Vitamin D is produced in sun exposed skin and retrieved from the diet and dietary supplements. It is metabolized in the liver and kidneys to its active form [1]. Even if dietary intake is low, the skin has the capability to produce adequate amounts of vitamin D given enough sunlight but due to our indoor lifestyle, and use of sunscreens, it often does not suffice; vitamin D deficiency is common worldwide [1]–[3].

An inverse association between vitamin D status and all-cause mortality has been established in prospective studies [4]; [5]. A meta-analysis of vitamin D supplementation reported a decrease in mortality, whereas a recent one found a reduced mortality with vitamin D and calcium supplementation in the elderly but no effect of vitamin D supplementation alone [6]; [7]. The specific causes of death underlying the association with mortality lack clarity. Vitamin D deficiency is in observational studies associated with an increased risk of cancers such as colorectal cancer [8], lung cancer [9], and breast cancer [10]; cardiovascular disease (CVD) [11]; endocrine and metabolic diseases such as diabetes mellitus [12], obesity [13], and metabolic syndrome [14]; respiratory disease such as chronic obstructive pulmonary disease (COPD) [15]; [16], and respiratory infections [17]; diseases of the digestive system such as liver disease [18]; [19], inflammatory bowel disease [20], and celiac disease [20]; and mental disorders such as dementia [21]; [22], and depression [23]. To the best of our knowledge, no studies have investigated the association of vitamin D status and different specific causes of death in the same study population.

Most deaths were caused by neoplasms and diseases of the circulatory system accounting for approximately 40 percent, and one fourth of deaths, respectively (table 2). Vitamin D status was lowest among the persons dying of endocrine, nutritional and metabolic diseases, mental and behavioural disorders, and diseases of the digestive system, and highest among the persons dying of diseases of the nervous system or the circulatory system (table 2). The median follow-up time was approximately 10 years.

We found significant inverse associations between vitamin D status and death caused by diseases of the respiratory system, the digestive system, and endocrine, nutritional and metabolic diseases (table 3). The estimates were stable through multiple adjustments. The hazard ratio for the fourth vitamin D quartile with the first quartile as reference was approximately 0.25 for all three groups.

In model 1, we found a significant inverse linear trend between vitamin D quartiles and death caused by neoplasms. The association, however, was no longer significant in the fully adjusted model when further adjusting for intake of fish, physical activity, smoking habits, body mass index, and alcohol consumption.

We found non-significantly lower HRs for mental and behavioural diseases and diseases of the nervous system. However, we found no association between vitamin D status and death caused by diseases of the circulatory system.

Our results regarding an inverse association between vitamin D status and death caused by respiratory disease are in line with previous studies. Romme et al found that vitamin D deficiency was present in the majority of patients with COPD entering pulmonary rehabilitation [15], and Black et al found a dose-response relationship between the serum concentration of 25-hydroxyvitamin D and FEV₁ [16]. Likewise, a study by Ginde et al found an inverse association between 25-OH-D levels and recent upper respiratory tract infections [17]. Vitamin D could affect respiratory disease in a number of ways: it inhibits the formation of matrix metalloproteinases as well as fibroblast proliferation, and influences collagen synthesis thereby possibly influencing tissue remodeling [32]. In addition, it is suggested that vitamin D plays an important role in innate immunity, particularly through the antimicrobial peptide cathelicidin [33]. Since low BMI is an independent risk factor for mortality in subjects with COPD [34], it may be speculated whether vitamin D status is just a reflection of the level of malnutrition. The association, however, remained significant after adjusting for BMI and also after excluding the participants with a diagnosis of respiratory disease before the study, thereby providing some support for a possible causal effect of vitamin D on respiratory disease.

The observed inverse association between vitamin D status and death caused by digestive disease –liver disease accounting for over half– is consistent with previous findings of a high prevalence of vitamin D deficiency in patients with liver disease [18], and Putz-Bankuti et al found that low 25-OH-D levels predicted hepatic decompensation and mortality in patients with chronic liver failure [35]. Vitamin D deficiency might contribute to liver damage by increased inflammation and fibrosis and by reduced antiviral response [20]; [36]–[38]. Barchetta et al proposed a causal role of vitamin D in the development of non-alcoholic fatty liver disease by exerting a dose-dependent effect on fat accumulation into the hepatocytes [39].

