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Conjugated Hyperbilirubinemia
DEFINITION
Diseases that reduce the rate of secretion of conjugated bilirubin (a mixture of monoglucuronides and
diglucuronides) 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

EPIDEMIOLOGY
The age distribution of conjugated hyperbilirubinemia reflects the age distribution of the underlying cause, ranging
from the first month of life (as in cases of biliary atresia) through midlife (as in cases of viral hepatitis or primary
biliary cirrhosis) and senescence (as in cases of biliary stones and malignancies).

ETIOLOGY AND DIFFERENTIAL DIAGNOSIS

Conjugated hyperbilirubinemia is a common abnormality among patients with notable liver or biliary disease. It
may also be observed in patients with systemic illness, such as sepsis or cardiogenic shock.

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

Primary biliary cirrhosis

Cytomegalovirus (CMV) hepatitis

Epstein-Barr virus hepatitis
Sepsis

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
Ischemia ("shock liver")
Acute fatty liver of pregnancy
Alpha-1 antitrypsin deficiency
Preeclampsia
Reye syndrome
Total parenteral nutrition

C. Diffuse Infiltrative Diseases

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
Drug-induced cholestasis, as with the following:
- Chlorpromazine
- Erythromycin
- Estrogens
- Anabolic steroids
- Many others

Dubin-Johnson syndrome

Rotor syndrome

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Benign recurrent cholestasis

SIGN & SYMPTOMS

Symptoms of conjugated hyperbilirubinemia include the following:

Brownish discoloration of the urine: Commonly the first manifestation

Scleral icterus: May be present, but typically reflects the unconjugated fraction of bilirubin, which binds
tissues much more avidly.

Yellowish cast to the skin, sclerae, and mucous membranes: If sufficient unconjugated bilirubin is present

Stigmata of chronic liver disease: Depending on the underlying illness

In addition, cutaneous or neurologic findings of chronic alcoholism may be helpful diagnostic findings.
Symptoms, such as the following, may suggest the underlying cause of hyperbilirubinemia:

Colicky abdominal pain or fever: Gallstone disease

Weight loss or constitutional symptoms: Malignancy or chronic infection

Recent anesthesia with the use of halothane: Halothane hepatitis

History of intense pruritus: Cholestatic disease resulting from biliary obstruction or intrahepatic cholestasis

Family history of jaundice: Inborn errors of bilirubin metabolism

Severe intercurrent illnesses: Sepsis, hepatic ischemia, or opportunistic infections

Severe right heart failure or tricuspid insufficiency with hepatomegaly: Hepatic congestion

Acholic, light gray stool: Biliary obstruction or stasis

Unexplained darkening of the skin, diabetes, or heart failure: Hemochromatosis

Kaiser-Fleisher rings or a low serum ceruloplasmin concentration: Wilson disease

PATHOPHYSIOLOGY
Bile formation is sensitive to various hepatic insults, including high levels of inflammatory cytokines (as may exist
in patients with septic shock). Conjugated hyperbilirubinemia results from reduced secretion of conjugated bilirubin
into the bile, as found in Hepatitis, or it results from impaired flow of bile into the intestine, as occurs in patients
with biliary obstruction.
Biliary obstruction refers to the blockage of any duct that carries bile from the liver to the gallbladder or from the
gallbladder to the small intestine. This can occur at various levels within the biliary system.

Intrahepatic Cholestasis
Occurs at the level of the hepatocyte or biliary canalicular membrane. Causes include hepatocellular disease
(eg, viral hepatitis, drug-induced hepatitis), drug-induced cholestasis, biliary cirrhosis, and alcoholic liver
disease.
In hepatocellular disease, interference in the 3 major steps of bilirubin metabolism, ie, uptake, conjugation, and
excretion, usually occurs. Excretion is the rate-limiting step and is usually impaired to the greatest extent. As a
result, conjugated bilirubin predominates in the serum

Extrahepatic Cholestasis
May occur within the ducts or secondary to external compression. Overall, Gallstones are the most common
cause of biliary obstruction. Other causes of blockage within the ducts include malignancy, infection, and
biliary cirrhosis. External compression of the ducts may occur secondary to inflammation (eg, pancreatitis) and
malignancy

DIAGNOSIS
Physical Examination
Palpation of the abdomen may reveal the following:

A mass (eg, a distended gallbladder, abdominal tumors)

Tenderness over the liver (eg, as in hepatitis or hepatic distention resulting from congestion or infiltrative
disease)

Tenderness over the gallbladder fossa (as in cases of biliary disease or infection)
Other clinical signs include the following:

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

Laboratory Studies
All patients should undergo the following tests:

Complete blood count (CBC) 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)

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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 to 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
The following imaging studies may be used in the workup of conjugated hyperbilirubinemia:

Abdominal ultrasonography

Computed tomography (CT) scanning

Magnetic resonance imaging (MRI)

Endoscopic retrograde cholangiopancreatography (ERCP)

Percutaneous transhepatic cholangiography (PTC or PTHC)

Cholecystography

Radiography

TREATMENT
1.

2.

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
Newborns who require parenteral nutrition after undergoing surgery benefit more from the prophylactic
introduction of cyclic parenteral nutrition, before parenteral nutrition associated liver disease (such as
hyperbilirubinemia) develops, than from the therapeutic initiation of cyclic parenteral nutrition, after liver
disease has been diagnose

PROGNOSIS
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 and primary biliary cirrhosis, bilirubin levels correlate strongly
with, but do not contribute to, short-term mortality

References:
Medscape