by Talib F. Abbas
 Bile is made up of the bile acids, bile pigments, and
other substances dissolved in an alkaline electrolyte
solution that resembles pancreatic juice. About 500
mL is secreted per day. Some of the components of the
bile are reabsorbed reabsorbed in the intestine and
then excreted again by the liver (enterohepatic
circulation). The glucuronides of the bile pigments,
bilirubin and biliverdin, are responsible for the golden
yellow color of bile.
 The bile acids secreted into the bile are conjugated to
glycine or taurine, a derivative of cysteine. The bile acids
are synthesized from cholesterol. The four major bile acids
found in humans are list above. In common with vitamin
D, cholesterol, a variety of steroid hormones, and the
digitalis glycosides, the bile acids contain the steroid
nucleus . The two principal (primary) bile acids formed in
the liver are cholic acid and chenodeoxycholic acid. In the
colon, bacteria convert cholic acid to deoxycholic acid and
chenodeoxycholic acid to lithocholic acid. In addition,
small quantities of ursodeoxycholic acid are formed from
chenodeoxycholic acid. Ursodeoxycholic acid is a tautomer
of chenodeoxycholic acid at the 7-position. Because they
are formed by bacterial action, deoxycholic, lithocholic,
and ursodeoxycholic acids are called secondary bile acids.
 The bile salts have a number of important actions:
they reduce surface tension and, in conjunction
with phospholipids and monoglycerides, are
responsible for the emulsification of fat
preparatory to its digestion and absorption in the
small intestine. They are amphipathic, that is,
they have both hydrophilic and hydrophobic
domains; one surface of the molecule is
hydrophilic because the polar peptide bond and
the carboxyl and hydroxyl groups are on that
surface, whereas the other surface is hydrophobic.
Therefore, the bile salts tend to form cylindrical
disks called micelles.
 . Their hydrophilic portions face out and their
hydrophobic portions face in. Above a certain
concentration, called the critical micelle
concentration,
 all bile salts added to a solution form micelles. Lipids
collect in the micelles, with cholesterol in the
hydrophobic center and amphipathic phospholipids
and monoglycerides lined up with their hydrophilic
heads on the outside and their hydrophobic tails in the
center. The micelles play an important role in keeping
lipids in solution and transporting them to the brush
border of the intestinal epithelial cells, where they are
absorbed.
 Ninety to 95% of the bile salts are absorbed from the
small intestine. Once they are deconjugated, they can
be absorbed by nonionic diffusion, but most are
absorbed in their conjugated forms from the terminal
ileum by an extremely efficient Na+–bile salt
cotransport system powered by basolateral Na+–K+
ATPase. The remaining 5–10% of the bile salts enter
the colon and are converted to the salts of deoxycholic
acid and lithocholic acid. Lithocholate is relatively
insoluble and is mostly excreted in the stools; only 1%
is absorbed. However, deoxycholate is absorbed began
from sphincter of Oddi.

 The absorbed bile salts are transported back to the liver in
the portal vein and reexcreted in the bile (enterohepatic
circulation) Those lost in the stool are replaced by
synthesis in the liver; the normal rate of bile salt synthesis
is 0.2 to 0.4 g/d. The total bile salt pool of approximately
3.5 g recycles repeatedly via the enterohepatic circulation;
it has been calculated that the entire pool recycles twice
per meal and six to eight times per day. When bile is
excluded from the intestine, up to 50% of ingested fat
appears in the feces. A severe malabsorption of fat-soluble
vitamins also results. When bile salt reabsorption is
prevented by resection of the terminal ileum or by disease
in this portion of the small intestine, the amount of fat in
the stools is also increased because when the enterohepatic
circulation is interrupted, the liver cannot increase the rate
of bile salt production to a sufficient degree to compensate
for the loss.

 The various functions of the gastrointestinal tract,
including secretion, digestion, and absorption and
motility must be regulated in an integrated way to
ensure efficient assimilation of nutrients after a meal.
