![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Centre for International Health, Institute of Child Health, University College London, WC1N 1EH
3 To whom correspondence should be addressed. E-mail: atomkins{at}ich.ucl.ac.uk.
 |
ABSTRACT |
|---|
 TOP ABSTRACT LITERATURE CITED |
|---|
KEY WORDS: • micronutrients • acute phase proteins • inflammation
Assessing micronutrient status in human samples is difficult. Assays may be made for micronutrients in body fluids, such as serum, plasma or breast milk; tissues such as red blood cells and their binding or transport proteins; or measurement of micronutrient-dependent enzymatic activities. Many factors affect micronutrient levels, and plasma levels of several important micronutrients fluctuate considerably after meals. They change during the hemodilution at certain stages of pregnancy and are influenced by exercise. The most marked changes occur during the inflammatory processes of infection (1). This paper examines the ways in which inflammation alters indicators of micronutrient status, reviews which indicators are least affected by inflammation, attempts to make recommendations as to which of the indicators of micronutrient status is the most valuable for assessment of micronutrient status during inflammation and seeks to identify gaps in knowledge that require novel research approaches if micronutrient assessment during inflammation is to be improved.
The effect of inflammation on micronutrient status has been recognized for many decades. The classic publication Interactions of Nutrition and Infection by Scrimshaw, Taylor and Gordon in 1968 (2) reviewed what was known about the effect of inflammation on vitamin A, thiamin, riboflavin, ascorbic acid, vitamins D and K, iron, zinc and copper. Two lines of evidence were explored in that review. The first concerned the association between severe clinical infections and low plasma levels of micronutrients. Despite the close interaction between micronutrient malnutrition and inflammation, in which it is often rather difficult to know which is the prime driver, the authors identified reports of sequential measurements in infected individuals that showed a key role for inflammation as a primary cause of changes in levels in biological fluids. The second line of evidence was from animal and human volunteer experiments in which infections or inflammation were introduced under controlled conditions and micronutrient levels followed at different stages of the disease process. Subsequently, the work of Beisel et al. (3) identified the time course of changes in micronutrient levels during detailed experimental infections. Others also performed human studies using fever induced by injections of pyrogens: this enabled the time course, pattern and degree of changes in micronutrient levels to be observed (4).
The clinical studies were particularly interesting. Although 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 not present. This indicated that subclinical infections also played a key role in influencing micronutrient status.
Most of these studies relied on measurements of micronutrients in plasma or urine. They gave important information on the overall relationship between inflammation and micronutrient malnutrition, but key questions remained. How severe does inflammation have to be before it affects micronutrient status? How much is micronutrient status influenced in the apparently healthy individual who has a subclinical inflammation? What are the mechanisms by which the inflammatory response influences micronutrient status? Could improved methods of assessment of micronutrient status be developed and what is their validity and reliability in the presence of infection? Can any correction factors be used to allow for the changed levels, mostly reduced, of the micronutrients in populations with a high level of infection? Are there any assays that are less susceptible to the changes induced by inflammation? These are crucial, largely unresolved questions. Nevertheless the last few decades have seen important developments in understanding and some of these questions have been answered. An update of some of the new information has already been published (5) and reviews of studies show the importance of micronutrient deficiency in relation to maternal and child health (6, 7). The importance of micronutrient deficiencies within the overall attention toward improving maternal nutrition was highlighted recently (8). Furthermore knowledge of the nature of inflammation has steadily grown, which has helped our understanding of the significance of certain alterations in micronutrient levels during inflammation (9– 11).
The inflammatory response
The characteristics of the biochemical and immunological response to infection are now reasonably well characterised. The term "acute phase response" is used to describe a short-term metabolic change evidenced by increased plasma concentrations of certain proteins—positive acute phase proteins (APPs)
4—such as C-reactive protein (CRP), haptoglobin, fibrinogen and 
–1 antitrypsin and decreased concentrations of certain proteins—negative APPs—such as albumin, retinol binding protein (RBP), transthyretin (TTR), and high-density lipoprotein-apolipoprotein A1 (DHL-apo A), which tend to fall during infection. This is associated with a wide range of changes in circulating levels of cytokines and immunoglobulins. The metabolic changes are often supplemented by physiological changes such as altered pulse rate, temperature and blood pressure.
The inflammatory response occurs in a similar pattern within a wide range of illnesses and may last for several days; when the inflammatory process persists for weeks or even months the term "chronic inflammation" is used. Certain chronic infections, such as HIV, can persist for years in apparently healthy subjects and yet they cause sufficient metabolic change to alter micronutrient levels considerably (12). Infection with parasitic disease such as malaria causes a different metabolic response in those who are repeatedly exposed and therefore develop various forms of immunity in contrast to those who have no immunity. The changes in APPs are greater in those who develop malaria infection without immunity (13) than in those who are chronically exposed (14). This results in differences in the changes in retinol levels in response to malaria.
