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
2
Q
What enzyme breaks down alcohol?
A
Alcohol dehydrogenase to acetaldehyde
3
Q
What enzymes breaks down acetaldehyde?
A
Aldehyde dehydrogenase to acetate
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
5
Q
What enzymes apart from alcohol dehydrogenase break down alcohol?
A
CYP2E1 liver
Catalase in brain
6
Q
How much is 1 unit of alcohol?
A
10ml of pure alcohol = 8grams
7
Q
What is the elimination rate of alcohol?
A
7grams/hours
Constant rate of elimination
8
Q
Production of what enzymes causes the hangover feeling?
A
Acetaldehyde
9
Q
Why do people who drink alcohol need to urinate more frequently?
A
Ethanol inhibits ADH release -> increase water loss -> increase urinary frequency
10
Q
Excess of what 2 substances makes the liver undergo negative changes in alcohol excess?
A
NADH and Acteyl-CoA
11
Q
What are the 4 main end point of alcohol oxidation?
A
Lactic acidosis
Urate crystals accumulate in tissues -> gout
Hypoglycaemia
Fatty liver
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
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
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
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
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
17
Q
What are the two main groups of reactive species that cause oxidative damage?
A
ROS
RNS
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
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
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
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
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
23
Q
What are some endogenous sources of biological oxidants?
A
Electron transport chain
Nitric oxide synthases
NADPH oxidases
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
25
What amino acid is used to produce Nitric oxide and what is the resultant amino acid?
Arginine used
| Citrulline produced
26
What is the respiratory burst?
- Rapid release of superoxide (O2.) from phagocytic cells -> H2O2 -{Cl- + myeloperoxidase}-> HOCl (hypochlorite)
- O2. + NO. -> ONOO.
- ROS and peroxynitrite destroy invading bacteria
27
What enzymes are cellular defences to oxygen free radicals?
Superoxide dismutase and catalase
| Glutathione
28
How does superoxide dismutase work to reduce free radicals?
```
Converts superoxide (O2.) to H2O2 and oxygen
Primary defence as superoxide is strong initiator of chain reactions
```
29
How does catalase work to reduce free radicals?
Converts H2O2 to water and oxygen
| Declining levels in hair follicles -> explains grey hair
30
How does glutathione work against free radicals?
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
31
What is the pentose phosphate pathway?
Glucose-6-phosphate -{+NADP + glucose-6-phosphate dehydrogenase}-> {NADPH} + 6-phosphogluconate -{+NADP}-> {NADPH}->Ribulose-5-phosphate + {CO2} -> Ribose-5-phosphate
32
Why is the pentose phosphate pathway important in oxidative stress?
Source of NADPH which is a reducing agent for glutathione
| Produces C5-sugar= Nucleotides and DNA/RNA
33
What function does Vitamin E and C have in oxidate stress?
Vit E is a lipid soluble antioxidant that acts against lipid peroxidation
Vit C water soluble -> regeneration of Vit E
34
What is a potential complication of dietary lactose and an increased activity of aldose reductase?
Lactose -> glucose + galactose
Galactose -{NADPH + aldose reductase}-> Galactitol -> osmotic pressure effect in the eye -> cataracts (crystalline protein in lens of eye denatured)
35
Deficiency in which enzymes can lead to galactosaemia and cataracts?
Galactokinase
Uridyl transferase
UDP-galactose epimerase
36
What is the function of galactokinase in preventing galactosaemia?
Galactose -{galactokinase}-> Galactose-1-P -{uridyl transferase}-> Glucose-1P -> Glucose-6P -> glycolysis
37
What is the function of uridyl transferase in preventing galactosaemia?
(1) Galactose -{galactokinase}-> Galactose-1-P
(2) Galactose-1-P -{uridyl transferase}-> Glucose-1P ->
(3) Glu-1-P -{phosphoglucomutase}-> Glucose-6P -> glycolysis
38
What is the function of UDP-galactose epimerase in preventing galactosaemia?
(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
39
What are symptoms of galactosaemia?
```
Hepatomegaly+ cirrhosis
Renal failure
Vomiting
Seizure + brain damage
Cataracts
Hypoglycaemia
```
40
What is a G6PD deficiency and why does it cause problems?
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
41
What occurs in RBC in G6PD deficiency in case of oxidative stress?
Increased oxidative stress -> more O2 free radicals -> Protein damage -> aggregates of cross-linked Hb -> Heinz bodies (precipitated Hb)-> haemolysis
42
What can precipitate haemolysis in G6PD deficiency patients?
Infection
Drugs e.g. anti-malarials
Broad beans
43
What is the function of acetylcysteine treatment in paracetamol poisoning?
- 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
44
What are the major nitrogen containing compounds found in the body?
Amino acids
Proteins
Purines + pyrimidines (DNA/RNA)
45
What is nitrogen balance?
In equilibrium - intake=output
Positive balance - Intake > output
Negative balance - Intake < output
46
What states are in a positive nitrogen balance?
Normal state in growth
Pregnancy
Adults recovering from malnutrition
47
What states are in a negative nitrogen balance?
Net loss of body protein
Trauma
Infection
Malnutrition
48
How much nitrogen is required for intake?
16grams approx in the form of amino acids/ proteins
49
How is nitrogen used in the body in simple terms?
De novo amino acid synthesis
Glucogenic amino acids and ketogenic amino acids -> gluconeogenesis and ketone bodies -> energy
Amino group -> urea -> urine loss
50
Name one glucogenic, ketogenic and a combined glucogenic/ketogenic amino acid
Glucogenic - Aspartate
Ketogenic - Leucine
Both- tyrosine, threonine
51
What is the mnemonic for the essential amino acids and what are they
```
PVT TIM HALL
Phenyalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Alanine
Leucine
Lysine
```
52
In what two states would affect protein mobilisation and what hormones are involved?
-Insulin + growth hormone - protein synthesis predominantly
| Glucocorticoids (cortisol) - protein degradation predominantly
53
What are the two main pathways of removal of nitrogen from amino acids?
Transamination
| Deamination
54
What is the process of transamination?
- 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
55
What are the ALT and AST enzymes in relation to amino acid conversion?
```
ALT= alanine aminotransferase - converts alanine to glutamate
AST= aspartate aminotransferase - converts glutamate to aspartate
```
56
What is the process of deamination?
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
57
What is urea and how is it excreted?
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
58
What is the urea cycle?
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
59
What substance causes the N+V, delirium problems seen in refeeding syndrome?
Ammonia toxicity
| Avoided by gradual increase in protein ingested - waiting for enzymes to upregulate
60
What are symptoms of urea toxicity?
Vomiting, lethargy, irritability, mental retardation, seizures, coma
61
How do you manage hyperuraemia in the long term?
low protein diet
| replace amino acids with keto acids
62
What two transport mechanisms are there for handling nitrogen from Amino acids?
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
63
What is phenylketonuria?
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
64
What is homocystinuria?
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
65
What 4 tissues have an absolute requirement for glucose?
RBC
Neutrophils
Innermost cells of kidney medulla
Lens of the eye
66
At what blood glucose level would be enough to cause brain damage and death?
<0.6mmol/L
67
At what blood glucose level would be enough to cause confusion?
2.8mmol/L
68
What enzyme is responsible for converting glucose to glycogen?
Glycogen synthase
69
What is the difference between the storage of glycogen in muscles compared to liver?
Muscle - between intra and intermyofibrillar glycogen is stored
Hepatocyte - glycogen granules
70
What are the two types of bonds between glucose molecules that hold it in place within glycogen?
1-4, and 1,6 glycosidic bonds
71
What is the glycogenesis process?
(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
72
What are the steps of glycogenolysis?
Glycogen + Pi -{glycogen phosphorylase or de-branching enzyme}-> G1P + glycogen
73
What is the difference between the stores of glycogen in muscles and the liver, in terms of amount and why?
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
74
What effect does insulin have on the enzymes that convert glucose to glucose-6-phosphate?
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
75
Do muscles have a glucagon receptor and why?
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
76
What benefit would it be to have AMP an allosteric activator of muscle glycogen phosphorylase?
AMP - low energy signal ->activate glycogen phosphorylase -> glycogenolysis -> glucose released into cells -> glycolysis -> ATP production
77
What affect does glucagon have on the glycogen enzymes that maintain blood glucose?
Glycogen synthase - inhibited by phosphorylation
| Glycogen phosphorylase - activated - inhibited by phosphorylation
78
What affect does insulin have on the glycogen enzymes that maintain blood glucose?
Glycogen synthase - activated - dephosphorylation
| Glycogen phorphorylase - inhibited - dephosphorylation
79
What is a glycogen storage disease?
