Are Patients With A Vitamin-D Deficiency More Susceptible To Developing Ulcerative Colitis? — Research Paper

Are patients with a vitamin D deficiency more susceptible to developing ulcerative colitis? Inflammatory bowel disease, Crohn’s disease, and ulcerative colitis are autoimmune inflammatory diseases of the digestive tract that seem to be caused by the interaction of environmental factors, genetic factors, and diet and nutritional factors such as vitamin D (Mukhopadhya, Hansen, El-Omar, & Hold, 2012). Vitamin D provides a role in calcium and phosphate homeostasis and has been linked to autoimmune diseases such as multiple sclerosis and diabetes mellitus as well (Holick, 2004). Humans receive vitamin D by dermal synthesis of sunlight ultraviolet B radiation or from an intake of foods or supplements. However, only a small percentage of vitamin D intakes are supplied from food and thus, very large portions of leafy greens would need to be eaten in order to fulfill daily vitamin D requirements and a majority of adults are also lactose intolerant (Nowson, Diamond, Pasco, Mason, Sambrook, & Eisman, 2004).

Ulcerative colitis is a chronic inflammatory bowel disease that causes inflammation, irritation, swelling, and ulcers in the digestive tract (Loftus, 2004). It affects the innermost lining of the large intestine (colon) and rectum and symptoms usually begin gradually and worsens over time. The most common signs and symptoms of ulcerative colitis are abdominal discomfort and diarrhea with blood or pus. Other signs and symptoms are weight loss, feeling tired, nausea or loss of appetite, an urgent need to defecate, fever, and anemia (Kornbluth & Sachar, 2010). Less common symptoms include eye irritation, joint pain or soreness, and certain rashes. Most people with ulcerative colitis have mild to moderate symptoms and about 10 percent of people have severe symptoms, such as frequent, bloody bowel movements, severe abdominal cramping, and fevers (Shanahan, 2012).

Physicians classify ulcerative colitis based on its location in the body. There are different types of ulcerative colitis; ulcerative proctitis, left-sided colitis, pancolitis, proctosigmoiditis, and acute severe ulcerative colitis (Kornbluth & Sachar, 2010). Ulcerative proctitis is when the inflammation is confined to the area closest to the rectum. Left-sided colitis occurs when the inflammation extends from the anus up through the sigmoid and descending colon. Pancolitis affects the entire colon that causes bouts of bloody diarrhea. Proctosigmoiditis involves inflammation in the rectum and sigmoid colon. Acute severe ulcerative colitis is a rare form of colitis that affects the entire colon and causes severe pain and abundant diarrhea (Shanahan, 2012). A health care provider can diagnose ulcerative colitis through medical and family history, lab tests, physical exams, endoscopies of the large intestine, and perform more medical tests to rule out other bowel disorders that may cause similar symptoms to those of ulcerative colitis, such as Crohn’s disease, irritable bowel syndrome, and celiac disease (Kornbluth & Sachar, 2010).

The incidence of ulcerative colitis worldwide has increased over the years. These incidences has decreased in developed countries, such as Western Europe and North America (Molinié, Gower-Rousseau, Yzet, Merle, Grandbastien, Marti, Lerebours, Dupas, Colombel, & Salomez, 2004), and has increased in developing countries, such as Asia, Latin America, and Eastern Europe (Appleyard, Hernández, & Rios-Bedoya, 2004). There are differences in ulcerative colitis incidence and prevalence in different regions of the world and depending on the studied population, the incidence rate can vary from 0.5–31.5 per 100,000 people each year (Burisch & Munkholm, 2013). Prevalence of ulcerative colitis is lower in developing countries. For example, in Asian populations, the prevalence ranges from 5.3–63.6 per 100,000 people (Asakura, Nishiwaki, Inoue, Hibi, Watanabe, & Takebayashi, 2009), but in North America, it ranges from 37.5–238 per 100,000 people (Cosnes, Gower-Rousseau, Seksik, & Cortot, 2011).

