Liver and friends Flashcards
1
Q
what are xenobiotics?
A
foreign chemical substance not normally found/produced in the body - can’t be used for energy requirements
can be absorbed across lungs, skin or ingested
2
Q
what are drugs?
A
xenobiotics
3
Q
how are xenobiotics excreted?
A
in bile, urine, sweat, breath
4
Q
what are the characteristics of pharmacologically active compounds?
A
lipophilic, non-ionised at pH 7.4, bound to plasma proteins to be transported in blood
5
Q
what is a lipophilic compound?
A
able to pass through plasma membranes to reach metabolising enzymes
6
Q
what is a microsome?
A
a small particle consisting of a piece of endoplasmic reticulum to which ribosomes are attached
7
Q
where are microsomal enzymes found?
A
smooth endoplasmic reticulum
mostly found in liver hepatocytes, but also in kidneys and lungs
8
Q
what are examples of microsomal enzymes?
A
cytochrome P450, flavin monooxygenase, UDP, glucuronosyltransferase
9
Q
what types of reactions are microsomal enzymes involved in? what do they do?
A
mainly phase I, also phase II
oxidative, reductive, hydrolytic
phase I: biotransform substances (one chemical to another)
phase II: glucuronidation
10
Q
what is glucuronidation?
A
addition of glucuronic acid to a substance
11
Q
what can activity of microsomal enzymes be induced or inhibited by?
A
drugs, food, age, bacteria, alcohol
12
Q
where are non-microsomal enzymes located?
A
cytoplasm and mitochondria of hepatocytes in liver, in other tissue too
13
Q
what reactions are non-microsomal enzymes involved in?
A
non specific - both phase I and II
all conjugation reactions except glucuronidation
14
Q
what are examples of non-microsomal enzymes?
A
protein oxidases, esterases, amidases, conjugases, alcohol dehydrogenase, aldehyde dehydrogenase
15
Q
what is the aim of drug metabolism? where does it occur?
A
to make drugs more polar so they can’t get across membranes and are easily excreted
liver
16
Q
where are most drugs excreted? what is an exception?
A
kidneys
lipophilic drugs aren’t effectively removed as they’re passively absorbed, due to them diffusing through cell membranes easily
17
Q
what is a phase I reaction?
A
aim: make drug more hydrophilic/polar so it can be excreted by the kidneys -unmasks/inserts polar functional group (OH, SH, NH2)
introduce/expose hydroxyl groups/other reactive sites that can be used for conjugation reactions (phase II)
18
Q
what are the types of reactions in phase I reactions?
A
non-synthetic catabolic, oxidation, reduction, hydrolysis
19
Q
are hydrophilic molecules usually involved in phase I reactions? why/why not?
A
no - they don’t reach metabolising enzymes as they’re excreted easily
20
Q
what is involved in oxidation?
A
hydroxylation (add OH), dealkylation (remove CH side chains), deamination (remove NH), hydrogen removal
21
Q
what is involved in reduction?
A
add hydrogen (saturate unsaturated bonds)
22
Q
what is involved in hydrolysis?
A
split amide and ester bonds
23
Q
what is functionalism?
A
introduces reactive group to drug
includes adding/exposing OH, SH, NH2, COOH
product of reaction is usually more reactive
small increase in hydrophilicity
24
Q
what are phase I reactions mainly catalysed by?
A
p450 enzymes
25
what are cytochrome P450 enzymes?
type of microsomal enzyme
involved in phase I reactions
uses heme group (Fe2+) to oxidise substances
products are more water soluble
26
naming enzymes in cytochrome P450 family
prefix CYP
1st number = family enzyme belongs to
letter = subfamily
2nd number = individual genes involved
27
what are some important P450 isoenzymes?
```
CYP 1A2
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A4
```
28
what is involved in the overall phase I reaction?
cytochrome P450 reductase transfers electrons from NADPH to CYP 450
contains flavoprotein which consists of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)
29
what is FAD? what does it do?
flavin adenine dinucleotide
accepts electrons from NADPH
30
what is FMN? what does it do?
flavin mononucleotide
electron donor to CYPs
31
what is the equation for the overall phase I reaction?
NADPH + H+ + O2 + RH -> NADP+ + H2O + R-OH
32
what is drug metabolism?
metabolic breakdown of drugs by living organisms, usually through specialised enzymatic systems
33
what is xenobiotic metabolism?
set of metabolic pathways that modify the chemical structure of xenobiotics (foreign to an organism's normal biochemistry)
34
what can phase I reactions do?
inactivate drugs, further activate them, activate drug from pro-drug, make a drug into a reactive intermediate (could be carcinogenic or toxic)
35
what are examples of synthetic anabolic reactions?
glucuronidation, sulfation, glutathione conjunction, amino acid conjunction, acetylation, methylation, water conjunction
36
what is the donor compound in glucuronidation?
UDPGA
37
what is the donor compound in acetylation?
acetyl CoA
38
what is the donor compound in methylation?
S-adenodyl methionine
39
what is a conjugation reaction? what is it catalysed? what does it do?
attachment of substituent groups (endogenous molecules)
usually inactive products
catalysed by transferases
significantly increases hydrophilicity for renal excretion
mainly in liver, or other tissues e.g. lungs/kidneys
40
what is a glucuronidation reaction?
essentially adding a glucuronic acid group (glucuronide) to drug to make it more hydrophilic
41
what is the enzyme involved in glucuronidation?
glucuronosyltransferase (uridine 5'-diphosphoglucuronosyltransferase) (UGT) - microsomal enzyme, used in phase II reactions, catalyses reaction
42
what is required to conjugate glucuronic acid?
uridine diphosphoglucuronic acid (UDPGA) - coenzyme/donor compound
43
what does the glucuronidation reaction form?
covalent bonds
uridine diphosphate + drug-glucuronide (more hydrophilic)
44
what is aspirin?
analgesic, NSAID, antiplatelet, prodrug, irreversibly inhibits cyclooxygenase (COX)
45
role of aspirin in phase I metabolism
prodrug - activated upon metabolism
hydrolysis reaction
aspirin + H2O -> salicyclic acid + ethanoic acid
46
role of aspirin in phase II metabolism
conjugated with glycine or glucuronic acid
forms range of ionised metabolite
47
what is paracetamol?
acetaminophen
analgesic, antipyretic agent
48
metabolism of paracetamol
predominantly metabolised via a phase II reaction - conjugated with glucuronic acid and sulphate
49
toxicity of paracetamol
if stores of glucuronic acid and sulfate are running low, paracetamol undergoes phase I metabolism via oxidation to produce toxic NAPQI
removed by conjugation with glutathione
overdose - stores of glutathione can run low -> toxicity
50
what is paracetamol toxicity treated with?
