Bilirubin Metabolism: Hd. - Msc. (Biochemistry)

Bilirubin Metabolism
Fenk Bakir Maarouf

HD. _MSc. (biochemistry)
Objectives
• Understand Bilirubin Metabolism
• What is jaundice
• Types of Jaundice.
• Neonatal Jaundice.
• Hereditary hyperbilirubinemia
• Lab. Procedure for Bilirubin measurement
Definition of bilirubin
 Bilirubin is the product of normal heme catabolism .
 It’s a yellow pigment present in bile , urine and feces .
 Heme is found in hemoglobin, a principal component of

RBCs [Heme: iron + organic compound “porphyrin”].
 Heme source in body:

 80% from hemoglobin ( old RBCs)
 20% other hemo-protein: cytochrome, myoglobin)
Heme and bilirubin
 Heme is four pyrrols rings connected together to form

(porphyrin).
 Bilirubin consists of open chain of four pyrrols-like rings
Bilirubin Metabolism
1. Unconjugation process :
 RBCs are phagocytized in the spleen. Hemoglobin is
catabolized into amino acids, iron and heme.
 Heme ring is broken and converted to unconjugated

( indirect ) bilirubin.
 This unconjugated bilirubin is not soluble in water, It is

then bound to albumin and carried to the liver.
Hemoglobin degrading and bilirubin formation
Spleen Hemoglobin Plasma

globin Protein and a.a pool
Heme
iron Iron pool
Bilirubin Binds with albumin
Liver
Conjugation
process
2. Conjugation process:
 In liver: Bilirubin is conjugated with Glucouronic acid to
produce bilirubin diglucuronides, which is water soluble and
readily transported to bile.
Blilirubin + Glucouronic acid bilirubin diglucuronides

UDP-glucuronyl "water soluble"
"water insoluble" transferase "Conjugated BIL"
Bile
 Then conjugated bilirubin is excreted in bile through bile duct

to the deudenum which helps in fat digestion.
 UDPGT: Uridine Diphosphate Glucuronyl Transferase
 The excess amount transferred to intestine to be excreted in urine
and stool.
 Most of the secreted bile is reabsorbed from the terminal ilium
through portal vein to the liver. This process is known as
enterohepatic circulation
 The conjugated bilirubin remaining in the large intestine is

metabolised by colonic bacteria to form urobilinogen , which may
be further oxidized to urobilin and stercobilin . stercobilin give
feces its brown color.
 Elevated levels of bilirubin in blood and urine indicate certain

diseases.
 Indirect bilirubin: is unconjugated (water insoluble bilirubin) , it
reacts more slowly with reagent (reaction carried out in methanol).
 Direct bilirubin: is conjugated (water soluble ) , solution it reacts

rapidly with reagent (direct reacting).
 - both conjugated and unconjugated bilirubin are measured given

total bilirubin.
 Total bilirubin = D+ ID
• Knowing the level of each type of bilirubin has diagnostic

important.
• is the yellow discoloration of skin , sclera and mucous
membrane due to elevation of bilirubin in blood .
• Types of Jaundice:
• according to the cause of jaundice
it is classified to three main types:
Pre-hepatic jaundice
 Hepatic jaundice
 Post-hepatic .
haemolytic jaundice hepato-cellular jaundice obstructive jaundice
Pre-hepatic jaundice Hepatic jaundice Post-hepatic jaundice
 Due to increase in  Due to liver cell damage  Due to obstruction of

bile duct which prevents
RBCs breakdown
 Conjugation of bilirubin passage of bilirubin into
decreased (ID.Bil. ). intestine.
 The rate of RBCs lysis
and bilirubin production  Blilirubin that is conjugated  D.Bil will back to liver
more than ability of is not efficiently secreted and then to circulation
liver to convert it to the into bile but leaks to blood elevating its level in
Causes conjugated form (D.Bil. ) blood and urine.
 Occur in :  Occur in:

