Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels

Abstract

Background: Oxidation processes play an important role in atherogenesis. Bilirubin IXα is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). Methods: The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n=50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n=2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n=38) and control subjects (n=38). Results: The prevalence of IHD in GS subjects (aged 49.7±9.0 years) was 2% (0.05–10.7%, 95% confidence interval), compared to 12.1% in a general population (P<0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P<0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. Conclusions: In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity.

Introduction

Cardiovascular disease is the most common cause of death and is responsible for 50% of all mortality in developed countries [1]. A large number of risk factors have been described to be involved in the process of atherogenesis [1]. Among them, elevated levels of low density lipoprotein (LDL) cholesterol is the most important and its oxidative modification in the process of atherogenesis seems to be crucial [2]. LDL can be oxidatively modified by transition metals and by all major cells of the arterial wall [3]. Since oxidative modification of LDL results from lipid peroxidation, water- and lipid-soluble antioxidants should have a prominent effect in preventing this modification. This suggestion has been confirmed in numerous studies with a variety of natural or synthetic antioxidants such as vitamins A, C and E [4], probucol, phenothiazines, calcium antagonists, agents complexing copper and iron ions, and others [5].

Free radicals occur ubiquitously in the body and can disrupt the function of many cells and molecules. Natural antioxidant defences have evolved to protect humans against deleterious effects of free radicals. The primary enzymatic defences are intracellular, but other antioxidant defences are largely extracellular, including antioxidative substrates such as transferrin, ceruloplasmin, albumin, uric acid [6], [7], and unconjugated bilirubin (UCB), the predominant bile pigment in the intravascular compartment [8]. Its formation is mediated by heme-oxygenase (HO), the rate-limiting enzyme of the heme catabolism. Three distinct isoforms of HO have been identified; one is inducible (HO-1) belonging to the family of heat-shock protein [8], whereas the other forms are constitutive (HO-2 [9], and HO-3 [10]). The inducible form of HO is affected by numerous factors including oxidised hemoglobin, heavy metal ions, hydrogen peroxide, ultraviolet A radiation, nitric oxide, and free oxygen radicals [9], [11]. In this respect, bilirubin seems to represent an important endogenous agent with cytoprotective activity against oxidative stress, because of its potent antioxidant properties which were demonstrated in in vitro [8], [12], [13], [14], [15], [16], animal [17], [18] and human studies [19], [20], [21], [22], [23], [24], [25]. In addition to being a potent antioxidant, bilirubin is considered to play a role in tissue protection against inflammatory damage by its anticomplement action [26]. It has been reported that albumin, which appears in inflammatory exudate, carries bilirubin across the vascular wall into the sites of potential oxyradical damage by phagocytic cells [27]. Furthermore, bilirubin may reduce oxidative stress induced by hypertension [28].

Three major clinical studies regarding the possible influence of bilirubin levels on ischemic heart disease (IHD) have been published. In 1994, Schwertner et al. [21] described an inverse relationship between serum bilirubin concentrations and the risk of coronary artery disease. Breimer et al. [22] demonstrated in a prospective study of 7685 middle-aged British men an enhanced risk of IHD in patients with low bilirubin levels, although a similar tendency was also observed in the hyperbilirubinemic subjects, making the relationship U-shaped. In another study done by Hopkins et al. [23] significantly lower bilirubin levels in patients with coronary artery disease as compared to control subjects were documented. The relevance of serum bilirubin as a risk factor inversely related to the coronary artery disease was suggested also in other studies [24], [25].

In our study, we focused on the occurrence of IHD in a group of patients with confirmed diagnosis of Gilbert syndrome (GS) characterised by sustained unconjugated hyperbilirubinemia. GS is due to a partial deficiency of bilirubin UDP-glucuronosyltransferase in the liver tissue with ≈6% prevalence [29]. Mild unconjugated hyperbilirubinemia in the range of 20–100 μmol/l represents a typical clinical picture.