There are three main modalities for gastrointestinal
regulation that operate in a complementary fashion to
ensure that function is appropriate.
 1- Endocrine
 2-Paracrine
 3-extrinsic innervation (enteric nervous system)
( Lancaster ) secreto-motor neurons
 First, endocrine regulation is mediated by the release of
hormones by triggers associated with the meal. These
hormones travel through the bloodstream to change the
activity of a distant segment of the gastrointestinal tract,
an organ draining into it (eg, the pancreas), or both.
 Second, some similar mediators are not sufficiently stable
to persist in the bloodstream, but instead alter the function
of cells in the local area where they are released, in a
paracrine fashion.
 Finally, the intestinal system is endowed with extensive
neural connections. These include connections to the
central nervous system (extrinsic innervation), but also
the activity of a largely autonomous enteric nervous
system that comprises both sensory and secreto-motor
neurons.
 The enteric nervous system integrates central input to the
gut, but can also regulate gut function independently in
response to changes in the luminal environment. In some
cases, the same substance can mediate regulation by
endocrine, paracrine, and neurocrine pathways (eg,
cholecystokinin,).
 Peristalsis is a reflex response that is initiated when
the gut wall is stretched by the contents of the lumen,
and it occurs in all parts of the gastrointestinal tract
from the esophagus to the rectum. The stretch initiates
a circular contraction (felka)behind the stimulus and
an area of relaxation in front of it. The wave of
contraction then moves in an oral-to-caudal direction,
propelling the contents of the lumen forward at rates
that vary from 2 to 25 cm/s. Peristaltic activity can be
increased or decreased by the autonomic input to the
gut, but its occurrence is independent of the extrinsic
innervation. Indeed, progression of the contents is not
blocked by removal and resuture of a segment of
intestine in its original position and is blocked only if
the segment is reversed before it is sewn back into
place.
 Peristalsis is an excellent example of the integrated
activity of the enteric nervous system. It appears that
local stretch releases serotonin, which activates
sensory neurons that activate the myenteric plexus.
Cholinergic neurons passing in a retrograde direction
in this plexus activate neurons that release substance P
and acetylcholine, causing smooth muscle
contraction. At the same time, cholinergic neurons
passing in an anterograde the setting of segmentation.
This mixing pattern persists for as long as nutrients
remain in the lumen to be absorbed. It presumably
reflects programmed activity of the bowel dictated by
the enteric nervous system, and can occur
independent of central input, although the latter can
modulate it.
 The portion of the pancreas that secretes pancreatic
juice is a compound alveolar gland resembling the
salivary glands. Granules containing the digestive
enzymes (zymogen granules) are formed in the cell
and discharged by exocytosis. from the apexes of the
cells into the lumens of the pancreatic ducts. The
small duct radicles coalesce into a single duct
(pancreatic duct of Wirsung), which usually joins the
common bile duct to form the ampulla of Vater. The
ampulla opens through the duodenal papilla, and its
orifice is encircled by the sphincter of Oddi. Some
individuals have an accessory pancreatic duct (duct of
Santorini) that enters the duodenum more proximally.
 The pancreatic juice is alkaline and has a high HCO3–
content (approximately 113 mEq/L vs. 24 mEq/L in
plasma). About 1500 mL of pancreatic juice is secreted
per day. Bile and intestinal juices are also neutral or
alkaline, and these three secretions neutralize the
gastric acid, raising the pH of the duodenal contents to
6.0 to 7.0. By the time the chyme reaches the jejunum,
its pH is nearly neutral, but the intestinal contents are
rarely alkaline. The potential danger of the release into
the pancreas of a small amount of trypsin is apparent;
the resulting chain reaction would produce active
enzymes that could digest the pancreas. It is therefore
not surprising that the pancreas normally contains a
trypsin inhibitor.
