#7 Bilirubin metabolism

Objectives :
● Definition of bilirubin
● The normal plasma concentration of total bilirubin
● Bilirubin metabolism :
- Bilirubin formation
- Transport of bilirubin in plasma
- Hepatic bilirubin transport
- Excretion through intestine
● Other substances conjugated by glucuronyl transferase.
● Differentiation between conjugated & unconjugated bilirubin
● Other substances excreted in the bile
● Definition of Jaundice
● Classification of jaundice ( Prehepatic / Hepatic / poat-hepatic ).

Doctors’ notes

Extra

Important

Resources: 435 Boys’ & Girls’ slides | Guyton and Hall 12th & 13th edition
Editing file
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Overview- mind map
 Porphyrin Metabolism (Boys’ slides) :

● Porphyrins are cyclic compounds that readily bind metal ions usually Fe2+ or
Fe+3 which can carry O2.

● Porphyrins are heterocyclic macrocycles composed of four modified pyrrole (a

colorless, toxic, liquid, five-membered ring compound, C4 H5 N) subunits
interconnected at their α carbon atoms via methine bridges (=CH-).

● The most prevalent porphyrin in the human is heme, which consists of one
ferrous (Fe2+ ) iron ion coordinated in the center of tetrapyrrole ring of
protoporphyrin IX.

● Structure of Hemoglobin showing the polypeptides backbone that are

composed of four subunits: 2 α and 2 β subunits. Every subunit is consisted of
one ferrous (Fe2+ ) iron ion coordinated in the center porphyrin compound.

The most prevalent porphyrin in the human is heme

Definition of bilirubin :
● Bilirubin is the end product of heme degradation derived from breakdown senescent (aging)
erythrocytes by mononuclear phagocytes system specially in the spleen, liver and bone
marrow. (It is the water insoluble breakdown product of normal heme catabolism).

● Bilirubin is the greenish yellow pigment excreted in bile, urine and feces.
● The major pigment present in bile is the orange compound bilirubin.

● Heme is found in hemoglobin, a principal component of RBCs (Heme: iron + organic compound
“porphyrin”)
● Heme source in body:
➔ 80% from hemoglobin.
➔ 20% other hemo-protein: cytochrome, catalase, peroxidase, myoglobin.
● It is highly soluble in all cell membranes (hydrophobic) and is also very toxic. Therefore, its
excretion in the bile is one of the very important functions of the liver.
● Serum bilirubin level is an important clinical marker of hepatobiliary excretory function.
It’s one of the Liver function tests

Bilirubin metabolism :
❖ Bilirubin metabolism involves four discernible steps:

Bilirubin metabolism

Intestine
Formation Plasma Transport Hepatic Phase:
Excretion

Hepatic uptake

Conjugation

Biliary excretion

❖ The four steps are finely balanced, therefore:

- Reduction at any step may cause hyperbilirubinemia.

- Enhancement of the throughput requires induction of multiple genes, probably coordinated by

nuclear receptors.
1) Bilirubin formation :
● Life span of RBCs is 60-120 days.
● Senescent ”old” RBCs are phagocytosed intravascularly or extravascularly in the
reticulo-endothelial system. “Mainly extravascularly”
● The hemoglobin is first split into globin & heme.
● The Amino acids formed from breakdown of globin are stored in the body.

The heme ring is opened to give:

Free iron Transported in the blood by transferrin and stored in the body
as a reservoir for erythropoiesis.

Bile pigments (biliverdin) “it's the first bile pigment formed” Reduced by biliverdin
reductase to free bilirubin which is gradually released into the
plasma.

