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. Elevated conjugated bilirubin levels usually indicate hepatobiliary disease.
Normal serum values of total bilirubin typically are 0.2-1 mg/dL (3.4-17.1 µmol/L), of which no more than 0.2 mg/dL (3.4 µmol/L) are directly reacting.
For patient education resources, see Digestive Disorders Center and Infections Center, as well as Cirrhosis of the Liver, Gallstones, and Newborn Jaundice.
Pathophysiology
Bilirubin metabolism includes the following:
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Production of bilirubin from hemoglobin: Hemoglobin degradation results in the formation of heme. In the reticuloendothelial system, the enzyme heme oxygenase cleaves heme into biliverdin. Biliverdin is reduced to bilirubin by the cytosolic enzyme biliverdin reductase before being released into the circulation. In this unconjugated form, bilirubin is water insoluble and is transported to the liver tightly bound to albumin. In adults about 300 mg of bilirubin is produced daily. [1, 6]
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Uptake of bilirubin by the hepatocyte for conjugation: Inside the hepatocyte, the microsomal enzyme uridine diphosphate (UDP)–glucuronyl transferase (UGT) (UDP-GT) then conjugates the insoluble unconjugated bilirubin with glucuronic acid to form the water-soluble conjugated forms, bilirubin monoglucuronide (15%) and bilirubin diglucuronide (85%). [1]
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Excretion of bilirubin: Conjugated bilirubin is excreted from the hepatocyte into the bile canaliculus by an active transport mechanism. Excretion into bile is the rate-limiting step in bilirubin metabolism. After excretion, bile flows through the biliary ductal collecting system and enters the small intestines. In the terminal ileum and colon, bilirubin is converted by bacterial enzymes into urobilinogen. About 20% of the urobilinogen is reabsorbed from the intestine into the portal circulation, creating an enterohepatic circulation. This recycled urobilinogen may be re-excreted into the bile by the liver or into urine by the kidney. The remaining urobilinogen is converted to fecobilinogen. [6]
Abnormalities in any of the above metabolic steps can cause an increased level of bilirubin in the serum. A rise in serum bilirubin can be measured in unconjugated or conjugated forms. Studies have shown that bilirubin has antioxidant as well as vasodilatory properties. [7, 8]
A rise in conjugated bilirubin can occur from the following three mechanisms:
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Biliary obstruction causing impaired flow of bile into the intestine
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Intrahepatic cholestasis
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Hepatocellular injury impairing bile formation
High levels of conjugated bilirubin may secondarily elevate the level of unconjugated bilirubin. Although the mechanism of this effect is not fully defined, one likely cause is reduced hepatic clearance of unconjugated bilirubin that results from competition with conjugated bilirubin for uptake or excretion.
The gene that codes for UDP-GT is UGT1A1. A genetic variation in the promoter region of UGT1A1 is associated with Gilbert syndrome. [8]
More recently, Abby Philips et al have described a novel homozygous frameshift variant in the ABCC2-gene in Dubin-Johnson syndrome, which presents with conjugated hyperbilirubinemia, that appears to predispose to chronic liver disease. [9]
Etiology
In a 2015 review of the literature, in which Gottesman et al selected 17 studies comprising 1692 infants as meeting their selection criteria for the evaluation of the etiologies of conjugated hyperbilirubinemia, idiopathic neonatal hepatitis was the most common cause in infancy (26.0%), and extrahepatic biliary atresia (25.89%) and infection (11.4%) were the most commonly specified etiologies. [10] Selection criteria were the following [10] :
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Prospective/retrospective case series or cohort study with at least 10 patients
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Consecutive infants who presented with conjugated hyperbilirubinemia
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Patients who received appropriate diagnostic work-up for conjugated hyperbilirubinemia
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No specific diagnoses were excluded in the studied cohort
In a 2021 review of 255 endoscopic retrograde cholangiopancreatographies (ERCP) over 20 years in infants aged 1 year or younger with cholestasis and suspected biliary obstruction, Stovicek et al found biliary atresia (48%), choledochal cysts (13%), and choledocholithiasis (4%) were the most common diagnoses. [11]
A 2021 retrospective analysis has described a clinical association between conjugated hyperbilirubinemia and hyperinsulinism. Edwards et al found that nearly half (48%) of 63 infants with hyperinsulinemic hypoglycemia developed cholestasis (conjugated bilirubin > 17 μmol/L; median maximum level of 81 μmol/L), with spontaneous resolution in all of the affected infants. [12] The investigators suggest that although this patient population has an increased risk for cholestasis that is associated with fetal distress and prematurity, there is no apparent association between the development of conjugated hyperbilirubinemia with parenteral nutrition or other pharmacologic therapies.
A categoric listing of the most common diseases that produce conjugated hyperbilirubinemia is presented in the table below.
Table. Differential Diagnosis of Conjugated Hyperbilirubinemia (Open Table in a new window)
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:
|
Epidemiology
United States data
Conjugated hyperbilirubinemia is a common abnormality among patients with notable liver or biliary disease. It may also be observed in patients with systemic illnesses, such as sepsis and cardiogenic shock. The frequencies of the liver and biliary diseases that cause conjugated hyperbilirubinemia are described for each specific disease.
International data
In certain lesser-developed countries, parasitic diseases, such as clonorchiasis and ascariasis, commonly produce biliary obstruction. Hemolytic diseases, such as malaria, may predispose patients to biliary obstruction through the formation of pigment gallstones.
Race-, sex-, and age-related differences in incidence
Race- and sex-related differences reflect those for the specific disease states that cause conjugated hyperbilirubinemia.
The age distribution of those with conjugated hyperbilirubinemia reflects the age distribution of the underlying disease states and ranges from the first month of life, as in cases of biliary atresia; through midlife, as in cases of viral hepatitis or primary biliary cholangitis; and to senescence, as in cases of biliary stones and malignancies.
Prognosis
Morbidity/mortality
The morbidity and mortality associated with conjugated hyperbilirubinemia result from the underlying disease process. In certain disease states, such as alcoholic hepatitis or primary biliary cholangitis, bilirubin levels correlate strongly with, but do not contribute to, short-term mortality.
Unlike unconjugated bilirubin, conjugated bilirubin does not bind significantly to neural tissue and does not lead to kernicterus or other forms of toxicity.
Green, discolored teeth have been reported as a late complication (later infancy) of prolonged conjugated hyperbilirubinemia in extremely low birth weight infants. [13] [14]
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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:
|
