Liver Flashcards
1
Q
What are the functions of the liver
A
Carbohydrate metabolism
Fat metabolism
Protein metabolism
Hormone metabolism
Toxin/drug metabolism and excretion
Storage
Bilirubin metabolism and excretion
2
Q
Describe iron metabolism
A
IN - dietary iron to duodenum (average 1-2mg/day)
Becomes - plasma transferrin (3 mg)
OUT (of plasma transferrin) - iron utilisation
- muscle (myoglobin) 300mg
- bone marrow 300mg - circulating erythrocytes (haemoglobin) 1,800mg
IN (to plasma transferrin) - storage iron
- liver parenchyma 1000mg
- reticuloendothelial macrophages (600mg) - come from circulating erythrocytes
LOSS - iron loss average 1-2mg/day
- sloughed mucosal cells
- desquamation
- menstruation
- other blood loss
3
Q
Describe ferritin
A
Large spherical protein consisting of 24 noncovalently linked subunits
Subunits form a shell surrounding central core
Core contains up to 5000 atoms of iron
4
Q
Where is ferritin found
A
In cytoplasm of cells
Can be found in serum
5
Q
What is the concentration of ferritin directly proportional to
A
Total iron stores in the body
6
Q
What do vitamins act as
A
Gene activators
Free-radical scavengers
Coenzymes or cofactors in metabolic reactions
7
Q
Do water soluble of fat soluble vitamins require more intake
A
Water soluble as pass more readily through the body
8
Q
Name examples of water soluble vitamins
A
B and C
9
Q
Name examples of fat soluble vitamins
A
A, D, E and K
10
Q
What is another name for vitamin A
A
Retinoids
11
Q
How do vertebrates ingest retinal
A
Directly from meat or produce retinal from carbohydrates
12
Q
Name vitamin A sources
A
Retinols
- cereal
- dairy
- eggs
- dates
Carotenoids
- carrot
- spinach
- sweet potato
- tomato
13
Q
What is the requirement of vitamin A
A
0.6 mg/day in men
0.7 mg/day in women
14
Q
What are the functions of vitamin A
A
Vision used to form rhodopsin in the rod cells in the retina
Reproduction
- spermatogenesis in male
- prevention of foetal resorption of female
Growth
Stabilisation of cellular membranes
15
Q
What are the functions of vitamin D
A
Increased intestinal absorption of calcium
Resorption and formation of bone
Reduce renal excretion of calcium
16
Q
Describe the absorption of vitamin D
A
2 intakes
- sunlight
- penetrates the skin becomes 7-dehydrocholerstrol
- cholecalciferol (vitamin D3) - Dietary intake
D3 - fish, meat
D2 - supplements
To liver
Become - 25-hydroxyvitamin D3
To kidney
1,25-dihyroxyvitamin D3 - maintains calcium balance in body
17
Q
Where is vitamin E stored
A
Non-adipose cells e.g. liver and plasma - labile and fixed pool
Adipose tissue - foxed pool
18
Q
What is the role of vitamin E
A
Important antioxidant
19
Q
What are the requirements of vitamin E
A
4 mg/day in men
3 mg/day in women
20
Q
How is vitamin K taken up
A
Rapidly by the liver
Transferred to very low-density lipoproteins which carry it to the plasma
21
Q
What are the sources of vitamin K
A
K1 - phylloquinone
- synthesized by plants and present in food
K2 - menaquinone
- synthesised in humans by intestinal bacteria
Synthetic vitamin K’s
- K3 (menadione)
- K4 (menadiol)
22
Q
What is the functions of vitamin K
A
Activation of some blood clotting factors
Needed for liver synthesis of plasma clotting factors II, VII, IX and X
Can be assessed by measuring prothrombin time
23
Q
When is the intrinsic clotting factor pathway activated
A
By contact
24
Q
When is the extrinsic pathway activated
A
By FVII coming into contact with tissue factor
25
What do the intrinsic and extrinsic pathways do
Initiate a cascade - ultimately results in fibrin clot formation
26
What clotting factors are produced by the liver
I (fibrinogen)
II (prothrombin)
IV
V
VI
VII
1,2,4,5,6,7
27
How can the performance of clotting pathways be measured
Using:
- prothrombin time (PT) - extrinsic pathway
- International normalised ration (INR)
- Activated partial thromboplastin time (aPTT) - intrinsic pathway
28