Heme Globin

Iron Biliverdin

Bilirubin Amino acids

❖ Hemoglobin degrading and bilirubin formation :

Spleen
Plasma
Hemoglobin

Heme Globin Plasma and

AA pool
Bilirubin Iron Iron pool
For further metabolism
Binds with
albumin

Liver To liver
Conjugation
process

2) Transport of bilirubin in plasma :

❖ Bilirubin is formed in spleen .
❖ The free bilirubin is hydrophobic, immediately combines with plasma proteins (mainly
albumin and globulin) forming a water soluble compound (hemobilirubin, unconjugated,
indirect bilirubin) which is rapidly transported to hepatocytes for further metabolism, even
when bound to albumin it`s called free bilirubin.
‫ھﻧﺎ ﻻزم ﻧﻌرف إن اﻟﺑﯾﻠروﺑﯾن ﻟﻣﺎ ﯾوﺻل ﻟﻠﺑﻼزﻣﺎ ﯾﻛون ھﯾدروﻓوﺑﯾك )ﻛﺎره ﻟﻠﻣﺎء( ﺑﻌدﯾن ﯾرﺗﺑط ﺑﻣرﻛب ﯾﺧﻔف ﻛرھﮫ ﻟﻠﻣﺎء إﻟﻰ ﺣ ٍد ﻣﺎ ) أﻟﺑﯾوﻣن ( ﻓﻠﻣﺎ‬
‫ﯾرﺗﺑطون ﻣﻊ ﺑﻌض ﻣﺎﻧﻘدر ﻧﻘول إن اﻟﻣرﻛب اﻟﻧﺎﺗﺞ ﺻﺎر ھﯾدوﻓﯾﻠﯾك )ﻣﺣب ﻟﻠﻣﺎء( ﻟﻛن ﻧﻘدر ﻧﻘول إﻧﮫ ﺻﺎر أﻗل ﻛرھﺎ ً ﻟﻠﻣﺎء وأﻛﺛر ﺗﻘﺑﻼً ﻟﮫ‬

Albumin + Free Bilirubin Bilirubin ~ Albumin Complex

Unconjugated bilirubin
(hemobilirubin)

❖ Significance of bilirubin binding to albumin:

1. Increase the solubility of whole molecule. “‫ﻗﻠﻧﺎ ” إﻟﻰ ﺣ ٍد ﻣﺎ‬
2. Prevent unconjugated bilirubin freely come into other tissue, cause damage.
➔ Certain drugs as Sulfonamides and Salicylates compete with bilirubin for albumin binding
and displace bilirubin to enter into the brain in neonates and increase the risk of
kernicterus (a type of brain damage that can result from high levels of bilirubin in a
baby`s blood). It can cause cerebral palsy and hearing loss.“it’s common in babies
because of their incomplete formation of blood brain barrier”
3) Hepatic phase :

Hepatic phase
On coming in contact with the hepatocyte surface,
unconjugate bilirubin is preferentially metabolized which
involved 3 steps:
“Any problem in these steps can lead to high bilirubin”

Conjugation
Hepatic uptake Secretion in bile
In hepatocytes :

Bilirubin -Albumin *about 80% of bilirubin *Cholebilirubin

complex dissociate in conjugates with uridine (conjugated bilirubin) is
plasma of liver into
diphospho- glucuronic acid actively secreted by the
hemebilirubin & free
albumin . (UDPGA) catalyzed by the liver cells by an active
Dissociation of enzyme glucuronyl transport process into
hemebilirubin Inside transferase in the smooth ER. the bile canaliculi.
hepatocytes into free “To make it water soluble and *This energy-dependent,
bilirubin and free facilitate its excretion” rate –limiting step is
protein . *Each bilirubin molecule susceptible to
The Free Bilirubin is
reacts with 2 UDPGA impairment in liver
absorbed through the
hepatic cell membrane, molecules to form bilirubin disease.
mediated by a carrier diglucuronide (cholebilirubin,
protein (receptor) direct, conjugated bilirubin) Uncojugated bilirubin is
* bilirubin enters a hepatocyte which is more water soluble normally not excreted.
via facilitated diffusion, and
binds to intracellular proteins, than the free bilirubin.
particularly the protein ligandin. “hemobilirubin” *The color of bile is due to
bilirubin.
20% conjugate with sulphate *In normal adults this
combined with Y & Z
proteins that trap the or other substances. results in a daily load of
bilirubin inside the cells. 250-300 mg of bilirubin.
Any genetic defect in Inherited glucuronyl
carriers will lead to transferase deficiency causes
failure of hepatic jaundice.
uptake of bilirubin.

