Liver and Friends Flashcards
1
Q
what are the functions of the liver
A
- carb metabolism
- fat metabolism
- protein metabolism
- hormone metabolism
- toxin/drug metabolism and excretion
- storsage
- bilirubin metabolism and excretion
2
Q
where is iron used in the body?
A
in myoglobin in muscles (300mg)
in haemoglobin in erythrocytes (1,800mg)
3
Q
where in the body is iron stored?
A
- 1,000 mg stored in the liver parenchyma
- 600mg stored in reticuloendothelial macrophages
4
Q
what is ferritin?
A
- cytosolic protein that stores iron
- small amounts are secreted into the plasma where it acts as an iron carrier
- it acts as a buffer against iron deficiency and iron overload
- plasma ferritin can be used as a marker of overall iron levels stored in the body
5
Q
problems that can cause ferritin excess
A
- excess iron storage disorders
- haemolytic anaemia
- hereditary haemochromatosis
- iron replacement therapy
- non iron overload:
- liver disease
- malignancies
6
Q
ferritin deficiency
A
iron deficiency is the only known cause of low ferritin
this can result in anaemia
if ferritin is < 20 µg/L this indicates depletion
if ferritin is less than 12 µg/L then this suggests a complete absense of stored iron
7
Q
difference between RDA and AI
A
- recommended daily allowance
- AI is adequate intake which is for when there is no RDA
8
Q
retinal sources
A
- humans need to make retinal from vitamin A
- vit a includes retinal and carotines
- they can either absorb it directly from meat or produce
- or they can synthesise it form carotines (found in carrots)
9
Q
functions of vitamin A
A
- vision
- reproduction
- growth
- stabilising cellular membranes
10
Q
vit a deficiency
A
- blindness
- night blindness
- xeropthalmia
- rare in developed countries as the liver stores vitamin A well
- it could be as a consequence of fat malabsorbtion
11
Q
vitamin A excess
A
- acute
- abdo pain
- headaches, dizziness, sluggishness and irritability
- desquamation of the skin
- chronic
- joint and bone pain
- hair loss, dryness of the lips
- anorexia
- weight loss and hepatomegaly
- carotenemia
- reversible yellowing of the skin
- does not cause toxicity
12
Q
vitamin D
A
- increases intestinal absorbtion of Ca2+
- promotes resorption and formation of the bone
- deficiency
- demineralisation of the bone
- causes rickets in children
- causes osteomalicia (soft bones) in adults
- parathyroid gland secretes PTH
- sun acts on a cholesterol derivative in the skin to form vitamin D3
- both D2 and D3 can be from dietary intake
- inthe liver and kidneys these are processed into 1,25 dihydroxyvitamin D which does the job of maintaining calcium uptake
13
Q
Vitamin E
A
- stored in non-adipose cells such as liver and plasma
- there’s also a fixed pool in the adipose cells
- it’s an important antioxidant
- requirements in men
- 4mg/day
- requirements in women
- 3mg/day
- deficiency caused by
- fat malabsorbtion (e.g. CF)
- prem infants
- deficiency causes
- haemolytic anaemia
- myopathy
- retinopathy
- neuropathy
14
Q
Vitamin K
A
- rapidly taken up by the liver
- then transferred into very low density lipoproteins and low density lipoproteins which carry it into the plasma
- sources:
- vitamin K1
- present in leafy GREEEEEEEEENS
- vitamin K2
- synthesised by intestinal bacteria
- K3 and K4 are synthetic versions
- vitamin K1
- Necessary for activation of clotting factors 10, 7, 9 and 2
- deficiency
- haemorrhagic disease of the newborn
- rare in adults unless they are on warfarin
- excess?
