Development of an Optimal Micronutrient Reference Range for Adults
Condition: Micronutrients Reference Interval; Micronutrients Normal Range
Study type: Interventional

Summary: 
      This study aims to develop optimal micronutrient reference intervals from blood samples
      collected from "ideal" healthy adults and following micronutrient supplementation to minimise
      the chance of subclinical deficiencies.
    

Detailed description: 
      Vitamins, minerals and trace elements, collectively referred to us as micronutrients, are
      important enzyme co-factors and co-enzymes, antioxidants and gene transcription factors. Most
      micronutrients are provided to the body through the diet however the body can produce some of
      them, including vitamin D, vitamin K and niacin. Micronutrients are needed in much smaller
      amounts than the macronutrients.

      Vitamins have diverse biochemical functions, including cellular growth and differentiation,
      and organ and immune function. Minerals are inorganic substances which are involved in nerve
      and muscle function, enzymatic systems and bone. Adequate dietary vitamin and mineral intake
      is crucial, as deficiencies have been associated with a number of specific and non-specific
      symptoms which lead to loss of body homeostasis and disease onset. Beyond a suboptimal
      dietary intake, in illness, the aetiology of micronutrient deficiencies can be multifactorial
      and include malabsorption, excessive losses, increased nutrient requirements and
      drug-nutrient interactions.

      There is continuous interest in the role of the micronutrients; both from a public health
      point of view, to prevent disease onset, and from a clinical practice perspective to monitor
      and treat deficiencies and optimise clinical outcomes. This interest stems from our
      increasing understanding in the biological roles of these nutrients, findings from
      epidemiological research, and the public interest on the potential health promoting benefits
      of these nutrients, as these are often portrayed to them by the commercial manufacturers of
      such supplements. It is also a common outcome that hypotheses generated from association
      studies and nutritional epidemiology are not replicated by intervention studies particularly
      when the latter ones aim to correct reduced blood concentrations of micronutrients or
      suboptimal intakes. These counterintuitive findings can be explained by other, often unknown,
      confounding factors that explain the relationship between the micronutrient status in the
      body and health or clinical outcomes, but also due to the fact that in several of these
      previous studies the methodology applied to assess the body micronutrient status in patient
      or population groups was insufficient or interpretation of the assessment outcomes were not
      reflective of the true micronutrient status of the body. From a clinical practice perspective
      there are five fundamental reasons why assessment of micronutrients is important: a) confirm
      the clinical manifestation of micronutrient deficiencies or toxicity; b) to screen and
      identify those at risk of micronutrient deficiencies or toxicity and refer them for further
      assessment; c) to prevent under or over-supplementation and its effects on patients
      prognosis; d) to supplement and potentially to improve the clinical outcomes of a patients
      with acute or chronic illness; e) to reduce health care associated expenditure from
      un-necessary use of resources to assess micronutrient status and from un-necessary
      interventions to correct non-existing deficiencies.

      The mainstream approach to assess the micronutrient status of an individual, in-vivo, is the
      direct measurement of a micronutrient or its derivative concentration in biological fluids,
      mostly blood. However, there are several limitations with the use of laboratory biomarkers in
      ascertaining the micronutrient status of an individual. Development of blood micronutrient
      references for adults and children rely often on 95% confidence intervals established from
      measurements in samples drawn from the general population. Contrary to the concept of the new
      WHO centile growth charts, which describe the optimal pattern of growth for children, rather
      than the prevailing pattern in a population which is likely to be affected by environmental
      factors, there are no such standards for assessment of micronutrient status. Several of the
      micronutrient reference intervals used in health services and laboratories, particularly for
      the less commonly measured micronutrients (e.g. trace elements and B complex vitamins), are
      derived from very small convenience samples of essentially healthy individuals. It is
      therefore possible that these values are based on selective populations, and do not represent
      the distribution of the biomarker in the population and most importantly it may be based on
      populations in areas where there is a subclinical micronutrient insufficiency epidemic in the
      general population, (e.g. Vit D or Selenium in Scotland). As a result, use of such reference
      ranges may mask deficiency in an individual and underestimate the proportion of subjects with
      micronutrient deficiencies in a diseased population.

      In human, a highly complex system also regulates redistribution of micronutrients in the
      presence of illness. It is believed that this system ensures that there is the right
      concentration of each micronutrient in the right tissue or body fluid at the various phases
      of the illness. The mechanisms behind these effects include uptake of nutrients to other
      tissues, shifts in vascular fluids and capillary permeability, loss of nutrient carrier
      protein, including serum albumin and lipoproteins and increased urinary excretion. As a
      result of these effects the blood concentration of several micronutrients will be affected,
      regardless of the actual body stores. A substantial amount of research shows that acute and
      chronic illness will affect blood micronutrient concentrations assayed in plasma with those
      measured in erythrocytes affected less or remain unaffected . Plasma concentrations of
      several nutrition-related biomarkers are known to be affected by inflammatory response,
      including vitamins retinol, C, B6, C, E and D, carotenoids, ferritin, zinc, copper and
      selenium. Where the nutrient or metabolite is a nutritional biomarker a depression in its
      concentrations will result in an overestimate of a deficiency. In contrast, where the
      biomarker is increased, as the results of an inflammatory illness, such as in infection and
      trauma, and as in the case of plasma ferritin and caeruloplasmin concentrations, this will
      result in an underestimate of iron and copper deficiency.

      In conclusion, there are two unmet needs this proposal will try to address:

        1. First, to develop optimal micronutrient reference ranges to overcome the inherent
           limitations of the existing ones.

        2. Second, to develop novel, surrogate biomarkers, such as measurements in erythrocytes and
           other functional markers, whose levels remain uninfluenced by inflammatory diseases.

      This study aims to develop optimal micronutrient reference intervals from blood samples
      collected from "ideal" healthy adults and following micronutrient supplementation to minimise
      the chance of subclinical deficiencies.
    

Intervention name(s): OMIS
Intervention type(s): Dietary Supplement
Intervention description(s): This is an open-label micronutrient supplementation trial in healthy adult volunteers. We are planning to supplement healthy adult volunteers, once a day, with a standard over-the-counter multivitamin supplement for a period of 30 consecutive days.
Intervention model: Single Group Assignment
Intervention model description: This is an open-label micronutrient supplementation trial in healthy adult volunteers. We are planning to supplement healthy adult volunteers, once a day, with a standard over-the-counter multivitamin supplement for a period of 30 consecutive days.
Masking: None (Open Label)
Primary purpose: Diagnostic