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Ms. B is a 56-year-old woman who comes to your office because her skin and eyes have been yellow for the past 2 weeks.

What is the differential diagnosis of jaundice? How would you frame the differential?

The differential diagnosis of jaundice, or hyperbilirubinemia, is often organized pathophysiologically. It is helpful to review some basic physiology first.

  1. Oxidation of the heme moiety of Hgb generates biliverdin, which is metabolized into unconjugated bilirubin, and then bound to albumin.

  2. There are 3 steps in bilirubin metabolism in the liver:

    1. Uptake: The unconjugated bilirubin-albumin complex reaches the liver cell, bilirubin dissociates, and then enters the hepatocyte.

    1. Conjugation: Unconjugated bilirubin and glucuronic acid combine to make conjugated bilirubin.

    1. Excretion: The hepatocyte excretes conjugated bilirubin into the bile.

      1. The rate-limiting step of bilirubin metabolism in the liver

      1. If excretion is impaired, conjugated bilirubin travels back through the sinusoidal membrane of the hepatocyte into the bloodstream.

  3. Conjugated bilirubin in the bile is transported through the biliary ducts into the duodenum; it is not reabsorbed by the intestine.

    1. Can be excreted unchanged in the stool

    1. Can be converted to urobilinogen by colonic bacteria

      1. Urobilinogen can be reabsorbed, entering the portal circulation.

      1. Some is taken up by the liver and re-excreted into the bile.

      1. Some bypasses the liver and is excreted by the kidney, thus appearing in the urine in small amounts.

  4. Unconjugated bilirubin is not found in the urine because it is bound to albumin and cannot be filtered by the glomeruli.

  5. Conjugated bilirubin is filtered and excreted in the urine when there is hyperbilirubinemia.

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The first key point in the differential diagnosis of hyperbilirubinemia is determining which kind of bilirubin is elevated.
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Dark, tea-colored urine means the patient has conjugated hyperbilirubinemia.
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Light stools, often described as “clay colored,” occur when extrahepatic obstruction prevents bilirubin from entering the intestine.

If there is unconjugated hyperbilirubinemia (when > 80% of the bilirubin is unconjugated), use a pathophysiologic framework:

  1. Increased bilirubin production

    1. Hemolysis

    1. Dyserythropoiesis

    1. Extravasation of blood into tissues

  2. Impaired hepatic bilirubin uptake

    1. Heart failure

    1. Sepsis

    1. Drugs (rifampin, probenecid, chloramphenicol)

    1. Fasting

    1. Portosystemic shunts

  3. Impaired bilirubin conjugation (decreased hepatic glucuronosyltransferase activity)

    1. Hereditary

      1. Gilbert syndrome

      1. Crigler-Najjar syndrome

    1. Acquired

      1. Neonates

      1. Hyperthyroidism

      1. Ethinyl estradiol

      1. Liver disease (causes mixed hyperbilirubinemia; usually predominantly conjugated)

      1. Sepsis

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Most patients with unconjugated hyperbilirubinemia have hemolysis, Gilbert syndrome, heart failure, or sepsis.

Although many sources organize the differential diagnosis for conjugated hyperbilirubinemia (when > 50% is conjugated) using a pathophysiologic framework, a more practical, clinical approach uses the results of other liver function tests:

  1. Normal liver enzymes (ALT [SGPT], ...

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