Original Article

Volume 16, Number 10, October 2024, pages 483-490

Assessing the Impact of Serum Calcium, 25-Hydroxy Vitamin D, Ferritin, and Uric Acid Levels on Colorectal Cancer Risk

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, ranking as the third most frequent cancer in males and the second most frequent cancer in females [1]. In the year 2020 alone, there were over 1.9 million new cases of CRC reported. However, the morbidity and mortality of CRC vary significantly from country to country [1-3]. While the highest incidence rates of CRC are found in the wealthiest developed countries, the lowest rates are observed in some of the poorest developing nations. This geographical diversity is primarily linked to differences in nutrition, lifestyle, genetics, and environmental factors [3-7]. Specifically identified diet risk factors for CRC include the consumption of red meat, processed meat, high-fat diets, and alcohol intake [2, 3]. Conversely, diets rich in plant-based fiber, as well as the consumption of whole grains or dairy products, have been shown to provide protection against CRC development [2-4], Nonetheless, in developing countries, CRC rates are rapidly increasing, potentially attributed to the adoption of Western lifestyles by these societies [5-7]. An increase in the incidence of early-onset CRC, defined as CRC diagnosed before the age of 50, has been globally confirmed within the past 50 years [1-8].

It is known that vitamin D and calcium reduce CRC incidence by influencing cell proliferation, differentiation, and apoptosis [8-14]. Studies have reported that higher serum levels of vitamin D may reduce the risk of CRC, and findings also suggest that calcium intake plays a beneficial role in reducing the incidence of CRC [11-13]. However, there are few intervention studies defining the relationship between vitamin D, calcium, and CRC [11-15].

Previous reviews on colon cancer have focused on specific risk factors such as lifestyle [7, 16-21], iron [16], obesity [17], physical inactivity [18], dietary fiber intake [22-24], red meat consumption [25, 26], and hereditary CRC [5, 19]. Currently, there are no prospective studies that have explored the impact of vitamin D, calcium, ferritin, and uric acid on the formation of CRC [27, 28]. Nevertheless, the clinical evidence regarding the preventive role of vitamin D, calcium, ferritin, and uric acid supplementation in CRC remains uncertain [10-14]. The aim of this study is to investigate whether vitamin D, calcium, ferritin, and uric acids play a beneficial biomarker role in the prevention of CRC risk.

A cross-sectional investigation was carried out involving participants aged 35 to 70 years who sought medical care at the Oncology and Gastrointestinal Clinics, as well as Out-Patient Clinics, at the Istanbul Medipol University Hospital. The study adhered to the principles outlined in the Declaration of Helsinki (1964) and obtained ethical clearance and approval from the Ethics Committee (RP# and IRB# E-10840098-772.02-2645).

The determination of the sample size was based on the anticipated proportion in controls (P = 0.01), assumed odds ratio (OR = 4), confidence interval (CI = 0.99), and power = 0.80. Consequently, the final sample comprised 650 subjects with CRC compared to 650 controls (without CRC), encompassing both males and females aged 35 - 70 years.

The study encompassed diverse demographic factors, including age, gender, body mass index (BMI), smoking and alcohol habits, physical activity, intestinal inflammations, abdominal pain and cramps, diarrhea, constipation, irritable bowel, blood in the stool, and pre-existing health conditions. Patient evaluation was conducted through magnetic resonance angiography (MRA), magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and colonoscopy.

Biochemical parameters measured in the study included hemoglobin, serum ferritin, magnesium, potassium, phosphorous, creatinine, fasting glucose levels, glycated hemoglobin (HbA1c), high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol, albumin, triglyceride, uric acid, bilirubin, triglyceride, systolic and diastolic blood pressure (SBP and DBP). The serum levels of vitamin D in the participants were measured using competitive radioimmunoassay (RIA) with the 25-hydroxy vitamin D test, which was conducted using DiaSorin method as described in previous studies [9, 10, 15].

Student’s t-test was used to ascertain the significance of differences between mean values of two continuous variables. Chi-square analysis was performed to test for differences in proportions of categorical variables between two or more groups. OR and 95% CI were calculated by using Mantel-Haenszel test. The stepwise logistic regression analysis was performed to find out the best predictors for diagnosis of malignancy as dependent variable. The level P < 0.05 was considered as the cut-off value for significance.

There were statistically significant differences between CRC and control groups in terms of age, diagnostic radiology, tomography, PET/CT, colonoscopy, CRC awareness, risk factors, age, genetics, exposure to chemicals, inadequate nutrition, smoking, hookah/nargile, and alcohol use, intestinal inflammations, obesity, and processed foods (P < 0.001). Demographic and clinical characteristics comparisons of risk factors between CRC and control subjects are presented in Table 1.