- It is Very important to understand this concept:

★ unconjugated is a lipid soluble but when it combines with plasma protein it increases its water
solubility but it still lipid soluble.
★ conjugated is a water soluble

Very helpful
 Fate of conjugated bilirubin

1-A small portion of the conjugated 2-Small amount is 3-The majority of conjugated
bilirubin returns to the plasma and deconjugated in the bilirubin passes via the bile
bound less tightly to albumin & is small intestine and ducts to the intestine where it is
excreted in the urine. this causes a absorbed into the transformed through
small portion of the bilirubin in the portal blood to the bacterial action into urobilinogen
ECF to be of the conjugated type. liver which is highly soluble.

Fate of Urobilinogen

3a- Most of urobilinogen (70%) is 3b-Some of 3c-Small amount of urobilinogen

converted into stercobilinogen in urobilinogen (20 %) is escapes to the general circulation
the intestine , oxidized and reabsorbed through and excreted by the kidneys in the
excreted in the feces as the intestinal mucosa urine where it is oxidized to urobilin
stercobilin that causes dark into the portal vein when the urine is exposed to
brown color of the feces.“Patients and reexcreted by air.Only urobilin and conjugated
with obstruction of bile duct won’t the hepatic cells in bilirubin can be found in urine. NOT
have stercobilin in their stool the bile the unconjugated form.
making it pale & grayish in color” (enterohepatic
circulation).

● Guyton corner :
Briefly, when the red blood cells have lived out their life span (on average,
120 days) and have become too fragile to exist in the circulatory system, their cell
membranes rupture, and the released hemoglobin is phagocytized by tissue
macrophages (also called the reticuloendothelial system) throughout the body. The
hemoglobin is first split into globin and heme, and the heme ring is opened to give
(1) free iron, which is transported in the blood by transferrin, and (2) a straight
chain of four pyrrole nuclei, which is the substrate from which bilirubin will
eventually be formed. The first substance formed is biliverdin, but this is rapidly
reduced to free bilirubin, also called unconjugated bilirubin, which is gradually
released from the macrophages into the plasma. This form of bilirubin
immediately combines strongly with plasma albumin and is transported in this
combination throughout the blood and interstitial fluids.
Within hours, the unconjugated bilirubin is absorbed through the hepatic
cell membrane. In passing to the inside of the liver cells, it is released from the
plasma albumin and soon thereafter conjugated about 80 percent with glucuronic
acid to form bilirubinglucuronide, about 10 percent with sulfate to form
bilirubin sulfate, and about 10 percent with a multitude of other substances. In
these forms, the bilirubin is excreted from the hepatocytes by an active transport
process into the bile canaliculi and then into the intestines.

Formation and Fate of Urobilinogen.

Once in the intestine, about half of the “conjugated” bilirubin is converted by

bacterial action into the substance urobilinogen, which is highly soluble. Some of
the urobilinogen is reabsorbed through the intestinal mucosa back into the blood.
Most of this is re-excreted by the liver back into the gut, but about 5 percent is
excreted by the kidneys into the urine. After exposure to air in the urine, the
urobilinogen becomes oxidized to urobilin; alternatively, in the feces, it becomes
altered and oxidized to form stercobilin.
8
 Summary of bilirubin metabolism :

1) Senescent red cells are major 2) Breakdown of heme to bilirubin occur in

source of hemeproteins macrophage of reticuloendothelial system
( tissue macrophages, spleen and liver).

3) Unconjugated bilirubin is 4) Bilirubin is taken into liver and conjugate

transported through blood (complex to with glucuronic acid.
albumin) to liver.

5) Bile is secreted into intestine where 6) A portion of urobilinogen is reabsorbed

glucuronic acid is removed and the into blood, where it is converted to the
resulting bilirubin is converted to yellow urobilin and excreted by kidneys.
urobilinogen.

