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

III. Clinical Manifestations of Hepatic Insufficiency
381
concentration, and contribute to meeting systemic energy
requirements. The Glut-1 transporter is present only in the
plasma membranes of Zone 3 ( Tal et al., 1990 ). The affinity
of Glut-1 for glucose is much higher (Km 1–2 mM)
than that of Glut-2. The Glut-1 gene is transcribed and
translated by all hepatocytes of the acinus; however, by
means of a post-translational control mechanism, Glut-1
is inserted into the plasma membrane of only pericentral
hepatocytes ( Bilir et al., 1993 ).
The liver plays a critical role in the removal of ammonia
from the blood. Two separate reactions within the liver acinus
are involved. The concentration of ammonia in the Zone
1 sinusoids is high compared to that of the Zone 3 sinusoids.
Most of the ammonia that enters the liver diffuses into the
hepatocytes of Zones 1 and 2, and a relatively small amount
of ammonia reaches the hepatocytes of Zone 3. Hepatocytes
of Zones 1 and 2 contain carbamoyl phosphate synthase and
other enzymes of the urea cycle that are responsible for conversion
of ammonia to urea. The activity of glutamine synthase
is confined to the hepatocytes located adjacent to the
terminal hepatic vein, and in these perivenous hepatocytes,
glutamate synthase is responsible for the use of ammonia
in the catalytic amination of glutamate forming glutamine.
The Km of carbamoyl phosphate synthase for ammonia is
approximately 1.2 mM, whereas that of glutamine synthase
for ammonia is 0.3 mM ( Gumucio and Berkowitz, 1992;
Gumucio et al., 1994 ). Synthesis of urea from ammonia in
periportal hepatocytes and of glutamine from ammonia in
pericentral hepatocytes represents complementary enzymatic
processes. Ammonia is first seen by hepatocytes that synthesize
urea utilizing a low-affinity, high-capacity system. At the
end of passage through the hepatic sinusoid, the small amount
of ammonia remaining is removed for glutamine synthesis
using a relatively high-affinity, low-capacity mechanism.
Zone 1 and 2 hepatocytes are responsible primarily for
the bile salt-dependent fraction of bile formation and appear
to be the primary site of bile salt synthesis. The enzymes
necessary for fatty acid synthesis, CoA carboxylase and
fatty acid synthase, are located primarily in Zone 3 hepatocytes.
Drug-metabolizing enzymes of the cytochrome P-450
family are located predominantly in Zone 2 and 3 hepatocytes,
explaining hepatocellular damage and fatty metamorphosis
preferentially in Zone 3 hepatocytes ( Jungermann
and Katz, 1989 ) after exposure to toxins such as carbon
tetrachloride.
III . CLINICAL MANIFESTATIONS OF
HEPATIC INSUFFICIENCY
A . Icterus
1 . Formation of Bile Pigments
Bilirubin is a yellow pigment produced by the enzymatic
degradation of heme. Approximately 80% of the bilirubin
produced normally by mammals is derived from the
removal of senescent erythrocytes from the circulation
by the reticuloendothelial systems (Landau and Winchell,
1970; Robinson et al., 1966 ). Degradation of heme from
other sources (myoglobin, cytochromes, peroxidase, catalase,
guanylate cyclase) accounts for production of the
remaining bilirubin. Significant amounts of microsomal
cytochromes (P-450, b 5 ) are present in the liver and are the
most important non-erythroid source of bilirubin.
The initial step in bilirubin formation is the opening of
the heme (ferriprotoporphyrin) ring at the α-methene bridge
( Fig. 13-1 ). This reaction is catalyzed by microsomal heme
oxygenase ( Tenhunen et al., 1968, 1969, 1970a, 1970b ).
Cytochrome P450 serves as the terminal oxidase and
requires reduced nicotinamide adenine dinucleotide phosphate
(NADPH) and molecular oxygen. The products of
heme degradation are equimolar amounts of iron, biliverdin,
and carbon monoxide ( Sassa, 2004 ; Tenhunen et al.,
1968, 1969 ). It has been estimated that more than 86% of
HEME
BILIVERDIN
BILIRUBIN
HO
HO
N
P
V
Microsomal
Heme Oxygenase
M
M
Fe
CO
V
N
N
M P P M M V
C C C
N H N H N H N
H
N
P
M
V
HC
HC
Biliverdin
Reductase
C
H
NADP
M P P M M V
N
H
Fe
C
H 2
M
M
N
P450 . 0
P450 P450
Fp
N
H
CH
CH
Fp
NADPH
C
H
M
V
H 2 O
O 2
N
NADPH
NADP
OH
OH
FIGURE 13-1 Enzymatic degradation of heme (ferriprotoporphyrin)
and formation of bilirubin.