Vitamin D and cancer, particularly CLL

When I started my series on vitamins I intended to deal with the question of vitamin D and CLL, but I got sidetracked. I have seen a number of comments on various sites about using vitamin D3 to slow down CLL so I guess I should write about it now.

Vitamin D is a precursor to a hormone that controls calcium metabolism. There are two major forms: vitamin D2, or ergocalciferol, and vitamin D3, or cholecalciferol. Vitamin D2 is made naturally by plants, and vitamin D3 is made in animals. In humans D3 is made in the skin when it is exposed to UVB irradiation. Both can also be synthesized.

The active form is 1,25-dihydroxyvitamin D, or calcitriol, which can be made in the body from either vitamin D2 or vitamin D3. the functions of vitamin D are:
To help improve muscle strength and immune function.
To reduce inflammation.
To promote the absorption of calcium from the small intestine.
To helps maintain adequate blood levels of the calcium and phosphate needed for bone formation, mineralization, growth and repair.

Most people get the vitamin D they need through sunlight exposure. It is also present in the diet. Foods containing Vitamin D include fatty fish, fish liver oil, and eggs, with smaller amounts in meat and cheese. Most dietary vitamin D comes from fortified foods, such as milk, juices, yogurt, bread, and breakfast cereals. A serum level of calcitriol lower than 15 ng/ml (37.5 nmol/L) is generally considered inadequate for a healthy person to maintain bone health and normal calcium metabolism, but some experts suggest that the optimal level may be as high as 80 nmol/L. The Institute of Medicine of the National Academies has developed the following recommended daily intakes of vitamin D: Birth to age 50 - 5 µg (200 iu); 51-70 - 10 µg (400 iu); 71+ 15 µg (600 iu). The 2005 Dietary Guidelines for Americans recommends that older adults, people with dark skin, and people exposed to insufficient sunlight should consume extra vitamin D (25 µg, or 1,000 iu) from vitamin D-fortified foods and/or supplements.

The proven problems of insufficient vitamin D are rickets in children and osteomalacia in adults. Excessive vitamin D intake increases calcium levels which can lead to the deposit of calcium salts in soft tissues of the body, such as the kidneys, heart, and lungs and high blood levels of calcium. Patients with high calcium levels can get heart rhythm abnormalities, changes in mental status, pain, conjunctivitis, loss of appetite, fever, chills, thirst, vomiting, weight loss and if unchecked they can lead to coma and death.

Is there any evidence that vitamin D prevents cancer? Well yes, there is some, though it is far from conclusive. First, there are epidemiologic studies which show an inverse relationship between sunlight exposure and the rates of incidence and death for certain cancers. There may be many reasons for this, but one possibility is that more sunlight leads to more D3 being produced.

When cancer cells are cultured in the laboratory vitamin D promotes their differentiation and apoptosis and it slows their proliferation.

Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have also provided evidence that higher vitamin D intakes may reduce the risk of cancer. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium and vitamin D (28 μg vitamin D, or 1,100 iu) or a placebo for 4 years. The women who took the supplements had a 60 percent lower overall incidence of cancer). This was an incidental finding since the principle end point was fracture incidence; it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake on cancer incidence.

Observational studies to determine whether vitamin D reduces the risk of particular cancers, have been carried out but they have yielded inconsistent results. Information about dietary intakes was obtained from the participants through questionnaires, diet records, or interviews. Such information is not very reliable. Of course it is possible to measure blood levels of vitamin D to avoid reliance on individuals' memories but vitamin D levels in the blood can vary seasonally and with the laboratory technique used to measure them so if only a single measurement of vitamin D is made (as was the case in most studies) interpretation is difficult.

To fully understand the effect of vitamin D on cancer, new randomized trials will need to be carried out, but there is disagreement on what dose of vitamin D to use.

Let's look at individual cancers. Although the studies are inconsistent, epidemiologic studies of the association between vitamin D and the risk of colorectal cancer have provided some suggestion of protection.

In the American Cancer Society's Cancer Prevention Study II Nutrition Cohort, the diet, medical history, and lifestyle of more than 120,000 men and women were analyzed. Men with the highest intakes of vitamin D had a slightly lower risk of colorectal cancer than those with lowest intakes, but among women there was no difference. When this study was pooled with 9 other studies there was still a difference between men with the highest and lowest intakes, but it was no longer statistically significant.

In the Women's Health Initiative randomized trial, vitamin D supplementation did not reduce the incidence of colorectal cancer, though this study has been criticized by enthusiasts because of too low a dose and too short of duration.

Among the 16,818 participants in the Third National Health and Nutrition Examination Survey, those with higher vitamin D blood levels (≥ 80 nmol/L) had a 72 percent lower risk of colorectal cancer death than those with lower vitamin D blood levels (< 50 nmol/L).

Since most colorectal cancers develop from pre-existing adenomas, any interventions that reduce the risk of adenoma development or recurrence are likely to reduce the risk of colorectal cancer. Several large studies have investigated the association of vitamin D intake or serum status with adenoma risk.

A cohort from the National Cancer Institute (NCI)-sponsored Polyp Prevention Trial (PPT) was evaluated for the association of vitamin D intake with recurrence of colorectal adenomas in individuals who previously had one or more adenomas removed during a qualifying colonoscopy. PPT was a multicenter randomized clinical trial to determine the effects of a diet high in fiber, fruits, and vegetables and low in fat on adenoma recurrence. The detailed dietary information obtained during the trial allowed the researchers to investigate the association between additional dietary factors and adenoma recurrence. Total vitamin D intake (that is, from dietary sources and supplements combined) was not associated with a reduced risk of adenoma recurrence. However, individuals who used any amount of vitamin D supplements had a lower risk of adenoma recurrence.

In another study, the vitamin D intakes of 3,000 people from several Veterans Affairs medical centers were examined to determine whether there was an association between intake and advanced colorectal neoplasia (an outcome that included high-risk adenomas as well as colon cancer). Individuals with the highest vitamin D intakes (more than 16 μg, or 645 iu, per day) had a lower risk of developing advanced neoplasia than those with lower intakes.

A pooled analysis of data from these and a number of other observational studies found that higher circulating levels of vitamin D and higher vitamin D intakes were associated with lower risks of colorectal adenoma. Inverse associations were seen with both dietary and total vitamin D intake but not with supplemental vitamin D intake. However, the associations with dietary intake were not statistically significant.

Another large, NCI-sponsored randomized, placebo-controlled trial explored the effects of calcium supplementation and blood levels of vitamin D on adenoma recurrence. Calcium supplementation reduced the risk of adenoma recurrence only in individuals with vitamin D blood levels above 73 nmol/L. Among individuals with vitamin D levels at or below this level, calcium supplementation was not associated with a reduced risk.