Gilbert’s syndrome: protective effect on endothelial dysfunction

Erdim Sertoğlu 1 , Serkan Tapan 2 , Teoman Doğru 3 , Ramazan Acar 4 , Tolga Doğan 5 , Selami İnce 6  and Cumhur Bilgi 7
  • 1 GATA Haydarpasa Training Hospital, Department of Medical Biochemistry, İstanbul, Turkey, Tel.: +90 312 304 2000
  • 2 Yuksek Ihtisas University School of Medicine, Department of Medical Biochemistry, Ankara, Turkey
  • 3 Gülhane Military Medical Academy, Department of Gastroenterology, Ankara, Turkey
  • 4 Beytepe Military Hospital, Department of Internal Medicine, Ankara, Turkey
  • 5 Gülhane Military Medical Academy, Department of Internal Medicine, Ankara, Turkey
  • 6 Beytepe Military Hospital, Department of Radiology, Ankara, Turkey
  • 7 Koru Hospital, Department of Biochemistry, Ankara, Turkey
Erdim Sertoğlu, Serkan Tapan, Teoman Doğru, Ramazan Acar, Tolga Doğan, Selami İnce and Cumhur Bilgi

Abstract

Objective:

Gilbert’s syndrome (GS), is a benign condition characterized by unconjugated hyperbilirubinemia related to a decreased hepatic glucuronidating activity without symptoms and signs of liver disease or overt hemolysis. In the present study, we aimed to assess circulating levels of asymmetric dimethylarginine (ADMA), pentraxin-3 (PTX-3) and high sensitivity C-reactive protein (hs-CRP) between patients with GS and controls and determine the correlation of unconjugated bilirubin (UCB) levels with these molecules as prognostic factors for vascular risk stratification and endothelial dysfunction.

Methods:

Forty two patients with GS and 37 age and sex matched control subjects were enrolled in this study. The diagnosis of GS was made by unconjugated hyperbilirubinemia (1 mg/dL or >17.1 μmol/L) on at least two occasions with normal values of other liver function tests, normal hepatic imaging, and absence of hemolysis.

Results:

Serum ADMA, PTX-3 and hs-CRP levels were significantly lower in GS than the healthy controls (p=0.037, p=0.025 and p=0.040, respectively). In correlation analysis, UCB was negatively correlated with ADMA, PTX-3 and hs-CRP (r=−0.239, p=0.034; r=−0.280, p=0.012 and r=−0.224, p=0.047, respectively).

Discussion and conclusion:

The present study showed for the first time that decreased levels of ADMA, PTX-3 and hs-CRP may prove the protective effects of hyperbilirubinemia on the endothelial dysfunction.

  • 1.

    Gilbert A, Lereboullet P. La cholemie simple familiale. Sem Med 1901;21:241–3.

  • 2.

    Tapan S, Karadurmus N, Dogru T, Ercin CN, Tasci I, Bilgi C, et al. Decreased small dense LDL levels in Gilbert’s syndrome. Clin Biochem 2011;44:300–3.

    • Crossref
    • PubMed
    • Export Citation
  • 3.

    Hsieh TY, Shiu TY, Chu NF, Chao TY, Chu HC, Chang WK, et al. Rapid molecular diagnosis of the Gilbert’s syndrome-associated exon 1 mutation within the UGT1A1 gene. Genet Mol Res 2014;13:670–9.

    • Crossref
    • PubMed
    • Export Citation
  • 4.

    Sieg A, Arab L, Schlierf G, Stiehl A, Kommerell B. Prevalence of Gilbert’s syndrome in Germany. Dtsch Med Wochenschr 1987;112:1206–8.

    • PubMed
    • Export Citation
  • 5.

    Vítek L, Kráslová I, Muchová L, Novotný L, Yamaguchi T. Urinary excretion of oxidative metabolites of bilirubin in subjects with Gilbert syndrome. J Gastroenterol Hepatol 2007;22:841–5.

    • Crossref
    • PubMed
    • Export Citation
  • 6.

