Are Higher Bilirubin Levels Linked to Lower Mortality, Improved Outcomes in COPD?

A systematic review evaluates the association between serum bilirubin levels and lung function, the prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality.

In patients with chronic obstructive pulmonary disease (COPD), higher serum bilirubin levels within the normal range may be associated with lower mortality and risk for exacerbations, a reduced incidence of COPD diagnoses, and improved lung function. Results of the analysis were published in the journal BMC Pulmonary Medicine.

The investigators sought to evaluate the link between serum bilirubin levels and lung function (forced expiratory volume in 1 second [FEV1]), the prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality. A systemic review on the subject was conducted. The review included studies that measured serum bilirubin concentrations and outcomes of interest in adults both with and without underlying lung disease. Studies that examined liver disease or drug-induced elevations in bilirubin levels were excluded from the analysis. Reports were eligible if they were randomized or observational (ie, cohort, case-control, cross-sectional) studies that enrolled participants >18 years of age. Studies that were based on pulmonary diagnoses or pulmonary function were not excluded from the analysis. Further, studies conducted both in general populations and in samples that were restricted to individuals with obstructive lung disease were also eligible for inclusion. Case series and case reports, studies in abstract form only, and those with a full text publication in English, however, were excluded from the analysis. 

Evidence on potential protective benefits of benign elevations in serum bilirubin levels in patients were COPD were evaluated based on 3 key questions: (1) Is serum bilirubin associated with better lung function as measured by FEV1? (2) Is serum bilirubin associated with a lower prevalence/incidence of COPD and/or better (higher) FEV1/forced vital capacity (FVC) ratio? (3) Is serum bilirubin level associated with improved clinically relevant outcomes (respiratory events/exacerbations, respiratory symptoms, respiratory health status, and mortality)?

A total of 13 studies were included in the review—5 with a low risk for bias, 3 with a moderate risk for bias, and 5 with a high risk for bias. Of the 13 studies, 4 were from North America (United States and Canada), 4 were from Europe, 4 were from East Asia (China or South Korea), and 1 was conducted in a cohort of participants in 20 countries.

Results showed a low strength of evidence for the association between higher bilirubin levels and lower risk for acute COPD exacerbations in 2 studies, mortality in 3 studies, diagnosis of COPD in 4 studies, and lung function per FEV1 measurements in 8 studies. Further, insufficient evidence was found with respect to the relationship between serum bilirubin levels and respiratory health status/exercise capacity in 1 study and airflow obstruction (ie, FEV1/FVC ratio) in 4 studies.

Due to clinical and methodological heterogeneity and data reporting limitations, the researchers were not able to perform a meta-analysis or quantitative analyses. Moreover, the analysis may be limited by reporting bias.

The investigators concluded that randomized controlled trials are needed, in order to evaluate the effects of medications that raise serum bilirubin levels on COPD outcomes. Further, the relationship between serum bilirubin levels and patient-centered outcomes, such as respiratory health status and exercise capacity, warrants exploration in future studies.


MacDonald DM, Kunisaki KM, Wilt TJ, Baldomero AK. Serum bilirubin and chronic obstructive pulmonary disease (COPD): a systematic review. BMC Pulm Med. 2021;21(1):33. doi:10.1186/s12890-021-01395-9