sistem bilier

1. THE LIVER AND HEPATOBILIARY SYSTEM
Adiartha Griadhi
Physiology Department

2. The Liver and Biliary System

3. LIVER FUNCTION

4. Liver Function
• The digestive and excretory functions of the
liver are associated with the secretion of bile
via the biliary tract. Bile is a complex fluid
that contains organic and inorganic secretions
from the liver, which are important in the
digestion of fats

5. Liver Function
• The liver also serves many other functions,
some of which are:
1. Carbohydrate metabolism
2. Fat metabolism.
3. Cholesterol metabolism.
4. Amino acid and protein synthesis.
5. Storage functions.
6. Detoxification and biotransformation.
7. Immune function.

6. Carbohydrate Metabolism
• The liver is both a source and a “sink” for
glucose, and is a key effector in control of the
blood glucose concentration.
– Glycogenolysis and gluconeogenesis add glucose to
the blood.
– Glycogen synthesis, glycolysis, oxidative metabolism,
and fat synthesis all consume blood glucose.
– The liver also converts excess carbohydrates to
triglycerides for storage in adipose tissue.

7. Fat Metabolism
• Dietary lipids circulating in the form of chylomicrons
(see fat absorption) are partially broken down during
passage through the microcirculation by the enzyme
endothelial lipoprotein lipase.
• The glycerol and fatty acids that are produced then
enter the adipose and muscle cells.
• Remnant chylomicrons containing cholesterol, as well
as long-chain fatty acids, are taken up by the liver.
• The liver uses fatty acids for energy metabolism via
beta oxidation or for the synthesis of ketones.

8. Cholesterol Metabolism
• The major sources of cholesterol are found in
the diet plus de novo synthesis of cholesterol
by the liver.
• The major elimination pathway for cholesterol
is in bile, as native cholesterol, and via hepatic
synthesis of bile acids. Bile acids are
subsequently excreted in feces.

9. Amino Acid and Protein Synthesis
• The liver expresses a wide range of amino acid
uptake carriers.
• A large amount of amino acid is consumed for
synthesis of serum proteins (e.g., albumin,
clotting factors, and hormone-binding proteins).
• Amino acids can also be used for oxidative
metabolism and form Urea as the final amino
acid breakdown product.

10. Storage Functions
• The liver is the main storage site for the fat-
soluble vitamins A, D, E, and K, and vitamin
B12, iron, and copper.
• Pathologic iron overload, a condition known as
hemochromatosis, can cause liver damage
due to excessive iron deposition in the liver.

11. Detoxification & Biotransformation
• Removal of the bioactivity of many organic
molecules, including steroids and hydrophobic
drugs, occurs in the liver, generally in two phases:
– Phase I biotransformation involves the cytochrome
P450 enzymes.
– Phase II biotransformation involves conjugation to
generate products that are more soluble for
excretion. Conjugation reactions involve the addition
of glucuronate, sulfate, or glutathione to the parent
molecule.

12. Immune Function
• Kupffer cells in the liver are the largest group
of fixed macrophages in the body. These cells
are responsible for ingesting foreign bodies
entering the blood via the gastrointestinal
tract.

13. FUNCTIONAL ANATOMY OF
LIVER

14. FUNCTIONAL ANATOMY OF THE LIVER
• Liver lobule is a convenient histologic structure to
visualize. But it is not regarded as the functional unit of
the liver.
• The function of hepatocytes is strongly influenced by the
cellular microenvironment (function of the blood supply).
• The liver acinus is the smallest functional unit of the liver
-hepatocytes (receive a blood supply from the same
hepatic arteriole & portal venule).
• A liver acinus is a three-dimensional ball of cells spanning
more than one lobule.

15. 15

17. • Hepatocytes secrete bile into the canaliculi, which
are small
• 1-μm spaces bounded by neighboring hepatocytes.
• Canaliculi
• join together and convey hepatic bile toward small
terminal
• ductules at the periphery of the liver lobules.
• Bile moves
• through a sequence of progressively larger ducts in
each lobe of
• the liver and emerges in a hepatic duct.

