Serum bilirubin level is associated with exercise capacity and quality of life in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation caused by significant exposure to noxious particles or gases [1]. Oxidative stress is an important mechanism in the development, progression, and exacerbation of COPD. Biomarkers of oxidative stress are elevated in the exhaled breath, sputum, and blood of patients with COPD [2].

Bilirubin is known as a potential antioxidant and possesses anti-inflammatory properties [3]. Elevated bilirubin levels have a protective effect in cardiovascular disease and cardiovascular disease–related diseases [4]. Several reports demonstrate the relationship between bilirubin level and respiratory diseases. In the United Kingdom, higher level of bilirubin was associated with a lower risk of COPD, lung cancer, and all-cause mortality [5]. In the Swiss general population, serum bilirubin was positively associated with lung function [6]. In COPD, bilirubin level was inversely related to COPD disease severity and progression, and a higher bilirubin level was associated with a lower risk for acute COPD exacerbation, suggesting that bilirubin can be a biomarker of COPD exacerbation [7, 8].

However, previous studies have a potential limitation with respect to the acquisition of serum bilirubin level at one time point and analyzing it with serial clinical parameters. Brown et al. analyzed the serum bilirubin level through repeated measurements, but the interval of measurement and total duration of the study were too short to assess the relationship of serum bilirubin level with various clinical outcomes in COPD [8]. For comparison with the results of previous conflict results, we aimed to evaluate the association of both baseline and repeatedly measured serum bilirubin levels with various clinical outcomes of COPD in Korea, including lung function, quality of life (QoL), exercise capacity, exacerbation, and mortality.

This study investigated the association of serum bilirubin levels with several clinical aspects, such as lung function, exercise capacity, QoL, exacerbation, and mortality, through the Korean COPD cohort study. We found that higher serum bilirubin level was associated with longer 6 MW distance, better QoL, and higher risk of acute exacerbation after adjusting for age, sex, BMI, smoking status, and baseline FEV₁. When stratifying patients according to severity of airflow limitation, the association with better exercise capacity and better QoL persisted only in the GOLD I-II group, whereas the association with a higher risk of exacerbation persisted only in the GOLD III-IV group.

Bilirubin is a potential antioxidant against peroxyl radicals and protects cells from toxic levels of hydrogen peroxide [3]. Powerful antioxidant actions of bilirubin arise from rapid regeneration to bilirubin via biliverdin reductase after being oxidized back to biliverdin [11, 12]. Additionally, bilirubin attenuates vascular endothelial activation and dysfunction in response to proinflammatory stress [13].

These may explain how higher serum bilirubin levels are associated with better exercise capacity in COPD. This is the first study to demonstrate a positive association between serum bilirubin level and 6 MW distance in COPD patients. However, the association was only observed in the GOLD I-II group. In COPD patients with severe airflow limitation, other factors such as BMI, muscle weight, baseline saturation, level of dyspnea, and lung function have greater influence on exercise capacity. Handgrip strength was independently and positively related to serum total bilirubin level in both sexes among Japanese community-dwelling persons [14]. Reactive oxygen species and reactive nitrogen species are generated in skeletal muscle both during rest and contractile activity [15]. Intense and prolonged exercise can result in oxidative damage to both proteins and lipids in contracting myocytes. Low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species promote contractile dysfunction, resulting in muscle weakness and fatigue [16]. Bilirubin is one of the numerous nonenzymatic antioxidants located within skeletal muscle fibers, and it inhibits both lipid and protein oxidation [14]. In addition, bilirubin attenuates vascular endothelial activation and dysfunction in response to proinflammatory stress [13]. Albumin-bound bilirubin protects human ventricular myocytes against oxyradical damage [17].

