vitamin D and CLL

I wrote about vitamin D in January this year, but I am prompted to write about it again by the recent announcement by the Institute of Medicine that older people should take a bigger dose, and the identification of low vitamin D levels as a poor prognostic factor in CLL by the Mayo Group. A further prompt was the suggestion by my oncologist that my steroid-induced proximal myopathy might benefit from some vitamin D, and why didn't I go outside and bear my skin to the sunlight? At minus 17 degrees Centigrade?

None of this changes what I wrote about vitamin D back in January; the idea that it can prevent or ameliorate cancer is still to be formally tested.

The level of vitamin D supplement required by most people was set at 200 iu in 1997. The new recommendation is 600 iu or 800 if you are over 70.

Although we know that apart from controlling calcium metabolism, vitamin D controls over 2000 genes and interferes with the functioning of many tissues, the Institute of Medicine, an arm of the National Academy of Sciences that sets US governmental nutrient levels, said there wasn't enough evidence to prove that low vitamin D causes chronic diseases; it based its new recommendations on the levels needed to maintain strong bones alone. The panel also raised the acceptable upper limit of daily intake to 4,000 IUs for adults, from 2,000 previously.

The panel dismissed concerns that many Americans and Canadians are vitamin D deficient, noting that there is no scientifically validated level that's considered optimum. Even so, the panel concluded that for 97% of the population, a blood level of 20 nanograms of vitamin D per milliliter is sufficient. However, several major medical groups, including the Endocrine Society and the International Osteoporosis Foundation, have concluded that a level of 30 ng/ml is necessary for optimal bone health. Others have set far higher levels.

The panel was also concerned about emerging evidence of concern about possible ill effects of too much vitamin D. Besides a risk of kidney and heart damage noted with vitamin D levels of 10,000 iu per day. They said that they had seen higher death rates from pancreatic cancer, prostate cancer and other causes in men whose blood levels were above 50 ng/ml. The link is still tentative and may never be proven.

But the real concern is about serum calcium levels, which constitute a risk for everybody. High levels of calcium cause thirst, constipation, dehydration, sleepiness and coma. In diseases like myeloma and breast cancer they are recognized as medical emergencies which could prove fatal in a day or so. Other less dramatic features of a high serum calcium are deposits of calcium in soft tissues including the prostate gland and kidney. Kidney stones are a painful complication.

A high calcium can be caused by increased resorption from the bones or increased absorption from the bowel. Vitamin D controls the absorption and parathormone the resorption. The commonest abnormal finding on blood test screening is a high serum calcium, almost invariable due to secretion of parathormone by a parathyroid adenoma. I have one of these and a consequent high calcium. One of the ways that parathormone works is by converting vitamin D into its active form of vitamin D3. So some patients are walking around with high vitamin D3 levels because their bodies are mistakenly manufacturing it.

Before embarking on a megadose regime for vitamin D, always check serum calcium first.

Now, how about the Mayo paper.

They found that low levels of serum vitamin D3 were an adverse prognostic factor in CLL. In a multivariate analysis it was independent of most of the usual adverse prognostic factors for time to treatment, though not for overall survival. The study was perhaps insufficiently powered to show that.

Several reports have suggested that low serum vitamin D3 levels may be associated with increased incidence of colorectal, breast, and other cancers. One population based, double-blind, randomized placebo-controlled trial found women who increased their daily vitamin D intake by 1100 IU reduced their risk of cancer by 60-77%.

Recent data suggest low vitamin D3 levels at diagnosis may be associated with poorer prognosis in colorectal, breast, melanoma, and lung cancer, although these data have not yet been replicated in independent cohorts.

Sounds an open and shut case, doesn't it?

The problem is that association does not prove causation.

Here is another example of an association being unrelated to causation: A low Hb is a poor prognostic factor in CLL. If you correct the Hb does it make the prognosis better? Of course not! the problem is that the CLL is destroying the bone marrow; raising the Hb artificially by blood transfusion or erythropoietin won't affect that.

One possible reason for a low vitamin D3 being a poor prognostic factor is that D3 is protective against CLL and if you have low levels it roars away. But equally it may be that aggressive CLL consumes vitamin D3 and that's why the level is low. If you give more D3 you might be feeding the flames.

Generally there seems no downside to giving megadoses of D3 as long as you keep the serum calcium in check, but so far no-one has shown any benefit in CLL. The Mayo group are right to call for clinical trials

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.