Although a considerable body of knowledge now exists on the different components of inflammation involving many different cytokines, immunoglobulins, APPs, genes and secreted proteins, less information is available on what these changes mean in terms of whole-body micronutrient status or function. There are several possible explanations for changes in plasma levels of an APP. Alteration in dietary intake, absorption, synthesis or metabolism of the individual inflammatory protein together with change in urinary losses, alteration in plasma volume or extrusion from intravascular into tissue spaces are all possibilities. Changes of all of these have been documented during inflammation but there are remarkable powers of adaptation, and deficiency in a micronutrient level does not necessarily mean that micronutrient status and physiology is perturbed.
Using a combination of biochemical, immunological and stable isotope techniques, studies on the acute phase response in evidently healthy subjects with HIV have demonstrated some of the mechanisms that account for plasma changes in inflammatory proteins (15). The plasma concentrations, fractional synthetic rates and absolute synthetic rates of positive APPs were higher in HIV subjects than in control subjects. The fractional synthesis rates of the negative APPs were also elevated in the HIV subjects. These data indicate that measurement of plasma levels of APPs alone is insufficient to explain what is going on metabolically.
The changes in plasma levels of inflammatory proteins, both 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 plasma levels of inflammatory proteins. The importance of these findings with respect to micronutrient levels is perhaps greatest in relation to the reduction in plasma levels of RBP that is observed in many inflammatory processes. Reduced ability to carry retinol is important, especially for vitamin A–dependent tissues such as the eye, epithelial surfaces and immune cells. Thus a decreased plasma level of RBP may indicate a considerable risk of functional vitamin A deficiency. On the other hand, increased rates of turnover might allow delivery of sufficient micronutrients to target organs such that function is maintained despite a reduction in RBP. Until results of metabolic turnover studies of vitamin A and better measures of functional deficiency at the tissue level are available, it is not clear whether increased rates of synthesis of RBP achieve sufficient compensation for a reduced level of RBP in the plasma. The situation was summarized by Fleck (16), who concluded that in all likelihood the concentration of albumin and other negative APPs, such as RBP, decrease precipitously in response to infection, severe trauma and inflammation because of an increased transcapillary escape route and an increased catabolic rate.
The physiological roles of APPs are now better understood (17). CRP, for example, activates the classical pathway of complement, one of the main mechanisms in providing host defense. CRP also interacts with cells of the immune system by binding to the Fc gamma receptors. It may thus bridge the gap between innate and adaptive immunity and provide an early effective bacterial response. CRP also appears to protect against the damaging inflammatory response induced by lipopolysaccharides and cytokines (18, 19).
CRP immune expression, by liver hepatocytes in response to cytokines such as interleukin-6, requires several transcription factors that interact; CRP has been proposed to be one of the links between nonspecific innate immunity and specific clonal immunity. Although most is known about CRP, knowledge is increasing about the role of serum amyloid A (SAA), which also rises rapidly during the acute phase response and tends to return to normal with a few days of the acute event. Similar patterns occur with the chronic phase proteins such as -1 chymotrypsin (ACT) and -1 acid glycoprotein (AGP) (20).
In recent years the development of reactive oxygen species has been described during the acute inflammatory phase of many illnesses and experimental studies (21). This development leads to oxidative stress in which there is increased use of antioxidants such as vitamins C and E, selenium and carotenoids, with a reduction in plasma levels (22). There seems to be an increased consumption of antioxidants leading to lower plasma levels but whether changes in rates of turnover of these antioxidants compensates for their lower levels in plasma is not yet clear (23).
Measurements of inflammatory responses have been used to detect systemic infection in several clinical conditions. Children with elevated CRP and SAA who had acute or persistent diarrhea were more likely to have a severe complicating clinical illness such as meningitis, septicaemia or pneumonia. Raised tumor necrosis factor- in umbilical cord samples was a good indicator of sepsis in premature neonates (24). Even single organ infection, uveitis for example, is associated with raised inflammatory cytokines (25). More recently, studies of other inflammatory proteins such as calprotectin have been used to assess clinical severity of infection (26).
Subclinical infection
Most of the new clinical information on the metabolic responses to subclinical infection comes from studies on HIV and malaria in immune subjects. High levels of CRP and haptoglobin were shown to relate to the density of malarial parasites in Tanzanian children (27). Low levels of micronutrients are frequently described in subclinical infection. The levels appear to be lowest where there are highest levels of inflammatory proteins. The levels of plasma retinol in apparently healthy children in Ghana were lowest in those with raised AGP and SAA (20). Inflammatory processes are described in subclinical mastitis, a low-grade inflammation of breast milk in around 20–30% of lactating women in several studies in Asia and Africa, but it is not yet clear whether this inflammation changes micronutrient levels in milk (28).
