Post on 07-May-2015
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Evaluation of jaundice
Bilirubin metabolism - Physiology and Biochemistry
Clinical evaluation – adult, child, infant, and pregnant woman
Post-operative jaundice
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80% of bilirubin Degradation of the hemoglobin
Old or injured RBCs
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Bilirubin formation
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Old RBC 80%
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Major source of bilirubin
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Breakdown of hemoproteins in the liver Catalase Cytochrome oxidases
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20%
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Destruction of newly formed erythrocytes
Bone marrow itself Normally account for <15% of
bilirubin produced
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Ineffective erythropoiesis
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Increased in1. Thalassemia major 2. Megaloblastic anemias 3. Congenital erythropoietic
porphyria4. Lead poisoning 5. Dyserythropoietic anemias
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Ineffective erythropoiesis
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250 to 300 mg
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How much bilirubin is produced daily?
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Reticuloendothelial cells Spleen Liver Bone marrow
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Site of bilirubin synthesis
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HemeHeme ----------------------→ CO + Biliverdin ( green color)
+ Iron
oxygenase ↓ ↓ Biliverdin reductase
↓Bilirubin(released into blood)
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Formation of bilirubin
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Not soluble in water Potentially toxic Made soluble by its reversible,
binding to albumin
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Bilirubin
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Insoluble Made soluble by its reversible,
binding to albumin
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Bilirubin
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<2mg% Tightly but reversibly bound to
albumin
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Bilirubin in plasma
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Transported to the liver Bilirubin taken up by liver cells
Albumin not taken by liver
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Bilirubin bound to albumin
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Conjugates bilirubin Water-soluble
Excreted into bile
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Liver
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Bilirubin taken up across the sinusoidal (basolateral) membrane Carrier-mediated mechanism
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Bilirubin uptake
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With glucuronic acid Bilirubin UDP-glucuronyl
transferase (UGT1A1) Monoglucuronide (BMG)
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Conjugation in liver
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Induced by phenobarbitone
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Glucoronyltransferase
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Majority converted to BDG Actively excreted in bile
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BMG
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85% Diglucuronides
15% Monoglucuronide
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Bilirubin in bile
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Directed toward the canalicular (apical) membrane Transported into the bile
canaliculus ATP-dependent export pump
Canalicular membrane protein called multidrug resistance-associated protein 2
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Conjugated bilirubin
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Results from mutations in MRP2
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Dubin-Johnson syndrome
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Transported into plasma also < 5% of total serum bilirubin
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BMG and BDG
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Not absorbed up by intestinal mucosa
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Conjugated bilirubin
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Conjugated bilirubin hydrolyzed to unconjugated bilirubin
By bacterial glucuronidases
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Distal ileum and colon
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Reduced by normal gut bacteria Colorless urobilinogen
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Unconjugated bilirubin
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85% Excreted in feces unchanged Oxidized to orange derivatives
(urobilins) 15%
Enterohepatic circulation Up to 20% passively absorbed
Enter the liver through portal venous blood Re-excreted by liver
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Urobilinogen
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Small fraction escapes hepatic uptake
Reaches systemic circulation < 3 mg/dL filtered by renal
glomerulus Excreted in urine.
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Urobilinogen
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Hepatic excretion
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Rate-limiting step in bilirubin metabolism
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< 1 mg/dL
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Normal serum concentration of bilirubin
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< 1 mg/dL Almost entirely unconjugated
When measured with sensitive techniques
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Normal serum concentration of bilirubin
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98 % Unconjugated
Bound to albumin
2% Conjugated bilirubin
Water-soluble
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Serum bilirubin
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Cleared by the kidney
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Conjugated bilirubin
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Also bind reversibly to albumin When present in abnormally high
concentrations for a long time BMG or BDG bind irreversibly with
albumin BR-albumin conjugates
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BMG and BDG in plasma
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Loosely bound to albumin Filtered at the glomerulus
Appear in urine
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BMG and BDG
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All enter the kidney via the bloodstream
Only BMG and BDG appear in urine.
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UCB, BMG, BDG, and BR-albumin conjugates
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25 mg Bilirubin in excess of this is
bound only loosely Detach easily
Can diffuse into tissues
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How much bilirubin can be tightly bound in 100 ml of plasma?
