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HISTORICAL CONSIDERATIONS

For many years after its discovery in the early part of the 20th century, the endocrine, autocrine and paracrine vitamin D was thought to have functions largely related to bone, manifesting in children as rickets and in adults as osteomalacia and osteoporosis. The widespread use of fish liver oil in the mid-20th century and emphasis on sun exposure led to a marked decline in rickets and osteomalacia, while osteoporosis became a major problem in ageing populations. With time, reports have grown which indicate that vitamin D deficiency remains common throughout the life-cycle and that this applies to North-East Asia as it does elsewhere.1,2 Its manifestations are pleiotropic which is to say that, on account of its many functions, its health effects are diverse and complex.3 It is a good example of why ‘clinical nutrition’ needs a wide embrace and to be multidisciplinary.4
Here we consider how the problem of vitamin D deficiency can be identified, prevented and managed by clinicians.

EVIDENCE BASED NUTRITION AND VITAMIN D

Contemporary health care practice aims to operate in accordance with scientific evidence, so-called ‘evidence -based medicine’. Its nutrition counterpart is ‘evidence-based nutrition’ (EBN).5 It has been argued that EBN is best served by ‘portfolios of evidence’ including clinical trials, observational studies, experimental studies on animals along with ex vivo, in vivo and in vitro investigations, rather than ‘hierarchies of evidence’ with clinical trials as the best evidence.6 The limitations of nutrient trials with calcium and vitamin D have been reviewed by Lappe and Heaney.7

Clinical Nutrition Epidemiology and Vitamin D

There are several major studies in North-East Asia, from greater China,8-16 Korea17,18 and Japan19 which demonstrate the considerable prevalence of biochemical vitamin D deficiency in the region. This is not always accompanied by population-wide low intakes as in Taiwan,15 which indicates that environmental (especially sun-exposure), behavioural (e.g., sun-avoidance by women, outdoor or indoor recreation or employment, smoking) or other clinical factors (e.g., malabsorption; drug interactions; obesity and weight management; dietary restrictions) play a role as determinants of vitamin D deficiency. The seasons vary from north to south in sunshine and vitamin D status and health vary accordingly, as can be seen with the multiple sclerosis gradients where vitamin D is involved.

CLINICAL RELEVANCE

Preventive opportunities

Given the extensive biological effects of vitamin D, throughout the life-cycle from conception, during pregnancy and lactation, growth and development, adulthood and later life, there are substantial opportunities for clinicians and those in public health to minimise deficiency in the interests of healthy life expectancies.

Organ, System and Ecological Dysfunction

There is probably no branch of health care where vitamin D deficiency is not relevant. No organ or system is spared. Vitamin D is indicative of our links with the ecosystems of which we are part, through our diurnal and seasonal biorhythms, the food we eat and the health of our microbiomic interface with nature.20, 21

Mortality

While vitamin D deficiency is associated with increased mortality in a meta-analysis,22 in Linxiang, China, noted for its micronutrient deficiencies and a link between vitamin D deficiency and oesophageal cancer,8 mortality has not been found associated with vitamin D status.12 It is possible that this incongruous finding is related to competing risks for mortality.

DIAGNOSIS

Index of suspicion

The likelihood of vitamin D deficiency should be suspected in precarious ecological situations which affect sun exposure or the food supply, as winter approaches and exits, where occupation or activities are mainly indoor, with a family history of osteoporosis or fracture, cancer (perhaps related to vitamin D receptor polymorphisms), where diet or dietary patterns are restricted as in vegans where animal food derived vitamin is absent or with very low fat intakes also low in other fat-soluble vitamins A, E and K (the co-operativity of these vitamins is also relevant). Other diseases (e.g., with malabsorption) may also be causes of secondary vitamin D deficiency. With practice most health care professionals will develop efficient “Clinical Repertoires”.23

Institutionalisation, indoor employment

At considerable risk of vitamin D deficiency are those who have the twin problems of lack of sunshine and dependency on others for their food supply. Where biochemical assessment is available it is not uncommon to find very low or even unmeasurable vitamin D concentrations. Examples are institutionalised elders and computer scientists.

Constellation of symptoms and signs

In patients with a constellation of bone disease, muscle dysfunction or weakness, body compositional disorders (e.g., overfatness, sarcopenia), diabetes, reproductive dysfunction, recurrent or persistent infection (especially respiratory tract, tuberculosis and HIV positivity), autoimmune disease, neoplastic disease, malabsorption, cognitive impairment or other neurodegenerative disease, or multiple sclerosis, vitamin D deficiency is a possibility. In some the deficiency will be a pathogenetic factor in the disorder or disease; in others it will be a secondary deficiency. It may also serve to create a spiral of increasing morbidity involving an array of organs and systems.1,2

Biochemical and endocrine function

Serum 25 OH vitamin D: 1,25OH vitamin D may be measured depending on the clinical picture, especially whether there is hepatic or renal disease which could impair, respectively, 25-hydroxy or 1,25-dihydroxy vitamin D synthesis. To be confident that there is functional deficiency, the presence of secondary hyperparathyroidism can be established by measurement of serum PTH (parathyroid hormone). The PTH response to treatment is also helpful in judging progress. A steady state urinary calcium excretion will reflect calcium balance, and, for comparison, usual intake can be estimated by asking about calcium-rich foods consumed. Its response to treatment can also be reassuring or otherwise. These investigations may be out of financial and pathology services reach for many. In these circumstances, the clinician must depend on quality history-taking

Early and delayed recognition

Without clinical alertness to the problem of vitamin D deficiency when symptoms are non-specific, delayed recognition can lead to considerable accumulated pathology and frailty. On the other hand, early recognition can allow rapid resolution of related health problems and reduced health costs. The nutritional economics of these different scenarios requires analysis.24

MANAGEMENT

Clearly the most important aspects of management of Vitamin D deficiency are to deal with the underlying causes. But these may themselves be complex especially insofar as the likely multifactorial pathogenesis which will usually obtain involving environmental (place of abode, occupation, recreation) behavioural (diet, physical activity and habits like smoking), gender and bio-medical considerations. Time and commitment to facilitatory counselling, perhaps with a team, is to be encouraged.
Optimal vitamin D intakes are dependent on behavioural and environmental considerations.25 But the optimal serum concentrations of active forms of vitamin D are generally higher than commonly encountered in surveys or clinical practice. Zittermann et al found that there was “a nonlinear decrease in mortality risk as circulating 25(OH) D increases, with optimal concentrations ~75-87.5 nmol/L”.22 Although DRIs ( Dietary Recommended Intakes) in the USA as from 2010 are 15 ng for most but the elderly, with estimated average requirement 10 ng and an upper limit of 100 ng, it is not uncommon in clinical practice to be able to achieve the optimal serum 25-hydroxy vitamin D without pushing towards the upper limit, especially in older people. That there may be vitamin D resistance is suggested by a PTH which remains high.