Vitamin D insufficiency: Definition, diagnosis and management

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Severe vitamin D deficiency can be defined as the dose of vitamin D or serum 25OHD concentrations needed to prevent nutritional rickets or osteomalacia. There is large international consensus that these diseases can be prevented by 400 IU of vitamin D/d and 25OHD above 30 nmol/l (12 ng/ml). Vitamin D deficiency can also accelerate the risk of fractures and probably also of falls in elderly subjects but there is no consensus on the required daily doses or minimal 25OHD threshold for these endpoints. The majority of experts consider 800 IU/d and serum 25OHD above 50 nmol/l (20 ng/ml) as sufficient, with a minority opinion aiming for 75 nmol/l or even higher. For other extra-skeletal endpoints, no hard evidence is available to define whether or not this is causally related to vitamin D status. Therefore, for these endpoints no minimal dosage or 25OHD threshold can be defined.

Section snippets

Rickets: Historical overview

Vitamin D was discovered about a century ago and enabled us to prevent or cure rickets in humans or animals. The disease itself was described extensively during the mid-17th century but the etiology of the disease remained enigmatic until it was discovered that exposure to sun light or intake of cod liver oil could prevent or cure the disease [1], [2], *[3]. The chemical identity of vitamin D was later on confirmed by its synthesis by Windhaus [4].

All vitamin D comes from photochemical

Vitamin D metabolism and choice of marker of vitamin D status

Serum vitamin D itself is not a good marker of the access to vitamin D or for the overall vitamin D status. Indeed, shortly after its synthesis in the skin or its uptake from the gut it rapidly disappears from the circulation. Thereafter, it reappears as 25OHD, tightly bound to serum vitamin D binding protein (DBP). The conversion efficacy of vitamin D into 25OHD can be evaluated by comparing the increase in serum 25OHD after either intake of vitamin D itself or 25OHD [12]. Based on 9 RCTs we

Vitamin D status in case of rickets or osteomalacia

In view of the consensus about the vitamin D requirements to prevent rickets *[15], [16],2 it is highly relevant to try to compare the required intake with the minimal threshold of serum 25OHD

Vitamin D status and bone health in adults and elderly subjects

The vitamin D endocrine system primarily defends serum calcium homeostasis, if needed, at the expense of bone [20], [21]. In case of poor vitamin D status, serum PTH increases with consequently stimulation of bone turnover. This regulation is similar to the increase in serum TSH in case of thyroid or iodine deficiency. For unknown reasons, however, this secondary hyperparathyroidism is not uniformly present in all patients with mild vitamin D deficiency. Therefore, serum PTH cannot be used as a

Vitamin D status and extra-skeletal health

In contrast to the large degree of worldwide unanimity regarding the amount of vitamin D needed to prevent rickets, and reasonable agreement on the minimal thresholds for vitamin D intake or 25OHD concentrations for bone health in adults, there is great discrepancy in the opinion of governmental organizations, scientific societies and experts with regard to the daily requirement of vitamin D for extra-skeletal or global health. These debates are sometimes very lively (and this may even be an

Vitamin D and cancer

Cell proliferation and cancer was the first potential extra-skeletal target identified by (1) the presence and functionality of the VDR in several cancer cell lines [58], [59] and (2) the geographic link between UVB radiation and cancer incidence in several countries as first described by the Garland brothers [60]. By now, there are very solid data on the anti-proliferative and anti-cancer activities of 1,25(OH)2D and its analogs and a wide variety of molecular and genetic mechanisms underpin

Vitamin D and the immune system

All cells of the immune system express the VDR and nearly all cytokines involved in the immune system are known to be under the control of 1,25(OH)2D. Moreover the vitamin D endocrine system has coherent actions on the innate immune system, thereby activating the cellular (monocytic/macrophage) and molecular (e.g. defensing) defense mechanisms. By contrast, the vitamin D endocrine system has a coherent effect of down tapering the acquired immune system (starting with antigen presenting cells to

Vitamin D and cardiovascular diseases

The possible link between vitamin D status and cardiovascular risks and events is based on in vitro and preclinical studies, indicating that a number of genes, critical for cardiovascular function are under the control of 1,25(OH)2D. These genes include renin, thrombomodulin, genes involved in prostaglandin homeostasis or NO production or inflammation. However, too high concentrations of 1,25(OH)2D may stimulate the transdifferentiation of vascular smooth muscle cells into osteoblast like cells

Vitamin D and metabolic diseases

Vitamin D deficiency has been associated with nearly all aspects of the metabolic syndrome, including type 2 diabetes and obesity [76].

