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Liver Physiology Flashcards

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1
Q

Hepatic Lobule

A

Basic histological or anatomical unit of the liver

Shaped like a hexagon
At centre is central vein
Radiating out are rows of sinusoids and hepatocyte.
At each corner of the hexagon is a hepatic triad.

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2
Q

Hepatic Triad

A

Portal vein, hepatic artery and bile duct.

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3
Q

Acinus of the liver

A

Functional unit of the liver
Consists of the parenchymal mass between two centrilobar veins

Diamond shape
- Long corners: two portal veins
- Short corners: two hepatic triads

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4
Q

Functional zones of the Acinus

A

There are 3 functional zones
- Zone 1: Periportal
- Zone 2: Mediolobular
- Zone 3: Centrilobular

Radiate out from the centre of the diamond from 1 - 3, along the long axis.

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5
Q

Periportal zone of acinus

A

Periportal zone = zone 1
- Closest to the hepatic arteriole
- Hepatocytes receive blood with the highest oxygen content
- These hepatocytes have the highest metabolic rate and are especially involved in protein synthesis.
- Secrete glucose into the sinusoidal blood

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6
Q

Centrilobular Zone of acinus

A

Centrilobular zone = zone 3
- Furthest from hepatic arterial
- lowest content of O2 delivery.
- contain high concentrations of CyP450s
- important sites for drug biotransformation.
- Involved in utilising glucose, particularly secreted from periportal cells into the sinusoidal blood.

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7
Q

Mediolobular Zone of the Acinus

A

Mediolobular zone = zone 2
- Intermediate O2 content between z1 and z2
- Has intermediate enzyme activités.

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8
Q

Hepatic Sinusoids

A

From a low pressure microcirculatory system of the acinus w sphincters at the hepatic arterioles, venous sinusoid and arteriolar portal shunts.
- Significant reservoir for blood depending on the tone of the sphincters.

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9
Q

Cells of the Liver

A
  1. Hepatocytes = 60% of liver mass, 80% of liver volume.
  2. Kupffer cells = 40% mass, 20% volume.
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10
Q

Hepatocyte shape

A

polygonal
3 surface types
1= facing space of disse and sinusoid
2= facing bile canaliculi
3 = facing adjacent hepatocytes.
Microvili project from the surfaces of 1 and 2
Increase SA of cell for active secretory and absorption functions.

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11
Q

Hepatocyte Organelles

A
  1. SER = drug biotransformation
  2. RER = presence of aggregates of ribosomes on tubules therefore responsible for protein synthesis.
  3. Peroxisomes = contiguous w SER and RER. Sites of b oxidation of FAs and storage of catalase.
  4. Mitochondria= metabolism, production of ATP, particularly steroid and nucleic acid metabolism and deamination of catecholamines.
  5. Golgi complex = stores albumen, liopproteins and bile and synthesise glycoprotein.
  6. Lysozymes = autolysis of hepatocytes when needed, also sites of pigment deposition - ferritin, lipofuscin, copper and bile pigment
  7. Microtubules = bile secretion
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12
Q

Kupffer Cells

A

Macrophages
form part of the reticuloendothelial system
line the sinusoids
Function
- phagocytose bacteria
- destruction of endotoxin
- protein denaturation
- accumulation of ferritin and haemosiderin.

Have a haemopoietic function - ceases within a few weeks of birth

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13
Q

Ito Cells

A

Found in sinusoids
Contain fat
Store vitamin A and other retinoids

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14
Q

Pitt Cells

A

Found in sinusoids
mobile lymphocytes attached to endothelium

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15
Q

Space of Disse

A

lies between endothelial cells of the sinusoid and the hepatocyte membrane
Collagen, fibronectin, proteoglycans are found in this space.

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16
Q

Functions of the liver
- Rapid Fire

A

MEDICABRUSH

  1. Metabolic
  2. Endocrine
  3. Detoxification + metabolism of drugs.
  4. Immunological
  5. Coagulation
  6. Acid Base
  7. Bile formation
  8. Reservoir for blood
  9. Urea formation
  10. Storage function
  11. Hematopoiesis
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17
Q

Metabolic Functions of the Liver

A

Metabolic:
- Carbohydrate metabolism
- Lipid Metabolism
- Protein Metabolism
- Plasma protein production

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18
Q

Carbohydrate Metabolism in the liver

A

1.Glycostat function
- maintains strict BGL.
2. Glycogenesis (formation of glycogen).
- Glucose -> G6P by glucokinase. -> G1P.
- G1P -> Glycogen using glycogen synthase using energy from UTP
3. Glycolysis
- Glucose broken down to produce energy.
- Occurs in cytoplasm of cell.
- Results in 2 pyruvate, 2 ATP and 2 NADH molecules.
4. Glycogenolysis
- Breakdown of glycogen to G-1-P and glucose.
- Glucose: facilitated diffusion channels in hepatocyte membrane (GLUT2)
- G-1-P used in glycolysis
5. Gluconeogenesis
- Creation of new glucose from non carbohydrate procursers
- glucagon enhances transport of non carb substance across hepatocyte membrane.

