The liver is the largest internal organ located in the upper right and partially left abdomen. It has both exocrine and endocrine functions performed by hepatocytes. Hepatocytes are arranged in plates separated by sinusoids, with a space of Disse between hepatocytes and sinusoidal cells. The liver lobule is the basic functional unit, and has a dual blood supply from the hepatic artery and portal vein. The liver performs many vital roles including bile production, lipid and carbohydrate metabolism, protein synthesis, hormone degradation, detoxification, and immune functions.

1. Ali Al-Alwani & Saja Al rikabi
117 i-6

2. The Structure
The liver is the largest mass of glandular tissue in the body
and the largest internal organ, weighing approximately 1,500 g
and accounting for nearly 2.5% of adult body weight It is located
in the upper right and partially in the upper left quadrants of the
abdominal cavity, protected by the ribcage .The liver is enclosed
in a capsule of fibrous connective tissue (Glisson’s capsule); a
serous covering (visceral peritoneum) surrounds the capsule,
except where the liver adheres directly to the diaphragm or the
other organs.
The liver is anatomically divided by deep grooves
into two large lobes (the right and left lobes) and
two smaller lobes (the quadrate and caudate
lobes)
the liver has both endocrine and exocrine functions, however,
the same cell (the hepatocyte) in the liver is responsible for
the formation of bile—the liver’s exocrine secretion—and its
numerous endocrine products. In addition, hepatocytes convert
noxious substances into nontoxic materials that are excreted in
bile.

3. General Hepatic Structure
and Vascular Supply
The liver is completely enveloped by peritoneum,
which forms a simple squamous epithelium covering
over the dense, irregular connective tissue capsule
(Glisson’s capsule) of the gland. Glisson’s capsule is
loosely attached over the entire circumference of the
liver except at the porta hepatis, where it enters the liver,
forming a conduit for the blood and lymph vessels and
bile ducts. the bulk of the liver is composed of uniform
parenchymal cells, the hepatocytes.
The superior aspect of the liver is convex, whereas its
inferior region presents a hilum-like indentation, the
porta hepatis. The liver has a dual blood supply,
receiving oxygenated blood from the left hepatic
artery and the right hepatic artery (25%) and
nutrient-rich blood via the portal vein (75%). Both
vessels enter the liver at the porta hepatis. Blood leaves
the liver at the posterior aspect of the organ through the
hepatic veins, which deliver their contents into the
inferior vena cava. Bile also leaves the liver at the porta
hepatis, by way of the right and left hepatic ducts, to be
delivered to the gallbladder for concentration and
storage.
Hepatocytes are arranged in hexagon-shaped lobules
(classical lobules) about 2 mm in length and 700 μm
in diameter. These lobules are clearly demarcated by
slender connective tissue elements (known as portal
tracts) in animals such as the pig and the camel.
However, because of the scarcity of connective tissue and
the closely packed arrangement of the lobules in
humans, the boundaries of the classical lobules can only
be approximated. Where three classical lobules are in
contact with each other, the connective tissue elements
are increased, and these regions are known as portal
areas(triads)

