Bile and bilirubin metabolism Flashcards
Where is bile generated?
liver
where is bile stored
gallbladder
what are the components of bile?
o Bicarbonate o Cholesterol o Phospholipids o Bile pigments o Bile salts
What are the two important functions of bile?
Bile acids are critical for digestion and absorption of
fats and fat-soluble vitamins in the small intestine.
Many waste products, including bilirubin, are
eliminated from the body by secretion into bile and
elimination in faeces.
What can be excreted into bile?
- cholesterol
Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lecithin.
What are gallstones?
o Gallstones, most of which are composed predominantly of cholesterol, result from processes
that allow cholesterol to precipitate from solution in bile
How are bile pigments formed?
Produced when RBC are broken down; generated from breakdown of haem group from haemoglobin
Where are bile pigments formed?
Occurs in macrophages of the reticulo-endothelial (RE) system* in the spleen/bone marrow/liver
What happens to the products of RBC breakdown?
Globin is broken down to constituent amino acids and recycled
Fe2 + is recycled
The porphyrin ring is converted to bilirubin for transport to the liver for modification and
excretion
What is the reticular endothelial system?
Part of theimmune system; consists of the phagocytic cells located inreticular connective tissue, primarily monocytes andmacrophages.
(Also called the mononuclear phagocytic system)
What are the reticuloendothelialcellsfound inthebloodcavitiesoftheliver called?
Kupffer cells
What is the function of Kupffer cells?
Thesecellsareconcernedwithbloodcellformationanddestruction,storage
offattymaterials,metabolismofironandpigment; also playaroleininflammationandimmunity
can transform the haemoglobin from disintegrated RBC into bile pigment
How is haem broken down into bilirubin?
Haemoxygenase breaks up the Hb ring to form biliverdin
Biliverdin is acted on by biliverdin reductase, reducing the double bond to form bilirubin
At this point the bilirubin is
unconjugated and hydrophobic
Must bind to serum albumin for transport from the RE system to the liver for biotransformation and
excretion in bile
What is bilirubin?
Bilirubin is an orange-yellow pigment
Normal plasma samples will be roughly this colour
Icteric samples (contain excess bilirubin) are dark greenish
How is bilirubin conjugated in the liver?
Unconjugated bilirubin is bound to albumin and transported to hepatocytes in the blood
In the liver, bilirubin is conjugated to make it water soluble via UDP glucuronyl transferase
Conjugated bilirubin is transported into bile canaliculi and accumulates in bile within the gallbladder
From the gallbladder, it can be excreted into the duodenum
How is bilirubin metabolised in the intestines?
In the small intestine, beta-glucoronidase converts bilirubin back to its unconjugated form
Intestinal microflora act on the unconjugated form to convert it to metabolites
o Mesobilinogen
o Stercobilinogen
o Urobilinogen
W£hat happens to the metabolites of bilirubin?
acted on by flora in the large intestine to form:
o Mesobilin
o Stercobilin - gives faeces brown colour
o Urobilin - gives urine yellow colour
Why are bile salts recycled?
Bile salts present in the body are not enough to fully process the fats in a typical meal = they need to be recycled by the enterohepatic circulation
How does the pH effect bile salts?
Due to the pH of the small intestine, most of the bile acids are ionized and mostly occur as their sodium
salts - primary conjugated bile salts
How do bile salts differ in the lower small intestine?
In the lower small intestine andcolon, bacteria dehydroxylate some of the primary bile salts to form
secondary conjugated bile salts (which are still water-soluble).
Where are primary bile salts reabsorbed?
Along the proximal and distal ileum, primary bile salts are reabsorbed into the portal circulation.
Where are secondary bile salts reabsorbed from?
Secondary bile acids are reabsorbed predominantly in the colon.
How are bile acids reabsorbed from the blood?
Hepatocytes actively extract bile acids from the blood
o This is very efficient, and little escapes the healthy liver into systemic circulation.
What is the function of bile salts?
Act as biological emulsifiers, promote emulsification
What are bile salts made from?
Consist of cholesterol plus associated acids
Bile acids are derivatives of cholesterol synthesized in the hepatocyte.
How is cholesterol used in the production of bile salts?
Cholesterol, ingested as part of the diet or derived from hepatic synthesis, is converted into the bile acids
cholic and chenodeoxycholic acids
These are then conjugated to an amino acid (glycine or taurine) to yield the conjugated form that is
actively secreted into canaliculi.
Describe the chemical feature of bile acids
Bile acids are facial amphipathic - contain both hydrophobic and hydrophilic faces.
o Cholesterol-derived portion of a bile acid has one face that is hydrophobic (that with methyl
groups) and one that is hydrophilic (that with the hydroxyl groups)
o Amino acid conjugate is polar and hydrophilic.
What is significant about bile acids amphipathic nature?
two important functions:
- emulsification of lipid aggregates
- solubilisation and transport of lipids in an aqueous environment
How does bile acids help break down fat?
