Physiology of liver

Anatomical aspects

Liver is the largest visceral organ

Essential for life
Hepatic lobule –Contains Central efferent hepatic venule with cords of hepatocytes and
sinusoids converging on to the venule.

Arrangement of Liver cells

Liver Acinus

Functional unit of liver.

Lie as parenchymal mass between 2 centrilobular veins.

Core of acinus contains portal triad

Liver acinus

Acinus mainly consist of – 3 functional zones

Zone 1- Periportal

• Highest O2 consumption
  
  
• Highest metabolic rate
  
  
• Protein synthesis
  
  
• Secrete glucose into sinusoids.
  
  

Zone 2 – mediolobular

Intermediate oxygen supply

Intermediate enzyme activity

Zone 3 - centrilobular

• Least oxygen supply
  
  
• High concentration cytochrome P-450
  
  
• Drug biotransformation
  
  
• Utilize glucose
  
  

Liver Sinusoids

• Liver sinusoids are low pressure microcirculatory system
  
  
• Sphincters at hepatic arteriole, hepatic venous sinusoid and arteriolar portal shunts.
  
  
• Reservoir for blood  
  
  

Types of Cells

Cells of Liver

1. Hepatocyte
2. Kupffer cell

Functions of Liver

Carbohydrate metabolism

• Maintain blood glucose – glucose buffer function
• Stores glycogen
  
  

Glucose uptake

• Into portal venous system from gut– energy dependent active process
• Into hepatocyte from portal venous system - passive
  
  

Major components of Carbohydrate Metabolism handled by liver

• Glycogen synthesis
• Gluconeogenesis
• Glycolysis
• Reduced NADPH formation
  
  

Lipid Metabolism

Synthesis of fatty acids which are converted to triacylglycerol & VLDL

Partial oxidation of FA to ketone bodies

Cholesterol metabolism

80% converted to bile

20% bound to lipoprotein in blood

Bile production

At a rate of 1L/day.

Concentrated in gall bladder

Produce bile acids from cholesterol– cholic acid & chenodeoxycholic acid

Bile acids + glycine/taurine = bile salts

Bile salts - Emulsify dietary fat

Absorb fat soluble vitamins- A,D,E,K

Reabsorbed at terminal ileum- portal circulation- liver “enterohepatic circulation”

Bilirubin Metabolism

Formed in RES from haemoglobin

Transported to liver bound to albumin

Conjugated with glucuronide; secreted in bile

Conjugated bilirubin - Urobilinogen in gut

Protein Metabolism

Anabolism

Catabolism

Remove AA’s from blood for gluconeogenesis and protein synthesis

Release AA’s into blood for other tissues

Breakdown AA’s – remove N2 as urea

Protein Anabolism

AA’s & short peptides delivered to liver from gut

Synthesize

Albumin – 120-300mg/kgBW/day

α1, α2, β globulins – transport proteins

Haptoglobulin, α1 anti-trypsin, α2 macroglobulin, antithrombin III, α1 acid glycoprotein &

C reactive protein

Vitamin K dependent clotting factors – II, VII, IX, X

Vit K independent clotting factors – V, VIII, IX, XII, XIII

Purine & Pyrimidine bases  

Protein Catabolism

Rate of protein turnover – 10 days

Muscle – 180 days

AA degradation by transamination, deamination and decarboxylation.

Produce acetyl CoA, oxyglutarate, succinyl CoA, fumarate – enter citric acid cycle

Urea synthesis

AA degradation         ammonia – toxic

Converted to urea- in ornithine cycle

100 g protein – 30g urea

Creatine synthesis

Synthesized from methionine, glycine and arginine.

Phosphocreatine stored in muscle – back up energy

Phosphocreatine        creatinine

Phagocytic function

By Kupffer cells

Infective, inflammatory and tissue injury substances

Phagocytosed material degraded by lysosomal enzymes  

Storage functions

Glycogen

Triglycerides

Vitamins – A, D, E, K and B’s

Iron – excess as ferritin

Copper

Drug Metabolism

Eliminate exogenous and endogenous compounds

Lipophilic /partially ionised     hydrophilic

2 phases

Phase I – oxidation, reduction, hydrolysis

Phase II- Glucuronidation, Sulphation, acetylation

Phase I

Increase hydrophilicity

Oxidative catalysed by cytochrome P-450 in smooth ER

Reductase & hydrolase – cytoplasm

Some products - active

Phase II

Occur In cytoplasm

Glucuronidation – glucuronosyl transferases

Most inactive products

Drug clearance affected by

Hepatic blood flow

Plasma protein binding

Enzymatic activity

Liver Blood Flow

1.5 L/min

25% of cardiac output

Hepatic artery & portal vein

Hepatic artery

30% total hepatic flow

40-50% total hepatic oxygen supply

Oxygen saturation 98%.

