I. Problem/Condition.

Liver enzymes are frequently checked during inpatient hospitalization, and elevated serum bilirubin is a common finding. This hyperbilirubinemia is often caused by an underlying hepatic or hematologic derangement, but can also be a benign finding. The astute clinician must be able to identify the underlying cause when appropriate.

Bilirubin is a normal by-product of hemoglobin metabolism. Plasma unconjugated (indirect) bilirubin is bound to albumin and taken up by hepatocytes, where it is conjugated with glucuronic acid. Conjugated (direct) bilirubin is secreted into bile and excreted. Hyperbilirubinemia can be caused by conditions leading to primarily unconjugated or primarily conjugated hyperbilirubinemia. Jaundice, or yellowing of the skin, sclera, and mucous membranes by bilirubin is typically detectably clinically once serum bilirubin rises above 2.5 milligrams/deciliter (mg/dL) and is often first detectable in the conjunctiva or under the tongue.

Hyperbilirubinemia is only dangerous in and of itself in newborns, where it can cross the blood brain barrier, deposit, and cause encephalopathy (kernicterus) at levels of 20-25mg/dL. Potentially life-threatening conditions that may present with hyperbilirubinemia and jaundice include acute cholangitis, fulminant hepatic failure, massive hemolysis and acute fatty liver of pregnancy.

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II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The differential diagnosis for hyperbilirubinemia is quite broad, and includes hepatic causes, hematologic causes, and inborn errors of metabolism. It is important to note if the hyperbilirubinemia is an isolated lab abnormality, or if it is associated with other liver enzyme or hematologic lab abnormalities.

In newborns, isolated hyperbilirubinemia is frequently associated with inborn errors of bilirubin metabolism, and includes:

  • Physiologic jaundice (generally resolves by day 10)

  • Breast milk jaundice (resolves if breast milk is discontinued)

  • Gilbert syndrome (benign)

  • Dubin Johnson syndrome (benign)

  • Crigler-Najjar syndrome, type I and type II. Crigler-Najjar syndrome can cause kernicterus, which must be treated.

In adults, the differential diagnosis for hyperbilirubinemia should still include the inborn errors of bilirubin metabolism (Gilbert syndrome, Dubin Johnson syndrome, Rotor syndrome, and Crigler-Najjar syndrome) and acquired disorders of bilirubin metabolism.

Unconjugated (indirect) hyperbilirubinemia can be caused by overproduction, impaired uptake by the liver or abnormalities of conjugation, including:

  • Hemolysis

  • Gilbert syndrome

The intrahepatic causes of conjugated (direct) hyperbilirubinemia include:

  • Hepatitis (viral, alcohol-induced, autoimmune, drug-induced)

  • Pregnancy

  • Total parenteral nutrition

  • Primary biliary cirrhosis

  • Toxin/drug induced cholestasis

  • Sepsis

The extrahepatic causes of conjugated hyperbilirubinemia include:

  • Gallstones (cholelithiasis/choledocholithiasis), strictures

  • Malignancy

  • Primary sclerosing cholangitis

  • Infection (cholangitis/cholecystitis)

  • Pancreatitis

Each of these individual conditions will be discussed in a separate review.

Gilbert syndrome is a hereditary condition present in 5-10% of Western European populations that causes a 70% decrease in the liver’s ability to conjugate bilirubin. This results in intermittent episodes of unconjugated hyperbilirubinemia, often precipitated by fasting, infection, overexertion or medications. Gilbert’s should only be diagnosed after excluding liver disease or hemolysis, and typically total bilirubin is <5mg/dL and conjugated <20% of the total fraction.

B. Describe a diagnostic approach/method to the patient with this problem

There are several schema available to help to determine the etiology of hyperbilirubinemia:

1. Age-based classification

  • Adult causes (with subsets congenital & acquired)

  • Pediatric causes

Please refer to the prior section for specific causes.

