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Phase 2 1. Gastroenterology > Bile and bilirubin metabolism > Flashcards

Bile and bilirubin metabolism Flashcards

1
Q

Where is bile generated?

A

liver

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2
Q

where is bile stored

A

gallbladder

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3
Q

what are the components of bile?

A 
o Bicarbonate
o Cholesterol
o Phospholipids
o Bile pigments
o Bile salts
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4
Q

What are the two important functions of bile?

A

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.

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5
Q

What can be excreted into bile?

A
  • cholesterol
    Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lecithin.
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6
Q

What are gallstones?

A

o Gallstones, most of which are composed predominantly of cholesterol, result from processes
that allow cholesterol to precipitate from solution in bile

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7
Q

How are bile pigments formed?

A

Produced when RBC are broken down; generated from breakdown of haem group from haemoglobin

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8
Q

Where are bile pigments formed?

A

Occurs in macrophages of the reticulo-endothelial (RE) system* in the spleen/bone marrow/liver

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9
Q

What happens to the products of RBC breakdown?

A

 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

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10
Q

What is the reticular endothelial system?

A

 Part of theimmune system; consists of the phagocytic cells located inreticular connective tissue, primarily monocytes andmacrophages.
(Also called the mononuclear phagocytic system)

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11
Q

What are the reticuloendothelialcellsfound inthebloodcavitiesoftheliver called?

A

Kupffer cells

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12
Q

What is the function of Kupffer cells?

A

Thesecellsareconcernedwithbloodcellformationanddestruction,storage
offattymaterials,metabolismofironandpigment; also playaroleininflammationandimmunity

can transform the haemoglobin from disintegrated RBC into bile pigment

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13
Q

How is haem broken down into bilirubin?

A

 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

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14
Q

What is bilirubin?

A

 Bilirubin is an orange-yellow pigment
 Normal plasma samples will be roughly this colour
 Icteric samples (contain excess bilirubin) are dark greenish

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15
Q

How is bilirubin conjugated in the liver?

A

 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

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16
Q

How is bilirubin metabolised in the intestines?

A

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

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17
Q

W£hat happens to the metabolites of bilirubin?

A

acted on by flora in the large intestine to form:
o Mesobilin
o Stercobilin - gives faeces brown colour
o Urobilin - gives urine yellow colour

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18
Q

Why are bile salts recycled?

A

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

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19
Q

How does the pH effect bile salts?

A

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

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20
Q

How do bile salts differ in the lower small intestine?

A

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).

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21
Q

Where are primary bile salts reabsorbed?

A

Along the proximal and distal ileum, primary bile salts are reabsorbed into the portal circulation.

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22
Q

Where are secondary bile salts reabsorbed from?

A

Secondary bile acids are reabsorbed predominantly in the colon.

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23
Q

How are bile acids reabsorbed from the blood?

A

Hepatocytes actively extract bile acids from the blood

o This is very efficient, and little escapes the healthy liver into systemic circulation.

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24
Q

What is the function of bile salts?

A

Act as biological emulsifiers, promote emulsification

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25
Q

What are bile salts made from?

A

Consist of cholesterol plus associated acids

 Bile acids are derivatives of cholesterol synthesized in the hepatocyte.

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26
Q

How is cholesterol used in the production of bile salts?

A

 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.

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27
Q

Describe the chemical feature of bile acids

A

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.

28
Q

What is significant about bile acids amphipathic nature?

A

two important functions:

  • emulsification of lipid aggregates
  • solubilisation and transport of lipids in an aqueous environment
29
Q

How does bile acids help break down fat?

A

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

30
Q

How to bile acids help transport lipids?

A

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

31
Q

What are micelles?

A 
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

32
Q

What is the function of micelles?

A

Results in efficient digestion and adsorption of lipids and lipid-soluble vitamins (A, D,E,K)

33
Q

What are micelles composed of?

A

Made of bile salts, fatty acids, monoglycerides, phospholipids, cholesterol and fat soluble vitamins

34
Q

Why do micelles continuously breakdown and reform?

A

each time the contents are released and some can diffuse across the intestinal lining

35
Q

How do TAGs reform?

A

in epithelial cells and are packaged into chylomicrons, which enter the blood via the lymph

36
Q

What are the steps in fat absorption?

