Heme Degradation

HEME
METABOLISM
B: HEME
DEGRADATION
OBJECTIVES
By the end of this session, everyone should be able to:
1. Describe the process of heme degradation
2. Explain the clinical relevancies of bilirubin metabolism
INTRODUCTION
What are the sources of heme in the body?
~85% of degraded heme is from Red Blood Cells.
After ~120 days in the circulation/cellular damage RBCs are degraded together with the
hemoglobin they contain.
On average, a 70-kg human turns over approximately 6 g of hemoglobin daily.
 Globin is degraded to its constituent amino acids, and iron enters the iron pool.
 Free porphyrin is also degraded, mainly in the reticuloendothelial cells of the
liver and spleen.
The liver can conjugate and
excrete >3,000 mg of
bilirubin/day,
normal production of bilirubin
is only 300 mg/day.
– Heme oxygenase catalyzes
reactions that opens the
porphyrin ring (converting
cyclic heme to linear
biliverdin) , producing carbon
monoxide (CO), and releasing
Fe2+
– The body is unable to further

degrade the pyrrole rings
Biliverdin (green pigment) is reduced
to bilirubin(red-orange) catalyzed by
biliverdin reductase
Bilirubin is slightly soluble in plasma,

it is transported through blood to the
liver by binding non-covalently to
albumin.
Bilirubin dissociates from albumin and
enters hepatocytes by facilitated
diffusion
In hepatocyte, glucuronic acid is
added onto bilirubin increasing its
solubility- conjugation. Catalyzed by
bilirubin UDP-
glucuronosyltransferase
Bilirubin diglucuronide
•Bilirubin diglucuronide is actively transported against
concentration gradient into thin bile capillaries (bile
canaliculi) This is a rate-limiting step
•Conjugated bilirubin in the intestines is hydrolyzed and

reduced by gut bacteria to yield urobilinogen, a colorless
compound.
FATES OF UROBILONOGEN
Enters enterohepatic
urobilinogen cycle
Reabsorbed into
portal blood.
UROBILINOG transported to
EN Oxidized by kidney, excreted in
bacteria to urine as
stercobilin (gives urobilin(yellow)
feces brown
color)
MEASUREMENT OF BILIRUBIN
IN SERUM
•The levels of bilirubin are detected spectrophotometrically based on the
reddish-purple color formed when bilirubin reacts with diazo reagents
(diazotized sulfanilic acid)
•In the reaction, tetrapyrrole is broken into two azodipyrroles.
•Unconjugated bilirubin reacts slowly because the central carbon bridge is
buried within the hydrogen bonds, conjugated bilirubin lacks these bonds,
hence the reaction occurs rapidly even in the absence of accelerators-such as
caffeine or methanol which disrupts the hydrogen bonds
•When conducted in the absence of added methanol measures
“direct bilirubin,” which is bilirubin glucuronide(conjugated
bilirubin).
•When conducted in the presence of added methanol measures
total bilirubin.
Total bilirubin -direct bilirubin=indirect bilirubin

(unconjugated bilirubin)
CLINICAL RELEVANCE
Hyperbilirubinemia: bilirubin levels >1 mg/dL
(17μmol/L) may result from:
⁃↑Production of bilirubin > liver capacity
⁃Damaged liver
⁃Obstruction of the bile ducts
When the blood concentration of bilirubin reaches 2-2.5
mg/dL, it diffuses into the tissues and turns them
yellow- jaundice
Forms of hyperbilirubinemia include:
• Retention hyperbilirubinemia due to overproduction of bilirubin
(Unconjugated)
• Regurgitation hyperbilirubinemia due to reflux into the bloodstream
because of biliary obstruction (conjugated)
⁃Because of its hydrophobicity, only unconjugated bilirubin can

