Colorectal Neoplasia and Vitamin D
From all study participants, a detailed drug and medical history and a routine physical examination were obtained. Following an overnight fast, venous blood was collected and an oral glucose tolerance test (OGTT) was performed. On the following day subjects underwent colonoscopy. The design and details of the study have been reported previously. Screening colonoscopies were performed in subjects with average risk or with a family history of CRC in the absence of any gastrointestinal symptoms according to the recommendation of the Austrian Society of Gastroenterology and Hepatology (OEGGH) and the Austrian Cancer Aid.
From a total of 891 initially screened male subjects, 59 (6.6%) were excluded from the study because of incomplete colonoscopies (N = 15), a history of previous colorectal polypectomy (N = 27), newly diagnosed and to date asymptomatic inflammatory bowel disease (N = 3), other extra-intestinal malignancies (N = 11) or systemic autoimmune diseases (N = 3; rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis). Fifty-two (8.9%) women of 851 initially screened were excluded because of incomplete colonoscopies (N = 20), a history of previous colorectal polypectomy (N = 21), to date asymptomatic inflammatory bowel disease (N = 2), extra-intestinal malignancies (N = 3), or systemic autoimmune disease (N = 6). Thus, the study cohort consisted of 832 consecutive caucasian males (aged between 33 and 87 years) and 799 females (31–88 years), who underwent colonoscopy for CRC screening according to national screening recommendations for CRC at a single centre from October 2010 to January 2013. Any study participants regularly taking VD or VD in combination with calcium at the time of colonoscopy were defined as VD users. Most participants on VD substitution took 800 IU/day (range 400–1200 IU/day over 8.8 ± 5.3 years). Eighty women and 13 men were on current VD supplementation and these were analysed separately, hence, data from 819 males (85.9%) and 719 females (89.4%) were included in the final analysis. These were allocated to sex-specific tertiles according to serum VD concentrations obtained at the time of colonoscopy. Family history of CRC was obtained from all participants. The study was approved by the local ethics committee and informed consent was obtained from all participants.
Full blood counts were obtained in all subjects by standard laboratory methods. Erythrocyte sedimentation rate was measured in citrate plasma. Vitamin D was measured by the electrochemiluminescence-based Cobas e 411 analyser (TM) employing the respective Elecsys (TM) reagents (Roche Diagnostics GmbH, Mannheim, Germany). The laboratory performed regular quality control measurements, including a pooled serum sample analysis with batches of study samples to monitor precision and identify possible laboratory shifts over time, as well as testing duplicates in different batches. The coefficient of variation was <6% for 25(OH)D3 between-batches analyses. All analyses were conducted in a blinded fashion. A standardised OGTT was performed with 75 g of glucose in 300 mL of water. HbA1c was measured by HPLC using Adamts H-8160 (Menarini, Florence, Italy). The homoeostasis model assessment [HOMA-IR; fasting insulin (μU/L) × fasting glucose (mmol/dL)/22.5] was used to assess insulin resistance (IR). Type 2 diabetes was classified as use of diabetes medication or Hba1c ≥6.5% or OGTT >11.1 mmol/L after 2 h or fasting glucose >7.0 mmol/L.
The laxative Klean–Prep® (containing macrogol 59.0 g, sodium sulphate 5.68 g, sodium bicarbonate 1.68 g, NaCl 1.46 g and potassium chloride 0.74 g; Norgine, Marburg, Germany) was used for bowel preparation before colonoscopy. Colonoscopic findings were classified as tubular adenoma, advanced neoplasia, including polyps with villous or tubulovillous features, size ≥1 cm or high-grade dysplasia or carcinoma after a combined analysis of macroscopic and histological results. Hyperplastic polyps were not counted. Lesions were classified by location (i.e. proximal colon including caecum, ascending colon and transverse colon, distal colon ranging from the splenic flexure to the sigmoid and rectum alone).
For all analyses SigmaStat 3.1 or STATA 8.0 software packages were used. Data are presented as mean ± s.d., unless otherwise indicated. anova was used for comparison of continuous variables. The Pearson χ test was used to compare rates and proportions. The Fisher's exact test was used for cell frequencies <10. Since the results of univariate analyses showed associations only in women, a multivariate logistic regression analysis was performed in women to control for potential confounders.
In multivariate logistic regression analysis, the absence or presence of adenomas in the proximal colon was used as dependent variable and age, body mass index (BMI), seasonal variation, glucose metabolism and VD as independent variables. Seasonal variation was defined by seasonal quarters: 1, January–March; 2, April–June; 3, July–September; 4, October–December. In the regression model, seasonal quarters were coded 0, 1, 2 and 3 for the first, second, fourth and third seasonal quarter, respectively. Normal and impaired glucose metabolism including type 2 diabetes and/or impaired fasting glucose and/or impaired OGTT and was coded 0 and 1, respectively. Throughout, a two-tailed P < 0.05 was considered statistically significant.
