Review: The multifaceted roles of bilirubin in liver health and disease

Bilirubin, the byproduct of hemoprotein breakdown, particularly hemoglobin, is a critical marker in diagnosing, prognosing, and managing liver diseases. This review delves into bilirubin's multifaceted roles, not only as a diagnostic marker but also as a molecule with antioxidant and immunomodulatory properties. In both acute and chronic liver conditions, such as viral hepatitis, alcohol-related liver disease, and autoimmune liver disease, bilirubin offers insight into disease severity and progression, as well as potential therapeutic implications.

Bilirubin metabolism

The metabolism of bilirubin begins with its production from heme in the spleen and bone marrow, followed by transportation to the liver, where it undergoes enzymatic conversion. The liver plays a key role in bilirubin conjugation and excretion. Any disruption in this process-;whether in the production, metabolism, or excretion of bilirubin-;leads to conditions such as hyperbilirubinemia. Elevated levels can signify liver dysfunction or blockages within the hepatic or extrahepatic bile ducts.

Molecular mechanisms in liver diseases

In liver diseases, bilirubin metabolism can be altered in multiple stages. Overproduction, faulty conjugation, or defective excretion mechanisms are common in conditions like cirrhosis or genetic disorders, such as Gilbert's or Crigler-Najjar syndromes. Genetic mutations affecting enzymes and transporters responsible for bilirubin processing lead to these disorders. Furthermore, cholestatic diseases and liver conditions like MASLD (metabolic dysfunction-associated steatotic liver disease) present with distinctive bilirubin metabolism changes.

Bilirubin's antioxidant and anti-inflammatory properties

Beyond its role as a biomarker, bilirubin's antioxidant properties reduce oxidative stress and protect cells from damage. Its immunomodulatory effects reduce inflammation by suppressing pro-inflammatory cytokines. These protective functions highlight the dual nature of bilirubin in liver diseases-;both as a diagnostic tool and a potential therapeutic agent.

Neurotoxicity of bilirubin

In severe cases of hyperbilirubinemia, bilirubin can cross the blood-brain barrier, causing neurotoxicity, as seen in bilirubin encephalopathy. This condition is characterized by oxidative stress in neural tissues, mitochondrial dysfunction, and inflammation, leading to neuronal damage.

Gut-liver axis and bilirubin

The gut microbiota plays a crucial role in bilirubin metabolism. Specific bacterial species are responsible for converting bilirubin into urobilinogen. Dysregulation of this gut-liver axis can lead to hyperbilirubinemia, impacting both liver function and overall health. Additionally, new research has identified key enzymes responsible for bilirubin reduction, emphasizing the importance of gut microbial balance in bilirubin homeostasis.

Clinical implications and therapeutic potential

Bilirubin is a reliable marker in liver disease management. Elevated bilirubin levels are used in prognostic scoring systems like MELD (Model for End-Stage Liver Disease) and the Maddrey Discriminant Function for assessing disease severity and guiding treatment, particularly in conditions like acute liver failure and alcoholic hepatitis. While hyperbilirubinemia in genetic conditions such as Gilbert's syndrome or Dubin-Johnson syndrome often poses minimal risk, severe cases like Crigler-Najjar syndrome necessitate early intervention.

Conclusions

Bilirubin's traditional role as a waste product has evolved, with its importance in liver metabolism and disease management becoming increasingly evident. Its antioxidant and anti-inflammatory properties offer therapeutic potential, while its neurotoxic effects in extreme cases highlight the need for careful clinical management. Understanding bilirubin's complex roles provides valuable insights for both diagnostics and treatment in liver diseases, warranting further research to unlock its full potential.