18. FUNCTIONAL ANATOMY OF THE LIVER
• The vascular anatomy of the liver results in a “zonal”
relationship between hepatocytes :
– Zone I is closest to the arteriole, where cells receive the
greatest delivery of oxygen and nutrients. Cells in zone I
preferentially undertake oxidative metabolism,
ureagenesis, and bile acid production.
– Zone II is a transitional zone between zones I and III.
– Zone III is furthest away from the arteriole, where the
concentration of oxygen and nutrients is the lowest. Zone
III cells undertake glycolysis, ketogenesis, and detoxifi
cation reactions.

19. BILIARY SYSTEM

20. BILIARY SYSTEM
• Bile is a complex fluid secreted by the liver and
consists of organic molecules in an alkaline
solution.
• The biliary tract consists of a series of ducts
that convey bile from the liver to the
duodenum.

22. BILIARY SYSTEM
Bile has three functions:
1. It facilitates the assimilation of dietary lipid;
2. It provides a pathway to excrete hydrophobic
molecules
3. It assists in neutralizing gastric acid because
it is an alkaline solution.

23. BILE FORMATION

24. BILE FORMATION
• Hepatic bile is a combination of canalicular
bile and ductular bile.
• Canalicular bile is secreted by Hepatocyte. Its
an isotonic fluid, together with organic
molecules : bile salts, cholesterol,
phospholipids & bile pigments.

25. BILE FORMATION
• Ductular bile is added by epithelial cells called
cholangiocytes, which line the biliary ducts.
• Cholangiocytes produce a HCO3−
-rich fluid in
response to the hormone secretin. It resemble
pancreatic duct cells.

26. ORGANIC MOLECULS IN BILE
• Bile acids (70%), Phospolipid (20%) and
Cholesterol (4%), bile pigment and proteins.
• Bile acids are amphipathic molecules with a
hydrophobic nucleus on one side and several
polar groups on the other.
• Hepatocytes synthesize and secrete the primary
bile acids : cholic acid and chenodeoxycholic
acid, which are mostly conjugated.

27. • Conjugation causes bile acids to ionize more readily into bile
• salts, which are more soluble in water (Figure 7-20). When bile
• acids are exposed to the small intestinal lumen, some of the
primary
• bile salts undergo bacterial modifi cation. About 10–20%
• of bile salts undergo deconjugation, returning them to native
• bile acids. Native bile acids are reabsorbed in the small intestine
• and reconjugated in the liver prior to being secreted again.

28. • Primary bile acids :
conjugated with either
glycine or taurine 
glycocholate and
taurocholate.
Conjugated : ionized 
bile salt, more water
soluble
• Dehydroxylation may
also occur  Secondary
bile acids : deoxycholic
acid, lithocholic acid.

29. Bile components. Bile contains electrolytes, bile salts (bile acids),
cholesterol, lecithin (phosphatidylcholine), bilirubin
diglucuronide, steroid hormones, medications etc. (!A). Bile salts
are essential for fat digestion. Most of the other components of
bile leave the body via the feces (excretory function of the liver !p.
250). Bile formation. Hepatocytes secrete ca. 0.7 L/day of bile
into biliary canaliculi (!A), the fine canals formed by the cell
membranes of adjacent of hepatocytes. The sinusoidal and
canalicular membranes of the hepatocytes
contain numerous carriers that absorb bile components from the
blood and secrete them into the canaliculi, resp. Bile salts (BS).
The liver synthesizes cholate and chenodeoxycholate (primary
bile salts) from cholesterol. The intestinal bacteria convert some
of them into secondary bile salts such as deoxycholate and
lithocholate. Bile salts are conjugated with taurine or glycine in
the liver and are secreted into the bile in this form (!A). This
conjugation is essential for micelle formation in the bile and gut.