Type 2 diabetes mellitus

Vitamin D deficiency may impair insulin secretion directly in rodents, rabbits and humans [77], [78]. Secondly, vitamin D deficiency is linked to enhanced inflammation, which is strongly linked with increased risk for type 2 diabetes (T2DM). Finally, poor vitamin D status is linked with insulin resistance, which is the hallmark of T2DM. A large number of cohort or observational studies have found an association of low serum 25OHD with higher risk or prevalence of type 2 diabetes [69], [76], [79]

Obesity

Overweight and obesity is nearly consistently associated with a lower vitamin D status in comparison with healthy lean people. The causality is highly debated. VDR and CYP27B1 are present in adipocytes and these cells, or especially their precursor cells, are responsive to 1,25(OH)2D, including effects on essential aspects of their function such as uncoupling factors. Animal models of Vdr or Cyp27b1 deficiency consistently found a lean phenotype due to increased energy expenditure. As this

Vitamin D and muscle function or falls

Very severe vitamin D deficiency as found in subjects with congenital absence of CYP27B1 and patients with end stage renal disease may result in severe proximal muscle myopathy up to the need for wheelchair usage. This muscle phenotype can disappear in days after start of treatment with 1,25(OH)2D [49]. Whether skeletal muscle is a direct target for the vitamin D endocrine system is hotly debated, as some experts did not find measurable concentrations of VDR mRNA or protein in skeletal muscle,

Vitamin D and mortality

If the vitamin D status would indeed have numerous extra-skeletal effects and even exert just a minor impact on so many major diseases, mentioned above, it would not be a surprise to find an association between vitamin D status and mortality risks. Large cross-sectional studies such as NHANES have repeatedly found a higher mortality rate in subjects with the lowest serum 25OHD concentration. This association is confirmed even when only looking at mortality occurring more than 2 years after the

Vitamin D and other health outcome events

As VDR and VDR action is found in nearly all cells of the body, an association between vitamin D status and nearly all human health issues has been evaluated, apart from the diseases discussed above. For most of these other possible effects, the evidence for a causal link is lower than for the diseases discussed above. These conditions include among others: different diseases related to mental health such as autism, Alzheimer or Parkinson disease, non-alcoholic fatty liver disease, male and

Overall interpretation of extra-skeletal health effects of vitamin D

Different experts interpret the massive amount of data concerning the possible extra-skeletal health effects of vitamin D in different ways. Here, we will try to formulate our interpretation without detailing our arguments as we refer to previous publications *[3], [17], *[22], [53].

  • 1.

    The in vitro and preclinical data are very suggestive for a broad spectrum of activities of the vitamin D endocrine system, very much in line with similar broad activity of most ligands of nuclear receptors.

Conclusions

Rather than summarizing the personal views of the authors of this manuscript (as formulated in *[3], *[22]), we prefer to compare the conclusions about optimal vitamin D status as formulated in recent (or older) governmental or scientific society guidelines written by a very large number of experts [7].

Defining vitamin D deficiency is still problematic and there is so far no unanimity. The best proof of this statement is an overview of the guidelines formulated by more than 40 institutions

Conflicts of interest

RB declares to have received lecture fees from Abiogen and l’Oréal and is co-owner of a university patent on vitamin D analogs licensed to HYBRIGENIX (France); GC has nothing to declare.

Acknowledgments

Grant support: FWOG0A2416N to GC. The authors thank Evelyne Van Etten for expert help.

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