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Finding the Source of an Elevated Billirubin


80% is from the breakdown of Hemoglobin ... Cholelithiasis, Pancreatic Tumor, etc.. Elevated Direct Billirubin with normal alkaline phos ... – PowerPoint PPT presentation

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Title: Finding the Source of an Elevated Billirubin

Finding the Source of an Elevated Billirubin
  • Hrach Ike Kasaryan MSIII

What is Billirubin?
  • Billirubin is a bi-product of Heme metabolisn
  • 250-350mg is produced daily from an adult
  • 80 is from the breakdown of Hemoglobin
  • The remaining 25 is from hepatic turnover of
    molecules such as myoglobin, cytochromes, and
  • Billirubin in its natural state (unconjugated) is
    hydrophobic, and insoluble in blood,
  • In order for it to be excreted in the bile, hence
    eliminated from the body, it must be made more
    water soluble.

What is Billirubin?
  • Uncojugated billirubin is transported bound to
    albumin in blood, and is delivered to the
  • It is than taken up into the hepatocyte by
    facilitated diffusion
  • Once inside the hapatocyte it is moved to the
    Endoplasmic Reticulim where the enzyme bilirubin
    uridine-diphosphate glucuronosyltransferase
    (billirubin-UGT) is found
  • This enzyme conjugates one molecule of
    gluco-uronic acid to billirubin, thus making it
    more water soluble
  • This more soluble form (conjugated billirubin) is
    than secreted from the hepatocyte into the
    biliary system via an ATP-dependant transporter.

What are the normal ranges in serum?
  • Total bilirubin 0.2-1 mg/dl (this does not
    differentiate conjugated from uncojugated)
  • Indirect bilirubin 0-0.1 mg/dl (a measure of
    the unconjugated form)
  • Direct bilirubin 0-0.2 mg/dl (a measure of the
    conjugated form)

When do you see Jaundice?
  • Clinical signs of jaundice will start to show up
    when the total billirubin levels get to around 3
  • The best place to look for the earliest signs of
    jaudice is under the tongue.

So you have an elevated Total Billirubin, NOW
Approach to elevated Billirubin
  • Any disease process that interferes with the
    production, transport, uptake, conjugation,
    secretion and elimination of billirubin can cause
    the levels to rise
  • The differential diagnosis of causes of an
    elevated billirubin is exhaustive and it is
    important to have a systematic approach to narrow
    the differential as specific as possible
  • So what is the first step?

Approach to elevated Billirubin
  • The first step is to see what is the major
    molecule accumulating, uncojugated (indirect) or
    conjugated (direct)
  • By knowing if it is conjugated or uncojugated you
    can start to narrow your thinking to the cause
  • Since the hepatocyte is the point at which
    billirubin is conjugated we can either conclude
    that the cause is at or before the site of
    cojugation with an elevated indirect, or after
    the point of conjugation with an elevated direct

Elevated Indirect Billirubin
  • The differential for elevated indirect-billirubin
    is still very exhausting
  • You can have an elevated indirect for
  • Increased production of Billirubin
  • Decreased Uptake into the Hepatocyte
  • Decreased Conjugation in the hepatocyte

Elevated Indirect Billirubin
  • The next step is to evaluate the CBC and the
    Liver Function Tests
  • When evaluating the CBC, the value of importance
    is the Hgb.
  • If there is a depressed level of Hgb, either
    acute or chronic, the chances are there is a
    hemolytic process going on.
  • Hemolysis is increased destruction of RBCs hence
    leading to increased billirubin production
  • In a hemolytic pattern the LFTs (particularly
    the ALT and AST) should be normal

Elevated Indirect Billirubin
  • If the indirect billirubin is due to hemolysis,
    than it is important to further differentiate the
    cause from intravascular and extravascular
  • One can do so by evaluating the serum haptoglobin
  • If the serum haptoglobin is depressed, the
    diagnosis is intravascular hemolysis, because the
    haptoglobin will be used up to bind up the lysed
    products of the RBCs
  • If the haptoglobin is normal, the diagnosis is
    extravascular hemolysis

Elevated Indirect Billirubin with depressed Hgb
and normal LFTs
  • Now at this point you have narrowed the
    differential down to a managable amount of dxs
    that can be easily searched for
  • Some examples that cause Intravascular Hemolysis
  • Drug induced (eg. Methyldopa)
  • Sickle Cell Anemia
  • Cold Agglutin (mycoplasma infection)
  • Malaria

Elevated Indirect Billirubin with depressed Hgb
and normal LFTs
  • Some causes of Extravascular Hemolysis
  • Splenomegaly
  • Auto-immune destruction of RBC
  • In-effective Erythropoeisis

Elevated Indirect Billirubin
  • If the Hgb level is normal, you can safely rule
    out hemolytic causes.
  • The next laboratory values to look at would be
    the Liver function tests.
  • With normal ALT, AST and Alkaline Phosphotase,
    the differential has now narrowed to problems
    with uptake into the hepatocyte or problems
    conjugating billirubin

Elevated Indirect Billirubin, normal Hgb, Normal
  • With normal Hgb and Normal LFTs, the
    differential is down to a few diseases
  • Decreased uptake
  • eg. Gilberts Disease ,
  • Drug inhibition of Uptake
  • Decreased conjugation
  • Eg. Crigler-Najjer
  • Drug inhibition of Conjugation

Elevated Indirect Billirubin, normal Hgb,
Abnormal LFTs
  • If it is discovered that there is a normal Hgb,
    and a hepatocellular pattern present (abnormal
    ALT and AST due to liver cell damage) than in
    this case, there is a decrease in cells to
    conjugate billirubin leading to a back up
  • In this case, the Alkaline Phosphatase should be
  • Examples of this type
  • Hepatitis
  • Drug induced liver damage
  • Liver Mets

Elevated Direct Billirubin
  • Now what if the Direct Billirubin is elevated?
  • Some clues to the presents of an elevated Direct
  • Billirubin present in the urine (b/c it is water
  • The differential now narrows a lot more with an
    elevated direct Billirubin, which would be due to
    anything disrupting transport out of the
    hepatocyte and out of the billiary system

Elevated Direct Billirubin, elevated Alkainw
Phosphotse and GGT
  • The next lab to look at with an elevated direct
    billirubin is the Alkaline Phosphotase(AP) and
    the GGT.
  • AP can be elevatied in many dz
  • however in the setting of elevated direct billi,
    and elevated GGT, you have now localized the
    problem to the billiary tree.
  • Now the differential has norrowed to things that
    would cause billiary obstruction
  • Eg. Cholelithiasis, Pancreatic Tumor, etc..

Elevated Direct Billirubin with normal alkaline
  • In this case the problem is a defect in secretion
    out of the hepatocytes
  • Eg. Dubins Johnson syndrome

  • The first step in elevated T. Billi is to
    subclassify into direct and indirect billirubin
  • The next step is to look at additional labs to
    help understand where the exact cause of the
    increased billirubin, direct or indirect, is
    coming from
  • Finally, come up with a short differential
    diagnosis of possible dz that could cause the
    scenario you are presented with
  • By following this approach, you can quickly asses
    and find the source for an elevated billirubin