N-Acetyl Cysteine
51
what is the overall reaction of alcohol metabolism?
ethanol -(ADH)-> acetaldehyde -(ALDH)-> acetate -> CO2 + H2O
52
what is ADH?
alcohol dehydrogenase
53
what is ALDH?
aldehyde dehydrogenase
54
what are effects of acetaldehyde?
carcinogenic - indications of high levels are facial flushing, rapid heartbeat, nausea
55
what are the uses of iron?
haemoglobin, myoglobin, bone marrow
56
what are sources of iron?
meat, liver, shell fish, egg yolk, beans, nuts, cereals
57
where does homeostatic control of iron balance occur? what is it regulated by?
intestinal epithelium (duodenum), actively absorbs iron from ingested foods
negative feedback - depending on body's iron balance
58
how much of ingested iron is absorbed?
about 10%
59
what happens to iron ions once actively transported into duodenal intestinal epithelial cells?
incorporated into ferritin (protein-iron complex) that acts as an intracellular store for iron
most is released back into intestinal lumen (bound to ferritin) - tips of villi disintegrate. iron is excreted into faces
60
what happens when the body store of iron is enough?
increased conc of free iron in plasma and intestinal epithelial cells leads to increased transcription of the gene encoding for ferritin -> increased synthesis
-> increased binding of Fe in cells and reduction in amount of iron released into blood
61
what happens when body stores of iron are low?
production of intestinal ferritin decreases -> decreased amount of iron bound to ferritin -> increasing unbound iron released into blood
62
what is iron bound to in the blood?
plasma protein transferrin
63
where does transferrin take the iron?
to bone marrow to be incorporated into new erythrocytes
64
how is iron stored?
once in blood, there are v little means of excreting it - accumulates in tissues (most in liver in liver ferritin within Kupffer cells)
50% in haemoglobin
25% in heme containing proteins (mainly cytochromes)
25% in liver ferritin
65
what proteins does the liver produce?
plasma proteins, clotting factors and complement factors
66
what is albumin?
most abundant plasma protein
67
what are the functions of albumin?
binding and transport of large hydrophobic compounds e.g. bilirubin, FAs, hormones, drugs
maintenance of colloid osmotic pressure
68
what is colloid osmotic pressure?
effective osmotic pressure across blood vessels that are permeable to electrolytes but not large molecules
69
how does albumin maintain osmotic pressure?
its presence means the water conc. of the blood plasma is slightly lower than that of the interstitial fluid -> net flow of water out of the interstitial fluid, into the blood plasma
70
what do opposing forces do? what are they called?
act to move fluid across the capillary wall
Starling Forces
71
what are the Starling Forces? what do each of them do?
capillary hydrostatic pressure (favouring fluid movement out of capillary)
interstitial hydrostatic pressure (favouring fluid movement into the capillary)
osmotic force due to plasma protein conc. (favouring fluid movement into the capillary)
osmotic force due to interstitial fluid protein conc. (favouring fluid movement out of capillary)
72
what are forces at the arterial ends of the capillaries?
hydrostatic pressure from capillary = 38 mmHg > interstitial fluid HP (0) as fluid is quickly picked up by lymphatics
interstitial fluid protein conc. = 3mmHg, osmotic pressure due to plasma proteins = 28mmHg
net outward pressure exceeds net inward pressure -> bulk filtration of fluid out of capillaries
73
what are forces at the venous ends of the capillaries?
only difference in Starling forces is the capillary hydrostatic pressure - decreased to 15mmHg due to resistance
others are same
net inward pressure exceeds net outward pressure -> bulk absorption into capillaries
74
what is hypoalbuminea?
liver failure -> reduction in albumin in blood -> decreased capillary oncotic pressure -> accumulation of water in interstitial fluid -> oedema
75
apart from liver failure, why may albumin also decrease?
nephrotic syndrome, haemorrhage, gut loss, burns
76
what is nephrotic syndrome?
increased glomerular permeability, allowing proteins to filter through BM -> loss of up to several grams of protein a day
77
what is gut loss?
rare syndrome - wall of gut is unusually permeable to large molecules -> albumin loss
78
how can burns lead to albumin decrease?
extensive tissue damage to capillaries -> loss of proteins through walls of capillaries
79
what are globulins? what do they transport?
antibody functions
most are gamma-globulins (not made in liver), some are alpha/beta globulins (made in liver)
lipids by lipoproteins
iron by transferrin
copper by caeruloplasmin
80
liver production of clotting factors
produces all except calcium (IV) and vWF (VIII)
bile salts - essential for vit K absorption
vit K essential for synthesis of clotting factors 10,9,7,2
81
what are complement factors?
plasma protein which stick to pathogens
recognised by neutrophils - mark pathogens to kill
82
what is protein turnover?
continuous degradation and resynthesis of cellular proteins
83
when does rate of protein turnover increase?
tissues are undergoing structural rearrangement e.g. damage due to trauma, uterine tissue in pregnancy and skeletal muscle during starvation
severe burns - attempts at remodelling, significant amounts of protein lost in exudate
84
what are the primary methods of protein breakdown?
lysosomal and ubiquitin-proteasome pathway
85
what is the lysosomal pathway of protein breakdown?