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Bacterial beta-glucoronidase Remove glucoronide
Colorless urobilinogen form
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Terminal ileum and large intestine
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Oxidized in the colon to colored stercobilinogen Excreted in the feces
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Urobilinogen
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Small amount of urobilinogen is reabsorbed
Re-excreted through the liver Small amount bypass the liver and
enter systemic circulation Excreted in urine as urobilinogen
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Enterohepatic circulation
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Present normally
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Urobilinogen in urine
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Absent in urine Complete obstruction of the bile
duct Since no bilirubin reaches the intestine.
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Urobilinogen
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Due to increased production of bilirubin
Bilirubin is not present in urine Unconugated bilirubin does not
appear in the urine
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Urobilinogen in urine increased in hemolytic jaundice
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Bound to albumin Not filtered by the normal
glomerulus Normally not present in urine
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Unconjugated bilirubin
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Always conjugated form Water soluble
Indicates hepatobiliary disease
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Bilirubin in the urine
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< 1.5 mg/dL Jaundice
Serum bilirubin > 4 mg/dL
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Normal bilirubin concentration
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Bilirubin cleaved by diazotized sulfanilic acid Colored azo-dipyrole formed
Assayed by spectrophotometry
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Van den Bergh reaction
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Water soluble Reacts rapidly (“directly”) with
diazo reagents
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Conjugated bilirubin
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Not water soluble Reacts quite slowly with diazo
reagents
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Unconjugated bilirubin
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Ethanol or urea Facilitates the reaction of
unconjugated bilirubin with the diazo reagent
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“Accelerator” compound
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Subtract direct bilirubin concentration (i.e., accelerator compound absent) from that of the total concentration (i.e., accelerator compound present)
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Indirect bilirubin fraction
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Not equivalent to conjugated bilirubin levels
Similarly, indirect bilirubin is not equivalent to unconjugated bilirubin
Many laboratories Now not doing direct and indirect
bilirubin measurements
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Direct bilirubin concentration
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Same as uncongugated Free bilirubin is going to the
liver from reticuloendothelial cells
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Free bilirubin
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Conjugated bilirubin bound to albumin
Also called biliprotein Does not appear in the urine
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Delta bilirubin
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2 weeks
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Half-life of albumin-bound bilirubin
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Albumin = 2 to 3 weeks Delta bilirubin = 15 days Bilirubin = 4 h
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Half-life
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Bilirubinuria may disappear before hyperbilirubinemia
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Delta bilirubin
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Presence of bile pigments in urine
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Choluria
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Occur only in uncogugated hyperbilirubinemia
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Acholuric jaundice
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Increased bilirubin production Hemolysis Ineffective erythropoiesis Resorption of a hematoma
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Unconjugated hyperbilirubinemia
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Increased destruction of erythrocytes Unconjugated hyperbilirubinemia.