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19
Q

Glycolysis

A

Glucose broken down to produce energy
Results in 2 pyruvate, 2 ATP and 2 NADH molecules

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20
Q

Lipid Metabolism

A
  1. Synthesis of fatty acids which are then converted to triacylglycerol and VLDLs.
  2. Partial oxidation of FA to ketone bodies.
  3. Synthesis
    - Cholesterol may come from diet but most is synthesised in the liver from acetyl CoA.
    - Cholesterol made in liver: 80% converted to bile, remainder transported in the blood by lipoproteins.
  4. Oxidation of FFAs to Ketone bodies
    - TG is absorbed from diet
    - 50% are hydrolysed to glycerol and FAs.
    - 40% is partially hydrolysed to monoglycerides.
    - Short chain FAs -> liver and enter the fat utilisation pathway.
    - FA in liver -> b oxidation to acetyl CoA
    - acetyle CoA -> ketone bodies
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21
Q

Protein Metabolism

A
  1. Synthetic Processes
    - Albumin: at rate of 120-300mg/kg body weight per day. Long half life, poor marker of liver damage.
    - a1, a2, b globulins = transport binding proteins + complement proteins
    - Haptoglobin = binds free Hb.
    - a1 anti trypsin, a2 macroglobulin, AT3, CRP.
    - Vitamin K dependent clotting factors.
    - Liver makes all proteins except immunoglobulins.
  2. Protein Degradation
    - AA: aa are delivered to the liver after uptake in the SI. Liver will then complete deamination of aa so they can be used in gluconeogenesis
    - interconversions between different AAs - for protein synthesis.
    - formation of urea as part of alanine cycle.
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22
Q

Endocrine functions of the liver

A
  1. 25(OH) cholecalciferol production
    - Cholecalciferol synthesised in skin from UVB light.
    - Converted to calcifediol in liver. (measured for vitamin D level in serum) by hydroxylation.
    - Calcifediol is converted to active vitamin D in kidney.
  2. Synthesis of some hormone precursors
  3. Inactivation of hormones
  4. EPO production -> fetal.
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23
Q

Detoxification

A

Detoxification of endogenous and exogenous substances.

1) Biotransformation:
- Cytochrome p450 enzymes in hepatocytes (SER) perform phase 1 and 2 reactions.

Phase 1 reactions
- Oxidation, reduction and hydroxylation
- increase the hydrophilicity of drugs.
- Oxidative reactions catalysed by p450.
- reductase and hydrolase enzymes are mainly located in the cytoplasm.
- some products of phase 1 reactions may be active.

Phase 2 reactions
- glucuronidation, sulphating and acetylation.
- Occur primarily in cytoplasm
- produce more polar compounds.
- Majority of phase 2 reactions produce inactive compounds, however there are some exceptions

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24
Q

Immunological

A

Largest organ in tissue macrophage system (RES)

The RES:
- Ag processing and presentation
- Phagocytosis of bacteria and cell debris
- secretion of cytokines
(Innate Immune System)
- Functional cell of the RES = kuppfler cells.

Also synthetic immunological role
- synthesises plasma proteins: Complement, CRP.