Bile acids have detergent action on particles of dietary fat which causes fat
globules to break down or be emulsified into minute, microscopic droplets.
o Hydrophobic portion binds to and disperses large triglyceride lipid droplets
o Hydrophilic portion prevents large droplets reforming
o Increases surface area on which triglyceride lipase can act
How to bile acids help transport lipids?
Bile acids are lipid carriers and can solubilize many lipids by formingmicelles- aggregates of lipids such as
fatty acids, cholesterol and monoglycerides - that remain suspended in water.
Bile acids are also critical for transport and absorption of thefat-soluble vitamins
What are micelles?
very small (4-7 nm) lipid aggregates with hydrophilic (polar) head groups on outside and hydrophilic (non-polar) tails pointing in
Bile salts promote micelle formation
What is the function of micelles?
Results in efficient digestion and adsorption of lipids and lipid-soluble vitamins (A, D,E,K)
What are micelles composed of?
Made of bile salts, fatty acids, monoglycerides, phospholipids, cholesterol and fat soluble vitamins
Why do micelles continuously breakdown and reform?
each time the contents are released and some can diffuse across the intestinal lining
How do TAGs reform?
in epithelial cells and are packaged into chylomicrons, which enter the blood via the lymph
What are the steps in fat absorption?
1) Bile salts emulsify the fat globules in the intestines
2) Bile salts form micelles with FFA produced
3) The absorbed FFAs form TGs and are packaged into chylomicrons for secretion in lacteals
Describe the regulation of bile secretion in the interdigestive period
The flow of bile is lowest during fasting, and most that is diverted into the gallbladder for concentration.
During this period (between meals), the sphincter of Oddi is contracted (closed)
Sphincter of Oddi: a muscular valve that controls flow of bile and pancreatic fluid into the duodenum
Because the sphincter is shut, pressure increases in the common bile duct, and bile flows into the
gallbladder
Epithelial cells reabsorb water and electrolytes, thus concentrating the bile
Describe the regulation of bile secretion in the digestive period
Fatty acids and amino acids entering the duodenum (after a meal) stimulate endocrine cells to release
cholecystokinin (CCK)
CCK stimulates contraction of gallbladder smooth muscle and relaxes the sphincter of Oddi
o The name of this hormone describes its effect on the biliary system - cholecysto = gallbladder
and kinin = movement.
o The most potent stimulus for release of cholecystokinin is the presence of fat in the duodenum.
Acidic chyme in the duodenum stimulates other endocrine cells to release secretin
o Secretin stimulates duct cells in the liver to release bicarbonate into the bile
o Secretin also stimulates bile production
What are the three groupings of jaundice?
o PRE-HEPATIC – elevated haemolysis
o HEPATIC – liver damage
o POST-HEPATIC – blockage of bile ducts
How are different grouping of jaundice distinguished?
proportion of unconjugated:conjugated bilirubin
What is prehepatic jaundice?
(Overproduction of bilirubin - above the capacity of the normal liver to metabolise it)
What causes prehepatic jaundice?
- Present in several conditions associated with elevated haemolysis 1) More RBC breakdown 2) More Haemoglobin 3) More bilirubin produced (UCB)
- Liver cannot cope with increased levels of
unconjugated bilirubin
o Tropical diseases - Yellow Fever, Malaria
o Side-effect of quinine-based anti-malarial drugs
o Genetic disorders associated with
increased haemolysis (e.g. sickle cell anaemia)
What are the causes of neonatal jaundice?
1) Physiological Jaundice of the newborn
2) Haemolytic disease of the newborn
Describe the pathophysiology of physiological jaundice of the newborn
After birth, newborns must destroy foetal haemoglobin and replace it with adult haemoglobin
The undeveloped liver (with lack of glucuronyltransferase) has insufficient capacity to cope with this
elevated haemolysis
On top of that, there are inhibitors of conjugation in breast milk
Bilirubin peaks at 3-5 days and lasts < 14 days
Condition can be treated with phototherapy
o Blue light changes the unconjugated bilirubin to a water soluble form that can be excreted
Describe Haemolytic disease of the newborn
alloimmunecondition that develops in afoetus, when maternal IgG passes through theplacenta.
o immune responseto nonselfantigensfrom members of the samespecies (alloantigens)
Rh incompatibility between mother and foetus may also cause haemolysis as antibodies
attackantigenson thered blood cellsin thefoetal circulation, breaking down and destroying the cells
Maternal Rh- blood sensitized by previous pregnancy with RH+ foetus or Rh+ blood transfusion
Can cause very high bilirubin concentration
Risk of kernicterus – bilirubin crosses immature blood brain barrier, deposition of bilirubin in basal
ganglia and brainstem nuclei resulting in brain damage if untreated
Treatment – high dose phototherapy and blood transfusion
What is hepatic jaundice?
failure of a damaged liver to conjugate bilirubin produced in normal amounts
What causes hepatic jaundice?
results from a problem at any point in system:
- Impaired uptake of unconjugated bilirubin
- Impaired conjugation of bilirubin
e. g. Gilberts (reduced glucuronyl transferase activity) - Impaired transport of conjugated bilirubin into bile canaliculi (out of hepatocytes)
e. g. primary biliary cholangitis (PBC) (autoimmune destruction of small bile ducts) - Present in conditions that result in liver damage causing cholestasis due to swelling and oedema resulting from inflammation
What is the effect of hepatocellular disease on bilirubin metabolism?
there is usually interference in all major steps of bilirubin metabolism—uptake, conjugation and excretion. However, excretion is the rate-limiting step, and usually impaired to the greatest
extent. As a result, conjugated hyperbilirubinaemia predominates
What is post-hepatic jaundice?
