Urea Cycle Flashcards
bilirubin
toxic waste product, extracted and biotransformed mainly in the liver, excreted in bile and urine.
= a bile pigment
breakdown of RBC
go to the spleen, Hb broken down to heme and globin
globin reused as amino acid, heme taken up by reicoendothelial cells of the spleen and called unconjugated bilirubin
bilirubin then transported to liver in bloodstream bound to albumin and is taken up by hepatic cells
what happens to bilirubin in the liver
In liver cells, bilirubin is conjugated by addition of glucuronic acid to produce bilirubin diglucuronide (conjugated or water-soluble bilirubin). This reaction is catalyzed by uridyldiphosphate glucuronyl transferase (UDPGT)
Elevations of serum and urine bilirubin levels are normally associated with Jaundice
Hemoglobin’s journey to bilirubin (enzymes, etc.)
Hemoglobin –> globin and heme
Heme oxygenase turns heme into biliverdin
NADPH joins it and biliverdin reductase forms bilirubin (water insoluble)
In the liver: glucoronyltransferase helps 2 UDP-glucoronic acid join to make bilirubin diglucuronide (water soluble)
–> via bile duct to intestins
Urobilinogen formed by bacteria in the intestin. Stercobilin excreted in feces, Urobilin excreted in urine.
Heme degradation - bilirubin
Transfer of bilirubin from blood to bile involves 4 distinct but interrelated steps
Hepatocellular uptake: Uptake of bilirubin by hepatocyte has carrier-mediated kinetics
Intra-cellular binding: Within the hepatocyte, bilirubin is kept in solution as a non substrate ligand to several of glutathione-S-transferases, formerly called ligandins
Conjugation: bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronyl transferase to form bilirubin mono or diglucuronide. Conjugation disrupts the internal hydrogen bonding that limits aqueous solubilty of bilirubin, and the resulting glucuronide conjugates are highly soluble in water. Conjugation is obligatory for excretion of bilirubin acroscc the bile canalicular membrane into bile. The UDP-glucuronosyl transferases have been classified into gene families (UGT1 family)
Biliary excretion: Bilirubin mono- and diglucuronides are excreted across the canalicular plasma membrane into bile canaliculi by an ATP-dependent transport process mediated by a canalicular membrane protein called multidrug resistance-associated protein 2 (MRP2). Mutations of MRP2 result in Dubin-Johnson syndrome.
Unconjugated bilirubin does not reach the gut except in neonates or, by ill-defined alternative pathways as seen in unconjugated hyper-bilirubinemia (e.g. Crigler-Najjar syndrome type I)
bilirubin metabolism
Conjugated bilirubin flows into bile ducts and is secreted with bile into intestines
Converted to urobilinogen by intestinal bacteria
Oxidized urobilinogen is excreted in stool as urobilin and stercobilin.
A small portion is reabsorbed and recycled back into bile.
Another small portion remains in blood and is filtered and excreted by kidney in urine
Bilirubin excretion
Conjugated bilirubins are poorly reabsorbed, but are partly hydrolyzed back
to unconjugated bilirubin by catalytic action of bacterial b glucuronidases
In the distal ileum and colon, anaerobic flora mediate further catabolism of
bile pigments: 50% of conjugated bilirubin is converted into urobilinogen by
intestinal bacteria
Hydrolysis of conjugated bilirubin to unconjugated
bilirubin by bacterial b glucuronidases
Multistep hydrogenation (reduction) of unconjugated bilirubin
to form colorless urobilinogens: and
Oxidation of unconjugated bilirubin to brown colored mesobilifuscins
5% of urobilinogen is excreted by kidney through urine
Urobilinogens
Urobilinogens is a collective term for a 3 group of 3 tetrapyrroles:
- Stercobilinogen - Mesobilinogen - Urobilinogen
In the lower intestinal tract, the 3 urobilinogens spontaneously oxidize to
produce the corresponding bile pigments:
- Stercobilin
- Mesobilin and,
- Urobilin
Which are orange-brown color and are the major pigments of stool
Stercobilinogen
Some of the urobilinogen is excreted in feces as stercobilinogen.
In feces, stercobilinogen is oxidized to stercobilin (red-brown color).