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
80
Name 2 glycogen storage diseases and what enzyme is affected
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
81
Where does gluconeogenesis occur?
Liver
| Lesser extent in kidney cortex
82
What are 3 main precursors to gluconeogenesis?
Lactate
Glycerol
Amino acids
83
What is the Cori Cycle?
Lactate produced in the muscles -> blood -> liver -> 2xlactate -> glucose -> blood -> muscles
84
What are the 3 control enzymes in gluconeogenesis from pyruvate?
1 - phosphoenolpyruvate carboxykinase
2 - fructose 1,6,-bisphosphatase (opposite of phosphofructokinase)
3 - glucose-6-phosphatase (opposite of hexokinase)
85
Is gluconeogenesis just a reversal of glycolysis/ Krebs?
No
| The pathway goes backwards but from pyruvate-> oxaloacetate in Krebs -> phosphoenolpyruvate -> back to glucose
86
What activities release hormones that regulate the enzymes for gluconeogenesis?
Starvation - glucagon
Prolonged exercise - insulin
Stress - cortisol
87
What 2 enzymes of gluconeogenesis are regulated by hormones in response to starvation?
fructose 1,6-bisphophatase
| Phosphoenolpyruvate carboxykinase
88
What happens to fructose 1,6-bisphophatase and
| phosphoenolpyruvate carboxykinase when glucagon and cortisol are released?
fructose 1,6-bisphophatase - increased amount and activity
| Phosphoenolpyruvate carboxykinase - increased amount
89
What happens to fructose 1,6-bisphophatase and
| phosphoenolpyruvate carboxykinase when insulin is released?
fructose 1,6-bisphophatase - decreased amount and activity
| phosphoenolpyruvate carboxykinase - decreased amount
90
How many hours after consuming a meal does glycogenolysis and gluconeogenesis occur?
Glycogenolysis - from 2 hours after eating till 8-10 hours after eating.
Gluconeogenesis - from 8-10 hours onwards
91
During which processes are lipids/ triacylglycerol used?
Prolonged exercise, stress, starvation, during pregnancy
92
Where does lipogenesis occur mainly in the body?
Liver
93
How is glucose converted to fatty acids?
Glucose -> pyruvate -> mitochondrion -> acetyl-CoA + oxaloacetate (OAA) -> citrate -> cytoplasm -> Acetyl-CoA + OAA -> acetyl-CoA carboxylase produces malonyl-CoA -> FA synthase complex + malonyl-CoA -> FA
94
Where in the cell does FA oxidation and FA synthesis occur?
FA oxidation = mitochondria
| FA synthesis = cytoplasm
95
How does insulin and glucagon and adrenaline affect FA oxidation and synthesis?
Insulin - FA synthesis = stimulation, FA oxidation = inhibits
Glucagon/ adrenaline - FA synthesis =inhibits, FA oxidation = stimulates
96
What is the enzyme that is activated by glucagon and adrenaline that leads to the break down of TAG?
Hormone sensitive lipase
97
What tissues can not use fatty acids?
RBC
Brain
CNS
98
What is the main enzyme regulator of glycolysis?
Phosphofructokinase
99
What glucose transporter does insulin promote the translocation of?
GLUT4
100
How are lipids transported around the body?
~2% bound to albumin
| ~98% lipoprotein particles
101
What are the 2 apolipoprotein groups?
Integral - e.g. ApoA and ApoB
| Peripheral - e.g. ApoC and ApoE
102
What are the 5 distinct classes of lipoproteins?
```
Chylomicrons
VLDL
IDL
LDL
HDL
```
103
Of the lipoprotein classes which carry fats and which carry cholesterol esters?
Chylomicrons and VLDL - fats
| IDL,LDL,HDL - cholesterol esters
104
How many hours after a meal are chylomicrons still be found in blood?
4-6hours
105
How many classes of apolipoproteins are there and which ones are they?
6 classes
| A,B,C,D,E and H
106
What lipoproteins are apoB associated with?
VLDL, IDL, LDL
107
What lipoproteins are apoA1 associated with?
HDL
108
What are the functions of apolipoproteins?
Structural - packaging water insoluble lipid
| Functional - co-factor for enzymes, ligands for cell surface receptors
109
What apolipoprotein is added to chylomicrons before entering lymphatic system?
ApoB-48
110
What apoliproproteins are added to chylomicrons when they are in the blood from the thoracic duct into left subclavian?
apoC and poE
111
What is the function of apoC on the chylomicrons?
ApoC binds lipoprotein lipase on adipocytes and muscle
| Releases FA depleting chylomicron of its FAT content
112
When does apoC dissociate from a chylomicron?
When triglyceride reduced to 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
113
What happens to a chylomicron remnant?
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
114
What is the purpose of a VLDL?
VLDL made in liver for transporting TAG to other tissues
115
How do you remember what apoC and apoE are for?
ApoC- Cleaves = binding to LPL to release FA
| ApoE - hepatic Emptying = release to the liver
116
What apolipoprotein is added to VLDL's during formation in the hepatocyte?
ApoB100
117
What apolipoproteins are added to VLDL's during their transit in the blood?
From HDL's
| Obtain ApoC and ApoE
118
How are IDL and LDL formed?
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)
119
What is the primary function of LDL?
Provide cholesterol from liver to peripheral tissues
| Peripheral LDL receptors take up LDL as receptor mediated endocytosis
120
Why are LDL's in the blood for a long period of time?
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
121
How are LDL's and oxidative stress connected?
LDL's have a long half life -> more likely to get oxidative damage
Oxidised LDL taken up by macrophages -> foam cells -> atherosclerotic plaques formed
122
What is the function of apoB-100 and what is the result of the interaction?
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
123
What are 3 methods by which HDL's are synthesised?
(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
124
How are HDL's matured?
Nascent-HDL accumulates phospholipids and cholesterol from cells lining blood vessels
Hollow core fills
Transfer of lipids to HDL doesn't require enzyme activity
125
How are HDL's able to remove cholesterol from the periphery?
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
126
Once a HDL has acquired its cholesterol what does it do with it?
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
127
What are the consequences of hyperlipoproteinaemia?
Defective LPL - chylomicrons in fasting plasma
LDL receptor deficiency - CHD
Defective apoE - raised IDL, chylomicron remnants - CHD
Raised chylomicrons + VLDL in fasting plasma - CHD
128
What are 3 main signs of hypercholesterolaemia?
Xanthelasma
Corneal arcus
Tendon xanthoma
129
What are the treatments of hyperlipoproteinaemias?
Diet, lifestyle modifications
Statins - HMG-CoA reductase inhibitor
Bile acid sequestrates - cholestyramine
130
What areas of the body in adults does haemopoiesis occur?
Pelvis, sternum, skull, ribs, vertebrae
131
What hormone causes platelets to be produced?
Thrombopoietin
132
What hormone causes basophils and neutrophils to be produced?
G-CSF
133
What hormone causes lymphocytes to be produced?
Interleukins and TNF's
134
What hormone causes RBC's to be produced?
Erythropoietin
135
What phagocytic cells are found in the reticuloendothelial system?
Monocytes, macrophages, Kupffer cells, Tissue histiocytes, Microglial cells in CNS
136
What organs are part of the reticuloendothelial system?
Spleen and liver
137
What are the main parts of the spleen?
Red pulp- sinuses lined by endothelial macrophages and cords
| White pulp - similar structure to lymphoid follicles
138
What type of cells pass through the red pulp and white pulp?
Red pulp - RBC's preferentially pass through it
| White pulp - WBC and plasma pass through it
139
What are the 4 functions of the spleen in adults?
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
140
Why would the spleen grow?
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
141
Define hyposplenism
Lack of adequately functioning splenic tissue
142
What are 3 causes of hyposplenism?
Splenectomy
Sickle cell disease
Coeliac disease
143
On blood film what is seen in patients with hyposplenism?
Howell Jolly Bodies
144
What encapsulated organisms are patients who are hyposplenic at risk of getting?
Pneumococcus
Haemophilus influenzae
Meningococcus
145
What protein is the cytoskeleton?
Spectrin and ankyrin
146
What is the process that occurs if a patient becomes anaemic due to poor RBC production?
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
147
What is the term that describes a reduction in the number of blood cells?
Cytopenia
148
What cells are included in pancytopenia?
RBC's, WBC's, and platelets
149
What suffixes are used to describe increased number of blood cells?
-cytosis or -philia
150
What type of immune system is the neutrophil part of?
Innate immune system
151
From which pre-cursor is a neutrophil from?
Myeloblast
152
What are the biggest causes of neutrophilia?