carried out in reticulo-endothelial system of liver
sinusoidal endothelial cells remove soluble proteins and fragments from blood through fenestrations (sieve plates) on luminal surface . in liver, proteins are fused into lysosomes containing lysozyme - hydrolytic enzyme that breaks it down into amino acids
Kupffer cells (resident macrophages) phagocytose particulate matter, packaging them into phagosomes containing hydrolytic enzymes
86
what do sinusoidal endothelial cells do in the lysosomal pathway? what proteins do they remove?
remove soluble proteins and fragments from blood through fenestrations (sieve plates) on luminal surface
fibrin, fibrin degradation products, collagen, IgG complexes
proteins then fused into lysosomes in liver
87
where does the ubiquitin-proteasome pathway occur?
in cytoplasm of cells
88
what proteins does the ubiquitin-proteasome pathway degrade?
those defective due to incorrect amino acid sequences
damage to normal function (denatured)
89
what does the rate of degradation depend upon in the ubiquitin-proteasome pathway?
denatured (unfolded) protein is more readily digested than a protein with an intact conformation
90
what is the process of the ubiquitin-proteasome pathway?
proteins targeted for degradation by attachment of small peptide ubiquitin
directs protein to protein complex (proteasome) - unfolds the protein and breaks it down into small peptides
91
where does amino acid degradation and catabolism occur?
in hepatocytes of liver
92
what happens to amino acids not required as building blocks for protein synthesis?
must undergo degradation to specific compounds
93
what is catabolism?
break down of complex substances to simpler ones accompanied by release of energy
94
what does amino acid catabolism require?
alpha amino group (nitrogen containing) to be removed
95
what does amino acid catabolism produce?
nitrogen - incorporated into other compounds or excreted
carbon skeleton - metabolised and used in Kreb's cycle
96
what are the 2 main catabolism processes?
oxidative deamination and transamination
97
what is the reaction of oxidative deamination?
liberation of amino group as free ammonia
amine group from amino acid is replaced by an oxygen from water to form an alpha-keto acid
coenzyme involved, in products is bound to 2H from water
98
what is the overall equation for oxidative deamination?
amino acid + water + coenzyme -> alpha-keto acid + ammonia + coenzyme-2H
99
what is the only amino acid that undergoes rapid oxidative deamination?
glutamate
100
what happens to the alpha-keto acid formed from oxidative deamination?
used in Kreb's cycle for use in glucose production - gluconeogenesis
101
what are the coenzymes/enzymes involved in oxidative deamination?
coenzyme: NAD+ (forwards) and NADPH (backwards)
enzyme: glutamate dehydrogenase
102
what happens to the ammonium produced in oxidative deamination?
quickly dissociates to form ammonia, which can be converted to urea via the urea cycle as it's toxic
103
what does oxidative deamination depend on?
readily reversible
depends on concentrations of glutamate, alpha-ketoglutarate, ammonia
104
what is the most abundant amino acid in the body?
glutamate
105
what happens when there is excess ammonia?
it can easily cross the BBB and react with alpha-ketoglutarate -> decrease in ATP. dangerous
106
what is transamination?
transfer of an alpha-amino group from an amino acid to a keto-acid to form an alpha-keto-acid
107
what happens if the amino acid alanine is transaminated?
amino group is transferred to alpha-ketoglutarate, forming pyruvate (used in Krebs cycle for gluconeogenesis) and glutamate (oxidatively deaminated)
108
what is the enzyme involved in transamination?
aminotransferase - found in cytosol of mitochondria through body, esp. in kidneys and liver
specific to one or few amino group donors
alanine - alanine aminotransferase (ALT)
109
what is nitrogen balance?
a measure of the equilibrium of protein turnover
110
what is anabolic/catabolic nitrogen balance?
anabolic - positive balance, net gain in amino acids
catabolic - negative balance, net loss in amino acids
111
what are the essential amino acids?
histidine, isoleucine, leucine, lycine, methionine, phenylalanine, threonine, tryptophan, valine
body cannot synthesise them
112
what are the conditionally non-essential amino acids?
arginine, asparagine, glutamine, glycine, proline, serine, tyrosine
113
what are the non-essential amino acids?
alanine, asparatate, cysteine, glutamate
114
what is the most common cause of an anabolic nitrogen balance?
intake > loss
pregnancy
115
what are the recommended daily intakes of amino acids?
0. 8g/kg (normal men and women)
1. 3g/kg (pregnant women)
2. 4g/kg (first few months of life)
116
what are the causes of negative nitrogen balance?
intake < loss
malnutrition, multiple trauma/extensive trauma where there's lots of tissue damage
117
action of ALT in muscles
utilises pyruvate from glycolysis as an alpha-keto acid for transamination
converts glutamate to a-ketoglutarate
produces alanine and alphaketoglutarate (krebs cycle to produce glucose via gluconeogenesis)
118
what happens to alanine in the liver?
travels via blood to liver
converted back to pyruvate by transamination
119
what happens to pyruvate produced from alanine in the liver?
source of carbons for glucose production via gluconeogenesis
enters blood as glucose, used in muscles to produce pyruvate via glycolysis - used again to remove excess ammonia (NH3)
120
what is the aim of the glucose-alanine cycle?
to remove excess ammonia/ammonium from amino acids from muscle protein
121
what happens to the glutamate produced from alanine in the liver via reverse transamination?
converted to ammonium via oxidative deamination, producing ammonium which rapidly dissociates into ammonia
ammonia can be converted to urea via urea cycle
122
where are the enzymes involved in the urea cycle found?
in liver in the mitochondria/cytosol of hepatocytes
123
what is the process of the urea cycle?
arginine (from diet/protein breakdown) is cleaved by arginase to form urea and ornithine
ammonia and CO2 is added on the ornithine to form citrulline
another molecule of ammonia is added to citrulline to regenerate arginine and let the cycle go around again
124
what is consumed by one turn of the urea cycle?
