Bilirubin Metabolism and Excretion (Choudhury) Flashcards
Source of bilirubin
Dead RBC’s broken down by macrophages of RES
Hemoglobin breakdown
First–> heme-iron complex + globin chain
Second –> Heme complex is broken down to Fe and biliverdin
Fate of iron after broken down from hemoglobin?
Binds to transferrin and recycled to be used in formation of new RBC’s
“bili light” phototherapy?
Converts unconjugated bilirubin from “trans” to “cis” form using light.
cis form is more easily excreted in the urine
Used in treatment of infants with high levels of unconjugated bilirubin
unconjugated bilirubin
Water In-soluble
Biliverdin –> unconjugated bilirubin
carried in blood with albumin
how does unconjugated bilirubin enter hepatocytes
through the sinusoids via:
Passive diffusion
Receptor mediated endocytosis
Where is unconjugated bilirubin converted to conjugated bilirubin
Liver (SER)
Conjugated bilirubin
Water-Soluble
aka Direct
made in the liver by UDPGT
UDPGT
(uridine 5’-diphosphate glucuronyl transferase in liver
adds 2 glucuronic acids to bilirubin molecule to form conjugated bilirubin (water soluble)
without this enzyme bilirubin would not be able to be excreted (b/c it would remain water insoluble)
Fate of globin chain after RBC breakdown
broken down to aa’s
Elevated Urinary urobilinogen
occurs during hyperbilirubinemia
majority of urobilinogen is reabsorbed by the gut and re-excreted by the liver with a small amount being excreted in the urine…
Jaundice
Accumulation of conjugated or unconjugated bilirubin in the serum, usually due to hepatocellular disease or biliary obstructive disease (bilirubin is not excreted normally)
> 2.0 mg/dL
Increased urinary bilirubin
occurs when there is an increase in serum conjugated bilirubin
since the conjugated bilirubin is water-soluble, it can also be filtered by the glomerulus and excreted in the urine
Causes of elevated serum unconjugated bilirubin
1) Hemolysis
2) Gilbert’s syndrome
3) Crigler-Najjar Syndrome
Hemolysis
Hemolytic anemia due to sickle cell disease, autoimmune process, drug-induced
Results in premature release of hemoglobin from RBC’s
Rate of cell destruction and release of unconjugated bilirubin overcomes rate of liver clearance –> increase in serum levels
can be due to immature liver or shitty UDPGT activity
Gilbert’s syndrome
Genetic cause of hyperbilirubinemia (total t show it)
caused by enzyme mutation
increased urinary bilirubin
point mutation. slightly defective
Crigler-Najjar Syndrome
Genetic cause of hyperbilirubinemia (unconj. bili)
gene for enzyme UDPGT defective, cannot conjugate bilirubin, increased urinary bilirubin
die 6mo - 1 year
homozygous type I–> >5mg/dL often over 30-50 mg
heterozygous type II–> less severe, can live to adulthood
use phototherapy
Types of hepatic jaundice
1) Gilbert’s syndrome
2) Crigler-Najjar Syndrome
3) Dubin-Johnson
4) Hepatitis
Types of prehepatic jaundice
1) Hemolysis (due to sickle cell disease, autoimmune disease, drug-induced, break down of red blood cells due to HbF–> HbA (23BPG))
total bili usually does not exceed 5 mg/dL
negative urine bilirubin
negative urinary urobilinogen
Types of posthepatic jaundice
