Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 13 Hepatic Function
Lymphatic vessels also are present in the portal tracts, but
because of their small size and thin walls they are difficult
to recognize morphologically. Although the classical lobular
architecture of the liver remains in use for the morphological
description of pathological lesions of the liver, most
analyses indicate that the functional unit of the liver is the
hepatic acinus in which blood flows from terminal hepatic
artery and terminal portal vein of the portal tracts toward
two, three, or more terminal collecting veins (central veins).
Significant structural and functional heterogeneity has been
demonstrated between hepatocytes of the periphery of the
hepatic acinus (zone 1), the midzonal hepatocytes (zone 2),
and perivenous hepatocytes (zone 3) ( Jungermann and
Katz, 1989 ). The functional significance of some of these
differences will be discussed in this chapter.
Hepatocytes are the principal cell type of the liver and
make up approximately 70% of the total volume. Kupffer
cells are the macrophages of the liver located in the sinusoids
with pseudopodia that are attached to endothelial
cells and hepatocytes. The Kupffer cells and other perisinusoidal
cells are responsible for local inflammatory and
other immune responses. The stellate cells or Ito cells are
found in the space of Disse where they are identified are
the vitamin A-containing vacuoles in the cytoplasm. When
activated by Kupffer cells, the stellate cells transform into
myofibroblasts and are responsible for the production of
collagen in liver diseases that are associated with fibrosis
or cirrhosis.
The hepatocytes are arranged in single-cell plates separated
by sinusoids lined by vascular endothelial cells.
Blood from the terminal branches of the hepatic artery and
the hepatic portal vein enters and mixes in the periphery
of the liver acinus and percolates through the sinusoids to
the terminal hepatic vein. The vascular endothelium lining
the hepatic sinusoids differs from that of other capillaries
in two ways. Under normal conditions, hepatocytes do not
rest on a basement membrane but are separated from endothelial
cells by the perisinusoidal space of Disse. Second,
dynamic fenestrations of the sinusoidal endothelium are
responsible for formation of hepatic lymph that has a protein
content much higher than that of the lymph formed
in other tissues, which is an ultrafiltrate of plasma with a
characteristically low protein content.
Blood exits the liver through branches of the hepatic
vein and obstruction of hepatic vein outflow increases the
formation of hepatic lymph that is rich in protein. This may
occur in congestive heart failure, in mechanical obstruction
of hepatic vein outflow (Budd-Chisari syndrome), and in
the early stages of hepatic fibrosis. In advanced hepatic
cirrhosis, dense intracellular matrix forms in the space of
Disse. “ Capillarization ” of the sinusoids develops reducing
the fenestrations of the sinusoidal endothelium, and in
formation of hepatic lymph that is typically low in protein,
closely resembling the lymph produced by other normal
tissues (see Section III.D) .
Bile is secreted via the microvillous membrane of bile
canaliculus located in the apical cell membrane of the
hepatocyte and flows in the direction of the portal tracts in
channels formed by the canaliculi of 2, 3, or more adjacent
hepatocytes. These channels converge near the portal
tracts forming the canals of Herring through which bile
drains into the bile ductules of the portal tracts and finally
into the ducts of the biliary tree. Hepatic lymph formed in
the space of Disse flows in a similar direction and exits
the liver via lymphatics vessels located in the portal tracts.
Hepatic lymph leaves the liver primarily via the hilar lymphatic,
hilar lymph nodes, and the thoracic duct. Hepatic
lymph also leaves the liver by lymph vessels associated
with the hepatic vein.
Cells of the periportal Zone 1 of the acinus are more
likely to divide than other hepatocytes ( Grisham, 1959 ).
Mitochondria are larger and more numerous in Zone 1
hepatocytes than are those of Zone 3 ( Loud, 1968 ; Uchiyama
and Asari, 1984 ). Fenestrae of Zone 1 sinusoidal endothelial
cells are larger than those of the Zone 3 region, and this may
account for selective uptake of large, more complex molecules
such as remnants of chylomicrons by Zone 1 hepatocytes
( Wisse et al., 1985 ).
A significant oxygen gradient has been demonstrated
between sinusoids of Zones 1 and 3. The concentrations
of glucose and amino acids that arrive primarily from the
hepatic portal vein are higher in zone 1 sinusoids during
digestion. Such metabolic differences are associated with
important functional differences between Zones 1 and 3.
The enzymes of glycolysis, gluconeogenesis, and glycogen
metabolism have different activities within zones. Glucose-
6-phosphatase, phosphoenolpyruvate carboxykinase, and
fructose-1,6-diphosphatase activities are higher in periportal
hepatocytes, whereas glucokinase and pyruvate kinase activities
are higher in pericentral hepatocytes ( Zakim, 1996 ).
Glycogen appears to be uniformly distributed within the
cells of the acinus during steady-state conditions, but during
fasting, glycogen of periportal hepatocytes is utilized
more rapidly and, during feeding, is replaced more rapidly.
Two plasma membrane transporters for glucose are
expressed in the liver. Glut-2 is the primary glucose transporter
of the liver and is expressed in plasma membranes
of all hepatocytes. The Km of Glut-2 for glucose is 15 to
20 mM, a concentration of glucose that can be reached
or exceeded in the hepatic portal vein during and immediately
after feeding. Under these conditions, glucose is
transported into hepatocytes for the synthesis of glycogen,
amino acids, and triglycerides. Between meals, the glucose
concentration in the portal vein is approximately 5mM and
is similar to that in the peripheral circulation. During the
interdigestive period, the concentration of glucose in hepatocytes
is high relative to that of sinusoidal blood. Glut-2
also facilitates transport of glucose from the cytoplasm of
hepatocytes into the sinusoid. Glucose reaching the systemic
circulation, maintains the peripheral blood glucose