 Another enzyme activated by trypsin is phospholipase
A2. This enzyme splits a fatty acid off
phosphatidylcholine (PC), forming lyso-PC. Lyso-PC
damages cell membranes. It has been hypothesized that
in acute pancreatitis, a severe and sometimes fatal
disease, phospholipase A2 is activated in the pancreatic
ducts, with the formation of lyso-PC from the PC that is
a normal constituent of bile. This causes disruption of
pancreatic tissue and necrosis of surrounding fat. Small
amounts of pancreatic digestive enzymes normally leak
into the circulation, but in acute pancreatitis, the
circulating levels of the digestive enzymes rise markedly.
Measurement of the plasma amylase or lipase
concentration is therefore of value in diagnosing the
disease.
 The presence in the pancreatic islets of hormones that
affect the secretion of other islet hormones suggests that
the islets function as secretory units in the regulation of
nutrient homeostasis. Somatostatin inhibits the secretion
of insulin, glucagon, and pancreatic polypeptide; insulin
inhibits the secretion of glucagon; and glucagon stimulates
the secretion of insulin and somatostatin. As noted above,
A and D cells and pancreatic polypeptide-secreting cells are
generally located around the periphery of the islets, with
the B cells in the center. There are clearly two types of
islets, glucagon-rich islets and pancreatic polypeptide-rich
islets, but the functional significance of this separation is
not known. The islet cell hormones released into the ECF
probably diffuse to other islet cells and influence their
function (paracrine communication;. It has been
demonstrated that gap junctions are present between A, B,
and D cells and that these permit the passage of ions and
other small molecules from one cell to another, which
could coordinate their secretory functions.
 Human pancreatic polypeptide is a linear polypeptide that
contains 36 amino acid residues and is produced by F cells
in the islets. It is closely related to two other 36-amino acid
polypeptides, polypeptide YY, a gastrointestinal peptide,
and neuropeptide Y, which is found in the brain and the
autonomic nervous system. All end in tyrosine and are
amidated at their carboxyl terminal. At least in part,
pancreatic polypeptide secretion is under cholinergic
control; plasma levels fall after administration of atropine.
Its secretion is increased by a meal containing protein and
by fasting, exercise, and acute hypoglycemia. Secretion is
decreased by somatostatin and intravenous glucose.
Infusions of leucine, arginine, and alanine do not affect it,
so the stimulatory effect of a protein meal may be mediated
indirectly. Pancreatic polypeptide slows the absorption of
food in humans, and it may smooth out the peaks and
valleys of absorption. However, its exact physiologic
function is still uncertain.
 Secretion of pancreatic juice is primarily under
hormonal control
 Secretin
 acts on the pancreatic ducts to cause copious secretion
of a very alkaline pancreatic juice that is rich in HCO3–
and poor in enzymes. The effect on duct cells is due to
an increase in intracellular cAMP. Secretin also
stimulates bile secretion.
 Secretion of pancreatic juice is primarily under
hormonal control
 CCK
 acts on the acinar cells to cause the release of zymogen
granules and production of pancreatic juice rich in
enzymes but low in volume. Its effect is mediated by
phospholipase C. The response to intravenous
secretin.
 Note that as the volume of pancreatic secretion
increases, its Cl–concentration falls and its HCO3–
concentration increases. Although HCO3–is secreted
in the small ducts, it is reabsorbed in the large ducts in
exchange for Cl–. The magnitude of the exchange is
inversely proportionate to the rate of flow.
 Like CCK, acetylcholine acts on acinar cells via
phospholipase C to cause discharge of zymogen
granules, and stimulation of the vagi causes secretion
of a small amount of pancreatic juice rich in enzymes.
There is evidence for vagally mediated conditioned
reflex secretion of pancreatic juice in response to the
sight or smell of food.
 An important function of the liver is to serve as a filter
between the blood coming from the gastrointestinal
tract and the blood in the rest of the body. Blood from
the intestines and other viscera reach the liver via the
portal vein. This blood percolates in sinusoids between
plates of hepatic cells and eventually drains into the
hepatic veins, which enter the inferior vena cava.