7) Urobilinogen is oxidized by intestinal

bacteria to the brown stercobilin.
 Other substances conjugated by glucuronyl transferase:
● The glucuronyl transferase system in the smooth endoplasmic reticulum catalyzes the formation of
the glucuronides of a variety of substances in addition to bilirubin.
● The list includes steroids & various drugs.
● These compounds can compete with bilirubin for the enzyme system when they are present in
appreciable amounts. Therefore, Bilirubin won’t be conjugated and excreted in bile leading to excess
bilirubin in blood and aggravating clinical condition of jaundice
● In addition several barbiturates, antihistamines, anticonvulsants and other compounds can cause
marked proliferation of the smooth endoplasmic reticulum in the hepatic cells, with a concurrent
increase in hepatic glucuronyl transferase activity.
● Phenobarbital has been used successfully for the treatment of a congenital disease in which there is
a relative deficiency of glucuronyl transferase (type 2 UDP-glucuronyl transferase deficiency).

Types of bilirubin in serum :

Types of bilirubin in serum

Direct bilirubin is conjugated (water soluble) bilirubin, it reacts rapidly with reagent (direct
reacting).

Indirect bilirubin is unconjugated (water insoluble) bilirubin because it is less soluble, it reacts
more slowly with reagent (reaction carried out in methanol).
‫ ھو ﺣﺳب ﺗﻔﺎﻋﻠﮭم ﻣﻊ اﻟﻛﺎﺷف‬direct & indirect ‫اﻟﺳﺑب ﺧﻠف ﺗﺳﻣﯾﺗﮭم‬
unconjugated ‫ أو ﻏﯾر ﻣﺑﺎﺷر ﻣﺛل‬conjugated ‫إذا ﻛﺎن ﺑﺷﻛل ﻣﺑﺎﺷر ﻣﺛل‬

Total bilirubin in this case both conjugated and unconjugated bilirubin are measured given
total bilirubin. Unconjugated will calculated by subtracting direct from total
and so called indirect.
➔ Total bilirubin = D+ ID
Knowing the level of each type of bilirubin has diagnostic importance.We can
specify the type jaundice if its pre-hepatic, hepatic, or post-hepatic

Normal Range of bilirubin

Normal Occult Jaundice
pre-clinical jaundice
(not seen clinically)

<1 mg/dl 1-2 mg/dl >2 mg/ dl

1～16 mol/l (0.1 ～1mg/dl)
Hyperbilirubinemia
➔ 4/5 are unconjugated bilirubin,
others are conjugated bilirubin.
“We’ll find mainly hemobilirubin in serum”
 Other substances excreted in the bile

◄ Cholesterol & alkaline phosphatase are excreted in the bile.

◆ In patients with jaundice due to intra or extra hepatic obstruction of the
bile duct, the blood levels of these 2 substances usually rise.
◆ A much smaller rise is generally seen when the jaundice is due to non
obstructive hepatocellular disease.

◄ Adrenocortical, other steroid hormones & a number of drugs are excreted in the
bile and subsequently reabsorbed (enterohepatic circulation). Impairment of this
metabolic function can increase estrogen in men causing gynecomastia

Major differences between unconjugated and conjugated

bilirubin : (very important)

Feature Unconjugated bilirubin Conjugated bilirubin

(Hemobilirubin) (Cholebilirubin)

Normal serum level The chief form of bilirubin in the Present in low conc. in the
blood blood

Water solubility Absent Present (Water soluble)

Affinity to lipids Present Absent

Binding Bind to albumin Bind to glucuronic acid

Reaction to reagents Indirect (Total minus direct) Direct

Renal excretion Absent Present

(Not filtered through renal glomeruli, is (Filtered through renal glomeruli
not excreted in urine) and excreted in urine)

Affinity to brain tissue Present (kernicterus), toxic Absent , less toxic

Toxicity Toxic Non-toxic

 Jaundice : (Boys’ slides)
● It is the yellow coloration of the skin, sclera, mucous membranes and deep tissues.
● The usual cause is large quantities of bilirubin in the ECF, either free or conjugated bilirubin.
● The normal plasma concentration of total bilirubin is 0.3-1.2 mg/dl of blood.
● However, in certain abnormal conditions this can rise up to 40 mg/dl of blood. But the skin usually
begins to appear jaundiced when the concentration of total bilirubin in the plasma is greater than
2 - 2.5 mg/dl of blood. ‫ﻣﺛل ﻣﺎﻗﻠﻧﺎ ﺑﺎﻟﺟدول اﻟﺳﺎﺑق‬

● Bilirubin level from 0.5 to 2 mg/dl is called subclinical jaundice.

