Gender- and site-specific differences of colorectal neoplasia relate to vitamin D
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Gender- and site-specific differences of colorectal neoplasiarelate to vitamin DE. Aigner*,,,1, A. Stadlmayr*,1, U. Huber-Schonauer*, J. Zwerina, E. Husar-Memmer, D. Niederseer*, M. Trauner,A. Heuberger**, F. Hohla*, G. Schett, W. Patsch & C. Datz*,
*Department of Internal Medicine,Oberndorf Hospital, Teaching Hospitalof the Paracelsus Medical UniversitySalzburg, Salzburg, Austria.First Department of Medicine,Paracelsus Medical UniversitySalzburg, Salzburg, Austria.Obesity Research Unit, ParacelsusMedical University Salzburg, Salzburg,Austria.First Medical Department, LudwigBoltzmann Institute of Osteology,AUVA Trauma Center Meidling,Hanusch Hospital, Vienna, Austria.Division of Gastroenterology andHepatology, Department of MedicineIII, Medical University of Vienna,Vienna, Austria.**Department of Surgery, OberndorfHospital, Teaching Hospital of theParacelsus Medical UniversitySalzburg, Salzburg, Austria.Department of Internal Medicine III,Institute for Clinical Immunology,University of Erlangen-Nuremberg,Erlangen, Germany.Department of Pharmacology andToxicology, Paracelsus MedicalUniversity Salzburg, Salzburg, Austria.
Correspondence to:Dr C. Datz, Department of InternalMedicine, General HospitalOberndorf; Paracelsusstrasse 37,A-5110 Oberndorf, Austria.E-mail: firstname.lastname@example.orgEA and AS contributed equally tothis manuscript as first authors.Publication dataSubmitted 28 July 2014First decision 14 August 2014Resubmitted 29 August 2014Resubmitted 15 September 2014Accepted 15 September 2014EV Pub Online 2 October 2014
This article was accepted for publicationafter full peer-review.
BackgroundThe effect of vitamin D on colorectal adenomas may vary with regard togender, localisation and histological type of the lesion.
AimTo define the role of vitamin D and gender in a Caucasian cohort of sub-jects undergoing screening colonoscopy after consideration of establishedrisk factors.
MethodsOne thousand five hundred and thirty-two subjects (813 males,58.8 9.7 years; 719 females, 59.7 10.7 years) were allocated to tertiles of25-hydroxyvitamin D3 [25(OH)D3] serum concentrations. The number, locali-sation, size and histology of the detected colonic lesions were recorded.
ResultsAmong men, no association was found between vitamin D and the total num-ber, size and histological stage of adenomas at any site. In female subjects, lesswomen with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%;P = 0.035). In particular, the number of women with adenomas in the proxi-mal colon was significantly lower in the highest tertile (N = 21/239, 8.8%)compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). Therates at other sites were not different. The inverse association of vitamin Dserum concentrations with the presence of adenomas in the proximal colonwas maintained after adjustment for potential confounders. In 80 women onvitamin D supplementation, the rate of adenomas was lower compared tothose not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016).
ConclusionsA potential preventive effect of vitamin D on colorectal adenomas wasfound in the proximal colon in women. This observation is supported byfurther decrease of lesions in the proximal colon of women on vitamin Dsupplementation.
Aliment Pharmacol Ther 2014; 40: 13411348
2014 John Wiley & Sons Ltd 1341doi:10.1111/apt.12981
Alimentary Pharmacology and Therapeutics
INTRODUCTIONBesides its well-defined role in calcium and bone homo-eostasis, other nonskeletal effects of vitamin D (VD)have received increasing attention. Mostly epidemiologi-cal data suggest that lower serum VD concentrations arelinked to multiple adverse health-related outcomes suchas autoimmune disease, type 2 diabetes, cardiovasculardisease, asthma and colon cancer.1, 2
Although 1,25(OH)vitamin D3 is the active metabolitebinding to the VD nuclear receptor (VDR), determina-tion of the relatively stable precursor molecule 25(OH)vitamin D3 is commonly used to assess VD status.Higher serum concentrations of VD may decrease cancerrisk by facilitating apoptosis and differentiation and byinhibiting proliferation, invasion and neoangiogenesis.3, 4
Epidemiological studies already suggested a lower riskfor colorectal adenomas with higher sun exposure morethan 30 years ago.5 A recent meta-analysis suggested a7% risk reduction for colorectal adenoma per 10 ng/mLincrease in VD serum concentration.6 A 34% risk reduc-tion of the top vs. the lowest quintile of VD serum con-centrations was also reported.7
The chemopreventive effect of adequate VD serumconcentration may be different in men and women andalso be different at various anatomical sites of the colon,i.e. proximal colon, distal colon or rectum.8 In Japanesemen, a higher prevalence of distal colonic adenoma waslinked to low VD status.9 A reduced risk for distal ade-noma was found particularly in women with higher VDintake in a sigmoidoscopy study.10
Molecular interactions have been demonstratedbetween oestrogen and VD in the colonic epitheliumproviding a potential molecular explanation for the dif-ferences observed between men and women. In particu-lar, oestrogens may increase colonic 1-a-hydroxylase inthe colonic epithelium and thereby increasing intracellu-lar availability of the active VD metabolite. In addition,oestrogens appear to increase VD receptor levels in thecolonic epithelium.11
As these reports suggest a potentially profound effectof sex hormones on the effect of VD in carcinogenesis,we hypothesised that the associations between VD statusand colorectal polyps could differ between men andwomen in a screening cohort. We thus performed adetailed analysis of the data obtained from a Caucasiancohort undergoing screening colonoscopy. We aimed tostudy the rate, histology and localisation of the colorectallesions in men and women according to their VD statusand after consideration of confounding risk factors such
as gender, age, a family history of colorectal cancer(CRC), smoking status and impaired glucose metabolism.
