3. OVERVIEW
• Bile is a physiological aqueous solution produced and secreted by the
liver
• The hepatocyte produces bile continuously and excretes it into bile
canaliculi
• Bile leaves the liver through the right and left hepatic ducts,into
common hepatic duct and then the common bile duct
• With an intact sphincter of Oddi, tonic contraction diverts bile flow
into the gallbladder for storage, while mealtime stimulation allows it
passage into the duodenum
• About 500mL is secreted per day
• In the small intestines, bile acids facilitate lipid digestion and
absorption
• 5% excreted
• 95% reabsorbed from the ileum, secreted into the portal venous
system, and returned to the liver in a process known as enterohepatic
recirculation
4.
5.
6. BILE SALTS
• Bile salts (including bile acids) constitute 50-65% of
the organic component of bile
• The total bile salt pool is approximately 2.5 g
• Hepatocytes synthesize two primary bile acid (cholic
and chenodeoxycholic) from cholesterol by the
process of hydroxylation
• When these primary bile acids are secreted into the
lumen of the intestine, a portion of each is
dehydroxylated by intestinal bacteria to produce two
secondary bile acids, deoxycholic acid and
lithocholic acid
• The liver conjugates the bile acids with the amino
acids glycine or taurine to form bile salts
• This conjugation step causes them to become much
more water soluble
7. BILE SALTS CONCENTRATION
IN GALLBLADDER
• In the fasting state , approximately 80% of the
bile secreted by the liver is stored in the
gallbladder
• Gallbladder can hold up to 30-60mL of bile
• Concentration of bile occurred by:
1. Active absorption of Na+, Cl-and HCo3 by the
lining epithelium
2. Associated passive water movement out of the
lumen
This process concentrating the remaining bile
constituents that contain the bile salts,
cholesterol, lecithin, and bilirubin up to 5 to 20
fold
8.
9. FUNCTION OF BILE SALTS IN FAT DIGESTION
AND ABSORPTION
• The function of bile salt is to solubilize dietary lipids
• Amphipathic properties ( Hydrophilic : water soluble ) ( hydrophobic : lipid soluble)
1. Hydrophilic side :
- negatively charged groups point outward from a hydrophobic steroid nucleus
- dissolves in the aqueous phase
2. Hydrophobic side:
- dissolves in the oil phase.
Roles of bile salts:
1. Emulsify dietary lipids
2. Micelles formation
10. 1. EMULSIFY DIETARY LIPIDS
Through the process of emulsification, bile acids break down large lipid droplets into smaller
ones
The negatively charged bile salts surround the lipids, creating small lipid droplets in the
intestinal lumen.
The negative charges on the bile salts repel each other, so the droplets disperse, rather than
coalesce, thereby increasing the surface area for digestive enzymes
11. 2. MICELLES FORMATION
• Bile salts also allow the products of lipid digestion
to be transported as micelles.
• The core of the micelle contains monoglycerides,
lysolecithin, fatty acids, and the hydrophobic
portion of the bile salt.
• The hydrophilic portion of the bile salt surrounds
the lipid core, increasing solubility.
• Without bile salts, the fat-soluble vitamins (A, D, E,
K) cannot be absorbed.
12.
13. ENTEROHEPATIC CIRCULATION OF BILE SALTS
• most of the secreted bile salts are recirculated to the
liver via an enterohepatic circulation
• In the ileum, the bile salts are transported from the
intestinal lumen into the portal blood by
1. Simple diffusion
2. Na+-bile salt cotransporters , aka apical-sodium
bile acid transporter (ASBT)
• The portal blood carries bile salts to the liver
• The liver extracts the bile salts from portal blood and
adds them to the hepatic bile salt/bile acid pool
• the fecal loss is about 600 mg/day (out of the total bile
salt pool of 2.5 g)
21. GALLSTONES FORMATION
• Gallstones form as a result of solids settling out of solution
• Gallstones are classified by their cholesterol content as either
1. cholesterol stones (80-85 % )
2. pigment stones/ calcium bilirubinate stones (15-20%) – black/brown
Factors involved in stone formation
1. Supersaturation of the bile
2. Bile stasis
3. Nucleation factors that favors formation of stones from the supersaturated
bile
22. CHOLESTEROL STONES
• Pure cholesterol stones are uncommon and account for <10%
of all stones
They usually occur as a single large stone with a smooth
surface
• The majority of cholesterol stones are mixed but are at least
70% cholesterol by weight in addition to variable amounts of
bile pigments and calcium
multiple, of variable size, and may be hard and faceted or
irregular, multilobed, and soft
• Colors range from whitish yellow to green or black
• Most cholesterol stones (>90%) are radiolucent, though some
have a high calcium carbonate component and become
radioopaque
23. Pathophysiology of cholesterol stones:
- The primary event in the formation of cholesterol stones is
supersaturation of bile with cholesterol
- its solubility in water and bile depends on the relative
concentration of cholesterol, bile salts, and lecithin
- When cholesterol hypersecretion is present, either through
increased intake or dysfunctional processing
supersaturation occurs
- When cholesterol concentrations exceed the ability of the
bile salts and phospholipid to maintain solubility, the
cholesterol precipitates out of solution into a solid, forming a
cholesterol stone
Ratio of bile acids : phospholipids (Lecithin) : cholesterol 10:
ADMIRAND TRIANGLE
24. PIGMENTED STONES
• Pigmented stones contain <20% cholesterol and are dark because of the presence of calcium bilirubinate.