- k1 relatively safe
- synthetic versions are more dangerous
- could cause oxidative damage, red cell fragility
15
Q
water soluble vitamins
A
- move more quickly through the body and therefore require more regular intake than fat soluble
- they include
- C
- B12
- folate (one of the B vitamins)
16
Q
Vitamin C
A
- found in citrus fruits
- adults need 40mg/day
- functions:
- collagen synthesis
- carnitine sunthesis
- neurotransmitter synthesis
- antioxidant
- iron absorbtion
- deficiency = scurvy within 50-100 days without VC
- teeth and gum disease
- easy bruising
- hair loss
- treatment for scurvy with vitamin C very quickly relieves symptoms
- full recovery within 48 hours
- excess
- some GI side effects
- no evidence that vitamin c reduces the incidence or duration of colds
17
Q
vitamin B12
A
- Found in fish eggs meat and milk
- binds to R proteins which protect it from destruction in the stomach
- IF is produced by parietal cells
- IF-B12 complex is absorbed in the terminal ileum
- B12 is then stored in the liver
- deficiency caused by
- pernicious anaemia
- malabsorbtion
- veganism
- symptoms
- macrocytic anaemia
- peripheral neuropathy in prolonged deficiency
18
Q
folate
A
- found in many foods
- a type of vitamin B
- higher requirements during pregnancy
- coenzyme for methylation reactions so is needed for DNA synthesis
- deficiency caused by:
- malabsorbtion
- drugs (e.g. methotrexate)
- diseases that increase cell turnover (e.g. leukaemia)
- deficiency symptoms:
- macrocytic anaemia
- foetal development abnormalities - involving neural tube
19
Q
clotting factors produced in the liver
A
- I (fibrinogen)
- II (prothrombin)
- IV
- V
- VI
- VII
20
Q
measuring clotting factor performance
A
prothrombin time (extrinsic pathway)
international normalised ratio
Activated partial thromboplastin time (intrinsic pathway
an increased PT could mean liver disease but is not specific to liver disease
21
Q
what are xenobiotics
A
- foreign substances that are not normally found in the body and which cannot be used for energy
- can be absorbed from the lungs, skin or ingested
- drugs are xenobiotics
22
Q
xenobiotic metabolism
A
- the kidney only excretes water soluble material so xenobiotics need to be converted to hydrophillic metabolites for excretion
- most of this metabolism takes place in the liver
- it normally happens in two phases
23
Q
biotransformation reactions
A
- some compounds can be excreted after phase I
- some compounds go on to phase II without a phase I
- most biotransformation occurs in the SER
24
Q
Cytochrome P450 enzymes
A
- responsible for most phase I reactions
- there are at least 10 main groups of cytochrome-P450 enzymes
- they are encoded by a family of 57 genes
- features they all have in common:
- present in SER
- oxidise substrate and reduce oxygen
- in electron transport chain, cytochromes reduce O2 as the final electron acceptor
- have a reductase unit which utilises NADPH
- generate reactive free radicals
- inducible
- sustained exposure to substances leads to up-regulation
- patients may need increasingly large doses
25
Q
one cytochrome-P450 isoform to remember
A
- CYP3A4
- it is involved in the metabolism of about 50% of all clinically prescribed drugs
- statins
- in the above the 3 refers to the subfamily and the A4 refers to the isoenzyme
- Grapefruit juice inhibits CYP3A4 causing increased blood levels of the drug
26
Q
anti-psychotics and smoking
A
- clozapine is an anti-psychodit med
- undergoes serious hepatic metabolism by cytochromes
- CYP1A2 is considered to be the main one
- CYP1A2 is induced by smoking
- smoking cessation while on clozapine needs to be accompanied by a dose reduction of 30-50%
- dose should be increased if someone on clozapine takes up smoking
- things that do the same thing as smoking:
- grilled meat
- rifampicin
- Antibiotic ciprofloxacin inhibit CYP1A2 resulting in higher concentration of clozapine
27
Q
Four outcomes of drug metabolism
A
- active drug to inactive metabolite
- active drug to active metabolite
- inactive drug to active metabolite
- active drug to reactive intermediate (may be toxic)
28
Q
inactivation of a xenobiotic example
A
- Phenolarbitol is a sedative and anti-epileptic
- lipophilic so distributes into fat tissue
- so only a small amount of active drug is dissolved in plasma and can be excreted by kidneys
- elimination requires
- phase I: introduction of a functional group (OH group)
- phase II: conjugation (to either a glucaronic acid or a sulphate)
- products are polar enough to dissolve and be excreted by the kidneys
29
Q
example of an active drug being converted to an active metabolite
A
- morphine is a metabolite of codeine
30
Q
inactive drug to active metabolite example
A
- nitroglycerin is metabolised by cytochrome p450 enzymes to produce NO as the active principle
31
Q
active drug to reactive intermediate (toxification of xenobiotics)
A
