Cause-Specific Outcomes Associated with Hypovitaminosis D

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Vitamin D has indirectly been linked to the development of atherosclerosis (shown here).
Vitamin D has indirectly been linked to the development of atherosclerosis (shown here).

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Part 1 of this article reviewed studies describing the incidence and prevalence of hypovitaminosis D in various populations—in both the general population and in patients with chronic kidney disease (CKD). It further probed the adverse clinical outcomes that low serum vitamin D has been associated with in all-cause mortality. To participate in Part 1 of this educational activity, please go to www.myCME.com
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In this second installment, a discussion of the harmful effects of low vitamin D levels will concentrate on conditions related to cardiovascular disease (CVD) morbidity and mortality due to the significance of these issues in patients with CKD, with additional mention of the effects of hypovitaminosis D on malignancies.


Key Points

  • Several observational studies have examined associations of 25(OH)D levels with the incidence and prevalence of various morbid conditions, and the most clinically relevant conditions are cardiovascular disease and cancer.
  • More research is needed to clarify the association between vitamin D levels and cancer-related mortality.
  • Epidemiologic data suggest a significant and worsening prevalence of hypovitaminosis D in the general population, which is exacerbated in certain patient groups, such as those with chronic kidney disease.

Vitamin D and cause-specific 
outcomes


Studies of all-cause mortality do not provide detailed information on the mechanisms of action responsible for the observed effects. To gain a better understanding about these, one has to explore a link between hypovitaminosis D and disease states that could explain a resultant higher mortality. There are ample basic science data that link vitamin D to pathologic processes such as cardiomyocyte hypertrophy, cell proliferation, and renin-angiotensin system activation.1

Several observational studies have examined associations of 25(OH)D levels with cause-specific mortality and with the incidence and prevalence of various morbid conditions. Of these, the most clinically rele­vant are cardiovascular disease (CVD)—and its multiple different risk factors—and cancer.


Hypovitaminosis D and 
cardiovascular risk factors


One plausible explanation for the higher all-cause mortality associated with hypovitaminosis D is that lower vitamin D levels may be associated with increased cardiovascular morbidity and mortality. This could be related to the direct effect of hypovitaminosis D on vascular function.2 It also might be due to the effect of various morbid states that are themselves known to be risk factors of CVD and thus could act as intermediaries between hypo­vitaminosis D and higher mortality.


An important risk factor for CVD 
is hypertension. Due to the possible 
link of vitamin D with blood pressure regulation2 it is possible that low 25(OH)D levels can be causative of hypertension. Several ecologic studies have linked exposure to ultraviolet (UV) radiation to lower blood pressure,3-8 indirectly implicating vitamin D deficiency in hypertension.

However, such studies can only offer circumstantial evidence linking vitamin D to blood pressure regulation, as higher sunshine exposure is linked to other plausible factors affecting blood pressure besides higher vitamin D levels (e.g., diets rich in fresh fruits and vegetables, more active lifestyle, etc.). A more direct link between vitamin D and hypertension was to be established by studies that examined associations between measured dietary vitamin D intake and incident hypertension.

The results of these studies were discordant; a small study detected an association between higher vitamin D intake and lower blood pressure,9 but two larger ones did not.10,11 Dietary vita­min D intake may, however, have a very small effect on serum 25(OH)D levels,12 which could explain the negative results of the latter two studies; hence it is important to examine associations between directly measured serum 25(OH)D levels and blood pressure. A large U.S. population-based study indeed found a significant association between lower serum 25(OH)D levels and the risk of incident hypertension.13

Contrasting this was another population-based study of elderly Europeans that did not detect an association between 25(OH)D levels and systolic or diastolic blood pressure.14 The reason for the discrepancy between these two studies remains unclear. 


A second relevant risk factor for CVD is diabetes mellitus. An association between lower serum 25(OH)D 
and diabetes mellitus or impaired glucose tolerance was shown in several observational studies.15-17 Interestingly, in a study using data from NHANES III the association between 25(OH)D 
levels and diabetes mellitus appeared to be present only in non-Hispanic white and in Mexican-American par­ticipants, and not in non-Hispanic blacks.18

Lower 25(OH)D levels 
were also associated with a lower insulin sensitivity index and with higher glucose concentrations during an oral glucose tolerance test19 suggesting that the association between 25(OH)D levels and diabetes mellitus could be explained by a direct effect of vitamin D on pancreatic beta cell function.20 Other studies established significant associations between 25(OH)D levels and combinations of cardiovascular risk factors such as diabetes mellitus, hypertension, obesity and lipid abnormalities21 or with metabolic syndrome.22,23

Taken together, the preponderance of the observational evidence supports an association between hypovitamin­
osis D and various established risk factors 
for CVD, suggesting a potential mechanism of action for how low 25(OH)D levels could cause higher morbidity and mortality.


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