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Journal of Clinical Gastroenterology:
doi: 10.1097/MCG.0b013e3182702c62
Editorials

Metabolic Syndrome and Colorectal Neoplasm: Cause-Effect or Effect-Cause Relationship

Li, Tsai-Chung PhD*,†; Lin, Cheng-Chieh MD, PhD‡,§

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*Graduate Institute of Biostatistics, College of Public Health

§School of Medicine, College of Medicine, China Medical University

Department of Healthcare Administration, College of Health Science, Asia University

Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan

The authors declare that they have nothing to disclose.

Reprints: Cheng-Chieh Lin, MD, PhD, School of Medicine, College of Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung 40421, Taiwan (e-mail: cclin@mail.cmuh.org.tw).

In this issue of the journal, Jinjuvadia et al1 systematically reviewed case-control studies and cohort studies and then conducted a meta-analysis to explore the association between metabolic syndrome (MetS) and colorectal neoplasm.

It is well recognized that MetS is a cluster of endocrine-metabolic disturbances, which are characterized by insulin resistance, impaired glucose regulation, hypertension, raised triglycerides, and low high-density lipoprotein cholesterol.2 The World Health Organization (WHO) was the first to propose criteria for the diagnosis of MetS in 1998,3 followed by the European Group for the Study of Insulin Resistance (EGIR).4 In the WHO and EGIR definitions, the presence of insulin resistance was a prerequisite. In addition, WHO defined individuals with MetS as those showing at least 2 of 4 factors, which included hypertension, hyperlipidemia, obesity, and microalbuminuria. National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) assigned MetS as a secondary target for intervention in 2001.5 The ATP-III definition required 3 of the following 5 factors to be present: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and elevated fasting glucose. In 2005, the International Diabetes Federation (IDF) presented a MetS definition,6 in which central obesity was the prerequisite and different cutoff values for waist circumference were introduced for different ethnic groups. The American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) modified the NCEP criteria by decreasing the glucose cutoff value from 110 to 100 mg/dL.7

MetS may lead to the development of colorectal cancer (CRC) through several mechanisms. Insulin may act directly on tissue as a mitogenic and antiapoptotic growth factor.2,8 Insulin can also increase insulin-like growth factor-1 bioactivity.2,9,10 The shared metabolic factors underlying both type 2 diabetes and cancer include visceral adiposity, inflammation, hyperglycemia, and hyperinsulinemia, all of which lead to increased insulin receptor substrate (IRS), and IRS potentially increases tumor cell growth and proliferation. Another possible reason is that IRS-associated PI3K11 signaling is compromised by insulin-resistant states, which can affect both the metabolic and mitogenic pathway.

A novel aspect of the current study is the analysis of a large collection of results from individual studies focusing on the association between MetS and CRC for the purpose of integrating the findings. This study described the existing research in the area of MetS and CRC and analyzed its characteristics including study design, characteristics of study subjects, type of neoplasm, potential confounding factors, and definitions of MetS. It also identified heterogeneity in effects among multiple studies and had increased statistical power to detect an association compared with individual studies. The methodology of a systematic review reduces the subjectivity of study comparisons by using systematic and explicit comparison procedures. Most importantly, it identifies data gaps in the knowledge base and suggests directions for future research.

The study by Jinjuvadia and colleagues considered 4 definitions of MetS: WHO, ATP-III, IDF, and AHA/NHLBI in addition to that with ≥3 metabolic abnormalities (based on ATP-III). The type of colorectal lesions included colorectal adenoma and cancer. The agreement between reviewers for inclusion or exclusion of studies was high, with a Cohen κ coefficient of 0.84. They included 18 studies (10 cohort and 8 case-control studies) in the final analysis.12–29 The authors were careful to evaluate the methodological quality of these studies by using the Newcastle-Ottawa Scale with an averaged 7.2 stars for the 10 cohort studies and an averaged 8.1 stars for the 8 case-control studies. Eighteen studies involving 703,992 individuals provided data to obtain the relative risk (RR) for CRC. Among them, 10 studies (7 cohort and 3 case-control studies) focused on CRC, 8 (3 cohort and 5 case-control studies) on colorectal adenoma, and 2 (2 cohort studies) on colorectal adenoma and cancer combined. Their findings indicated that individuals with MetS had increased risk for CRC (RR: 0.542; 95% confidence interval, 0.307-0.958), colorectal adenoma (1.37; 1.26-1.49), and CRC and adenoma combined (1.76; 1.16-2.66). Subgroup analyses revealed that the significant association between MetS and CRC remains similar, with little variation across subgroups of sex, the potential confounding factor of smoking, and various definitions of MetS, except for higher RR of CRC observed in case-control studies than in cohort studies. Findings on visual inspection of funnel plots and test results of Egger’s or Begg’s and Mazumdar’s showed no evidence of publication bias for CRC, colorectal adenoma, or CRC and adenoma combined.

In summary, the authors are to be congratulated for conducting this systematic review and meta-analysis. It seems from a large number of studies that there is epidemiologic evidence that MetS increases the risk for colorectal neoplasm. Most studies show the magnitude of risk for colorectal neoplasm in the individual with MetS as a hazard ratio between 1.3 and 2.0; however, the risk may be much higher in a few circumstances. This study described the existing research on the association between MetS and CRC. It also identified gaps in the data; for example, most studies did not consider possible confounding factors such as physical activity, fruit and vegetable consumption, body mass index, family history of colon cancer, and alcohol use. The limitations of this pooled analysis include some heterogeneity among studies and possible recall bias inherent from the case-control design. Although it is easy to recommend large prospective studies, avoiding confounding remains a challenge. Even with powerful techniques to control for confounding effects by multivariate regression, variations in other putative confounding factors may be relevant. For example, a genetic variant with opposite effects on the risk of MetS may confound the association between MetS and colorectal neoplasm. Most importantly, this study did not exclude those diagnosed as having cancer within 1 to 5 years of baseline in order to rule out the possibility of effect-cause relationship. This is the first published meta-analysis examining this topic. Larger prospective studies on this topic that avoid the drawbacks of previous studies are warranted.

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