3 ATP equivalents
| 4 high energy nucleotides (PO4-)
125
what is/are the compound(s) produced by the urea cycle?
urea
arginine, ornithine and citrulline are recycled
126
deficiencies/absences of enzymes involved in urea cycle
arginase
deficiencies: higher levels of ammonia in blood, neurotoxicity
absences: incompatible with life
127
enzymes involved in the urea cycle
```
N-acetylglutamate synthase (NAGS)
carbamylphosphate synthetase (CPS I)
ornithine transcarbamylase (OTC)
argininosuccinate synthetase (ASS)
argininosuccinate lyase (ASL)
arginase
```
128
neurotoxicity due to high ammonia levels
ammonia can cross BBB very easily
converted to glutamate by glutamate dehydrogenase
depletion in alpha-ketoglutarate
as alpha-ketoglutarate falls, so does oxaloacetate -> krebs cycle stopping
irreparable cell damage and neural cell death
129
what is the absorptive state?
ingested nutrients are absorbed from GI tract into blood
proportion of nutrients are catabolised and used
remainder converted and stored for future use
130
what happens during the absorptive state?
glucose used to generate ATP
amino acids converted to proteins
glycerol and FAs converted to lipids
glucose converted to glycogen
131
what is the post-absorptive state?
nutrients no longer absorbed in GI tract
nutrient stores must supply energy requirements of body
132
what is glucose regulation in the post-absorptive state?
glucose no longer absorbed from GI tract
133
why is it essential to maintain the plasma glucose concentration in the post-absorptive state?
CNS always using it for fuel
134
what are the main sources of glucose in the post-absorptive state?
glycogenolysis, lipolysis, protein
135
what is glycogenolysis?
hydrolysis of glycogen to monomers of glucose-6-phosphate
136
where does glycogenolysis occur?
liver and skeletal muscles
137
what happens in hepatic glycogenolysis?
in liver, glucose-6-phosphate enzymatically converted to glucose, which enters the blood
begins within seconds of stimulus (e.g. sympathetic nervous activation)
138
how long can glucose from the liver supply body requirements?
several hours
139
what happens in skeletal muscle glycogenolysis?
skeletal muscle doesn't have enzyme needed to make glucose
glucose-6-phosphate undergoes glycolysis to produce ATP, pyruvate and lactate
140
what happens to the products of skeletal muscle glycogenolysis?
ATP and pyruvate used directly by the muscle cell
some lactate enters blood, circulates to liver and is converted to glucose which enters the blood (contributes indirectly to blood glucose)
141
what is lipolysis?
catabolism of triglycerides in adipose tissue via hydrolysis of triglycerides to produce glycerol and fatty acids
142
how do glycerol and fatty acids enter the blood?
diffusion
143
what happens to glycerol from lipolysis?
enters liver which enzymatically converts it to glucose
144
what is a source of blood glucose a few hours into the post-absorptive state?
protein
145
what does protein loss during a prolonged fast lead to?
disruption of cell function, sickness and death
146
how do proteins produce glucose?
supply amino acids, which enter blood and are taken up by the liver and converted to glucose via the alpha-keto acid pathway - then released into blood
147
what is gluconeogenesis?
synthesis of glucose from precursors e.g. amino acids and glycerol, i.e. non-carbohydrate precursors
148
how much ATP is consumed per glucose formed?
6
149
where is fat stored?
mostly in adipocytes - form tissues called adipose tissue
hepatocytes
150
what are triglycerides?
3 fatty acids bound to a glycerol molecule
151
what kind of energy is stored in the body?
78% - triglycerides
21% - proteins
1% - carbohydrates
152
what do dietary lipids consist of?
95% - triglycerides
| 5 - phospholipids, FFAs, cholesterol, fat soluble vitamins
153
what are lipids?
esters of fatty acids and certain alcohol compounds
154
what are functions of lipids?
energy reserves, structural part of cell membrane, hormone metabolism
155
what are lipoproteins?
used to transport cholesterol in the blood
156
what is HDL? what does it do?
formed in liver
remove excess cholesterol from blood and tissue, deliver this to liver which secretes into the bile and converts it into bile salts
157
why is HDL called good cholesterol?
removes other forms of cholesterol from bloodstream
higher levels of it is associated with lower risk of heart disease
158
what is LDL? what does it do?
formed in plasma
main cholesterol carriers - deliver cholesterol to cells throughout body
bind to plasma membrane receptors specific for a protein component of LDLs - taken up by cells via endocytosis
159
why is LDL called bad cholesterol?
high plasma concentrations can be associated with increased deposition of cholesterol in arterial walls and higher incidence of heart attacks
160
what is a good thing that LDL does?
essential in supplying cells with cholesterol needed to synthesise cell membranes
steroid hormone production in gonads and adrenal glands - aldosterone and cortisol
161
what is VLDL? what does it do?
synthesised in hepatocytes
carries triglycerides from glucose in liver to adipocytes
162
where is half of the energy used by muscle, liver and kidneys derived from under resting conditions?
catabolism of fatty acids
163
where is most of adipose tissue deposited?
underlying skin or surrounding internal organs
164
what is the function of adipocytes?
to synthesise and store triglycerides during periods of food uptake
when food is not being absorbed - release FAs and glycerol into blood to provide energy for ATP formation
165
where does fatty acid catabolism occur?
mitochondria of hepatocytes
166
what are the steps of fatty acid catabolism?
molecule of coenzyme A links to carboxyl at end of fatty acid
breakdown of ATP -> AMP + 2Pi
coenzyme A derivative of fatty acid goes through beta oxidation
molecule of acetyl-CoA is split off from fatty acid and 2 pairs of hydrogen atoms are transferred to coenzymes (one to FAD and other to NAD+)
hydrogen atoms from coenzymes enter oxidative phosphorylation to form ATP
another coenzyme A attaches to fatty acid, cycle is repeated
167
what does one turn of fatty acid catabolism do?
shortens fatty acid chain by 2 carbon atoms until all have been transferred to coenzyme A molecules
lead to production of CO2 and ATP via krebs and oxidative phosphorylation
168
what enzymes are involved in the hepatic metabolism of lipids?
