Hyperbilirubinemia Differential Diagnosis

Hyperbilirubinemia Differential Diagnosis:

Bilirubin is a yellow colored pigment that the liver produces when red blood cells are broken down and recycled. It is a byproduct that occurs after the breakdown of hemoglobin. The red blood cells in the body are constantly building and breaking down and as a result many by products are released as waste. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is responsible for the yellow color of bruises, the color of urine, the brown color of feces and the yellow discoloration in jaundice.

Unconjugated “Indirect” Bilirubin:

Red blood cells (Erythrocytes) generated in the bone marrow and once they get old or damaged they are disposed in the spleen to be removed. The spleen breaks down the red blood cells. This releases hemoglobin which is the main component of red blood cells that binds oxygen, and is further broken down to heme as the globin. The heme is then turned into unconjugated bilirubin in the reticuloendothelial cells of the spleen. This unconjugated bilirubin is not soluble in water, due to intramolecular hydrogen bonding, so is bind to albumin and is sent to the liver.

Conjugated “Direct” Bilirubin:

In the liver, bilirubin becomes conjugated with glucuronic acid by the enzyme glucuronyltransferase, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. However, 95% of the secreted bilirubin is reabsorbed by the Terminal Ileum and reaches the liver by portal circulation and then resecreted by the liver into the small intestine. This process is known as enterohepatic circulation.

About half of the conjugated bilirubin remaining in the large intestine and is metabolized by colonic bacteria to form urobilinogen, which may be further oxidized to urobilin and stercobilin. Urobilin, stercobilin and their degradation products give feces its brown color.  However, just like bile, some of the urobilinogen is reabsorbed. A small amount of the reabsorbed urobilinogen is excreted in the urine following further oxidation to urobilin, which gives urine its characteristic yellow color.

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Hyperbilirubinemia differential diagnosis - Medical Institution

Hyperbilirubinemia differential diagnosis – Medical Institution


Hyperbilirubinemia results from a higher-than-normal level of bilirubin in the blood.
– Mild rise in bilirubin may be caused by the following:

  • Hemolysis or increased breakdown of red blood cells
  • Gilbert’s syndrome – a genetic disorder of bilirubin metabolism that can result in mild jaundice, found in about 5% of the population
  • Rotor syndrome: non-itching jaundice, with rise of bilirubin in the patient’s serum, mainly of the conjugated type.

– Moderate rise in bilirubin may be caused by:

  • Pharmaceutical drugs (especially antipsychotic, some sex hormones, and a wide range of other drugs)
  • Hepatitis (levels may be moderate or high)
  • Chemotherapy
  • Biliary stricture (benign or malignant)

– Very high rise in bilirubin may be caused by:

  • Neonatal hyperbilirubinaemia, where the newborn’s liver is not able to properly process the bilirubin causing jaundice
  • Stone in common bile duct,
  • Tumor obstructing common bile duct (eg, Tumor of the head of pancreas)
  • Cirrhosis
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Crigler–Najjar syndrome
  • Dubin–Johnson syndrome
  • Choledocholithiasis (chronic or acute)


Hyperbilirubinemia - Jaundice
The word “jaundice” comes from the French word jaune, which means yellow. Jaundice is a yellowish staining of the skin, sclera, and mucous membranes by bilirubin.  Jaundice is classified depending upon whether the bilirubin is free or conjugated to glucuronic acid into conjugated jaundice or unconjugated jaundice.

To further illuminate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., hepatitis A, B, C, delta, E, etc.).


Laboratory Studies:

All patients should undergo the following tests:

  • Complete blood count (CBC) to screen for hemolysis
  • Serum aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT])
  • Serologic screen for hepatitis, including hepatitis C virus (HCV) antibody and hepatitis B surface antigen (HBsAg) or antihepatitis B core antibody (anti-HBcAb)
  • Alkaline phosphatase (ALP): If elevated or if an obstruction is suspected, images of the bile ducts should be obtained; gamma-glutamyl transpeptidase (GGTP) results may help to differentiate a hepatic source from bone or other causes.
  • Fractionated bilirubin
  • Blood alcohol or acetaminophen levels upon admission (may be useful in certain cases)
  • Antimitochondrial antibody when considering primary biliary cirrhosis
  • Antinuclear antibodies (ANAs), smooth-muscle antibodies, and other serologic studies when considering autoimmune hepatitis
  • Iron and genetic studies when considering hemochromatosis
  • Copper studies when considering Wilson disease
  • Alpha-1 antitrypsin fractionation and other studies when considering hereditary liver diseases

Imaging Studies:

  • Abdominal ultrasonography should be performed to exclude biliary obstruction and to evaluate the liver parenchyma for possible cirrhosis, tumor, steatosis, or congestion.
  • Abdominal CT scanningmay be the initial imaging modality in some cases of conjugated hyperbilirubinemia, but it can also provide additional information about patients with abnormal ultrasonograms.
  • bdominal MRI produces images comparable in quality to CT scans without patient exposure to ionizing radiation. Following the administration of suitable contrast agents, detailed imaging of the biliary tract is possible. Magnetic resonance cholangiopancreatography (MRCP) may be particularly useful when evaluating cholestasis of pregnancy or patients who are too debilitated to tolerate traditional cholangiography.
  • Endoscopic retrograde cholangiopancreatography (ERCP) is useful in cases in which biliary obstruction is strongly suspected. It is the imaging modality of choice for the detection and treatment of common bile duct stones and is also useful for making a diagnosis of pancreatic cancer. Other conditions in which ERCP may be useful include primary sclerosing cholangitis and the presence of choledochal cysts.
  • Percutaneous transhepatic cholangiography (PTC or PTHC) offers most of the diagnostic and therapeutic possibilities of ERCP and may be more readily available in some settings. It can be useful in cases in which ERCP has been unsuccessful or is not available.
  • Oral cholecystography fails to visualize the gallbladder in patients with DJS, but patients with this condition tend to have unique findings on hepatobiliary scans. Specifically, the liver is visualized immediately following IV administration of the radiopharmaceutical dye and remains intensely and homogeneously visualized for up to 120 minutes.
[expand title=”References for Hyperbilirubinemia Differential Diagnosis “] References:
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