98% mostly Infection related
| Tissue damage, acute inflammation, cancer, acute haemorrhage
153
A neutrophil count of what number counts as neutropenia?
<1.5x10^9/L
| Severe if <0.5x10^9/L
154
What are normal causes of neutropenia?
Benign ethnic neutropenia
| Cyclic neutropenia
155
What is aplastic anaemia in terms of causing neutropenia?
Empty bone marrow, no precursors
156
What are consequences of neutropenia?
Severe life threatening bacterial and fungal infections
Mucosal ulceration
Neutropenia itself predisposes to infections occurring but doesn't always lead to neutropenic sepsis
157
What are 4 causes of monocytosis?
Chronic inflammatory conditions
Chronic infection
Carcinoma
Myeloproliferative disorders/ leukaemias
158
What are some causes of eosinophilia?
Allergic disease, drug hypersensitivity
Parasitic infections
Hodgkin lymphoma, acute myeloid leukaemia, eosinophilic leukaemia
159
What are some causes of basophilia?
Immediate hypersensitivity reactions
Ulcerative colitis
Rheumatoid arthritis
CML
160
What are the subgroups of lymphocytes?
B cells
T cells
NK cells
161
What are some causes of lymphocytosis?
```
Viral infections
Bacterial infections
Stress related MI/cardiac arrest
Post splenectomy
Smoking
Malignant - chronic lymphocytic leukaemia, lymphoma
```
162
What is the purpose of K-EDTA in a blood test tube?
Chelates calcium ions which stops blood coagulation
163
Which gender has a higher haematocrit and red cell count?
Males
164
What is serum?
Plasma minus clotting factors
165
What is plasma?
Water, proteins, nutrients, hormones etc
| The clear layer above the white buffy coat when blood is centrifuged
166
What is packed cell volume?
Same as haematocrit - the portion of blood made up of RBC's
167
What condition would lead to a raised haematocrit?
polycythaemia
168
What can cause a low haemoglobin reading on a blood test?
Acute bleed, haemolysis, bone marrow disorders
169
What can cause a high haemoglobin reading on a blood test?
Dehydration, diuretics, burns
170
What is the difference between polycythaemia and erythrocytosis?
Polycythaemia - actual physical increase in RBC's
| Erythrocytosis - a measured raised RBC mass
171
What happens to red cell count in microcytic anaemia?
Reduced in iron deficiency anaemia
| Increased in thalassaemia trait
172
If suspecting erythrocytosis what would red cell count show if this was a true diagnosis?
A raised red cell count - polycythaemia
| A non-raised red cell count would be indicative that it was not true polycythaemia
173
What can cause a raised mean cell volume?
```
Megaloblastic anaemia (B12, folate deficiency)
Liver disease
Alcoholism
Haemolytic anaemia
Hypothyroidism
Drugs
Myelodysplasia
Myeloma
```
174
What can cause a reduced mean cell volume?
Iron deficiency anaemia
Thalassaemia
Anaemia of chronic disease
Lead poisoning
175
What would a raised red cell distribution width mean?
Anisocytosis - RBC's of unequal size
| Post blood transfusion
176
What happens to red cell distribution width in the short and long term stages of iron deficient anaemia?
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
177
What would a decreased red cell distribution width mean?
Iron deficiency anaemia - chronic
| Normal in thalassaemia
178
When is mean cell haemoglobin usually reduced or increased?
Reduced - iron deficiency
| Raised - macrocytic anaemia
179
What would cause a raised reticulocyte count?
```
Haemolytic anaemia
Recent blood loss
Response to iron, Vit B12, folate replacement
Response to EPO
Recovery from bone marrow suppression
```
180
What would cause a reduced reticulocyte count?
```
Haematinic deficiency (B12, folate, iron)
Bone marrow failure
```
181
What causes schistiocytes?
RBC broken up in the circulation
182
What are inclusions in erythrocytes and describe them?
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,
183
How would you describe cellular colour in iron deficient anaemia?
Hypochromic microcytic
184
What is anaemia?
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
185
What are signs and symptoms of anaemia?
Symptoms: SOB, Tiredness, Cardiac failure, Palpitations, Headache
Signs: Pallor, Tachycardia, Tachypnoea, Hypotension
186
What is a specific sign of iron deficiency?
(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
187
What is a specific sign of fit B12 deficiency?
Glossitis - enlarged shiny tongue
188
What is a specific sign of thalassaemia?
Abnormal facial bone development
189
What are 2 methods of causing reduced erythropoiesis?
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
190
What is dyserythropoiesis and what is the result?
(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
191
What causes iron not being released for use in bone marrow in dyserythropoiesis?
Cytokines during inflammation reduce life span of RBC's
| Macrophages will be prevented from releasing the iron once they have been destroyed
192
What are defects in Hb synthesis?
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
193
What are the 3 main inherited RBC structure defects?
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
194
What are 3 areas of acquired defects in RBC membrane structure?
- Mechanical damage - heart valves, vasculitis, microangiopathies, DIC
- Heat damage - Burns
- Osmotic change - Drowning
195
What are defects in RBC metabolism?
G6PD deficiency
| Pyruvate kinase deficiency
196
Why does splenomegaly cause anaemia?
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
197
What 2 areas are RBC's damaged?
Intravascular
| Extravascular - reticuloendothelial system
198
What is the result of autoimmune haemolytic anaemia and why?
Anaemia result
| Autoantibodies attack the RBC's - cells in the RES recognise the Ab and remove the RBC from circulation
199
How do you treat autoimmune haemolytic anaemia?
Steroids, folic acid, rituximab, IVIG
200
What is the result of myelofibrosis of RBC's?
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
201
What are the 3 stages of development of the RBC to become an erythrocyte?
1 - ribosome synthesis
2 - Hb accumulation
3 - ejection of nucleus (reticulocyte)
-> Erythrocyte
202
What is the mechanism for causing reticulocytosis in anaemia?
Bone marrow compensates for reduced O2 carrying capacity by releasing more immature RBC's
203
When would anaemia with reticulocytosis occur?
Acute blood loss
Splenic sequestration
Haemolysis - immune, non-immune, haemoglobinopathies etc
204
What is the mnemonic used to help remember the causes of anaemia in low reticulocyte counts?
```
MICRO TAILS - micro= microcytic TAILS = causes
T- thalassaemia trait
A - anaemia of chronic disease
I - iron deficiency
L - Lead poisoning
S - sideroblastic anaemia
```
205
What MCV is seen in anaemia with low reticulocyte count?
```
High MCV (macrocytic)
Vit B12 deficiency, Folate deficiency, MDS, Liver disease, Hypothyroidism, Alcohol
```
206
What causes anaemia with low reticulocyte count but also is normocytic/ normal MCV?
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
207
What type of anaemia is caused by B12 deficiency?
Macrocytic anaemia MCV >100fL
208
How is B12 absorbed into the body?
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
209
How long do normal B12 stores last?
3-6 years
210
What are common causes of B12 deficiency?
Vegan diet, poor diet
Pernicious anaemia (autoimmune condition affecting parietal cells), gastrectomy
Crohn's disease, ideal resection
Lack of trans cobalamin - congenital deficiency
211
How long does 5mg of folate store for?
3-4 months
212
What are 4 causes of deficiency of folate?
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)
213
What is the function of B12 and B9 (folate) together?
B12 reactivates B9 (folic acid) back into tetrahydrofolate.
| B12 deficiency causes a functional folate deficiency
214
Why does B12 and folate deficiency cause megaloblastic anaemia?
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
215
What is a B12 deficiency associated with?
Neurological disease
| Focal demyelination affecting the spinal cord, peripheral nerves and optic nerves
216
How do you treat a B12/ Folate deficiency?
B9 - oral folic acid
| B12 - IM hydroxocobalamine
217
After how many months of B12/ folate treatment should blood counts be fully back to normal?
3-6months
| 2 months there should be resolution of anaemia
218
What is the difference between ferric and ferrous iron?
```
Ferrous = Fe2+
Ferric = Fe3+
```
219
What is the difference between haem iron and non-haem iron?
Dietary iron = haem iron = Fe2+
| Non - haem iron = Mixture of Fe2+ and Fe3+
220
What charge of iron can only be absorbed by the body?
Fe2+
221
How does an acidic environment help with absorbing iron?
Acidic environment helps convert Fe3+ + e- =Fe2+
| Fe2+ is the absorbed iron
222
How much maintenance iron is needed per day?
10-15mg/day
223
Where does haem iron and non-haem iron get absorbed?
Duodenum/ Jejunum
224
How much of ingested iron is absorbed/ day?
5-15%
225
What is the process of iron absorption from ingestion?