30. Bile salts and fat
digestion
• Bile salts interact to form
aggregates known as
micelles.
• The micelle provides a polar
outer shell, which interacts
with water, and a
hydrophobic inner region.
Long-chain fatty acids,
cholesterol, and other
hydrophobic molecules
readily dissolve inside the
micelles.

31. ENTEROHEPATIC CIRCULATION OF BILE
ACIDS
• The enterohepatic circulation is a circuit in
which solutes are secreted by the liver only to
be returned to the liver via intestinal
reabsorption.
• Enterohepatic recycling is physiologically
important for bile salts and bile acids because
the bile acid pool is not large enough to
assimilate the lipid content of a typical meal

32. ENTEROHEPATIC CIRCULATION OF BILE
ACIDS
Molecules in the enterohepatic circulation are:
1. Secreted into bile by hepatocytes.
2. Delivered to the small intestine via the biliary
tract.
3. Reabsorbed from the small intestine.
4. Returned to the liver via the portal venous
system to become available again for uptake
and secretion by hepatocytes.

34. • Bile salts and bile acids are recycled approximately two times
duringeach meal, and about six to eight times each day via
the enterohepatic
• circulation. About 95% of the bile salts that arrive in the
intestine are reabsorbed. Bile salts that become deconjugated
• revert to bile acids, which are mostly undissociated and are
reabsorbed by simple diffusion in the jejunum. Most primary
and
• secondary bile salts are reabsorbed via Na+-bile salt
cotransport when they reach the distal ileum. A small
amount of bile acid
• (mostly as lithocholic acid) is lost in fecal excretion each day.
The rate of bile acid loss in feces is matched by the rate of
hepatic bile
• acid synthesis, thereby maintaining the bile acid pool.

35. ENTEROHEPATIC CIRCULATION OF BILE
ACIDS
• Bile salts and bile acids are recycled approximately
two times during each meal, and about six to eight
times each day via the enterohepatic circulation.
• About 95% of the bile salts are reabsorbed.
– Deconjugated bile salts revert to bile acids, which
are mostly undissociated and are reabsorbed by
simple diffusion in the jejunum.
– Primary and secondary bile salts are reabsorbed via
Na+-bile salt cotransport when they reach the distal
ileum.

36. ENTEROHEPATIC CIRCULATION OF BILE
ACIDS
– A small amount of bile acid (mostly as lithocholic
acid) is lost in fecal excretion each day. The rate of
bile acid loss in feces is matched by the rate of
hepatic bile acid synthesis, thereby maintaining
the bile acid pool.

37. CHOLERESIS
• Choleresis is the secretion of bile fluid by the
liver. Choleretics are substances that stimulate
choleresis.
• Fluid secretion into bile occurs by osmosis
following the secretion of solutes:
– Bile salts (most important choleretics).
– Nonbile acids, fairly constant background of bile
fluid secretion,
– Ductular bile : NaHCO3 secretion.

38. CHOLERESIS

39. • Choleresis. Enterohepatic circulation raises the bile salt
concentration in the portal vein to
• a high level during the digestive phase. This (a) inhibits the hepatic
synthesis of bile salts
• (cholesterol-7!-hydroxylase; negative feedback; (!B) and (b)
stimulates the secretion of
• bile salts into the biliary canaliculi. The latter effect increases the
bile flow due to osmotic
• water movement, i.e., causes bile salt-dependent choleresis (!C).
Bile salt-independent
• choleresis is, caused by secretion of other bile components into the
canaliculi as well as of
• HCO3 – (in exchange for Cl–) and H2O into the bile ducts (!C). The
latter form is increased by
• the vagus nerve and secretin.

40. CHOLERESIS

41. GALLBLADER

42. GALLBLADDER
• The gallbladder is a blind outpouching of the
biliary tree. It is a distensible muscular organ
with a capacity of only 20–50 mL.
• The function of the gallbladder is to store and
concentrate bile between meals and to eject
bile into the duodenum during the digestion
of a meal.