Previous studies have shown that the mortality rates of patients with ulcerative colitis was higher in the first half of the 20th century. Despite the ongoing increase in incidence in the mid-1950s, there was a drop in the number of deaths due to the use of sulfasalazine, corticosteriods, and the advancement of surgical procedures (Evans, 1971), but in the 1980s, the mortality rates were higher than the general population (Gyde, Prior, Dew, Saunders, Waterhouse, & Allan, 1982). Overall, people with ulcerative colitis possessed similar rates of mortality to or slightly higher than the rate in the general population that might have been the consequence of increased immunosuppressive therapy usage (Jess, Gamborg, Munkholm, & Sørensen, 2007).

The majority of patients with ulcerative colitis are within the age of 30–40 years old at diagnosis (Cosnes, Gower-Rousseau, Seksik, & Cortot, 2011) and is slightly higher in Asian countries compared to Western countries (Prideaux, Kamm, De Cruz, Chan, & Ng, 2012). A research study by Souza et al in southeastern Brazil revealed that there was a second incidence peak in an older age group of 60–69 years old according to hospital admissions due to ulcerative colitis (Souza, Troncon, Rodrigues, Viana, Onofre, Monteiro, Passos, Martinelli, & Meneghelli, 2002). Recent studies also shows that that the number of pediatric and adolescent patients with ulcerative colitis have increased. For example, in Scottland, there was an increased incidence of ulcerative colitis in patients under 16 years old. A publication by Pant et al demonstrated that between 2000 and 2009 in the United States, the number of pediatric patients hospitalized with ulcerative colitis increased from 4,171 to 7,127 per year (Pant, Anderson, Deshpande, Grunow, O’Connor, Philpott, & Sferra, 2013).

Ulcerative colitis is slightly more common in males (Cosnes, Gower-Rousseau, Seksik, & Cortot, 2011) and the exact causes of the disease are unknown, but some speculations have been made from the environmental, socioeconomic, and genetic factors (Loftus, 2004). For example, studies has shown that ulcerative colitis is more common among nonsmokers and people who have quit smoking (Loftus, 2004), more prevalent in white-collar occupations (Sonnenberg, 1989), and less common in groups with higher income and education (Bernstein, Kraut, Blanchard, Rawsthorne, Yu, & Walld, 2001). Another possible cause is when the immune system tries to fight off a bacterium or virus, which leads to the immune system attacking the cells in the digestive tract (Wallace, Zheng, Kanazawa, & Shih, 2014). Ulcerative colitis is more common in individuals who have family members with the disease, although people who have ulcerative colitis usually do not have a family history of it. It is also more likely to develop in people of the Jewish descent (Peeters, Cortot, Vermeire, & Colombel, 2000).

Complications of ulcerative colitis are rectal bleeding, changes in bone composition, dehydration and malabsorbtion, megacolon, and inflammation in the joints, skin, eyes, and liver (Loftus, 2004). Individuals with the disease are also more likely to develop colon cancer if it affects the entire colon, the inflammation is consistent, they had it for 8 years, they are male, or they have primary sclerosing cholangitis (Kornbluth & Sachar, 2010). This condition is relevant to public health because it is affecting a lot of people in specific areas and populations and objectives need to be created with the provided information about ulcerative colitis in order to maintain the future health of the public. Physicians could recommend patients with ulcerative colitis to continue receiving treatment in order to remain in remission, how often they should get screened for colon cancer because an early cancer diagnosis can improve the chances for survival and recovery, and if surgery to remove the entire colon would be the best option (Kornbluth & Sachar, 2010).