Causes of Jaundice

Excessive ↓ hepatocyte Impaired bile

↓ hepatocyte Impaired
production of excretion of bilirubin flow (obstruction
uptake conjugation
bilirubin glucuronides of bile duct)

Jaundice types

Pre-hepatic (hemolytic) Hepatic (hepatocellular)

Post-hepatic jaundice
jaundice jaundice

1) Pre-hepatic (hemolytic) jaundice

● In hemolytic jaundice, the excretory function of the liver is NOT impaired.

● It results from excess production of bilirubin (beyond the liver’s ability to conjugate it)
following hemolysis of erythrocytes (RBCs).
● Excess RBC lysis is due to:
○ Autoimmune disease
○ Hemolytic disease of the newborn
○ Rh- or ABO- incompatibility
○ Structurally abnormal RBCs (Sickle cell disease)
○ Breakdown of extravasated blood

● Therefore, the plasma concentrations of free bilirubin rises to levels much above normal but it
is NOT filtered through the kidney, because they are unconjugated bilirubin.
● The urine is free from bilirubin.
● The stools appear darker than the normal color due to excessive stercobilin formation.
 2) Hepatic (hepatocellular) jaundice

● Hyper-bilirubinemia (increased levels of bilirubin in the blood) may be due to:

- Impaired uptake of bilirubin into hepatic cells.
- Disturbed intra cellular protein binding or conjugation.
- Disturbed active secretion of bilirubin into bile canaliculi.
● The main causes of Hepatic jaundice are:
- Damage of liver cells: e.g., viral hepatitis, drugs, chemical, alcohol, or toxins.
- Genetic errors in bilirubin metabolism.
- Genetic errors in specific proteins.
- Autoimmune hepatitis.

● The diseased liver cells are unable to take all the unconjugated bilirubin formed, increasing its
concentration in the blood.

● Also, there is intrahepatic biliary duct obstruction that leads to regurgitation of conjugated
bilirubin to blood (swelling of cells and edema due to inflammation cause mechanical
obstruction of intrahepatic biliary tree).

● BOTH types of bilirubin (conjugated & unconjugated) are present in blood in high concentration.

- Stools appear pale grayish in color due to deficiency of stercobilin.

- Urine appears dark brown due to filtration of excess conjugated bilirubin through
clinical Features

the kidney (probably by rupture of the congested bile canaliculi and direct emptying
of the bile into the lymph leaving the liver).

- In this case, hyper-bilirubinemia is usually accompanied by other abnormalities in

biochemical markers of liver function such as: Alanine amine transferase (ALT),
Aspartate amine transferase (AST), alkaline phosphatase (ALP) and
Gamma-glutamyltransferase (GGT).

- By looking at the ratio between these different liver enzymes, we can distinguish the
causes of jaundice whether it is from biliary (cholestatic) or liver (hepatic). The main
diagnostic tip is in the biliary obstruction: the ALT goes up and down (pulsatile
increase) and the bilirubin concentration in the blood is high. But in hepatic jaundice,
ALT shows persistent increase for along period of time (months).
 3) Post-hepatic jaundice
Caused by an obstruction of the biliary tree :

Intra-hepatic bile duct obstruction Extrahepatic bile duct obstruction

- Drugs - Gallstones.
- Primary biliary cirrhosis - Cancer at the head of pancreas.
- Cholangitis. - Cholangiocarcinoma.

● The rate of bilirubin formation is normal. bilirubin enters the liver cells and become
conjugated in the usual way.
● The conjugated bilirubin formed simply can not pass into small intestine and it returns back
into blood.
● In this type of jaundice, conjugated bilirubin is filtered through the kidney and appears in
urine giving it dark brown color.
● Urine is free from urobilinogen.
● Stools are clay (mud) color due to absence of stercobilin.

