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Biliary Physiology
The liver produces bile continuously and excretes it into
the bile canaliculi. The normal adult produces 500 to
1,000 mL of bile daily. The secretion of bile is responsive
to neurogenic, humoral, and chemical stimuli. Parasympathetic stimulation via the vagus nerve increases bile
secretion, whereas sympathetic stimulation via splanchnic nerves decreases bile flow. Hydrochloric acid, partly
digested proteins, and fatty acids in the duodenum stimulate the release of secretin from the duodenum that subsequently increases bile production and flow. Bile flows
from the liver through to the hepatic ducts, into the
common hepatic duct, through the common bile duct, and
finally into the duodenum. With an intact sphincter of
Oddi, bile flow is directed into the gallbladder.
Bile is mainly composed of water, electrolytes, bile
salts, proteins, lipids, and bile pigments. Bile concentrations of sodium, potassium, calcium, and chloride are
equal to plasma or extracellular fluid. The pH of hepatic
bile is usually neutral or slightly alkaline but varies with
diet; an increase in protein shifts the bile to a more acidic
pH. The primary bile salts cholate and chenodeoxycholate are synthesized in the liver from cholesterol.They
are conjugated there with taurine and glycine and act
within the bile as anions (bile acids) that are balanced by
sodium. Cholesterol and phospholipids from the liver are
the principal lipids found in bile. The synthesis of phospholipids and cholesterol by the liver is in part regulated
by bile acids. Bile color is due to the pigment bilirubin
diglucuronide, a metabolic product from hemoglobin
breakdown. In the intestine, bacteria convert it into urobilinogen, a small fraction of which is absorbed and
secreted into the bile and may be secreted in urine.
Bile salts are excreted into the bile by the hepatocytes
and aid in the digestion and absorption of fats in the
intestines. Eighty percent of the conjugated bile acids are
absorbed in the terminal ileum. The remainder is dehydroxylated (deconjugated) by gut bacteria, forming the
secondary bile acids deoxycholate and lithocholate.These
are absorbed in the colon, transported to the liver, con-
jugated, and secreted into the bile. Eventually, about 95%
of the bile acid pool is reabsorbed and returned via the
portal venous system to the liver. Five percent is excreted
in the stool, leaving the relatively small amount of bile
acids to have maximum effect.
The gallbladder, the bile ducts, and the sphincter of
Oddi act together to store and regulate bile flow. The
gallbladder’s main function is to concentrate and store
hepatic bile and deliver bile into the duodenum in
response to a meal. In the fasting state, 80% of bile is
stored in the gallbladder. This storage is due to the
absorptive capacity of the gallbladder. It rapidly absorbs
sodium, chloride, and water against significant concentration gradients, concentrating the bile 10-fold and
leading to a marked change in bile composition. This
rapid absorption is one mechanism that prevents a rise in
pressure within the biliary system under normal circumstances. Gradual relaxation and emptying of the gallbladder during the fasting period also plays a role in
maintaining a relatively low intraluminal pressure in the
biliary tree.
The gallbladder’s epithelial cells secrete two important
products: glycoproteins and hydrogen ions. Glycoproteins are believed to protect the mucosa from the lytic
action of bile and to facilitate the passage of bile through
the cystic duct. Hydrogen ions transported in the lumen
lead to a decrease in the gallbladder bile pH. The acidification promotes calcium solubility, thereby preventing
its precipitation as calcium salts.
Gallbladder filling is facilitated by tonic contraction of
the sphincter of Oddi, which creates a pressure gradient
between the bile ducts and the gallbladder. During
fasting the gallbladder does not simply fill passively. In
association with phase II of the interdigestive migrating
myenteric motor complex in the gut, the gallbladder
repeatedly empties small volumes of bile into the duodenum. This process is mediated in part by the hormone
motilin. In response to a meal, the gallbladder empties by
a coordinated motor response of gallbladder contraction
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and sphincter of Oddi relaxation. One of the main stimuli
to gallbladder emptying is the hormone cholecystokinin
(CCK), which is released endogenously from the duodenal mucosa in response to a meal. When stimulated by
eating, the gallbladder empties 50% to 70% of its contents within 30 to 40 minutes. Over the following 60 to 90
minutes the gallbladder gradually refills, correlated with
a reduced CCK level. Defects in the motor activity of
the gallbladder are thought to play a role in cholesterol
nucleation and gallstone formation.
The vagus nerve stimulates contraction of the gallbladder, and splanchnic sympathetic stimulation is
inhibitory to its motor activity. Parasympathomimetic
drugs contract the gallbladder, whereas atropine leads to
relaxation. Neurally mediated reflexes link the sphincter
of Oddi with the gallbladder, stomach, and duodenum to
coordinate the flow of bile into the duodenum.Antral distention of the stomach causes both gallbladder contraction and relaxation of the sphincter of Oddi.
Hormonal receptors are located on the smooth
muscles, vessels, nerves, and epithelium of the gallbladder. Cholecystokinin is released into the bloodstream by
acid, fat, and amino acids in the duodenum. Cholecystokinin acts directly on smooth muscle receptors of the
gallbladder and stimulates gallbladder contraction. It also
relaxes the terminal bile duct, the sphincter of Oddi, and
the duodenum. Cholecystokinin stimulation of the gall-
Part XII. Gastrointestinal Disorders
bladder and the biliary tree also is mediated by cholinergic vagal neurons. Vasoactive intestinal peptide (VIP)
inhibits contraction and causes gallbladder relaxation.
Somatostatin and its analogues are potent inhibitors of
gallbladder contraction. Other hormones such as substance P and enkephalin affect gallbladder motility;
however, the physiologic role is unclear.
The sphincter of Oddi regulates flow of bile (and pancreatic juice) into the duodenum, prevents the regurgitation of duodenal contents into the biliary tree, and diverts
bile into the gallbladder. It is a complex structure that is
functionally independent of the duodenal musculature
and creates a high-pressure zone between the bile duct
and the duodenum. The sphincter of Oddi is 4 to 6 mm
in length and has a basal resting pressure of about
13 mm Hg above the duodenal pressure. On manometry,
the sphincter shows phasic contractions with a frequency
of about four per minute and an amplitude of 120 to
140 mm Hg. The sphincter primarily controls the regulation of bile flow. Relaxation occurs with a rise in CCK
level, leading to diminished amplitude of phasic contractions and reduced basal pressure, thereby allowing
increased flow of bile into the duodenum. During fasting,
the sphincter of Oddi activity is coordinated with the
periodic partial gallbladder emptying and an increase in
bile flow that occurs during phase III of the migrating
myoelectric complexes.