1) Biliary obstruction (impaired excretion of bilirubin)
increased serum and urine conj. bilirubin
decreased level of urobilin/stercobilin (clay stools)
negative urinary urobilinogen
Causes of elevated serum conjugated bilirubin
1) Dubin Johnson
2) Biliary obstruction (inflammation of the biliary tract, bile stones)
Causes of elevated serum conjugated and unconjugated bilirubin
1) Hepatitis
Dubin-Johnson Syndrome
Impaired excretion of conjugated bilirubin from liver
Due to inborn error of metabolism (defect in ATP binding cassette) transportation problem
Conjugated bilirubin accumulates in liver and backs up into the circulation (detected in serum)
Black Liver, brown urine (due to spillage of direct bilirubin into blood and kidney)
Biliary obstruction
Type of posthepatic jaundice causing increase serum conj. bilirubin
Includes Cholelithiasis (bile stones) blocking common bile duct, or inflammation of biliary tract
since conj. bili can’t reach the intestine, not broken down to stercobilin so have clay colored stools
no urobilinogen in urine, but lots of conjugated bilirubin backs up and is secreted in urine
Hepatitis
causes increase in both conj. and unconj. bili in serum
causes:
impaired conjugation ability
blockage of excretion from liver
total bili 5-10 mg
Adult reference range for serum conjugated bilirubin
<0.2 mg/dL
Adult reference range for serum unconjugated bilirubin
0.1-1.0 mg/dL
Adult reference range for Total Bilirubin
0.1-1.2 mg/dL
Kernicterus
conc. of unconjugated bilirubin exceeds 15-20mg
condition in newborn due to massive destruction of RBC’s (Hb F does not respond to 2-3BPG) and due to UDPGT taking time to be induced/function
to actually conjugate bilirubin
bilirubin is toxic, when enters CNS it causes severe motor dysfunction and retardation
Albumin
This is what carries unconjugated bilirubin in plasma (b/c unconj. bilirubin is usually a lipid so needs protein carrier and it is water insoluble)
Gilbert’s syndrome
Genetic cause of hyperbilirubinemia
type of hepatic jaundice
mild elevation of unconj. bili
“student” stressed
caused by enzyme mutation and/or transport deficit in the hepatocyte
Gilbert’s syndrome
Genetic cause of hyperbilirubinemia
type of hepatic jaundice
mild elevation of unconj. bili
“student” stressed
caused by enzyme mutation and/or transport deficit in the hepatocyte
Crigler-Najjar Syndrome
Genetic cause of hyperbilirubinemia (unconj. bili)
type of hepatic jaundice
homozygous type I–> >5mg/dL often over 20 mg
kernicterus, use phototherapy for treatment
heterozygous type II–> less severe, can live to adulthood
True or false… Bilirubin is formed in the liver
FALSE. bilirubin is formed outside the liver
Types of hepatic jaundice
1) Gilbert’s syndrome
2) Crigler-Najjar Syndrome
3) Dubin-Johnson
4) Hepatitis
Types of hepatic jaundice
1) Gilbert’s syndrome
2) Crigler-Najjar Syndrome
3) Dubin-Johnson
4) Hepatitis
Types of prehepatic jaundice
1) Hemolysis (due to sickle cell disease, autoimmune disease, drug-induced)
Treatment of Kernicterus
Phototherapy (blue light)
changes from trans to cis form
cis is more easily excreted in urine
Kernicterus caused by ….