Chronic inflammation in noninfectious disease
Diseases that are not considered infectious by normal criteria may be associated with elevated plasma levels of inflammatory proteins. Several studies have emphasized the important role that inflammation plays in the progression of atheromatous lesions; gene knockout experiments producing CRP-deficient animals show that atheroma can be prevented by removing the inflammatory mediators (29). CRP is associated with poor renal function in patients with chronic renal disease (30). Furthermore, the plasma level of CRP provides considerable prognostic value for susceptibility to development of atheroma and clinically evident coronary syndromes in later life. It is not yet clear what role inflammation plays in the development of coronary artery disease, but it raises the possibility that inflammation increases micronutrient requirements. The increasing recognition of gene-inflammation interactions raises the possibility that micronutrient-inflammation interactions may explain susceptibility to cardiac disease. Inflammatory responses and raised levels of reactive oxygen species increase requirements for micronutrients, leading to low circulating levels of plasma micronutrients (21). The beneficial effects of aspirin during unstable angina is associated with changes in CRP and improved clinical outcome (11). As more diseases are shown to be associated with a low-grade inflammation it will be important to determine the importance of low levels of plasma micronutrients (31).
In predialysis patients an increase in CRP and interleukin-6 have been noted as predictors of impaired renal function (32). When aspirin is provided to subjects with unstable angina, CRP levels are reduced and numbers of cardiac events are reduced, thereby emphasizing the potential role of inflammation in chronic diseases that have until now been attributed to diet, genes and environmental toxins (33, 34). These findings open up new lines of inquiry for inflammation-micronutrient interactions as contributing factors in the pathogenesis of a much wider range of illnesses than infectious diseases alone.
A reduction in levels of inflammatory proteins after anti-inflammatory treatment is well recognized but the accompanying changes in micronutrient levels have now been described (33). Patients with cancer had different plasma levels of CRP, albumin, transferrin and ceruloplasmin than did control subjects. They also had different levels of plasma retinol, -tocopherol, lutein, lycopene, - and ß-carotene, zinc, copper, iron and selenium. After a course of ibuprofen there were significant changes in the inflammatory proteins along with changes in lutein, lycopene and ß-carotene, iron, selenium and ceruloplasmin
Vitamin A. The changes in vitamin A metabolism during the acute phase response have been reviewed extensively (35, 36). Reductions in plasma retinol are described during the acute phase of a wide range of infections (6). They also occur in asymptomatic subjects in whom an inflammatory protein response is present. The effect of inflammation on plasma retinol appears to depend on the underlying nutritional status. Inflammatory stress reduced plasma retinol in Ghanaian children eating a consistently deficient diet (14) but a reduction in retinol was not marked in South African children in severe metabolic stress after accidental kerosene poisoning (37) or in Nigerian children with acute respiratory infection but who were apparently vitamin A replete (A). It was hoped that the relative dose response, a novel method for assessing vitamin A status that involves measurement of two forms of vitamin A, the naturally occurring form and a nonmetabolizable analog, would indicate vitamin A status, which was unaffected by the presence of inflammation. However, measurements of the relative dose response taken shortly after a metabolic stress resulting from accidental kerosene poisoning in South Africa showed that the relative dose response changed along with the expected changes in inflammatory proteins and plasma retinol (37).
Plasma retinol changes quickly as inflammation starts and CRP rises. As inflammation persists CRP levels return toward normal levels but levels of ACT and AGP become elevated. Several groups have examined different cutoffs for inflammatory proteins to see if they could correct for individual retinol levels (20, 38). However, although there is an overall association between inflammatory proteins and retinol, it has not proven possible to adjust satisfactorily for plasma retinol levels in inflammation. A composite of RBP and TTR was used to assess its potential value for controlling for the effect of inflammation on plasma retinol (39). Unfortunately the combination of individual levels of TTR and RBP did not provide a sufficiently sensitive or specific adjustment.
At a cellular level there was some evidence of reduction of liver RBP synthesis in animals injected with endotoxin (40), which was followed by whole-body turnover studies by Jahoor et al. (15). RBP may well escape into the extravascular space, possibly more so if it is not bound efficiently to TTR. Several studies demonstrated urinary losses of retinol and RBP (3). It was postulated that the plasma retinol-retinol binding polar concentrations might change at different rates; to assess the potential effect of inflammation on retinol and the binding proteins, RBP and TTR were analyzed in children who had suffered severe inflammation from acute respiratory distress (37). The RBP-to-TTR ratio was significantly decreased in inflammation; the results were compared with other measures of vitamin A status including plasma retinol and the modified relative dose response. Overall there was a weak association between vitamin A status and RPB and TTR.