Pressure similar to systemic BP

High resistance in hepatic arteriole – pressure 35mmHg

Hepatic sinusoidal pressure 2 mmHg – due to ratio of pre sinusoidal/post sinusoidal resistance  

Innervated muscular coat.

Portal vein

70% of liver blood flow

50-60% of basal oxygen supply

Oxygen sats – fasting state – 85%

increased gut activity – reduced

Valveless vein

Low pressure (5-10mmHg), low resistance, low velocity system

Hepatic veins

To IVC via R & L hepatic veins

Hepatic veno-constriction

• Norepinephrine
  
  
• Angiotensin
  
  
• Hepatic nerve stimulation
  
  
• Histamine
  
  

Hepatic venous pressure influenced by

• IPPV
  
  
• IAP
  
  
• Gravity
  
  
• Gut wall activity
  
  

Hepatic Microvasculature

Sinusoid – formed by hepatic arteriole and portal venule

Flow to central vein

Pressure 2mm Hg.

Oxygen consumption increased by increased oxygen extraction at sinusoids.

Capacitance function

Reservoir volume 450ml

Mobilized in hypovolaemia by catecholamines.

Act as buffer against increased blood volume

Regulation

High blood flow

Increased oxygen demand leads to increased oxygen extraction ; not an increase in blood flow

• Intrinsic control
  
  
• Extrinsic control
  
  

Intrinsic control

Autoregulation

In hepatic artery

When pressure reduce flow is maintained by lowering resistance until SBP<80mmHg.

Portal vein

No autoregulation

Flow related linearly to pressure

Semi-reciprocal interrelationship

Reduction in portal venous blood flow increase hepatic arterial blood flow

by decreasing hepatic arterial resistance.

No change in portal venous blood flow with reduction in

hepatic arterial blood flow – no autoregulation

“Hepatic arterial buffer response”

Due to intrahepatic adenosine - Reduced portal blood flow –

adenosine build up- hepatic artery vasodilatation

Myogenic mechanism

Increased hepatic venous pressure increase hepatic arterial resistance and

decrease hepatic arterial blood flow.

eg. CCF

Extrinsic Control

Hepatic artery – α & β adrenergic receptors & dopamine receptors

Portal vein – α adrenergic & dopamine receptors  

Epinephrine –

• Portal venous constriction
  
  
• Initial vasoconstriction followed by vasodilatation of hepatic artery
  
  

Dopamine- minimal effects at physiological concentrations

Glucagon – increase hepatic blood flow by vasodilatation

VIP & secretin – Vasodilate hepatic artery; no effects on portal vein

Angiotensin II- Vasoconstrict both

Vasopressin – Vasoconstrict and reduce portal blood flow

Increase hepatic blood flow

Feeding

Hypercapnia

Decrease hepatic blood flow

Spontaneous breathing – hepatic venous outflow reduced in inspiration and vice versa

Vigorous exercise – splanchnic vasoconstriction – reduced hepatic blood flow.

IPPV- reduced CO

Hypocapnia – increase resistance in portal system.

Hyperoxia- little effect

Hypoxia – initial increase return to baseline in 20 min.

Acute Haemorrhage

Portal venous flow reduced than hepatic arterial flow.

Increased oxygen extraction

Mobilize 50% of reservoir blood into systemic circulation by sympathetic stimulation.

Effect of anaesthetic agents

• Epidural & spinal – reduce total hepatic blood flow – reduced portal venous blood flow and MAP.
  
  
• Halothane – greatest reduction in total hepatic blood flow.
  Reduce hepatic arterial flow and portal blood flow. ‘Reduce buffer response’
• Enflurane- lesser reduction
  
  
• Isoflurane – reduced portal venous flow; normal or increased hepatic arterial flow;
  preserved buffer response
• TPS, etomidate, propofol
  
  

Dose dependent reduction in hepatic blood flow –

reduced CO and obtundation of buffer response.