9. The Three Concepts of Liver Lobules
The classic
lobule
• Consists of stacks of anastomosing plates of hepatocytes, one cell thick, separated by the anastomosing system of
sinusoids that perfuse the cells with the mixed portal and arterial blood. Each lobule measures about 2.0 0.7 mm.
At the center of the lobule is a relatively large venule, the terminal hepatic venule (central vein), into which the
sinusoids drain. The plates of cells radiate from the central vein to the periphery of the lobule, as do the sinusoids.
At the angles of the hexagon are the portal areas (portal canals), loose stromal connective tissue characterized by
the presence of the portal triads. This connective tissue is ultimately continuous with the fibrous capsule of the
liver
The portal
lobule
• The major exocrine function of the liver is bile secretion. Thus, the morphologic axis of the portal
lobule is the interlobular bile duct of the portal triad of the classic lobule. Its outer margins are
imaginary lines drawn between the three central veins that are closest to that portal triad (Fig.
18.5). These lines define a roughly triangular block of tissue that includes those portions of three
classic lobules that secrete the bile that drains into its axial bile duct. This concept allows a
description of hepatic parenchymal structure comparable to that of other exocrine glands.
The liver
acinus
• The liver acinus is lozenge shaped and represents the smallest functional unit of the hepatic parenchyma.
The short axis of the acinus is defined by the terminal branches of the portal triad that lie along the
border between two classic lobules. The long axis of the acinus is a line drawn between the two central
veins closest to the short axis. Therefore, in a two-dimensional view the liver acinus occupies parts of
adjacent classic lobules. This concept allows a description of the exocrine secretory function of the liver
comparable to that of the portal lobule.

11. Hepatic Sinusoids and Hepatocyte Plates
Hepatic sinusoids are lined with a thin discontinuous
endothelium. The discontinuous sinusoidal
endothelium has a discontinuous basal lamina that is
absent over large areas. The discontinuity of the
endothelium is evident in two ways:
• Large fenestrae, without diaphragms, are present
within the endothelial cells.
• Large gaps are present between neighboring
endothelial cells. Hepatic sinusoids differ from other
sinusoids in that a second cell type, the stellate sinusoidal
macrophage, or Kupffer cell, is a regular
part of the vessel lining.
Plates of hepatocytes, no more than two cells thick
prior to the age of 7 years and one cell thick after that
age, radiate from the central vein toward the periphery of
the classical lobule . The spaces between the plates of
hepatocytes are occupied by hepatic sinusoids, and the
blood flowing in these wide vessels is prevented from
coming in contact with the hepatocytes by the presence
of an endothelial lining composed of sinusoidal lining
cells.
Resident macrophages, known as Kupffer cells, are
associated with the sinusoidal lining cells in the
sinusoids . Frequently, phagosomes of Kupffer cells
contain endocytosed particulate matter and cellular
debris, especially defunct erythrocytes that are being
destroyed by these cells. Electron micrographs
of Kupffer cells display numerous filopodia-like
projections, mitochondria, some RER, a small Golgi
apparatus, and an abundance of lysosomes and late
endosomes. Because these cells do not make
intercellular junctions with the neighboring cells, it
has been suggested that they may be migratory
scavengers

12. Perisinusoidal Space (Space of Disse)
The sinusoidal lining cells are separated from the
hepatocytes by a narrow space of Disse (perisinusoidal
space), and plasma escaping from the sinusoids has free
access to this space. Microvilli of the hepatocytes occupy
much of the space of Disse; the extensive surface area of
the microvilli facilitates exchange of materials between
the bloodstream and the hepatocytes. Hepatocytes do
not come into contact with the bloodstream; instead, the
space of Disse acts as an intermediate compartment
between them.
The perisinusoidal space contains type III collagen fibers (reticular
fibers) that support the sinusoids, as well as a limited amount of type
I and type IV collagen fibers, a basal lamina is absent. Occasionally,
nonmyelinated nerve fibers and stellate-shaped hepatic stellate
cells (also known as Ito cells and fat storing cells) have been
noted in this space. It is believed that hepatic stellate cells store
vitamin A, manufacture and release type III collagen into the space of
Disse, secrete growth factors required by the liver for generating new
hepatocytes, and form fibrous connective tissue to replace
hepatocytes damaged by toxins. In addition, pit cells, which display
short pseudopodia and cytoplasmic granules, have been noted in the
perisinusoidal space of mice and rats. These cells, believed to be
natural killer cells, are also assumed to be in the human liver.