Other researchers examined the use of CRP, SAA or ACT in controlling the levels of inflammatory proteins in an attempt to correct for the plasma retinols. So far these approaches have not found a sufficiently close interaction between APPs and retinol for them to be useful in clinical or epidemiological studies (38). The use of breast milk retinol as an indicator of vitamin A status is widely recommended because it fluctuates less than plasma retinols, but it is uncertain whether inflammation is localized to the breast or systemically changes the breast milk retinol status (41, 42).
Several studies have shown reduced levels of vitamin A in HIV and AIDS (43). Subjects with more severe clinical grades of AIDS have lower levels of vitamin A, probably representing the effect of inflammation rather than an increased severity of infection resulting from vitamin A deficiency. In a group of Zimbabwean women who were HIV positive but asymptomatic, ACT was not particularly elevated; within the group as a whole, ACT level explains a considerable proportion of the variance in serum ß-carotene and retinol (44). Adjustments for plasma retinol were performed using RBP, TTR and ACT. RBP, TTR and ACT concentrations of 0.3–0.4, 0.4–0.5 and >0.5 g/L gave 0.05, 0.14 and 0.38 µmol/L lower serum retinol concentration, respectively. In Ghanaian children, those with an AGP >1 g/L had a 24% lower serum retinol (20). Malaria has a variable effect on plasma retinol, probably because the metabolic stress is more determined by parasite-immune relationships rather than parasite density alone (12, 45). Several studies observed marked seasonal changes in plasma retinol. Although there are often striking variations in dietary intake because of seasonal availability of fruits such as papaya and mangoes, there are often quite marked seasonal changes in morbidity with associated changes in inflammatory proteins (46).
A recently published study showed that Wuchereria bancrofti infection was associated with lower levels of -tocopherol but the infection did not appear to be associated with lowered levels of retinol (47). There were many intestinal parasites present. Their presence appeared not to elevate the levels of inflammatory proteins. However it is interesting that W. bancrofti takes up tocopherol from its host to protect itself against the oxidative stress that it is exposed to within the intestine as part of the host immune rejection. The effect of intestinal helminths on micronutrient nutrition has been documented well with respect to iron but there are few studies on their effect on other micronutrients (48,
49).
Overall it appears logical to use plasma retinol levels for assessment of vitamin A status, certainly at a population level. Unfortunately it is not yet clear whether levels of inflammatory proteins can be used to control accurately for the reduction in plasma levels attributable to inflammation.
Iron. The lability of serum iron during infection is well known. In view of the ubiquitous requirement for iron by microbes infecting humans, it is just as well that the inflammatory response reduces levels of free circulating iron and increases levels of circulating of binding proteins (50). Iron supplements may be harmful; the progression of HIV to AIDS is faster in those with high iron stores (51). The protective effect of iron deficiency in individuals exposed to malaria and certain bacterial infections has been extensively reviewed (52). Iron deficiency is particularly protective in malarial infection (53); the pooling of red blood cells is thought to enhance malaria replication. Iron-deficient subjects vary in their susceptibility to infection, partly because of the NRAMP 1 gene, which controls the interaction between iron and intracellular pathogens (54).
In recent years plasma ferritin, a reputedly more stable marker of iron status than serum iron, has been widely used in nutritional surveys and clinical assessment (55). However, many studies show the marked elevation of ferritin during the acute and chronic phases of inflammation (56). When ferritin levels are low (e.g., <10 µg/L), there can be little doubt that iron status is deficient. However when inflammation is present, ferritin levels may often be >20 µg/L even in the presence of marked iron deficiency, as assessed by red blood cell indices and plasma ferritin levels when the infection is gone. Paracha et al. (38) used ACT and AGP to adjust for the effect of infection on ferritin. In a group of pregnant women in Zimbabwe, HIV infection, malaria parasitemia and raised plasma ACT levels were associated with increased plasma ferritin (57). In this study mild elevations of ACT were not a predictor of raised serum ferritin, but ACT concentrations of 0.4–0.5 and >0.5 g/L were associated with 1.26 and 3.16 µg/L higher ferritin levels, respectively. Overall this study showed that iron deficiency occurred in around two-thirds of the women when ferritin was used as a marker of iron stores, but infection caused high levels if ACT was >0.4 g/L. Interestingly, an effect on retinol but not iron was observed if ACT was >0.3 g/L.
As in the case of vitamin A, investigators have used different levels of cutoff for different acute phase responses seeking to distinguish between inflamed and noninflamed individuals. However, there is no widely accepted agreement on what cutoff levels should be used for proteins such as CRP and AGP in indicating whether a normal or high level of ferritin can truly represent adequate iron stores.
