Infection and Inflammation

Infection and Inflammation Assessing Micronutrient Status in the Presence of Inflammation1,2 Andrew Tomkins3 Centre for International Health, Institute of Child Health, University College London, WC1N 1EH ABSTRACT Measurement of micronutrient status in the presence of inflammation is difficult for several reasons. Changes in levels of acute phase proteins are associated with increased plasma levels of some indicators of Downloaded from https://academic.oup.com/jn/article/133/5/1649S/4558564 by guest on 30 September 2021 micronutrient status, such as ferritin, and decrease of others, such as retinol. Alterations in the plasma levels of acute phase proteins can occur from hemodilution, sequestration and increased or decreased rates of synthesis and breakdown. How much these relate to functional deficiency is not known. Assays that are less perturbed by inflammation, such as the transferrin receptor assay, and adjustment of plasma micronutrient levels according to different cutoff levels for acute phase proteins are helpful but they do not enable precise assessment of micronutrient status among individuals who are infected. Improving assessment of micronutrient status is important if micronutrient interventions are to be targeted to those with the greatest need. J. Nutr. 133: 1649S–1655S, 2003. KEY WORDS: micronutrients acute phase proteins inflammation Assessing micronutrient status in human samples is difficult. the effect of inflammation on vitamin A, thiamin, riboflavin, Assays may be made for micronutrients in body fluids, such as ascorbic acid, vitamins D and K, iron, zinc and copper. Two serum, plasma or breast milk; tissues such as red blood cells lines of evidence were explored in that review. The first con- and their binding or transport proteins; or measurement of cerned the association between severe clinical infections and micronutrient-dependent enzymatic activities. Many factors low plasma levels of micronutrients. Despite the close in- affect micronutrient levels, and plasma levels of several im- teraction between micronutrient malnutrition and inflamma- portant micronutrients fluctuate considerably after meals. They tion, in which it is often rather difficult to know which is change during the hemodilution at certain stages of pregnancy the prime driver, the authors identified reports of sequential and are influenced by exercise. The most marked changes occur measurements in infected individuals that showed a key role for during the inflammatory processes of infection (1). This paper inflammation as a primary cause of changes in levels in examines the ways in which inflammation alters indicators of biological fluids. The second line of evidence was from animal micronutrient status, reviews which indicators are least affected and human volunteer experiments in which infections or by inflammation, attempts to make recommendations as to inflammation were introduced under controlled conditions and which of the indicators of micronutrient status is the most micronutrient levels followed at different stages of the disease valuable for assessment of micronutrient status during inflam- process. Subsequently, the work of Beisel et al. (3) identified mation and seeks to identify gaps in knowledge that require the time course of changes in micronutrient levels during novel research approaches if micronutrient assessment during detailed experimental infections. Others also performed human inflammation is to be improved. studies using fever induced by injections of pyrogens: this The effect of inflammation on micronutrient status has been enabled the time course, pattern and degree of changes in recognized for many decades. The classic publication micronutrient levels to be observed (4). Interactions of Nutrition and Infection by Scrimshaw, Taylor The clinical studies were particularly interesting. Although and Gordon in 1968 (2) reviewed what was known about there were striking changes in micronutrient levels during the clinically apparent illness and during the periods of peak pyrexia, important changes also occurred during the incubation and convalescent periods when pyrexia and clinical illness were 1 Manuscript prepared for the USAID-Wellcome Trust workshop on ‘‘Nutrition as a preventive strategy against adverse pregnancy outcomes,’’ held at Merton not present. This indicated that subclinical infections also College, Oxford, July 18–19, 2002. The proceedings of this workshop are played a key role in influencing micronutrient status. published as a supplement to The Journal of Nutrition. The workshop was Most of these studies relied on measurements of mi- sponsored by the United States Agency for International Development and The Wellcome Trust, UK. USAID’s support came through the cooperative agreement cronutrients in plasma or urine. They gave