Conjugated bilirubin in chronic liver disease: an underutilised prognostic biomarker?—a narrative review

Abstract

Background and Objective

Chronic liver disease (CLD) is a major global health burden, often progressing to cirrhosis, decompensation, and hepatocellular carcinoma. Prognostic models typically rely on serum total bilirubin. However, recent evidence suggests that conjugated bilirubin (C-BIL) may offer superior prognostic utility in assessing disease severity and outcomes in CLD. This narrative review aims to examine the emerging evidence supporting C-BIL as a prognostic and disease stratification biomarker across various clinical contexts, where it has demonstrated enhanced predictive accuracy over traditional measures.

Methods

A comprehensive, non-systematic review of the published literature was undertaken using major bibliographic databases and predefined keywords. Relevant studies were selected based on the following criteria: English-language publications, studies conducted in human populations, and articles with clear clinical applicability. Emphasis was placed on studies evaluating C-BIL in prognostic or disease-stratification contexts within CLD.

Key Content and Findings

Emerging evidence indicates that incorporation of C-BIL into clinical prognostic models may enhance risk stratification and support more informed clinical decision-making in CLD. Elevated C-BIL appears to reflect impaired hepatocellular excretory function and fibrosis-related biliary obstruction. In addition, recent studies suggest that hepatocyte senescence may represent an additional, biologically plausible mechanism underpinning its prognostic relevance.

Conclusions

This review highlights the potential clinical utility of C-BIL as a prognostic biomarker in CLD. While existing evidence supports its role in disease stratification and outcome prediction, further prospective validation and mechanistic studies are required before C-BIL can be adopted as a standard component of prognostic assessment in CLD.

Introduction

Chronic liver disease (CLD) is an increasingly prevalent global health concern, associated with considerable morbidity and mortality (1,2). A defining feature of CLD is the progressive accumulation of liver fibrosis, which advances from mild through moderate to severe stages, ultimately leading to cirrhosis and its complications—most notably decompensation and hepatocellular carcinoma (HCC)—regardless of the underlying aetiology (3). The majority of liver-related complications and deaths occur in individuals with severe fibrosis or cirrhosis, collectively termed “advanced chronic liver disease (ACLD)”. This designation recognises the continuum between severe fibrosis and cirrhosis, which are frequently indistinguishable on clinical grounds (4).

CLD is the third leading cause of premature death in the UK and the only major cause of death that continues to rise, with a four-fold increase since 1970 (5). Globally, CLD and HCC rank as the 11^th and 16^th most common causes of death, respectively (6,7). It is estimated that ACLD imposes an annual economic burden of between £5 and £17 billion. The cost of HCC treatment alone was £245 million over a five-year period as of 2017—a figure that has likely increased in line with rising incidence (8). Several prognostic and disease severity models are widely used in hepatology, including the Child-Pugh score, the Model for End-Stage Liver Disease (MELD) score, the United Kingdom Model for End-Stage Liver Disease (UKELD) score, Maddrey’s Discriminant Function, and the Albumin-Bilirubin (ALBI) score. The vast majority of these models incorporate serum total bilirubin as a key parameter. However, emerging evidence suggests that conjugated bilirubin (C-BIL) may provide additional prognostic value beyond total bilirubin.

This review aims to evaluate the current literature on the utility of C-BIL as a prognostic biomarker in CLD, exploring its potential to improve risk stratification and guide clinical decision-making. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-132/rc).

Methods

To evaluate the existing literature, a non-systematic, targeted search was conducted using Ovid MEDLINE, PubMed, and Google Scholar from database inception to 2025. The search strategy combined terms related to CLD (“cirrhosis”, “liver disease”, “chronic liver disease”, “advanced chronic liver disease”, “liver fibrosis”) with terms related to C-BIL (“conjugated bilirubin”, “direct bilirubin”, “water-soluble bilirubin”, “conjugated hyperbilirubinaemia”, “bilirubin diglucuronide”, “bilirubin monoglucuronide”) and biomarker-related terms (“biomarker”, “prognostication”, “risk stratification”, “prediction”, “outcome”). Animal studies, non-English publications, and studies not focused on CLD were excluded. Particular emphasis was placed on high-quality original research published within the last decade [2015–2025]. Studies were selected based on their relevance to emerging clinical applications of C-BIL for prognostication in CLD, with a focus on real-world utility, clinical applicability, and outcome-related significance (search strategy summarised in Table 1).