More recently the transferrin receptor (TfR) assay has been used because it was hoped that TfR would be more stable than ferritin (58). Several studies showed an effect of infection such as malaria on plasma TfR levels (59); although changes occur during acute infection in nonimmune subjects, these are considerably less than changes in ferritin. Changes in TfR levels between the infected and noninfected states in the same individual with malaria were <10% whereas the change in ferritin was fivefold (13). Chronic malaria in immune subjects is associated with elevated plasma TfR levels. A recent study showed that infection with W. bancrofti was associated with elevated plasma ferritin levels, contrasting with the generally low levels of plasma ferritins in the iron-deficient control population (49). Chronic inflammation can have profound effect on anemia (60) via a series of complex mechanisms whereby iron is inefficiently used (61).
Zinc. Zinc status is often assessed by measurements of zinc in plasma, white blood cells or hair (62). However many dietary and physiological factors such as exercise, eating, pregnancy and rapid growth in childhood may all alter plasma zinc levels (63). Whether this really represents zinc deficiency is arguable, and Golden (64) has discussed the criteria for assessing zinc status. Attempts at measuring metallothionein, an alternative indicator of zinc deficiency, have not resulted in robust indicators of assessment. Overall, mean plasma zinc levels in a population can be used to indicate deficiency. Plasma zinc and metallothionein are both reduced during acute phase response In addition there are considerable urinary losses of zinc in systemic infection, particularly those with a pronounced metabolic stress leading to breakdown of muscle (3, 17). The reduction of circulating zinc reduces zinc availability for microbial metabolism during infection (65, 66), providing an advantage similar to that achieved by reducing iron levels The recent recognition that calprotectin is released (from damaged neutrophils) during inflammation provides another mechanism for reducing plasma zinc levels during inflammation There is controversy about the role of circulating zinc in the control of replication rates of HIV. Zinc is bound to the nucleocapsid protein NCp7 and forms fingers that are essential for the formation of viral structure, proviral DNA synthesis and production of infectious viruses (67).
The amount by which plasma zinc falls in spontaneous infection was examined in Peruvian children in whom infection was diagnosed according to clinical signs or elevated CRP (68). A plasma zinc difference of around 0.5 mmol/L was noted between infected and noninfected children. This contrasted with more striking differences in mean ferritin levels (10.0 µg/L in uninfected vs. 3.9 µg/L in infected children). Even asymptomatic HIV depresses plasma zinc levels (69). An indirect method of assessing zinc status using alkaline phosphatase has been recognized for years. This changes when zinc supplements are given to children but its functional importance is difficult to assess because of the changes in plasma alkaline phosphatase during rapid growth (70).
Folate. A reduction in serum folate levels during acute inflammation is well recognized. Red cell folate levels however are much more stable; they are much less susceptible to recent changes in dietary intake than plasma levels. Chronic inflammation is associated with low red cell folate levels as are subclinical infections and these probably present the true condition of micronutrient deficiency. Overall red cell folate levels seem to be least affected by inflammatory responses and appear to be satisfactory markers of folate status. Among HIV-positive women in Zimbabwe, HIV and ACT were independently associated with lower serum folate levels (57). Women with an ACT level of >0.4 g/L had a serum folate level around 1 nmol/L. Interestingly low serum folate but normal homocysteine levels are found in patients with atherosclerotic heart diseases (71).
Selenium. Selenium status is often measured directly in serum, plasma, whole blood and hair. It has also been measured indirectly by assays of plasma glutathione peroxidase levels (72). Both serum and whole blood levels are decreased during the acute phase response. Low levels occur in several infections (73, 74). Several viral infections appear to stimulate the production of selenoproteins, leading to low serum levels of selenium. Patients with the lowest levels of selenium have the highest levels of morbidity and mortality but a causal effect has not yet been demonstrated (75). Morbidity and mortality appear to be less vulnerable to changes in inflammatory response, but short- and long-term studies are not available. Low levels occur in HIV and AIDS (76). Overall it is noted that selenium levels are low in infection. It has been postulated that this is due to the consumption of selenium as an antioxidant as part of the process of quenching free radicals (77). Whether plasma selenium is also reduced as part of the inflammatory process has not been studied intensively and there are no published attempts to control for changes in selenium due to changes in inflammatory proteins.
Copper. Copper is measured within the copper-binding protein complex of ceruloplasmin This is a positive APP that is elevated during the acute and chronic inflammatory response (78). There are no studies on the interaction between different levels of the acute phase responses and the copper-binding protein levels.
