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 phase 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 , thiamin, riboflavin, Assays may be made for micronutrients in body fluids, such as ascorbic acid, vitamins D and K, iron, 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 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 . 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 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 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 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 , 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.

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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 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 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 -apolipoprotein A1 (DHL-apo A), which tend to despite a reduction in RBP. Until results of metabolic turnover fall during infection. This is associated with a wide range of studies of vitamin A and better measures of functional deficiency changes in circulating levels of and immunoglobulins. at the tissue level are available, it is not clear whether increased The metabolic changes are often supplemented by physiological rates of synthesis of RBP achieve sufficient compensation for changes such as altered pulse rate, temperature and blood a reduced level of RBP in the plasma. The situation was pressure. summarized by Fleck (16), who concluded that in all likelihood The inflammatory response occurs in a similar pattern within the concentration of albumin and other negative APPs, such as a wide range of illnesses and may last for several days; when the RBP, decrease precipitously in response to infection, severe inflammatory process persists for weeks or even months the trauma and inflammation because of an increased transcapillary term ‘‘chronic inflammation’’ is used. Certain chronic infec- escape route and an increased catabolic rate. tions, such as HIV, can persist for years in apparently healthy The physiological roles of APPs are now better understood subjects and yet they cause sufficient metabolic change to alter (17). CRP, for example, activates the classical pathway of micronutrient levels considerably (12). Infection with parasitic complement, one of the main mechanisms in providing host disease such as malaria causes a different metabolic response defense. CRP also interacts with cells of the by in those who are repeatedly exposed and therefore develop binding to the Fc gamma receptors. It may thus bridge the gap various forms of in contrast to those who have no between innate and adaptive immunity and provide an early immunity. The changes in APPs are greater in those who effective bacterial response. CRP also appears to protect against develop malaria infection without immunity (13) than in those the damaging inflammatory response induced by lipopoly- who are chronically exposed (14). This results in differences in saccharides and cytokines (18,19). the changes in retinol levels in response to malaria. CRP immune expression, by hepatocytes in response to Although a considerable body of knowledge now exists on cytokines such as -6, requires several transcription the different components of inflammation involving many factors that interact; CRP has been proposed to be one of the different cytokines, immunoglobulins, APPs, genes and se- links between nonspecific innate immunity and specific clonal creted proteins, less information is available on what these immunity. Although most is known about CRP, knowledge is changes mean in terms of whole-body micronutrient status or increasing about the role of (SAA), which function. There are several possible explanations for changes also rises rapidly during the acute phase response and tends to in plasma levels of an APP. Alteration in dietary intake, return to normal with a few days of the acute event. Similar absorption, synthesis or metabolism of the individual in- patterns occur with the chronic phase proteins such as a-1 flammatory protein together with change in urinary losses, chymotrypsin (ACT) and a-1 acid (AGP) (20). In recent years the development of has been described during the acute inflammatory phase of many illnesses and experimental studies (21). This develop- 4 Abbreviations used: ACT, a-1 chymotrypsin; AGP, a-1 acid glycoprotein; ment leads to oxidative stress in which there is increased use APP, acute phase protein; CRP, C-reactive protein; DHL-apo A, high-density lipoprotein-apolipoprotein A1; RBP, retinol binding protein; SAA, serum amyloid A; of antioxidants such as vitamins C and E, selenium and TfR, transferrin receptor; TTR, transthyretin. carotenoids, with a reduction in plasma levels (22). There MICRONUTRIENT STATUS IN 1651S seems to be an increased consumption of antioxidants leading inflammation in chronic diseases that have until now been to lower plasma levels but whether changes in rates of turnover attributed to diet, genes and environmental (33,34). of these antioxidants compensates for their lower levels in These findings open up new lines of inquiry for inflammation- plasma is not yet clear (23). micronutrient interactions as contributing factors in the Measurements of inflammatory responses have been used of a much wider range of illnesses than in- to detect systemic infection in several clinical conditions. fectious diseases alone. Children with elevated CRP and SAA who had acute or A reduction in levels of inflammatory proteins after anti- persistent diarrhea were more likely to have a severe