Bilirubin Metabolism Flashcards
What are bile salts
Act as biological emulsifiers
What are bile salts formed from
They are formed from bile acids which stem from cholesterol
Glycine and taurine are added into bile acids to form bile salts
What is emulsification
The breakdown of large lipid droplets into small uniformly distributed droplets
• Hydrophobic portion binds to and disperses large triglyceride lipids
• Hydrophilic portion prevents large droplets from reforming
Why is emulsification important
Increases the surface area on which triglyceride lipase can act
What are the steps of lipid emulsification
- Bile salts emulsify the fat globules in the intestines
Digestion by pancreatic lipase. - Free fatty acids (FFA-) produced
- Bile salts make micelles from the FFA produced
- FFAs from micelles are absorbed into the epithelium.
- Absorbed FFAs form TGs (triglycerides).
- TGs are packaged into chylomicrons for secretion into lacteals (the lymphatic vessels of the small intestine which absorb digested fats).
check lecture pic for more understanding
Where is the sphincter of Oddi (SO) located
located at the junction of the common bile duct (CBD), main pancreatic duct, and the duodenum.
What is the sphincter of oddi (SO)
muscular valve that controls flow of bile and pancreatic fluid into the duodenum
What happens to SO during interdigestive period
sphincter of Oddi contracts
Pressure increases in the common bile duct and bile flows into the gallbladder. Epithelial cells reabsorb water and electrolytes, thus concentrating the bile in the gall bladder.
What hormones are involved in the hormonal regulation of bile secretion
CCK
Secretin
How is CCK released and what is its function
Fatty acids and amino acids entering the duodenum (after a meal) stimulate enteroendocrine cells to release cholecystokinin (CCK)
CCK stimulates contraction of gallbladder smooth muscle and relaxes the sphincter of Oddi -> Bile release from the GB
How is Secretin released and what is its function
Acidic chyme in the duodenum stimulates other endocrine cells to release secretin.
Secretin stimulates duct cells in the liver to release bicarbonate into the bile.
Secretin also stimulates bile production
What is hyperbilirubinaemia
Raised levels of bilirubin in the blood stream
What are the reference ranges for TOTAL BILIRUBIN and CONJUGATED BILIRUBIN in an adult?
Total bilirubin (adult) < 21 mmol/L Conjugated Bilirubin (adult) < 7 mmol/L
What does (Total bilirubin > 30 mmol/L) suggest?
jaundice may be visible in the sclera
What does (Total bilirubin > 100 mmol/L) suggest?
Jaundice may be visible in the skin
What are the types of jaundice
- Prehepatic- elevated haemolysis (destruction of RBCs)
- Hepatic- liver damage
- Post Hepatic- blockage of bile ducts
Describe pre-hepatic jaundice
- Elevated haemolysis (destruction of RBCs)
- Liver cannot cope with increased levels of unconjugated bilirubin
- More RBC breakdown -> More haemoglobin -> More Unconjugated bilirubin
What are the causes of pre-hepatic jaundice
- Tropical diseases, e.g. Yellow Fever, Malaria
- Side-effect of quinine-based anti-malarial drugs
- Genetic disorders associated with increased haemolysis (e.g. sickle cell anaemia)
What type of jaundice causes neonatal jaundice
Pre-hepatic jaundice
What are the two types of neonatal jaundice
- physiological jaundice
- Haemolytic disease of the new born:
describe physiological jaundice of the new born
- Common & usually harmless
- After birth, new-borns must destroy foetal Hb and replace it with adult Hb, RBCs have a short lifespan than adult
- Undeveloped liver (with lack of glucuronyltransferase- enzyme that conjugates bilirubin) has insufficient capacity to cope with elevated haemolysis
- ALSO there are inhibitors of bilirubin conjugation in breast milk
- bilirubin peaks at 3-5 days and returns to normal within <14 days
How is physiological jaundice of the new born treated
• Treated with phototherapy
Blue light changes unconjugated bilirubin to a water-soluble form that can be excreted
Describe haemolytic disease of the new born
• Rh incompatibility between mother and foetus may also cause haemolysis
–> Can cause very high bilirubin concentration
What is a complication of haemolytic disease of the new born
• At risk of kernicterus – bilirubin crosses immature blood brain barrier, deposition of bilirubin in basal ganglia and brainstem nuclei resulting in brain damage if untreated
How do you treat haemolytic disease of the new born
high dose phototherapy
blood transfusion
Describe Hepatic Jaundice
Related to problems during bilirubin metabolism cycle
• Impaired uptake of unconjugated bilirubin
• Impaired conjugation of bilirubin
• Impaired transport of conjugated bilirubin into bile caniculi
Give example of a disease that causes impaired conjugation of bilirubin, consequently causing hepatic jaundice
Impaired conjugation of bilirubin
- E.g. Gilberts syndrome (reduced UGT glucuronyl transferase activity)
Give examples of conditions/diseases that cause impaired transport of conjugated bilirubin into bile caniculi consequently causing hepatic jaundice
• Impaired transport of conjugated bilirubin into bile caniculi
- 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
Describe post hepatic jaundice
Present in conditions associated with obstruction of hepatic, cystic or common bile duct. Prevents bile from being released into the small intestine = Cholestasis
What are the main causes of post hepatic jaundice
- Gallstones – small pebbles made of cholesterol that move from gall bladder to block ducts. Arise if capacity of bile salts and phospholipids to solubilise cholesterol is exceeded.
