Background
Unconjugated hyperbilirubinemia results from disease states that lead to bilirubin accumulation in plasma, such as increase the rate of bilirubin formation (eg, hemolysis) or reduce the rate of bilirubin conjugation (eg, Gilbert syndrome).
Bilirubin is a byproduct of heme metabolism. About 80% of bilirubin is derived from the breakdown of hemoglobin; the remainder (about 20%) is from the breakdown of other heme proteins such as cytochrome, myoglobin, and tryptophan. [1]
Unconjugated bilirubin is highly insoluble in water; therefore, it must be converted to a soluble conjugate before elimination from the body. In the liver, uridine diphosphate (UDP)-glucuronyl transferase (UGT) converts bilirubin to a mixture of monoglucuronides and diglucuronides, referred to as conjugated bilirubin, which is then secreted into the bile canaliculi by an adenosine triphosphate (ATP)-dependent transporter. This process is highly efficient under normal conditions, such that plasma unconjugated bilirubin concentrations remain low. The bilirubin measured in serum reflects a balance between production and clearance.
Accumulation of bilirubin or its conjugates in body tissues produces jaundice (ie, icterus), which is characterized by high plasma bilirubin levels and the deposition of yellow bilirubin pigments in the skin, sclerae, mucous membranes, and other less visible tissues. [2, 3, 4, 5]
Diseases that reduce the rate of secretion of conjugated bilirubin into the bile or the flow of bile into the intestine produce a mixed or predominantly conjugated hyperbilirubinemia due to the reflux of conjugates back into the plasma.
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Conjugated Hyperbilirubinemia. This gross liver specimen from a patient with Dubin-Johnson syndrome shows multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.
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Conjugated Hyperbilirubinemia. The microscopic histologic image of the liver in Dubin-Johnson syndrome shows multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.
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Conjugated Hyperbilirubinemia. This liver biopsy specimen demonstrates the ground-glass appearance of hepatocytes in a patient with hepatitis B.
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Conjugated Hyperbilirubinemia. A plain abdominal radiograph in a patient with a clinical diagnosis of acute cholecystitis is shown. The diagnosis was confirmed by means of abdominal ultrasonography. The radiograph shows faint opacities in the region of the gallbladder fossa (red circle) and dilated loops of small bowel in the epigastrium and midabdomen secondary to localized ileus.
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Conjugated Hyperbilirubinemia. A 26-year-old man known to be positive for human immunodeficiency virus (HIV) presented with pain in the right upper quadrant and mild jaundice. This axial sonogram through the gallbladder (GB) and pancreas (P) shows sludge within the gallbladder and the lower common bile duct (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.
Tables
I. Acute or Chronic Hepatocellular Dysfunction |
II. Diseases That Prevent Flow of Bile Into the Intestine |
A. Infection |
A. Damage to Intrahepatic Bile Ducts or Portal Tracts |
Viral hepatitis A-E Cytomegalovirus (CMV) hepatitis Epstein-Barr virus (EBV) hepatitis Sepsis |
Primary biliary cholangitis Veno-occlusive disease |
B. Inflammation Without Infection |
B. Damage to or Obstruction of Larger Bile Ducts |
Toxic liver injury Drug toxicity (eg, acetaminophen) Halothane hepatitis Alcoholic hepatitis Iron overload (hemochromatosis) Copper overload (Wilson disease) Autoimmune hepatitis |
Sclerosing cholangitis Acquired immunodeficiency syndrome (AIDS) cholangiopathy Hepatic arterial chemotherapy Postsurgical strictures Bile duct cancers Developmental disorders of the bile ducts (eg, Caroli disease) Extrinsic compression of the bile duct Tumors Acute pancreatitis |
C. Metabolic Dysfunction |
C. Diffuse Infiltrative Diseases |
Ischemia ("shock liver") Acute fatty liver of pregnancy Alpha-1 antitrypsin deficiency Preeclampsia Reye syndrome Total parenteral nutrition |
Granulomatous diseases Sarcoidosis Disseminated mycobacterial infections Lymphoma Wegener granulomatosis Diffuse malignancy |
D. Inborn Errors of Metabolism |
D. Diseases That Interfere With Biliary Secretion of Bilirubin |
Dubin-Johnson syndrome Rotor syndrome Benign recurrent cholestasis |
Drug-induced cholestasis, as with the following:
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