com- inflammatory treatment is well recognized but the accompany- plicating clinical illness such as , septicaemia or ing changes in micronutrient levels have now been described . Raised tumor factor-a in umbilical cord (33). Patients with had different plasma levels of CRP, samples was a good indicator of in premature neonates albumin, transferrin and than did control (24). Even single organ infection, for example, is subjects. They also had different levels of plasma retinol, associated with raised inflammatory cytokines (25). More a-tocopherol, lutein, lycopene, a-andb-carotene, zinc, recently, studies of other inflammatory proteins such as cal- copper, iron and selenium. After a course of there Downloaded from https://academic.oup.com/jn/article/133/5/1649S/4558564 by guest on 30 September 2021 protectin have been used to assess clinical severity of infec- were significant changes in the inflammatory proteins along tion (26). with changes in lutein, lycopene and b-carotene, iron, selenium and ceruloplasmin Subclinical infection Vitamin A. The changes in vitamin A metabolism during the acute phase response have been reviewed extensively Most of the new clinical information on the metabolic (35,36). Reductions in plasma retinol are described during the responses to subclinical infection comes from studies on HIV acute phase of a wide range of infections (6). They also occur and malaria in immune subjects. High levels of CRP and in asymptomatic subjects in whom an inflammatory protein haptoglobin were shown to relate to the density of malarial response is present. The effect of inflammation on plasma parasites in Tanzanian children (27). Low levels of micro- retinol appears to depend on the underlying nutritional status. nutrients are frequently described in subclinical infection. Inflammatory stress reduced plasma retinol in Ghanaian The levels appear to be lowest where there are highest levels children eating a consistently deficient diet (14) but a reduction of inflammatory proteins. The levels of plasma retinol in in retinol was not marked in South African children in severe apparently healthy children in Ghana were lowest in those metabolic stress after accidental kerosene poisoning (37) or in with raised AGP and SAA (20). Inflammatory processes are Nigerian children with acute respiratory infection but who were described in subclinical , a low-grade inflammation of apparently vitamin A replete (A). It was hoped that the relative breast milk in around 20–30% of lactating women in several dose response, a novel method for assessing vitamin A status studies in Asia and Africa, but it is not yet clear whether this that involves measurement of two forms of vitamin A, the inflammation changes micronutrient levels in milk (28). naturally occurring form and a nonmetabolizable analog, would indicate vitamin A status, which was unaffected by the Chronic inflammation in noninfectious disease presence of inflammation. However, measurements of the relative dose response taken shortly after a metabolic stress re- Diseases that are not considered infectious by normal sulting from accidental kerosene poisoning in South Africa criteria may be associated with elevated plasma levels of showed that the relative dose response changed along with the inflammatory proteins. Several studies have emphasized the expected changes in inflammatory proteins and plasma retinol important role that inflammation plays in the progression of (37). atheromatous lesions; gene knockout experiments producing Plasma retinol changes quickly as inflammation starts and CRP-deficient animals show that can be prevented CRP rises. As inflammation persists CRP levels return toward by removing the inflammatory mediators (29). CRP is as- normal levels but levels of ACT and AGP become elevated. sociated with poor renal function in patients with chronic Several groups have examined different cutoffs for inflamma- renal disease (30). Furthermore, the plasma level of CRP tory proteins to see if they could correct for individual retinol provides considerable prognostic value for susceptibility to de- levels (20,38). However, although there is an overall asso- velopment of atheroma and clinically evident coronary syn- ciation between inflammatory proteins and retinol, it has not dromes in later life. It is not yet clear what role inflammation proven possible to adjust satisfactorily for plasma retinol levels plays in the development of , but it raises in inflammation. A composite of RBP and TTR was used to the possibility that inflammation increases micronutrient re- assess its potential value for controlling for the effect of inflam- quirements. The increasing recognition of gene-inflammation mation on plasma retinol (39). Unfortunately the combina- interactions raises the possibility that micronutrient-inflamma- tion of individual levels of TTR and RBP did not provide tion interactions may explain susceptibility to cardiac disease. a sufficiently sensitive or specific adjustment. Inflammatory responses and raised levels of reactive oxygen At a cellular level there was some evidence of reduction species increase requirements for micronutrients, leading to low of liver RBP synthesis in animals injected with endotoxin circulating levels of plasma micronutrients (21). The beneficial (40), which was followed by whole-body turnover studies by effects of during unstable angina is associated with Jahoor et al. (15). RBP may well escape into the extra- changes in CRP and improved clinical outcome (11). As more vascular space, possibly more so if it is not