Liver Secretion of Cholesterol and Gallstone Formation :

● Under abnormal conditions, the cholesterol may precipitate in the gallbladder, resulting in the
formation of cholesterol gallstones. The amount of cholesterol in the bile is determined partly by
the quantity of fat that the person eats, because liver cells synthesize cholesterol as one of the
products of fat metabolism in the body. For this reason, people on a high-fat diet over a period of
years are prone to the development of gallstones.

● Inflammation of the gallbladder epithelium, often resulting from low-grade chronic infection, may
also change the absorptive characteristics of the gallbladder mucosa, sometimes allowing excessive
absorption of water and bile salts but leaving behind the cholesterol in the bladder, and then
progressing to large gallstones.
 SUMMARY (IMPORTANT/ READ IT)
❖ Bilirubin Is the Major Component of Bile Pigments, ( Steps of Excretion ):

1. Hemoglobin is first dissociated into heme and globin.

2. In the presence of NADPH and O2, the Heme oxygenase enzyme hydroxylates
Heme, with a concomitant oxidation of ferrus Fe2+ iron to ferric Fe+3 , and
converts it into Biliverdin.

3. Biliverdin is then reduced or converted into bilirubin by biliverdin reductase

enzyme. Bilirubin is transported in blood bound to albumin forming a water
soluble compound called hemobilirubin (unconjugated bilirubin, free
bilirubin) which is rapidly transported to hepatocytes for further metabolism
(even when bound to albumin, it’s called free bilirubin).

4. The liver removes bilirubin from the circulation rapidly, mediated by a carrier
protein (receptor), and conjugates it with glucuronic acid. This reaction is
catalyzed by the enzyme glucuronyl transferase in the smooth endoplasmic
reticulum to have conjugated bilirubin, which is more water soluble than
bilirubin.

5. The bilirubin-glucuronide (conjugated bilirubin) is secreted into the

bile canaliculi through an active carrier-mediated process. ( Note:
the unconjugated bilirubin is normally not secreted.)

6. In the small intestine, bilirubin glucuronide is poorly absorbed. In

the gut, however, bacteria deconjugate it back to bilirubin, and
convert it to the highly soluble colorless compound called
Urobilinogen.

7. Only 20% of Urobilinogen can be absorbed by the small intestine

(this represents the enterohepatic circulation of bile pigments). 70%
of the Urobilinogen can be oxidized in the large intestine to
Stercobilin (by bacteria).
➔ Urobilinogen is excreted in either urine (where it is converted to
yellow urobilin in the kidney) or fesses (after it is converted to
Stercobilin which is responsible for the brown color of fesses).

❖ Fate of the bilirubin-glucuronide (conjugated bilirubin) after they leave the hepatocytes (liver):

● A small portion of the conjugated bilirubin returns to the plasma either directly into the liver sinusoids or
indirectly by absorption into the blood from the bile ducts or lymphatics. This represents 10% only).
● This causes a small portion of the bilirubin in the extracellular fluid always to be of the conjugated type
rather than of the free type. These conjugated bilirubin that escaped into the blood, they bind less tightly
to albumin & are excreted readily in the urine.
● Small amount of bilirubin glucuronide (20%) is de-conjugated (and converted to Urobilinogen) and
absorbed by the small intestine into the portal blood to the liver where it is extracted by the liver cells
and is conjugated again and excreted in the bile (enterohepatic circulation of bile pigments).
 SUMMARY
Bilirubin formation RBCs lysis in spleen or blood strem >hemoglobin> bile pigment
(biliverdin)--(by biliverdin reductase) >free bilirubin (hydrophopic)

Transport of Bilirubin Bilirubin in spleen> go to bood strem > combines with(mainly albumin
in Plasma and globulin)> hemobilirubin, unconjugated bilirubin (hydrophilic)

