EDITORIAL
Does Serum Bilirubin Predict Incident Metabolic Syndrome? Metabolic syndrome1 is a constellation of interrelated cardiometabolic risk factors that promote the development of cardiovascular disease. Metabolic syndrome may be the systemic manifestation of inflammatory changes in adipose tissue characterized by an increased aggregation of activated macrophages into adipose tissue induced by chronic energy overload and is related with many other complex pathophysiologic mechanisms, such as systemic inflammation, insulin resistance, and endothelial dysfunction, which are closely associated with oxidative stress.1 Although there have been controversies regarding the criteria of metabolic syndrome, the harmonizing worldwide criteria have been agreed on by international academic societies.2 However, some professional societies have pointed out the limitations of metabolic syndrome as a clinical and epidemiologic tool.3,4 Meanwhile, bilirubin is a potent antioxidant5 and proven to have anti-inflammatory properties.6 Cross-sectional inverse associations between serum bilirubin and metabolic syndrome are well known. Patients with Gilbert syndrome have low levels of oxidative stress and enhancement of endothelium-dependent vasodilation.7 Serum bilirubin has been demonstrated to be negatively associated with cardiovascular disease and is suggested to be a negative predictor of end-stage kidney disease.8 In the current issue of The American Journal of Medicine, Huang et al9 report that serum bilirubin levels predict incident metabolic syndrome in healthy, middleaged, nonsmoking Chinese men. Lee et al10 also reported that serum bilirubin was a predictor of incident metabolic syndrome in healthy Korean men. However, the relationship between serum bilirubin and incident metabolic syndrome is controversial. Oda and Aizawa11 investigated the relationship between baseline serum bilirubin and incident metabolic syndrome in a Japanese health-screening population. They found that baseline serum bilirubin is not associated with incident metabolic syndrome and suggested that a decrease in serum bilirubin was not a cause of metabolic
Funding: None. Conflict of Interest: None. Authorship: The author had access to the data and played a role in writing this manuscript.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.022
syndrome but a marker of oxidative stress that is closely related to metabolic syndrome. Further prospective studies are required to conclude whether a decrease in serum bilirubin is a risk factor of incident metabolic syndrome. Eiji Oda, MD Medical Check-up Center Tachikawa Medical Center Nagaoka, Niigata, Japan
References 1. Oda E. Metabolic syndrome: its history, mechanisms, and limitations. Acta Diabetol. 2012;49:89-95. 2. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120: 1640-1645. 3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28:2289-2304. 4. Simmons RK, Alberti KG, Gale EA, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010;53:600-605. 5. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043-1046. 6. Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1-57. 7. Maruhashi T, Soga J, Fujimura N, et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in gilbert syndrome. Circulation. 2012;126:598-603. 8. Oda E, Aoyagi R, Aizawa Y. Hypobilirubinemia might be a possible risk factor of end-stage kidney disease independently of estimated glomerular filtration rate. Kidney Blood Press Res. 2012;36:47-54. 9. Huang S-S, Chan W-L, Leu H-B, Huang P-H, Lin S-J, Chen J-W. Serum bilirubin levels predict future development of metabolic syndrome in healthy middle-aged non-smoking men. Am J Med. 2015. XX: XX. 10. Lee MJ, Jung CH, Kang YM, et al. Serum bilirubin as a predictor of incident metabolic syndrome: a 4-year retrospective longitudinal study of 6205 initially healthy Korean men. Diabetes Metab. 2014;40: 305-309. 11. Oda E, Aizawa Y. Total bilirubin is inversely associated with metabolic syndrome but not a risk factor for metabolic syndrome in Japanese men and women. Acta Diabetol. 2013;50:417-422.
Does Serum Bilirubin Predict Incident Metabolic Syndrome? Metabolic syndrome1 is a constellation of interrelated cardiometabolic risk factors that promote the development of cardiovascular disease. Metabolic syndrome may be the systemic manifestation of inflammatory changes in adipose tissue characterized by an increased aggregation of activated macrophages into adipose tissue induced by chronic energy overload and is related with many other complex pathophysiologic mechanisms, such as systemic inflammation, insulin resistance, and endothelial dysfunction, which are closely associated with oxidative stress.1 Although there have been controversies regarding the criteria of metabolic syndrome, the harmonizing worldwide criteria have been agreed on by international academic societies.2 However, some professional societies have pointed out the limitations of metabolic syndrome as a clinical and epidemiologic tool.3,4 Meanwhile, bilirubin is a potent antioxidant5 and proven to have anti-inflammatory properties.6 Cross-sectional inverse associations between serum bilirubin and metabolic syndrome are well known. Patients with Gilbert syndrome have low levels of oxidative stress and enhancement of endothelium-dependent vasodilation.7 Serum bilirubin has been demonstrated to be negatively associated with cardiovascular disease and is suggested to be a negative predictor of end-stage kidney disease.8 In the current issue of The American Journal of Medicine, Huang et al9 report that serum bilirubin levels predict incident metabolic syndrome in healthy, middleaged, nonsmoking Chinese men. Lee et al10 also reported that serum bilirubin was a predictor of incident metabolic syndrome in healthy Korean men. However, the relationship between serum bilirubin and incident metabolic syndrome is controversial. Oda and Aizawa11 investigated the relationship between baseline serum bilirubin and incident metabolic syndrome in a Japanese health-screening population. They found that baseline serum bilirubin is not associated with incident metabolic syndrome and suggested that a decrease in serum bilirubin was not a cause of metabolic
Funding: None. Conflict of Interest: None. Authorship: The author had access to the data and played a role in writing this manuscript.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.022
syndrome but a marker of oxidative stress that is closely related to metabolic syndrome. Further prospective studies are required to conclude whether a decrease in serum bilirubin is a risk factor of incident metabolic syndrome. Eiji Oda, MD Medical Check-up Center Tachikawa Medical Center Nagaoka, Niigata, Japan
References 1. Oda E. Metabolic syndrome: its history, mechanisms, and limitations. Acta Diabetol. 2012;49:89-95. 2. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120: 1640-1645. 3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28:2289-2304. 4. Simmons RK, Alberti KG, Gale EA, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010;53:600-605. 5. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043-1046. 6. Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1-57. 7. Maruhashi T, Soga J, Fujimura N, et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in gilbert syndrome. Circulation. 2012;126:598-603. 8. Oda E, Aoyagi R, Aizawa Y. Hypobilirubinemia might be a possible risk factor of end-stage kidney disease independently of estimated glomerular filtration rate. Kidney Blood Press Res. 2012;36:47-54. 9. Huang S-S, Chan W-L, Leu H-B, Huang P-H, Lin S-J, Chen J-W. Serum bilirubin levels predict future development of metabolic syndrome in healthy middle-aged non-smoking men. Am J Med. 2015. XX: XX. 10. Lee MJ, Jung CH, Kang YM, et al. Serum bilirubin as a predictor of incident metabolic syndrome: a 4-year retrospective longitudinal study of 6205 initially healthy Korean men. Diabetes Metab. 2014;40: 305-309. 11. Oda E, Aizawa Y. Total bilirubin is inversely associated with metabolic syndrome but not a risk factor for metabolic syndrome in Japanese men and women. Acta Diabetol. 2013;50:417-422.