Nutrition, diet, and eating are not known to cause ulcerative colitis, but good nutrition can manage the disease and dietary changes can reduce symptoms (Prince, Whelan, Moosa, Lomer, & Reidlinger, 2011). Physicians could start recommending not only patients with ulcerative colitis, but also healthy patients to drink more fluids, avoid carbonated beverages, eat smaller meals more often, avoid foods that are high in fiber, and keep a food diary. Vitamins, supplements, and specific diets could also be recommended to individuals who are malnourished (Lucendo & De Rezende, 2009). Examples of these diets are, high-calorie diets, low-fat diets, low-fiber diets, lactose-free diets, and low-salt diets depending on the physiological severity and symptoms of a patient (Yamamoto, Nakahigashi, & Saniabadi, 2009). In general, healthy adjustments in life should significantly improve the health of the public and decrease the susceptibility of diseases.

“Vitamin D Status and Its Relation to Inflammatory Markers in Patients with Mild to Moderate Ulcerative Colitis” by Amrollah Sharifi, Saharnaz Nedjat, Homayoon Vahedi, Gholamreza Veghari, and Mohammad Javad Hosseinzadeh-Attar explores vitamin D status and its associations with erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hs-CRP) as inflammatory markers in patients with ulcerative colitis. A recent meta-analysis revealed that patients with inflammatory bowel disease had higher odds of vitamin D deficiency than healthy patients (Del Pinto, Pietropaoli, Chandar, Ferri, & Cominelli, 2015). Most organs including the immune cells, and small and large intestine have vitamin D receptors (Alpert & Shaikh, 2007). Mucosal vitamin D receptors is lower in patients with ulcerative colitis compared to healthy patients (Wada, Tanaka, Maeda, Inoue, Noda, & Amano, 2009). In addition, the intestine of vitamin D receptors knock-out murine is affected by spontaneous inflammation, which might support the hypothesis that vitamin D deficiency is related to inflammatory bowel disease (Yu, Bruce, Froicu, Weaver, & Cantorna, 2008).

The study was a cross-sectional design that recruited 129 Tehran inhabitants with ulcerative colitis who were referred to the Digestive Disease Research Center of Shariati Hospital in Tehran and their disease status were mild to moderate. They were aged between 18–50 years old and their body mass indexes were between 18.5–30 Kg/m2. Patients with current infections, involved in anti-Tumor necrosis factor–alpha therapy, taking any form of vitamin D3 supplement in the 3 months preceding the study, has a history of hyperparathyroidism, nephrolithiasis, malignancy, and renal or hepatic failure, and women who are pregnant and breast feeding were excluded. Out of the remaining patients, 39 declined to participate and finally, 90 patients with ulcerative colitis were assessed. The choice of using a cross-sectional design has its advantages and disadvantages. Advantages include data that is collected only once at a certain point in time, ability to measure prevalence for all factors under investigation, examination of multiple outcomes and exposures, descriptive analyses, and quick and easy conducts. Disadvantages include difficulty in determining whether the outcome followed exposure or exposure followed outcome, inability to measure incidence, associations that are difficult to interpret, and susceptibility to bias due to low response rates and misclassification due to recall bias. Therefore, I think that an ethical quasi-experimental design would be more appropriate because it can increase the external validity of the experiment for a disease that is known to affect a variety of populations.

Blood sample were taken in plain tubes and separated by centrifuging at 2500 rpm for 10 minutes after 30 minutes of incubation at 37°C, and stored at -80°C. Levels of 25-OH-vitamin D3 were determined by using the commercial ELISA kit (Calbiotech, CA, USA; Intra-assay variation < 6% and CV < 8%). Serum high-sensitivity C-reactive protein levels were also measured using ELISA kit (Monobind, CA, USA) and parathyroid hormone serum levels were assessed using ELISA kit (Euroimmun, Luebeck, Germany). Erythrocyte sedimentation rates were measured by the erythrocyte sedimentation rate tube and the demographic data were collected by personal interviews with the use of a short questionnaire. Statistical analyses were performed using STATA V (Yu, Bruce, Froicu, Weaver, & Cantorna, 2008) software and the results are expressed as a mean ± standard deviation or percentage. Pearson’s correlation coefficient (r) was also disclosed to examine the relationship between variables. I believe that this is most effective in determining the strength in a linear relationship between two variables in the experiment, which can be alternated between vitamin D status and erythrocyte sedimentation rate, and vitamin D and high-sensitivity C-reactive protein to observe if there is any correlation. The coefficient of determination (r²) can be measured afterwards to determine the portion of variability in one of two the variables in the correlation that can be accounted for by the variability in the second variable and then compared to the correlation coefficient for a clearer picture. As a result, with the average amount of serum 25-OH-vitamin D3 being 33.1 ± 8.3 ng/mL, 38.9% of the patients were vitamin D deficient because their serum 25-OH-vitamin D3 were below 30 ng/mL. 41% of women and 37.3% of men were vitamin D deficient or insufficient. Correlations between serum 25-OH-vitamin D3 and hs-CRP, ESR, BMI, and disease duration were not found. There was also no significant differences between women and men either in serum 25-OH-vitamin D3 or in dietary vitamin D intake.