Where does more detoxification take place
What occurs
In the liver
Inactivation and facilitated elimination of drugs and other xenobiotics
Formation of active metabolites with similar or occasionally enhanced activity
Activation of pro-drugs
Toxification of less toxic xenobiotics
29
What are the features of cytochrome P450 enzymes
Present in the smooth endoplasmic reticulum
Oxidise the substrate and reduce oxygen
Have cytochrome reductase subunit which uses NADH
Inducible - enzyme activity may be increased by certain drugs, some dietary components and some environmental toxins e.g. smoking
Generate a reactive free radical component
30
Describe inactivation of xenobiotic (e.g. phenobarbital)
Phenobarbital is a barbiturate derivative
Relatively lipophilic - drug distributes into fat tissue
Amount that remains in plasma is mostly bound to plasma proteins
Only small fraction of drug is found freely dissolved in blood plasma
Elimination of the unmodified drug is thus very slow, and most of the drug is excreted after enzymatic conjugation
31
Define xenobiotic
Chemical compounds that are present in, but foreign to, biologic systems
32
Give examples of an active drug may be converted to another active form
Opiates - Codeine metabolised to morphine (phase 1 reaction)
Benzodiazepines - diazepam is demethylated in liver (phase-1 reaction) to nordiazepam
33
What happens to a pro-drug in the liver
Inactive drug (pro-drug) may be converted in the liver to an active agent
e.g. loratadine is the pro-drug of desloratadine
34
What are phase 2 reactions
Glycoside conjugation - glucuronidation (most common)
Sulphate - sulphation (second most common)
Glutathione (GSH)
Methylation
Acylation
Phosphate conjugation
35
What enzymes are responsible for phase 2 reactions
Transferase enzymes
- uridine diphosphoglucuronsyl transferase
- N-acetyl transferase
- glutathione S-transferase
- sulphotransferase
36
What substance does not fit into phase 1 or phase 2 categories
What happens
Ethanol - does not need to be conjugated for excretion
Only 2-10% is usually excreted in the urine - is used in the liver as a dietary fuel
Major route via alcohol dehydrogenase (ADH)
37
What is are the routes ethanol can use to be metabolised
Using ADH
Via microsomal ethanol oxidising system
38
What is the role of phase 1 reactions
Add functional groups
39
What is the role of phase 2 reactions
Conjugation
40
What is the metabolic role of the liver
Maintains a continuous supply of energy to the body by controlling the metabolism of CHO and fats
41
What is the liver regulated by
Endocrine glands e.g. pancreas, adrenal, thyroid
Nerves
42
Define lipids
Esters of fatty acids and glycerol or other compounds (cholesterol)
Large and diverse group of naturally occurring organic compounds that are insoluble in water
Variety of structures and functions
43
What is the composition of a tri(acyl)glyceride
1 glycerol molecule esterified to 3 fatty acids (bonded at carboxyl head)
44
Describe saturated fatty acids
Solid at room temp
45
Describe unsaturated fatty acids
Liquid at some temp
46
What are the functions of lipids
Energy reserve
Structure and other functions
- part of cell membranes
- integral to form and functions of cells
- inflammatory cascades
Hormone metabolism
- cholesterol is backbone of adrenocorticoid and sex hormones
- vitamin D
47
Where is the main storage place for glycogen
Liver
48
How are lipids transported
A TGs or FAs bounded to albumin or within lipoproteins
TGs - cannot diffuse through cell membrane
FA - released through lipase to facilitate transport into cells
FA are re-esterified into TG in cells
49
How are fatty acids uptake
Diffusion through the lipid bilayer of the cell membrane
Facilitated transport
- increases if increased substrate (increased supply)
- increases in receptor molecules (increased demand
50
What is insulin action
Insulin
- fat storage in adipocyte
- stimulates LPL - breakdown of TG
