CHAPTER 29
Transport & Metabolic Functions of the Liver 485ammonia in the circulation is cleared into the hepatocytes.
There, it is converted in the mitochondria to carbamoyl phos-
phate, which in turn reacts with ornithine to generate citrul-
line. A series of subsequent cytoplasmic reactions eventually
produce arginine, and this can be dehydrated to urea and
ornithine. The latter returns to the mitochondria to begin
another cycle, and urea, as a small molecule, diffuses readily
back out into the sinusoidal blood. It is then filtered in the
kidneys and lost from the body in the urine.
THE BILIARY SYSTEM
BILE FORMATION
Bile contains substances that are actively secreted into it across
the canalicular membrane, such as bile acids, phosphatidyl-
choline, conjugated bilirubin, cholesterol, and xenobiotics.
Each of these enters the bile by means of a specific canalicular
transporter. It is the active secretion of bile acids, however,
that is believed to be the primary driving force for the initial
formation of canalicular bile. Because they are osmotically ac-
tive, the canalicular bile is transiently hypertonic. However,
the tight junctions that join adjacent hepatocytes are relatively
permeable and thus a number of additional substances pas-
sively enter the bile from the plasma by diffusion. These sub-
stances include water, glucose, calcium, glutathione, amino
acids, and urea.
Phosphatidylcholine that enters the bile forms mixed
micelles with the bile acids and cholesterol. The ratio of bile
acids:phosphatidylcholine:cholesterol in canalicular bile is
approximately 10:3:1. Deviations from this ratio may cause
cholesterol to precipitate, leading to one type of gallstones
(Figure 29–8).
The bile is then transferred to progressively larger bile
ductules and ducts, where it undergoes modification of its
composition. The bile ductules are lined by cholangiocytes,
specialized columnar epithelial cells. Their tight junctions are
less permeable than those of the hepatocytes, although they
remain freely permeable to water and thus bile remains iso-
tonic. The ductules scavenge plasma constituents, such as glu-
cose and amino acids, and return them to the circulation by
active transport. Glutathione is also hydrolyzed to its constit-
uent amino acids by an enzyme, gamma glutamyltranspepti-
dase (GGT), expressed on the apical membrane of the
cholangiocytes. Removal of glucose and amino acids is likely
important to prevent bacterial overgrowth of the bile, particu-
larly during gallbladder storage (see below). The ductules also
secrete bicarbonate in response to secretin in the postprandial
period, as well as IgA and mucus for protection.FUNCTIONS OF THE GALLBLADDER
In normal individuals, bile flows into the gallbladder when the
sphincter of Oddi is closed (ie, the period in between meals).
In the gallbladder, the bile is concentrated by absorption of
water. The degree of this concentration is shown by the in-
crease in the concentration of solids (Table 29–2); liver bile is
97% water, whereas the average water content of gallbladder
bile is 89%. However, because the bile acids are a micellarFIGURE 29–7
Whole body ammonia homeostasis in health.
The majority of ammonia produced by the body is excreted by the
kidneys in the form of urea.
Portal
circulatio
nSyst
emic
cir
cula
tionUrea NH 3NH 4 +H+Proteins
+
Amino
acidsUrinary
excretion
as urea Fecal excretion
as ammonium ionUreaNH 325%
75%15%
85%Systemic
circulationFIGURE 29–8
Cholesterol solubility in bile as a function of
the proportions of lecithin, bile salts, and cholesterol.
In bile that
has a composition described by any point below line ABC (eg, point P),
cholesterol is solely in micellar solution; points above line ABC de-
scribe bile in which there are cholesterol crystals as well.
(Reproduced
with permission from Small DM: Gallstones. N Engl J Med 1968;279:588.)Percent lecithinPercent cholesterol10080020406080100
100 80 60 40 20 0
0204060Micellar
liquidTwo or more phases
(cholesterol crystals and
micellar liquid)
B
A CPercent bile saltP