A

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

37
Q

Describe the regulation of bile secretion in the interdigestive period

A

 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

38
Q

Describe the regulation of bile secretion in the digestive period

A

 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

39
Q

What are the three groupings of jaundice?

A

o PRE-HEPATIC – elevated haemolysis
o HEPATIC – liver damage
o POST-HEPATIC – blockage of bile ducts

40
Q

How are different grouping of jaundice distinguished?

A

proportion of unconjugated:conjugated bilirubin

41
Q

What is prehepatic jaundice?

A

(Overproduction of bilirubin - above the capacity of the normal liver to metabolise it)

42
Q

What causes prehepatic jaundice?

A 
- 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)
43
Q

What are the causes of neonatal jaundice?

A

1) Physiological Jaundice of the newborn

2) Haemolytic disease of the newborn

44
Q

Describe the pathophysiology of physiological jaundice of the newborn

A

 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

45
Q

Describe Haemolytic disease of the newborn

A

 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

46
Q

What is hepatic jaundice?

A

failure of a damaged liver to conjugate bilirubin produced in normal amounts

47
Q

What causes hepatic jaundice?

A

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
48
Q

What is the effect of hepatocellular disease on bilirubin metabolism?

A

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

49
Q

What is post-hepatic jaundice?

A

Obstruction of the excretory ducts of the liver that preventing the excretion of bilirubin

50
Q

How can post-hepatic jaundice occur?

A

Present in conditions associated with obstruction of hepatic, cystic or common bile duct.
 Prevents bile from being released into the small intestine = Cholestasis

51
Q

What conditions are common causes of post-hepatic jaundice

A
  • gallstones
  • pancreatitis
  • pancreatic tumours
52
Q

How do gallstones contribute to jaundice?

A

– 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

53
Q

How does pancreaitis contribute to jaundice?

A

acute or chronic inflammation of the pancreas following infection or damage.
o Swelling can block bile flow.

54
Q

How does pancreatic tumours contribute to jaundice?

A

tumour growth can

block bile flow

55
Q

What is the link between location of gallstones and symptoms?

A

Gallstones can be asymptomatic

Become increasingly problematic when
gallbladder contractions cause stones to move
further along the bile ducts

56
Q

What symptoms are present with cystic bile duct gallstones?

A

(joins gallbladder to common
bile duct)
 Painful contractions

57
Q

What symptoms are present with common bile duct gallstones?

A

(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)

58
Q

What symptoms are associated with gallstones at the duodenal papilla

A

(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

59
Q

Describe the implications Post-hepatic jaundice and has on surgery

A

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

60
Q

How is conjugated bilirubin tested

A
  1. Add diazo reagent to serum.
  2. 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
  3. Measurement of absorbance @ 530-545 nm proportional to conjugated bilirubin (not unconjugated).
  4. Compare to known standards to calculate concentration.
61
Q

How is total bilirubin tested?

A
  1. Add diazo reagent with caffeine to serum.
  2. Caffeine displaces unconjugated bilirubin from albumin.
    -Free unconjugated bilirubin can now react with the diazo reagent
  3. Both conjugated and unconjugated bilirubin converted to blue/purple diazo derivative of
    bilirubin (Azobilirubin).
  4. Measurement of absorbance @ 530-545 nm proportional to BOTH conjugated and
    unconjugated bilirubin
  5. Compare to known standards to calculate concentration.
62
Q

What are the reference ranges of bilirubin in a normal adult?

A

 Conjugated Bilirubin (adult) < 7 µmol/L

 Total bilirubin (adult) < 21 µmol/L

63
Q

How are bile salts measured in the urine?

A

Achieved by MultiStix urinalysis - commercially available test strips
 Dip in urine, wait, and check colour change

64
Q

What is the significance of finding bilirubin on a multistix urinalysis?

A

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)

65
Q

What is the implications of urobilinogen results from a urine sample?

A

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)

66
Q

How are bile pigments measured in the faeces?

A

Visual inspection of faeces (colour) is easy and free
 Absence of stercobilin is obvious – pale faeces
o Indicates biliary obstruction (post-hepatic jaundice)

Phase 2 1. Gastroenterology (20 decks)

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