Transcript Conjugated bilirubin

Anatomy
 The liver is a large,
bilobed, complex organ.
 receiving a large amount of
blood and nutrients from
the gastrointestinal system
 Hepatic artery: Provides it’s
blood supply
 Portal vein: Transports
absorbed substances from
the GI tract
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Structural Unit
 Lobules are the functional units,
 consisting of clusters of hepatocytes
around a central vein
 Sinusoids, vascular spaces, are lined by
Kupffer cells.
 Blood from these spaces drain into the central
veins.
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Major functions of the liver
 The liver performs four major functions:
 excretion,
 synthesis,
 detoxification,
 and storage.
 The liver is so important that if the liver
becomes nonfunctional, death will occur
with 24 hours due to hypoglycemia.
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1- Excretory Function
 One of the most important liver
functions, and one that is disturbed in a
large number of diseases is the excretion
of bile
 Bile comprises:
 bile acids or salts,
 bile pigments & others
 Total bile production averages 3 liters/ day
 Bilirubin is the principal pigment in bile
 Derived mainly from breakdown of hemoglobin
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Bile Acids
 The primary bile acids are:
 cholic acid
 and chenodeoxycholic acid
 Formed in the liver from cholesterol.
 Bile acids are conjugated with the amino acid
glycine or with taurine (derivative of the sulfurcontaining amino acid) forming bile salts.
 Gall bladder empties bile salts in the small
intestine where the bile is involved in digestion
and absorption of lipids.
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Bile Acids
 Bacteria in ileum and colon dehydrate bile
salts to secondary bile acids "deoxycholic
and lithocholic" which are subsequently
absorbed.
 The absorbed bile acids enter the portal
circulation to the liver where they are
reconjugated and excreted.
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Enterohepatic circulation of bile salts and bile acids.
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Formation of Bilirubin
1. Aged RBCs are
phagocytized by
reticuloendothelial system
(RE) in the spleen, liver and
bone marrow.
•
Hemoglobin is catabolized
into amino acids, and heme.
2. Heme ring is broken open
and porphyrin converted to
Biliverdin, and then to
unconjugated (indirect)
bilirubin.
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Formation of Bilirubin
3. RE cells secrete unconjugated bilirubin into
the plasma, where bilirubin is bound by
albumin.
4. Albumin – bilirubin complex travels to the
liver.
5. Hepatocytes conjugates bilirubin with
gluconic acid by uridyl diphosphate
glucuronyl transferase (UDPGT) enzyme to
form Conjugated bilirubin
6. Conjugated bilirubin (water soluble) secreted
into the bile ducts (GI tract)
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Formation of Bilirubin
7. GI bacterial normal flora convert
conjugated bilirubin into urobilinogen
(colorless).
• Oxidation of urobilinogen → urobilin (redbrown pigment)
8. Urobilinogen may be excreted into the
stool, small portion reabsorbed into the
plasma and excreted in the urine
• 80% of bilirubin comes from Hb and 20%
from heme containing protein (myoglobin)
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hemoglobin
Globin
Iron
Heme
porphyrin
Bilirubin
Diglucuronide
(conjugated)
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Major functions of the liver
2. Synthetic
 Carbohydrate metabolism


gluconeogenesis,
glycogen synthesis and breakdown
 Fat metabolism



fatty acid synthesis,
cholesterol synthesis and excretion,
lipoprotein synthesis…..
 Protein metabolism

synthesis of plasma proteins (including some coagulation
factors but not immunoglobulins)
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Major functions of the liver
3. Detoxification and Drug Metabolism
 Every substance that is absorbed in the GIT must first
pass through the liver (first pass).
 This allows important substances to reach the
circulation and prevent toxic or harmful substances
from reaching the circulation
 The body has two mechanisms for detoxification of
foreign materials and metabolic products:


It may either bind the material reversibly so as to inactivate the
compound,
or it may chemically modify the compound so it can be excreted
4. Storage
 Glycogen, vitamin A , vitamin B12
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Disorders of Liver
 Jaundice
 Cirrhosis
 Tumors
 Hepatitis
 Drug & Alcohol related disorders
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Jaundice
 Jaundice or Icterus
 Yellowish discoloration of the skin and sclera from
increased plasma bilirubin
 Usually the concentration of bilirubin in the blood must
exceed 2–3 mg/dl for the coloration to be easily visible
 Icteric: Plasma /serum with yellowish color from ↑
bilirubin
 Reference ranges
 Total Bilirubin (conjugated + unconjugated) 0.2 - 1.0 mg / dl
 Conjugated bilirubin
 Fullterm newborns
0.0 - 0.2 mg / dl
2.0 – 6.0 mg / dl
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Jaundice

General classifications of jaundice
1.
Prehepatic


Excess RBC destruction,
Excessive amounts of bilirubin is presented to
the liver (Not impaired liver function )



Increased unconjugated bilirubin
Unconjugated bilirubin is water insoluble and is
bound to albumin
It is not filtered by the kidney and will not
appear in urine.
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General classifications of jaundice
2. Hepatic
 Defective liver function
 May result from:



Gilbert syndrome
 Less in UDPGT enzyme activity (20%-30%)
Crigler-Najjar Syndrome
 type 1, complete absence of enzyme
 type II, severe deficiency of the enzyme
Dubin-Johnson syndrome
 removal of conjugated bilirubin from the
liver cell and the excretion into the bile is
defective
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General classifications of jaundice
3. Posthepatic