important infor- managed by the International Life Sciences Institute Research Foundation. mation on the overall relationship between inflammation and Supplement guest editors were Zulfiqar A. Bhutta, Aga Khan University, Pakistan, micronutrient malnutrition, but key questions remained. How Alan Jackson (Chair), University of Southampton, England, and Pisake Lumbiga- non, Khon Kaen University, Thailand. severe does inflammation have to be before it affects 2 I acknowledge with gratitude the research funding from the Wellcome Trust, micronutrient status? How much is micronutrient status DFID, UNICEF, the support of the Great Ormond Street Hospital NHS Trust and influenced in the apparently healthy individual who has the Special Research Funds of the Hospital for Tropical Diseases, London. 3 To whom correspondence should be addressed. E-mail: [email protected]. a subclinical inflammation? What are the mechanisms by which ac.uk. the inflammatory response influences micronutrient status? 0022-3166/03 $3.00 Ó 2003 American Society for Nutritional Sciences. 1649S 1650S SUPPLEMENT Could improved methods of assessment of micronutrient status alteration in plasma volume or extrusion from intravascular be developed and what is their validity and reliability in into tissue spaces are all possibilities. Changes of all of these the presence of infection? Can any correction factors be used have been documented during inflammation but there are to allow for the changed levels, mostly reduced, of the remarkable powers of adaptation, and deficiency in a micro- micronutrients in populations with a high level of infection? nutrient level does not necessarily mean that micronutrient Are there any assays that are less susceptible to the changes status and physiology is perturbed. induced by inflammation? These are crucial, largely unresolved Using a combination of biochemical, immunological and questions. Nevertheless the last few decades have seen im- stable isotope techniques, studies on the acute phase response portant developments in understanding and some of these in evidently healthy subjects with HIV have demonstrated questions have been answered. An update of some of the new some of the mechanisms that account for plasma changes in information has already been published (5) and reviews of inflammatory proteins (15). The plasma concentrations, frac- studies show the importance of micronutrient deficiency in tional synthetic rates and absolute synthetic rates of positive relation to maternal and child health (6,7). The importance of APPs were higher in HIV subjects than in control subjects. The micronutrient deficiencies within the overall attention toward fractional synthesis rates of the negative APPs were also Downloaded from https://academic.oup.com/jn/article/133/5/1649S/4558564 by guest on 30 September 2021 improving maternal nutrition was highlighted recently (8). elevated in the HIV subjects. These data indicate that mea- Furthermore knowledge of the nature of inflammation has surement of plasma levels of APPs alone is insufficient to steadily grown, which has helped our understanding of the explain what is going on metabolically. significance of certain alterations in micronutrient levels during The changes in plasma levels of inflammatory proteins, both inflammation (9–11). an increase or a decrease, were associated with faster rates of synthesis of both positive APPs and negative APPs. This implies that more than protein turnover accounts for alterations in The inflammatory response plasma levels of inflammatory proteins. The importance of these The characteristics of the biochemical and immunological findings with respect to micronutrient levels is perhaps greatest response to infection are now reasonably well characterised. in relation to the reduction in plasma levels of RBP that is The term ‘‘acute phase response’’ is used to describe a short- observed in many inflammatory processes. Reduced ability to term metabolic change evidenced by increased plasma con- carry retinol is important, especially for vitamin A–dependent centrations of certain proteins—positive acute phase proteins tissues such as the eye, epithelial surfaces and immune cells. (APPs)4—such as C-reactive protein (CRP), haptoglobin, fib- Thus a decreased plasma level of RBP may indicate a consider- rinogen and a–1 antitrypsin and decreased concentrations of able risk of functional vitamin A deficiency. On the other hand, certain proteins—negative APPs—such as albumin, retinol increased rates of turnover might allow delivery of sufficient binding protein (RBP), transthyretin (TTR), and high-density micronutrients to target organs such that function is maintained lipoprotein-apolipoprotein A1 (DHL-apo A), which tend to despite a reduction in RBP. Until results

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