lipoprotein lipase
hepatic lipase
169
what does lipoprotein lipase do?
hydrolyses triglycerides in lipoproteins (chylomicrons and VLDLs) into 2 free fatty acids and 1 glycerol molecule
170
what does hepatic lipase do?
expressed in liver and adrenal glands
converts IDL (intermediate density lipoprotein) into LDL - packages it with more triglycerides to be released into body
171
what is bile? where is it stored and concentrated?
secreted in hepatocytes continuously
emulsifies fats
excretory pathway for most steroid hormones, drugs and toxins
stored and concentrated in gall bladder as some NaCl and water are absorbed into blood
172
where does the gall bladder lie?
at junction of right-mid-clavicular line and costal margin
173
what is the functional unit of the liver?
hepatic lobule - formed by hepatic plates stacked on top of eachother
174
what are hepatic lobules?
hexagonal in cross section, portal triad at each corner
wedge-like arrangements of hepatocytes 1-2 cells deep, surrounded by sinusoids
175
what does the portal triad consist of?
hepatic portal vein, hepatic artery, bile duct
176
what runs up the centre of the hepatic lobule?
central vein - eventually becomes hepatic vein
177
what does the hepatic sinusoid contain?
substances absorbed from SI end up in hepatic sinusoid, containing oxygen rich blood from hepatic artery and nutrient rich blood from portal vein
178
what is the structure of a hepatic sinusoid?
fenestrated, discontinuous endothelium
179
what is the space of Disse?
separates hepatocytes from sinusoid
180
what happens to substances absorbed from the SI from the sinusoid?
reach vena cava via central vein or taken up by hepatocytes for modification
181
what is the blood supply of the liver?
80% from portal vein
| 20% from hepatic artery
182
what happens to the blood when it leaves the branches of artery and vein when it leaves the portal triad?
blood is mixed as it enters the sinusoids
183
what direction does the bile flow in?
opposite direction to the blood
184
what are Kupffer cells? where are they found?
resident macrophage population in liver
sinusoids, which are lined by a continuous layer of specialised endothelial cells interspersed with them
185
what are stellate cells?
undersurface of sinusoids
produce extracellular matrix in space of Disse
186
what are bile canaliculi? what are their structure? how is bile pumped towards bile ducts?
between adjacent hepatocytes
not true vessels - don't have specialised walls
groove running along side of hepatocytes
bound together by tight junctions, gap junctions, desmosomes which cross both cell membranes
actin filaments are in areas around the canaliculi and pump bile towards bile ducts
187
where do the common bile duct and pancreatic duct join, and enter the duodenum?
join at ampulla of Vater
enter duodenum at major duodenal papilla (2nd part of duodenum)
sphincter forms around 2 ducts to regulate entry of bile into duodenum - called sphincter of Oddi
188
what does bile contain?
bile salts, lecithin (phospholipids), HCO3- and other salts, cholesterol, bile pigments, trace metals
189
why are components of bile aggregated into micelles?
bile salts, cholesterol and lecithin
maintain aggregation even when concentrated
bile salts are powerful detergents (for fat emulsification, anionic) - damage cell membrane
190
what are bile salts produced by?
hepatocytes
191
what is the role of HCO3- in bile?
neutralise acids in duodenum
192
what are the most important digestive components of bile?
bile salts
193
what secretes components of bile?
hepatocytes - bile salts, cholesterol, lecithin, bile pigments
epithelial cells lining bile ducts - most of HCO3- rich solution
194
what stimulates secretion of bile/pancreas solution?
secretin - in response to presence of acid in duodenum
195
what does secretin do?
stimulates secretion of bile/pancreatic solution in response to acid in duodenum
196
concentration of bile
hepatic bile enters gallbladder via cystic duct and stored and concentrated here - hepatic bile is dilute
197
what stimulates gallbladder contraction?
cholecystokinin due to amino and fatty acids in duodenum by I cells of duodenum
198
what does CCK do? what is it secreted by?
stimulates gallbladder contraction and the sphincter of Oddi to relax - causes bile to flow into duodenum
I cells of duodenum, due to amino and fatty acids in duodenum
199
vasculature of gallbladder
cystic artery supplies oxygenated blood to gallbladder
no venous drainage - stuck to liver bed and blood drains directly into the liver, no identified pathway
200
what happens to the bile salts during digestion of a fatty meal?
most entering the intestinal tract via bile are absorbed by specific Na+ coupled transporters in the jejunum and terminal ileum
returned via portal vein - secreted into bile
uptake of bile salts from portal blood into hepatocytes by secondary active transport coupled to Na+
201
what is the enterohepatic circulation?
recycling pathway from the liver to the intestine
often recycles bile salts
202
what happens to bile that doesn't enter the enterohepatic circulation?
small amount (5%) escape recycling and are lost in faeces
liver synthesises new bile salts from cholesterol to replace it
203
bile synthesis
liver synthesises it from cholesterol
it secretes cholesterol extracted from blood into bile
204
how is cholesterol homeostasis maintained?
bile secretion and excretion of cholesterol in the faeces
205
cholesterol in water
insoluble - solubility in bile is achieved via micelles.
in blood, it's bound into lipoproteins
206
when is bile secretion the greatest?
during and just after a meal - liver always secreting some
207
what type of muscle is the sphincter of Oddi?
smooth
208
how is bile concentrated? where?
dilute bile secreted by liver is shunted into the gallbladder
some of NaCl and water is absorbed into the blood
209
what is adaptive relaxation? how does it apply to the gallbladder?
size increases but pressure doesn't
happens when gallbladder fills with bile
210
what are bile pigments?
substances formed from the haem portion of haemoglobin when old/damaged erythrocytes are broken down in the spleen and liver
211
what is the predominant bile pigment?
bilirubin
212
what is bilirubin?
yellow substance that's extracted from the blood by hepatocytes and actively secreted into bile
213
what contributes to the colour of bile?
yellow bilirubin
214
where are erythrocytes broken down?