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25
Coagulation
Synthesis of Vitamin K dependent clotting factors - 2,7,9,10 Synthesis of Protein C and S
26
Acid Base Functions of the Liver
Liver can be a NET producer or consumer of H+ 1) CO2 - Produces about 20% of body CO2. - mostly produced during oxidation of substrates. 2) Metabolism of acid anions - lactic acid, ketones, acetate, lactate, citrate. - metabolism consumes H+ therefore NET production of Bicarb anions. 3) AA metabolism. - results in av net production of 70% of total daily fixed acids. 4) Ammonia metabolism - Produces H+ ion.
27
Bile Production
28
What does bile consist of
Electrolytes Water Protein Bilirubin Bile Salts Lipids
29
What are bile salts
Primary formed in liver Secondary = made in colon by bacterial action on primary acids. Primary: - Steroid compound made in the liver from cholesterol - Conjugated w glycine or taurine - Become more water soluble and less lipid soluble which limits passive absorption in the small intestine. Secondary: - Primary acids (Cholic acid, lithocholic acid, chenocholic acid) - Bacterial action on primary acids
30
Function of bile acids
1) Facilitate lipid absorption from the small intestine via: - Emulsification of dietary fat, breaks down into small particules. - Micelle formation (water soluble) - Reabsorbed at the terminal ileum by apical sodium dependent bile transporter. - Bind plasma proteins - Carried to liver. 2) Major excretory route for lipid soluble waste products 3) Absorption of fat soluble vitamins - A,D,E,K
31
What is bilirubin
Breakdown product of Hb. - Hb broken down in the reticuloendothelial system, particularly in the spleen.
32
How Does Hb become Bilirubin
Haem ---- macrophage haem oxygenase----> Iron (into body iron pool), CO (only endogenous source of CO) and biliverdin. Biliverdin ---- biliverdin reductase -----> Bilirubin (unconjugated)
33
Bilirubin metabolism.
1) Blood - Hepatocyte Bilirubin in blood - bound to albumin -- taken to liver. Bili dissociates from albumin --- free bili enters liver. Bili uptake into the hepatocyte via facilitated diffusion. 2) Hepatocyte In the hepatocyte bili is conjugated w glucuronides Unconj Bili ---- UDP glucuronyl transferase ---> Bilirubin glucoronide (Conj Bili). Conj bili is now more water soluble than unconj bili Conj bili is then actively transported into the bile canaliculi. - Small amount escapes to blood (bound alb) excreted in kindey. 3) Intestine intenstine mucosa is impermeable to conj bili but permeable to unconj and urobilinogens. 50% of Conj Bili is broken down to urobilinogens by gut bacteria. 4) Urobilinogens - Most excreted in stool - Some is reaborbed (as the intestinal mucosa is permeable) - reabsorbed part is either excreted again via liver into intestine, or enters systemic circ (5%) and excreted in the urine.
34
Reservoir of Blood
Normal liver blood volume ~500ml - 10% circulating volume. Liver is able to mobilise ~350mls of blood to the circulation w acute SNS stimulation. Increased R atrial pressure = Increase in liver blood vol up to 1L due to back pressure.
35
What is Urea
Nitrogenous end product of ammonia Synthesized from ammonia in the liver by the urea cycle as a way to excrete ammonia Liver is only organ that can complete the urea cycle
36
What is ammonia
Ammonia (NH3) is a waste product that is primarily produced by bacteria in the gut during the breakdown of proteins. also in breakdown of RBC. Toxic to CNS, freely crosses BBB Increased levels of circulating ammonia -> Hepatic encephalopathy
37
Cause of high circulating ammonia
1) Loss of functional hepatocytes to covert to urea 2) Shunting of portal blood around hardened liver
38
Use of Lactulose in Hepatic Encephalopathy
Reduces the amount of ammonia load by preventing it from being absorbed into blood. Lactulose traps luminal ammonia in ionized form Poop it out
39
What does the liver store
1. Glycogen - glucostat function 2. TGs 3. Lipid soulble vitamine s (ADEK) 4. Folic acid 5. B12 6. Iron 7. copper 8. Blood
40
Haematopoesis
In fetus
41
How much store of A, D, B12 does the liver keep?
A = 10 months D= 4 months B12 = 1 year.
42
Total Liver blood flow
1.5L/min or 25% of cardiac output Both hepatic artery and HPV>
43
How much blood does the Hepatic Artery supply
High pressure, High resistance system. 30% of total Liver blood flow. 40-50% of total hepatic oxygen supply.
44
Hepatic A Pressure
Similar to systemic A pressure Hepatic arteriole P = 35mmHg. Therefore large ratio between presinusoidal and post sinusodal pressure. This results in low sinusoidal pressure
45
Portal Vein blood supply