MATERIAL AND METHODS
Study conceptFrom all study participants, a detailed drug and medicalhistory and a routine physical examination wereobtained. Following an overnight fast, venous blood wascollected and an oral glucose tolerance test (OGTT) wasperformed. On the following day subjects underwent col-onoscopy. The design and details of the study have beenreported previously.12 Screening colonoscopies were per-formed in subjects with average risk or with a family his-tory of CRC in the absence of any gastrointestinalsymptoms according to the recommendation of the Aus-trian Society of Gastroenterology and Hepatology(OEGGH) and the Austrian Cancer Aid.13
Study subjectsFrom a total of 891 initially screened male subjects, 59(6.6%) were excluded from the study because of incom-plete colonoscopies (N = 15), a history of previous colo-rectal polypectomy (N = 27), newly diagnosed and to dateasymptomatic inflammatory bowel disease (N = 3), otherextra-intestinal malignancies (N = 11) or systemic auto-immune diseases (N = 3; rheumatoid arthritis, systemiclupus erythematosus, autoimmune hepatitis). Fifty-two(8.9%) women of 851 initially screened were excludedbecause of incomplete colonoscopies (N = 20), a historyof previous colorectal polypectomy (N = 21), to dateasymptomatic inflammatory bowel disease (N = 2),extra-intestinal malignancies (N = 3), or systemicautoimmune disease (N = 6). Thus, the study cohort con-sisted of 832 consecutive caucasian males (aged between33 and 87 years) and 799 females (3188 years), whounderwent colonoscopy for CRC screening according tonational screening recommendations for CRC at a singlecentre from October 2010 to January 2013. Any study par-ticipants regularly taking VD or VD in combination withcalcium at the time of colonoscopy were defined as VDusers. Most participants on VD substitution took 800 IU/day (range 4001200 IU/day over 8.8 5.3 years). Eightywomen and 13 men were on current VD supplementationand these were analysed separately, hence, data from 819males (85.9%) and 719 females (89.4%) were included inthe final analysis. These were allocated to sex-specific ter-tiles according to serum VD concentrations obtained atthe time of colonoscopy. Family history of CRC was
1342 Aliment Pharmacol Ther 2014; 40: 1341-1348
2014 John Wiley & Sons Ltd
E. Aigner et al.
obtained from all participants.14 The study was approvedby the local ethics committee and informed consent wasobtained from all participants.
Laboratory assessmentFull blood counts were obtained in all subjects by standardlaboratory methods. Erythrocyte sedimentation rate wasmeasured in citrate plasma. Vitamin D was measured bythe electrochemiluminescence-based Cobas e 411 analyser(TM) employing the respective Elecsys (TM) reagents(Roche Diagnostics GmbH, Mannheim, Germany). Thelaboratory performed regular quality control measure-ments, including a pooled serum sample analysis withbatches of study samples to monitor precision and identifypossible laboratory shifts over time, as well as testingduplicates in different batches. The coefficient of variationwas 11.1 mmol/L after 2 h or fasting glucose >7.0 mmol/L.
ColonoscopyThe laxative KleanPrep (containing macrogol 59.0 g,sodium sulphate 5.68 g, sodium bicarbonate 1.68 g, NaCl1.46 g and potassium chloride 0.74 g; Norgine, Marburg,Germany) was used for bowel preparation before colo-noscopy. Colonoscopic findings were classified as tubularadenoma, advanced neoplasia, including polyps with vil-lous or tubulovillous features, size 1 cm or high-gradedysplasia or carcinoma after a combined analysis of mac-roscopic and histological results.15 Hyperplastic polypswere not counted.16 Lesions were classified by location(i.e. proximal colon including caecum, ascending colonand transverse colon, distal colon ranging from the sple-nic flexure to the sigmoid and rectum alone).