13. Hepatic Ducts
The system of hepatic ducts is composed of cholangioles,
canals of Hering, and bile ducts leading to larger and
larger bile ducts that finally culminate in the right and
left hepatic ducts.Bile canuliculi anastomose with one another,
forming
labyrinthine tunnels among the hepatocytes. As these bile
canaliculi reach the periphery of the classic lobules, they
merge with cholangioles, short tubules composed of a
combination of hepatocytes and low cuboidal cells, and
occasional oval cells. Bile from cholangioles enters the
canals of Hering, slender branches of the interlobular
bile ducts, that radiate parallel to the inlet arterioles and
inlet venules. Interlobular bile ducts merge to form
increasingly larger conduits, which eventually unite to
form the right hepatic duct and the left hepatic duct.
The extrahepatic system of bile ducts is described later.
Most of the cells of the canals of Hering are composed of
low cuboidal cells, but interspersed among them are
some ovoid cells that are capable of proliferation. The
progeny of these oval cells may give rise to cuboidal cells
of the bile duct system as well as to hepatocytes.
The cuboidal epithelial cells of the cholangioles,
canals of Hering, and interlobular bile ducts secrete a
bicarbonate-rich fluid similar to that produced by the
duct system of the pancreas. The formation and release
of this alkaline buffer are controlled by the hormone
secretin, produced by diffuse neuroendocrine system
(DNES) cells of the duodenum. This fluid acts, with
fluid from the pancreas, to neutralize the acidic chyme
that enters the duodenum.

14. Hepatocytes
Hepatocytes are 5- to 12-sided
polygonal cells, approximately 20 to 30
μm in diameter, that are closely packed
together to form anastomosing plates
of liver cells, one cell in thickness.
These cells exhibit variations in their
structural, histochemical, and
biochemical properties, depending on
their location within liver lobules

15. Domains of Hepatocyte Plasmalemma
The plasma membranes of hepatocytes are said to have
two domains: lateral and sinusoidal.
• The lateral domains
are responsible for the
formation of bile
canaliculi.
LATERAL
DOMAINS
• The sinusoidal
domains form
microvilli that
protrude into the
perisinusoidal space of
Disse.
SINUSOIDAL
DOMAINS

17. Hepatocyte Organelles and Inclusions
Hepatocytes constitute only 60% of the total
cell number, they compose about 75% of the weight of
the liver. These cells manufacture primary bile, which
is modified by the epithelial cells lining the bile ducts
and gallbladder and becomes bile. Approximately 75%
of the hepatocytes have a single nucleus, and the
remainder have two nuclei. The nuclei vary in size, the
smallest ones (50% of the nuclei) being diploid and
the larger ones being polyploid, with the largest nuclei
reaching 64 N.
Hepatocytes actively synthesize proteins for their
own use as well as for export. Thus, they have an
abundance of free ribosomes, RER, and Golgi apparatus
. Each cell houses several sets of Golgi apparatuses,
located preferentially in the vicinity of bile canaliculi. .
Liver cells also have a rich complement of endosomes,
lysosomes, and peroxisomes. The complement of
smooth endoplasmic reticulum (SER) of hepatocytes
varies not only by region but also by function. Cells in
zone 3 of the liver acinus have a much richer endowment
of SER than those in the periportal area. Moreover, the
presence of certain drugs and toxins in the blood
induces an increase in the SER
content of liver cells because detoxification occurs
within the cisternae of this organelle.