bound efficiently diseases are shown to be associated with a low-grade in- to TTR. Several studies demonstrated urinary losses of reti- flammation it will be important to determine the importance of nol and RBP (3). It was postulated that the plasma retinol- low levels of plasma micronutrients (31). retinol binding polar concentrations might change at different In predialysis patients an increase in CRP and interleukin- rates; to assess the potential effect of inflammation on retinol 6 have been noted as predictors of impaired renal function and the binding proteins, RBP and TTR were analyzed in (32). When aspirin is provided to subjects with unstable children who had suffered severe inflammation from acute re- angina, CRP levels are reduced and numbers of cardiac spiratory distress (37). The RBP-to-TTR ratio was signifi- events are reduced, thereby emphasizing the potential role of cantly decreased in inflammation; the results were compared 1652S SUPPLEMENT with other measures of vitamin A status including plasma controls the interaction between iron and intracellular path- retinol and the modified relative dose response. Overall there ogens (54). was a weak association between vitamin A status and RPB In recent years plasma ferritin, a reputedly more stable and TTR. marker of iron status than serum iron, has been widely used in Other researchers examined the use of CRP, SAA or ACT nutritional surveys and clinical assessment (55). However, in controlling the levels of inflammatory proteins in an attempt many studies show the marked elevation of ferritin during the to correct for the plasma retinols. So far these approaches have acute and chronic phases of inflammation (56). When ferritin not found a sufficiently close interaction between APPs and levels are low (e.g., ,10 mg/L), there can be little doubt that retinol for them to be useful in clinical or epidemiological iron status is deficient. However when inflammation is present, studies (38). The use of breast milk retinol as an indicator of ferritin levels may often be .20 mg/L even in the presence of vitamin A status is widely recommended because it fluctuates marked iron deficiency, as assessed by indices and less than plasma retinols, but it is uncertain whether in- plasma ferritin levels when the infection is gone. Paracha et al. flammation is localized to the breast or systemically changes the (38) used ACT and AGP to adjust for the effect of infection on breast milk retinol status (41,42). ferritin. In a group of pregnant women in Zimbabwe, HIV Downloaded from https://academic.oup.com/jn/article/133/5/1649S/4558564 by guest on 30 September 2021 Several studies have shown reduced levels of vitamin A in infection, malaria parasitemia and raised plasma ACT levels HIV and AIDS (43). Subjects with more severe clinical grades were associated with increased plasma ferritin (57). In this of AIDS have lower levels of vitamin A, probably representing study mild elevations of ACT were not a predictor of raised the effect of inflammation rather than an increased severity of serum ferritin, but ACT concentrations of 0.4–0.5 and .0.5 infection resulting from vitamin A deficiency. In a group of g/L were associated with 1.26 and 3.16 mg/L higher ferritin Zimbabwean women who were HIV positive but asymptomatic, levels, respectively. Overall this study showed that iron ACT was not particularly elevated; within the group as a whole, deficiency occurred in around two-thirds of the women when ACT level explains a considerable proportion of the variance in ferritin was used as a marker of iron stores, but infection caused serum b-carotene and retinol (44). Adjustments for plasma high levels if ACT was .0.4 g/L. Interestingly, an effect on retinol were performed using RBP, TTR and ACT. RBP, TTR retinol but not iron was observed if ACT was .0.3 g/L. and ACT concentrations of 0.3–0.4, 0.4–0.5 and .0.5 g/L gave As in the case of vitamin A, investigators have used different 0.05, 0.14 and 0.38 mmol/L lower serum retinol concentration, levels of cutoff for different acute phase responses seeking to respectively. In Ghanaian children, those with an AGP .1 g/L distinguish between inflamed and noninflamed individuals. had a 24% lower serum retinol (20). Malaria has a variable However, there is no widely accepted agreement on what cutoff effect on plasma retinol, probably because the metabolic stress levels should be used for proteins such as CRP and AGP in is more determined by parasite-immune relationships rather indicating whether a normal or high level of ferritin can truly than parasite density alone (12,45). Several studies observed represent adequate iron stores. marked seasonal changes in plasma retinol. Although there are More recently the transferrin receptor (TfR) assay has been often striking variations in dietary intake because of seasonal used because it was hoped that TfR would be more stable than availability of fruits such as papaya and mangoes, there are ferritin (58). Several studies showed an effect of infection such often quite marked seasonal changes in morbidity with as- as malaria on plasma TfR levels (59); although changes occur sociated changes in inflammatory proteins (46). during acute infection in nonimmune subjects, these are A recently published study showed that Wuchereria bancrofti considerably less than changes in ferritin. Changes in TfR levels infection was associated with lower levels of a-tocopherol but between the infected and noninfected states in the same the infection did not appear to be associated with lowered levels individual