- benzo(a)pyrene from cigarette smoke is converted to very reactive carcinogenic metabolites
- paracetamol is another one
- the product is innocuous and easily excreted
- but the intermediate NAPQI is toxic
- if it’s taken at therapeutic doses then not too much damage can be caused before the intermediate is excreted
- if taken in overdose it overwhelms the phase II enzymes and causes cell damage
- hepatocytes worst affected because they have the highest quantity of cytochrome enzymes
- the person may develop fulminant hepatic failure
- has the same cytochrome enzyme as alcohol
- because it’s inducible, more paracetamol is metabolised to NAPQI in people who drink more
32
Q
Phase I reactions
A
- oxidation, reduction or hydrolysis reactions to expose functional groups
- this is so that phase II reactions can take place
33
Q
Phase II reactions
A
- these are conjugation reactions to make the compound more water-soluble
- glucoronidation is the most common phase II reaction
- transferase enzymes are mainly responsible for phase II reactions
34
Q
phase II enzymes can be:
A
- Microsomal
- found in SER
- inducible by drugs and diet
- Non-microsomal
- found in cytoplasm and mitochondria of hepatocytes
- non inducible
35
Q
pseudocholinesterase
A
- a non-microsomal enzyme that acts on succinylcholine
- succinylcholine is a muscle relaxant that is used in anaesthesia
- normally 90-95% of succinycholine is inactivated by pseudocholinesterase
- this means only 5-10% of the drug reaches the neuromuscular junction and paralysis onlu lasts about 5-10 minutes
- in pseudocholinesterase deficiency, paralysis could last 8 hours
36
Q
metabolism of ethanol
A
- doesn’t fit phase I and phase II because it doesn’t need to be conjugated for excretion
- only 2-10% is urinated out though because it is used in the liver as a dietary fuel
- this is mainly via the enzyme alcohol dehydrogenase
- ADH creates the toxic intermediate acetaldehyde
- theres another route which uses cytochrome P450 enzymes
- normally this only accounts for about 20%
- but chronic alcohol use can INDUCE 5-10 times as much of the cytochrome p450 enzyme
- this also produces toxic acetaldehyde
- it just does it at a very fast rate and overwhelms the enzymes responsible for clearing the acetaldehyde
- this means that it accumulates in the liver and causes damage
37
Q
main source and loss of nitrogen in the body
A
source: dietary protein
loss: gut and kidneys (as urea)
38
Q
metabolic use of amino acids
A
- body maintains a pool of free amino acids in the blood
- in the fed state the net contributor is the diet
- in the fasting state the main contributor is skeletal muscle
- bodily protein is in constant turn-over
- degradation via lysosomal and ubiquitin pathways
- protein resynthesis
- amino acids can be used to:
- make protein
- make other nitrogenous products
- synthesise glucose by first removing the amino group
- removed nitrogen is excreted in urea
39
Q
recommended dietary protein
A
0.75g/kg/day
50-60g in normal adults
40
Q
what is the nitrogen balance
examples of positive and negative nitrogen balance
A
where intake and excretion of nitrogen is roughly equal
41
Q
important derivatives of glycine
A
- haem
- creatinine
- purine bases
42
Q
important derivatives of aspartate
A
- purine bases
- pyrimidine bases
43
Q
important derivatives of tyrosine
A
dopamine
catecholamines
thyroid hormones
melanin
44
Q
How much total body protein is turned over each day?
How much is excreted as nitrogen?
A
1-2% of total bodily protein
20-30g of bodily protein
45
Q
Why are blisters firm?
A
- high amount of protein in the exudate
- this draws water in
- this is why burns are accompanied by sucha acute protein loss
- widespread tissue damage
- lots of protein lost in the exudate
- increased metabolic requirement for protein at the SAME time as increased protein loss
46
Q
Two different types of protein degradation
A
Lysosomal and non-lysosomal
- Lysosomal
- takes place in the reticulo endothelial system of the liver
- sinusoidal epithelial cells
- kupffer cells - immune cells of the liver
- pit cells
- Non-lysosomal degradation
- Normally in a proteasome and is ubiquitin dependent
47
Q
Protein digestion summary and enzymes
A
48
Q
why might the body degrade proteins
A
- faulty/aging/obsolete proteins
- as a part of signal transduction
- as part of a flexible system that needs to meet the energy requirements of its environment
49
Q
ubiquitin
A
- tag for degradation by the proteosome
- it’s a small protein
- three enzymes are involved in making the chains
- E1: ubiquitin-activating enzyme
- E2: ubiquitin-conjugating enzyme
- E3: ubiquitin-protein ligase
- the longer the chain the stronger the signal
- especially if it’s >4
50
Q
Protein half lives
A
- some are short and some are long and it’s dependent on their N terminal residues
- some amino acids at the N terminus have a stabilising effect
- some amino acids at the N terminus have a destabilising effect
