THE LIVER STRUCTURE AND FUNCTION

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THE LIVERSTRUCTURE AND FUNCTION

• Richard Hinton,
• School of Biological Sciences
• University of Surrey

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Functions of the Liver

• 1) The liver is both an exocrine gland,
  secreting bile, but also and endocrine organ
  making plasma proteins
• 2) The liver degrades worn out plasma proteins
  and red blood cells prepares hydrophobic
  materials for excretion
• 3) The liver plays a major protective role
  preparing lipid soluble xenobiotics for
  excretion, removing particulates such as bacteria
  and viruses and synthesising protective proteins
  in theacute phase response
• 4) The liver is the principal site for
  interconversion of fats, sugars and amino acids
  and is mainly responsible for the synthesis of,
  for example, haem and cholesterol. The liver
  also synthesises blood lipoproteins and stores
  glycogen

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Gross anatomy of the liver

• The liver has a dual blood supply. Only 20 of
  the blood derives from the hepatic artery, the
  remainder comes from the portal veins which drain
  the stomach and all the intestines except the
  rectum. The liver hence can remove damaging
  materials before they reach the systemic
  circulation
• Blood leaves the liver via the hepatic veins
  which join with the ascending vena cava

4
Continued

• The exocrine secretion of the liver, bile, is
  carried from the liver to the intestine by the
  bile duct. In most species, but not in rats or
  horses, a small sac, the gall bladder, buds off
  the upper part of the bile duct and stores and
  concentrates bile between meals. In some
  species, such as rats, pancreatic ducts fuse with
  the bile duct, in others such as humans they
  remain separate until they reach the intestine
• Some lymph is formed in the portal tree and this
  leaves by a lymphatic. No lymph is formed in the
  parenchyma as the fenestrated endothelium means
  that proteins can pass freely from the lumen of
  the vessel to the space of Disse

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The Internal Anatomy of the Liver

• The portal vein, hepatic artery, bile duct and
  lymphatics enter the liver at a single point, the
  porta hepatis. Once inside the liver these
  vessels run in a connective tissue matrix and the
  assemblage is called the portal tract. This
  branches to form the portal tree. Each branch
  of the tree contains all four types of vessel

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Continued

• The hepatic veins also branch in a tree like
  pattern which interdigitates with the portal tree

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Intrahepatic bile ducts

• The bile ducts are surrounded by a network of
  small blood vessels, supplied from the hepatic
  artery. The direction of blood flow is opposite
  to that of bile so recovering low molecular
  weight materials which heve entered the bile by
  mistake

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Structure of the hepatic parenchyma

• ..

• The parenchyma is the functional part of the
  gland as opposed to the supporting connective
  tissue which is termed the stroma..
• Blood from the terminal hepatic arterioles and
  portal venules is discharged into the capillaries
  of the liver

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Why liver capillaries are called sinusoids

• These vessels are unusual in that their lining
  cells contain sieve plates which allow proteins
  to pass through into the Space of Disse and there
  contact the underlying hepatocytes. Because of
  this they are termed sinusoids

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Bile Formation

• Bile consists principally of bile acids and bile
  salts. These are detergents which assist in
  digesting fat and show entero-hepatic
  recirculation
• Glucuronide and glutathione conjugates are also
  excreted in bile. Bile also contains lipids and
  distinctive enzymes extracted from hepatocytes
• Bile is initially formed by transfer of bile
  acids and salts into small spaces between
  hepatocytes termed bile canaliculi. These are
  sealed by tight junctions, however these allow
  the passage of water to hydrate the secretion
• An actin corset prevents expansion of the
  canaliculi forcing the bile to flow towards the
  portal tracts

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Structure of hepatocytes

• Hepatocytes are epithelial cells but, in the
  liver, there is no well defined basement membrane
  although collagen fibres are seen in the space of
  Disse and can increase in liver damage
• Hepatocytes are large cells with central nuclei.
  Cells may be bi-nucleate or polyploid - this
  varies with species. The microtubule organising
  centre, and hence the golgi apparatus lie between
  the nucleus and the bile canaliculus. Lysosomes
  remain close to the golgi apparatus. Mitochondria
  and peroxisomes are scattered through the
  cytoplasm.

