AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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.

Because bilirubin is highly insoluble in water, it must be converted into a soluble conjugate prior to 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 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, while conjugated bilirubin reacts rapidly. Total bilirubin is measured in the presence of an accelerator, while 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 two 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.

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 resulting 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 also may 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 the condition.

Sex

Sex differences reflect those for the specific disease states causing the condition.

Age

The age distribution 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

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

Evaluation always starts with obtaining a full history.

• Potential toxins (eg, drugs), environmental chemicals (eg, solvents), or wild mushrooms must be carefully excluded. Failure to diagnose toxic hepatitis promptly 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 icteric
• Colicky abdominal pain or fever suggests gallstone disease.
• Weight loss or constitutional systems suggests malignancy or chronic infection.
• Recent anesthesia using 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 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 because of 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 categorical listing of the most common diseases that produce conjugated hyperbilirubinemia is presented in the Table.

  Differential Diagnosis of Conjugated Hyperbilirubinemia

  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 hepatitis Sepsis	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 injury Drug toxicity (eg, acetaminophen) Halothane hepatitis Alcoholic hepatitis Iron overload (hemochromatosis) Copper overload (Wilson disease) Autoimmune hepatitis	Choledocholithiasis Sclerosing cholangitis AIDS cholangiopathy Hepatic arterial chemotherapy Postsurgical strictures Bile duct cancers Developmental disorders of the bile ducts (eg, Caroli) 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 Amyloidosis 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: Chlorpromazine Erythromycin Estrogens Anabolic steroids Many others

Physical

• The first manifestation commonly is a brownish discoloration of the urine. Although scleral icterus also may 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 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 distension 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.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

• CMV hepatitis
• Drug toxicity, especially the following: acetaminophen, allopurinol, anabolic steroids, chlorpromazine, estrogens, halothane, isoniazid, methyldopa, phenytoin, protease inhibitors, quinidine, rifampicin, statins, and sulfa drugs
• Exposure to environmental hepatotoxins (eg, beryllium, "nutraceuticals" [eg, herbal tea], organic solvents)
• Acute fatty liver of pregnancy
• Inherited disorders of bilirubin conjugation (eg, Rotor syndrome)
• Liver congestion
• Liver ischemia (shock liver)
• Rejection of transplanted liver
• Reye syndrome
• Total parenteral nutrition (TPN) toxicity
• Veno-occlusive disease associated with chemotherapy

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Appropriate initial laboratory testing depends on clinical history and physical examination.
• All patients should receive the following:
• • Complete blood count (CBC) to screen for hemolysis
  • Serum aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT])
  • Serologic screen for hepatitis, including hepatitis C virus antibody and hepatitis B surface antigen or antihepatitis B core antibody
  • Alkaline phosphatase: If elevated or if an obstruction is suspected, images of the bile ducts should be obtained. Gamma-glutamyl transpeptidase (GGTP) may help 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, 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 trypsin and other studies when considering hereditary liver diseases

Imaging Studies

• Abdominal ultrasound should be performed to exclude biliary obstruction and to evaluate the liver parenchyma for possible cirrhosis, tumor, steatosis, or congestion.
• • Advantages
  • • Safe
    • Noninvasive
    • Portable
    • Provides good visualization of gallbladder, bile ducts, and cystic lesions
    • Can detect parenchymal liver disease, such as cirrhosis or infiltration, and signs of portal hypertension
  • Disadvantages
  • • Limited resolution
    • May not detect common bile duct stones because of bowel gas
• Abdominal CT scans provide additional information about patients with abnormal ultrasound scans, but they may be the initial imaging test in some cases.
• • Advantages
  • • Better resolution
    • Provides good evaluation of the entire bile duct
    • Can define the anatomy better, especially if contrast agents are used
    • Better for evaluating suspected malignancies, especially with evaluation of the arterial phase
    • Permits guided needle biopsies
  • Disadvantages
  • • More expensive and less portable than sonography
    • Requires radiation exposure
    • Requires IV contrast for best results
    • Less sensitive than ultrasound for gallbladder stones
• Abdominal magnetic resonance imaging (MRI) produces images comparable in quality to CT scans without exposure to ionizing radiation. Following 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.
• • Advantages
  • • Requires no exposure to ionizing radiation (ie, safe in pregnancy)
    • Permits multiple contrast agents and multiple scanning techniques, which enhance potential information content
    • Permits guided needle biopsies (open MRI systems only)
    • With special contrast agents, can evaluate bile and pancreatic ducts
  • Disadvantages
  • • Not universally available
    • Cannot be used in most patients with metallic implants
    • Requires IV contrast for best results
    • Clinical experience is still somewhat limited
• Endoscopic retrograde cholangiopancreatography (ERCP) is useful in cases where biliary obstruction is strongly suspected. It is the investigation of choice to detect 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.
• • Advantages
  • • Allows treatment of obstruction using sphincterotomy, stone extraction, stent placement, or balloon-dilation of strictures
    • Permits biopsies under direct visualization
    • Provides excellent visualization of bile ducts
  • Disadvantages
  • • Requires conscious sedation and radiation exposure
    • Not always successful, especially after gastroduodenal surgery
• Percutaneous transhepatic cholangiography (PTC) 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.
• • Advantages
  • • Successful in most cases of biliary obstruction
    • Allows treatment of obstruction by stone extraction, balloon-dilation of strictures, or stent placement
    • Permits biopsies or brush cytology
    • Provides excellent visualization of bile ducts
  • Disadvantages
  • • Typically more invasive than ERCP
    • Normally successful only when bile ducts are dilated
    • Requires radiation exposure and use of contrast

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Consultations

• In most patients, the cause of conjugated hyperbilirubinemia is apparent, such as those with viral hepatitis or sepsis.
• When this is not the case or when multiple causes are possible, consultation with a gastroenterologist or hepatologist may be helpful.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Patient Education

• 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.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose liver toxicity due to ongoing drug or toxin exposure may lead to liver failure and death. For this reason, it is best to stop all potentially hepatotoxic drugs until the cause of the conjugated hyperbilirubinemia can be determined.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jan 9, 2007