Published online May 2, 2005
PEDIATRICS Vol. 115 No. 5 May 2005, pp. 1411-1412 (doi:10.1542/peds.2004-1796)
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vítek, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vítek, L.
Related Collections
Right arrow Premature & Newborn
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

COMMENTARY

Impact of Serum Bilirubin on Human Diseases

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

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.


   FOOTNOTES
 
Accepted Sep 23, 2004.

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.


   REFERENCES
TOP
 REFERENCES
 

  1. Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics. 2004;113 :1776 –1782[Free Full Text]
  2. Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160 :449 –456[CrossRef][Web of Science][Medline]
  3. Shimomura H, Ogawa H, Takazoe K, et al. Comparison of urinary biopyrrin levels in acute myocardial infarction (after reperfusion therapy) versus stable angina pectoris and their usefulness in predicting subsequent cardiac events. Am J Cardiol. 2002;90 :108 –111[CrossRef][Web of Science][Medline]
  4. Morita Y, Takahashi H, Kamihata H, Yamamoto Y, Hara K, Iwasaka T. Urinary excretion of biopyrrins, oxidative metabolites of bilirubin, increases after spasm provocation tests in patients with coronary spastic angina. Int J Cardiol. 2001;80 :243 –250[CrossRef][Web of Science][Medline]
  5. Hokamaki J, Kawano H, Yoshimura M, et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure. J Am Coll Cardiol. 2004;43 :1880 –1885[Abstract/Free Full Text]
  6. Tsukahara H, Haruta T, Todoroki Y, et al. Oxidant and antioxidant activities in childhood meningitis. Life Sci. 2002;71 :2797 –2806[Medline]
  7. Kozaki N, Shimizu S, Chijiiwa K, et al. Bilirubin as an anti-oxidant for surgical stress: a preliminary report of bilirubin oxidative metabolites. HPB Surg. 1999;11 :241 –248[Medline]
  8. Tsujinaka T, Fujita J, Morimoto T, et al. Increased urinary excretion of bilirubin metabolites in association with hyperbilirubinemia after esophagectomy. Surg Today. 1998;28 :1119 –1123[Medline]
  9. Yamaguchi T, Shioji I, Sugimoto A, Yamaoka M. Psychological stress increases bilirubin metabolites in human urine. Biochem Biophys Res Commun. 2002;293 :517 –520[CrossRef][Medline]
  10. Yoshida R, Ogawa Y, Shioji I, et al. Urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine and biopyrrins levels among construction workers with asbestos exposure history. Ind Health. 2001;39 :186 –188[Medline]
  11. Kimpara T, Takeda A, Yamaguchi T, et al. Increased bilirubins and their derivatives in cerebrospinal fluid in Alzheimer’s disease. Neurobiol Aging. 2000;21 :551 –554[CrossRef][Web of Science][Medline]
  12. Vitek L, Kraslova I, Muchova L, Dudkova L, Novotny L, Yamaguchi T. Urinary excretion of oxidative metabolites of bilirubin in subjects with Gilbert syndrome [abstract]. FASEB J. 2004;18 :A1189
  13. Wei M, Schwertner HA, Gibbons LW, Zheng Q, Mitchell TL. Low fasting serum bilirubin as a predictor of cancer mortality in men [abstract]. Hepatology. 2000;32 :427A[CrossRef]
  14. Ko WF, Helzlsouer KJ, Comstock GW. Serum albumin, bilirubin, and uric acid and the anatomic site-specific incidence of colon cancer. J Natl Cancer Inst. 1994;86 :1874 –1875[Free Full Text]
  15. Zucker SD, Qin XF, Yu F, Goessling W. Inhibition of breast cancer cell proliferation by unconjugated bilirubin is associated with enhanced expression of apolipoprotein D and increased nuclear translocation of transcription factor NF-kappa B [abstract]. Hepatology. 1999;30 :498A[CrossRef]
  16. Goessling W, Zucker SD. Role of apolipoprotein D in the transport of bilirubin in plasma. Am J Physiol Gastrointest Liver Physiol. 2000;279 :G356 –G365[Abstract/Free Full Text]
  17. Sanchez LM, Vizoso F, Diez-Itza I, Lopez-Otin C. Identification of the major protein components in breast secretions from women with benign and malignant breast diseases. Cancer Res. 1992;52 :95 –100[Abstract/Free Full Text]