- reduces hormone sensitive lipase - reduces FA export from adipocytes
51
Describe lipoproteins
Consist of a core containing TGs and cholesterol-esters and a surface monolayer of phospholipids, cholesterol and specific protein
Protein to lipid ratio varies
Defined by density
52
When do chylomicrons carry lipids
From gut to muscle and adipose tissue
Remnants taken up by liver via receptor mediated endocytosis
53
Describe cholestrol
Liver is major organ in which cholesterol is processed
90% cholesterol is endogenous
Excretion of cholesterol through bile is only export system of cholestrol
Lipoproteins carry TG and cholesterol through the circulatory system
54
What are the three locations of oxidation in the liver
Peroxysomal B-oxidation
Mitochondrial B-oxidation
ER oxidation
55
What is fatty acid oxidation proportional to
Plasma levels of FFA released from adipocytes
56
What is mitochondrial B oxidation involved in
Oxidation of fatty acids of various chain lengths
Multistep process
57
What is the main role of peroxisomal B oxidation
Very long chain fatty acids (>C 20)
2-methyl-branched FAs
Dicarbolic acid - very toxic - inhibiting mitochondrial fatty acid oxidation
Prostanoids
C-27 bile acid intermediaries
4 step process - repeated to shorten chain length. Carried out by at least 2 enzymes
58
What is the role of mitrochondrial oxidation
Minor metabolic pathway - in fat overload increases
CYP4A enzymes oxidise saturated and unsaturated fatty acids
59
Describe albumin
Single polypeptide protein MW 66000
9-12g produced by the liver each day
Possible to increase this threefold
Leaves circulation via intersititium
Collected by lymphatics
Returned via thoracic duct
Rate known as - transcapillary escape rate
60
What are the roles of albumin
Binding and transport
Maintainance of colloid osmotic pressure
Free radicals
Anticoagulant effects
61
What are the reasons for albumin decrease
Decreased synthesis
Increased catabolism
Increased loss
62
What are the consequences for decreased albumin
Decreased colloid osmotic pressure
Decreased ligand binding
63
What diseases are associated with low albumin
Malnutrition
Liver disease
Renal disease
Burns/trauma
Sepsis
64
What is the role of bile
Lipid digestion and absorption
Cholesterol and homeostasis
Excretion of lipid soluble xenobiotics/drug metabolise/heavy metals
65
Describe bile
Complex lipid-rich micellar solution (water, inorganic electrolytes and organic solutes - bile acids, phospholipids, cholesterol, bile pigments)
Isosmotic with plasma
66
How much bile is produced a day
500-600 mls
67
What does the formation of bile depend on
Hepatic synthesis and canalicular secretion of bile acids
68
What is the maintenance of hepatic bile formation essential for
Normal liver function
69
What are most (95%) of bile acids secreted by
Hepatocyte have been previously secreted into intestines (enterohepatic circulation)
70
What does bile acids being amphipathic do
Amphipathic - hydrophilic and hydrophobic parts
Reduce surface tension and aid emulsification
71
Describe emulsification
Fat (TG) is insoluble in water
Emulsification - acts to increase SA for lipolysis. Stable emulsion important for the close apposition of lipase and TG
Lipases act at the surface of emulsified droplets and liberate FA from the glycerol backbone of G (lipolysis)
72
What are the functions of bile acids
Induce bile flow (osmotic effect)
Secretion of biliary lipids (PL and cholesterol)
Digestion of dietary fats
Facilitates protein absorption
Cholesterol homeostasis
Antimicrobial
Prevent calcium gallstones and oxalate renal stones
73
What are the two variations adipose tissue
White or brown
74
Where is white adipose tissue mainly found
Adults
75
Where is brown adipose tissue mainly found
Newborns
76
What are the histological features of white fat
Large unilocular lipid droplet pushing the organelles to the periphery of the cell
Look - a network of white polygonal structures