However, the relationship of bilirubin and clinical outcomes should be cautiously assessed in various settings when other health statuses could confound the results. Brown et al. showed that higher bilirubin level was associated with lower risk of acute exacerbation of COPD from the secondary analyses of data in the Simvastatin for Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE) and the Azithromycin for Prevention of Exacerbations of COPD (MACRO) studies [8]. However, we found contradicting results, as a higher bilirubin level was associated with higher risk of exacerbation of COPD, especially in the GOLD III-IV group. This result could be cautiously explained by the relationship between bilirubin and right-heart function. Poelzl et al. showed that the median total bilirubin level increased with every New York Heart Association class [18]. Moreover, Samsky et al. reported that several echocardiographic indices of right-heart dysfunction were related to elevated total bilirubin levels, with increased portal vein pulsatility index having the best predictive value in patients with exacerbation of chronic heart failure. Abnormal liver function test results were observed in patients with heart failure as a result of impaired perfusion or increased right-sided cardiac pressures [19]. COPD patients with right-sided heart failure were at higher risk of severe exacerbations [20]. Relative pulmonary artery enlargement (ratio of the main pulmonary artery diameter to the aortic diameter > 1) was a significant biomarker for predicting future exacerbation in the COPD gene study [21]. The ratio of the main pulmonary artery diameter to the aortic diameter was positively related with right ventricular pressure, and a high ratio was a significant risk factor of COPD exacerbation in Korean COPD patients [22]. In this study, the relationship between serum bilirubin and exacerbation was only significant in the GOLD III-IV group, which had more severe airflow limitation, but the cardiac function status in this group is not exactly known. In STATCOPE and MACRO, COPD patients with predicted FEV₁ < 80% were enrolled, and one-third were categorized into the GOLD II group [23, 24]. Moreover, the study duration of STATCOPE (median = 1.74 years) and MACRO (median = 0.55 years) was shorter than that of our study (mean = 5.4 years).

In contrast to the findings of several previous studies, serum bilirubin level was not associated with pulmonary function in COPD patients. Curjuric et al. studied the association of bilirubin with lung function in the Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. High bilirubin levels were significantly associated with higher FEV₁/FVC and forced expiratory flow at 25–75% of the pulmonary volume (FEF_25–75%) overal l[6]. Leem et al. found significant associations of serum bilirubin levels with FEV₁, FVC, and FEF_25–75% in the general population, especially in never-smokers. Moreover, serum bilirubin levels were related to an annual decline in FEV₁, FVC, and the FEV₁/FVC ratio [9]. Apperley et al. reported that bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin concentration was associated with a higher FEV₁ and less annual decline in FEV₁ [7]. In the study by Apperley et al., participants were active smokers with mild to moderate airflow limitation, defined as FEV₁ between 55 and 90% predicted, and their mean FEV₁ was 75% predicted. In the GOLD I-II group of our study, the mean FEV₁ was 66.7% predicted, and half of the group had FEV₁ < 70% predicted (data not shown), meaning that airflow limitation was more severe in our study than that in the study by Apperley et al. Milevoj Kopcinovic et al. assessed the association of bilirubin as an oxidative stress marker with stable COPD patients. Although the number of participants was small, the total bilirubin levels were not different between patients with different COPD severities [25].

The association of serum bilirubin level with mortality is controversial, depending on the subtypes of mortality. Its association with overall mortality in COPD has not been reported previously in accordance with our study. In mild COPD, bilirubin was only inversely correlated with coronary heart disease mortality, but not with overall mortality [7].

Our study had several limitations. First, methodologically, the causality between serum bilirubin level and clinical consequences of COPD could not be established. Although it is currently impossible to conduct a prospective study with supplementation of bilirubin to investigate the clinical effects of bilirubin in patients with COPD, pretreatment with gavage of indirect bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion and increasing anti-inflammatory cytokine levels and antioxidant superoxide dismutase activity in a rat model of smoking-induced emphysema [26]. Second, a smaller number of patients were included in our study compared with previous large-cohort studies. However, the strength of our study is that data from repeated measurements over a long-term period were used. We evaluated the association of serum bilirubin levels with clinical outcomes using two different methods: (1) analysis of the relationship between the baseline serum bilirubin level with serial data of various clinical parameters, (2) analysis of all repeated serum bilirubin levels with serial measurements of clinical parameters using the clustered analysis method. Third, this cohort study did not include other factors that may affect bilirubin levels, such as previous medication, alcohol consumption, or diet. Moreover, parameters of cardiac functions were not fully evaluated in KOLD cohort. Therefore, our assumption of relationship between heart failure and high serum bilirubin levels in severe airflow limitation cases could not be proved in this study. Additionally, mortality could not be solely by the effects of acute exacerbation because death was defined as all cause death in our study.

This is the first COPD cohort study to investigate the relationship of repeatedly measured serum bilirubin levels and COPD-related clinical outcomes every year. A higher serum bilirubin level was independently associated with increased exercise capacity, a better QoL in patients with mild-to-moderate COPD, and a higher risk of exacerbation in those with severe-to-very severe COPD. Bilirubin possesses potential antioxidant and anti-inflammatory effects. However, bilirubin should be cautiously considered as a biomarker for predicting clinical consequences in various settings of COPD.