43. 43
GALLBLADDER

44. GALLBLADDER
• Interdigestive phase  the gallbladder is
relaxed and the sphincter of Oddi is contracted
 promoting storage of hepatic bile in the
gallbladder.
• Intestinal phase  the gallbladder is
contracted and the sphincter of Oddi is relaxed
 delivers the maximum amount of bile into
the small intestine at the time when nutrients
are present.

45. Direct Reflexes Digestive Action

46. Intestinal Phase: Exocrine Response
• Pancreatic bicarbonate secretions
• Secretin stimulates bicarbonate release. Neutralize
HCl, add bile & enzymes
• Pancreatic exocrine enzyme secretions
• CCK stimulates pancreatic release of inactive
enzymes
• Liver adds bile via gall bladder
• CCK stimulates gall bladder contraction
• Bile : Bile salts, Bilirubin, cholesterol

47. The control of the gallbladder
1. During the cephalic phase, there is gradual rhythmic contraction
of the gallbladder, mediated by the cholinergic vagal neurons.
2. The entry of a meal into the small intestine stimulates CCK
secretion. CCK is the most powerful signal for gallbladder
contraction and also mediates the relaxation of the sphincter of
Oddi, allowing biliary and pancreatic secretions to enter the
duodenum.
3. During the intestinal phase, increasing levels of secretin
stimulate cholangiocyte secretion, providing additional HCO3 −
to neutralize acidic chyme.
4. Once enterohepatic recycling of the bile acids begins, choleresis
occurs and hepatic bile secretion accelerates.

48. The control of the gallbladder

49. Therefore, the control of the gallbladder has several
components (Figure 7-23A):
During the cephalic phase, there is gradual rhythmic
■
contraction of the gallbladder, mediated by the cholinergic
vagal neurons.
The entry of a meal into the small intestine stimulates
■ CCK
secretion. CCK is the most powerful signal for gallbladder
contraction and also mediates the relaxation of the sphincter
of Oddi, allowing biliary and pancreatic secretions to enter the
duodenum.
During the intestinal phase, increasing levels of
■ secretin
stimulate cholangiocyte secretion, providing additional HCO3
− to neutralize acidic chyme.
Once enterohepatic recycling of the bile acids begins,
■
choleresis occurs and hepatic bile secretion accelerates.

50. The control of the gallbladder

51. Gallbladder. When the sphincter of Oddi between the
common bile duct and duodenum is closed, hepatic bile
(C bile) is diverted to the gallbladder, where it is
concentrated (1 : 10) and stored (!D). The gallbladder
epithelium reabsorbs Na+, Cl– and water (!D1) from
the stored bile, thereby greatly raising the
concentration of specific bile components (bile salts,
bilirubin-di-glucuronide, cholesterol,
phosphatidylcholine, etc.). If bile is used for fat
digestion (or if a peristaltic wave occurs in the
interdigestive phase,!p. 240), the gallbladder contracts
and its contents are mixed in portions with the
duodenal chyme (!D2).

52. Concentrated Bile
• At interdigestive period : constant rate secretion of
bile, more than 50% of the daily hepatic bile
produced entering the gallbladder during this period.
• This volume far exceeds the volume of gallbladder,
and the excess fluid volume must be absorbed by
epithelial cells lining the gallbladder.

53. Concentrated Bile
• Concentrated bile is more effective for promoting fat
digestion. The mechanism of salt and fluid absorption
is shown in Figure 7-23B. The surface epithelium of
the gallbladder secretes mucins and H+ for
protection against the alkaline bile in the gallbladder
lumen.

54. Salt and fluid absorption in Gallbladder

55. • This volume of hepatic bile far exceeds the volume of
bile in the gallbladder,
• and the excess fluid volume must be absorbed by
epithelial cells lining the gallbladder. Concentrated bile
is more effective
• for promoting fat digestion. The mechanism of salt
and fluid absorption is shown in Figure 7-23B. The
surface epithelium of
• the gallbladder secretes mucins and H+ for protection
against the alkaline bile in the gallbladder lumen.