cross the blood–brain barrier into the central nervous system resulting
to Encephalopathy due to hyperbilirubinemia called kernicterus
⁃Because of its water solubility, only conjugated bilirubin can appear
in urine
Choluria- the presence of bile pigments in the urine occurs only
in regurgitation hyperbilirubinemia.
Acholuria-occurs only in the presence of an excess of
unconjugated bilirubin.
DISORDERS RESULTING TO
UNCONJUGATED BILIRUBIN
1. Neonatal Jaundice
•Accelerated hemolysis and an immature hepatic system for the uptake,
conjugation, and secretion of bilirubin.
•Babies at higher risk: premature babies, Rh incompartibility, poor
feeding
•Unconjugated bilirubin accumulates in blood and can penetrate BBB
•Untreated forms result in mental retardation, motor impairement,
hearing loss
•Treatment depending on severity:
• Exposure to blue light (phototherapy): converts unconjugated bilirubin to
derivatives that can be excreted
• Exchange transfusion
2. Defects of Bilirubin UDP-Glucuronosyltransferase
•Glucuronosyltransferases help increase the polarity of various

metabolites facilitating their excretion e.g drugs, bilirubin
•Mutations in the gene that encodes bilirubin UDP-

glucuronosyltransferase can result into:
i. Gilbert syndrome
ii. Crigler-Najjar syndrome.
GILBERT SYNDROME
•Autosomal recessive form of inherited hyperbilirubinemia
•Around 1/3rd normal functioning of the bilirubin UDP-
glucuronosyltransferase activity, hence relatively mild symptoms.
CRIGLER-NAJJAR
SYNDROME
•Rare autosomal recessive disorder of bilirubin conjugation
•In this syndrome, bilirubin UDP-glucuronosyltransferase is
either completely inactive (CNS type I) or severely
reduced,<10% (CNS type II).
•In CN-I, there is severe unconjugated hyperbilirubinemia which
begins in the neonatal period and continues throughout life.
•These patients are at high risk for developing bilirubin-induced
neurological dysfunction in early life.
3. Liver dysfunction
•Acquired disorders involving hepatic parenchymal cell damage,
impairs bilirubin conjugation resulting to unconjugated
hyperbilirubinemia
•E.g. chloroform poisoning, acetaminophen poisoning, hepatitis,
cirrhosis, or Amanita mushroom poisoning.
DISORDERS RESULTING TO
CONJUGATED BILIRUBIN
1. Dubin-Johnson Syndrome
•Autosomal recessive disorder presenting with conjugated

hyperbilirubinemia.
•It is caused by mutations in the gene encoding the protein
involved in the secretion of conjugated bilirubin into bile
2. BILIARY TREE OBSTRUCTION
E.g. gallstone, cancer of the head of the pancreas

Bilirubin diglucuronide regurgitates into the hepatic
veins and lymphatics, thus appears in the blood and
urine (choluric jaundice), and the stools typically
are a pale color(absence of stercobilin)
SUMMARY
Sickle cell disease, G6PD deficiency, Malaria
• UCB >>liver capacity, UCB levels elevated in blood
• Also more CB is made and excreted into the bile
• Increased amount of urobilinogen enters enterohepatic
circulation and urinary urobilinogen is increased.
• ↑Unconjugated hyperbilirubinemia due to decreased

conjugation.
• ↑Urobilinogen in urine due to decreased enterohepatic
circulation, urine darkens, stools may be a pale, clay color.
• Additionally, Plasma ALT and AST are elevated.
• Patients with obstructive jaundice produce pale, clay color
stool.
• The CB regurgitates into blood(conjugated
hyperbilirubinemia).
• Urinary urobilinogen is absent.
Thank you

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HEME

– The body is unable to further

Bilirubin is slightly soluble in plasma,

•Conjugated bilirubin in the intestines is hydrolyzed and

Total bilirubin -direct bilirubin=indirect bilirubin

⁃Because of its hydrophobicity, only unconjugated bilirubin can

•Glucuronosyltransferases help increase the polarity of various

•Mutations in the gene that encodes bilirubin UDP-

•Autosomal recessive disorder presenting with conjugated

E.g. gallstone, cancer of the head of the pancreas

• ↑Unconjugated hyperbilirubinemia due to decreased

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