when old/damaged, they're broken down by macrophages (phagocytic)
spleen and bone marrow, also Kupffer cells of the liver
215
how is haemoglobin broken down?
erythrocytes ingested into macrophages
broken down into haem and globin
globin broken down into amino acids - used to generate new erythrocytes in bone marrow
haem further broken down, under action of hemoxygenase into biliverdin and Fe2+ and CO
216
breakdown of haem. enzymes? products?
hemoxygenase
biliverdin and Fe2+ and CO
217
what happens to the Fe2+ generated from haem breakdown?
bound to iron transporter transferrin - shuttled to bone marrow, incorporated into new erythrocytes
218
what happens to biliverdin from haem breakdown?
reduced by biliverdin reductase (enzyme) into unconjugated bilirubin
219
what is unconjugated bilirubin? what happens to it?
produced from reduction of biliverdin (from haem) by biliverdin reductase
toxic - lipid soluble and insoluble in blood
bound to albumin, transported to liver
220
movement of unconjugated bilirubin. what is it bound to?
albumin - transported to liver, as it's insoluble in blood
221
what happens to unconjugated bilirubin in the liver?
glucuronidation (addition of a glucuronic acid) by enzyme UDP glucuronyl transferase - converted into conjugated bilirubin
222
what is conjugated bilirubin?
formed from unconjugated bilirubin in the liver by glucuronidation by UDP glucuronyl transferase
soluble and able to be excreted
223
what happens to conjugated bilirubin after being formed in the liver?
dissolved in bile (as it is soluble) and travels down right/left hepatic ducts, common hepatic ducts and in the cystic duct, and into the common bile duct to enter the duodenum
224
what happens to the conjugated bilirubin in the small intestine?
enters duodenum, and reaches ileum/large intestine
reduced through hydrolysis reaction (glucuronic acid group removed) by intestinal bacteria to form urobilinogen
225
what is urobilinogen?
formed from conjugated bilirubin in the ileum/large intestine, where it undergoes a hydrolysis reaction by intestinal bacteria
lipid soluble
226
what happens to 10% of urobilinogen?
reabsorbed into the blood and bound to albumin, transported into liver - oxidised to urobilin
227
what is urobilin? what happens to it?
formed from urobilinogen that's reabsorbed from the blood - oxidation reaction
recycled into bile/transported into kidneys and secreted in urine - yellow colour
228
what happens to 90% of the urobilinogen?
oxidised by different type of intestinal bacteria to form stercobilin
229
what is stercobilin? what happens to it?
formed from urobilinogen by oxidation by different type of intestinal bacteria
excreted into faeces - responsible for brown colour
230
what is jaundice?
a yellow discolouration of skin caused by a high serum bilirubin level (detectable clinically when bilirubin is above 50 micromole/L)
231
what are the 3 main types of jaundice?
pre-hepatic, hepatic/intra-hepatic, post-hepatic/obstructive
232
what is pre-hepatic jaundice? what is its pathology?
increased breakdown of erythrocytes -> increased levels of serum unconjugated bilirubin without excess bilirubin in urine
stools brown, urine normal
yellow skin
enlarged spleen (excess breakdown)
233
why may the spleen be enlarged in pre-hepatic jaundice?
excess breakdown of erythrocytes -> increased serum levels of unconjugated bilirubin
234
what are the causes of pre-hepatic jaundice?
malaria, sickle cell anaemia, thalassaemia, physiological jaundice of the newborn
235
what is physiological jaundice of the newborn caused by?
excess breakdown of foetal haemoglobin as it's no longer required - increase in unconjugated bilirubin and liver can't conjugate it fast enough due to not being developed properly
236
what is hepatic/intra-hepatic jaundice?
due to hepatocellular swelling
impaired cellular uptake, defective conjugation/abnormal secretion of bilirubin by hepatocytes
liver is damaged - unable to metabolise unconjugated bilirubin so it builds up, also raised serum conjugated bilirubin
237
what are the manifestations of hepatic/intra-hepatic jaundice?
increased conjugated and unconjugated bilirubin
decreased urobilinogen
dark urine, pale/normal stools
enlarged spleen
yellow skin
238
what is hepatic/intra-hepatic jaundice caused by?
viral hepatitis, drugs, alcohol hepatitis, cirrhosis, jaundice of newborn
239
what is post-hepatic/obstructive jaundice? what is its pathology?
biliary system is damaged, inflamed or obstructed
elevated serum conjugated bilirubin
dark urine, pale stools
normal unconjugated bilirubin
decreased urobilinogen
no enlarged spleen
yellow skin
240
what are the causes of post-hepatic/obstructive jaundice?
gallstones, pancreatic cancer, gallbladder cancer, bile duct cancer, pancreatitis (acute or chronic)
241
why can cancer/inflammation of the pancreas cause jaundice?
head of pancreas is situated in duodenal loop, near common bile duct
eventually causes obstruction of the duct -> jaundice
242
where will acute pancreatitis pain be?
radiate from the back
243
what is Gilbert syndrome? what is its pathology?
shortage of UDP glucuronyl transferase - small amounts of conjugation occur
normal conjugated bilirubin level but raised unconjugated bilirubin level
244
what causes gall stones to form?
bile salts, cholesterol and phospholipids are water-insoluble and are maintained in a soluble form as micelles
when conc. of cholesterol becomes high in relation to conc. of phospholipid and bile salts, cholesterol crystallises out of solution forming gall stones
245
small bile stones
may pass freely through common bile duct into intestine without complications
246
larger bile stone
may lodge in opening of gallbladder -> painful contractile spasms of smooth muscles
serious problems if it's lodged in common bile duct, preventing bile from entering intestines
247
what can stop bile from entering the intestines?
stone becoming lodged in common bile dut
248
what are the consequences of a significant decrease in bile due to gall stones?
decreased fat digestion and absorption
impaired absorption of fat-soluble vitamins, clotting problems (vit K) or calcium malabsorption (vit D)
steatorrhea
diarrhea and fluid and nutrient loss
249
what are fat soluble vitamins?