77
What are the histological features of brown fat
Centrally positioned nucleus surrounded by multiple lipid droplets on the periphery of the cell
Look - a net of cells filled with numerus empty vacuoles
78
What is the main role of white adipocytes
Energy storage
Store fat in form of triglycerides inside their cytoplasmic lipid droplets - helps to maintain free fatty acid levels in the blood
79
What is adipose tissue considered as
Endocrine organ
Leptin
80
Describe lipolysis
Triglycerides hydrolysed (by triglyceride lipase) forms fatty acids + glycerol
Fatty acids bind to albumin - transported to liver - enter hepatocytes
Glycerol converted to glycerol-3-phopshate - enters glycolysis pathway
81
Describe beta-oxidation
Fatty acids are oxidised and degregated (in mitochondria)
Two carbon segments are progressively released from fatty acid chain until acetyl CoA generated
NADH and FADH2 = biproducts
Acetyl-CoA immediately binds with oxaloacetate = forms citrate = enters TCA cycle
82
Where does the urea cycle occur
Mitochondria and cytoplasm of hepatocyte
83
What is the importance of urea cycle
Convert toxic ammonia to harmless urea which is excreted
84
What is liver synthesis stimulated by
Insulin
Growth homrone
85
What are the plasma proteins synthesised in the liver
Albumin
Globulin
Fibrinogen
CRP (an infection marker)
Clotting factors - 2, 7, 9 and 10 - vitamin K dependent
Thrombopoietin
Angiotensinogen
86
What happens in tissue amino acid depletion
Plasma proteins can be degraded and released back into the blood as amino acids for tissue to use in protein synthesis
87
What vital role do plasma proteins play
Provide oncotic pressure in the blood - meaning they hold water in the plasma
88
What does UV (sunlight) convert 7-dehydrocholestrol into
Cholecalciferol (Vitamin D3)
89
What does the liver convert Cholecalciferol (vitamin D3 into)
25-hydroyvitamin D3
90
What is vitamin C found in
Fresh fruit and vegetables
91
How much vitamin C does an adult need a day
40mg/day
92
What are the functions of vitamin C
Collagen synthesis
Antioxidant
Iron absorption
93
What are the two active forms of vitamin B12
Methylcobalamin
5-deoxyadenosylcobalamin
94
What is vitamin B12 important in
Intrinsic factor production in the stomach
95
Where is vitamin B12 absorbed
Terminal ileum
96
Where is vitamin B12 stored
In the liver
97
Where is folate found
Foods fortified with folic acid
98
When are requirements of folate higher
Pregnancy
99
What are the functions of folate
Coenzyme in methylation reactions
DNA synthesis
Synthesis of methionine from homocysteine
100
What is the role of phase 1 reactions
Functionalisation - non synthetic
Add or expose functional groups -OH, -SH, -NH2, -COOH
Small increase in hydrophilicity
101
What is the role of phase 2 reactions
Conjugation - biosynthetic
Conjugation with endogenous molecules - glucuronic acid, sulphate, glutathione
Covalent bond formed
Large increase in hydrophilicity
102
Which reaction has a large increase in hydrophilicity
Phase 2 reaction
103
Are glucuronides polar or non polar
Polar - hydrophilic
104
What predominates in phase 1 metabolism
Cytochromes
Induction - one drug can induce numerous cytochrome isoenzymes
Genetics - genetic variation especially in CYP2D6
105
Give examples of CYP3A4
Paracetamol
Codeine
Diazepam
106
Give examples of CYP2D6
Amitriptyline
Codeine
107
What drug causes reactive intermediates
Paracetamol
108
What are two types of enzymes involved in phase 2 reactions
Microsomal enzymes
Non microsomal enzymes
109
Describe microsomal enzymes
Location
Sites
Enzymes
Reactions
Inducible?
Location - SER
Sites - liver, then kidney, lungs, intestinal mucosa
Enzymes - mono-oxygenase
Reactions - majority of drug biotransformation reaction, oxidative, reductive and hydrolytic and glucuronidation
Inducible by drugs and diet
110
Describe non microsomal enzymes
Location
Sites
Enzymes
Reactions
Inducible?