During its passage through the hepatic plates, it is
extensively modified chemically. Bile is formed on the
other side at each plate. The bile passes to the intestine
via the hepatic duct. In each hepatic lobule, the plates
of hepatic cells are usually only one cell thick
 Large gaps occur between the endothelial cells, and
plasma is in intimate contact with the cells . Hepatic
artery blood also enters the sinusoids. The central
veins coalesce to form the hepatic veins, which drain
into the inferior vena cava. The average transit time for
blood across the liver lobule from the portal venule to
the central hepatic vein is about 8.4 s. Additional
details of the features of the hepatic micro- and
macrocirculation, which are critical to organ function,
are provided below. Numerous macrophages (Kupffer
cells) are anchored to the endothelium of the
sinusoids and project into the lumen.
 Each liver cell is also apposed to several bile canaliculi .
The canaliculi drain into intralobular bile ducts, and
these coalesce via interlobular bile ducts to form the
right and left hepatic ducts. These ducts join outside
the liver to form the common hepatic duct. The cystic
duct drains the gallbladder. The hepatic duct unites
with the cystic duct to form the common bile duct.
The common bile duct enters the duodenum at the
duodenal papilla. Its orifice is surrounded by the
sphincter of Oddi, and it usually unites with the main
pancreatic duct just before entering the duodenum.
The sphincter is usually closed, but when the gastric
contents enter the duodenum, cholecystokinin (CCK)
is released and the gastrointestinal hormone relaxes
the sphincter and makes the gallbladder contract.
 The walls of the extrahepatic biliary ducts and the
gallbladder contain fibrous tissue and smooth muscle.
They are lined by a layer of columnar cells with
scattered mucous glands. In the gallbladder, the
surface is extensively folded; this increases its surface
area and gives the interior of the gallbladder a
honeycombed appearance. The cystic duct is also
folded to form the so-called spiral valves. This
arrangement is believed to increase the turbulence of
bile as it flows out of the gallbladder, thereby reducing
the risk that it will precipitate and form gallstones.
 It is beyond the scope of this volume to touch upon all of
the metabolic functions of the liver. Instead, we will
describe here those aspects most closely aligned to
gastrointestinal physiology. First, the liver plays key roles in
carbohydrate metabolism, including glycogen storage,
conversion of galactose and fructose to glucose, and
gluconeogenesis. The substrates for these reactions derive
from the products of carbohydrate digestion and
absorption that are transported from the intestine to the
liver in the portal blood. The liver also plays a major role in
maintaining the stability of blood glucose levels in the
postprandial period, removing excess glucose from the
blood and returning it as needed—the so-called glucose
buffer function of the liver. In liver failure, hypoglycemia
is commonly seen.
 Similarly, the liver contributes to fat metabolism. It
supports a high rate of fatty acid oxidation for energy
supply to the liver itself and other organs. Amino acids
and two carbon fragments derived from carbohydrates
are also converted in the liver to fats for storage. The
liver also synthesizes most of the lipoproteins required
by the body and preserves cholesterol homeostasis by
synthesizing this molecule and also converting excess
cholesterol to bile acids. The liver also detoxifies the
blood of substances originating from the gut or
elsewhere in the body . Part of this function is physical
in nature—bacteria and other particulates are trapped
in and broken down by the strategicallylocated Kupffer
cells.
 The remaining reactions are biochemical, and
mediated in their first stages by the large number of
cytochrome P450 enzymes expressed in hepatocytes.
These convert xenobiotics and other toxins to inactive,
less lipophilic metabolites. Detoxification reactions are
divided into phase I (oxidation, hydroxylation, and
other reactions mediated by cytochrome P450s) and
phase II (esterification). Ultimately, metabolites are
secreted into the bile for elimination via the
gastrointestinal tract. In this regard, in addition to
disposing of drugs, the liver is responsible for
metabolism of essentially all steroid hormones. Liver
disease can therefore result in the apparent
overactivity of the relevant hormone systems.