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Relationship Between Gilbert Syndrome and Prevalence of Vascular Complications in Patients With Diabetes
To the Editor: There is limited human evidence indicating beneficial effects of antioxidants on diabetic vascular complications.1 Although bilirubin has been recognized as an important endogenous antioxidant,2 whether hyperbilirubinemia affects the development of diabetic vascular complications is unknown. We therefore compared the prevalence of vascular complications in patients with diabetes and Gilbert syndrome (a congenital hyperbilirubinemia) and in patients with diabetes without Gilbert syndrome.
Methods
Screening of 5080 patients with diabetes who visited Kyushu University Hospital and 12 other hospitals and clinics in the Kyushu District of Japan from April to June 2006 yielded 96 consecutive patients with Gilbert syndrome, all of whom were enrolled. Determination of Gilbert syndrome was based on the presence of unconjugated bilirubin-dominant hyperbilirubinemia (serum bilirubin level >1.2 mg/dL; to convert to µmol/L, multiply by 17.104) for 3 or more months in the absence of hemolytic disease and/or hepatic dysfunction.3 Patients with diabetes for less than 5 years were excluded. Metabolic variables were based on blood and urine samples. For vascular outcomes, retinopathy was assessed by funduscopic examination; macroalbuminuria was defined as a ratio of urinary albumin to creatinine higher than 300 mg/g; coronary artery disease was defined as a history of acute myocardial infarction, angina confirmed by clinically significant obstruction on coronary angiography, or revascularization; cerebrovascular disease was defined as a history of symptomatic stroke confirmed by brain imaging.
Metabolic variables and the prevalence of vascular complications were compared with those of 426 patients with diabetes without Gilbert syndrome who visited Kyushu University Hospital during the same period. Stepwise logistic regression was performed to evaluate the relationship between Gilbert syndrome and the prevalence of vascular complications, adjusted for age, sex, duration of diabetes, hypertension, systolic and diastolic blood pressure, body mass index (calculated as weight in kilograms divided by height in meters squared), cigarette smoking, hemoglobin A1c, low-density lipoprotein cholesterol, total cholesterol, triglyceride level, high-density lipoprotein cholesterol, and uric acid; Gilbert syndrome was fixed in each model. A 2-sided P level of less than .05 was considered significant. The sample size had a power of at least 80% to detect a 60% reduction in each outcome, with a 2-sided  level of .05. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, North Carolina). The study was approved by the ethics committees of each institute and the participants provided written consent.
Results
Serum bilirubin levels were approximately 2.5-fold higher in patients with Gilbert syndrome (Table). There was no significant difference in age or duration of diabetes between the 2 groups. Patients with Gilbert syndrome had a significantly lower prevalence of hypertension; lower levels of systolic blood pressure, hemoglobin A1c, low-density lipoprotein cholesterol, total cholesterol, and triglyceride; and higher levels of high-density lipoprotein cholesterol. Urinary 8-hydroxy-2'-deoxy-guanosine excretion (a marker for oxidative stress) and serum high sensitivity C-reactive protein levels were significantly lower in patients with Gilbert syndrome.
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Table. Comparison of Metabolic Variables and Prevalence of Vascular Complications in Patients With Diabetes With and Without Gilbert Syndrome
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Logistic regression models showed that for retinopathy there was significant independent association with Gilbert syndrome, diabetes duration, and hemoglobin A1c; for macroalbuminuria, there was significant independent association with Gilbert syndrome, diabetes duration, and triglyceride level; for coronary artery disease, there was significant independent association with Gilbert syndrome, diabetes duration, and systolic blood pressure; and for cerebrovascular disease, there was significant independent association with age and triglyceride level but not with Gilbert syndrome. The adjusted odds ratio for the association of Gilbert syndrome with retinopathy was 0.22 (95% confidence interval [CI], 0.10-0.45; P < .001); with macroalbuminuria, 0.20 (95% CI, 0.06-0.69; P = .01); with coronary artery disease, 0.21 (95% CI, 0.05-0.88; P = .04); and with cerebrovascular disease, 0.50 (95% CI; 0.20-1.84, P = .22).
Comment
To our knowledge, this is the first study to show lower prevalence of vascular complications in patients with diabetes and Gilbert syndrome, as well as reduced markers of oxidative stress and inflammation. In addition to a radical scavenging activity, bilirubin has an inhibitory effect on the activity of NAD(P)H oxidase,4 which may be an important source for increased superoxide production in diabetic vascular tissues.5 It is therefore possible that sustained hyperbilirubinemia inhibits oxidative stress and prevents the development of vascular complications.
However, important limitations of this study must be considered. It is cross-sectional, precluding assessment of causal temporal associations. The differences in metabolic characteristics between the 2 groups could represent mediators of a protective effect, but also raise the possibility of selection bias or unmeasured confounders. These factors, along with the wide 95% CIs, make these findings hypothesis-generating and require confirmation in prospective studies.
Author Contributions: Dr Inoguchi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Inoguchi, Takayanagi.
Acquisition of data: Inoguchi, Sasaki, Kobayashi.
Analysis and interpretation of data: Inoguchi, Yamada, Takayanagi.
Drafting of the manuscript: Inoguchi, Sasaki, Takayanagi.
Statistical analysis: Yamada, Inoguchi.
Study supervision: Inoguchi.
Financial Disclosures: None reported.
Funding/Support: This work was supported in part by a Grant-in-Aid for Scientific Research (No. 16590888) from the Ministry of Education, Scientific and Culture, Japan.
Role of the Sponsor: The Ministry of Education, Scientific and Culture had no input in the design and conduct of this study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Additional Contributions: Mark F. McCarty (NutriGuard Research Inc) and Hajime Nawata, MD (Fukuoka Prefectural University) provided helpful suggestions. Teruaki Yamauchi, MD (Yukuhashi Central Hospital), Yuji Tajiri, MD (Fukuoka City Medical Association Hospital), Hideaki Tanaka, MD (Tanaka Clinic), Toshihiko Hashimoto, MD (Fukuoka City Hospital), Makoto Kunisaki, MD (Kunisaki Clinic), Hidehiro Ishii, MD (Kitakyushu Municipal Medical Center), Hidekatsu Sugimoto, MD (Sugimoto Clinic), Toshiyo Sonta, MD (Harasanshinkai Hospital), Schoichiro Ikuyama, MD, Masakazu Fujii, MD, Zheng Jing, MD, Yasutaka Maeda, MD, Fumi Sawada, MD, Ryoko Saito, MD, and Naoki Nakashima, MD (all from Kyushu University) provided assistance with the acquisition of the data. None of the persons listed received compensation for their contributions.
Toyoshi Inoguchi, MD
toyoshi{at}intmed3.med.kyushu-u.ac.jp
Shuji Sasaki, MD;
Kunihisa Kobayashi, MD;
Ryoichi Takayanagi, MD
Department of Medicine and Bioregulatory Science
Tomomi Yamada, PhD
Department of Medical Information Science
Faculty of Medical Sciences
Kyusyu University
Fukuoka, Japan
1. Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic vascular complications. JAMA. 2002;288(20):2579-2588.
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2. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043-1046.
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3. Gilbert syndrome. In: Diseases of the Liver and Biliary System. 7th ed. Osney Mead, UK: Blackwell Science; 2002:213-215.4. Lanone S, Bloc S, Foresti R, et al. Bilirubin decreases NOS2 expression via inhibition of NAD(P)H oxidase: implication for protection against endotoxic shock in rats. FASEB J. 2005;19(13):1890-1892.
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5. Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49(11):1939-1945.
ABSTRACT
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2007;298:1398-1400.
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