What causes an increase in total bilirubin (a yellow compound that occurs in the normal catabolic pathway that breaks down heme in red blood cells) in a patient (pt)?

From the Guidelines

Elevated total bilirubin in a patient is primarily caused by conditions that either increase bilirubin production or impair its elimination from the body, with the most common cause being Gilbert's syndrome, as stated in the guidelines on the management of abnormal liver blood tests 1.

Causes of Elevated Total Bilirubin

• Liver diseases such as hepatitis, cirrhosis, and alcoholic liver disease, which reduce the liver's ability to process bilirubin
• Biliary obstruction from gallstones, tumors, or strictures can block bilirubin excretion into the intestines
• Hemolytic conditions like sickle cell disease, thalassemia, and autoimmune hemolytic anemia increase bilirubin production by accelerating red blood cell breakdown
• Certain medications including some antibiotics, anti-seizure drugs, and anabolic steroids can cause drug-induced liver injury leading to hyperbilirubinemia
• Genetic disorders such as Gilbert's syndrome, Crigler-Najjar syndrome, and Dubin-Johnson syndrome affect bilirubin metabolism
• Sepsis and severe infections can impair liver function, while prolonged fasting may temporarily elevate bilirubin levels

Evaluation of Elevated Total Bilirubin

When evaluating elevated total bilirubin, it's essential to check direct (conjugated) and indirect (unconjugated) bilirubin fractions, liver enzymes, and complete blood count to determine the underlying cause and guide appropriate treatment, as recommended in the consensus guidelines for detection, assessment, and management of suspected acute drug-induced liver injury 1.

Importance of Direct and Indirect Bilirubin Fractions

• Conjugated hyperbilirubinemia can occur due to obstruction of the biliary tract or liver parenchymal disease, as stated in the ACR Appropriateness Criteria for abnormal liver function tests 1
• Unconjugated hyperbilirubinemia is typically seen in hemolysis or Gilbert's syndrome, as noted in the guidelines on the management of abnormal liver blood tests 1

Clinical Approach

A thorough clinical evaluation, including laboratory tests and medical history, is necessary to determine the underlying cause of elevated total bilirubin and guide appropriate treatment, as emphasized in the American Gastroenterological Association medical position statement on the evaluation of liver chemistry tests 1.

From the Research

Causes of Increased Total Bilirubin

• Elevated plasma bilirubin levels can be secondary to alterations in any stage of its metabolism, including:
  • Excess bilirubin production (i.e., pathologic hemolysis) 2
  • Impaired liver uptake, with elevation of indirect bilirubin 2
  • Impaired conjugation, prompted by a defect in the UDP-glucuronosyltransferase 2
  • Bile clearance defect, with elevation of direct bilirubin secondary to defects in clearance proteins, or inability of the bile to reach the small bowel through bile ducts 2
• A liver lesion of any cause can reduce hepatocyte cell number and may impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts 2
• Certain liver diseases, such as primary biliary cirrhosis and chronic hepatitis, can cause increased total bilirubin levels 3, 4, 5
• Ursodeoxycholic acid therapy has been shown to improve liver function indices, including total bilirubin levels, in patients with chronic liver disease 3, 4, 5, 6

Laboratory Tests for Bilirubin

• Serum bilirubin can be measured using various analytical methods, including:
  • Diazo transfer reaction, currently the gold-standard 2
  • High-performance liquid chromatography (HPLC) 2
  • Oxidative, enzymatic, and chemical methods 2
  • Direct spectrophotometry 2
  • Transcutaneous methods 2

Clinical Usefulness of Bilirubin Measurement

• Bilirubin is a well-established marker of liver function, but it does not always identify a lesion in this organ 2
• Alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations 2