Location - cytoplasm and mitochondria of hepatocytes, other tissue
Enzymes - protein oxidases, esterase, amidases, conjugates
Reactions - non specific enzymes that catalyse few oxidative, a number of reductive and hydrolytic reactions. Conjugate reactions other than glucuronidation
Not inducible but having polymorphism
111
Do all drugs go through phase 1 and 2
No - most do
Some can just 1 or 2, or some can do 2-1
112
What is the role of liver detoxification
Active drug into inactive drug to excreted by kidneys or faeces
Can
- toxic to non toxic metabolise
- prodrug to inactive dug
113
What are the two most important families of the cytochrome P450
CYP3A4 (50%)
CYP206 (20%)
Do most of the detoxification
114
What it the role of cytochrome P450 - phase 1
Oxidation
Reduction
Hydrolyse
To make a non polar drug to a polar and water soluble
115
What can affect phase 1
Polymorphism - rapid metabolism (CYP2D6) = decrease in active drug
OR
Slow metabolism = takes a while to make it an active drug. Toxic side effects
Liver disease - can develop toxicity
116
Describe phase 2
Take a drug that's not water/polar enough = aim is to make it more polar and more water soluble
Transferase enzymes add groups - conjugation reactions
- methyl
- acetyl
- sulphate
- glutathione
- glucoronate
May have come from phase 1 may not have
Aim it to excrete easier
117
What reactions occur in phase 2
Conjugation reactions by transferase enzymes
118
What reactions occur in phase 1
Oxidation, reduction, hydrolysis by cytochrome P450
119
Define oxidation
Substance reacting with an oxygen to produce an oxide
120
Define hydrolysis
Broken down into its components by adding water
121
Define reduction
Loss of electrons
122
How long do lipid reserves last
30-40 days
123
How long do muscle (protein) reserves last
7-10 days
124
Describe a white fat cell
Uniocular cell
Contain a lipid droplet and cytoplasm
Have a nucleus which is flat and at the edge of the cell
Usually around 0.1mm in diameter
125
What is the fat inside white fat cells
Mainly made up of triglycerides and cholesterol ester
Stored in semi-liquid form
126
Describe brown fat cells
Multicular cell
Multiple vacuoles
Shaped like polygons
Contain more cytoplasm than white cells
Fat droplets are scattered throughout them
Nucleus is round and at the centre of the cell
127
What is the role of brown fat
Generate heat energy
Contain many mitochondria - gives the brownish appearance
128
What is the role of white fat cells
Energy storage
129
What type of fat is mainly found in newborns
Brown adipose tissue
130
Where in an adult would you find brown fat
It remains in some regions only, such as; retroperitoneal space, around major vessels, deep cervical and supraclavicular regions of the neck, interscapular, paravertebral regions of the back and mediastinum.
131
Describe the location of Calot's triangle
Small anatomical space in the abdomen
Located at the porta hepatis in the liver - where the hepatic ducts and neurovascular structures enter/exit the liver
132
What are the borders of the Calot's triangle
Medial - common hepatic duct
Inferior - cystic duct
Superior - inferior surface of the liver
133
What are the contents of the Calot's triangle
Right hepatic artery
Cystic artery
Lymph node of Lund - the lymph node of the gallbladder
Lymphatics
134
Describe the segments of the liver
Eight functional segments.
Each segment is served by its own branch of the hepatic artery and portal vein, and by its own hepatic duct.
135
What are the impressions on the visceral surface of the liver
Gastric
Oesophageal
Suprarenal
Renal
Colic
Duodenal area
Gallbladder fossa
136
Describe albumin
Single polypeptide protein MW 6600
9-12g produced by the liver each day
137
Define Transcapillary escape rate
Albumin leaves the circulation via interstitium
Collected by lymphatics
Returned via thoracic duct
138
What are the 4 functions of albumin
Binding and transport
Maintenance of colloid osmotic pressure
Free radicals
Anticoagulant effects
139
What are the 3 reasons for a decrease in albumin
Decreased synthesis
Increases catabolism
Increased loss
140
What are the 2 consequences of decreased albumin
Decreased colloid oncotic pressure
Decreased ligand binding
141
Where is albumin synthesised
By liver hepatocytes
Rapidly excreted into the blood stream at a rate of about 10gm to 15gm per day
142
What can Transcapillary Escape rate by determined by
1. Capillary and interstitial free albumin concentration
2. Capillary permeability to albumin
3. Movement of solute/solvent
4. Electric charges across the capillary wall (albumin has a strongly negative charge)
143
Describe complement factors
Part of the innate immune system
Underlies one of the main effector mechanisms of antibody-mediated immunity
144
How is alcohol metabolised in the liver
Alcohol converted to acetaldehyde by alcohol dehydrogenase
Acetaldehyde dehydrogenase then coverts acetaldehyde into acetate
Then this is broken down into carbon dioxide and CO2