A, D, K, E
250
what is steatorrhea?
caused by decreased bile due to gall stones
fat that's not absorbed enters large intestine and appears in faeces
251
what causes diarrhea and fluid/nutrient loss in gall stones?
bacteria in large intestine covert some unabsorbed fat into fatty acid derivatives, and alter salt and water movements
leads to net flow of fluid into large intestine
252
is the pancreas intraperitoneal or retroperitoneal?
completely retroperitoneal apart from the tail
253
what is the tail of the pancreas attached to?
spleen - intraperitoneal
254
what can happen to the body of the pancreas?
crushed against vertebral bodies during trauma
255
what can happen to the head of the pancreas?
closely related to the common bile duct
carcinoma/inflammation of head of pancreas can block bile duct -> post-hepatic/obstructive jaundice
256
what is the uncinate process?
comes from ventral bud (rest of it is from dorsal bud) - SM artery and vein are entrapped between head and uncinate process
257
what is between the head and uncinate process of the pancreas?
superior mesenteric artery and vein
258
what artery runs in close proximity to the duodenum? what could happen to it?
superior gastroduodenal artery
duodenal ulcer can erode the gastroduodenal artery -> haemorrhage and haematemesis
259
what is haematemesis?
vomiting of blood
260
what is the development of the pancreas?
develops as 2 separate outgrowths - ventral and dorsal pancreas
ventral pancreas rotates around and fuses with dorsal pancreas - becomes head
biliary bud
261
what forms the main pancreatic duct during development?
dorsal - Santorini's duct
| ventral - Wirsung's duct
262
what is the blood supply of the pancreas?
celiac trunk
SMA runs through the head because it's enveloped during the rotation when dorsal and ventral pancreas fuse
dorsal pancreatic artery (from splenic artery), transverse pancreatic artery (from dorsal pancreatic artery), ant. and post. inferior (from SMA)/superior (from gastroduodenal artery from hepatic artery from CT) pancreaticoduodenal arteries
263
what is the venous drainage of the pancreas?
splenic vein - joins superior mesenteric vein to form portal vein
264
what does the exocrine pancreas secrete?
HCO3- (bicarbonate)
| digestive enzymes
265
what is the process of exocrine pancreas secretion?
arise from acinar tissue of the pancreas
secreted into ducts which converge into the pancreatic duct which joins the common bile duct, then enters duodenum at ampulla of Vater
266
what is the function of the sphincter of Oddi?
circular smooth muscle
regulates flow into duodenum, prevents mixing of bile and pancreatic juice in duct
267
what does reflux of bile down the pancreatic duct cause?
acute inflammation due to detergent properties
268
when does the accessory pancreatic duct usually emerge?
above the ampulla of Vater
269
what is pancreatic HCO3- secreted by?
epithelial cells lining ducts - duct cells
270
what is the function of pancreatic HCO3-?
protect duodenal mucosa from gastric acid
buffers material entering the duodenum to a pH suitable for enzyme action
271
what stimulates the secretion of HCO3-?
secretin - due to acid in duodenum. from pancreas and liver. potentiates acion of hormone CCK
272
what is secretin secreted by? what is its function?
S cells of duodenum - due to acid in duodenum
stimulates secretion of HCO3- from pancreas and liver
potentiates action of CCK
inhibits acid secretion and gastric motility in stomach
273
how is HCO3- secreted into the duct lumen by pancreatic duct cells?
apical membrane Cl/HCO3- exchanger
formed by H+ pumped out
274
where is the energy for HCO3- secretion from?
Na+/K+ ATPase pumps on basolateral membrane
275
why does Cl- not accumulate in the cell?
ions are recycled into the lumen via the CFTR channel (Cystic Fibrosis Transmembrane Conductance Regulator)
276
what does CFTR stand for?
cystic fibrosis transmembrane conductance regulator
277
what is transcellular transport?
through membrane porters or channels
lumen to interstitium
278
what is paracellular transport?
through tight junctions (spaces between cells)
279
what else moves into the pancreatic duct lumen?
Na+ and water via a paracellular route, due to the electrochemical gradient established through the CFTR channel
280
what moves into the capillary from pancreatic duct cells?
H+ from H2CO3 and Na+ and K+
281
secretion of digestive enzymes by the pancreas
enzymes are secreted by gland cells at pancreatic end of duct system
secreted as active or precursors (in inactive form zymogens)
282
what are zymogens?
inactive form of digestive enzymes
283
what do the pancreatic enzymes digest?
triglycerides (fat) to fatty acids and monoglycerides, polysaccharides to sugar, proteins to amino acids and nucleic acids to nucleotides
284
what are active pancreatic digestive enzymes?
alpha-amylase and lipase
285
what is alpha-amylase?
active pancreatic digestive enzyme
converts starch to maltose (glucose disaccharide)
286
what is lipase?
active pancreatic digestive enzyme
converts triglycerides to monoglyceride and fatty acids
287
what is the function of zymogens?
protects pancreatic cells from autodigestion
288
what is a key step in the activation of precursors secreted by pancreas?
enterokinase
289
what is enterokinase?
proteolytic enzyme embedded in luminal plasma membranes of intestinal epithelial cells
splits off a peptide from pancreatic trypsinogen forming active enzyme trypsin
290
what is trypsinogen?
pancreatic proteolytic enzyme
activated by enterokinase to form trypsin
291
what is trypsin?
pancreatic proteolytic enzyme activated by enterokinase
activates other pancreatic zymogens by splitting off peptide fragments
292
what is chymotrypsinogen?
pancreatic zymogen which is activated into the enzye chymotrypsin by trypsin
293
what are the functions of trypsin and chymotrypsin?
enzymes used to break peptide bonds in proteins to form peptide fragments - digest ingested proteins
294
inhibition of pancreatic exocrine secretion
somatostatin produced by D cells in pancreatic islets/islets of Langerhans
295
what is somatostatin produced by? what is its function?
