Faculty Peer Reviewed
Case: A 45-year-old woman presents to your office for an annual check-up. She states that her grandmother was recently diagnosed with colon cancer at the age of 90, and she wants to know what she can do to reduce her own risk for the disease. She recently read an article about the benefits of vitamin D and wants to know if they extend to protecting against colon cancer. In particular, she is concerned that her recent level of vitamin D was determined to be low at 12 ng/mL.
Colorectal cancer is the third leading cancer diagnosis in the United States and the second leading cause of cancer death overall [1,2]. While some risk factors for colon cancer can not be changed (gender, race/ethnicity, genetics), other risk factors are modifiable, including obesity, red meat intake, and smoking. Vitamin D has been determined as an important risk factor for several key diseases including osteoporosis , diabetes , and prostate cancer . Vitamin D insufficiency has also been proposed to be an independent risk factor for colorectal cancer.
Vitamin D primarily regulates calcium absorption and homeostasis. It is most efficiently synthesized in human skin, but it is also found in dietary sources, such as fatty fish and milk products. During exposure to sunlight, 7-dehydrocholesterol in the skin absorbs solar ultraviolet B radiation and is converted to previtamin D. Once formed, previtamin D undergoes thermally induced transformation to vitamin D-3. This product enters the circulation and is metabolized in the liver by vitamin D-25-hydroxylase to 25-hydroxyvitamin D. 25-hydroxyvitamin D is converted in the kidney to 1,25-dihydroxyvitamin D, and this final product regulates calcium metabolism through its interaction with bone and intestine . Serum 25-hydroxyvitamin D is the best measurement of an individual’s vitamin D status. Vitamin D deficiency is defined at a level <20 ng/mL, and vitamin D insufficiency 21-29 ng/mL .
Several molecular mechanisms have been proposed for vitamin D’s protective influence on colorectal tumorigenesis. 1,25-dihydroxyvitamin D likely acts as a transcription factor via the vitamin D receptor to modulate various genes in normal and cancerous colon cells, inhibiting cellular proliferation and promoting terminal differentiation . In addition to its synthesis within the kidney, 1,25-dihydroxyvitamin D can also be generated in colon tissue and effect its protective properties locally . Degradation of vitamin D occurs though the enzyme 24-hydroxylase. This key vitamin D catabolizing enzyme is often amplified and over-expressed in colon cancer cells .
Several epidemiologic studies have described an inverse relationship between serum vitamin D levels and colorectal cancer risk [10-15,19,20]. In 2006, a meta-analysis was performed on five nested case-control studies examining the relationship between serum vitamin D levels and colorectal cancer risk among average risk subjects . These five retrospective studies included 535 colorectal cancer cases and 913 controls. The time period between patient enrollment and follow-up ranged from 8-17 years. The pooled results were divided into quintiles with median 25(OH)D values of 6, 16, 22, 27 and 37 ng/mL. The pooled odds ratio for the highest quintile versus the lowest was 0.49 (p<0.01). The analysis revealed that individuals with serum levels of 25(OH) vitamin D >33 ng/mL had 50% lower incidence of colorectal cancer than individuals with levels <12 ng/mL (p<0.01). A potential confounder in these studies include subjects who lead unhealthy lifestyles—smoking, low physical activity, high BMI—predisposing them to both colon cancer and vitamin D insufficiency.
The above meta-analysis consisted of studies examining white populations. Research on vitamin D has shown that light-skinned individuals are more likely to have higher serum vitamin D levels than dark-skinned people [11,17-18]. Increased melanin in dark-skinned individuals competes with the vitamin D precursor, 7-dehydrocholesterol, for UVB photons, making dark-skinned individuals less efficient at synthesizing vitamin D than fair-skinned individuals . Dark-skinned individuals can require as much as 50 times sun exposure than fair-skinned people to produce an equal amount of vitamin D . Research on vitamin D and colorectal cancer has shown higher rates of vitamin D insufficiency and colorectal cancer among blacks when compared to whites [11,17-18]. It is not known if this clinical observation exists in other U.S. ethnic groups.
Current evidence supports a protective role for vitamin D against colorectal tumorigenesis among average risk patients. Normal levels of serum vitamin D appear to maintain healthy colonic epithelium. When levels become markedly low, <30 ng/mL, colon mucosal epithelium is at increased risk of tumorigenesis. Several key questions remain unanswered in regards to the relationship of vitamin D and colon cancer: 1. Does vitamin D supplementation in individuals with normal baseline values reduce the risk of colon cancer below what is expected for an average individual? 2. Does the duration of vitamin D insufficiency influence the extent of colon cancer risk? 3. Once vitamin D levels are normalized in individuals previously with insufficiency, how soon is the risk of colorectal cancer returned to an average level?
While we hypothesize that vitamin D’s protective features require several years or decades to influence colorectal cancer development, more studies are needed to assess the time needed for vitamin D to impact tumorigenesis. It is also unknown if patients at increased risk of colorectal cancer (e.g.: first-degree relative, hereditary polyposis syndromes) may benefit from vitamin D.
For the patient in this case, the serum vitamin D level should be raised to >30 ng/mL. A level >30 is needed to prevent vitamin D-related illnesses (eg: osteomalacia, osteoporosis) in all people, regardless of colorectal cancer risk . Vitamin D repletion can be aided by intake of high doses of oral vitamin D supplements. For oral supplementation, oral vitamin D 50,000 IU/weekly for 8 weeks is recommended to achieve a level >30 ng/mL. Another 8-week course of therapy may be needed if the first cycle does not achieve this minimal level . The patient should also be counseled on dietary sources of vitamin D such as fortified milk, tuna, salmon, and sardines. Given the patient’s risk for developing vitamin D insufficiency, once normal levels are achieved, daily vitamin D supplementation of 400 IU is advisable. Increased daily sunlight exposure would also help augment serum vitamin D, but there are no widely accepted guidelines for increasing sunlight exposure in vitamin D deficient individuals.
Although rare, vitamin D toxicity is a known complication of excess vitamin D supplementation. Hypervitaminosis may be seen at serum 25(OH)D levels >100 ng/mL . Supratherapeutic levels of vitamin D cause hypercalcemia. The signs and symptoms of hypervitaminosis include nausea, constipation, confusion, kidney stones, and arrhythmias. Treatment is the same as the treatment for hypercalcemia—stopping supplements, fluid hydration and possibly hospitalization. There is no evidence that supratherapeutic levels of serum vitamin D confer increased protection against colorectal cancer. There is no recommendation to supplement vitamin D in average risk patients with normal vitamin D levels. Patients with normal vitamin D levels should be counseled and encouraged to maintain adequate intake of dietary vitamin D as well as to obtain adequate sunlight exposure to maintain healthy levels.
It should be noted that currently there are no recommendations for universal vitamin D screening. Serum vitamin D testing may benefit individuals with risk factors for vitamin D insufficiency including those who are obese or physically inactive, reside in regions with low sunlight exposure, and/or have dark skin. As it relates specifically to risk stratification for colorectal cancer, vitamin D testing or supplementation does not fall under current recommendations.
Dr. Sanchez is a former resident at NYU Langone Medical Center and a current instructor, Clinical Medicine at Memorial Sloan Kettering Hospital
Dr. Francois is an Assistant Professor of Medicine (Gastroenterology) NYU Langone Medicacl Center
Faculty peer reviewed by Michael Poles, MD, Section Editor, GI, Clinical Correlations
Image courtesy of Wikimedia Commons.
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