  18. Rodriguez JC, Diaz M, Gonzalez LO, et al. Apolipoprotein D expression in benign and malignant prostate tissues. Int J Surg Investig. 2000;2 :319 –326[Medline]
  19. Keshavan P, Schwemberger SJ, Smith DL, Babcock GF, Zucker SD. Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization. Int J Cancer. 2004;112 :433 –445[CrossRef][Web of Science][Medline]
  20. Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology. 2004;40 :827 –835[CrossRef][Web of Science][Medline]
  21. Guillemette C, Millikan RC, Newman B, Housman DE. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Cancer Res. 2000;60 :950 –956[Abstract/Free Full Text]
  22. Adegoke OJ, Shu XO, Gao YT, et al. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) and risk of breast cancer. Breast Cancer Res Treat. 2004;85 :239 –245[CrossRef][Medline]
  23. Guillemette C, De Vivo I, Hankinson SE, et al. Association of genetic polymorphisms in UGT1A1 with breast cancer and plasma hormone levels. Cancer Epidemiol Biomarkers Prev. 2001;10 :711 –714[Abstract/Free Full Text]
  24. Nicholl P, Mikhailidis D, Hamilton G, Spyropolous LK, Winder AF. Bilirubin and peripheral vascular disease [abstract]. Br J Surg. 1995;82 :1561 –1562
  25. Krijgsman B, Papadakis JA, Ganotakis ES, Mikhailidis DP, Hamilton G. The effect of peripheral vascular disease on the serum levels of natural anti-oxidants: bilirubin and albumin. Int Angiol. 2002;21 :44 –52[Web of Science][Medline]
  26. Cerne D, Ledinski G, Kager G, Greilberger J, Wang XS, Jurgens G. Comparison of laboratory parameters as risk factors for the presence and the extent of coronary or carotid atherosclerosis: the significance of apolipoprotein B to apolipoprotein all ratio. Clin Chem Lab Med. 2000;38 :529 –538[CrossRef][Web of Science][Medline]
  27. Kangas E, Teittinen K, Vilkko P, Utriainen S. Bilirubin and peripheral vascular disease. Br J Surg. 1999;86(5) :713
  28. Krijgsman B, Mikhailides DP, Winder AF, Hamilton G. Bilirubin and peripheral vascular disease [letter]. Br J Surg. 2000;87 :251 –252
  29. Vitek L, Novotny L, Spacil J, Sperl M, Holaj R. The role of elevated serum bilirubin levels on carotid atherosclerosis [abstract]. Hepatology. 2003;38 :383A
  30. Ko GT, Chan JC, Woo J, et al. Serum bilirubin and cardiovascular risk factors in a Chinese population. J Cardiovasc Risk. 1996;3 :459 –463[Medline]
  31. Papadakis JA, Ganotakis ES, Jagroop IA, Mikhailidis DP, Winder AF. Effect of hypertension and its treatment on lipid, lipoprotein(a), fibrinogen, and bilirubin levels in patients referred for dyslipidemia. Am J Hypertens. 1999;12 :673 –681[CrossRef][Web of Science][Medline]
  32. Vitek L, Novotny L, Muchova L, Tesar V, Schwertner H. Decreased levels of serum bilirubin as a risk factor in lupus nephropathy. J Am Soc Nephrol. 2003;14 :381A –382A
  33. Ohrui T, Yasuda H, Yamaya M, Matsui T, Sasaki H. Transient relief of asthma symptoms during jaundice: a possible beneficial role of bilirubin. Tohoku J Exp Med. 2003;199 :193 –196[CrossRef][Web of Science][Medline]
  34. Ohrui T, Higuchi M, Kanda A, Matsui T, Sato E, Sasaki H. A patient with exacerbation of idiopathic pulmonary fibrosis which was resolved probably due to the coexisting hyperbilirubinemia? Tohoku J Exp Med. 2001;193 :245 –249[Medline]
  35. Oren DA, Desan PH, Boutros N, Anand A, Charney DS. Effects of light on low nocturnal bilirubin in winter depression: a preliminary report. Biol Psychiatry. 2002;51 :422 –425[Medline]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 JAMAHome page
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]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vítek, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vítek, L.
Related Collections
Right arrow Premature & Newborn
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?