Statistical analysisFor all analyses SigmaStat 3.1 or STATA 8.0 softwarepackages were used. Data are presented as mean s.d.,unless otherwise indicated. ANOVA was used for compari-son of continuous variables. The Pearson v2 test was usedto compare rates and proportions. The Fishers exact testwas used for cell frequencies
diabetes. Therefore, all results presented are from calcu-lations including the subjects with diabetes in men andwomen. Likewise, fourteen women were on hormonereplacement therapy (HRT) and the results of calcula-tions were not different when these were excluded. VDserum concentrations were significantly higher in menthan in women (Table 1). There was a significant sea-sonal variation of VD concentrations in men and womenand gender differences were maintained through all sea-sons. The lowest concentrations were measured in thefirst quarter, followed by the second, fourth and thirdquarter (P < 0.001 in men and women). Data on sea-sonal variation are summarised in Figure S1.
Prevalence, localisation and histology of colorectalneoplasias in men and womenMen and women were equally apportioned to tertiles ofVD serum concentrations and the rate of adenomas ateach colonic site, histology and size were recorded. Therate of adenomas in men was significantly higher com-pared to the rate in women (P < 0.001). The differencebetween men and women was significant in all sub-categories presented except for advanced adenomas andcancers (details not shown). In men, no differences werefound in the total number, histological results or numberof adenomas at any colonic site among the three VDcategories. However, in women the total number ofneoplastic lesions was inversely correlated with VD serumconcentrations. When investigating the localisation ofadenomas, we found that this reduction was mainly dueto a significant reduction in the rate of adenomas in theproximal colon whereas the rate of adenomas in the distalcolon or the rectum was not different among the VD ter-tiles in females. Additionally, both carcinomas weredetected in the proximal colon of women of the lowestVD tertile. The detailed summary of these analyses isgiven in Table 2. There was no association of adenomasize with VD concentrations in either men or women(data not shown). In total, 199 of 1631 subjects (12.2%)had a positive family history for CRC. Of note, a positivefamily history was not associated with colorectal polypsat any location or the total number of polyps in ourcohort in neither men nor women or in both combined.Hence, family history did not meet the criteria to beincluded as a parameter in the regression models.
We then analysed colonic lesions in females in furtherdetail. In the proximal colon (120 lesions), we found 31(25.8%) flat, 4 (3.3%) pedunculated, 83 (69.2%) sessilelesions and 2 (1.7%) carcinomas; in the distal colon (78lesions), there were 9 (11.5%) flat, 11 (14.1%) pedunculated,
58 (74.4%) sessile lesions; in the rectum (19 lesions), thecorresponding figures were 1 (5.3%), 4 (21.0%) and 14(73.7%). Thus, a higher number of flat adenomas was foundin the proximal colon (P = 0.015) compared to the distalcolon. Fifteen flat adenomas were found in the lowest tertilecompared to 6 in the highest (P = 0.043). Three subjectshad 2 flat lesions in the proximal colon in the low VDgroup and one in the highest tertile; only one subject had 2flat lesions in the distal colon and none in the rectum. Thesedifferences were not significant.
Prevalence of colorectal adenomas in subjects oncurrent VD supplementationNinety-three subjects (13 males and 80 females) with cur-rent VD supplementation were identified. These subjectshad higher VD serum concentrations compared to non-u-sers of VD supplementation (Table 3). Due to the smallnumber of men on supplementation all analyses wereunderpowered and the results are not reported. Amongwomen, the difference between users and non-users of VDsupplementation was not statistically significant withregard to the number of subjects with adenomas, the totalnumber of lesions, size or morphological subtypes. How-ever, in the proximal colon 3 (3.75%) of women on sup-plementation had adenomas compared to 90 (12.5%) noton supplementation (P = 0.016; Fishers test). Likewise,the numbers of subjects with 1 (N = 2/80 vs. 70/719) and2 or more adenomas (N = 1/80 vs. 20/719) also werelower in users (P = 047; Fishers test). No significant dif-ferences were detected in the distal colon or rectum.
Multivariate logistic regression analysisUnivariate correlation analysis was performed to identifypotential confounders for the association of VD with prox-imal colon adenomas in women. All variables with a sig-nificance level P < 0.05 were considered and afterchecking for plausibility the following variables wereselected for a multivariate logistic regression analysis: age,seasonal variation, BMI, glucose metabolism. VD serumconcentrations remained independently associated withthe absence/presence of proximal colon adenomas in themultivariate regression model (Table 4...