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COMMENTARY |
4th Department of Internal Medicine and Institute of Clinical Biochemistry and Laboratory Diagnostics
1st Medical Faculty
Charles University of Prague
U Nemocnice 2, Praha 2, 128 08, Czech Republic
Abbreviations: GS, Gilbert syndrome • PVD, peripheral vascular disease
Bilirubin, a major product of heme catabolism, belongs to compounds with pleiotropic biologic effects. Although for decades it was considered as a metabolite dangerous for human health, recent data indicate that bilirubin exhibits potent antioxidant properties with substantial positive clinical consequences. In a recent issue of Pediatrics, Sedlak and Snyder1 comprehensively reviewed available data on the beneficial role of bilirubin. Although the article covers current knowledge of all the aspects of this topic almost completely, I would like to mention more data that further support a salutary role of bilirubin in the human body.
In addition to studies cited in the Sedlak and Snyder article, total serum antioxidant capacity was found to correlate with serum bilirubin levels in our study on adult Gilbert syndrome (GS) patients, and this relation was confirmed in an in vitro study.2 In regard to the cited bilirubin oxidation metabolite study in septic patients, recent studies (mainly from Japan) demonstrated close correlation between these markers (called biopyrrins) and many other pathologic conditions including ischemic heart disease,3,4 congestive heart failure,5 atopic dermatitis,6 and surgical7,8 or even psychological stress.9 The same relationship was also found for asbestos-induced oxidative stress.10 Close associations between biopyrrin levels in cerebrospinal fluid and childhood meningitis6 and Alzheimer’s disease11 were also demonstrated, suggesting that bilirubin consumption during oxidative stress may belong to the major pathways, preventing deleterious effects of oxidative stress. It is interesting to note that low urinary biopyrrin excretion in patients with GS was described recently,12 which is consistent with low oxidative stress in patients with benign hyperbilirubinemia.2
In terms of potential protective effects of elevated serum bilirubin levels on cancerogenesis, several other articles should be noted. Although not yet published as a full article, results of an 11-year follow-up study by Wei et al13 on >17000 men without known cancer at baseline brought very suggestive evidence of an inverse relationship between risk of cancer development and serum bilirubin levels. The authors found means of baseline fasting serum bilirubin concentrations of 11.3 µmol/L for men with cancer death versus 13.7 µmol/L for the controls (P < .001). Similar values of serum bilirubin and colon cancer were reported by Ko et al.14 Although bilirubin levels were lower among colon cancer patients than controls (11.5 vs 13.3 µmol/L), the difference was not statistically significant, presumably because of the low number of patients involved in the study. Antiproliferative effects of bilirubin were proved also in an in vitro study by Zucker et al,15 who showed that proliferation of a breast cancer cell line is inhibited in a dose-dependent manner by unconjugated bilirubin at physiologic concentrations through the induction of apolipoprotein D. It is interesting to note that apolipoprotein D is a principal nonalbumin carrier of bilirubin in human plasma,16 and increased expression of apolipoprotein D, which may aim bilirubin to the cancer tissue, was demonstrated to be associated with a better prognosis for breast17 and prostate18 cancer. Additional evidence has been published very recently by Zucker and co-workers, who demonstrated in in vitro19 and in vivo epidemiologic20 studies protective effects of bilirubin against colorectal cancer. On the other hand, the lower expression alleles of UGT1A1, the bilirubin conjugation gene in the liver tissue, were found to be associated with increased risk of breast cancer in premenopausal black21 and Chinese22 women, possibly as a result of impaired biotransformation of estrogens. However, these results were not confirmed in a subsequent study on white women, suggesting that other factors might be responsible.23 It is unfortunate that a population study on the bilirubin levels among patients with cancer to determine the impact of low bilirubin concentrations have not been performed yet.
In regard to peripheral vascular disease (PVD), a direct link between low serum bilirubin levels and carotid atherosclerosis was described first by Nicholl et al24 in 1995. An extension of this retrospective study was published 7 years later,25 and the authors reported a significantly higher prevalence of PVD in male patients with a bilirubin level <6.5 µM/L. In another study by Cerne et al,26 decreased serum bilirubin levels were associated with peripheral atherosclerosis only in smokers. Low serum bilirubin in patients with PVD was detected also in a small study by Kangas et al.27 Although the difference between patients and controls was not statistically significant (10 vs 13 µmol/L), it was proposed that the observed trend might achieve significance if a larger study were conducted.28 A low prevalence of carotid atherosclerosis was detected also in our study on GS patients,29 which is in line with the low incidence of ischemic heart disease detected in a previous study.2 It is known also that patients with impaired glucose tolerance, diabetes,30 or arterial hypertension,31 risk factors known to be closely associated with atherosclerosis, have lower serum bilirubin levels.
Furthermore, low serum bilirubin levels were found to be associated with lupus nephritis,32 indicating that serum bilirubin may contribute to protection against oxidative stress-mediated diseases, presumably in a general manner. In support of this are interesting case reports on complete resolution of persistent difficult-to-treat asthma, possibly as a result of hepatitis B-induced hyperbilirubinemia33 as well as idiopathic pulmonary fibrosis caused by hyperbilirubinemia elicited by biliary tract obstruction.34 Moreover, low serum bilirubin also may be associated with mental illnesses, as suggested by studies by Oren et al,35 who reported that patients with winter depression exhibited lower nocturnal bilirubin levels compared with controls and suggested that bilirubin may serve as an important chronobiological photoreceptor.
In summary, based on available data and in accord with the analysis by Sedlak and Snyder,1 it may be postulated that serum bilirubin is a major clinically relevant cytoprotectant, contributing substantially to protection against oxidative stress. However, additional studies are necessary to uncover all the pathophysiologic associations and mechanisms involved.
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FOOTNOTES |
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Address correspondence to Libor Vítek, MD, PhD, 4th Department of Internal Medicine and Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Medical Faculty, Charles University of Prague, U Nemocnice 2, Praha 2, 128 08, Czech Republic. E-mail: vitek{at}cesnet.cz
No conflict of interest declared.
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REFERENCES |
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This article has been cited by other articles:
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  T. W. Sedlak and S. H. Snyder Messenger Molecules and Cell Death: Therapeutic Implications JAMA, January 4, 2006; 295(1): 81 - 89. [Abstract] [Full Text] [PDF]
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