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    Bilirubin Secretion,Jaundice and Evaluation

    of Liver FunctionHoward J. Worman, M. D.

    Evaluation of Liver Disease andHepatic Function

    HistoryPhysical ExaminationLaboratory TestsSometimes Radiological/Nuclear MedicineSometimes Liver Biopsy

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    Jaundice occurs as a result of excess bilirubin inthe blood. It is a hallmark of liver disease butnot always present in liver disease. Jaundiceoccurs when the liver fails to adequatelysecrete bilirubin from the blood into the bile.To understand how jaundice occurs, you mustfirst understand bilirubin synthesis,metabolism and secretion.

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    BilivirdinReductase

    Kikuchi et al.NatureStructuralBiology 8, 221 -225 (2001)

    HemeOxygenase

    Schuller et al.NatureStructuralBiology 6, 860 -867 (1999)

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    Bilirubin is frequentlydepicted as a lineartetrapyrrole.

    However, intramolecularhydrogen bonding fixesit in a rigid structure thatblocks exposure of itspolar groups to aqueoussolvents, making it veryinsoluble in blood.

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    OATP-C?

    Bilirubin in Blood is Bound to Albumin: Uptake intoHepatocyte at Basolateral (Sinusoidal) Membrane

    Some bilirubinstored in cytosol boundto proteins

    Bilurubin UDP-glucuronosyltransferase is localized to the endo-plasmic reticulum; it catalyzes conjugation to a diglucuronide, making it more water soluble.

    A: Labeling of periphery of cell hepatocyte nucleusB: Labeling of ER with antibody to UDP-glucuronosyltransferase

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    Alternative RNA splicing of different first exons ofUGT1 gives different isoforms with different substratespecificities, some for bilirubin and others to differentsubstrates, such as phenol.

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    ABCC2(MRP2, cMOAT)

    Bilirubin glucuronide is secreted from hepatocytes by an ATP-binding cassette protein. This is the rate limiting step in hepatocytebilirubin metabolism and disrupted in most acquired liver diseases

    Bilirubin is Only Approximately 2% of Bile

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    Stercobilins/Urobilins in Stool

    Some urobilinogenexcreted by kidney

    Diagnostic Consequences ofEnterohepatic Circulation of Bilirubin

    In hepatocyte dysfunction (hepatocellular) May see increased urobilinogen in urine because it is

    less efficiently reabsorbed by hepatocytes In biliary obstruction

    Stools may appear white because bilirubin does not getinto intestine and therefore not converted tostercobilins/urobilins

    No urobilinogen detected in urine

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    Measurement of Bilirubin in Blood

    Normally 17 M (1 mg/dl) >35 M: can begin to detect jaundice clinically, (sclera,

    mucus membranes early) Discoloration of skin with higher concentrations

    When measured precisely (e. g. by HPLC), around96% of serum bilirubin is unconjugated

    Clinical laboratory generally overestimates amountof conjugated bilirubin (up to 30%) because of method reported as total, direct (approximates conjugated) and

    indirect (approximates unconjugated)

    van den Berghand

    MullerReaction (1916)

    Using this method,20% to 30% serumdirect bilirubin isnormal value

    R R

    CONJUGATED

    BILIRUBIN

    UNCONJUGATED

    BILIRUBIN

    N+

    N

    SO3H

    + + ACCELERATOR

    (ALCOHOL, CAFFEINE)

    TOTAL DIRECT INDIRECT=

    TOTAL DIAZO REACTION OF PLASMA

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    Excess conjugated bilirubin in serum may be excreted by kidneys (dark urine).Albumin-bound unconjugated bilirubin cannot be excreted by kidneys.

    With longstanding elevated serum conjugated bilirubin, less is in urine because of covalent binding to albumin.

    Causes ofHyperbilirubinemia and

    Jaundice

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    Most Common Cause of UnconjugatedHyperbilirubinemia Western Countries

    Gilbert syndrome is not really a disease but a normal variant.

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    High blood concentrations of lipid solubleunconjugated bilirubin in infants that alsohave poorly developed blood-brain barrier

    can lead to kernicterus (brain damagecaused by bilirubin deposition).

    Treatments include exchance transfusionand phototherapy. Heme oxygenase

    inhibitors are also being studied for thisindication.

    Treatment of Neonatal Jaundice by Phototherapy

    Less intramolecular hydrogen bonding of E diasteriomers make them more aqueous soluble for renal excretion.

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    Caused by mutation in ABCC2 encoding canalicular transporter.

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    With abnormal secretion from hepatocytes, most excess bilirubin inblood is conjugated by can get mixed picture because of

    backup of unconjugated bilirubin.

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    Laboratory Tests inLiver Diseases

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    Liver Enzymes

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    Liver Biopsy in the Evaluation of Liver Disease

    Dr. Lefkowitch Next