Bilirubin Cancer Risk and the Science Behind It

Bilirubin, a byproduct of red blood cell breakdown, has long been a marker for liver function. Emerging research suggests it may influence cancer risk, with both protective and harmful effects depending on its levels and metabolism.

Understanding bilirubin’s role in cancer requires examining its different forms, genetic influences, and biological mechanisms.

Types Of Bilirubin

Bilirubin exists in multiple forms, each with distinct biochemical properties and physiological roles. These variations affect how bilirubin is processed and may influence cancer risk.

Unconjugated

Unconjugated bilirubin is produced from the breakdown of heme, primarily in the spleen and liver. It is hydrophobic and binds to albumin for transport in the bloodstream. This form is not water-soluble and cannot be directly excreted by the kidneys. Research suggests it has antioxidant properties that help neutralize reactive oxygen species (ROS) and reduce oxidative stress, a factor in carcinogenesis. A 2021 study in Free Radical Biology and Medicine found that moderate elevations of unconjugated bilirubin correlated with a lower incidence of certain cancers, likely due to its antioxidative effects. However, excessive accumulation, as seen in Gilbert’s syndrome, may alter metabolic pathways and influence cancer susceptibility in complex ways.

Conjugated

Conjugated bilirubin forms in the liver when unconjugated bilirubin undergoes glucuronidation, catalyzed by the enzyme UDP-glucuronosyltransferase (UGT1A1). This process makes bilirubin water-soluble for excretion into bile and the intestines. Unlike unconjugated bilirubin, conjugated bilirubin lacks significant antioxidant activity. Its accumulation often signals hepatobiliary dysfunction, which is linked to malignancies such as cholangiocarcinoma and hepatocellular carcinoma. A 2022 study in Liver International found that elevated conjugated bilirubin in liver disease patients was associated with increased hepatic tumor progression. Disruptions in bile flow and liver enzyme function may also affect cancer development, particularly in gastrointestinal malignancies.

Delta

Delta bilirubin forms when conjugated bilirubin binds covalently to albumin, prolonging its presence in circulation. Unlike other forms, it is not readily excreted and remains detectable even after liver function improves. This characteristic is relevant in chronic hepatobiliary disorders, where prolonged bilirubin elevation can complicate diagnostics. Research on delta bilirubin and cancer is limited, but its persistence has been observed in patients with liver metastases and obstructive jaundice due to malignancies. A 2023 study in Clinical Chemistry and Laboratory Medicine found disproportionately elevated delta bilirubin levels in individuals with pancreatic and biliary tract cancers, suggesting potential diagnostic or prognostic relevance. Further studies are needed to determine whether delta bilirubin contributes to tumor biology or merely reflects hepatic impairment.

Serum Bilirubin Assessment In Oncology

Measuring serum bilirubin levels is critical in oncology for evaluating liver function, monitoring treatment toxicity, and assessing disease progression. Deviations from normal levels provide insights into cancer-related complications. Oncologists use bilirubin assessments to determine treatment eligibility, adjust chemotherapy doses, and identify hepatic dysfunction caused by metastases or drug-induced liver injury.

Total serum bilirubin, which includes unconjugated and conjugated fractions, is commonly measured in blood panels. Distinguishing between these fractions is essential, as different forms indicate distinct pathological processes. Elevated unconjugated bilirubin may result from hemolysis or genetic conditions like Gilbert’s syndrome, which can affect chemotherapy metabolism. Increased conjugated bilirubin often signals hepatobiliary obstruction, a frequent issue in pancreatic, gallbladder, or liver malignancies. Direct bilirubin measurements help differentiate whether hyperbilirubinemia is due to hepatic disease, bile duct obstruction, or systemic hemolysis, aiding clinical decision-making.

Bilirubin levels are also factored into prognostic models such as the Child-Pugh score and the Model for End-Stage Liver Disease (MELD), which help stratify patients based on liver function. These models guide therapeutic choices and surgical planning. For example, hepatocellular carcinoma patients with significantly elevated bilirubin may have limited treatment options due to compromised liver function. Patients with obstructive jaundice from tumor compression of the bile ducts may require biliary stenting or surgery before systemic therapy.