    Bulmer AC, Blanchfield JT, Toth I, Fassett RG, Coombes JS. Improved resistance to serum oxidation in Gilbert’s syndrome: a mechanism for cardiovascular protection. Atherosclerosis 2008;199:390–6.

    • Crossref
    • PubMed
    • Export Citation
  • 7.

    Boon AC, Hawkins CL, Coombes JS, Wagner KH, Bulmer AC. Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum. Free Radic Biol Med 2015;86:259–68.

    • Crossref
    • PubMed
    • Export Citation
  • 8.

    Ghem C, Sarmento-Leite RE, de Quadros AS, Rossetto S, Gottschall CA. Serum bilirubin concentration in patients with an established coronary artery disease. Int Heart J 2010;51:86–91.

    • Crossref
    • PubMed
    • Export Citation
  • 9.

    Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem 1995;41:1504–8.

    • Crossref
    • PubMed
    • Export Citation
  • 10.

    Djousse L, Levy D, Cupples LA, Evans JC, D’Agostino RB, Ellison RC. Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol 2001;87:1196–200.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Gullu H, Erdogan D, Tok D, Topcu S, Caliskan M, Ulus T, et al. High serum bilirubin concentrations preserve coronary flow reserve and coronary microvascular functions. Arterioscler Thromb Vasc Biol 2005;25:2289–94.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 1994;40:18–23.

    • Crossref
    • PubMed
    • Export Citation
  • 13.

    Antoniades C, Demosthenous M, Tousoulis D, Antonopoulos AS, Vlachopoulos C, Toutouza M, et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension 2011;58:93–8.

    • Crossref
    • PubMed
    • Export Citation
  • 14.

    Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G, Boehm BO, Winkelmann BR, et al. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study). Clin Chem 2007;53:273–83.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Isıklar OO, Barutcuoglu B, Kabaroglu C, Mutaf I, Ozmen D, Bayındır O, et al. Do cardiac risk factors affect the homocysteine and asymmetric dimethylarginine relationship in patients with coronary artery diseases? Clin Biochem 2012;45:1325–30.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 2008;28:1–13.

    • Crossref
    • Export Citation
  • 17.

    Mantovani A, Garlanda C, Bottazzi B, Peri G, Doni A, Martinez de la Torre Y, et al. The long pentraxin PTX3 in vascular pathology. Vascul Pharmacol 2006;45:326–30.

    • Crossref
    • Export Citation
  • 18.

    Fazzini F, Peri G, Doni A, Dell’Antonio G, Dal Cin E, Bozzolo E, et al. PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation. Arthritis Rheum 2001;44:2841–50.

    • Crossref
    • PubMed
    • Export Citation
  • 19.

    Jylhävä J, Haarala A, Kähönen M, Lehtimäki T, Jula A, Moilanen L, et al. Pentraxin 3 (PTX3) is associated with cardiovascular risk factors: the Health 2000 Survey. Clin Exp Immunol 2011;164:211–7.

    • Crossref
    • PubMed
    • Export Citation
  • 20.

    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation 2012;126:598–603.

    • Crossref
    • PubMed
    • Export Citation
  • 22.

    Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:115–26.

    • Crossref
    • PubMed
    • Export Citation
  • 23.

    Mazzone GL, Rigato I, Ostrow JD, Bossi F, Bortoluzzi A, Sukowati CH, et al. Bilirubin inhibits the TNFalpha-related induction of three endothelial adhesion molecules. Biochem Biophys Res Commun 2009;386:338–44.

    • Crossref
    • PubMed
    • Export Citation
  • 24.

    Mazzone GL, Rigato I, Ostrow JD, Tiribelli C. Bilirubin effect on endothelial adhesion molecules expression is mediated by the NF-kB signaling pathway. BioSci Trends 2009;3:151–7.

    • PubMed
    • Export Citation
  • 25.

    Kocaman SA, Sahinarslan A, Biberoglu G, Hasanoglu A, Akyel A, Timurkaynak T, et al. Asymmetric dimethylarginine and coronary collateral vessel development. Coron Artery Dis 2008;19:469–74.