Thiamin. Thiamin is mostly assayed using the indirect enzymatic method of erythrocyte transketolase. Levels are known to be low in populations with poor thiamin intakes and there are associations between thiamin deficiency and malaria (79). However the comparison of erythrocyte transketolase and APPs such as CRP or SAA have not been performed.
Riboflavin. This nutrient is normally assayed by measurement of the erythrocyte glutathione reductase activation coefficient. Abnormal riboflavin levels are noted in dietary deficiency and malaria but there is little information on levels of APPs and alteration in erythrocyte glutathione reductase activation coefficient status (80, 81).
Niacin. Niacin levels estimated indirectly by measurement of nicotinamide adenine dinucleotide have been noted to be deficient in patients with HIV. Niacin interacts with certain antiretrovirus drugs but so far there is no link described with inflammation (82, 83).
Vitamin C. Vitamin C is normally assayed by measurement of ascorbic acid in plasma or leukocytes. There is marked change in the plasma ascorbic acid in inflammation but no clear association between a level of AGP or CRP at which the changes occur (84).
Vitamin D. Plasma levels of 25–cholecalciferol are used to assess vitamin D status because this is the circulating physiologically active form. There is no information on the effect of inflammation on these levels.
Vitamin E. The plasma level of tocopherol is known to be reduced during inflammation but there is no information on the association between tocopherol and APPs or chronic phase proteins (22).
How much does inflammation change micronutrient status?
This key question has several components. The first is whether it is possible to measure micronutrient status in an individual even without the presence of inflammation. The studies reviewed here indicate that for certain micronutrients such as folate, assays exist that are robust indicators of nutritional status. For others such as iron, the position is less satisfactory. The second component concerns the proportion by which micronutrient levels become changed as a result of the inflammatory process.
For no micronutrient is there a linear relationship between change in inflammatory protein and change in micronutrient status. Around 10 y ago Brown et al. (85) concluded that the effect of concurrent infections may differ by nutrient, nutritional status of the population and prevalence and severity of the infection. Although this is still true overall, there have been some recent developments in measurement technology and analysis. Work in progress seems likely to clarify the position considerably.
Is there a way forward for us to be able to make adjustments for the presence of inflammation in order to estimate true micronutrient status? There seem to be several important steps. First, using agreed-upon assay methods and standards together with a range of cutoff points for inflammatory proteins, the relationship between micronutrients and inflammation should be examined more carefully using pooled data. Second, an infective load should be described more precisely, but this will be difficult because of the difference in inflammatory response during infection in immune and nonimmune individuals. Third, ways to measure micronutrient levels in tissues or biopsy samples should be devised. Fourth, how circulating levels relate to deficiency at the tissue level should be better understood; this is likely to require a better understanding of the transport process and tissue function. If the first two steps could be achieved, it would be possible to correct for micronutrient levels in samples taken during inflammation.
These relationships are of more than just an academic interest. According to international criteria there are levels of ferritin and retinol at which iron deficiency and vitamin A deficiency, respectively, are recognized. There are clear guidelines for public health nutrition interventions. However, using the available indicators in populations burdened with a high prevalence of infection may lead to an underestimate of some micronutrient deficiencies (iron for example) and an overestimate of others (zinc for example).
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 I acknowledge with gratitude the research funding from the Wellcome Trust, DFID, UNICEF, the support of the Great Ormond Street Hospital NHS Trust and the Special Research Funds of the Hospital for Tropical Diseases, London.
4 Abbreviations used: ACT, -1 chymotrypsin; AGP, -1 acid glycoprotein; APP, acute phase protein; CRP, C-reactive protein; DHL-apo A, high-density lipoprotein-apolipoprotein A1; RBP, retinol binding protein; SAA, serum amyloid A; TfR, transferrin receptor; TTR, transthyretin.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTLITERATURE CITED |
|---|
1. Beisel, W. R., Pekarek, R. S., Van Ormer, D. & Wannemacher, R. W., Jr. (1971) Influence of acute infection on the metabolism of zinc and other trace elements. Psychopharmacol. Bull. 7: 34–35.[Medline]
2. Scrimshaw, N. S., Taylor, C. & Gordon, J. E. (1968) Interactions of Nutrition and Infection. World Health Organization, Geneva.
3. Beisel, W. R. (1995) Herman Award Lecture, 1995: Infection-induced malnutrition—from cholera to cytokines. Am. J. Clin. Nutr. 62: 813–819.
4. Garlick, P. J., McNurlan, M. A., Fern, E. B., Tomkins, A. M. & Waterlow, J. C. (1980) Stimulation of protein synthesis and breakdown by vaccination. BMJ 281: 263–265.