Table 1. The search strategy summary.

Items	Specification
Date of search	01 September 2025
Databases and other sources searched	Ovid MEDLINE, PubMed, Google Scholar
Search terms used	cirrhosis, liver disease, chronic liver disease, advanced chronic liver disease, liver fibrosis, conjugated bilirubin, direct bilirubin, water-soluble bilirubin, conjugated hyperbilirubinaemia, bilirubin diglucuronide, bilirubin monoglucuronide, biomarker, prognostication, risk stratification, prediction, outcome
Timeframe	Databases searched up to 1 September 2025
Eligibility criteria	English language articles only; all articles related to search terms were evaluated. Studies not focused on CLD and animal studies were excluded
Selection process	All titles/abstracts identified in the electronic databases were screened by both authors independently of one another. Discrepancies were resolved by discussion

CLD, chronic liver disease.

C-BIL metabolism

Bilirubin is a by-product of haem breakdown, primarily from senescent erythrocytes, with up to 20% derived from non-erythroid sources such as cytochromes and other haemoproteins (9). Approximately 200–300 mg of bilirubin is produced daily in healthy adults, entirely in the unconjugated form, which is hydrophobic, lipid-soluble, and transported to the liver bound to albumin (10,11).

In the liver, unconjugated bilirubin dissociates from albumin in the space of Disse and is taken up into hepatocytes via transporters, as well as through passive diffusion (12-14). Within hepatocytes, unconjugated bilirubin is directed to the endoplasmic reticulum, where it undergoes conjugation with glucuronic acid by UDP-glucuronosyltransferases (UGTs), particularly UGT1A (15-17). This conjugation renders bilirubin water-soluble and represents the rate-limiting step in its metabolism; disruption of UGT expression or activity can significantly impair bilirubin clearance (18). The resulting C-BIL is excreted into bile via the ATP-dependent transporter MRP2, located on the bile canalicular membrane of hepatocytes, while MRP3, located on the basolateral membrane, returns a portion to the sinusoidal plasma for potential reuptake (10,18-20). Most C-BIL is eventually eliminated in the faeces, primarily as stercobilinogen, following modification in the gut, with a small proportion excreted in the urine as urobilinogen (21).

Prognostic and pathophysiological role of C-BIL in CLD

More recently, there has been growing interest in exploring the potential role of C-BIL as a prognostic or stratification biomarker in CLD, prompting studies into its relevance across various forms of CLD (summarised in Table 2).

Table 2. Summary of key characteristics of clinical studies investigating conjugated bilirubin as a prognostic marker in liver disease.

Study	Country	Year	Number of participants	Aetiology	Stage of CLD	Relevant findings
Castillo-Castañeda SM, et al., Int J Mol Sci, 2024 (22)	Mexico	2021–2023	45	Mixed (excluding biliary liver disease and individuals with extrahepatic malignancies, HIV, prior liver transplantation, or severe systemic or psychiatric illness)	ACLF occurring in the context of underlying cirrhosis	· ACLF patients have higher conjugated/unconjugated bilirubin ratios than compensated cirrhosis patients and healthy controls
						· Conjugated bilirubin levels are significantly elevated in ACLF
						· Conjugated bilirubin demonstrates sensitivity and specificity comparable to Child-Pugh and MELD for prognosis
López-Velázquez JA, et al., Annals of Hepatology, 2013 (23)	Mexico	2005–2012	65	Mixed (e.g., HCV, ALD, cryptogenic and HCC) (excluding cholestatic and autoimmune liver diseases, and individuals with extrahepatic malignancies, HIV, prior liver transplantation, or severe systemic or psychiatric illness)	ACLF developing on a background of cirrhosis	· Conjugated, unconjugated, and total bilirubin were each independently associated with 1-week mortality
						· Conjugated bilirubin predicted 1-week mortality more accurately than MELD and Child-Pugh scores
						· The most predictive cutoff was a high conjugated bilirubin level
Qin FF, et al., World J Gastointest Surg, 2024 (24)	China	2020–2023	186	Hepatectomy for primary liver cancer	Patients with or without post-hepatectomy liver failure. Post-hepatectomy for HCC	· Total bilirubin, conjugated bilirubin, albumin and INR were significantly higher in post-hepatectomy liver failure-associated mortality
						· Bilirubin strongly predicts infection and mortality in surgical or hepatic trauma patients
						· Post-hepatectomy liver failure patients had markedly higher albumin-bilirubin scores
Lee HA, et al., Gut Liver, 2021 (25)	Korea	2004–2018	983	Mixed (excluding patients with HCC, immunosuppression, multiple comorbidities, or those who die of non-liver-related causes)	Patients with either compensated or decompensated cirrhosis	· INR, total bilirubin, conjugated bilirubin, creatinine, MELD, and conjugated bilirubin-MELD were significantly higher in patients with 6-month mortality compared to controls
						· Conjugated bilirubin outperformed total bilirubin in predicting mortality
						· DiBIC score (incorporating conjugated bilirubin) predicted 6-month mortality more accurately than MELD

