eMedicine Specialties > Gastroenterology > Liver

Hyperbilirubinemia, Conjugated

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

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

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.

Differential Diagnoses

Acute Liver Failure	Graft Versus Host Disease
Alcoholic Hepatitis	Hemochromatosis
Amyloidosis, Overview	Hepatitis, Viral
Autoimmune Hepatitis	Miliary Tuberculosis
Biliary Obstruction	Pancreatic Cancer
Cardiac Cirrhosis	Pancreatitis, Acute
Cholangiocarcinoma	Primary Biliary Cirrhosis
Cholangitis	Sarcoidosis
Cholecystitis	Septic Shock
Choledocholithiasis	Shock, Hemorrhagic
Cirrhosis	Tricuspid Regurgitation
Cytomegalovirus	Wilson Disease
Dubin-Johnson Syndrome

Workup

Laboratory Studies

Appropriate initial laboratory testing in cases of conjugated hyperbilirubinemia depends on the clinical history and physical examination findings.^2,3,5
All patients should be tested for the following:
- Complete blood cell (CBC) count 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 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.
- Advantages
  - Safe
  - Noninvasive
  - Portable
  - Provides good visualization of the 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 computed tomography (CT) scans provide additional information about patients with abnormal ultrasonography scans, and CT scanning may be the initial imaging modality in some cases.
- Advantages
  - Better resolution than ultrasonography
  - Provides good evaluation of the entire bile duct
  - Can define the anatomy better than ultrasonography, 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 ultrasonography
  - Requires radiation exposure
  - Requires IV contrast medium for best results
  - Less sensitive than ultrasonography for gallbladder stones
Abdominal magnetic resonance imaging (MRI) produces images comparable in quality to CT scans without patient 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 medium 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 and treat 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
  - May cause pancreatitis and other complications
  - Not always successful, especially after gastroduodenal surgery
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.
- 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 the bile ducts
- Disadvantages
  - Typically more invasive than ERCP
  - May not be successful unless the bile ducts are dilated
  - Requires radiation exposure and use of contrast medium

Treatment

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.

Miscellaneous

Medicolegal 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

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Keywords

conjugated hyperbilirubinemia, hyperbilirubinemia, icterus, jaundice, kernicterus, bilirubin accumulation, bilirubin formation, tetrapyrrole, hemoglobin, unconjugated bilirubin, conjugated bilirubin, liver disease, biliary disease

Contributor Information and Disclosures

Author

Richard A Weisiger, MD, PhD, Director, GI and Liver Faculty Practice, Professor, Department of Internal Medicine, University of California San Francisco
Richard A Weisiger, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases and American Society for Clinical Investigation
Disclosure: Nothing to disclose.

Medical Editor

Vivek V Gumaste, MD, Associate Professor of Medicine, Mt Sinai School of Medicine, Adjunct Clinical Assistant, Mt Sinai Hospital; Director, Division of Gastroenterology, City Hospital Center, Elmhurst, NY
Vivek V Gumaste, MD is a member of the following medical societies: American College of Gastroenterology and American Gastroenterological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

Further Reading