Hepatic uptake:
Bilirubin absorbed through the hepatiocytes membrane and traped
inside the cell by Y & Z proteins
Conjugation :
Bilirubin + 2 uridine diphospho-glucuronic acid– (by glucuronyl
transferase) > bilirubin diglucuronide (cholebilirubin, direct, conjugated
Hepatic phase bilirubin) (highly hydrophilic)
Bilirubin Secretion in Bile :
Cholebilirubin secreted by the liver cells by an active transport process
into the bile canaliculi Unconjugated bilirubin normally not excreted in
bile

Fate of conjugated majority of conjugated bilirubin transformed through bacterial action

bilirubin into > urobilinogen > stercobilin > feces .
Small amount deconjugated back by circulation > enterohepatic
circulation
small amountof conjugated bilirubin returns to the plasma and bound
less tightly to albumin > excreted in the urine
 SUMMARY (GUYTON)
Jaundice—Excess Bilirubin in the Extracellular Fluid
Jaundice refers to a yellowish tint to the body tissues, including a yellowness of the skin and deep tissues. The usual cause of
jaundice is large quantities of bilirubin in the extracellular fluids, either unconjugated or conjugated bilirubin. The normal plasma
concentration of bilirubin, which is almost entirely the unconjugated form, averages 0.5 mg/dl of plasma. In certain abnormal
conditions, this can rise to as high as 40 mg/dl, and much of it can become the conjugated type. The skin usually begins to
appear jaundiced when the concentration rises to about three times normal—that is, above 1.5 mg/dl.
The common causes of jaundice are (1) increased destruction of red blood cells, with rapid release of bilirubin into the blood,
and (2) obstruction of the bile ducts or damage to the liver cells so that even the usual amounts of bilirubin cannot be excreted
into the gastrointestinal tract. These two types of jaundice are called, respectively, hemolytic jaundice and obstructive
jaundice. They differ from each other in the following ways.

Hemolytic Jaundice Is Caused by Hemolysis of Red Blood Cells.

In hemolytic jaundice, the excretory function of the liver is not impaired, but red blood cells are hemolyzed so rapidly that the
hepatic cells simply cannot excrete the bilirubin as quickly as it is formed. Therefore, the plasma concentration of free bilirubin
rises to above-normal levels. Likewise, the rate of formation of urobilinogen in the intestine is greatly increased, and much of
this is absorbed into the blood and later excreted in the urine.

Obstructive Jaundice Is Caused by Obstruction of Bile Ducts or Liver Disease.

In obstructive jaundice, caused either by obstruction of the bile ducts (which most often occurs when a gallstone or cancer
blocks the common bile duct) or by damage to the hepatic cells (which occurs in hepatitis), the rate of bilirubin formation is
normal, but the bilirubin formed cannot pass from the blood into the intestines. The unconjugated bilirubin still enters the liver
cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood, probably by rupture of
the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver. Thus, most of the bilirubin in the
plasma becomes the conjugated type rather than the unconjugated type.
 MCQs
1:Bilirubin is absorbed through the hepatic cell 6:The effect of steroid:
membrane by: A. Compete with bilirubin on conjugation
A. secondary cotransport with amino acid.
B. proliferation of the smooth endoplasmic
B. Carrier protein combined with albumin
reticulum in the hepatic cells
C. Carrier protein combined with Y & Z proteins
D. none of them C. increase in hepatic glucuronyl transferase
activity
2:The intestinal mucosa is relatively
D. none of them
impermeable to......bilirubin but permeable to
7: enzyme responsible to change biliverdin into
.........bilirubin:
free bilirubin:
A. unconjugated –conjugated
A. Bilirubin anhydrease
B. conjugated –unconjugated
B. biliverdin reductase
C. heme oxygenase
3:Urobilinogen is converted to …….., which is
D. Biliverdin activator
excreted in the feces:
A. Stercobilinogen
8: Which of the following can be found in urine:
B. Urobilin
A. Unconjugated bilirubin
C. A&B
B. urobilin
4 :The direct bilirubin (conjugated) is converted
C. Conjugated bilirubin
to __________ by bacteria in the intestine:
A. Biliverdin D. B&C