5. Tomkins, A. (2000) Malnutrition, morbidity and mortality in children and their mothers. Proc. Nutr. Soc. 59: 135–146.[Medline]
6. Filteau, S. M. & Tomkins, A. M. (1994) Micronutrients and tropical infections. Trans. R. Soc. Trop. Med. Hyg. 88: 1–3.[Medline]
7. Tomkins, A. M. (2001) Nutrition and maternal morbidity and mortality. Br. J. Nutr. 85 (Suppl. 2), S93–S99.
8. Mora, J. O. & Nestel, P. S. (2000) Improving prenatal nutrition in developing countries: strategies, prospects, and challenges. Am. J. Clin. Nutr. 71: 1353S–1363S.
9. Tschaikowsky, K., Hedwig-Geissing, M., Schiele, A., Bremer, F., Schywalsky, M. & Schuttler, J. (2002) Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C–reactive protein, and changes in T–cell subsets in septic and postoperative patients. Crit. Care Med. 30: 1015–1023.[Medline]
10. Whicher, J., Bienvenu, J. & Monneret, G. (2001) Procalcitonin as an acute phase marker. Ann. Clin. Biochem. 38, 483–493.[Medline]
11. Kennon, S., Price, C. P., Mills, P. G., Ranjadayalan, K., Cooper, J., Clarke, H. & Timmis, A. D. (2001) The effect of aspirin on C–reactive protein as a marker of risk in unstable angina. J. Am. Coll. Cardiol. 37: 1266–1270.
12. Friis, H. & Michaelsen, K. F. (1998) Micronutrients and HIV infection: a review. Eur. J. Clin. Nutr. 52: 157–163.[Medline]
13. Beesley, R., Filteau, S., Tomkins, A., Doherty, T., Ayles, H., Reid, A., Ellman, T. & Parton, S. (2000) Impact of acute malaria on plasma concentrations of transferrin receptors. Trans. R. Soc. Trop. Med. Hyg. 94: 295–298.[Medline]
14. Filteau, S. M., Morris, S. S., Abbott, R. A., Tomkins, A. M., Kirkwood, B. R., Arthur, P., Ross, D. A., Gyapong, J. O. & Raynes, J. G. (1993) Influence of morbidity on serum retinol of children in a community-based study in northern Ghana. Am. J. Clin. Nutr. 58: 192–197.
15. Jahoor, F., Gazzard, B., Phillips, G., Sharpstone, D., Delrosario, M., Frazer, M. E., Heird, W., Smith, R. & Jackson, A. (1999) The acute-phase protein response to human immunodeficiency virus infection in human subjects. Am. J. Physiol. 276, E1092–E1098.
16. Fleck, A. (1989) Clinical and nutritional aspects of changes in acute-phase proteins during inflammation. Proc. Nutr. Soc. 48: 347–354.[Medline]
17. Dinarello, C. A. (1984) Interleukin–1 and the pathogenesis of the acute-phase response. N. Engl. J. Med. 311: 1413–1418.[Medline]
18. Mold, C., Gresham, H. D. & Du Clos, T. W. (2001) Serum amyloid P component and C–reactive protein mediate phagocytosis through murine Fc gamma Rs. J. Immunol. 166: 1200–1205.
19. Wessels, F. J. & Moldawer, L. L. (2000) Nutritional modulation of the sepsis response: fish oils and innate immunity. Nutrition 16: 308–309.[Medline]
20. Filteau, S. M., Morris, S. S., Raynes, J. G., Arthur, P., Ross, D. A., Kirkwood, B. R., Tomkins, A. M. & Gyapong, J. O. (1995) Vitamin A supplementation, morbidity, and serum acute-phase proteins in young Ghanaian children. Am. J. Clin. Nutr. 62: 434–438.
21. Diplock, A. T. (1998) Defense against reactive oxygen species. Free Radic. Res. 29: 463–467.[Medline]
22. Allard, J. P., Aghdassi, E., Chau, J., Tam, C., Kovacs, C. M., Salit, I. E. & Walmsley, S. L. (1998) Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS 12: 1653–1659.[Medline]
23. Allard, J. P., Royall, D., Kurian, R., Muggli, R. & Jeejeebhoy, K. N. (1994) Effects of beta-carotene supplementation on lipid peroxidation in humans. Am. J. Clin. Nutr. 59: 884–890.
24. Dollner, H., Vatten, L., Linnebo, I., Zanussi, G. F., Laerdal, A. & Austgulen, R. (2001) Inflammatory mediators in umbilical plasma from neonates who develop early-onset sepsis. Biol. Neonate 80: 41–47.[Medline]
25. Yorston, D., Whicher, J., Chambers, R., Klouda, P. & Easty, D. (1985) The acute phase response in acute anterior uveitis. Trans. Ophthalmol. Soc. U. K. 104, 166–170.
