Catabolism of heme to bile pigments and hyperbilirubinemia
Objective
• At the end of this lecture, student
will be able to
– Explain Porphyrin
– Explain
formation of bile pigments
– Discuss
hyperbilirubinemia
Porphyrin
• Porphyrins are cyclic compounds
composed of 4 pyrrole rings held together by methenyl (=CH-) bridges
• Metal ions can bind with nitrogen
atoms of pyrrole rings to form complexes
• Eg: Heme is an iron-containing
porphyrin while chlorophyll is a magnesium-containing porphyrin
• Heme and chlorophyll are the
classical examples of metalloporphyrins
Structure of heme
• The
characteristic red color of hemoglobin (ultimately blood) is due to heme
• Heme
contains a porphyrin molecule namely protoporphyrin lX, with iron at its center
• Protoporphyrin
lX consists of four pyrrole rings to which four methyl, two propionyl and two
vinyl groups are attached
Structure of globin
• Globin
consists of four polypeptide chains of two different primary structures(
monomeric units)
• The
common form of adult hemoglobin (HbA1) is made up of two α-chains and two β-chains(α2 β2)
• The
four subunits of hemoglobin are held together by non-covalent interactions
primarily hydrophobic, ionic and hydrogen bonds. Each subunit contains a heme
group.
Degradation of heme to bile pigments
Degradation of heme to bile pigments
• Erythrocytes have a life span of 120
days
• At the end of this period, they are
removed from the circulation
• Erythrocytes are taken up and
degraded by the macrophages of the reticuloendothelial (R E) system in the spleen and liver
• Hemoglobin is cleaved to the protein
part globin and non-protein heme
• About 6 g of hemoglobin per day is
broken down, and resynthesized in an adult man (70 kg)
• Fate of globin: globin may be
reutilized as such for the formation of hemoglobin or degraded to the
individual amino acids
Formation of Bile Pigments
• Non
protein heme: 80% of heme that is subjected for degradation comes from
erythrocytes and 20% from immature RBC & cytochromes
• Normal
concentration in male is 14-16 g/dl, and in female 13-15 g/dl
• Heme
oxygenase is a complex microsomal enzyme utilize NADPH & O2 to
cleaves the methenyl bridge between two pyrrole ring (A&B) to form
biliverdin, simultaneously ferrous ion
(Fe2+) is oxidized to ferric form(Fe3+) and released in
circulation
• The
product of heme oxygenase is biliverdin, Fe3+ and carbon monoxide
• Biliverdin
reductase reduce biliverdin to bilirubin (yellow pigment) by reducing methylene
group
• 1gm of hemoglobin on degradation
finally yields about 35 mg bilirubin
• Approximately 250-350 mg of bilirubin is daily
produced in human adults
Transport
of Bilirubin in Plasma
Bilirubin on release from macrophages circulates
as unconjugated bilirubin in plasma tightly bound to albumin.
Albumin + free Bilirubin ó Bilirubin ~ Albumin
Complex à unconjugated bilirubin
Why bound to albumin?
Significance:
★Increase the solubility of
whole molecule
★ Prevent unconjugated bilirubin
freely come into other tissue, cause damage.
• Bilirubin is lipophilic and
therefore insoluble in aqueous solution
• Bilirubin is transported in the
plasma in a bound form to albumin
• Albumin has two binding sites for
bilirubin- high affinity site and a low
affinity site
• Albumin-bilirubin complex enters the
liver, bilirubin dissociates and is taken up by hepatocytes by a carrier
mediated active transport
• Conjugated bilirubin is excreted
into the bile canaliculi against a concentration gradient which then enters the
bile.