Chemotherapy-induced liver injury is another concern, as certain drugs affect bilirubin metabolism. Agents such as irinotecan, methotrexate, and oxaliplatin can impair bilirubin excretion, increasing toxicity risk. Treatment guidelines often include bilirubin thresholds to ensure patient safety. The National Comprehensive Cancer Network (NCCN) recommends dose modifications or alternative regimens for patients with bilirubin levels exceeding 1.5 times the upper limit of normal. Monitoring bilirubin trends during treatment helps detect early signs of hepatotoxicity and prevent severe adverse effects.

Genetic Variants Affecting Bilirubin Metabolism

Bilirubin metabolism is regulated by enzymes and transporters, with genetic variations influencing bilirubin levels and clearance. The UGT1A1 gene, which encodes UDP-glucuronosyltransferase 1A1, is a key determinant. This enzyme conjugates bilirubin for excretion. Polymorphisms in UGT1A1, particularly the UGT1A128 variant, reduce enzymatic activity, leading to elevated unconjugated bilirubin levels. Individuals with homozygous UGT1A128 mutations often develop Gilbert’s syndrome, a benign condition characterized by mild hyperbilirubinemia. While not harmful, Gilbert’s syndrome affects drug metabolism, particularly in oncology.

Other genetic factors also impact bilirubin metabolism. Variants in the SLCO1B1 and SLCO1B3 genes, which encode organic anion-transporting polypeptides (OATPs), affect bilirubin uptake into hepatocytes. Mutations impairing OATP function can lead to conjugated bilirubin accumulation, resembling hepatobiliary disease patterns. Additionally, polymorphisms in the ABCC2 gene, which encodes multidrug resistance-associated protein 2 (MRP2), influence bilirubin excretion. Reduced MRP2 activity is linked to Dubin-Johnson syndrome, a rare hereditary disorder causing chronic conjugated hyperbilirubinemia. Though generally asymptomatic, this condition complicates bilirubin level interpretation in oncology patients, especially those undergoing treatments dependent on hepatic clearance.

These genetic variations also impact pharmacogenomics, affecting drug response and toxicity. For example, irinotecan, used in colorectal cancer, is metabolized into SN-38, an active compound conjugated by UGT1A1. Patients with UGT1A128 polymorphisms exhibit reduced SN-38 clearance, increasing the risk of severe neutropenia and diarrhea. Pharmacogenetic testing for UGT1A1 variants is often recommended before irinotecan-based regimens. Similarly, SLCO1B1 polymorphisms influence hepatic uptake of chemotherapeutic agents, affecting drug distribution and efficacy. These insights are becoming increasingly relevant in personalized medicine, guiding dose adjustments to minimize adverse effects while maximizing therapeutic benefit.

Proposed Mechanisms Linking Bilirubin And Cancer

Bilirubin’s relationship with cancer is complex, with potential protective and tumor-promoting effects depending on its concentration and metabolic state. One of the most studied mechanisms is its role as an antioxidant. Unconjugated bilirubin, at low to moderate levels, neutralizes reactive oxygen species (ROS), which cause DNA damage and genomic instability. By reducing oxidative stress, bilirubin may help prevent mutations that drive cancer initiation. Studies suggest individuals with slightly elevated bilirubin levels, such as those with Gilbert’s syndrome, have lower rates of certain cancers, likely due to bilirubin’s ability to mitigate oxidative damage.

Beyond its antioxidant properties, bilirubin influences cellular signaling pathways that regulate proliferation and apoptosis. Experimental models indicate it can affect key regulators of cell cycle progression, such as the p53 tumor suppressor protein and cyclin-dependent kinases. Some evidence also suggests bilirubin interferes with mitochondrial metabolism, altering bioenergetic pathways that cancer cells rely on for rapid proliferation.

Observed Associations In Different Cancer Types

Bilirubin’s relationship with cancer risk varies by malignancy. Some cancers show an inverse association, while others correlate with increased disease progression. Large-scale studies suggest bilirubin levels may serve as both a biomarker and a modulator of cancer susceptibility.

Liver-related cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma, often present with elevated bilirubin due to impaired hepatic function and bile duct obstruction. In these cases, high bilirubin primarily reflects liver damage rather than a direct oncogenic effect. Conversely, population-based studies report lower incidences of colorectal and lung cancer in individuals with moderately elevated unconjugated bilirubin, suggesting a protective role linked to its antioxidant properties. A UK Biobank analysis found that individuals in the highest bilirubin quartile had a 30% reduced risk of lung cancer compared to those in the lowest quartile, particularly among nonsmokers. However, in pancreatic and biliary tract cancers, elevated bilirubin typically signals disease progression due to tumor-induced biliary obstruction.