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Functional Blood Chemistry Manual

Bilirubin, total

Marker Name: Bilirubin, total


Laboratory reference range: 0–1.2 mg/dL

Functional reference range: 0.1–1.2 mg/dL


Bilirubin is the waste product of heme catabolism.1 Bilirubin may be found in the bloodstream, in the liver, within bile, or in the intestines as it makes its way from a red blood cell degradation byproduct to eventual elimination in the feces.1 Under physiologic concentrations, bilirubin may serve as an antioxidant.2 Moreover, the pigmented molecule is responsible for the characteristic color of bile and feces.3,4 However, elevated bilirubin levels may be toxic to cells and intracellular organelles.1,5 Markedly elevated serum bilirubin concentrations in neonates may cause neurological disturbances or even death.6,7

Approximately 80 percent of bilirubin comes from hemoglobin, with the remaining 20 percent derived from other heme-containing molecules including myoglobin, cytochromes, catalases, and peroxidases.1 Heme is converted into biliverdin by heme oxygenase, which is then converted to bilirubin by biliverdin reductase.9

Bilirubin levels are controlled by complex physiologic mechanisms that keep bilirubin from reaching toxic levels under normal circumstances.1,8 These mechanisms include uptake and storage in the liver, conjugation with glucuronic acid, binding to serum proteins, and enzymatic degradation in the gastrointestinal tract.1

Bilirubin is fairly insoluble in water, so it is usually carried by albumin in the blood. The bilirubin-albumin complex shuttles bilirubin to the liver, where it is taken up by hepatocytes.1 Within liver cells, bilirubin is conjugated with glucuronide, rendering it water soluble.10 Conjugated bilirubin is then excreted into the bile. Bacteria within the intestines further metabolize conjugated bilirubin into urobilinogens, which are either reabsorbed by the ileum and large intestine (20 percent) or excreted in the feces (80 percent). Reabsorbed urobilinogen is either metabolized by the liver and again excreted in the bile, or excreted in the urine. When this excretory system is dysfunctional, the kidney may excrete between 50 and 90 percent of conjugated bilirubin.11

As the name implies, total bilirubin provides a measure of all bilirubin molecules in the serum. This includes both conjugated and unconjugated forms of bilirubin. Unconjugated bilirubin is very poorly soluble in water and must be bound to protein within blood. Unconjugated bilirubin binds to albumin and, to a lesser extent, to lipoproteins as it is secreted by the liver.1 Very little unconjugated bilirubin is free (i.e., unbound to protein) in blood under normal conditions. Nevertheless, excessive amounts of unconjugated bilirubin can exceed the binding capacity of albumin and circulate freely in the blood. All known toxic effects of bilirubin are associated with elevations in the unconjugated form.1

Laboratories may report direct and indirect bilirubin rather than conjugated and unconjugated. Direct bilirubin is a measure of water-soluble forms of bilirubin and is essentially equivalent to the conjugated bilirubin in the sample.12 Total bilirubin minus direct bilirubin yields indirect bilirubin (i.e., unconjugated bilirubin).

The etiology of elevated total bilirubin (hyperbilirubinemia) can be understood based on whether bilirubin accumulated before or after conjugation. Unconjugated hyperbilirubinemia is due to increased bilirubin production, impaired hepatic bilirubin uptake, or impaired bilirubin conjugation.13,14 Conjugated hyperbilirubinemia, on the other hand, is due to either extrahepatic cholestasis (i.e., biliary obstruction) or intrahepatic cholestasis. Elevated total bilirubin is usually due to elevated unconjugated (i.e., direct) bilirubin.12 Almost every neonate develops a level of plasma/serum bilirubin that exceeds adult normal levels, though few experience clinical issues from bilirubin toxicity. Severe neonatal hyperbilirubinemia, however, can cause long-term neurological complications and death.

Little work has been done to explore the causes of low total serum bilirubin. However, bilirubin levels may be decreased in patients with nephrotic syndrome in the context of generalized protein wasting in the urine.15 The molecule may also be a prognostic indicator for other conditions such as albuminuria in type 2 diabetes or chronic kidney disease.16,17

Bilirubin is one of the six components of the standard liver panel, which includes alanine aminotransferase (ALT), acetate aminotransferase (AST), alkaline phosphatase, albumin, and total protein.18


High in:13,14

  • Unconjugated hyperbilirubinemia
    • Increased bilirubin production (e.g., hemolysis, extravasation of blood)
    • Impaired hepatic bilirubin uptake
      • Heart failure
      • Portosystemic shunt
      • Drugs (e.g., rifampin, probenecid)
    • Impaired bilirubin conjugation
      • Crigler-Najjar syndrome types I and II
      • Gilbert syndrome (most common cause of bilirubin elevation)
      • Neonates (normal in most neonates, very high levels can be dangerous)
      • Hyperthyroidism
      • Chronic liver disease
      • Ethinyl estradiol
    • Conjugated hyperbilirubinemia
      • Extrahepatic cholestasis
        • Biliary atresia
        • Choledocholithiasis
        • Tumor (e.g., cholangiocarcinoma)
        • Primary sclerosing cholangitis
        • AIDS cholangiopathy
        • Acute and chronic pancreatitis
        • Parasites (e.g., Ascaris lumbricoides, liver flukes)
      • Intrahepatic cholestasis
        • Hepatitis (e.g., viral, alcoholic, nonalcoholic, neonatal)
        • Primary biliary cholangitis
        • Drugs/toxins (e.g., alkylated steroids, chlorpromazine, arsenic)
        • Sepsis
        • Shock
        • Infiltrative diseases (e.g., amyloidosis, lymphoma, sarcoidosis)
        • Total parenteral nutrition
        • Postoperative cholestasis
        • Hepatic crisis in sickle cell disease
        • Pregnancy
        • End-stage liver disease

Low in:15

  • Nephrotic syndrome


High in:

  • Same as conventional indications

Low in:

  • Same as conventional indications




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