What are the causes of isolated hyperbilirubinemia (elevated bilirubin levels)?

From the Guidelines

Isolated hyperbilirubinemia is most commonly caused by Gilbert syndrome, which affects approximately 5-10% of the population and results from reduced activity of the enzyme UDP-glucuronosyltransferase, leading to mild unconjugated hyperbilirubinemia. The causes of isolated hyperbilirubinemia can be categorized into several conditions that increase bilirubin levels without affecting other liver function tests. Some of the key causes include:

• Gilbert syndrome, which is an inherited disorder of metabolism and leads to impaired conjugation via reduced activity of the enzyme glucuronyltransferase 1
• Crigler-Najjar syndrome types I and II, which are rare genetic disorders with severe or partial deficiency of the same enzyme, causing more significant unconjugated hyperbilirubinemia 1
• Hemolytic conditions like hereditary spherocytosis, sickle cell disease, and autoimmune hemolytic anemia, which increase bilirubin production through excessive red blood cell breakdown
• Drug-induced hyperbilirubinemia, which can occur with medications such as rifampin, probenecid, and atazanavir, which compete with bilirubin for hepatic uptake or conjugation
• Dubin-Johnson syndrome and Rotor syndrome, which are rare inherited disorders affecting bilirubin transport, causing conjugated hyperbilirubinemia
• Neonatal jaundice, which is common in newborns due to immature liver function and increased red cell turnover Evaluation of isolated hyperbilirubinemia should include determining whether the hyperbilirubinemia is conjugated or unconjugated, complete blood count to assess for hemolysis, and liver function tests to confirm the isolated nature of the condition 1. It is essential to note that the most recent and highest quality study, published in 2020, provides consensus guidelines for the detection, assessment, and management of suspected acute drug-induced liver injury, which may be relevant in some cases of isolated hyperbilirubinemia 1. However, the study from 2019 provides a more comprehensive overview of the causes and evaluation of jaundice, including isolated hyperbilirubinemia 1. Therefore, the most appropriate approach to evaluating isolated hyperbilirubinemia is to consider the causes mentioned above and to perform a thorough evaluation, including laboratory tests and medical history, to determine the underlying cause.

From the Research

Causes of Isolated Hyperbilirubinemia

The causes of isolated hyperbilirubinemia can be attributed to various factors, including:

• Familial conditions, which are found in 5-10% of the population in Western countries 2
• Impaired bilirubin metabolism, which can increase susceptibility to drug toxicity 2
• Genetic factors, such as mutations in the UGT1A1 gene, which can lead to decreased UGT1A1 activity and abnormal bilirubin metabolism 3
• Hepatic inflammation, biliary obstruction, and impaired bilirubin conjugation 4
• Drug-induced hyperbilirubinemia, which can be caused by certain clinical drugs, especially in patients with certain pathologic conditions or genetic variations 5
• Cytarabine-based chemotherapy, which can cause hepatic dysfunction characterized by jaundice, hyperbilirubinemia, and increases in liver enzymes 6
• Epstein-Barr virus infection and secondary cold agglutinin syndrome, which can cause life-threatening jaundice and hepatic failure 4

Molecular Mechanisms

The molecular mechanisms underlying isolated hyperbilirubinemia involve:

• The regulation of bilirubin metabolism by nuclear receptors (NRs) and genetic factors 2
• The crosstalk relationship between low UGT1A1 activity, bilirubin, and liver damage 3
• The activation of the NF-κB pathway and induction of DNA damage in hepatocytes by unconjugated bilirubin 3

Diagnostic and Therapeutic Approaches

The diagnostic and therapeutic approaches for isolated hyperbilirubinemia include:

• A diagnostic algorithm to identify the underlying cause of hyperbilirubinemia 2
• A multidisciplinary approach to manage the condition, involving multiple clinical specialists 4
• The use of rituximab to treat life-threatening jaundice and hepatic failure caused by Epstein-Barr virus infection and secondary cold agglutinin syndrome 4
• The consideration of a lower dose of cytarabine for future treatment in patients who experience isolated hyperbilirubinemia after cytarabine-based chemotherapy 6