Drains from large and small intestines, spleen, stomach and pancreas and Gb to liver. - 70% of total liver blood flow. - 50-60% of oxygen supply. - O2 sat = 85% at rest. decreases with increased gut activity. Higher O2 sat than regular venous blood because of the high mesenterial arterial shunting though intestinal caps.
46
HPV pressure
Low pressure, low resistance, low velocity system - flow is half of HA. - P = 5-10mmHg. Dependent on the state of constriction/dilation of Mesenteric arterioles, intrahepatic resistance.
47
Hepatic Veins
Liver - R and L hepatic V - Inferior vena cava. Caudate lobe is drained by separate veins.
48
Hepatic venous pressure influencers
1) hepatic vasoconstriction by various stimuli - NA, AT, histamine, Hepatic n stimulation. 2) IPPV 3) Intrabdo pressure 4) Gravity 5) gut wall activity
49
Regulation of increased O2 demand - liver
Given high blood flow at rest, its hard to increase much more in when there is a increased O2 demand. Therefore >O2 demand is met by >O2 extraction. Reduction in HPV + increase in HA flow by 22-100%.
50
Intrinsic control of hepatic blood flow
1) Autoregulation 2) Hepatic arterial buffer response
51
Autoregulation of hepatic blood flow
Hepatic artery only Flow maintained until below S80mmHg. When HA pressure decreased, flow is maintained by a decrease in HA resistance, until <80syst.
52
Hepatic Arterial Buffer response
semi recuprocal interrelationship between HPV and HA flows. - < in HPV low = < HA resistance and >HA flow. - Doesnt work in opposite way. Due to intrhepatic levels of adenosine - < HPV flow = build up of adenosine in liver = HA vasodilation.
53
Extrinsic Control of Hepatic blood flow
1) Neural 2) Feeding - > BF 3) Ventilation 4) CO2 5) Anaesthesia
54
Neural/hormonal control of hepatic blood flow
HA = a, b adrenergic receptors and dopamine receptors HPV = a adrenergic and dopamine receptors. Adrenalin = - a effect = vasoconstriction - b effect = vasodilaton (HA) Vasodilation: - Glucagon - VIP - Secretin Vasoconstriction - AT2 - Vasopressin
55
Ventilatory Changes and HBF
Normal Spont respiration - Inspiration = hepatic venous outflow PPV - < HBF due to < in CO CO2: - CO2 = vasodilation = >HBF.
56
Anaesthesia Caused Changes in Hepatic Blood Flow
1. Regional 2. Inhalational 3. IV 1. Regional: - Spinal and epidural = < total hepatic blood flow due to
57
Hepatic Arterial flow equation
(mHAP - HVenousP) / hepatic arteriolar resistance - mHAP = mAP = 70mmHg. - HVP = CVP = 0-5mmHg - R = (8 x length x viscosity) / (pie x radius 4)
58
SAQ outline Describe the factors influencing hepatic blood flow
1. Hepatic circulation summary - total = 1.5L/min, 30% of CO - Blood = 70% HPV, 30% HA. - Oxygen = 50% HPV, 50% HA. 2. Intrinsic HBF regulation - Myogenic - Hepatic arterial buffer response (adenosine) 3. Extrinsic - ANS: activation can mobilise blood in time of sympathetic stress - HA has a,b adreno, dopamine. - HV has a adreno. - Endo and hormonal - Constriction/Reduced HBF: Adrenalin, AT2, vasopressin, CO2. 4. External factors - Venous return -> increased affects hepatic venous drainage. - PPV, Heart failure, pneumoperitoneum - CO -> directly influences HA flow. - Shock states and exercise -
59
Hepatic Extraction Ratio
Fraction of the drug entering the liver in the blood, which is extracted during one pass of the blood through the liver. Determined largely by the free unbound fraction of the drug and by the intrinsic clearance rate AS HBF increases, HER will decrease for all drugs.
60
Intrinsic Clearance
The intrinsic ability of the liver to metabolise the drug in the absence of restrictions imposed on drug delivery to the hepatocyte (flow or protein binding) Low intrinsic clearance = less blood flow dependent Higher the intrinsic clearance, the more blood flow dependent
61
High Extraction ratio
rapid uptake and high capacity elimination is perfusion dependent Dependent on Liver flow Independent of protein binding
62
Low Extraction Ratio
Elimination is capacity dependent - Amount of free drug available for metabolism is greatly affected by the degree of protein binding Largely independent of flow Dependent on Hepatocyte function and protein binding
63
Drug Metabolism and HBF
Rate of metabolism will decrease when HBF decreases as HBF is important determinent of hepatic clearance Depends on HER / Intrinsic clearance rate - Drugs w a higher incrinsic clearance rate, and ER are perfusion dependent therefore more effected. - Drugs w a lower intrinsic clearance rate are not dependent on perfusion.
64
Tests evaluating synthetic function of the liver
1. Albumen 2. INR 3. Total protein
65
Tests evaluating metabolic functions of liver
1. Total bili 2. Glucose 3. Ammonia
66
Tests of Hepatobiliairy injury
1. AST 2. ALT 3. GGT
67
Cholangiocytes
Concentrate bile from 500-1L by liver to less stored.

GI System (2 decks)

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