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
226
What controls the absorption of iron from the basolateral surface of the enterocytes?
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
227
What could high transferrin levels indicate?
Iron deficiency anaemia
228
What do low levels of transferrin levels indicate?
Liver disease / haemolytic anaemia
229
What function does Vitamin C play in iron absorption?
Anti-oxidant therefore prevents iron being turned into Fe3+ which can't be absorbed
230
What negative factors affect absorption of non-haem iron from food?
Tannins (tea)
Phytates (chapattis, pulses)
Fibre
Antacids
231
What positive factors affect absorption of non-haem iron from food?
Vitamin C and citrate
232
What is the total iron stored in the body and how much of it is functional and stored?
Total iron = 3350mg
Functional: Hb = 2000mg, Myoglobin = 300mg, Enzymes = 50mg, Transported iron in transferring = 3mg
Stored: 1000mg - Ferritin (soluble) and haemosiderin (insoluble)
233
Where does haemosidderin accumulate?
Liver, spleen, bone marrow
234
How do cells take up iron?
(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
How is iron recycled?
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
What regulates iron absorption?
- 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
What is the function of 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
238
How does chronic disease cause anaemia of chronic disease?
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
What are non specific signs and symptoms of iron deficiency?
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
On a peripheral blood smear what type of RBC's would be seen on iron deficiency anaemia?
RBC's are microcytic and hypochromic
Anisopoikilocytosis = change in size and shape
Sometimes pencil cells and target cells
241
What blood tests would be done to diagnose anaemia?
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
What conditions can cause ferritin to be raised and would give a false negative of iron deficiency?
```
Cancer
Infection
Inflammation
Liver disease
Alcoholism
Iron deficiency anaemia
```
243
How do you treat iron deficiency anaemia?
Dietary advice
Oral iron supplementation
IM, IV iron
Blood transfusion
244
What type of response would be suitable for iron replacement in anaemia?
20g/L rise in Hb in 3 weeks
245
Why is iron excess dangerous?
Excess iron can exceed binding capacity of transferrin ->
| iron deposited in end organs as haemosiderin -> iron promotes free radical formation and organ damage
246
What 2 conditions are caused by iron excess?
Transfusion associated haemosiderosis
| Hereditary haemochromotosis
247
How much iron is found in 1 unit of blood?
200mg
248
What are the end organ effects of iron accumulation?
```
Liver cirrhosis
Diabetes mellitus
Hypgonadism
Cardiomyopathy
Arthropathy
Inc skin pigmentation
```
249
What drug can be given to patients with excess iron?
Desferrioxamine
250
What is hereditary haemochromatosis?
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
How do you treat hereditary haemochromatosis?
Venesection
252
What is a myeloproliferative disorder?
Myeloproliferative neoplasms - dysregulation at the multipoint haematopoietic stem cell level
253
What are the 4 need to know myeloproliferative disorders?
Essential thrombocythaemia
Polycythaemia vera
Myelofibrosis
Chronic myeloid leukaemia
254
Describe what the bone marrow would look like in a myeloproliferative disorder?
Hypercellular bone marrow / marrow fibrosis
255
Where would haemopoiesis occur in myeloproliferative disorders?
Extramedullary - liver or spleen
256
What is the potential for myeloproliferative disorders to become?
Acute leukaemia
257
What specific mutation is found in many myeloproliferative disorders?
JAK2 = janus kinase 2 gene
| Causes increased proliferation and survival of haematopoietic precursors
258
What is polycytheamia Vera?
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
What are symptoms and signs of polycythaemia vera?
```
Arterial thrombosis
Venous thrombosis
Haemorrhaging in skin, GIT
Pruritis
Splenic discomfort, splenomegaly
Gout
```
260
How is polycythaemia vera managed?
Venesection
Aspirin
Manage CVS risk factors
261
Define polycythaemia
Increase in circulating red cell concentration typified by a persistently raised haematocrit
262
What are the subtypes of polycythaemia?
```
Primary = polycythaemia vera
Secondary = EPO driven production
```
263
What are the methods of producing ectopic EPO?
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
What is essential thrombocythaemia?
Excess platelets in blood
| Large and excess megakaryocytic in bone marrow
265
How is essential thrombocythaemia managed?
Aspirin
| CV risk factors managed
266
What are reactive causes for a high platelet count?
```
Infection
Inflammation
Tissue injury
Haemorrhage
Cancer
Redistribution of platelets
```
267
What is a complication of myelofibrosis?
- Massive splenomegaly +/- hepatomegaly due to extra medullary haematopoiesis
- Progresses to pancytopenia
268
What is myelofibrosis?
Fibrotic marrow with little space for haemopoiesis
| Clonal haemopoietic stem cell proliferation causes it
269
What are clinical features of myelofibrosis?
Fatigue, sweats, weight loss
Consequences of massive splenomegaly - pain, early satiety, splenic infarction
Progressive marrow failure - requiring transfusions of blood products
Early death
270
What is chronic myeloid leukaemia?
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
What are the myeloid cells?
```
Neutrophils
Macrophages
Basophils
Eosinophils
Thombocytes
Erythrocytes
```
272
What are the lymphoid cells?
B lymphocyte
| T lymphocyte
273
What is the genetic problem with CML?
BCR-abl fusion
Chromosomes 9 and 22 have rearranged
Switches on a receptor tyrosine kinase which drives proliferation
274
Define pancytopenia
Reduction in white cells, red cells and platelets
| NOT neutrophils
275
What are the 2 areas which would cause pancytopenia?
```
Reduced production (most common)
Increased removal of cells - immune destruction, splenic pooling
```
276
What are causes of reduced production in pancytopenia?
```
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
What is aplastic anaemia?
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
What are causes of thrombocytopenia?
Acquired - Decreased production, increased consumption, inc destruction
Inherited - rare syndromes
279
What are consequences of severe thrombocytopenia?
```
Patients not symptomatic until platelet count <30
Easy bruising
Petechiae, purport
Mucosal bleeding
Severe bleeding after trauma
Intracranial haemorrhage
```
280
What is immune platelet destruction?
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
What are hereditary disorders of platelet function?
Bernard Soulier syndrome
| Glandmann's thrombasthenia
282
What are acquired disorders of platelet functions?
Aspirin, NSAIDs
| Uraemia
283
What is thalassaemia?
Normal alpha or beta globin chains - the alpha and beta thalassaemias
284
What is the problem caused in thalassaemia?
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
What is a alpha-thalassaemia trait?
Deletion of 2 alpha-globin genes
Minimal or no anaemia and no physical signs
Findings are identical to those of beta-thalassaemia minor
286
What is haemoglobin H disease?
Deletion of 3 alpha-globin genes
Tetramers of beta-globin, called HbH are formed
Moderately severe anaemia, resembling beta-thalassaemia intermedia
287
What cells would be in anaemia with haemoglobin H disease?
Microcytic, hypochromic anaemia with target cells and Heinz bodies in the blood film
288
What is hydrops foetalis?
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
What is beta-thalassaemia?
Gene mutations rather than deletions
Beta-0 = total absence of production
Beta+ = reduction of globin production
290
What is beta thalassaemia major?
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
What is beta thalassaemia minor?
Usually asymptomatic with mild anaemia (very microcytic and hypochromic)
Heterozygous
One normal gene (Beta-0/Beta or Beta+/Beta)
292
What is beta thalassaemia intermedia?
Severe anaemia, but not enough so to require regular blood transfusions
Genetically heterozygous
Mild variants of homozygous beta-thalasaemia
Severe
293
What are the variants of beta thalassaemia intermedia?
Mild - variants of homozygous beta-thalassaemia
Severe - Beta-0/Beta or Beta/Beta
Double heterozygosity Beta-0/Beta
294
What are the consequences of thalassaemia?
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
What is the treatment for thalassaemia?
```
Transfusions -2 weekly
Iron chelation
Folic acid
Immunisation
Stem cell transplant
Pre-conception counselling
```
296
What is sickle cell?
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
What are symptoms of sickle cell disease?
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
What are the 3 sickle cell crises?
1 - vaso-occlusive - painful bone crises
2 - Aplastic - triggered by parvovirus
3 - Haemolytic
299
What are the treatments for sickle cell patients?
```
Folic acid
Penicillin prophylactically
Splenectomy
Hydroxycarbamide - increases HbF levels
Red cell exchange
```
300
What are long term consequences of sickle cell?
Stroke
Cognitive and neurological problems
Kidney failure
Priapism
301
What does haemolytic anaemia result in?