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Table 1. Sociodemographic and Lifestyle Habits by CRC and Control (N = 1,300)

Table 2 presents statistically significant differences in the comparison of functional gastrointestinal disorders (FGID) symptoms between CRC and control groups: abdominal pain, abdominal cramps, diarrhea, constipation, blood in stool, bloating (gas), irritable bowel, nausea/vomiting, anemia, stress, feeling of fatigue, weakness, and weight loss (P < 0.001).

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Table 2. Comparison of CRC Developing Functional Gastrointestinal Symptoms With Controls (N = 1,300)

When compared with control subjects, CRC subjects showed a significant decrease in hemoglobin, vitamin D, red blood cell (RBC), white blood cell (WBC), lymphocyte, platelet levels, hematocrit, potassium, sodium (Na), creatinine, cholesterol, HDL, LDL, bilirubin, iron (Fe), ferritin, C-reactive protein (CRP) levels, while HbA1c, fasting blood glucose (FBG), neutrophil level, platelet, calcium, triglyceride, uric acid, total protein, SBP, and DBP increased significantly. Statistical analysis revealed a correlation of r = 0.278 and P < 0.001 between carcinoembryonic antigen (CEA) and 6-month follow-up. Comparisons of clinical biochemistry parameters between CRC and control subjects are presented in Table 3.

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Table 3. Clinical Biochemistry Baseline Value Among CRC and Control Subjects (N = 1,300)

Multivariate stepwise regression analysis was conducted to identify the best risk factors for patients diagnosed with CRC as the dependent variable. In the analysis, intestinal inflammation (P < 0.001), nausea/vomiting (P < 0.001), stomach pain (P ≤ 0.003), hookah/nargile use (P = 0.034), uric acid (P < 0.001), bilirubin (P < 0.001), cigarette smoke (P = 0.033), processed foods (P = 0.002), calcium (P = 0.029), vitamin D deficiency (P < 0.001), and ferritin (P < 0.001) were identified as significant determinants for CRC. Risk factors in CRC subjects are provided in Table 4.

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Table 4. The Predictor Risk of CRC Using Multivariate Stepwise Regression Analysis (N = 1,300)

CRC is one of the most prevalent cancers worldwide. In numerous evidence-based studies, dietary patterns, dairy and dairy products, meat, vegetables, milk, cheese, smoking and e-cigarettes, hookah/nargile, BMI, obesity, alcohol consumption, physical activity and exercise, and sedentary lifestyle have been well established as risk factors for CRC [5-9]. This is the first prospective case-control study investigating the relationship between CRC and levels of vitamin D, calcium, ferritin, and uric acids. These clinical biochemistry parameters may play a useful marker role in reducing the risk of CRC for participant patients. Therefore, in addition to these modifiable risk factors, the clinical observation and statistical evaluation of biochemical parameters are crucial in preventing CRC risk. Most recently study reported that healthy lifestyle was strongly inversely associated with CRC risk [7]. This is consistent and confirmative with our current reported study.

While identifiable hereditary factors are found in approximately 20% of CRC diagnoses, specific germline mutations characterize about 5% of all colon cancer cases [29, 30]. The estimated incidence of Lynch syndrome, the most common hereditary syndrome, is 5-7% of all CRC cases [5, 7, 21, 29]. The current study revealed that genetic risk is statistically associated with CRC at 1.55 (1.39 - 1.73), P > 0.001 (Table 1).

There is evidence supporting the relationship between lifestyle factors such as diet, smoking, alcohol consumption, obesity, and exercise with CRC [7, 18, 19]. Various studies have shown that smoking is significantly associated with CRC incidence and mortality in individuals, and it also increases the risk of CRC development [20-26]. Smoking, hookah use, and alcohol consumption are risk factors for CRC [31-33]. Smoking increases CRC risk in a dose-dependent manner with intensity and duration, and quitting smoking reduces CRC risk [31, 32]. In our study, CRC risk linearly increased with smoking intensity and duration. Physical activity reduces CRC risk [34], but the available evidence is primarily derived from self-reported recreational and occupational activity, with less known about the contribution of other areas of physical activity, such as transportation and home-related activities. Engaging in 1 h of exercise per week was associated with a lower prevalence of CRC [34].