18. Histophysiology of the Liver
The liver has both exocrine and endocrine roles as well
as the protective function of detoxification of toxins and
elimination of defunct erythrocytes.
Bile Manufacture
Bile, a fluid manufactured by the liver, is composed of
water, bile salts, phospholipids, cholesterol, bile
pigments, and IgA
Bile salts constitute almost half of the organic components
of bile. Most of the bile salts are resorbed from
the lumen of the small intestine, enter the liver via the
portal vein, are endocytosed by hepatocytes, and are
transported into the bile canaliculi for subsequent rerelease
back into the duodenum (enterohepatic recirculation
of bile salts). The remaining 10% of bile salts
are manufactured de novo in the SER of hepatocytes
by the conjugation of cholic acid, a metabolic byproduct
of cholesterol, to either taurine (tauricholic
acid) or glycine (glycocholic acid).
Bilirubin, a water-insoluble, yellowish green
pigment, is the toxic degradation product of hemoglobin.
As defunct erythrocytes are destroyed by
macrophages in the spleen and by Kupffer cells in the
liver, bilirubin is released into the bloodstream and is
bound to plasma albumin. In this form, known as
free bilirubin, it is endocytosed by hepatocytes. The
enzyme glucuronyltransferase, located in the SER of
the hepatocyte, catalyzes the conjugation of bilirubin
with glucuronide to form the water-soluble bilirubin
glucuronide (conjugated bilirubin).

19. Lipid Metabolism
Chylomicrons released by surface-absorbing cells of the
small intestine enter the lymphatic system and reach the
liver through branches of the hepatic artery. Within
hepatocytes they are degraded into fatty acids and glycerol.
The fatty acids are subsequently desaturated and
are used to synthesize phospholipids and cholesterol or
are degraded into acetyl coenzyme A. Two molecules of
acetyl coenzyme A are combined to form acetoacetic
acid. Much of the acetoacetic acid is converted into β-
hydroxybutyric acid and some into acetone. These three
compounds—acidoacetic acid, β-hydroxybutyric acid,
and acetone—are known as ketone bodies. Phospholipids,
cholesterol, and ketone bodies are stored in
hepatocytes until their release into the space of Disse.
In addition, the liver manufactures VLDLs, which are
also released into the space of Disse as droplets 30 to
100 nm in diameter.
Carbohydrate and Protein Metabolism
Additional responsibilities of the liver include the
maintenance of normal blood glucose levels,
deamination of amino acids, and the synthesis of many
blood proteins.
Approximately 90% of the blood proteins are manufactured
by the liver . These proteins
and related products include:
 Factors necessary for coagulation (such as fibrinogen,
factor III, accelerator globulin, and prothrombin)
 Proteins required for the complement reactions
 Proteins that function in transport of metabolites
 Albumins
 All of the globulins except gamma (γ) globulins
 All of the nonessential amino acids that the body
requires

22. Vitamin Storage
Vitamin A is stored in the greatest amount in the liver,
but vitamins D and B12 are also present in substantial
quantities. The liver contains enough vitamin stores to
prevent deficiency of vitamin A for about 10 months,
vitamin D for about 4 months, and vitamin B12 for more
than 12 months.
Degradation of Hormones and
Detoxification of Drugs and Toxins
The liver endocytoses and degrades hormones of the
endocrine glands. The endocytosed hormones are transported
into the bile canaliculi in their native form to be
digested in the lumen of the alimentary canal or are
delivered into late endosomes for degradation by lysosomal
enzymes. Drugs, such as barbiturates and antibiotics, and
toxins are inactivated by microsomal mixed-function
oxidases in hepatocytes. These drugs and toxins are
usually inactivated in the cisterna of the SER by methylation,
conjugation, or oxidation. Occasionally, detoxification
occurs in peroxisomes rather than in the SER.
Immune Function
Hepatocytes complex IgA with secretory component and
release the secretory IgA into the bile canaliculi.
Kupffer cells, which are derived from monocyte
precursors, are long-lived cells that are located within the hepatic
sinusoids and adhere to the luminal surface
of endothelial cells. Kupffer cells have Fc receptors as
well as receptors for complement and thus can phagocytose
foreign particulate matter. The importance of
these cells is appreciable because blood from the portal
vein contains a considerable number of microorganisms
that enter the bloodstream from the lumen of the alimentary
canal. These bacteria become opsonized in the
lumen or mucosa of the gut or in the bloodstream.
Kupffer cells recognize and endocytose at least 99% of
these microorganisms. Kupffer cells also remove cellular
debris and defunct erythrocytes from the blood.