Bone marrow Capable of only eightfold increase
in erythrocyte production in response to a hemolytic stress
If the liver function is normal Hyperbilirubinemia is mild
< 4 mg%
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Hemolysis
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Shortened lifespan of transfused erythrocytes
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Jaundice may follow massive transfusion
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Hyperbilirubinemia Resorption of hematomas Blood transfusions
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Major trauma
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Bile stones Precipitation of bilirubin salts
within the gall bladder or biliary tree
Cholecystitis Biliary obstruction
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Prolonged hemolysis
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Most common cause of unconjugated hyperbilirubinemia
Immature liver bilirubin metabolism
UDP-glucoronyltransferase activity reduced
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Physiological jaundice
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Occur only with uncongugated hyperbilirubinemia
Only unconjugated bilirubin can cross the blood brain barrier
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Kernicterus
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Unconjugated bilirubin Penetrates BBB When the plasma level exceeds that
which can be tightly bound by albumin i.e., > 25 mg/dl
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Kernicterus
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Blue light Increases conversion of
uncongugated bilirubin to maleimide fragments
Can be excreted into the bile
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Phototherapy
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Direct bilirubin fraction > 50% of the total serum bilirubin
Due to defects in hepatic excretion Regurgitation of conjugated
bilirubin from hepatocytes into the serum
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Conjugated hyperbilirubinemia
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Neonatal liver Incompletely developed at birth
Levels of UDP-glucoronyltransferase enzymes are low
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Physiologic Neonatal Jaundice
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Mild unconjugated hyperbilirubinemia 2 to 5 days after birth
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Most neonates
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Bilirubin level is low at birth Bilirubin produced by the fetus
Cleared by the placenta Eliminated by the maternal liver
Jaundice at birth is pathological
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Physiologic Neonatal Jaundice
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Normal serum bilirubin Within 2 weeks
May last for up to 4 weeks Premature infants Exclusively breast fed babies
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Peak levels < 15 mg/dL
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Liver Immaturity is more severe
Higher levels of unconjugated hyperbilirubinemia develop
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Premature babies
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Bilirubin >20 mg/dL Uncongugated bilirubin crosses
immature blood-brain barrier Precipitates in the basal ganglia
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Risk for kernicterus
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Physiologic Jaundice usually does not need treatment
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Treatment
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Converts bilirubin into photoisomers Soluble
Can be excreted in bile without conjugation
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Phototherapy
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1. Diabetes in mother2. Polycythemia in infant3. Delayed cord clamping 4. Cephalhematoma5. Intraventricular hemorrhage
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Conditions that can exaggerate physiologic Jaundice
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6. Hypothyroidism (decreased UDP-glucoronyl transferase activity)
7. Congenital infections (decrease hepatic excretion of bilirubin)
8. Hypoxia9. Congenital heart disease (decrease
hepatic perfusion) 10. Unfed babies (Increased
enterohepatic circulation)
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Conditions that can exaggerate physiologic Jaundice
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Pathological Hemolytic disease Infection
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Jaundice at birth
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Pregananediol breast milk Interfere with bilirubin conjugation
Jaundice in second week of life. Temporary interruption of breast
feeding Reduce the bilirubin levels
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Breast milk jaundice
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UGT1A1 inhibitor is found in maternal serum. Transient familial neonatal
hyperbilirubinemia
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Lucey-Driscoll syndrome
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Bilirubin UGT-1 activity is absent
Severe unconjugated hyperbilirubinemia of about 20 to 45 mg/dL
Appears in the neonatal period Persists for life
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Type I Crigler-Najjar syndrome
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Unconjugated hyperbilirubinemia
Abnormal UDP-glucuronyl transferase activity
Type I Absent (severe)
Type II Crigler-Najjar < 10% (mild)
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Crigler-Najjar
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Phototherapy Required to prevent this
complication Liver transplantation
Lifesaving
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Many die of kernicterus in the neonatal period
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Liver biopsy Normal
No hemolysis
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LFTs are normal
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Bilirubin glucuronides Markedly reduced or absent.
Serum bilirubin concentration does not respond to enzyme inducers
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Bile is colorless
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Unconjugated bilirubin accumulates in plasma
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No bilirubin in urine
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For about 12 hours daily From birth throughout childhood
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Phototherapy
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Dehydration Increased insensible water loss Result from increase in
environment and body temperature.
Baby should be weighed twice daily.
Retinal damage May occur after several days Eyes should be kept covered
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Complications of phototherapy
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May be needed in the immediate neonatal period
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Exchange transfusion
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Indicated prior to the onset of brain damage
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Liver transplantation
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UGT-1 activity < 10% of normal Not ill during the neonatal period May not be diagnosed until early
childhood
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Type II Crigler-Najjar syndrome
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Deeply colored Bilirubin glucuronides are present
Increase in monoglucuronides Characteristic
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Bile
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Increases UGT-1 activity Fall in serum bilirubin concentration
to 2 to 5 mg/dL Distinguishes CN-II from CN-I.
