Introduction

The normal serum bilirubin concentration in children and adults is less than 1 mg/dL (17 micromol/liter), with less than 5 percent being conjugated. The measurement is usually made using diazo reagents and spectrophotometry. Conjugated bilirubin reacts rapidly (“directly”) with the reagents, while the measurement of unconjugated bilirubin requires the addition of an accelerator compound, often referred to as indirect bilirubin.

Jaundice, often used interchangeably with hyperbilirubinemia, cannot typically be detected until the serum bilirubin level is greater than 2 mg/dL (34 micromol/liter). The yellow discoloration is best seen in the peripheral ocular conjunctivae and oral mucous membranes (under the tongue and hard palate). Icterus can be the first or only sign of liver disease, making its evaluation crucial.

This topic reviews the causes of asymptomatic hyperbilirubinemia, with a separate discussion on the diagnostic approach to jaundice and neonatal hyperbilirubinemia.

Classification

Hyperbilirubinemia can be classified into two major categories based on the predominant type of bile pigments in plasma:

• Unconjugated Hyperbilirubinemia: This is caused by the overproduction of bilirubin, impaired bilirubin uptake by the liver, or abnormalities in bilirubin conjugation.
• Conjugated Hyperbilirubinemia: This occurs when both unconjugated and conjugated bilirubin levels increase, often due to hepatocellular diseases, impaired canalicular excretion, defective reuptake of conjugated bilirubin, or biliary obstruction.

Disorders Associated with Unconjugated Hyperbilirubinemia

Unconjugated hyperbilirubinemia is mainly caused by three mechanisms: overproduction of bilirubin, reduced bilirubin uptake, and impaired bilirubin conjugation.

Overproduction of Bilirubin

• Hemolysis: Increased destruction of erythrocytes, both intravascular and extravascular, leads to the overproduction of bilirubin. Hemoglobin is broken down into heme, which is converted to bilirubin.
• Dyserythropoiesis: Defective incorporation of hemoglobin into erythrocytes in conditions like megaloblastic anemia or lead poisoning results in increased heme degradation.
• Extravasation: Blood leakage into tissues causes the phagocytosis of erythrocytes, resulting in increased bilirubin formation from degraded heme.

Pattern of Bilirubin Elevation

• Patients without liver disease: In hemolysis, unconjugated bilirubin production may increase up to 10-fold without exceeding 4 mg/dL in patients with normal liver function.
• Patients with coexisting liver disease: In cases of hemolysis combined with liver disease, both conjugated and unconjugated bilirubin can accumulate.

Impaired Hepatic Bilirubin Uptake

• Medications: Drugs like rifamycin antibiotics and probenecid can impair bilirubin uptake, though this typically resolves within 48 hours after discontinuing the drug.
• Congestive Heart Failure: Reduced hepatic blood flow due to heart failure can also impair bilirubin uptake, leading to unconjugated hyperbilirubinemia.

Impaired Bilirubin Conjugation

• Inherited Disorders: Conditions like Crigler-Najjar syndrome and Gilbert syndrome reduce bilirubin conjugation due to a lack of UDP-glucuronosyltransferase activity.
• Acquired Conditions: Diseases such as chronic hepatitis, cirrhosis, and hyperthyroidism can also impair bilirubin conjugation.

Disorders Associated with Conjugated Hyperbilirubinemia

Conjugated hyperbilirubinemia is often caused by biliary obstruction, intrahepatic cholestasis, or hepatocellular injury.

Cholestatic Disorders

• Extrahepatic Cholestasis/Biliary Obstruction: Obstruction leads to the retention of conjugated bilirubin within hepatocytes, which may also result in the formation of unconjugated bilirubin.
• Intrahepatic Cholestasis: In conditions like Dubin-Johnson syndrome and Rotor syndrome, conjugated bilirubin accumulates due to impaired biliary excretion, even though the bile ducts remain patent.

Hepatitis

• Viral Hepatitis: Viral infections can present with a predominantly cholestatic syndrome, with marked pruritus.
• Alcoholic Hepatitis: Typically presents with cholestasis and fever, particularly in patients with ethanol dependency.

Drug-Induced Cholestasis

• Medications: Certain drugs, including methyltestosterone and ethinyl estradiol, can cause cholestasis, either in a dose-related manner or as an allergic reaction.

Sepsis and Low Perfusion States

• Bacterial Sepsis: Sepsis can cause cholestasis through hypotension, drugs, and bacterial endotoxins.
• Low Perfusion States: Cholestasis can also be seen in heart failure or hypotension that doesn’t lead to hepatic necrosis.

Infiltrative Disorders

• Amyloidosis and Lymphoma: Infiltrative diseases like amyloidosis and lymphoma can cause intrahepatic cholestasis, often leading to jaundice.
• Paraneoplastic Syndromes: Certain malignancies, such as renal cell carcinoma, can cause reversible cholestasis (Stauffer syndrome).

Intrahepatic Cholestasis of Pregnancy

• Pruritus and Jaundice: Pruritus during pregnancy, typically in the third trimester, may evolve into jaundice, indicating cholestasis, which can be associated with increased risks of stillbirth and prematurity.

Other Conditions Associated with Cholestasis

• Postoperative Jaundice: This can occur due to blood transfusions, hematoma resorption, or hemolysis, especially following heart surgery.
• Organ Transplantation: Cholestasis is common in transplant recipients, particularly in those receiving parenteral nutrition or immunosuppressive drugs.

End-Stage Liver Disease

• Chronic Hepatocellular Injury: As liver disease progresses to cirrhosis, biochemical profiles change, and jaundice develops, marked by both conjugated and unconjugated bilirubin elevation.