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Continued

• Hepatocytes contain a lot of rough endoplasmic
  reticulum which may form small stacks or be
  looped around mitochondria
• Smooth endoplasmic reticulum is in the form of
  small tubules and may be difficult to distinguish
  in the normal cell. It tends to localise, along
  with glycogen granules in the central part of the
  cell.
• There is a well developed cytoskeleton with
  microtubules transporting material between the
  sinusoidal surface of the cell and the peri-golgi
  zone
• Both the sinusoidal and bile canalicular faces of
  the cell have stubby microvilli

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Circulatory Zones in the Liver

• As blood flows from the portal tract to the
  hepatic venules it gradually loses oxygen.
  Although the hepatocytes in the well oxygenated
  periportal zone look similar to hepatocyes
  around hepatic veins (the centrilobular zone)
  their enzymology is different. Cells in the
  intermediate (midzonal) area are - intermediate
• Synthesis of blood proteins and gluconeogenesis
  occur principally in the periportal zone

Most isoforms of cytochrome P450 concentrate in
the centrilobular zone. Cells in this area are
also especially rich in peroxysomes
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The differences between the circulatory zones are
difficult to spot in control livers but show up
clearly in damaged livers
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Kuppfer cells

• We have already mentioned the sinusoid
  endothelial cell and its sieve plates. Like
  other endothelial cells it appears to be involved
  in message passing.

• Kupffer cells are fixed macrophages which live
  within the sinusoids and throw processes across
  the vessel. Their job is to remove particulate
  materials picked up in the intestine and worn out
  red blood cells. They are also very heavily
  involved in message passing

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The cells with every name

• Fat storing cells (also known as Ito or stellate
  cells) store retinoic acid and are also heavily
  involved in message passing. They are modified
  fibroblasts and, in the damaged liver, revert to
  type
• The very scarce pit cells are probably resident
  NK cells

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Control of the Liver

• The size of the liver is very carefully
  controlled and is regulated by the weight of the
  animal. Cells may be added by mitosis or removed
  by apoptosis. Normally turnover is slow (several
  months in rats)
• As the centre of intermediary metabolism the
  liver has receptors for a very large number of
  hormones including peptide hormones such as
  insulin and glucogon and nuclear-acting hormones
  such as steroids
• The liver is only lightly innervated and such
  innervation as there is does not seem to play a
  significant role - as witnessed by the normal
  function of the liver transplant

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Cross talk between liver cells

• All the major cell types of liver are capable of
  secreting cytokines which act on other liver
  cells. These are known to affect both the
  addition of cells by mitosis and the removal of
  cells by apoptosis.
• Mitosis of hepatocytes may be stimulated by TGF?,
  which is an autocrine factor made in hepatocytes
  and acting on hepatocytes and by HGF which is
  formed by fat storing cells.
• Once the liver cell number has reached the target
  size then division is halted by negative growth
  factors such as TGF?.

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Continued

• Transformation of fat storing cells into more
  typical fibrocytes appears to be due to the
  effect of factors released from Kupffer cells.
• It now seems that apoptosis in the liver is due
  to the interaction of a range of factors.
  Sporadic apoptosis is observed throughout life,
  the factors triggering this are unknown.
  Apoptosis is observed following treatment with a
  range of toxins and may be prevented by factors
  which cause loss of Kupffer cell function .
  However there seem to be other cases where
  Kupffer cells are not involved.

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Development of the Liver

• The liver develops from a pair of buds from the
  primitive gut. The liver develops rapidly for it
  several functions vital to the developing. In
  particular it makes blood proteins and is
  colonised by haematopoietic cells. In rats and
  mice the latter role continues for the first 3
  weeks of life.
• It would seem that hepatocytes, bile duct lining
  cells and the epithelial cells of the endocrine
  and exocrine pancreas have a common origin, their
  development being determined by their environment.

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Repair of the liver

• The liver has an immense capacity for
  regeneration. Repair is normally by division of
  hepatocytes drawn from all parts of the liver.
• If, for some reason, hepatocytes cannot divide
  (eg in galactosamine toxicity) small cells,
  thought to derive from a population on the edge
  of the portal tract divide and differentiate into
  hepatocytes. These oval cells are stem cells
  capable of differentiating into both liver and
  pancreas
• Repeated damage to the liver or haemorrhagic
  necrosis then the liver may repair by fibrosis