B. Urobilin 9: combining of bilirubin to albumin result in:

A. Conjugated bilirubin
C. Urobilinogen
B. Unconjugated bilirubin
D. Cholebilirubin
C. Cholebilirubin

5: what would be the result from reduction of D. Direct bilirubin

one step of Bilirubin metabolism:
10: most of conjugated bilirubin will convert into:
A. Hyperbilirubinemia
A. Deconjugated
B. Hypobilirubinemia
C. Anemia B. Urobilin
D. Increase bilirubin solubility
C. Strecobilin

D. Excreted in urine

11: most abundant form of bilirubin in blood is:

A. Conjugated

B. Unconjugated

answer key: 1:C , 2:B , 3:A , 4:C , 5:A , 6:A , 7:B , 8:D , 9:B , 10:C , 11:B.
 ‫ﻋﻣر آل ﺳﻠﯾﻣﺎن‬ ‫ﺧوﻟﺔ اﻟﻌﻣﱠﺎري‬
‫ﻋﺑداﻟﻌزﯾز اﻟﺣﻣﺎد‬ ‫ﻧﺟود اﻟﺣﯾدري‬
‫ﻋﺑداﻟرﺣﻣن اﻟﺳﯾﺎري‬ ‫ﻧورة اﻟطوﯾل‬
‫ﻣﺣﻣد أﺑوﻧﯾﺎن‬ ‫ﻟوﻟوة اﻟﺻﻐﯾر‬
‫ﻋﺑداﻟرﺣﻣن اﻟﺑرﻛﮫ‬ ‫ﻟﺟﯾن اﻟﺳواط‬
‫إﺑراھﯾم اﻟﻧﻔﯾﺳﮫ‬ ‫رزان اﻟﺳﺑﺗﻲ‬
‫ﻣﺣﻣد اﻟﺑﺷر‬ ‫رﺑﻰ اﻟﺳﻠﯾﻣﻲ‬
‫ﻋﻣر اﻟﻌﺗﯾﺑﻲ‬ ‫دﯾﻣﺎ اﻟﻔﺎرس‬
‫ﺣﻣزة اﻟﻔﻌر‬ ‫ﺧوﻟﺔ اﻟﻌرﯾﻧﻲ‬
‫ﻋﺑدﷲ اﻟﺟﻌﻔر‬ ‫ﻣﻼك اﻟﺷرﯾف‬
‫ﻋﺑدﷲ اﻟﺿﺣﯾﺎن‬ ‫ﻣﻧﯾرة اﻟﺣﺳﯾﻧﻲ‬
‫ﺣﺳن اﻟﺑﻼدي‬ ‫ﻣروج اﻟﺣرﺑﻲ‬
‫ﺣﺳن اﻟﺷﻣﺎﺳﻲ‬ ‫أﻓﻧﺎن اﻟﻣﺎﻟﻛﻲ‬
‫ﻣﺣﻣد اﻟﻔواز‬ ‫دﻻل اﻟﺣزﯾﻣﻲ‬
‫ﻣﺣﻣد اﻟﺳﺣﯾﺑﺎﻧﻲ‬ ‫رﻧﺎد اﻟﻘﺣطﺎﻧﻲ‬
‫واﺋل اﻟﻌود‬ ‫ﺳﺎرة اﻟﺧﻠﯾﻔﺔ‬
‫رواف اﻟرواف‬ ‫ﻓرح ﻣﻧدوزا‬
‫ﻋﻣر اﻟﺷﮭري‬ ‫ﻣﻲ اﻟﻌﻘﯾل‬
‫ﻧورة اﻟﺧراز‬
‫ﺳﺎرة اﻟﺧﻠﯾﻔﺔ‬
‫ﻧورة اﻟﺧﯾﺎل‬
‫رﻏد اﻟﻧﻔﯾﺳﺔ‬
‫ﻣﻧﯾرة اﻟﺳﻠوﻟﻲ‬
‫ﻧوف اﻟﻌﺑداﻟﻛرﯾم‬
‫ﺳﮭﺎ اﻟﻌﻧزي‬
‫ﻧورة اﻟﻘﺣطﺎﻧﻲ‬