The hypothesis of relation between inflammatory bowel disease and vitamin D deficiency arised from previous studies that revealed individuals living in southern areas having a lower risk of inflammatory bowel disease than those living in northern parts with low sunlight exposure due to geographical variation in vitamin D status caused by different exposure to ultraviolet B radiation (Khalili, Huang, Ananthakrishnan, Higuchi, Richter, and Fuchs, 2012; Nerich, Monnet, Weill, Vallier, Vanbockstael, & Auleley, 2010). Although the correlations in this study between serum 25-OH-vitamin D3 and erythrocyte sedimentation rate, high-sensitivity C-reactive protein, BMI, and disease duration were non-significant and weak, a recent randomized control trial showed that higher doses of vitamin D may have a beneficial effect on inflammation in patients with ulcerative colitis (Sharifi, Hosseinzadeh-Attar, Vahedi, & Nedjat, 2016), which supports that the immunological effects of vitamin D might be achieved at higher serum levels (Hewison, 2012; Spedding, 2014).

There were three limitations to this study; no control group was used to obtain the odds ratio for vitamin D deficiency in the patients, out of the 129 patients, 39 (30%) decided not to participate, and only patients with mild to moderate ulcerative colitis aged between 18–50 years old with a BMI between 18.5–30 kg/m2 were analyzed. Without a control group, the group being experimented on will not have anything to be compared to, which will make it difficult for researchers to pinpoint the exact cause and effect of ulcerative colitis. In addition, the 90 recruited patients were not representative of the population because they had to meet specific criteria to be considered eligible for the study and therefore, will have a low external validity. I believe that the authors work should be rejected because even if it were replicated, different and inconclusive results would occur with the constant change of serum levels used. More studies are needed to investigate the effect of vitamin D in the development of ulcerative colitis or as a part of its treatment.

“The effect of two vitamin D regimens on ulcerative colitis activity index, quality of life and oxidant/anti-oxidant status” by Sara Karimi, Sanam Tabataba-vakili, Zahra Yari, Forough Alborzi, Mehdi Hedayati, Nasser Ebrahimi-Daryani, and Azita Hekmatdoost explores the effects of two vitamin D routines in ulcerative colitis patients with a vitamin D deficiency. A few studies have been performed to evaluate the effectiveness of vitamin D in patients with inflammatory bowel disease and the possible link between vitamin D deficiency and disease activity, mortality and severity of the disease, and its early onset and risk of recurrence (Del Pinto, 2015), but the optimum supplementation dosage has not been found yet. This study was a double blind randomized clinical trial that included patients with mild to moderate ulcerative colitis (Samsami-kor, 2015). 65 out of 77 patients with ulcerative were interviewed and 50 patients remained to take part in the experiment.