• Black and brown pigment stones have little in common and should be considered as separate entities.
BLACK PIGMENT STONES:
- small, brittle, dark, and sometimes spiculated
- formed by supersaturation of unconjugated bilirubin within the bile
- Aetiology: excessive levels of conjugated bilirubin excretion
(hemolytic disorders like hereditary spherocytosis and sickle cell
disease) increased rate of production of unconjugated bilirubin.
- The insoluble unconjugated bilirubin will then precipitate with calcium as insoluble calcium
bilirubinate, forming a pigment stone
- Due to their high calcium content, pigment stones are often radiopaque.
- Higher percentage of gallstones in Asian Countries than in the Western hemisphere.
25. BROWN PIGMENT STONES:
- usually <1 cm in diameter
- Brownish yellow, soft, and often mushy
- form either in the gallbladder or in the bile ducts secondary to
bacterial infection and bile stasis
- Bacteria such as Escherichia coli secrete β-glucuronidase that
enzymatically cleaves conjugated bilirubin to produce the
insoluble unconjugated bilirubin
- This unconjugated bilirubin then precipitates with calcium, and along with dead bacterial cell
bodies, forms soft brown stones in the biliary tree
- Brown stones are typically found in Asian population
- Also associated with stasis secondary to parasite infection with Ascaris lumbricoides (roundworm)
or Clonorchis sinensis (liver fluke)
26. Resection of ileum
- most of the secreted bile acids are lost in feces, increasing the demand for synthesis of
new bile acids.
- The liver is unable to keep pace with the demand, causing a decrease in the total bile acid
pool
- emulsification of dietary lipids for digestion and micelle formation for absorption of lipids
are compromised
- dietary lipids are excreted in feces, seen as oil droplets in the stool (steatorrhea).
- high concentration of bile acid in colon lumen stimulate cAMP-dependent Cl−
secretion in colonic epithelial cells Na+ and water follow Cl− into the lumen
secretory diarrhea
- absorption of vitamin B12 impaired
27. EFFECTS OF CHOLECYSTECTOMY
• The periodic discharge of bile from the gallbladder aids digestion but is
not essential for it
• Cholecystectomized patients maintain good health and nutrition with a
constant slow discharge of bile into the duodenum
• although eventually the bile duct becomes somewhat dilated, and more
bile tends to enter the duodenum after meals than at other times.
28. REFERENCES
1. Ganong’s Review of Medical Physiology -25th Edition
2. Linda S. Contanzo – Physiology 6th edition
3. Schwartz’s Principle of Surgery 11th edition
4. Guyton and Hall Textbook of Medical Physiology 13th
edition
Editor's Notes
Assalammualiakum and good afternoon to consultants, specialist and fellow collegues
today im gonna present a cme entitles bile physiology
Mr name
my supervisor
from bile canaliculi --> the bile will flow into --> interlobular bile duct then to hepatic duct --> common hepatic duct --> common bile duct --> duodenuem
this is summary of secretion and circulation of bile salt
it involves a few step that i will describe it later
step 1: synthesis and secretion of bile salt from the liver
step 2 : concentrations of bile salt in the gallbladder
step 3 : flow of bile into the duodenum
step 4 : absorption of bile salt from the ileum into portal circulation
step 5 : extraction of bile salt from the portal blood by hepatocytes
composition of bile:
1. Organic constitutent - bile salts, phospholipids (lecithin), cholesterol, bile pigment (bilirubin), protein
2. water and electrolytes -- secreted by hepatocytes lining the ducts
1st step formation of bile salts in the liver
Hydroxylation : is an oxidation reactin in which carbon-hydrogen bond oxidizes into carbon-hydroxyl-bond
2nd step concentration of bile salts in gallbladder
differences in composition of liver bile and gallbaldder bile
Fat digestion and absorption
-function of bile acids:
emulsify the large fat particles of the food into many minute particles
aid in absorption of the digested fat end products through the intestinal mucosal membrane.
The critical property of bile salts is that they are amphipathic, meaning the molecules have both hydrophilic (water-soluble) and hydrophobic (lipid- soluble) portions.
Hydrophilic, negatively charged groups point outward from a hydrophobic steroid nucleus such that, at an oil-water interface, the hydrophilic portion of a bile salt molecule dissolves in the aqueous phase and the hydrophobic portion dissolves in the oil phase.
Without the bile salts, lipids would be insoluble in the aqueous solution in the intestinal lumen and less amenable to digestion and absorption.
Through the process of emulsification, bile acids break down large lipid droplets into smaller ones, increasing the surface area for digestive enzymes.
