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

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Chapter | 13 Hepatic Function
cholestatic liver injury and in susceptibility to development
of hepatocellular carcinoma ( Mauad et al., 1994 ). Finally,
Mdr1 that is present in the canaliculus is responsible for
transport of organic cations ( Trauner and Boyer, 2003 ).
In cholestasis, bile acids may accumulate in hepatocytes
and their toxicity may cause cell death ( Webster et al.,
2002; Webster and Anwer, 1998, 2001 ). In cholestatic syndromes,
expression of the multidrug resistance-associated
protein 3 (Mrp3), another ABC transporter located in the
sinusoidal plasma membrane, is increased. Mrp3 has broad
affinity for organic anions, has the capacity to excrete both
mono- and divalent bile acids ( Hirohashi et al., 2000 ; Ito
et al., 2001 ), and is believed to compensate for impaired
function of BSEP or Mrp2 in cholestatic syndromes
( Bohan et al., 2003 ; Chen et al., 2007 ).
In liver disease, synthesis of primary bile acids may be
decreased, the proportions of cholic acid and chenodeoxycholic
acid may be altered, or unusual bile acids may be
produced. Removal of bile acids from the hepatic portal
vein may be diminished by impaired hepatocellular function
or by vascular shunts, which divert portal blood from
the liver vasculature to the peripheral circulation. This is
particularly noticeable after meals in animals with congenital
or acquired hepatoportal shunts. The plasma bile acid
concentration is increased continuously in biliary obstruction
and, characteristically, urinary excretion of bile acids
is increased. Increases in the serum bile acid concentration
are seen in many forms of hepatic disease.
The measurement of total serum bile acids for assessment
of liver disease has been greatly facilitated by development
of a spectrophotometric assay that has now been
validated for use in most domestic species. The predictive
value of the serum bile acid test is remarkably high in the
dog ( Center, 1993 ; Center et al., 1984, 1991a ). In dogs with
portocaval vascular shunts, the fasting serum bile acid concentration
may be within normal limits but is increased diagnostically
2 h following a meal (Center et al., 1985a ). Serum
bile acid concentrations 20 μM/L in cats and 25 μm/L
in dogs are predictive of significant histopathological abnormalities
of the hepatobiliary system or of portosystemic vascular
anastomoses ( Center et al., 1991a, 1995 ).
The serum bile acid concentration has been used to
assess clinical hepatic function in cattle ( Craig et al., 1992 ;
Garry et al., 1994 ; Pearson et al., 1992 ; West, 1991 ) and
in horses ( Barton and LeRoy, 2007 ; Durham et al., 2003 ;
McGorum et al., 1999 ). In the horse, fasting alone has
been reported to increase the plasma bile acid concentration
by decreasing hepatic clearance ( Engelking and
Gronwall, 1979 ), so in the horse it is necessary to consider
food intake when interpreting the serum bile acid values.
D . Serum Proteins
The liver is the exclusive site of synthesis of albumin, the
most abundant of the plasma proteins. Unlike most plasma
proteins, which are glycoproteins, albumin contains no
carbohydrate. Degradation of albumin occurs in the liver
and in other tissues including muscle, kidney, and skin.
Degradation of albumin is probably favored in the liver
because of the fenestrated endothelial lining cells that
allow access of plasma proteins directly to the space of
Disse and to the sinusoidal surface of the hepatocyte. In the
general circulation, albumin has two major functions. It is
the most important determinant of plasma oncotic pressure
(colloid osmotic pressure) and is a major transport protein
for hydrophobic or amphophilic metabolites and xenobiotics
that, because of albumin binding, remain in stable aqueous
solution in the plasma.
The plasma albumin concentration is determined by
the hepatic synthetic rate that normally is in equilibrium
with degradation. Hypoalbuminemia may be caused by
defective albumin synthesis associated with severe hepatocellular
disease or may be caused by increased albumin
loss resulting from either glomerulopathy (protein-losing
nephropathy), severe intestinal inflammation, or intestinal
lymphangiectasia (protein-losing enteropathy). In severe,
chronic hepatopathy, there is a tendency for elevations in
IgM, IgG, and IgA. Both decreased albumin and increased
globulin result in a decrease in the albumin/globulin (A/G)
ratio.
The liver is the exclusive site of synthesis of coagulation
factors I (fibrinogen), II (prothrombin), V, VII, IX, X,
XI, and of protein C, protein S, and antithrombin. Factor
VIII is synthesized both in the liver and in multiple other
organs including the kidney and spleen ( Hollestelle et al.,
2001 ; Wion et al., 1985 ). Synthesis of coagulation proteins
tends to be diminished in liver disease, and decreased
plasma prothrombin synthesis is associated with a corresponding
increase in the prothrombin time. Factors that
contribute to increased prothrombin time include diminished
hepatic protein synthesis, increased consumption of
clotting factors associated with hemorrhage or hypercoagulation
states, and, in some cases, vitamin K deficiency
related to decreased intake or diminished absorption.
Vitamin K is essential not only for the hepatic synthesis
of prothrombin but also for factors VII, IX, X, and protein
C. Parenteral administration of vitamin K to individual
animal patients may result in improvement in prothrombin
time, but coagulation time may remain prolonged.
Individuals with obstructive jaundice absorb vitamin K
poorly, and defects in their clotting tests can be improved
rapidly by parenteral vitamin K administration. Fibrinogen
is an acute phase reactant, and its concentration in plasma
may be greatly increased in chronic inflammatory diseases
or in neoplasia. Plasma fibrinogen is generally normal in
mild or moderate liver disease, but it may be detectably
decreased in more severe acute or chronic liver disease.
Because of the rapid turnover of fibrinogen and prothrombin,
the concentrations of these proteins in the plasma may
decrease rapidly in fulminant hepatic injury. The turnover
rate of albumin is longer and the concentration of albumin