Anaemia symptoms
Accumulation of bilirubin -> jaundice
Splenomegaly
Massive sudden haemolysis - cardiac arrest - lack of O2 delivery to tissues and hyperkalaemia
302
What are the 4 inherited haemolytic anaemia causes?
Glycolysis defect - pyruvate kinase deficiency
Pentose-p-pathway - G6PDHH deficiency
Membrane protein - hereditary spherocytosis
Haemoglobin defect - sickle cell
303
What are the categories of autoimmune haemolytic anaemia?
Warm - IgG - maximally active at 37 degrees
| Cold - IgM - maximally active at 4 degrees
304
What can cause autoimmune haemolytic anaemia?
Infections
| Cancers of lymphoid system
305
What happens to core body temperature when a person sleeps?
Temperature decreases as sleep progresses but rises as sleep comes to an end
306
What happens to cortisol levels during sleep?
Initially decreases till mid way through sleep but then increases rapidly before waking
307
What happens to melatonin during sleep?
Initially rises till the mid point of sleep then drops rapidly to pre sleep levels
308
Where in the brain is the biological clock?
Suprachiasmatic nucleus
309
From where in the pituitary does ADH get released from?
Posterior pituitary
310
From which part of the brain controls the release of ADH?
Osmoreceptors in the hypothalamus
311
What is autocrine communication?
Hormone signal acts back on the cell of origin
312
What is paracrine communication?
Hormone signal carried to adjacent cells over a short distance via interstitial fluid
313
What is endocrine communication?
Hormone signal released into blood stream and carried to distant target cells
314
What is neurocrine communication?
Hormone originates in neurone and after transport down axon released into bloodstream and carried to distant target cells
315
What are the 4 classes of hormones?
Peptide
Amino acid derivative
Glycoproteins
Steroids
316
From which precursor molecule are steroid hormones synthesised from?
Cholesterol
317
What is the role of carrier proteins in hormone transport?
Increase solubility of hormone in plasma
Increase half life
Readily accessible reserve
318
What is the difference in lipid soluble and water soluble hormones in their receptor area of activity?
Lipid soluble - intracellular receptors
| Water soluble - extracellular/ cell surface receptors
319
Where is the control for appetite control?
Satiety centre in the hypothalamus - arcuate nucleus
320
What are the two types of primary neurone in the arcuate nucleus?
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
What hormone is released that causes excitation of the excitatory primary neurones arcuate nucleus?
Ghrelin
322
What is the function of ghrelin?
Stimulates appetite
323
What is the function of peptide tyrosine tyrosine (PYY)?
Inhibits excitatory primary neurones of the arcuate nucleus and stimulates the inhibitory neurones. Effect is therefore to suppress appetite.
324
What is the clinical correlation of peptide tyrosine tyrosine?
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
What 3 hormones are responsible for suppressing appetite that act on the hypothalamus?
Leptin, Insulin, Amylin
326
What releases leptin?
Adiopocytes
327
Where does leptin have its effects on the brain?
Arcuate nucleus:
1 - stimulates the inhibitory POMC neurones
2 - inhibits the excitatory (AgRP/NPY) neurones
328
What is the over effect of leptin?
Suppress appetite
329
How does insulin have its effects of appetite suppression on the brain?
Arcuate nucleus:
| Stimulates the inhibitory POMC neurones
330
What is the effect of amylin?
Secreted by beta cells in pancreas
Suppresses appetite
Decrease glucagon secretion and slow gastric emptying
331
Which organ secretes PYY?
Small intestine
332
What is the disease process of anaemia of chronic renal failure?
(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
How does uraemia affect lifespan of RBC and why?
It suppresses the bone marrow due to uraemic toxins
334
What is the treatment for anaemia of chronic renal failure?
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
What would cause low neutrophils in renal disease?
Immunosuppression due to post transplant drugs
| Marrow infiltration e.g. in myeloma
336
What would cause raised neutrophils in renal disease?
Inflammation
Connective tissue disease
Infection
Drugs: steroids cause neutrophilia
337
What would cause low platelets in renal disease?
Direct effect of uraemia on platelet production
Drugs
Haemolytic ureamic syndrome
338
What would cause raised platelets in renal disease?
Reactive
Bleeding
Iron deficiency
339
What is Felty's syndrome?
Triad of:
Splenomegaly
Neutropenia
Rheumatoid arthritis
340
What is the potential cause of neutropenia in Felty's syndrome in rheumatoid arthritis?
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
What is the haematological consequence of portal hypertension?
Splenomegaly -> splenic sequestration of cells, overactive removal of cells
342
What are the haematological features of liver disease?
```
Blood loss
Deficiencies in clotting factors
Endothelial dysfunction
Thrombocytopenia
Defective platelet function
```
343
What type of RBC's will be seen in liver disease?
Target cells
Spurr cells - found in end stage alcoholic liver disease
Accumulation of excess membrane cholesterol
344
Why is thrombocytopenia seen in alcoholic liver disease?
Thombopoietin is made in the liver - if liver damaged no hormone made
345
Why would low levels of neutrophils be seen in post op period?
Reactive changes - severe sepsis
346
Why would low levels of platelets be seen in the post op period
Medications - heparin
| Sepsis - DIC
347
What is the difference in the lymphocyte changes in amount depending on bacterial or viral infections?
Bacterial infections - neutrophils
| Viral infections - lymphocytosis
348
Why would there be leucoerythroblasts seen on a blood film?
```
Granulocyte precursors
Bone marrow infiltration by carcinoma or haematological malignancy
Causes severe megaloblastic anaemia
Primary myelofibrosis
AML/MDS
Storage diseases
```
349
What is diabetes?
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
What are the 2 main types of diabetes?
Type 1 and Type 2
| Different aetiologies BUT similar complications
351
What are the biggest problems with diabetes?
```
Blindness - retinopathy
ESRD - nephropathy
Amputation - peripheral vascular disease
15% life time risk of amputation
70% death from CVD and stroke
```
352
What is the pathophysiology of diabetes?
(1) inability to produce insulin due to beta cell failure
| (2) insulin production adequate but insulin resistance prevents insulin working effectively
353
What is type 1 diabetes?
Auto-immune beta cell destruction
Beta cells - secrete insulin
Autoantibodies made are directed against beta cells
Mostly a genetic pre-disposition
354
How does T2DM present?
Typical symptoms: Polyuria, polydipsia, blurring of vision, urogenital infections- thrush
Symptoms of poor energy utilisation: tiredness, weakness, lethargy, weight loss
355
How is diabetes diagnosed?
Lab testing
Fasting glucose
HbA1c
Symptoms and 1 abnormal test
356
How does T1DM present?
```
Rapid onset weight loss,
Polyuria
Polydipsia
Late presentation - DKA
Young age
Hyperglycaemia
Ketones present
```
357
How is T1DM treated?
Exogenous insulin - S/C injection
358
What is the theory why T2DM occurs?
Obesity
359
What can cause insulin resistance?
```
Obesity - central more specifically
Muscle and liver fat deposition
Elevated circulating free fatty acids
Physical inactivity
Genetic influences
```
360
How is a low calorie diet connected to diabetes?
600-800 calorie diet - T2DM almost disappears after 7 days
361
How is bariatric surgery related to diabetes?
Fasting plasma glucose drops considerably post surgery
| Almost full response for T2DM - normalisation of B cell function + decreased pancreatic and liver TAG
362
What is the best treatment for T2DM?
Weight loss
363
In general how do we currently treat T2DM?
```
Lifestyle factors
Non-insulin therapies
Insulin
Control other CV risk factors - hypercholesterolaemia, HTN, smoking, exercise, diet
Surveillance for chronic complications
```
364
What are acute complications for diabetes?
Massive metabolic decompensation =
DKA
Hyperosmolar non-ketotic syndrome in T2DM - hyperosmolar hyperglycaemic syndrome
Coma
365
What are chronic complications for diabetes?
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
What is metabolic syndrome?
Cluster of the most dangerous risk factors associated with cardiovascular disease: diabetes, raised fasting plasma glucose, abdominal obesity, high cholesterol and BP
367
what causes metabolic syndrome?
```
Insulin resistance
Central obesity
Genetics
Physical inactivity
Ageing
```
368
What are the 4 anatomical areas of the pancreas?
Head, neck, body, tail
369
What is the name of the ducts that release pancreatic juices into the GI?
Pancreatic duct and accessory pancreatic duct
370
What part of the GIT is the pancreas part of?
Embryologically outgrowth of the foregut
371
How much of the pancreas is exocrine and endocrine?
Exocrine - 99%
| Endocrine - 1%
372
What are the known hormones secreted from the endocrine functioning of the pancreas?