• The transport of bilirubin diglucuronide
is an active, energy-dependent and rate limiting process
• Bilirubin glucuronides are
hydrolysed in the intestine by specific bacterial enzymes namely
B-glucuronidases to liberate bilirubin
• The latter is then converted to
urobilinogen (colourles compound), a small part of which may reabsorbed into
the circulation
• Urobilinogen can be converted to
urobilin (an yellow colour compound) in the kidney and excreted
• The characteristic colour of urine
is due to urobilin A major part of urobilinogen is converted to stercobilin
which is excreted with feces The characteristic brown colour of feces is due to
stercobilin
Formation of urobilins in the intestine
Catabolism
of hemoglobin
Hyperbilirubinemia
Jaundice
• The normal serum total bilirubin
concertration is in the range of 0.2 to 1.0 mg/dl.
• About 0.2-0.6 mg/dl is unconjugated
whie 0.2 to 0.4 mg/dl is conjugated bilirubin
• Jaundice( French: Jaune-yellow) is a
clinical condition characterized by yellow colour of the white of the eyes
(sclerae) and skin, due to deposition of bilirubin and its elevation levels in the serum
• The term hyperbilirubinemia is often used to
represent the increase concentration of
serum bilirubin
• Classification of jaundice : Jaundice is classified into three major types-
hemolytic, hepatic and obstructive
1.
Hemolytic jaundice: This condition is associated with
increased hemolysis of erythrocytes (e.g. incompatible blood transfusion,
malaria, sickle-cell anemia).
• This results in the overproduction
of bilirubin beyond the ability of the
Liver to conjugate and excrete the same
• lt should, however be noted that
liver possesseas large capacity to conjugate about 3.0 g of bilirubin per day
against the normal bilirubin production is 0.3/day
• In hemolytic jaundice, more
bilirubin is excreted into the bile leading to the increased formation of
urobilinogen and stercobilinogen
• Hemolytic jaundice is characterized
by Elevation in the serum unconjugated bilirubin
• Increased excretion of urobilinogen
in urine
• Dark brown colour of feces due to
high content of stercobilinogen
2. Hepatic (hepatocellular) jaundice:
• caused by dysfunction of the Iiver
due to damage to the parenchymal cells
• This may be attributed to viral
infection (viral infection, hepatic poisons and toxins (chloroform, carbon tetrachloride, phosphorus etc.)
cirrhosis of liver,
cardiac failure etc
• Damage to the liver adversely
affects the bilirubin uptake and its conjugation by liver cells
• Hepatic jaundice is characterized by
increased levels of conjugated and unconjugated bilirubin in the serum
• Dark coloured urine due to the
excessive excretion of bilirubin and urobilinogen
• lncreased activities of alanine
transaminase (SGPT) and aspartate transaminase (SCOT)
• Released into circulation due to damage
to hepatocytes
• The patients pass pale, clay
coloured stools due to the absence of stercobilinogen
• The affected individuals experience
nausea and anorexia (loss of appetite)
3. Obstructive (regurgitation) jaundice:
• Due to an obstruction in the bile duct
that prevents the passage of bile into the intestine
• The obstruction may be caused by
gall stones, tumors etc
• Due to the blockage in bile duct,
the conjugated bilirubin from the liver enters the circulation
• Obstructive jaundice is
characterized by Increased concentration of conjugated bilirubin in serum
• Serum alkaline phosphatase is
elevated as it is released from the cells of the damaged bile duct
• Dark coloured urine due to elevated
excretion of bilirubin and clay coloured feces due to absence of stercobilinoge
• Feces contain excess fat indicating
impairment in fat digestion and absorption in the absenceo f bile
• The patients experience nausea and
gastrointestinal pain
Summary
• Porphyrins
are the cyclic compounds composed of 4 pyrrole ring held together by methlenyl (=CH-) bridges
• Biliverdin & Bilirubin are bile pigments
• Bile
is secreted into intestine where glucuronic acid is removed and the resulting
bilirubin is converted to urobilinogen
• Urobilinogen
is oxidized by intestinal bacteria to the brown stercobilin
• Jaundice is a clinical condition
characterized by yellow colour of the white of the eyes (sclerae) and skin, due
to deposition of bilirubin
• The term hyperbilirubinemia is often
used to represent the increase
concentration of serum bilirubin