with malaria were ,10% whereas the change in of retinol (47). There were many intestinal parasites present. ferritin was fivefold (13). Chronic malaria in immune subjects Their presence appeared not to elevate the levels of in- is associated with elevated plasma TfR levels. A recent study flammatory proteins. However it is interesting that W. bancrofti showed that infection with W. bancrofti was associated with takes up tocopherol from its host to protect itself against the elevated plasma ferritin levels, contrasting with the generally oxidative stress that it is exposed to within the intestine as part low levels of plasma ferritins in the iron-deficient control of the host immune rejection. The effect of intestinal helminths population (49). Chronic inflammation can have profound on micronutrient nutrition has been documented well with effect on anemia (60) via a series of complex mechanisms respect to iron but there are few studies on their effect on other whereby iron is inefficiently used (61). micronutrients (48,49). Zinc. Zinc status is often assessed by measurements of zinc Overall it appears logical to use plasma retinol levels for in plasma, white blood cells or hair (62). However many dietary assessment of vitamin A status, certainly at a population level. and physiological factors such as exercise, eating, pregnancy Unfortunately it is not yet clear whether levels of inflammatory and rapid growth in childhood may all alter plasma zinc levels proteins can be used to control accurately for the reduction in (63). Whether this really represents zinc deficiency is arguable, plasma levels attributable to inflammation. and Golden (64) has discussed the criteria for assessing zinc Iron. The lability of serum iron during infection is well status. Attempts at measuring metallothionein, an alternative known. In view of the ubiquitous requirement for iron by mi- indicator of zinc deficiency, have not resulted in robust crobes infecting humans, it is just as well that the inflam- indicators of assessment. Overall, mean plasma zinc levels in matory response reduces levels of free circulating iron and a population can be used to indicate deficiency. Plasma zinc and increases levels of circulating of binding proteins (50). Iron metallothionein are both reduced during acute phase response supplements may be harmful; the progression of HIV to AIDS In addition there are considerable urinary losses of zinc in is faster in those with high iron stores (51). The protective systemic infection, particularly those with a pronounced effect of iron deficiency in individuals exposed to malaria and metabolic stress leading to breakdown of muscle (3,17). The certain bacterial infections has been extensively reviewed (52). reduction of circulating zinc reduces zinc availability for mi- Iron deficiency is particularly protective in malarial infection crobial metabolism during infection (65,66), providing an ad- (53); the pooling of red blood cells is thought to enhance ma- vantage similar to that achieved by reducing iron levels The laria replication. Iron-deficient subjects vary in their susceptibil- recent recognition that is released (from damaged ity to infection, partly because of the NRAMP 1 gene, which ) during inflammation provides another mechanism MICRONUTRIENT STATUS IN INFLAMMATION 1653S for reducing plasma zinc levels during inflammation There is Riboflavin. This nutrient is normally assayed by measure- controversy about the role of circulating zinc in the control of ment of the erythrocyte glutathione reductase activation coef- replication rates of HIV. Zinc is bound to the nucleocapsid ficient. Abnormal riboflavin levels are noted in dietary protein NCp7 and forms fingers that are essential for the deficiency and malaria but there is little information on levels formation of viral structure, proviral DNA synthesis and of APPs and alteration in erythrocyte glutathione reductase production of infectious (67). activation coefficient status (80,81). The amount by which plasma zinc falls in spontaneous . Niacin levels estimated indirectly by measurement infection was examined in Peruvian children in whom infection of nicotinamide adenine dinucleotide have been noted to be was diagnosed according to clinical signs or elevated CRP (68). deficient in patients with HIV. Niacin interacts with certain A plasma zinc difference of around 0.5 mmol/L was noted antiretrovirus but so far there is no link described with between infected and noninfected children. This contrasted inflammation (82,83). with more striking differences in mean ferritin levels (10.0 mg/L Vitamin C. Vitamin C is normally assayed by measure- in uninfected vs. 3.9 mg/L in infected children). Even asymp- ment of ascorbic acid in plasma or leukocytes. There is marked tomatic HIV depresses plasma zinc levels (69). An indirect change in the plasma ascorbic acid in inflammation but no clear Downloaded from https://academic.oup.com/jn/article/133/5/1649S/4558564 by guest on 30 September 2021 method of assessing zinc status using association between a level of AGP or CRP at which the has been recognized for years. This changes when zinc supple- changes occur (84). ments are given to children but its functional importance is Vitamin D. Plasma levels of 25–cholecalciferol are used to difficult to assess because of the changes in plasma alkaline assess vitamin D status because this is the circulating phys- phosphatase during rapid growth (70). iologically active form. There is no information on the effect Folate. A reduction in serum folate levels during acute