eMedicine Specialties > Gastroenterology > Liver

Hyperbilirubinemia, Conjugated

Author: Richard A Weisiger, MD, PhD, Director, GI and Liver Faculty Practice, Professor, Department of Internal Medicine, University of California San Francisco
Contributor Information and Disclosures

Updated: Feb 16, 2009

Introduction

Background

Bilirubin is a tetrapyrrole created by the normal breakdown of heme. Most bilirubin is produced during the breakdown of hemoglobin and other hemoproteins. Accumulation of bilirubin or its conjugates in body tissues produces jaundice (ie, icterus), which is characterized by high plasma bilirubin levels and deposition of yellow bilirubin pigments in skin, sclerae, mucous membranes, and other less visible tissues.^1,2,3,4

Because bilirubin is highly insoluble in water, it must be converted into a soluble conjugate before elimination from the body. In the liver, uridine diphosphate (UDP)-glucuronyl transferase converts bilirubin to a mixture of monoglucuronides and diglucuronides, referred to as conjugated bilirubin, which is then secreted into the bile by an ATP-dependent transporter. This process is highly efficient under normal conditions, so plasma unconjugated bilirubin concentrations remain low.

A large number of disease states lead to bilirubin accumulation in plasma. Diseases that increase the rate of bilirubin formation, such as hemolysis, or diseases that reduce the rate of bilirubin conjugation, such as Gilbert syndrome, produce unconjugated hyperbilirubinemia.

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.

Laboratory assays for bilirubin typically involve its cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole that can be assayed spectrophotometrically. Because of its limited aqueous solubility, unconjugated bilirubin reacts slowly in the absence of an accelerator, such as ethanol, whereas conjugated bilirubin reacts rapidly. Total bilirubin is measured in the presence of an accelerator, whereas directly reacting bilirubin is measured without an accelerator. Indirectly reacting bilirubin is calculated by subtracting the directly reacting bilirubin score from the total bilirubin score.

Although the directly reacting bilirubin concentration approximates the conjugated bilirubin concentration in most cases, the 2 terms do not mean the same thing. Similarly, indirect bilirubin is not the same as unconjugated bilirubin.

The kidneys do not filter unconjugated bilirubin because of its avid binding to albumin. For this reason, the presence of bilirubin in the urine indicates the presence of conjugated hyperbilirubinemia.

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 excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education articles Cirrhosis, Gallstones, and Newborn Jaundice.

Pathophysiology

Conjugated hyperbilirubinemia results from reduced secretion of conjugated bilirubin into the bile, such as occurs in patients with hepatitis, or it results from impaired flow of bile into the intestine, such as occurs in patients with biliary obstruction. Bile formation is sensitive to various hepatic insults, including high levels of inflammatory cytokines, such as may occur in patients with septic shock.

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.

Frequency

United States

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

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.

Mortality/Morbidity

• Unlike unconjugated bilirubin, conjugated bilirubin does not bind significantly to neural tissue and does not lead to kernicterus or other forms of toxicity.
• 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 cirrhosis, bilirubin levels correlate strongly with, but do not contribute to, short-term mortality.

Race

Racial differences reflect those for the specific disease states causing conjugated hyperbilirubinemia.

Sex

Sex differences reflect those for the specific disease states causing conjugated hyperbilirubinemia.

Age

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 cirrhosis; to senescence, as in cases of biliary stones and malignancies.

Clinical

History

Clinical evaluation of those with suspected conjugated hyperbilirubinemia always starts with obtaining a full history.

• Potential toxins (eg, drugs), environmental chemicals (eg, solvents), or wild mushrooms must be carefully excluded. Failure to promptly diagnose toxic hepatitis may result in hepatic failure and death.
• Risk factors for viral hepatitis should be elicited. Possible risk factors include the following:
  • Transfusion
  • Intravenous (IV) drug use
  • Multiple sexual partners
  • Exposure to a person who is infected
• Colicky abdominal pain or fever suggests gallstone disease.
• Weight loss or constitutional systems suggests malignancy or chronic infection.
• Recent anesthesia with the use of halothane suggests halothane hepatitis.
• A history of intense pruritus suggests cholestatic disease resulting from biliary obstruction or intrahepatic cholestasis.
• A family history of jaundice suggests inborn errors of bilirubin metabolism.
• In patients with severe intercurrent illnesses, consider sepsis, hepatic ischemia, and opportunistic infections.
• Severe right heart failure or tricuspid insufficiency with hepatomegaly suggests hepatic congestion.
• Patients on parenteral nutrition may experience cholestasis that sometimes improves with the addition of lipid infusions.
• Patients with acquired immunodeficiency syndrome (AIDS) may experience biliary obstruction from opportunistic infection (eg, AIDS cholangiopathy).
• Patients with chronic liver disease may experience transient elevation of their bilirubin levels following blood transfusion, which results due to a more rapid turnover of the infused cells.
• In patients younger than 20-25 years, a history of a recent flulike syndrome treated with aspirin raises the possibility of Reye syndrome.
• Pregnancy suggests benign recurrent cholestasis or, in late pregnancy, acute fatty liver of pregnancy.
• A categoric listing of the most common diseases that produce conjugated hyperbilirubinemia is presented in the table below. Differential Diagnosis of Conjugated Hyperbilirubinemia

  Open table in new window

  [ CLOSE WINDOW ]