Fetus has Hb F
Adult has Hb A
2-3 BPG binds to adult hemoglobin and kicks out oxygen in low oxygen scenario
2-3 BPG can’t bind to Hb F in baby
Types of posthepatic jaundice
1) Biliary obstruction
Alcoholic cirrhosis of the liver leads to…
hyperbilirubinea due to decreased excretion of bilirubin into bile (stays in the bloodstream much longer)
Causes of elevated serum conjugated bilirubin
1) Dubin Johnson
2) Biliary obstruction (inflammation of the biliary tract, bile stones)
Causes of elevated serum conjugated and unconjugated bilirubin
1) Hepatitis
Causes of elevated serum conjugated and unconjugated bilirubin
1) Hepatitis
Dubin-Johnson Syndrome
Type of hepatic jaundice
Impaired excretion of conjugated bilirubin from liver
Due to inborn error of metabolism (defect in ATP binding cassette)
Conjugated bilirubin accumulates in liver and backs up into the circulation (detected in serum)
Dark/black liver
Dubin-Johnson Syndrome
Type of hepatic jaundice
Impaired excretion of conjugated bilirubin from liver
Due to inborn error of metabolism (defect in ATP binding cassette)
Conjugated bilirubin accumulates in liver and backs up into the circulation (detected in serum)
Dark/black liver
Biliary obstruction
Type of posthepatic jaundice causing increase serum conj. bilirubin
Includes Cholelithiasis (bile stones) blocking common bile duct, or inflammation of biliary tract
since conj. bili can’t reach the intestine, not broken down to stercobilin so have clay colored stools
no urobilinogen in urine, but lots of conjugated bilirubin backs up and is secreted in urine
Biliary obstruction
Type of posthepatic jaundice causing increase serum conj. bilirubin
Includes Cholelithiasis (bile stones) blocking common bile duct, or inflammation of biliary tract
since conj. bili can’t reach the intestine, not broken down to stercobilin so have clay colored stools
no urobilinogen in urine, but lots of conjugated bilirubin backs up and is secreted in urine
Hepatitis
causes increase in both conj. and unconj. bili in serum
causes:
impaired conjugation ability
blockage of excretion from liver
Hepatitis
causes increase in both conj. and unconj. bili in serum
causes:
impaired conjugation ability
blockage of excretion from liver
Adult reference range for serum conjugated bilirubin
<0.2 mg/dL
Adult reference range for serum conjugated bilirubin
<0.2 mg/dL
Adult reference range for serum unconjugated bilirubin
0.1-1.0 mg/dL
Adult reference range for serum unconjugated bilirubin
0.1-1.0 mg/dL
Adult reference range for Total Bilirubin
0.1-1.2 mg/dL
Adult reference range for Total Bilirubin
0.1-1.2 mg/dL
Kernicterus
Often displayed in infants with severe jaundice
causes severe motor dysfunction and retardation
Albumin
This is what carries unconjugated bilirubin in plasma (b/c bilirubin is usually a lipid so needs protein carrier)
only place in the body we make CO
spleen
made when heme is broken down to biliverdin
heme oxygenase
takes heme and makes biliverdin
also liberates Fe and CO from heme structure
biliverdin reductase
biliverdin –> unconjugated bilirubin
happening in spleen/RES
True or false… Bilirubin is formed in the liver
FALSE. bilirubin is formed outside the liver
Cholestasis
impaired bile flow
increased conc. of bilirubin in blood
icterus
bilirubin 3.0 mg or more
Hemolytic diseases that cause increase in indirect bilirubin (b/c breaking down lots of RBC’s)
G6PD deficiency
Pyruvate kinase deficiency (no ATP made so cells swell, lyse)
Vit K toxicity
Sickle cell disease
Treatment of Kernicterus
Phototherapy
changes from trans to cis form
cis is more easily excreted in urine
Kernicterus caused by ….
Fetus has Hb F
Adult has Hb A
2-3 BPG binds to adult hemoglobin and kicks out oxygen in low oxygen scenario
2-3 BPG can’t bind to Hb F in baby
Rotor Syndrome
elevated direct bilirubin due to transport and storage problem in the liver
liver normal
jaundice but normal
Alcoholic cirrhosis of the liver leads to…
hyperbilirubinea due to decreased excretion of bilirubin into bile (stays in the bloodstream much longer)
sulfonamides
increase unconjugated bilirubin leading to kernicterus
why do newborns have jaundice
At birth massive destruction of RBC’s due to wrong type of Hb
Neonatal hyperbilirubinemia- UDPGT is induced only at birth so the enzyme expression may be lacking (so have unconjugated)
Elevated AST or ALT or BUN
in laboratory studies this means that it is a hepatic type of dysfunction
amylase and lipase
in laboratory studies they tell us function of the pancreas so something is wrong post-hepatic
lipase and amylase are backed up and go back to the pancreas and cause digestion of pancreas –> pain