 Occur in:
Hepatitis (viral ,drug, alcoholic Biliary stricture
Hemolytic anemia ( autoimmune, steatohepatits) Cancer of the pancreas or
Thalassemia) gallbladder
Cirrhosis.
Transfusion reaction Gilbert's disease Gallstones
Type of Bil. ID.Bil > D.Bil D.Bil, ID.Bil, T.Bil all (High) D.Bil (High)
Conformationa K+ ( High)
ALT, AST (High) ALP, GGT ( High)
l test CBC (low Hb)
• High bilirubin levels is common in newborns after age (2-3 days).
• Due to breaking down the excess RBCs and, the newborn’s liver is
not fully mature. This situation usually resolves within a few days.
• is treated by phototherapy which breakdown bilirubin (ID D) and
convert it to the photo isomer form which is more water soluble.
• Very high unconjugated bilirubin is

danger and toxic. it cross the
blood -brain barrier, may cause
brain damage (Kernicterus) .
Heredatory unconjugated hyperbilirubinemia
1. Gilbert syndrome
• is the only common form of hereditary indirect hyperbilirubinemia,
they have an excellent prognosis;
• is due to a very mild deficiency of glucuronyl transferase.
• Incidence is 5 -7 % of population, Bilirubin usually < 6 mg/ dl with
no other abnormality of LFT, no treat is necessary.
2. CRYGLER-NAJJAR SYNDROME
TYPE I :Is due to a severe deficiency of glucuronyl tranferase.ID>20, .
Death usually in the first year with kernicterus.
TYPE II : Is due to a moderate deficiency of glucuronyl transferase,
Patients develop normally but some may suffer bilirubin encephalopathy,
kernicterus.
Heredatory conjugated hyperbilirubinemia
• DUBIN-JOHNSON SYNDROME.
• Is a chronic benign jaundice without pruritus or elevation
of serum ALP nor histological evidence of cholestasis. The
hepatocytes contain an abundance of coarse dark-brown
pgiment similar to melanin . The liver is black but normal.
S. bilirubin ranges between 2 and 20mg/dl.
• ROTOR SYNDROME.
• is a condition similar to Dubin-Johnson. There is
intermittent jaundice, similar clinical course, excellent
prognosis but no pigment in the liver tissue.
Why Bilirubin Test is Performed
1. Jaundice is the most common reason .
2. Most newborns have some jaundice.
3. liver or gallbladder problems.
Normal Bilirubin levels in adults

Total bilirubin 0.3–1.2 mg/dL
Direct bilirubin 0.1–0.4 mg/dL
Indirect bilirubin (total bilirubin 0.2–0.7 mg/dL
minus direct bilirubin )
mg/dl multiply by 17.1 convert to mmol/L

What Affects the Test?
• Caffeine, which can lower bilirubin levels.
• Avoid fasting, this normally increases indirect

bilirubin levels.
• Hemolysed sample : increase bilirubin level.
Procedure
Measuring serum bilirubin level
Principle:
Sulphanalic acid + NaNO3 diazotized sulphanalic acid (DSA)
DSA + Bilirubin “D” Azobilirubin “purple”

Bilirubin “ID”+ DSA + accelerator Total bil.
(methanol )
 Kit components
 Sulfanalic acid reagent
 Sodium nitrate reagent
 Methanol reagent

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Bilirubin Metabolism

Fenk Bakir Maarouf

 Heme is found in hemoglobin, a principal component of

 Heme source in body:

 Heme is four pyrrols rings connected together to form

 Heme ring is broken and converted to unconjugated

 This unconjugated bilirubin is not soluble in water, It is

Spleen Hemoglobin Plasma

Bilirubin Binds with albumin

Blilirubin + Glucouronic acid bilirubin diglucuronides

 Then conjugated bilirubin is excreted in bile through bile duct

 The conjugated bilirubin remaining in the large intestine is

 Elevated levels of bilirubin in blood and urine indicate certain

 Direct bilirubin: is conjugated (water soluble ) , solution it reacts

 - both conjugated and unconjugated bilirubin are measured given

• Knowing the level of each type of bilirubin has diagnostic

 Due to increase in  Due to liver cell damage  Due to obstruction of

 Occur in :  Occur in:

• Very high unconjugated bilirubin is

Normal Bilirubin levels in adults

mg/dl multiply by 17.1 convert to mmol/L

• Avoid fasting, this normally increases indirect

Sulphanalic acid + NaNO3 diazotized sulphanalic acid (DSA)

DSA + Bilirubin “D” Azobilirubin “purple”

 Sodium nitrate reagent

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