Page 470 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

458 FLUID THERAPY

There is a direct linear relationship between canalicular into glutamate or aspartate in the liver. Ammonia subse-
bile acid concentrations and bile flow. Non–micelle- quently is detoxified by conversion to urea (Figure 19-2).
forming bile acids (e.g., dehydrocholate) have the greatest Two mechanisms exist for hepatic nitrogen detoxifica-
effect. Hepatocellular uptake of bile acids is an energy- tion. The hepatic urea cycle is best known and involves
dependentprocesslinkedtosodiumtransport.Thisprocess a linked series of enzymatic reactions carried out in the
accounts for approximately 80% of taurocholate uptake but mitochondria and cytosol of the hepatocyte (see
only 50% of unconjugated cholate uptake. 142 Protein Figure 19-2). The second mechanism, the glutamine
carriers facilitate cytosolic transport of bile acids to canalic- cycle, involves transport of glutamine into mitochondria,
ular membranes. Efflux of bile acids into canaliculi involves where it is converted to ammonia and used as a precursor
several mechanisms including facilitated diffusion depen- of carbamoyl phosphate (see Figure 19-2). The urea cycle
dent on canalicular carrier proteins, an adenosine triphos- is a low affinity system, most important during alkalosis,
phate (ATP)-dependent mechanism, and exocytosis of whereas the glutamine cycle is a high affinity system, most
cytosolicvesicles.Collectively,transcellular transportofbile important during acidosis. Collectively, these systems
acids and micelle formation maintain a marked concentra- efficiently cleanse portal blood of ammonia. Approxi-
tion gradient between bile and blood, permitting biliary mately 25% of the ammonia for urea synthesis is derived
concentrations to exceed plasma bile acid concentrations directly from portal blood, and the remainder is derived
by 100- to 1000-fold. from catabolism of proteins, peptides, and amino acids.
Bile acid-independent bile flow is mediated byasodium Urea synthesis depends on substrate supply, hormonal
þ
þ
transport Na ,K -ATPase-linked mechanism, bicarbon- regulation, nutritional status, and liver cell volume. Reg-
ate transport (associated with carbonic anhydrase and a ulation of urea cycle enzymes corresponds to the level of
canalicular membrane pump), and transport of organic dietary nitrogen intake and possibly liver cell volume. The
solutes (e.g., glutathione [GSH]). As the most abundant urea cycle may play an important role in acid-base homeo-
organic molecule in canalicular bile (approximating 8 to stasis, as explained by the following reaction (using the
55
10 mM/L),GSHimposesthegreatestosmoticeffecteven amino acid alanine as an example of a nitrogen source) :
exceeding that of free bile salts. Approximately 50% of
hepatic GSH, most GSSG (oxidized GSH), and all ðalanineÞCH 3 CHðCO 2 ÞNH 3 þ 3O 2 ! 2CO 2 þ
GSH-conjugates are exported into the canaliculus. Mem- þ
HCO 3 þ NH 4 þ H 2 O
brane pumps (canalicular multispecific organic anion
transporter [cMOAT], also termed the multidrug resis-
Generation of one positive (NH 4 ) and one negative
þ
tance associated protein-2 [MRP2]) facilitate GSH expor-

(HCO 3 ) charge has the potential to maintain
tation. The strong osmotic influence of GSH on bile flow
electroneutrality. However, because physiologic pH is
derives from its hydrophilic nature, active membrane
in the range of 7.0 to 7.4, only 1% of ammonia exists as
exportation, and hydrolysis by membrane affiliated
ammonia. Therefore the protons represented by the
w-glutamyltransferase (wGT) into its three constituent
ammonium ions cannot be readily transferred to
amino acids (cysteine, glutamate, glycine), yielding three
HCO 3 , and thus catabolism of large amounts of amino

osmolar equivalents. The osmotic effect of catabolized
acids or protein can generate high bicarbonate
GSH draws water and electrolyte solutes through
concentrations resulting in metabolic alkalosis. Normally,
paracellular pathways or other hepatocellular conduits.
detoxification of ammonia to electroneutral urea prevents
Bile ducts contribute to bile formation and modification 55
changes in systemic pH :
as well as to bile flow. Production of ductular fluid primarily

þ
isunder theinfluenceofsecretin,whichregulatesspontane- 2NH 4 þHCO 3 !NH 2 CONH 2 ðureaÞþ2H 2 OþH þ
ous or basal bile flow. Gastrin (but not pentagastrin) also þ
HCO 3 þH !H 2 OþCO 2
increases bile duct secretion in dogs, whereas somatostatin

þ
decreases ductular bile flow. Increased ductular bile flow Net:2NH 4 þ2HCO 3 !NH 2 CONH 2 ðureaÞ
results in bile alkalinization and dilution. Disease states þCO 2 þ3H 2 O
causing bile ductule proliferation also increase bile flow
(e.g., cirrhosis, extrahepatic bile duct occlusion, inflamma- The preceding model probably is an oversimplification.
tory disorders). Bile ductules and ducts can also reabsorb Consumption of a diet composed of a complex mixture
bile as shown in cholecystectomized dogs. 74 of amino acids (anionic, cationic, and sulfate-containing
HEPATIC NITROGEN METABOLISM: amino acids) results in a net gain of protons that must
DETOXIFICATION, EXCRETION, AND be excreted or neutralized. Urinary excretion occurs via
ROLE IN ACID-BASE BALANCE dihydrogen phosphate (titratable acidity) and renal tubu-
lar production of ammonium from glutamine. Tradi-
Urea Cycle and Glutamine Cycle tional concepts of renal tubular acid titration consider
The liver converts waste nitrogen to an excretable form. 55 ammonium ion formation an important mechanism of
Nitrogen derived from amino acids can be converted acid-base regulation. However, ammonium ions excreted
to ammonia directly or indirectly after incorporation in urine are incapable of titrating acid because they are