- Pancreatitis – acute or chronic inflammation of the pancreas following infection or damage. Swelling can block bile flow.
- Pancreatic tumours – tumour growth can block bile flow
How are gall stones treated?
Usually removed surgically.
- Oral ursodeoxycholic acid treatment (dissolves small gallstones).
- Lithotripsy (ultrasonic shock waves)
describe gall stones severity and location
Severity of gallstones related symptoms depend on their location.
1) Cystic Bile duct
2) Common Bile duct
3) Duodenal Papilla (opening of pancreatic
duct into duodenum, surrounded by
sphincter of Oddi)
Describe gallstones in the cystic bile duct and symptoms
joins gallbladder to the common bile duct
→ Painful contractions
Describe gallstones in the common bile duct and symptoms
(links hepatic and cystic duct to the deuodeum)
→ No bile secretion into intestine
→ Steaorrhea (fatty faeces as no bile salts)
→ Grey faeces (as no bile pigments (stercobilin))
→ Post-hepatic jaundice (as reduced excretion of
bilirubin)
describe gallstones in the duodenal papilla and symptoms
(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
Why is it important that Vitamin K is digested and adsorbed through bile salts
- VitK required for efficient coagulation. Vit K is a Co-factor for liver g-glutamyl carboxylase (GGCX)
• GGCX is required to make active coagulation factors II VII IX X
–> so if no Vit K then no coagulation factors
If a patient presents with post-hepatic jaundice, what is given to prevent haemorrhage
Course of Vitamin K prior to surgery
What lipid soluble vitamins require bile salts for their digestion and adsorption?
Vitamins A, D, E and K
How are bile pigments measured in serum
i.e. Direct (CONJUGATED) bilirubin
To measure CONJUGATED bilirubin:
1. Add diazo reagent to serum.
2. Conjugated bilirubin converted to blue/purple diazo
derivative of bilirubin (Azobilirubin). (UB is bound to albumin so not water soluble so does not react with diazo)
3. Measurement of absorbance @ 530-545 nm. (more absorbance = more conjugated bilirubin in blood)
4.Compare to known standards to calculate concentration
How are bile pigments measured in serum
i.e. Total (CONJUGATED + UNCONJUGATED) bilirubin
To measure Total Bilirubin:
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 (water soluble)
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.
How would you find out UB levels from serum measurements
Find out serum levels of Total bilirubin (conjugated + unconjugated) and Direct (conjugated) bilirubin
Then, substract direct from total to find out unconjugated bilirubin levels
How would you measure bile pigments in urine
Use MultiStix urinalysis and wait for colour change
What are the reference ranges for total and conjugated bilirubin
Conjugated Bilirubin (adult) < 7 mmol/L Total bilirubin (adult) < 21 mmol/L
Why having conjugated bilirubin in urine a bad sign
- Conjugated bilirubin is water soluble but not detected in urine in normal health (low concentration)
- Detection of Conjugated bilirubin in urine = Hyperbilirubinuria. This is always pathological as it means conjugated bilirubin has leaked back into the blood stream.
- sign of hepatic or post-hepatic jaundice
why is UB not detected in urine
it is NOT water soluble so not filtered in the kidney and so not filtered into urine
How would you measure URObilinogen levels in urine
- test area impregnated with p dimethylaminobenzaldehyde – forms
a pink azo dye in the presence of urobilinogen - Normally present in low concentrations
What do high concentrations of URObilinogen in urine suggest
high concentrations can indicate increased haemolysis or liver disease (pre-hepatic/hepatic jaundice)
What does absence of any URObilinogen in urine suggest
Absence of raised urobilinogen in a jaundiced patient can indicate biliary obstruction (post-hepatic jaundice)
How would u measure bile pigments in faeces
- Not done – waste of time/money
- Visual inspection is easy and free
- Absence of stercobilin is obvious which Indicates biliary obstruction (post-hepatic jaundice)
What is a (icterometer/bilirubinometer)?
- Are not a substitute for laboratory measurements (need lab results as well to confirm diagnosis)
- Measures yellowness of skin due to bilirubin,
measures at multiple wavelengths to correct for
variations in haemoglobin, melanin and skin
thickness - Forehead or sternum measurements correlate
best with serum bilirubin concentration - Carried on neonates
List the causes of hepatic jaundice
o Cirrhosis (e.g. alcohol-induced) o Hepatotoxic drugs (e.g. paracetamol overdose) o Viral hepatitis