Impaired ability of liver to excrete bile into the
GI tract due to obstruction
 gallstones, tumors
Rise in serum level of conjugated bilirubin but
normal to elevated unconjugated bilirubin.
Conjugated bilirubin appears in urine
Serum enzymes that indicate biliary
obstruction, including alkaline phosphatase
and GGT, are also often elevated.
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Physiological Jaundice of the newborn
 Immature liver at birth
 Temporary deficiency of UDPGT
 Small / moderate elevated unconjugated
bilirubin lasting a few days.
 If not processed it is deposited in the
brain and nerve cells, causing cell damage
and death in the newborn
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Total Bilirubin
SERUM
Conjugated
Bilirubin
Unconjugated
Bilirubin
↑
↔
↑
• Gilbert disease
↑
↔
↑
• Crigler-Najjar syndrome
↑
↓
↑
• Dubin-Johnson
↑
↑
↔
• Jaundice of newborn
↑
↔
↑
↑
↑
↑
Type Of Jaundice
Prehepatic
Hepatic
Posthepatic
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Other Disorders of Liver
 Cirrhosis
 A consequence of chronic liver disease
characterized by replacement of liver tissue by
fibrous scar tissue leading to progressive loss
of liver function.
 Cirrhosis is most commonly caused by
alcoholism, hepatitis B and C and fatty liver
disease but has many other possible causes.
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Other Disorders of Liver
 Tumors
 Cancers of the liver are classified as:


Primary (cancer that begins in the liver cells)
metastatic when tumors from other parts of the body
spread (metastasize) to the liver.
 Cancers of the liver may also be classified as:


benign
or malignant
 Whether primary or metastasic, any malignant tumor
in the liver is:


a serious finding
and carries a poor prognosis, with survival times measured
in months.
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Other Disorders of Liver
 Drug- and Alcohol-Related Disorders
 most common mechanism of toxicity is via an
immune-mediated injury to the hepatocytes
 Hepatitis
 Inflammation of the liver
 Caused by viruses, bacteria, chemicals and
others
 Among viruses causing hepatitis are hepatitis
types A, B, C, D & E
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Assessment of Liver Function
 A liver function tests (LFT) are group of blood
tests that give an indication of whether the liver
is functioning properly.
 The tests are also very useful to see if there is
active damage in the liver (hepatitis) or slow bile
flow (cholestasis).
 Because the liver is the site for the conjugation of
bilirubin,
 The liver may be assessed by measurement of total
and conjugated bilirubin.
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Bilirubin Techniques
 Evelyn-Malloy Reaction
Bilirubin + Diazo + 50% Methanol
Red-blue chromogen
 Jendrassik–Grof Method
 carried out at a pH near 6.5, but the absorbance of the
reaction is measured after alkalinization of the
reaction solution to pH 13.
 At this pH the absorption spectrum of the azobilirubin
is shifted to a more intense blue color measured at 600
nm.
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Direct measurement of bilirubin
 Because bilirubin has a distinctive color, it
is possible to measure bilirubin directly
 No chemical reaction is necessary
 This procedure has limited value because of
other colored plasma substances that
interfere
 Only newborns lack these interfering
substances.
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Other tests related to hepatic disease
 Elevated Enzyme activity
 The enzymes ALP, ALT, AST, GGT, and 5′-nucleotidase
are helpful in the assessment of the proper functioning
and inflammatory status of the liver.
 Protein Synthesis
 Because the liver is the site for the synthesis of many
proteins, the liver may be assessed by measurement
total protein and albumin

Decreased levels of albumin usually develop only in severe
hepatic dysfunction,
 Plasma proteins
 ↑ Prothrombin time ( PT )
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Other tests related to hepatic disease
 Detoxification of drugs and other
substances
 Non – protein nitrogens

↑ Ammonia
 Serum immuological tests
 Hepatitis serology
 Serology is crucial for the specific diagnosis of hepatitis A, B, C
and D.
 Alpha-fetoprotein
 Specific marker for hepatocellular carcinoma
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 Correlation of laboratory results is an indication
of accuracy and appropriateness of results.
 In this case, increased levels of enzymes and
bilirubin and lowered protein correlate with
liver disease.
 The extent of the increased alkaline
phosphatase and the presence of increases in
both total and direct bilirubin help to specify
this liver disorder as obstructive jaundice
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Case Study
 The following laboratory test results were obtained
in a patient with severe jaundice, right upper
quadrant abdominal pain, fever, and chills
Serum ALP
Serum cholesterol
AST (SGOT)
4 times normal
Increased
Normal or slightly increased
5′-Nucleotidase
Increased
Total serum bilirubin
25 mg/dL
Conjugated bilirubin
19 mg/dL
Prothrombin time
Prolonged
but improves with a vitamin K injection
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Comment
 What is the most likely cause of
jaundice in the patient?
 The lab. Results suggest jaundice due to
extrahepatic obstruction either from:
 a stone in the common bile duct
 or a carcinoma of the head of the pancreas
 or a postoperative stricture
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Case Study
 A medical student recovering from an attack of
influenza was noticed to be slightly jaundiced.
Worried that he might have hepatitis, the student
had some blood taken for biochemical tests.
3.5 mg/dl
38–126
10–59
0.5–1.5%
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Comment
 The negative urine bilirubin indicates that
the excess bilirubin in the serum is
unconjugated.
 There is no evidence of hepatocellular
damage and the normal haemoglobin and
reticulocyte count indicate that
haemolysis cannot be the cause of the
raised bilirubin.
 By elimination, the diagnosis is Gilbert's
syndrome.
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 The laboratory test results suggest jaundice as a
result of extrahepatic obstruction:
 Causes
 A stone in the common bile duct,
 carcinoma of the head of the pancreas,
 or, possibly, a postoperative stricture.
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