  Table

  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-ECytomegalovirus (CMV) hepatitisEpstein-Barr virus hepatitisSepsis	Primary biliary cirrhosis Graft versus host disease Veno-occlusive disease Sclerosing cholangitis
  B. Inflammation Without Infection	B. Damage to or Obstruction of Larger Bile Ducts
  Toxic liver injuryDrug toxicity (eg, acetaminophen)Halothane hepatitisAlcoholic hepatitisIron overload (hemochromatosis)Copper overload (Wilson disease)Autoimmune hepatitis	Choledocholithiasis Sclerosing cholangitisAIDS cholangiopathyHepatic arterial chemotherapyPostsurgical stricturesBile duct cancersDevelopmental disorders of the bile ducts (eg, Caroli)Extrinsic compression of the bile ductTumorsAcute pancreatitis
  C. Metabolic Dysfunction	C. Diffuse Infiltrative Diseases
  Ischemia ("shock liver")Acute fatty liver of pregnancyAlpha-1 antitrypsin deficiencyPreeclampsiaReye syndromeTotal parenteral nutrition	Granulomatous diseasesSarcoidosisDisseminated mycobacterial infectionsLymphomaWegener granulomatosis Amyloidosis Diffuse malignancy
  D. Inborn Errors of Metabolism	D. Diseases That Interfere with Biliary Secretion of Bilirubin
  Dubin-Johnson syndrome Rotor syndromeBenign recurrent cholestasis	Drug-induced cholestasis, as with the following:- Chlorpromazine- Erythromycin- Estrogens- Anabolic steroids- Many others

  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-ECytomegalovirus (CMV) hepatitisEpstein-Barr virus hepatitisSepsis	Primary biliary cirrhosis Graft versus host disease Veno-occlusive disease Sclerosing cholangitis
  B. Inflammation Without Infection	B. Damage to or Obstruction of Larger Bile Ducts
  Toxic liver injuryDrug toxicity (eg, acetaminophen)Halothane hepatitisAlcoholic hepatitisIron overload (hemochromatosis)Copper overload (Wilson disease)Autoimmune hepatitis	Choledocholithiasis Sclerosing cholangitisAIDS cholangiopathyHepatic arterial chemotherapyPostsurgical stricturesBile duct cancersDevelopmental disorders of the bile ducts (eg, Caroli)Extrinsic compression of the bile ductTumorsAcute pancreatitis
  C. Metabolic Dysfunction	C. Diffuse Infiltrative Diseases
  Ischemia ("shock liver")Acute fatty liver of pregnancyAlpha-1 antitrypsin deficiencyPreeclampsiaReye syndromeTotal parenteral nutrition	Granulomatous diseasesSarcoidosisDisseminated mycobacterial infectionsLymphomaWegener granulomatosis Amyloidosis Diffuse malignancy
  D. Inborn Errors of Metabolism	D. Diseases That Interfere with Biliary Secretion of Bilirubin
  Dubin-Johnson syndrome Rotor syndromeBenign recurrent cholestasis	Drug-induced cholestasis, as with the following:- Chlorpromazine- Erythromycin- Estrogens- Anabolic steroids- Many others

Physical

• The first manifestation in cases of conjugated hyperbilirubinemia is commonly a brownish discoloration of the urine. Although scleral icterus may also be present, this typically reflects the unconjugated fraction of bilirubin that binds tissues much more avidly.
• If sufficient unconjugated bilirubin is present, the skin, sclerae, and mucous membranes take on a yellow cast, although this may be difficult to detect if the tissues are pigmented naturally.
• Depending on the underlying illness, stigmata of chronic liver disease may or may not be present.
• Palpation of the abdomen may reveal the following:
  • A mass (eg, a distended gallbladder, abdominal tumors)
  • Tenderness over the liver (eg, as in cases of hepatitis or hepatic distention resulting from congestion or infiltrative disease)
  • Tenderness over the gallbladder fossa (as occurs in cases of biliary disease or infection)
• In cases of biliary obstruction or stasis, stool may be acholic and light gray.
• Unexplained darkening of the skin, diabetes, or heart failure suggests hemochromatosis.
• Kaiser-Fleisher rings or a low serum ceruloplasmin concentration suggests Wilson disease.
• Cutaneous or neurologic findings of chronic alcoholism may be helpful diagnostic findings.

• Search for CME/CE on This Topic »

• Dubin-Johnson Syndrome (Pediatrics: General Medicine)
• Breast Milk Jaundice (Pediatrics: Cardiac Disease and Critical Care Medicine)
• Dubin-Johnson Syndrome (Gastroenterology)
• Hyperbilirubinemia, Unconjugated (Gastroenterology)

• Liver, Gallbladder, and Pancreas Center
• Cirrhosis Overview
• Cirrhosis Causes
• Gallstones Overview
• Hepatitis Center
• Cirrhosis Symptoms
• Cirrhosis Treatment
• Newborn Jaundice Overview

• Neonatal Phototherapy Not Linked to Nevus Count Later on
• IgG Subclasses Not Predictive of Hemolysis, Hyperbilirubinemia in ABO-Heterospecific Neonates
• Interleukin-4-Conjugated Exotoxin Active Against Biliary Tract Carcinoma

• Prenatal Diagnosis of Progressive Familial Intrahepatic Cholestasis Type 2
• Israel Guidelines for the Management of Neonatal Hyperbilirubinemia and Prevention of Kernicterus
• Conjugated Linoleic Acid Modulation of Risk Factors Associated With Atherosclerosis