```
Insulin
Glucagon
Somatostatin
Pancreatic polypeptide
Ghrelin
Gastrin
Vasoactive intestinal peptide
```
373
What cells in the pancreas produce insulin?
Beta cells
374
What cells in the pancreas produce Glucagon?
Alpha cells
375
What cells in the pancreas produce Somatostatin?
Delta cells
376
What cells in the pancreas produce pancreatic polypeptide?
PP cells
377
What cells in the pancreas produce Ghrelin?
Epsilon cells
378
What cells in the pancreas produce Gastrin?
G cells
379
In a pancreatic islet where can alpha and beta cells generally be found?
Alpha - outer area/ periphery
| Beta - Inner area/ central
380
What is the renal plasma glucose threshold?
10mmol/L
| The amount of glucose in the blood that the kidneys can't reabsorb above and it gets excreted
381
What is the half life of insulin and glucagon?
5 mins
382
Where is the insulin receptor found?
Cell surface
383
What is the difference between active and inactive insulin?
Inactive = structure that has all 3 alpha helices= A-chain, B- chain + C-peptide
384
What is the function of the C-peptide on the insulin structure?
Prevents peripheral damage of effects of insulin
385
What test could be used to tell if a patient has been given synthetic or natural insulin?
Synthetic doesn't have C-peptide whereas the natural insulin does
386
What is the synthesis process of insulin?
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
How is insulin released from the beta-islet cell?
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
What receptor attaches to the insulin receptor to promote insulin release?
Sulfonylurea receptor (SUR1)
389
What glucose channel does insulin cause to be translocated onto cell surfaces?
GLUT4 channels - glucose dependent
390
What receptor does glucagon activate?
GPCR
| Gs receptor -> Adenlyate cyclase -> cAMP -> PKA -> glycogenolysis, gluconeogenesis -> hyperglycaemia
391
What organ does glucagon mainly affect?
Liver - organ controlling blood glucose hence would act on it to maintain plasma glucose levels
392
What is margination and exocytosis of granules in the pancreatic islet cells?
Margination - granules move to the cell surface
| Exocytosis - fusion of vesicle with plasma membrane -> release of contents
393
Does glucagon cause glucose to be made from fatty acids?
No - just cause increased plasma fatty acids
| Gluconeogenesis is from amino acids
394
What glucose metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?
Fastest -> Slowest
| Glucose uptake into muscle and adipose tissue -> Glycolysis -> Glycogenesis
395
What glucose metabolism processes are the fastest and the slowest in producing glucose in response to hypoglycaemia?
Fastest -> slowest
| Gluconeogenesis -> glycogenolysis
396
What lipid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?
Fastest -> slowest
| Lipogenesis
397
What lipid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?
F->S
| Lipolysis -> ketogenesis
398
What amino acid metabolism processes are the fastest and the slowest in producing glucose in response to hyperglycaemia?
Amino acid uptake -> protein synthesis
399
With glucagon what other hormones are released?
Adrenaline and noradrenaline
400
What glucose levels would be enough to class someone as diabetic?
Fasting >7mmol/L
| Random >11mmol/L
401
What is the difference between absolute and relative insulin deficiency?
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
Would a gain of function mutation in the insulin channel cause a patient to become hyper or hypoglycaemic?
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
In T2DM what are the subtypes of pathophysiology?
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
What occurs in young people and insulin resistance - leading to the obesity epidemic?
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
How many hormones does the hypothalamus produce?
8
406
How many hormones does the pituitary produce in response to the hypothalamus?
anterior - 6
| posterior - 2
407
What bone does the pituitary sit in?
Sphenoid bone
408
What 8 processes does the hypothalamus modulate?
```
Body growth - GH
Reproduction / Puberty - LH/FSH
Adrenal gland - Cortisol
Water homeostasis - ADH
Milk secretion - oxytocin
Lactation - prolactin
Thyroid gland - thyroid hormones
```
409
What is the embryological origin of the anterior pituitary?
Rathke's pouch
Primitive gut tissue
Oral ectoderm
410
What is the embryological origin of the posterior pituitary?
Neuroectoderm
| Primitive brain tissue
411
What is the stalk that connects the hypothalamus and the pituitary called?
Infundibulum
412
What nuclei produce oxytocin?
Supraoptic
413
What nuclei produce ADH?
paraventricular
414
Where are the hormones synthesised in the adenohypophysis?
Hypothalamus
415
What are the hormones of the hypothalamus?
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
What are the hormones release by the anterior pituitary?
```
TSH
ACTH
LH
FSH
PRL
GH
```
417
What is the primary effect of growth hormone??
Acts on liver and skeletal muscle -> releases insulin-like growth factors - somatomedins
418
What hormone antagonises growth hormone release?
Somatostatin
| Growth-hormone inhibiting hormone
419
What is the effect of GH on bone and bone growth in childhood and teenage years?
Stimulate long bone growth -> length and width prior to epiphyseal closure - width after epiphyseal closure
IGF's stimulate both bone and cartilage growth
420
What is the effect of GH/ IGFs in adults?
Maintain muscle and bone mass
Promote healing and tissue repair
Modulate metabolism and body composition
421
What CNS effects regulate GH secretion?
Surge in GH secretion after onset of deep sleep
| REM sleep decreases GH secretion
422
How does stress affect GH secretion?
Increases GH secretion
423
How does exercise affect GH secretion?
Increases GH secretion
424
How does food alter GH secretion?
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
How does obesity and fasting affect GH secretion?
Obesity - dec GH secretion
| Fasting - inc GH secretion
426
What are the feedback loops of GH secretion?
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
What is the childhood result of GH deficiency?
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
What is the condition called when there is growth hormone excess in childhood?
Gigantism - rare condition in general
429
What is a common cause of growth hormone excess?
Rare - often cause is pituitary adenomas
430
What is the condition called when there is growth hormone excess in adulthood?
Acromegaly
431
How does GH exert its effects on cells?
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
What are the types of IGF and what do they do?
IGF1 - major growth factor in adults
| IG2- mainly involved in foetal growth
433
Apart from endocrine functions does IGF have any other function?
Paracrine and autocrine function
| Muscle repair and growt
434
What are the functions of IGFs?
Hypertrophy, hyperplasia,
| inc rate of: protein synthesis, lipolysis
435
How can IGFs have metabolic effects and insulin have mitogenic effects?
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
Apart from insulin and IGF what other hormones influence growth?
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
What's a common clinical presentation of pituitary tumours?
Mass effect of tumour on local structures causes visual loss and headaches
Abnormal in pituitary function -> hyper/hypo secretion -> effects of those
438
What visual field loss would be seen in a pituitary adenoma?
bitemporal hemianopia - tunnel vision
439
What symptoms would be seen in a lateral displacement of the pituitary tumour?
Pain and double vision
| Cranial nerve palsy
440
What are signs/symptoms of TSH deficiency?
Low thyroid hormone, Low T4 and non-elevated TSH (secondary hypothyroidism)
Cold, weight gain, tiredness, slow pulse
441
What are the signs and symptoms of ACTH deficiency?
```
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
What type of test would be done to diagnose a suspected hormone excess in the adrenal axis?
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
What type of test would be done to diagnose a suspected hormone deficiency in the adrenal axis?
Direct stimulation of adrenals by ACTH (synACTHen)
Response to hypoglycaemic stress test (insulin stress test)
Addisons disease - excess ACTH & deficiency in cortisol
444
What type of test would be done to diagnose a suspected hormone excess in the GH axis?
Suppress GH axis with glucose load (glucose tolerance test)
445
What type of test would be done to diagnose a suspected hormone deficiency in the GH axis?
Response to hypoglycaemic stress (insulin stress test)
446
How are prolactinoma's classed in terms of size?
Large tumour - macro-adenoma >1cm
| Small tumour - micro-adenoma <1cm
447
How are prolactinoma's treated?
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
How does protecting affect LH levels?
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
What are symptoms of hyperprolactinaemia in women?
Menstrual disturbances
Fertility problems
Galactorrhoea
450
What are symptoms of hyperprolactinaemia in men?
Man present later than women - therefore larger tumours
Symptoms of low testosterone are non-specific
May present with mass symptoms - visual disturbances
451
What would be the effect of anything blocking the infundibulum connecting the hypothalamus and the pituitary on prolactin levels?
Prolactin constitutively produced -> no inhibition -> production will be remain constant
452
What are long term complications of untreated acromegaly?
Premature cardiovascular death
Increased risk of colonic tumours
Probably increased risk of thyroid cancers
Disfiguring body changes that may be irreversible
HTN, DM
453
What biochemical tests would be done to confirm acromegaly?