51
Q
Ubiquitin targets
A
- PEST sequence
- proline, glutamic acid, serine and threonine all found in a region of 12aas
- these sequences promote ubiquiting chain formation
- they normally only become exposed when catabolism is needed
- Cyclin destruction box
- similar to PEST but found on cyclins
- obviously need to be degraded very rapildy - CDKs and cell cycle
52
Q
Proteosome
A
- Central proteosome with two regulatory caps
- one cap at either end
- the caps are what binds the polyubiquitin
- the cap unfolds the protein and feeds it into the central cylinder
- amino acids released by this process are re-cycled into new proteins
- those that aren’t are rapidly degraded by the urea cycle
53
Q
what happens to excess amino acids
A
- they are degraded by the urea cycle
- regardless of their source they are not stored
- those which aren’t immediately incorporated into proteins are degraded
54
Q
what are the names of enymes that attach and remove phosphate
A
- attach: kinase
- remove: phosphatase
55
Q
three amino acids in animals that can be phosphorylated
A
- serine
- threonine
- tyrosine
- ratio of phsophorylation is 1000:100:1 (in the order above)
- even though the level of tyrosine phosphorylation is minor, the effect is huge
- BCR-Abl is a constitutively active tyrosine kinase
56
Q
Two forms of malnutrition
A
- merasmus
- severe wasting simply form insufficient calorie intake
- cancer cachexia
- anorexia
- Kwashiokor
- swelling of the abdomen
- caused by hypoalbuminaemic oedema
- caloric intake is adequate but protein is not
- fatty liver
57
Q
THE FIVE KEY PLAYERS IN AMINO ACID CATABOLISM
A
62
Q
Glucose alanine cycle - can you draw the diagram and can you describe the function
A
- alanine is the principle ammonia scavenger
- glutamate collects the ammonia
- ALT shifts the amino group from the glutamate to pyruvate
- this forms an alanine
- alanine travels in the blood to the liver where the reverse happens
- the NH4+ produced is then turned into urea via the urea cycle
- the pyruvate produced is turned into glucose by gluconeogenesis
- solves two problems with one cycle. moves carbon atoms of pyruvate, as well as excess ammonia, from muscle to liver as alanine. in the liver the alanine gives pyruvate (for gluconeogenesis) and releases ammonia for conversion into urea. The energetic burden of gluconeogenesis being imposed on the liver rather than muscle, so that muscle ATP can be devoted to muscle contraction
76
Q
Fatty Acid Transporter systems
Can you draw the diagram?
A
- FA binding protein
- this can be induced by increased fatty acid uptake by the cell
- FAT - fatty acid translocase
- FATP - fatty acid transport polypeptide
79
Q
insulin resistance and fatty acid uptake (adipocytes and hepatocytes) can you draw the diagram
A
97
Q
Glucose and the Liver in the fed state: can you draw the diagram?
A
99
Q
Effects of cortisol on fuel metabolism
A
100
Q
Effects of adrenaline on fuel metabolism
A
109
Q
Hepatic plate can you draw the diagram
A
116
Q
liver embryology
A
- endodermal outgrowth of the foregut
- bile produced from 12th week
121
Q
overall describe the embryology of the liver
A
liver buds develop anteriorly and then swing to the right, fusing with the posterior abdominal wall
124
Q
give a very brief description of the embryology of the pancreas?
A
- The pancreas develops as dorsal and ventral buds
- They rotate posteriorly and fuse together
- The ventral pancreas becomes the head and uncunate process of the pancreas
- As a result, the superior mesenteric vein and artery get sandwiched
133
Q
What is this? talk about it
A
- these are biliary canaliculi and sinusoids
- sinusoids are fenestrated capillary vessels
- the capillary wall is too collapsed against adjoining cells to be seen
- the vessels sit on a mesh of reticulin (collagen III)
- they are seperated from the hepatocytes by the space of Disse
- endothelial cells discriminated from Ito cells and hepatocytes by their small dense nuclei
134
Q
what is this? what are the blue things? and what do they do? what dye has been used?
A
- these are Kupffer cells in the lining of the sinosoids
- they are the resident macrophages of the liver
- they are important for host defence as well as (in part) the production of bilirubin
- their presence has been demonstrated because they phagocytosed india ink
138
Q
what is this? what type of epithelium is it?
A
This is the wall of the gall bladder
- lining is towards the bottom
- this is a simple columnar epithelium
- the holes at the bottom are the poorly developed microvilli where the lining has been thrown into folds to reabsorb water
- you can see the wall above is connective tissue and smooth muscle
- it also contains blood vessels
142
Q
what is this and what are the arrows pointing to?
A
- this is exocrine pancreas
- the acini are the spherical clumps of cells
- the arrows point to centro-acinar cells which can be seen inside several of the acini