However, the low vitamin D levels associated with liver disease could be a consequence of the disease rather than a cause. Patients with digestive disease are particularly prone to vitamin D deficiency due to fat malabsorption; bile salt deficiency; loss of absorptive surface; increased intestinal permeability; loss of liver function causing impaired hepatic hydroxylation of vitamin D, reduced hepatic production of vitamin D binding protein (DBP); or an impaired cutaneous production due to reduced sun exposure or jaundice [18]; [20]. The total levels of 25-OH-D are highly correlated with levels of DBP and albumin, and adjusting for liver function would have been an advantage. We attempted to reduce the bias of reverse causation by excluding the persons with a diagnosis of digestive disease (including liver disease) before the study. The association remained significant, strengthening our belief in a causal relationship between vitamin D and development of liver disease.

The observed lack of association between vitamin D status and circulatory disease mortality supports the results from a study by Melamed et al [40]. It is, however, inconsistent with several other observational studies [4]; [41]; [42], including a recent study by Thomas et al who found an optimal vitamin D level to lower all-cause and cardiovascular disease mortality in patients with the metabolic syndrome [43]. There may be several reasons for the different results. Most of the mentioned studies examined older people, or subgroups, where vitamin D could be more important regarding CVD risk. Worth mentioning, two studies of vitamin D supplementation found no effect on CVD [44]; [45].

Our results regarding an association between vitamin D status and death caused by endocrine, nutritional and metabolic diseases – diabetes mellitus accounting for three fourths – conform with results from previous observational studies [12]; [46]. The possible mechanisms are uncertain but vitamin D may preserve glucose tolerance through effects on insulin secretion and sensitivity [47].

The observed lack of association between vitamin D status and death caused by neoplasms is consistent with a study by Freedman et al reporting no overall relationship between 25-OH-D and cancer mortality risk in the general population [48]. However, despite a proposed role for vitamin D in some of the common pathways of cancer –i.e. through induction of apoptosis and prevention of angiogenesis in malignant cells, thereby reducing the potential for the malignant cell to survive [1]– different types of cancer may not share the same possible vitamin D dependent pathway. A meta-analysis by Ma et al thus reported an inverse association between blood 25-OH-D levels and the risk of colorectal cancer [8], whereas a meta-analysis on 25-OH-D levels and breast cancer by Yin et al found no significant association in the cohort studies measuring vitamin D status at baseline before cancer diagnosis [49]. As yet, results regarding a potential role for vitamin D in the prevention of cancer are conflicting [50].

Although non-significant, the observed inverse association between vitamin D status and mental and behavioural disorders, is consistent with a previous study by Annweiler et al reporting an inverse association between vitamin D intake and risk of Alzheimer’s disease [21] and a study by Hogberg et al showing amelioration of depressive symptoms after vitamin D supplementation in 54 depressed adolescents [23]. On the one hand, low cognitive function may lead to low dietary intakes of vitamin D and a lack of sunlight exposure leading to lower vitamin D levels. On the other hand, since vitamin D is a steroid hormone exerting neurosteroid actions in the central nervous system, it may partially explain neuronal degeneration and dementia [51]. Interestingly, recent studies found yet a significant positive association of vitamin D with cognition after adjusting for nutritional and physical status [51].

As mentioned above, some of the diseases are likely to cause rather than be caused by the low vitamin D status. Possible examples include liver disease and mental disease caused by alcohol abuse which may also have reduced liver function. Likewise, vitamin D could simply be a marker of a healthy lifestyle as shown in table 1. Thus, the associations may at least be explained partly by residual confounding.

The strengths of our study include the longitudinal population-based design and the large random sample of the Danish population highly prevalent of low vitamin D status [28]; a long-term follow-up and the use of standardised registry-based diagnoses with almost no individuals lost to follow-up; and the available information on potential confounders.

The limitations of the study include the loss of information when merging studies; the different methods of vitamin D measurements in the merged studies; the non-specific nature of the main causes of death; the interventional design of the Inter99 study; the lack of objective markers of liver and kidney function; and the single vitamin D measurement. A single 25-OH-D measurement may lose predictive power over time. Thus, Grant found a diminishing utility over time of a single measurement of 25-OH-D for determining the effect of vitamin D in reducing the risk of cancer [52]. Somewhat supportive of the use of a single 25-OH-D measurement to predict future health outcomes, Jorde et al found vitamin D status to be as stable a predictor as blood pressure and lipids [53], but the findings are likely an underestimate of the true associations. The mortality is generally low in this general population sample with median age just below 50 years giving a low number of events in some of the major causes of death, especially among the non-cardiovascular and non-neoplasm groups. Thus, the power for statistical analysis in most of these categories is low.