Bilirubin; Total, Direct, and Indirect


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Subject: Bilirubin; Total, Direct, and Indirect

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  • These assays are commonly used tests to assess liver function. Daily production of unconjugated bilirubin is mainly from senescent erythrocytes. The half-life of unconjugated bilirubin is <5 minutes. UDP-glucuronyl transferase catalyzes rapid conjugation of bilirubin to the liver; conjugated bilirubin is excreted in bile and is essentially absent from the blood of the normal individuals. Delta bilirubin (bili protein) is produced by reaction of conjugated bilirubin with albumin, and its half-life is 17–20 days. Bilirubin is typically measured in two assays for “total” and “direct”; subtracting direct from total gives “indirect bilirubin.” The direct bilirubin measures the majority of delta and conjugated bilirubin and a small percentage of unconjugated bilirubin.

  • Normal range: age dependent (see Table 16.12).

TABLE 16–12
Normal Range of Bilirubin


  • Assessing liver function

  • Evaluating a wide range of diseases affecting the production, uptake, storage, metabolism, or excretion of bilirubin

  • Monitoring the efficacy of neonatal phototherapy


Increased In

  • Hepatocellular damage

  • Biliary obstruction

  • Hemolytic diseases

  • Neonatal physiologic jaundice

  • Gilbert disease, Crigler-Najjar syndrome

  • Hypothyroidism

  • Dubin-Johnson syndrome

  • Increased conjugated (direct) bilirubin in

    • Hereditary disorders (e.g., Dubin-Johnson syndrome, rotor syndrome).

    • Hepatic cellular damage (e.g., viral, toxic, alcohol, drugs). Increased conjugated bilirubin may be associated with normal total bilirubin in up to one third of patients with liver diseases.

    • Biliary duct obstruction (extrahepatic or intrahepatic).

    • Infiltrations, space-occupying lesions (e.g., metastases, abscess, granulomas, amyloidosis).

    • Direct bilirubin:

      • Twenty to forty percent of total: more suggestive of hepatic than of posthepatic jaundice

      • Forty to sixty percent of 1: occurs in either hepatic or in posthepatic jaundice

      • Greater than 50% of total: more suggestive of posthepatic than of hepatic jaundice

    • Total serum bilirubin >40 mg/dL indicates hepatocellular rather than extrahepatic obstruction.

  • Increased unconjugated (indirect) bilirubin in (conjugated, 20% of total)

    • Increased bilirubin production.

    • Hemolytic diseases (e.g., hemoglobinopathies, RBC enzyme deficiencies, DIC, autoimmune hemolysis).

    • Ineffective erythropoiesis (e.g., pernicious anemia).

    • Blood transfusions.

    • Hematomas.

    • Hereditary disorders (e.g., Gilbert disease, Crigler-Najjar syndrome).

    • Drugs (e.g., causing hemolysis).

Decreased In

  • Drugs (e.g., barbiturates)


  • Specimens should be protected from light and analyzed as soon as possible.

  • Compounds that compete for binding sites on serum albumin contribute to lower serum bilirubin levels (e.g., penicillin, sulfisoxazole, acetylsalicylic acid).

  • Day-to-day variations are 15–30% and increase an average of one- to twofold with fasting up to 48 hours.

  • Total bilirubin is 33% and 15% lower in African American men and women, respectively, compared to other racial/ethnic groups.

  • Light exposure can decrease total bilirubin up to 50% per hour.

  • Total serum bilirubin not a sensitive indicator of hepatic dysfunction; it may not reflect degree of liver damage. Must exceed 2.5 mg/dL to produce clinical jaundice; >5 mg/dL seldom occurs in uncomplicated hemolysis unless hepatobiliary disease is also present.

  • Total bilirubin is generally less markedly increased in hepatocellular jaundice (<10 mg/dL) than in neoplastic obstructions (≤20 mg/dL) or intrahepatic cholestasis.

  • In extrahepatic biliary obstruction, bilirubin may rise progressively to a plateau of 30–40 mg/dL (due in part to balance between renal excretion and diversion of bilirubin to other metabolites). Such a plateau tends not to occur in hepatocellular jaundice, and bilirubin may exceed 50 mg/dL (partly due to concomitant renal insufficiency and hemolysis).

  • Concentrations are generally higher in obstruction due to carcinoma than due to stones.

  • In viral hepatitis, higher serum bilirubin suggests more liver damage and longer clinical course.

  • In acute alcoholic hepatitis, >5 mg/dL suggests a poor prognosis.

  • Increased serum bilirubin with normal ALP suggests constitutional hyperbilirubinemias or hemolytic states.

  • Due to renal excretion, maximum bilirubin is 10–35 mg/dL; if renal disease is present, it may reach 75 mg/dL.

  • Conjugated bilirubin >1.0 mg/dL in an infant always indicates disease.

  • Serum bilirubin (conjugated-to-total):

    • Less than 20% conjugated: constitutional (e.g., Gilbert disease, Crigler-Najjar syndrome)

  • Hemolytic states:

    • Twenty to forty percent conjugated: favors hepatocellular disease rather than extrahepatic obstruction; disorders of bilirubin metabolism (e.g., Dubin-Johnson, Rotor syndromes)

    • Forty to sixty percent conjugated: occurs in either hepatocellular or extrahepatic type

    • Greater than 50% conjugated: favors extrahepatic obstruction rather than hepatocellular disease

Suggested Readings

Dufour  DR, Lott  JA, Nolte  FS Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem.  2000;46:2027–2049.
Stevenson  DK, Wong  RJ, Vreman  HJ. Reduction in hospital readmission rates for hyperbilirubinemia is associated with use of transcutaneous bilirubin measurements. Clin Chem.  2005;51:481–482.