Material and Methods
Study Concept
From all study participants, a detailed drug and medical history and a routine physical examination were obtained. Following an overnight fast, venous blood was collected and an oral glucose tolerance test (OGTT) was performed. On the following day subjects underwent colonoscopy. The design and details of the study have been reported previously. Screening colonoscopies were performed in subjects with average risk or with a family history of CRC in the absence of any gastrointestinal symptoms according to the recommendation of the Austrian Society of Gastroenterology and Hepatology (OEGGH) and the Austrian Cancer Aid.
Study Subjects
From a total of 891 initially screened male subjects, 59 (6.6%) were excluded from the study because of incomplete colonoscopies (N = 15), a history of previous colorectal polypectomy (N = 27), newly diagnosed and to date asymptomatic inflammatory bowel disease (N = 3), other extra-intestinal malignancies (N = 11) or systemic autoimmune diseases (N = 3; rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis). Fifty-two (8.9%) women of 851 initially screened were excluded because of incomplete colonoscopies (N = 20), a history of previous colorectal polypectomy (N = 21), to date asymptomatic inflammatory bowel disease (N = 2), extra-intestinal malignancies (N = 3), or systemic autoimmune disease (N = 6). Thus, the study cohort consisted of 832 consecutive caucasian males (aged between 33 and 87 years) and 799 females (31–88 years), who underwent colonoscopy for CRC screening according to national screening recommendations for CRC at a single centre from October 2010 to January 2013. Any study participants regularly taking VD or VD in combination with calcium at the time of colonoscopy were defined as VD users. Most participants on VD substitution took 800 IU/day (range 400–1200 IU/day over 8.8 ± 5.3 years). Eighty women and 13 men were on current VD supplementation and these were analysed separately, hence, data from 819 males (85.9%) and 719 females (89.4%) were included in the final analysis. These were allocated to sex-specific tertiles according to serum VD concentrations obtained at the time of colonoscopy. Family history of CRC was obtained from all participants. The study was approved by the local ethics committee and informed consent was obtained from all participants.
Laboratory Assessment
Full blood counts were obtained in all subjects by standard laboratory methods. Erythrocyte sedimentation rate was measured in citrate plasma. Vitamin D was measured by the electrochemiluminescence-based Cobas e 411 analyser (TM) employing the respective Elecsys (TM) reagents (Roche Diagnostics GmbH, Mannheim, Germany). The laboratory performed regular quality control measurements, including a pooled serum sample analysis with batches of study samples to monitor precision and identify possible laboratory shifts over time, as well as testing duplicates in different batches. The coefficient of variation was <6% for 25(OH)D3 between-batches analyses. All analyses were conducted in a blinded fashion. A standardised OGTT was performed with 75 g of glucose in 300 mL of water. HbA1c was measured by HPLC using Adamts H-8160 (Menarini, Florence, Italy). The homoeostasis model assessment [HOMA-IR; fasting insulin (μU/L) × fasting glucose (mmol/dL)/22.5] was used to assess insulin resistance (IR). Type 2 diabetes was classified as use of diabetes medication or Hba1c ≥6.5% or OGTT >11.1 mmol/L after 2 h or fasting glucose >7.0 mmol/L.
Colonoscopy
The laxative Klean–Prep® (containing macrogol 59.0 g, sodium sulphate 5.68 g, sodium bicarbonate 1.68 g, NaCl 1.46 g and potassium chloride 0.74 g; Norgine, Marburg, Germany) was used for bowel preparation before colonoscopy. Colonoscopic findings were classified as tubular adenoma, advanced neoplasia, including polyps with villous or tubulovillous features, size ≥1 cm or high-grade dysplasia or carcinoma after a combined analysis of macroscopic and histological results. Hyperplastic polyps were not counted. Lesions were classified by location (i.e. proximal colon including caecum, ascending colon and transverse colon, distal colon ranging from the splenic flexure to the sigmoid and rectum alone).
Statistical Analysis
For all analyses SigmaStat 3.1 or STATA 8.0 software packages were used. Data are presented as mean ± s.d., unless otherwise indicated. anova was used for comparison of continuous variables. The Pearson χ test was used to compare rates and proportions. The Fisher's exact test was used for cell frequencies <10. Since the results of univariate analyses showed associations only in women, a multivariate logistic regression analysis was performed in women to control for potential confounders.
In multivariate logistic regression analysis, the absence or presence of adenomas in the proximal colon was used as dependent variable and age, body mass index (BMI), seasonal variation, glucose metabolism and VD as independent variables. Seasonal variation was defined by seasonal quarters: 1, January–March; 2, April–June; 3, July–September; 4, October–December. In the regression model, seasonal quarters were coded 0, 1, 2 and 3 for the first, second, fourth and third seasonal quarter, respectively. Normal and impaired glucose metabolism including type 2 diabetes and/or impaired fasting glucose and/or impaired OGTT and was coded 0 and 1, respectively. Throughout, a two-tailed P < 0.05 was considered statistically significant.
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