Obstruction of the excretory ducts of the liver that preventing the excretion of bilirubin
How can post-hepatic jaundice occur?
Present in conditions associated with obstruction of hepatic, cystic or common bile duct.
Prevents bile from being released into the small intestine = Cholestasis
What conditions are common causes of post-hepatic jaundice
- gallstones
- pancreatitis
- pancreatic tumours
How do gallstones contribute to jaundice?
– small pebbles made of cholesterol that move from gall bladder to block ducts.
o Arise if capacity of bile salts and phospholipids to solubilise cholesterol is exceeded.
o Usually removed surgically
o Oral ursodeoxycholic acid treatment (dissolves small gallstones).
o Lithotripsy (ultrasonic shock waves) used to break up large stones into smaller stones that can be
excreted
How does pancreaitis contribute to jaundice?
acute or chronic inflammation of the pancreas following infection or damage.
o Swelling can block bile flow.
How does pancreatic tumours contribute to jaundice?
tumour growth can
block bile flow
What is the link between location of gallstones and symptoms?
Gallstones can be asymptomatic
Become increasingly problematic when
gallbladder contractions cause stones to move
further along the bile ducts
What symptoms are present with cystic bile duct gallstones?
(joins gallbladder to common
bile duct)
Painful contractions
What symptoms are present with common bile duct gallstones?
(links hepatic and cystic duct to the duodenum)
No bile secretion into gut
Steatorrhea
Grey faeces (as no bile pigments - stercobilin)
Post-hepatic jaundice (as reduced excretion of bilirubin)
What symptoms are associated with gallstones at the duodenal papilla
(opening of pancreatic duct into duodenum, surrounded by sphincter of Oddi)
No bile or pancreatic secretion into gut
Malnutrition (can’t digest chyme)
Acute pancreatitis
Describe the implications Post-hepatic jaundice and has on surgery
Bile salts are required for efficient digestion and adsorption of lipids and lipid-soluble vitamins (A,D,E,K)
Vitamin K is required for efficient coagulation factor production
a course of Vitamin K is administered parenterally to post-hepatic jaundice patients prior to
surgery to prevent haemorrhage
How is conjugated bilirubin tested
- Add diazo reagent to serum.
- Conjugated bilirubin is converted to blue/purple diazo derivative of bilirubin (Azobilirubin).
NB: unconjugated bilirubin is bound to albumin so it does not react with diazo reagent - Measurement of absorbance @ 530-545 nm proportional to conjugated bilirubin (not unconjugated).
- Compare to known standards to calculate concentration.
How is total bilirubin tested?
- Add diazo reagent with caffeine to serum.
- Caffeine displaces unconjugated bilirubin from albumin.
-Free unconjugated bilirubin can now react with the diazo reagent - Both conjugated and unconjugated bilirubin converted to blue/purple diazo derivative of
bilirubin (Azobilirubin). - Measurement of absorbance @ 530-545 nm proportional to BOTH conjugated and
unconjugated bilirubin - Compare to known standards to calculate concentration.
What are the reference ranges of bilirubin in a normal adult?
Conjugated Bilirubin (adult) < 7 µmol/L
Total bilirubin (adult) < 21 µmol/L
How are bile salts measured in the urine?
Achieved by MultiStix urinalysis - commercially available test strips
Dip in urine, wait, and check colour change
What is the significance of finding bilirubin on a multistix urinalysis?
Conjugated bilirubin is water soluble but not detected in urine in health (low concentration)
Hyperbilirubinuria (detection of Conjugated bilirubin in urine) is always pathological as it means conjugated bilirubin has leaked back into the blood stream (hepatic or post-hepatic jaundice)
What is the implications of urobilinogen results from a urine sample?
Urobilinogen – test area impregnated with p-dimethylaminobenzaldehyde – forms a pink azo dye in the
presence of urobilinogen (colourless)
Normally present in low concentrations: high concentrations can indicate increased haemolysis or liver
disease (pre-hepatic/hepatic jaundice)
Absence of raised urobilinogen in a jaundiced patient can indicate biliary obstruction (post-hepatic
jaundice)
How are bile pigments measured in the faeces?
Visual inspection of faeces (colour) is easy and free
Absence of stercobilin is obvious – pale faeces
o Indicates biliary obstruction (post-hepatic jaundice)