Oral glucose tolerance test
Failure to suppress GH
Elevated IGF-1 level (age related ref range)
Growth hormone day curve - elevated mean GH
454
What is the treatment of acromegaly?
(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
What is cushings disease?
Excess cortisol production usually due to ACTH secreting pituitary tumour
456
What are the 6 classical changes in appearance in Cushings disease?
```
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
What is the difference between Cushings disease and Cushings syndrome?
Disease - pituitary tumour
| Syndrome - Adrenal tumour, ectopic ACTH, steroid medication
458
What is diabetes insipidus?
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
What are the 2 subtypes of Diabetes Insipidus?
Cranial
| Nephrogenic
460
What is the difference between cranial diabetes insipidus and nephrogenic diabetes insipidus?
Cranial DI is vasopressin deficiency - pituitary disease
| Nephrogenic DI is vasopressin resistance - kidney disease
461
What are the consequences of untreated DI?
Severe dehydration
Severe hypernatraemia
Reduced consciousness, coma and death
462
What is the treatment for cranial DI?
synthetic vasopressin
| Desmopressin nasal spray, tablets or injection
463
What is pituitary apoplexy?
apoplexy = stroke
Sudden vascular event in the pituitary tumour
Infarction or haemorrhage
464
What is a clinical presentation of pituitary apoplexy?
```
Sudden onset headache
Double vision
Visual field loss
Cranial nerve palsy
Hypopituitarism - cortisol deficiency most dangerous
```
465
What autoantibodies can be detected in T1DM?
Islet cells auto-antibodies
Insulin auto-antibodies
IA2 - islet secretory protein
GAD - Glutamic acid decarboxylase
466
What the difference between glycosylation and glycation?
Glycosylation - post-translational modification - not associated with disease
Glycation - random non-enzymatic reaction - associated with disease
467
What are the layers of the adrenal glands?
Cortex (out to in)
Zona glomerulosa -> Zona fasciculata -> Zona reticularis
Medulla:
Chromaffin cells - adrenaline/ noradrenaline
468
What hormones are produced in the adrenal glands and at what layers?
Cortex
Zona glomerulosa - mineralocorticoids
Zona fasciculata - glucocorticoids
Zona reticularis - glucocorticoids and small amounts of androgens
Medulla:
Chromaffin cells - adrenaline/ noradrenaline
469
What are the 2 subtypes of hyperaldosteronism?
Primary and secondary
470
What is primary hyperaldosteronism?
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
What is secondary hyperaldosteronism?
(1) Renin producing tumour (juxtaglomerular tumour)
(2) Renal artery stenosis
(3) High renin levels (low aldosterone:renin ratio)
472
What are signs of hyperaldosteronism?
```
HTN
Left ventricular hypertrophy
Stroke
Hypernatraemia
Hypokalaemia
```
473
What is the treatment of hyperaldosteronism?
Depends on type
Aldosterone producing adenomas - surgical resection
Spironolactone/ eplerenone (mineralocorticoid receptor antagonist)
474
What is the plasma protein carrier for cortisol?
Transcortin
475
What are the 6 effects of cortisol?
(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
What are the effects of glucocorticoids on metabolism specifically in the liver?
Inc glycogen storage
| Inc gluconeogenesis by inc amount and activity of enzymes
477
What are the effects of glucocorticoids on metabolism specifically in the adipocytes?
Dec glucose utilisation
Dec sensitivity to insulin
Inc lipolysis
478
What are the effects of glucocorticoids on metabolism specifically in the muscle?
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
How do the skeletal muscles and adipocytes feedback onto the liver during glucocorticoid release?
Skeletal muscle - supplies amino acids for gluconeogenesis
| Adipocytes - supplies glycerol for glycogenesis
480
What are the effects of chronically high levels of cortisol?
```
Redistribution of fat to:
Abdomen
Supraclavicular fat pads
Dorso-cervical fat pad (Buffalo hump)
Moon face (moon face)
```
481
What is addisons disease and most common cause?
Reduced cortisol production
Destructive atrophy from autoimmune response
Women>Men
482
What are signs and symptoms of addisons disease?
Postural hypotension
Lethargy, Weight loss, Anorexia
Inc skin pigmentation, vitiligo, dizziness
Hypoglycaemia
483
Why do patients get skin hyperpigmentation in Addisons disease?
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
What is an Addisonian crisis?
Life threatening emergency due to adrenal insufficiency
485
What precipitates an Addisonian crisis?
Precipitated by: Severe stress, salt depravation, infection, trauma, cold exposure, over exertion, abrupt steroid drug withdrawal
486
What are symptoms of Addisonian crisis?
N+V
Pyrexia
Hypotension
Vascular collapse
487
What is the treatment for Addisonian crisis?
Fluid replacement
| Cortisol - dexamethasone
488
Why does the adrenal medulla secrete 80% adrenaline and 20% noradrenaline?
20% of the cells lack N-methyl transferase which is used to convert noradrenaline to adrenaline
489
What affects does cAMP and PKA have on the pacemaker current in the heart?
cAMP increases the slope of the upstroke during depolarisation
PKA decreases the time it takes for depolarisation to occur
490
What is phaeochromocytoma?
Rare - catecholamine secreting tumour mainly noradrenaline
| May precipitate life-threatening hypertension
491
What are the signs/symptoms of phaeochromocytoma?
```
Severe HTN
Headaches
Palpitations
Diaphoresis (excess sweating)
Anxiety
Weight loss
Elevated blood glucose
```
492
What are the signs/ symptoms of mineralocorticoid deficiency?
Dizziness
Low Na
High K
493
What are the signs/ symptoms of androgen deficiency?
Loss of body hair in women
| Low libido
494
What are the signs/ symptoms of excessive catecholamine secretion?
Acute episodes
Sweating, anxiety, palpitations, high or low BP, collapse
-> sudden death
495
How would you do a biochemical assessment of the adrenal medulla?
24hour urine catecholamines - adrenaline, NA, dopamine, 3-methoxy-tyramine
24hour urine metanephrines - metabolites of adrenaline and noradrenaline
Plasma metanephrines
496
What are causes of primary adrenal failure?
```
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
What is the treatment for addisons?
Glucocorticoid - hydrocortisone, prednisolone
| Mineralocorticoid - fludrocortisone
498
What is adrenal cushings syndrome?
ACTH is suppressed - ACTH independent
| Excess cortisol production usually due to tumour on adrenals
499
How would adrenal cushings syndrome present?
Adrogenic symptoms - hirsutism, acne, greasy skin
| Virilising features - androgenic alopecia, deep voice, clitoromegaly
500
What is the adrenal cushings syndrome treatment?
Surgical intervention - adrenalectomy
| Risk of hypoadrenalism due to contra-lateral adrenal suppression
501
What is congenital adrenal hyperplasia?
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
What is a paraganglioma?
Extra-adrenal tumour
| Chromaffin tissue origin
503
What neuroendocrine markers can be used to diagnose phaeochromocytoma and paraganglioma?
Chromogranin A
504
How do you manage phaeochromocytoma and paraganglioma?
Alpha-blockade = phenoxybenzamine
Beta-blocker = bisoprolol
Surgical excision
Unopposed alpha-stimulation can cause a hypertensive crisis therefore give both a + b - blockade
505
What is the cervical spinal level of the middle of the thyroid?
C7
506
During embryological development what does the thyroid gland descend through?
Thyroglossal duct
507
What is the histology of the thyroid tissue?
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
What do parafollicular cells release in the thyroid?
Calcitonin
509
How are the thyroid and parathyroid glands distinct?
Parathyroid gland - principal cells also called chief cells produce parathyroid hormone
Thyroid gland - thyroid follicular cells produce thyroid hormone, parafollicular cells produce calcitonin
510
What cells in the parathyroid gland produce PTH?
Principal cells - chief cells
511
Describe the molecule of the thyroid hormones?
2 tyrosine linked together with iodine at three or four positions on the aromatic rings
Monoiodotyrosine + diiodotyrosine = triiodothyronine
Diiodotyrosine + diiodotyrosine = tetraiodothyronine
512
What is the method of producing thyroid hormones?
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
What is the function of thyroid peroxidase?
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
What in the body is iodine used for?
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
How is iodine absorbed into the thyroid gland?
Iodide (I-) is taken up from blood by thyroid epithelial cells which has a sodium-iodide symporter or "iodine trap"
516
How much of the T4 is produced and converted into T3?
90% of thyroid hormone secreted is T4
T4 - longer half life than T3
80% T3 derived from T4
517
What is the difference between T3 and T4 apart from the iodine amount?
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
How is T3/T4 transported in the blood?
Thyroxine-binding globulin
519
What is the function of thyroid hormone?