The hydrophilic portion of the bile salts surrounds the lipid, forcing the lipid to disperse as the negative charges repel each othe
(Without emulsification, dietary lipids would coalesce into large “blobs,” with relatively little surface area for digestion.)
Phospholipids and cholesterol also are secreted into bile by the hepatocytes and are included in the micelles with the products of lipid digestion. Like the bile salts, phospholipids are amphipathic and aid the bile salts in forming micelles. The hydrophobic portions of the phospholipids point to the interior of the micelle, and the hydrophilic portions dissolve in the aqueous intestinal solution.
this is illustration of absorption of lipid from intestinal lumen into epithelial cell of small intestines
micelles --> acts as transportation, consists of cholesterol, monoglycerides, lysolecithin, and free fatty acid
the micelles diffuse into apical membrane of intestinal epithelial cell, then the lipid are released from micelle and diffuse into the cell
the bile salt are left behind in the intestinal lumen to absorbed at terminal ileum
inside the cell, the product of lipid digestion are re-esteriified with free fatty acid to form original ingested lipids : triglecerides, cholelsterol ester and phospholipid
they will packed with apoprotein to be called chylomicron
chylomicrons will be exocystosis into lymphatic capillaries into thoracic duct, which empties into the bloodstream
after the bile salt serve a function as a micelles, then it will be reabsorbed in the terminal ileum
IBABP : Ilieal Bile Acid binding protein
OST : organic solute transporter
this diagrahm showed summary of bile salt concentration
we can see the total is about 2-4g of bile acid pool on our body and about 5% (600mg) is excreted in the fecal
apart from digestion and absorption of lipid, bile also involve in bilirubin metabolism and excretion
In reticuloendotelial system (liver/spleen/lungs) , bilirubin is byproduct of hemoglobin
Hb is converted to biliverdin (green color) by the action of enzyme heme oxygenase, then converted to bilirubin ( yellow coloured) by the action of biliverdin reductase
The bilirubin is bound to albumin in the circulation and carried to the liver, where it taken up by the hepatocyctes
In the hepatic microsomes, bilirubin is conjugated with glucuronic acid via the enzymes UDP – glucuronyl transferase
Conjugated bilirubin is water soluble and a portion of it is excreted in the urine
The remainder of the conjugated bilirubin is secreted into bile, and then via bile into small intestines
The conjugated bilirubin travel down to the terminal ileum and colon, where it is deconjugated by bacterial enzymes and metabolised to urobilinogen
Some of the urobilinogen absorbed via enterohepatic circulation into the liver
The remainder of urobilinogen converted into urobilin and stercobilin,which are excreted in the feces
Crigler Najjar syndrome deficiency of glucorunoly transferase enzmyes --> unable to conjugated bilirubin
Gilbert syndrome
CCK : cholecystokinin
two important hormones involve in regulation of bile secretion
1. CCK - cholecystokinin
location : I cells of duodenum
stimuli : fatty acid. amino acids and small peptides
action :
-increase pancreatic ezymes secretion (amylase,lipase,protease)
-stimulates contraction of gallbladder and relaxation of sphincter of Oddii
2. secretion
location : S cells of duedunom
stimuli : H+ in duedenum and fatty acids
action :
increase biliary HCo3 secretion
increase pancreatic HCO3 secretion
Neuronal – parasympathetic (vagal)
Hormonal – CCK and secretion
Somatostation inhibit bile secretion
Nucleation formation of cholesterol monohydrate crystal
Pro nucleation : mucin/calcium
Antinucleation : apolipoprotein.lecithin
1. Bile stasis - stones form in the bile that is sequestrated in the gallbladder rather than the bile that is flowing in the bile ducts.
2. supersaturation: Cholesterol is very insoluble in bile, and it is maintained in solution in micelles only at certain concentrations of bile salts and lecithin. At concentrations above line ABC in Figure 28–7, the bile is supersaturated and contains small crystals of cholesterol in addition to micelles.
Phosphatidylcholine that enters the bile forms mixed micelles with the bile acids and cholesterol.
The ratio of bile acid s:phosphatidylcholine:cholesterol in canalicular bile is approxi- mately 10:3:1. Deviations from this ratio may cause cholesterol to precipitate, leading to one type of gallstones
3. The exact nature of the nucleation factors is unsettled, although glycoproteins in gallbladder mucus have been implicated. In addition, it is unsettled whether stones form as a result of excess production of components that favor nucleation or decreased production of antinucleation components that prevent stones from forming in normal individuals.
Normally, the ileum is the site of absorption of the intrinsic factor– vitamin B12 complex. Intrinsic factor is secreted by gastric parietal cells and forms a stable complex with dietary vitamin B12, and the complex is absorbed in the ileum. The patient cannot absorb vitamin B12 and must receive monthly injections, bypassing the intestinal absorptive pathway.
The drug cholestyramine, used to treat bile acid diarrhea, binds bile acids in the colon. In bound form, the bile acids do not stimulate Cl− secre- tion or cause secretory diarrhea. However, the woman will continue to have steatorrhea.