    • Crossref
    • PubMed
    • Export Citation
  • 26.

    Kocaman SA. Asymmetric dimethylarginine, NO and collateral growth. Anadolu Kardiyol Derg 2009;9:417–20.

    • PubMed
    • Export Citation
  • 27.

    Inoue K, Sugiyama A, Reid PC, Ito Y, Miyauchi K, Mukai S, et al. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol 2007;27:161–7.

    • Crossref
    • PubMed
    • Export Citation
  • 28.

    Savchenko A, Imamura M, Ohashi R, Jiang S, Kawasaki T, Hasegawa G, et al. Expression of pentraxin 3 (PTX3) in human atherosclerotic lesions. J Pathol 2008;215:48–55.

    • Crossref
    • PubMed
    • Export Citation
  • 29.

    Rolph MS, Zimmer S, Bottazzi B, Garlanda C, Mantovani A, Hansson GK. Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2002;22:e10–4.

  • 30.

    Jenny NS, Arnold AM, Kuller LH, Tracy RP, Psaty BM. Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2009;29:594–9.

    • Crossref
    • PubMed
    • Export Citation
  • 31.

    Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499–511.

    • PubMed
    • Export Citation
  • 32.

    Norata GD, Marchesi P, Pulakazhi Venu VK, Pasqualini F, Anselmo A, Moalli F, et al. Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation 2009;120:699–708.

    • Crossref
    • Export Citation
  • 33.

    Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99:3092–5.

    • Crossref
    • PubMed
    • Export Citation
  • 34.

    Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol 2010;11:328–34.

    • Crossref
    • Export Citation
  • 35.

    Kawamura K, Ishikawa K, Wada Y, Kimura S, Matsumoto H, Kohro T, et al. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 2005;25:155–60.

    • Crossref
    • PubMed
    • Export Citation
  • 36.

    Erdogan D, Gullu H, Yildirim E, Tok D, Kirbas I, Ciftci O, et al. Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima– media thickness in both men and women. Atherosclerosis 2006;184:431–7.

    • Crossref
    • PubMed
    • Export Citation
  • 37.

    Tapan S, Dogru T, Tasci I, Ercin CN, Ozgurtas T, Erbil MK. Soluble CD40 ligand and soluble P-selectin levels in Gilbert’s syndrome: a link to protection against atherosclerosis? Clin Biochem 2009;42:791–5.

    • Crossref
    • PubMed
    • Export Citation
  • 38.

    Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002;160:449–56.

    • Crossref
    • PubMed
    • Export Citation
  • 39.

    Yoshino S, Hamasaki S, Ishida S, Kataoka T, Yoshikawa A, Oketani N, et al. Relationship between bilirubin concentration, coronary endothelial function, and inflammatory stress in overweight patients. J Atheroscler Thromb 2011;18:403–12.

    • Crossref
    • PubMed
    • Export Citation
  • 40.

    Bhuiyan AR, Srinivasan SR, Chen W, Sultana A, Berenson GS. Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa Heart Study. Metabolism 2008;57:612–6.

    • Crossref
    • PubMed
    • Export Citation
  • 41.

    Boon AC, Hawkins CL, Bisht K, Coombes JS, Bakrania B, Wagner KH, et al. Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome. Free Radic Biol Med 2012;52:2120–7.

    • Crossref
    • PubMed
    • Export Citation
  • 42.

    Cheriyath P, Gorrepati VS, Peters I, Nookala V, Murphy ME, Srouji N, et al. High total bilirubin as a protective factor for diabetes mellitus: an analysis of NHANES data from 1999 – 2006. J Clin Med Res 2010;2:201–6.

    • PubMed
    • Export Citation
  • 43.

    Malhi H, Gores GJ. Mechanisms of Liver Injury. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s Diseases of the Liver. 9th Edition Lippincott, Philadelphia: Williams & Wilkins, 2003. pp. 231.

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