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
What are the similarities of TSH/ FSH/ LH?
They all have alpha subunits
| The beta subunits provide unique biological activity of each of them
521
What is the type of the TSH receptor and how it works?
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
On what organs do thyroid hormone not stimulate the metabolic rate?
Brain
Spleen
Testis
523
What is the cardiac response to thyroid hormone?
Increases heart's response to catecholamines
Inc cardiac output - +vely chronotropic and inotropic
Inc peripheral vasodilation
524
What is the nervous system response to thyroid hormone?
Essential for both development and adult function
| Inc myelination of nerves and development of neurones
525
What receptor does thyroid hormone work on?
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
What are some examples of thyroid hormone activated genes?
```
Phosphoenolpyruvate carboxylate kinase (PEPCK)
Ca/ATPase
Na/K ATPase
Cytochrome oxidase
6 - phosphogluconate dehydrogenase
```
527
What is the release profile of TSH?
Diurnal variation
528
What is a goitre?
Enlargement of the thyroid gland
May accompany either hypo or hyperthyroidism
Develops when the thyroid gland is overstimulated
529
What are causes of hypothyroidism?
- Failure of thyroid gland
- TSH/TRH deficiency
- Inadequate dietary supply of iodine
- radioactive iodine
- autoimmunity
- post surgery
- congenital
- anti-thyroid drugs
530
What are general symptoms of hypothyroidism?
Obesity, Lethargy, Intolerance to cold, Bradycardia, Dry skin, Alopecia, Hoarse voice, Constipation, Slow reflexes
531
What are the effects of hypothyroidism in infants and adults?
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
What is Hashimoto's disease?
Autoimmune disease resulting in destruction of thyroid follicles -> hypothyroidism
5x w>m
Plasma: low T3/T4 + high TSH
533
How do you treat Hashimoto's disease?
Oral thyroid hormone - T4 long half life
534
What are the causes of hyperthyroidism?
```
Autoimmune Grave's disease
Toxic multi nodular goitre
Thyroiditis
Excessive T4/T3 therapy
Drugs - amiodarone
Ectopic thyroid tissue
```
535
What are symptoms of hyperthyroidism?
Weight loss, irritability, heat intolerance, sweating warm vasodilator hands, tachycardia, fatigue, weakness, increased bowel movements, possible tremor, hyper-reflexia, breathlessness, loss of libido
536
What is Grave's disease?
Autoimmune condition causing hyperthyroidism
Cause by production of thyroid stimulating immunoglobulin -> continuously stimulates thyroid hormone secretion outside normal negative feedback control
537
What is an uncommon condition caused by Grave's disease?
Bulging eyes- not in every case
| TSI affect fibroblasts - CD20 receptor in eyes and extra-ocular muscles
538
What imaging technique would be used for thyroid function?
Technetium-99m - detection by gamma camera
1 day biological half life
Also used for: bone scan, MI perfusion, Brain imaging
539
What are antithyroid drugs - treatment for hyperthyroidism?
Carbimazole most commonly used
Prevents thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin - block formation of thyroid hormone
Propylthiouracil
Radioactive iodine
540
How long does hypothyroidism take to respond once treatment has started?
6-8 weeks
541
What is a potential serious problem with thyroid hormone deficiency?
Myxoedema coma
Severe hypothyroidism
Hypothermia and fluid overload in heart pericardial effusion
542
What is borderline or sub-clinical hypothyroidism?
Low normal fT4 and high TSH very common
543
What are the causes of thyroiditis?
```
Inflammation of thyroid
Release of thyroxine into circulation
Viral infection - de quervain's thyroiditis
After childbirth - post-partum
Medication - amiodarone
```
544
What is a thyroid storm?
Rare condition - excess thyroid hormone
| Hyperpyrexia, tachycardia, cardiac failure, liver dysfunction
545
What is the problem with pregnancy and Graves disease?
Graves disease autoantibodies can cross placenta - baby can be born with hyperthyroidism
546
What are the 4 subcategories of types of goitre?
Diffuse goitre
Nodular goitre
Fibrotic goitre
Iodine deficiency
547
How is most of the calcium in the body kept?
In hydroxyapatite crystals in the bone - 99%
548
How much calcium is exchanged between the bone and the ECF/ day?
300-600mg
549
What are the 3 interconvertible fractions of calcium storage in the body?
Ionised
Protein bound
Complexed in with phosphate or citrate
550
What 3 hormones regulate calcium and phosphate?
Parathyroid hormone - response to hypocalcaemia
Calcitonin - response to hypercalcaemia
Vit D - absorption of calcium
551
What cells produce calcitonin?
C cells in the thyroid
552
How many parathyroid glands do we have?
4
| 2 on each lobe
553
How is PTH synthesised and transported around the body?
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
What is important about the synthesis of PTH and the storage?
Synthesis is constitutively
T1/2 is 4 mins
released PTH cleaved in liver - active form
PTH not stored
555
How is PTH removed from circulation?
Chief cells degrade the hormone
| Cleavage of PTH in chief cells accelerated by high serum Ca levels
556
What type of receptor is a Calcium receptor and how does it function when it comes to Ca homeostasis?
GPCR - Gs
PIP2 -> DAG, IP3 -> IP3 releases calcium intracellularly -> PLA2 -> AA inhibits PTH secretion + increases VDR expression -> reduces PTH synthesis.
557
What are the PTH target organs and their effects?
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
Where are calcium, phosphate and magnesium resorbed the most in the kidneys?
PCT - Ca2+ and PO4-
| DCT - Mg2+ + thick ascending limb of loop of Henle
559
What is the process of Vit D synthesis?
Cholesterol in skin converted to Vit D3 by sun -> Liver converts to 25-dihydroxyvitamin D3 -> kidney converts to 1,25-dihydroxyvitamin D3
560
What two mechanisms does Vit D prevent bone resorption?
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
What is a problem with chronic hypercalcaemia?
```
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
What is the problem with hypocalcaemia?
```
Hyper-excitability of NMJ
Pins and needles, - paraesthesia
Tetany
Paralysis
Convulsions
```
563
What bone problem does prostate cancer mets cause?
Oestoblastic mets - no hypercalcaemia
564
What bone problems do most of the cancers that metastasise into the bone cause?
Hypercalcaemia
Osteolytic usually
Multiple myeloma commonly
565
What is primary hyperparathyroidism?
One of 4 parathyroid glands develops into an adenoma and secretes excessive PTH
Inc serum Ca and dec serum PO4-
566
What is secondary hyperparathyroidism?
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
How does calcium cause changes in neuronal activity?
Hypocalcaemia -> raises threshold for depolarisation -> easy to depolarise -> easy for action potential
Hypercalcaemia -> suppression of neuronal activity - lethargy, confusion, coma
568
What is an iatrogenic cause of symptomatic hypocalcaemia?
Post total-thyroidectomy - inadvertent removal/ ischaemia of parathyroid glands
569
When does most of the foetal growth occur during pregnanct?
last 1/3 pregnancy 2/3 foetal growth occurs
| 28 weeks onwards 1k to 3.5kg
570
What are the 2 phases of metabolic adaptation during pregnancy?
Anabolic and catabolic phase
Anabolic - building stores especially adipose
Catabolic - maternal metabolism adapts to meet increasing demand by foetus/placenta
571
What happens to insulin sensitivity during pregnancy?
(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
What glucose transporter facilitates glucose transport through the placenta?
GLUT1
573
What are anti-insulin hormones secreted by the placenta?
Placenta secretes: Corticotropin releasing hormone - inc 1000 fold in maternal blood.
Human placental lactogen + progesterone
574
How does oestrogen and progesterone affect insulin in pregnancy?
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
What are 3 underlying causes of gestational diabetes?
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
What are complications of gestational diabetes?
Inc incidence of miscarriage
Inc incidence of congenital malformations
Foetal macrosomia - leading to shoulder dystocia
Gestational HTN/ preeclampsia
577
What are risk factors for gestational diabetes?
Maternal age >25 yrs
BMI >25Kg/M2
Race/ethnicity - asian, black, Hispanic
FMHx - DM and macrosomia
578
How do you manage gestational diabetes?
Dietary modification
Insulin injection if persistent hyperglycaemia
Regular ultrasound scans
579
What are the metabolic responses to exercise?
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
How does energy requirement change from BMR to a marathon?
BMR - 4kJ/min
100m sprint - 200kJ/min
1500 race - 140kJ/min
Marathon - 80kJ/min
581
How long of anaerobic exercise can the body last by breaking down muscle glycogen?
2 minutes
582
How long does the ATP energy come from during exercise?
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