ACLF, acute-on-chronic liver failure; ALD, alcohol-related liver disease; CLD, chronic liver disease; DiBIC, direct bilirubin, INR, and creatinine score; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; INR, international normalised ratio; MELD, model for end-stage liver disease.

A study on acute-on-chronic liver failure (ACLF) unsurprisingly demonstrated significantly higher levels of C-BIL in patients with ACLF compared to those with compensated cirrhosis and healthy individuals (22). More notably, C-BIL levels showed a strong correlation with ACLF disease severity and were positively associated with inflammatory markers, suggesting a potential role for C-BIL as an indicator of the systemic inflammatory response syndrome that drives organ dysfunction and increased mortality in ACLF (22). A previous study in patients with ACLF similarly highlighted the prognostic value of C-BIL. More importantly, it demonstrated an independent association between C-BIL and short-term mortality, with C-BIL outperforming traditional scoring systems such as MELD and Child-Pugh in predicting outcomes (23).

In a study involving 186 patients who underwent elective open hepatectomy for HCC, C-BIL was identified as a predictor of post-hepatectomy liver failure, further supporting its prognostic value in CLD (24).

In a large retrospective cohort study of 983 patients with cirrhosis, the prognostic utility of serum C-BIL was compared with that of total bilirubin for predicting 6-month liver-related mortality (25). C-BIL demonstrated superior discriminatory ability, and a modified MELD score incorporating C-BIL outperformed the traditional MELD score. Furthermore, the authors developed and validated a novel prognostic model comprising C-BIL, International Normalized Ratio, and creatinine, which showed significantly improved predictive accuracy over MELD in both training and validation cohorts (25). These findings further support the prognostic value of C-BIL in cirrhosis models, with potential implications for risk stratification and liver transplant prioritisation.

Beyond its role as a prognostic marker in CLD, C-BIL can directly promote programmed erythrocyte death. This occurs through the induction of calcium influx and ceramide production, which disrupt the erythrocyte membrane and ultimately contribute to the development of anaemia in liver disease (26). Moreover, C-BIL has been implicated in renal impairment through multiple mechanisms, including the induction of oxidative stress and inflammation, proximal tubular dysfunction, cast formation, and haemodynamic disturbance, which collectively overwhelm glomerular filtration and tubular transport processes (27-29). Paradoxically, C-BIL has also been reported to alleviate oxidative stress, suggesting that it may exert nephroprotective effects. Specifically, C-BIL can neutralise hypochlorous acid, a reactive oxygen species generated by neutrophils, thereby acting as an antioxidant (30). In addition, C-BIL has been shown to adversely affect the heart, with evidence demonstrating an independent, dose–response association between circulating C-BIL levels and increased risk of coronary heart disease incidence (31).

