Finding the Source of an Elevated Billirubin

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Finding the Source of an Elevated Billirubin

• Hrach Ike Kasaryan MSIII

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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
  catalase
• 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.

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What is Billirubin?

• Uncojugated billirubin is transported bound to
  albumin in blood, and is delivered to the
  haptocytes
• 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.

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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)

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When do you see Jaundice?

• Clinical signs of jaundice will start to show up
  when the total billirubin levels get to around 3
  mg/dl.
• The best place to look for the earliest signs of
  jaudice is under the tongue.

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So you have an elevated Total Billirubin, NOW
WHAT?
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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?

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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

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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

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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

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Elevated Indirect Billirubin

• If the indirect billirubin is due to hemolysis,
  than it is important to further differentiate the
  cause from intravascular and extravascular
  hemolysis
• 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

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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

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Elevated Indirect Billirubin with depressed Hgb
and normal LFTs

• Some causes of Extravascular Hemolysis
• Splenomegaly
• Auto-immune destruction of RBC
• In-effective Erythropoeisis

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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

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Elevated Indirect Billirubin, normal Hgb, Normal
LFTs

• 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

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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
  normal
• Examples of this type
• Hepatitis
• Drug induced liver damage
• Liver Mets

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Elevated Direct Billirubin

• Now what if the Direct Billirubin is elevated?
• Some clues to the presents of an elevated Direct
  Billirubin
• PURITIS
• Billirubin present in the urine (b/c it is water
  soluble)
• 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

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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..

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Elevated Direct Billirubin with normal alkaline
phos

• In this case the problem is a defect in secretion
  out of the hepatocytes
• Eg. Dubins Johnson syndrome

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IN CONCLUSION

• The first step in elevated T. Billi is to
  subclassify into direct and indirect billirubin
  elevation
• 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