D cells in pancreatic islets/islets of Langerhans
inhibits pancreatic exocrine secretion
296
what are the cell types in the islets of Langerhans?
alpha, beta, delta/D, PP cells
297
what do pancreatic alpha cells produce?
in islets of Langerhans
glucagon
298
what do pancreatic beta cells produce?
in islets of Langerhans
insulin and amylin
299
what do pancreatic delta/D cells produce?
in islets of Langerhans
somatostatin - inhibitor of insulin and glucagon
300
what do pancreatic PP cells produce?
in islets of Langerhans
pancreatic polypeptide
301
pancreas and diabetes
autoimmune destruction of islets of Langerhans -> diabetes mellitus
type 1: pancreas fails to produce enough insulin
type 2: cells fail to respond to insulin properly
302
what are the phases of pancreatic secretion?
cephalic and gastric phase
303
how does the cephalic phase affect pancreatic secretion?
initiated by sensory experience of seeing and eating food
involves parasympathetic vagus nerve stimulation of acinar cells to produce digestive enzymes
304
how does the gastric phase affect pancreatic secretion?
initiate by presence of food within stomach - involves parasympathetic vagus nerve stimulation of acinar cells to produce digestive enzymes
305
what happens to the pancreas by the end of the cephalic and gastric phases?
pancreatic ducts are filled with inactive digestive zymogens ready for release into the intestinal lumen with bicarbonate, via sphincter of Oddi
306
what stimulates the secretion of digestive enzymes from the pancreas?
CCK
307
what empties into the sinusoids?
terminal branches of portal vein and hepatic artery
308
how does blood leave the liver?
via hepatic vein, which eventually drains into the IVC
blood is deoxygenated, detoxified, contains normal homeostatic nutrient levels
309
what is the primitive gut?
made from endoderm (epithelial lining, hepatocytes, endocrine and exocrine cells of pancreas)
visceral mesoderm (muscle and connective tissue)
310
what is the foregut?
oral pharyngeal membrane -> liver bud
celiac artery, oesophagus, stomach, liver, biliary apparatus, 1/2 of duodenum
311
what is the midgut?
liver bud -> 2/3rds transverse colon
SMA, distal half of duodenum, jejunum, ileum, appendix, cecum, ascending colon, right 2/3rds of transverse colon
312
what is the hindgut?
2/3rds transverse colon -> cloacal membrane
IMA, left 1/3 of transverse colon, sigmoid colon, rectum, anal canal
313
what is the hepatic diverticulum?
cellular expansion of the foregut which gives rise to the parenchyma (functional part) of the liver
314
when and where does the hepatic diverticulum appear?
middle of 3rd week as an outgrowth of the endodermal epithelium at the distal end of foregut (duodenum)
315
what does the liver bud contain?
rapidly proliferating cells that penetrate the septum transversum
316
what is the septum transversum?
thick mass formed in the embryo that gives rise to parts of the thoracic diaphragm and ventral mesentery
317
when does the bile duct form?
when connection between the liver diverticulum and the foregut narrows
318
what develops from the bile duct?
cystic diverticulum - ventral outgrowth. dives rise to the gallbladder and cystic duct
319
what gives rise to the gallbladder and cystic duct?
cystic diverticulum - ventral outgrowth of the bile duct
320
what develops with further growth of the liver bud?
allows epithelial liver cords to intermingle with umbilical and vitelline veins, forming the hepatic sinusoids
321
how are the hepatic sinusoids formed?
further growth of liver bud allows epithelial liver cords to intermingle with umbilical and vitelline veins - forms sinusoids
322
what do liver cords differentiate into?
hepatocytes (liver parenchyma) and form lining of biliary ducts
323
what forms the hepatocytes and the lining of the biliary ducts?
liver cords
324
what does the ventral mesentery develop into? when?
haematopoietic cells, Kuppfer cells, connective tissue cells
325
how much does the liver weigh at the 10th week? why?
10% of total body weight due to large numbers of sinusoids and involvement of liver in haematopoietic function
326
how much does the liver weigh at birth? why?
5% of total body weight due to small numbers of haematopoietic islands in the liver. haematopoietic function is greatly reduced
327
when do hepatic cells start production of bile?
12th week
328
when does the haematopoietic function of the liver subside?
during last 2 months of intrauterine life
329
what happens to liver structures after birth?
left umbilical vein obliterates to form the ligamentum teres
ductus venosus undergoes fibrosis leaving ligamentum venosum
330
what is a mesentery?
fold of tissue that attaches organs to the body wall
331
what is intraperitoneal?
double layer of peritoneum that completely surrounds the organ
332
what is retroperitoneal?
the organ is only covered by the peritoneum on its anterior side
333
where is the ventral mesentery?
occurs only in foregut
334
where is the ventral mesentery derived from?
septum transversum
335
what mesenteries do the foregut, midgut and hindgut have?
foregut has dorsal and ventral mesenteries
midgut and hindgut have only dorsal mesentery
336
formation of lesser omentum
stomach rotates 90 degrees along longitudinal axis (left becomes anterior)
posterior wall grows quicker (gives greater curvature)
rotates around anterior-posterior axis - pyloric region moves right and up and cardiac region moves left and down
337
what are the proportions of endocrine cells in the pancreas?
beta cells: 65-80%
alpha cells: 15-20%
delta cells: 3-10%
338
where does the pancreas develop from?
endodermal lining of the duodenum as dorsal and ventral buds
339
where are the dorsal and ventral buds located?
dorsal bud in dorsal mesentery
| ventral bud in ventral mesentery close to bile duct
340
what does the ventral/dorsal pancreatic bud form?
uncinate process and inferior part of head of pancreas
dorsal - remaining part
341
what forms the main pancreatic duct?
union of ventral pancreatic duct with distal part of duct of dorsal bud
342
what does the accessory pancreatic duct drain?
lower part of head and uncinate process
opens at minor papilla (3cm proximal to main duct)
343
where/when do islets of Langerhans develop from?
parenchyma of pancreas at third month
344
when does insulin secretion begin?
fifth month
345
where does pancreatic connective tissue develop from?
visceral surrounding mesoderm