Iron deficiency anemia is the most common symptom in CRC patients. While malignancy leads to functional iron deficiency, chronic blood loss can cause absolute iron deficiency and depletion of iron stores [35, 36]. In our study, hematocrit, RBC, WBC, and hemoglobin levels were significantly decreased in CRC patients. The decrease in Fe and ferritin levels in the CRC group indicates a significant reduction in hematopoiesis. Additionally, bilirubin, a byproduct of hemoglobin breakdown and an endogenous antioxidant believed to have cancer-preventive properties, was found to be significantly decreased in the CRC group in our study (Table 3).

Evaluation and treatment of biochemical parameters are of great importance in patients with CRC. Studies have reported a higher risk of CRC associated with lower HDL and higher triglycerides (TG, dyslipidemia markers) levels [6]. In our study, cholesterol, HDL, and LDL levels were significantly decreased in CRC patients. Considering that vitamin D synthesis occurs through cholesterol, our study revealed a significant decrease in vitamin D levels in the CRC group compared to the control group alongside the decreased cholesterol levels (Table 3).

Increased levels of FBG, along with increased HbA1c, have been previously reported as a risk factor in CRC patients [37]. Increased FBG not only directly affects the cardiovascular system but also affects the gastrointestinal system by causing epithelial dysfunction. An increase in platelet levels, which are procoagulant markers, accompanies increased neutrophil levels in tissues [38]. Our study supports this hypothesis, as we observed an increase in HbA1c, FBG, neutrophil levels, platelet levels, and calcium levels in CRC patients (Table 3).

Furthermore, the increase in calcium levels in CRC patients in our study may be a consequence of the decrease in vitamin D levels. Serum uric acid may play a significant role in the emergence of CRC in both men and women [27]. In a recent large-scale cohort study [28], authors found a positive relationship between serum uric acid and the risk of CRC occurrence, especially in men, in young and middle-aged individuals (≤ 65 years), and in normal individuals. Although the results vary among compiled studies, the outcomes of the meta-analysis suggest that, as in our study, elevated serum uric acid may be associated with an increased risk of CRC in the adult population [28].

Serum vitamin D levels in CRC patients indicate disruptions in steroid and lipid metabolism. The increase in LDL, platelet, and HbA1c levels, along with the accompanying rise in SBP and DBP, signifies the presence of epithelial tissue damage, as seen in cardiovascular diseases. Furthermore, the decrease in ferritin and uric acid levels, described as endogenous antioxidants in CRC patients, suggests that nutritional habits and environmental factors, including smoking, hookah (nargile) use, and alcohol consumption, are crucial contributors to damage at the core (Table 4).

The current study has several limitations. Firstly, the design of current study is not ideal matched case and control study. The results could not establish a causal relationship between vitamin D, calcium, uric acids, and CRC because of its observational nature. Second, the present study could not evaluate the effect of biochemistry lab parameters alterations on tumors over time, as they were measured only twice. Third, the study may not reach to the target patients in population as a bias, which is very hard to avoid. Fourth, the clinical assessment and test performed for the CRC might be misclassified; therefore, the results should be interpreted with great caution, even though they are based on a large sample size.

The current study revealed that vitamin D, calcium, ferritin and uric acids play a useful role as markers in reducing the risk of CRC in patients. The rising rates of CRC can be attributed to lifestyle, cigarette smoking, nargileh use, alcohol consumption, as well as dietary, environmental, and hereditary factors.

Acknowledgments

The authors would like to acknowledge the ethical approval and support provided by Istanbul Medipol University, specifically the Medipol International School of Medicine (RP# and IRB# E-10840098-772.02-2645).

Financial Disclosure

The authors declared that the present study has received no financial support.

Conflict of Interest

The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Informed Consent

All data published here are under the consent for publication. Written informed consent was obtained from all individual participants included in the study.

Author Contributions

Study design and conceptualization: AB, AEO, UVU, AFA, CCB. Data curation and supervision: AB, AEO, AFA. Project administration: AB, AEO, AFA, CCB. Formal analysis and validation: AB, AEO, UVU, ASD. Writing - original draft review and editing: AB, AEO, UVU, AFA, ASD. Approval of final manuscript: AB, AEO, UVU, CCB, ASD.

Data Availability

The authors declare that data supporting the findings of this study are available within the article. The data sets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Abbreviations

CRC: colorectal cancer; OR: odds ratio; CI: confidence interval; BMI: body mass index; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; PET/CT: positron emission tomography/computed tomography; HbA1c: glycated hemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein; RIA: radioimmunoassay; FGID: functional gastrointestinal disorder; RBC: red blood cell; WBC: white blood cell; CRP: C-reactive protein; FBG: fasting blood glucose; SBP: systolic blood pressure; DBP: diastolic blood pressure; Ca: calcium; Na: sodium; Fe: iron

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