2. Bilirubin processing based on conjugation

  • Conjugated hyperbilirubinemia is seen with elevated direct bilirubin; bile can be seen on urinalysis

  • Unconjugated hyperbilirubinemia is seen with elevated indirect bilirubin; bile should not be seen on urinanalysis

  • Elevated direct bilirubin (conjugated hyperbilirubinemia) can be caused by several factors:

    Intrahepatic cholestasis

    Hepatocellular injury

    Extrahepatic cholestasis

  • Elevated indirect bilirubin (unconjugated hyperbilirubinemia) can be caused by several factors:

    Increased production: Hemolysis, hematoma reabsorption

    Impaired uptake: Medications, portosystemic shunts, heart failure

    Impaired conjugation: Gilbert syndrome, Crigler-Najjar

3. Bilirubin processing based classification based on location

  • Prehepatic causes: Hemolysis, hematoma reabsorption

  • Intrahepatic causes: Can be broken down into unconjugated and conjugated

    Unconjugated: Gilbert syndrome

    Conjugated: Intrahepatic cholestatis, hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Dubin-Johnson syndrome, Rotor syndrome

  • Posthepatic causes: Cholelithiasis, neoplasm, and pancreatitis

1. Historical information important in the diagnosis of this problem.

Clinicians will want to ask about the age of the patient, associated symptoms such as fever, weight loss or abdominal pain, history of jaundice or abdominal surgery, social history to determine any risk factors for hepatitis (including alcohol use and viral risk factors), medication use including herbs/supplements, and family history, as each of these can help to diagnose the underlying etiology of hyperbilirubinemia.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Physical examination should look for signs of jaundice or underlying liver disease (ascites, splenomegaly, spider angiomata, gynecomastia), but there is no pathognomonic physical exam finding to suggest the etiology of hyperbilirubinemia.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Hyperbilirubinemia will obviously be detected by an elevated bilirubin level. Conjugated bilirubinemia is seen with elevated direct bilirubin; there may also be bilirubin seen on urinalysis as conjugated bilirubin is water soluble. Unconjugated bilirubinemia is seen with elevated indirect bilirubin; urinalysis will be negative for bilirubin. In predominately unconjugated hyperbilirubinemia, hemolysis should be excluded with a peripheral blood smear, haptoglobin and lactate dehydrogenase.

In predominately conjugated hyperbilirubinemia, liver enzymes (aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase, and alkaline phosphatase), prothrombin time and albumin should be obtained. Additional tests such as pregnancy testing, acetaminophen level, serologies for hepatitis or autoimmune disorders, radiographic tests (ultrasound typically first-line given lower cost, lack of radiation exposure and sensitivity for gallstones, CT scan, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography) or liver biopsy may be utilized pending the results of initial testing and suspected etiology.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

See above.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Consult a gastroenterologist when ordering magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography to ensure proper use of these imaging modalities.

Genetic testing for a UGT1A1 mutation in Gilbert’s syndrome is rarely necessary.

III. Management while the Diagnostic Process is Proceeding

A. Management of hyperbilirubinemia.

Newborns should be screened for jaundice, and severe hyperbilirubinemia should promptly be treated with phototherapy in order to prevent kernicterus.

Adults should undergo urinalysis and laboratory testing to determine if the etiology is conjugated or unconjugated hyperbilirubinemia. History, physical examination, and further laboratory testing and imaging should be performed as needed. Management should focus on the underlying etiology (see separate topic reviews).

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem


What's the evidence?

Dennery, PA,, Seidman, DS,, Stevenson, DK:. “Neonatal hyperbilirubinemia.”. NEJM. vol. 344. 2001. pp. 581-590.

Fabris, L,, Cadamuro, M,, Okolicsanyi, L. “The patient presenting with isolated hyperbilirubinemia.”. Digestive and Liver Disease. pp. 375-381.

Houlihan, DD,, Armstrong, MJ,, Newsome, PN. “Investigation of jaundice.”. Medicine. vol. 39. 2011. pp. 518-522.

Roche, SP,, Kobos, R. “Jaundice in the adult patient.”. American Family Physician. vol. 69. 2004. pp. 299-304.

vanWagner, LB and, Green, RM. “Evaluating elevated bilirubin levels in asymptomatic adults.”. JAMA.. vol. 313. 2015. pp. 516-7. (Part of JAMA's interpretation of diagnostic tests series. Nice review of approach to hyperbilirubinemia in the asymptomatic adult.)