Causes of jaundice
Causes of jaundice:
- excessive production of bilirubin
- reduced hepatocyte uptake
- impaired bilirubin conjugation
- impaired bile flow
In infants, bilirubin exceeding 15-20 mg/dL causes kernicterus
Kernicterus is a form of brain damage caused by excessive jaundice
Examples of hyperbilirubinemia
a. Hemolytic anemia
increased unconjugated bilirubin (in blood), increased congugated bilirubin (released to bile duct)
b. Hepatitis
increased unconjugated bilirubin (in blood), increased conjugated bilirubin (in blood)
c. Biliary duct stone
increased unconjugated bilirubin (in blood)
increased conjugated bilirubine (in blood)
Prehepatic jaundice
excessive bilirubin presented to liver for metabolism, hemolysis in most cases, liver function is normal. ↑ in serum unconjugated bilirubin. total bili usually does not exceed 5 mg/d negative urine bilirubin urinary urobilinogen ↑ dark brown color of feces due to high content of stercobilinogen
Examples: Malaria Sickle cell crisis Thalassemia G6PD Autoimmune disorders Rh- or ABO incompability Drugs or toxins
hepatic jaundice
abnormal hepatocyte function
cannot deal with normal load of bilirubin
Cause: enzyme mutation/impaired hepatocellular
uptake (Gilbert’s syndrome)
Findings: serum total bilirubin 5.0 mg/dL; ↑ urinary urobilinogen
Cause: defective secretion by hepatocyte
(Dubin-Johnson syndrome)
Findings: ↑ serum conjugated bili
Cause:hepatitis with lowered conjugation/excretion
Findings: ↑ serum direct and indirect bili with
total levels of 5-10 mg/dL
Darkcoloured urine due to the
excessive excretion of bilirubin and urobilinogen
Pale, clay coloured stools due to the absence of
Stercobilinogen
Increasedactivities of alanine and aspartate
transaminases.
Post-hepatic jaundice
impaired excretion of bilirubin
cause: mechanical obstruction of the flow
of bile into the intestines due to gallstones
or tumors
Findings: ↑ serum AND urine conjugated
bilirubin
↓ level of urobilin/stercobilin in
stool (clay-colored stools)
Negative urinary urobilinogen
Increased serum ALP
darkcoloured urine due to elevated
excretion of bilirubin and
clay coloured feces due to absence of stercobilinogen
What’s important to know about findings in various causes of jaundice?
Serum bilirubin: unconjugated in pre-hepatic, both in hepatic, conjugated in post hepatic
Urine bilirubin is absent in pre-hepatic (achloric jaundice)
Fecal stercobilinogen - markedly increased in pre-hepatic jaundice (dark brown stool)
reduced in hepatic (pale stool)
Absent in post hepatic (clay colored stool)
Fecal fat increased in hepatic and post hepatic jaundice
Liver function impaired in hepatic jaundice
alkaline phosphatase up in post hepatic
Vonden burg test biphasic in hepatic
Inherited Disorders of Bilirubin Metabolism
Gilbert’s Syndrome Crigler-Najjar (Type I) Crigler-Najjar (Type II) Lucey-Driscoll – (exclude) Dubin-Johnson Rotor’s Syndrome
Gilbert’s Syndrome
There is compensatory hemolysis, impaired uptake and conjugation
Gilbert’s syndrome is also called the familial non-hemolytic
non-obstructive jaundice
Mild unconjugated hyperbilirubinemia
It affects 3% - 5% of the population.
It is often misdiagnosed as chronic hepatitis
The concentration of bilirubin is serum fluctuates between
1.5 and 3 mg/dl
In this condition the activity of hepatic glucuronyltransferase
is low as a result of mutation in the bilirubin
–UDP-glucuronyltransferase gene (UGT 1A1)
Crigler Najjar Syndrome (Type I)
Crigler_Najjar Syndrome (Type I) is a rare genetic disorder caused by complete absence of UDP-glucuronyltransferase and manifested by very high levels of unconjugated bilirubin and often leads tobrain damage in infants.
characterised by aserum bilirubin usually above 345 µmol/l (310–755) (whereas thereference range for total bilirubin is 2–14 μmol/l).
NoUDP glucuronosyltransferase 1-A1 expression in theliver tissue Hence, there is no response to treatment withphenobarbital, which causesCYP450 enzyme induction
It is inherited as an autosomal recessive trait
Most patients die of severe brain damage caused by kernicterus
within the first year of life
Early liver transplant is the only effective therapy