Potential mechanisms of elevated C-BIL in CLD

Several hypotheses have been proposed to explain the prognostic significance of C-BIL in CLD. Impaired excretory function and retrograde leakage of bilirubin arising from hepatocellular dysfunction (32), together with obstruction caused by pericellular fibrosis obliterating biliary canaliculi and extensive fibrous bands producing architectural distortion and impaired intrahepatic bile flow, are plausible and intuitive mechanistic explanations. In addition, a particularly compelling explanation centres on cellular senescence. Cellular senescence is a state in which cells permanently cease to divide while retaining metabolic activity (33). In CLD, hepatocyte senescence has emerged as a key pathogenic process contributing to disease progression across a range of aetiologies (34). An increasing body of evidence suggests that the proportion of senescent hepatocytes is a strong predictor of poor clinical outcomes in CLD (35-37); that is, the greater the proportion of senescent hepatocytes in the liver, the higher the likelihood of adverse outcomes in the affected patient. Although metabolically active, senescent hepatocytes undergo significant functional changes that distinguish them from their non-senescent counterparts. Notably, they redirect C-BIL away from the bile canaliculi into the hepatic sinusoids. This results from marked downregulation of the MRP2 transporter on the canalicular membrane, coupled with compensatory upregulation of the MRP3 transporter on the sinusoidal surface of senescent hepatocytes (Figure 1). This shift promotes increased transport of C-BIL into the hepatic sinusoids and subsequently into the bloodstream, potentially accounting for the elevated serum C-BIL levels observed in advanced CLD (38), where senescent hepatocytes may comprise up to 80% of the liver parenchyma (35,36). It is therefore plausible that serum C-BIL levels serve as an indirect surrogate marker of hepatocyte senescence burden, with potential utility in prognosticating disease severity.

Figure 1.

Hepatocyte senescence and conjugated hyperbilirubinemia. While bilirubin uptake and conjugation are preserved in senescent hepatocytes, altered MRP2 and MRP3 expression re-directs conjugated bilirubin into the sinusoids instead of biliary canaliculi, leading to its accumulation in blood.

However, further research is required to elucidate the key pathological processes of CLD and the mechanistic pathways underlying C-BIL elevation, in order to determine whether the relationship between C-BIL and CLD is consistent across different disease stages and aetiologies.

Limitations and challenges

Although C-BIL shows considerable promise as a prognostic biomarker, several limitations must be recognised. Firstly, C-BIL levels can be affected by extrahepatic factors such as haemolysis, biliary obstruction, and concomitant renal dysfunction, potentially reducing its specificity for assessing the severity of CLD. Secondly, most existing studies are retrospective, single-centre, or include relatively small patient cohorts, which limits the generalisability of the findings across diverse populations and disease aetiologies and may impact the reproducibility and comparability of results. Moreover, while C-BIL correlates with hepatocyte senescence and fibrosis, the precise mechanistic pathways remain incompletely understood, and inter-individual differences in transporter expression (MRP2/MRP3) may contribute to variability in serum levels. Finally, longitudinal studies examining C-BIL dynamics over time are limited, and the role of serial measurements within existing prognostic models remains unclear. Addressing these issues through multicentre, prospective studies and standardisation of C-BIL measurement will be crucial before its routine integration into clinical practice.

Conclusions

The incorporation of C-BIL into prognostic models offers a potentially valuable tool for more accurate risk stratification in patients with CLD. Given its strong association with disease severity and outcomes, serum C-BIL could complement or even refine current prognostic scores, particularly where traditional models underperform. In liver transplant settings, where prioritisation is critical, C-BIL-adjusted algorithms may help identify patients at higher risk of deterioration who might otherwise be overlooked. Moreover, its association with markers of systemic inflammation suggests that C-BIL could serve as an indicator of multi-organ involvement in decompensated states such as ACLF, thereby supporting clinical decision-making in acute settings. Further, if C-BIL can be used to identify patients with compensated cirrhosis who are at risk of developing cirrhosis-associated complications, such as decompensation or HCC, these patients could be prioritised for access to advanced therapies and offered enhanced surveillance, for example using abbreviated MRI, to enable earlier detection of HCC. The availability of infrastructure for measuring C-BIL, together with its validation and routine use in clinical practice, makes it a low-cost, attractive biomarker for disease stratification and prognostication.

Despite these promising findings, the use of C-BIL in routine prognostic assessment is not yet standard practice. Future studies are required to validate C-BIL-based models across broader patient populations, disease stages, and clinical contexts. Prospective longitudinal studies and integration with non-invasive biomarkers of fibrosis and senescence could offer a more holistic approach to patient monitoring. Furthermore, mechanistic research exploring the regulation of bilirubin transporters in hepatocyte senescence may unlock new therapeutic targets and strategies for modulating disease progression. As the burden of CLD continues to rise globally, the refinement of prognostic tools like C-BIL holds particular relevance in resource-limited healthcare systems where early risk stratification is key.

Supplementary

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