of inflammation on these levels. inflammation is well recognized. Red cell folate levels however Vitamin E. The plasma level of tocopherol is known to be are much more stable; they are much less susceptible to recent reduced during inflammation but there is no information on changes in dietary intake than plasma levels. Chronic in- the association between tocopherol and APPs or chronic phase flammation is associated with low red cell folate levels as are proteins (22). subclinical infections and these probably present the true condition of micronutrient deficiency. Overall red cell folate How much does inflammation change levels seem to be least affected by inflammatory responses and micronutrient status? appear to be satisfactory markers of folate status. Among HIV- positive women in Zimbabwe, HIV and ACT were indepen- This key question has several components. The first is dently associated with lower serum folate levels (57). Women whether it is possible to measure micronutrient status in an with an ACT level of .0.4 g/L had a serum folate level around individual even without the presence of inflammation. The 1 nmol/L. Interestingly low serum folate but normal homo- studies reviewed here indicate that for certain micronutrients levels are found in patients with atherosclerotic heart such as folate, assays exist that are robust indicators of nutri- diseases (71). tional status. For others such as iron, the position is less satis- Selenium. Selenium status is often measured directly in factory. The second component concerns the proportion by serum, plasma, whole blood and hair. It has also been measured which micronutrient levels become changed as a result of the indirectly by assays of plasma glutathione peroxidase levels inflammatory process. (72). Both serum and whole blood levels are decreased during For no micronutrient is there a linear relationship between the acute phase response. Low levels occur in several infections change in inflammatory protein and change in micronutrient (73,74). Several viral infections appear to stimulate the status. Around 10 y ago Brown et al. (85) concluded that the production of selenoproteins, leading to low serum levels of effect of concurrent infections may differ by nutrient, nutri- selenium. Patients with the lowest levels of selenium have the tional status of the population and prevalence and severity of highest levels of morbidity and mortality but a causal effect the infection. Although this is still true overall, there have been has not yet been demonstrated (75). Morbidity and mortality some recent developments in measurement technology and appear to be less vulnerable to changes in inflammatory re- analysis. Work in progress seems likely to clarify the position sponse, but short- and long-term studies are not available. Low considerably. levels occur in HIV and AIDS (76). Overall it is noted that Is there a way forward for us to be able to make adjustments selenium levels are low in infection. It has been postulated that for the presence of inflammation in order to estimate true this is due to the consumption of selenium as an antioxidant as micronutrient status? There seem to be several important steps. part of the process of quenching free radicals (77). Whether First, using agreed-upon assay methods and standards together plasma selenium is also reduced as part of the inflammatory with a range of cutoff points for inflammatory proteins, the process has not been studied intensively and there are no relationship between micronutrients and inflammation should published attempts to control for changes in selenium due to be examined more carefully using pooled data. Second, an changes in inflammatory proteins. infective load should be described more precisely, but this will Copper. Copper is measured within the copper-binding be difficult because of the difference in inflammatory response protein complex of ceruloplasmin This is a positive APP that is during infection in immune and nonimmune individuals. elevated during the acute and chronic inflammatory response Third, ways to measure micronutrient levels in tissues or biopsy (78). There are no studies on the interaction between different samples should be devised. Fourth, how circulating levels relate levels of the acute phase responses and the copper-binding to deficiency at the tissue level should be better understood; protein levels. this is likely to require a better understanding of the transport Thiamin. Thiamin is mostly assayed using the indirect process and tissue function. If the first two steps could be enzymatic method of erythrocyte transketolase. Levels are achieved, it would be possible to correct for micronutrient known to be low in populations with poor thiamin intakes and levels in samples taken during inflammation. there are associations between thiamin deficiency and malaria These relationships are of more than just an academic (79). However the comparison of erythrocyte transketolase and interest. According to international criteria there are levels of APPs such as CRP or SAA have not been performed. ferritin and retinol at which iron deficiency and vitamin A 1654S SUPPLEMENT deficiency, respectively, are recognized. There are clear guide- 25. Yorston, D., Whicher, J., Chambers, R., Klouda, P. & Easty, D. lines for public health nutrition interventions. However, using (1985) The acute phase response in acute anterior uveitis. Trans. Ophthalmol. Soc. U. K. 104, 166–170. the available indicators in populations burdened with a high 26. 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