 1/3 pregnancy 2/3 foetal growth occurs

28 weeks onwards 1k to 3.5kg

570
Q

What are the 2 phases of metabolic adaptation during pregnancy?

A

Anabolic and catabolic phase
Anabolic - building stores especially adipose
Catabolic - maternal metabolism adapts to meet increasing demand by foetus/placenta

571
Q

What happens to insulin sensitivity during pregnancy?

A

(1) early pregnancy - small increase in level of insulin sensitivity
(2) late pregnancy - decrease in insulin sensitivity + increased insulin resistance - results in increase maternal glucose and free fatty acids in blood

572
Q

What glucose transporter facilitates glucose transport through the placenta?

A

GLUT1

573
Q

What are anti-insulin hormones secreted by the placenta?

A

Placenta secretes: Corticotropin releasing hormone - inc 1000 fold in maternal blood.
Human placental lactogen + progesterone

574
Q

How does oestrogen and progesterone affect insulin in pregnancy?

A

Increases sensitivity of maternal pancreatic beta-cells to blood glucose
Beta-cell hyperplasia and hypertrophy occurs
If beta cells don’t respond - gestational diabetes occurs

575
Q

What are 3 underlying causes of gestational diabetes?

A

1 - autoantibodies similar to T1DM
2 - genetic susceptibility to maturity onset diabetes
3 - beta-cell dysfunction in setting of obesity and chronic insulin resistance - i.e. evolving diabetes

576
Q

What are complications of gestational diabetes?

A

Inc incidence of miscarriage
Inc incidence of congenital malformations
Foetal macrosomia - leading to shoulder dystocia
Gestational HTN/ preeclampsia

577
Q

What are risk factors for gestational diabetes?

A

Maternal age >25 yrs
BMI >25Kg/M2
Race/ethnicity - asian, black, Hispanic
FMHx - DM and macrosomia

578
Q

How do you manage gestational diabetes?

A

Dietary modification
Insulin injection if persistent hyperglycaemia
Regular ultrasound scans

579
Q

What are the metabolic responses to exercise?

A

Inc energy demands of skeletal and cardiac muscle - mobilisation of energy stores
Minimal disturbances to metabolic homeostasis
Glucose supply to brain - maintained
End products removed quickly away

580
Q

How does energy requirement change from BMR to a marathon?

A

BMR - 4kJ/min
100m sprint - 200kJ/min
1500 race - 140kJ/min
Marathon - 80kJ/min

581
Q

How long of anaerobic exercise can the body last by breaking down muscle glycogen?

A

2 minutes

582
Q

How long does the ATP energy come from during exercise?

A

2 seconds = ATP concentration already inside the cells
5 seconds = muscle creatine phosphate
2 minutes = high intensity - muscle glycogen - glycolysis anaerobic production or low intensity - aerobic - 60minutes
>60 mins = low intensity - plasma FFA, adipose tissue triglycerides
60 mins - 4 hours = high intensity - muscle glycogen, plasma glucose, liver glycogen - aerobic

Medicine (15 decks)

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