Normal life expectancies
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Phenobarbital
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Rare in CN – 2
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kernicterus
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Type I Recessive
Type II Predominantly recessive (Harrison) Autosomal dominant (Sleizenger)
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Transmission of Crigler-Najjar
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UGT1A1 activity Reduced to < 35%
Defect in conjugation Defect also in bilirubin uptake
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Gilbert's Syndrome
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Isolated uncongugated hyperbilirubinemia (< 4 mg/dL)
Benign
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Gilbert’s syndrome
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Serum bilirubin rise Twofold to threefold
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Fasting
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Normalizes Serum bilirubin concentration
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Phenobarbital
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Topoisomerase 1 inhibitor Useful in
Colorectal cancer Uterine cancer Small cell lung cancer
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CPT-11 (irinotecan)
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Glucuronidated by bilirubin-UDP-glucuronosyltransferase
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CPT-11 (irinotecan)
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May cause Myelosuppression
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Irinotecan in GS
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MRP2 is defective ATP-dependent canalicular
membrane transporter Defective hepatic secretion of
conjugated bilirubin
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Dubin-Johnson Syndrome
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Autosomal recessive Conjugated hyperbilirubinemia
in childhood or early adult life
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Dubin-johnson syndrome
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Liver is black. Accumulation of dark, melanin-like
pigment Epinephrine metabolites that are not
excreted normally. Substrates for MRP2
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Cardinal feature
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Unnecessary Not associated with an adverse
clinical outcome
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Liver biopsy
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Dubin-Johnson syndrome Total coproporphyrin is normal > 80% is isomer I
Two naturally occurring coproporphyrin isomers in urine
I – 25% III - 75%
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Diagnostic of Dubin-Johnson syndrome
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Milder Dubin-johnson syndrome Conjugated hyperbilirubinemia
Liver histology Normal
No black pigment
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Rotor syndrome
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Increased by Oral contraceptive use Pregnancy Intercurrent illness
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Hyperbilirubinemia
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May be subclinical until the patient becomes pregnant or receives oral contraceptives
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Hyperbilirubinemia
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Normal Do not have pruritus
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Bile acid metabolism
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1. Neonatal jaundice2. Crigler-najjar syndrome 3. Gilbert syndrome
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Congugation abnormal
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Abnormal Dubin-johnson syndrome Rotor syndrome
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Secretion of bilirubin into bile
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Secretion into bile Dubin-johnson and Rotor
MRP 2 protein abnormal Congugation
UDP-GT abnormal1. Crigler-najjar - congugation 2. Gilbert – congugation and uptake3. Neonatal jaundice - congugation
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Abnormalities - Summary
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Yellow color of the skin Due to carotene
Occurs in normal persons who ingest excessive amounts of carotene Vegetables Carrots Oranges
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Carotenoderma
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Concentrated on the Palms Soles Forehead
Carotenoderma spares the sclerae
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Carotene
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Can cause discoloration of the sclerae
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Quinacrine
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Third trimester. Presents with pruritus Jaundice infrequent
Resolves within 2 weeks of delivery
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Intrahepatic cholestasis of pregnancy
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Tends to recur with subsequent pregnancies
Caused by an unusual sensitivity to circulating estrogens
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Intrahepatic cholestasis of pregnancy
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Third trimester Encephalopathy
Markedly increased levels of bilirubin and ammonia
Hypoglycemia May be fatal
Unless delivery is promptly performed
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Acute fatty liver of pregnancy
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Microvascular disorder BP> 140/90 mmHg Proteinuria >300 mg per 24 h
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Preeclampsia
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Affects the liver in about 10 %
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Vasospasm and endothelial injury in multiple organs
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Change the position from lateral recumbent to supine Increase in diastolic BP of 20 mmHg
or more Due to increased sensitivity to
angiotensin II
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“Roll-over test"
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Severe form and requires prompt delivery Hemolysis Elevated Liver function tests Low Platelet count
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HELLP
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Most commonly used to control blood pressure.
Calcium channel blockers may also be used
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IV labetalol
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Avoided in the second and third trimesters of pregnancy Oligohydramnios
Decreased fetal renal function
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ACE inhibitors
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For eclamptic seizures
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Magnesium sulfate
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Predisposing factors Inhalational anesthetic agents Hepatotoxic drugs Impaired hepatic perfusion Blood transfusions Occult sepsis
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Postoperative jaundice
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Self-limited <2 weeks
Transient hyperbilirubinemia Normal LFT
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Benign postoperative cholestasis
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