The participants were randomly divided into two groups (25 in the high dose group and 25 in the low dose group) to receive either a high-dose or a low-dose vitamin D supplement for the duration of 12 weeks (Pappa, 2012). Participants in high dose group received 2 capsules of 1000 IU vitamin D daily and those in the low dose group were given 1 capsule of 1000 IU of vitamin D supplements and 1 capsule of placebo daily, which appeared to look exactly alike. They were also informed not to change their diet and physical activity during the study period. There was a total of 46 patients left at the end of the study; 24 patients in the high dose group and the 22 patients in the low dose group because 4 patients did not follow up.

To be included into the study, participants must have a medical diagnosis of mild to moderate, vitamin D deficiency (< 30 ng/mL), the absence of other diseases, intestinal disorders, cancer, autoimmune diseases, inflammatory and infectious diseases, not using vitamin D supplements, omega-3, mineral-multivitamins, polyphenolic and antioxidant medications, and anticoagulants such as Warfarin and Heparin, non-steroid anti-inflammatory drugs such as Aspirin, Ibuprofen and Diclofenac, Antihistamines and calcium channel antagonists such as Nifedipine during the past month, above 18 years old, and experienced no changes in the type and dosage of their medicine over the past month. The study excluded participants who are pregnant or breastfeeding, women using contraceptives, individuals who are unwilling to continue, and people who have experienced changes in the type and dosage of the drug during the study. The inflammatory bowel disease questionnaire-9 (IBDQ-9) (Casellas, 2004) and the Simple Clinical Colitis Activity Index Questionnaire (SCCAIQ) would be completed before and after the study (Samsami-kor, 2015) in order to measure the quality of life affected by inflammatory bowel disease. It contains nine questions that assesses the condition from the four categories of gastrointestinal, social, systemic, emotional disturbances. Each question has seven choices that range from 1 (the worst) to 7 (the best). Higher scores represent a better quality of life in patients.

As a result, serum 25-OHD level showed minimal differences between the two groups at the beginning and the end of study. Serum 25-OHD significantly increased in the high dose group, but did not increase in the low dose group. Eventhough the mean score of IBDQ-9 after vitamin D supplementation increased in both groups compared to the baseline value, the IBDQ-9 mean score showed a higher increase in the high dose group compared to the low dose group. The SCCAI score in both high dose and low dose groups was reduced at the end of the study compared to the beginning of the study, but the SCCAI showed a higher decrease in the high dose group compared to the low dose group. This means that both doses of vitamin D improved patients’ quality of life; however, the level of disease activity only reduced by a daily dose of 2000 IU.

In a South African cohort study on Crohn’s disease, a relationship was found between low levels of vitamin D and increased activity of the disease (Raffner Basson, 2016). Two other studies have shown that low levels of vitamin D are common in patients with inflammatory bowel disease and is associated with mortality, severity of the disease, and the early onset of it, which could indicate the value of the role in this vitamin in the improvement of these patients (Ananthakrishnan, 2016). Another study showed that serum vitamin D levels of 35 ng/mL or less during a treatment period could increase the risk of ulcerative colitis recurrence (Gubatan, 2017). Sufficient Vitamin D in the body can reduce inflammation, promote immune tolerance, and increase the quality of the intestinal microbiome (Suaini, 2015), so it may play a vital role in the development of inflammatory bowel disease and is also considered a treatment factor for inflammatory bowel disease (Pappa, 2012).

One limitation of the study was the lack of a healthy control group to compare the results with the ulcerative colitis patients groups and overall, the study revealed that vitamin D supplementation of 2000 IU per day for 12 weeks could lead to an increase in serum 25-OHD levels, improvement of quality of life, and decrease in the disease activity in adult patients with active mild to moderate ulcerative colitis. Vitamin D supplementation of 1000 IU per day for 12 weeks only improved the quality of life of patients. But, do these studies indicate that patients with a vitamin D deficiency are more susceptable to the development of ulcerative colitis? No. But because it was evident that some participants with ulcerative colitis either had a vitamin D deficiency or had an improved quality of life and decrease in disease activity with a higher vitamin D dosage, lower vitamin D status might be associated with a higher risk for ulcerative colitis since vitamin D deficiency is known to worsen the disease.

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