26. Guibourdenche, J., Bedu, A., Petzold, L., Marchand, M., Mariani-Kurdjian, P., Marie, F., Hurtaud-Roux, O., Aujard, Y. & Porquet, D. (2002) Biochemical markers of neonatal sepsis: value of procalcitonin in the emergency setting. Ann. Clin. Biochem. 39, 130–135.[Medline]
27. Hurt, N., Smith, T., Tanner, M., Mwankusye, S., Bordmann, G., Weiss, N. A. & Teuscher, T. (1994) Evaluation of C–reactive protein and haptoglobin as malaria episode markers in an area of high transmission in Africa. Trans. R. Soc. Trop. Med. Hyg. 88: 182–186.[Medline]
28. Georgeson, J. C. & Filteau, S. M. (2000) Physiology, immunology, and disease transmission in human breast milk. Aids Patient Care STDS 14: 533–539.[Medline]
29. Whicher, J., Rifai, N. & Biasucci, L. M. (2001) Markers of the acute phase response in cardiovascular disease: an update. Clin. Chem. Lab. Med. 39: 1054–1064.[Medline]
30. Panichi, V., Migliori, M., De Pietro, S., Taccola, D., Bianchi, A. M., Norpoth, M., Metelli, M. R., Giovannini, L., Tetta, C. & Palla, R. (2001) C reactive protein in patients with chronic renal diseases. Ren. Fail. 23: 551–562.[Medline]
31. Diplock, A. T., Charleux, J. L., Crozier-Willi, G., Kok, F. J., Rice-Evans, C., Roberfroid, M., Stahl, W. & Vina-Ribes, J. (1998) Functional food science and defence against reactive oxidative species. Br. J. Nutr. 80 (Suppl. 1), S77–S112.
32. Panichi, V., Migliori, M., De Pietro, S., Taccola, D., Bianchi, A. M., Giovannini, L., Norpoth, M., Metelli, M. R., Cristofani, R., Bertelli, A. A., Sbragia, G., Tetta, C. & Palla, R. (2002) C-reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure. Nephron 91: 594–600.[Medline]
33. McMillan, D. C., Talwar, D., Sattar, N., Underwood, M., O'Reilly, D. S. & McArdle, C. (2002) The relationship between reduced vitamin antioxidant concentrations and the systemic inflammatory response in patients with common solid tumours. Clin. Nutr. 21: 161–164.[Medline]
34. Ikonomidis, I., Andreotti, F., Economou, E., Stefanadis, C., Toutouzas, P. & Nihoyannopoulos, P. (1999) Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 100: 793–798.
35. Filteau, S. M. (1999) Vitamin A and the acute-phase response. Nutrition 15: 326–328.[Medline]
36. Christian, P., Schulze, K., Stoltzfus, R. J. & West, K. P., Jr. (1998) Hyporetinolemia, illness symptoms, and acute phase protein response in pregnant women with and without night blindness. Am. J. Clin. Nutr. 67: 1237–1243.[Abstract]
37. Willumsen, J. F., Simmank, K., Filteau, S. M., Wagstaff, L. A. & Tomkins, A. M. (1997) Toxic damage to the respiratory epithelium induces acute phase changes in vitamin A metabolism without depleting retinol stores of South African children. J. Nutr. 127: 1339–1343.
38. Paracha, P. I., Jamil, A., Northrop-Clewes, C. A. & Thurnham, D. I. (2000) Interpretation of vitamin A status in apparently healthy Pakistani children by using markers of subclinical infection. Am. J. Clin. Nutr. 72: 1164–1169.
39. Filteau, S. M., Willumsen, J. F., Sullivan, K., Simmank, K. & Gamble, M. (2000) Use of the retinol-binding protein: transthyretin ratio for assessment of vitamin A status during the acute-phase response. Br. J. Nutr. 83: 513–520.[Medline]
40. Langley, S. C., Seakins, M., Grimble, R. F. & Jackson, A. A. (1994) The acute phase response of adult rats is altered by in utero exposure to maternal low protein diets. J. Nutr. 124: 1588–1596.
41. Lietz, G., Henry, C. J., Mulokozi, G., Mugyabuso, J. K., Ballart, A., Ndossi, G. D., Lorri, W. & Tomkins, A. (2001) Comparison of the effects of supplemental red palm oil and sunflower oil on maternal vitamin A status. Am. J. Clin. Nutr. 74: 501–509.
42. Stoltzfus, R. J. & Underwood, B. A. (1995) Breast-milk vitamin A as an indicator of the vitamin A status of women and infants. Bull. World Health Organ. 73: 703–711.[Medline]
43. Tang, A. M., Graham, N. M., Semba, R. D. & Saah, A. J. (1997) Association between serum vitamin A and E levels and HIV–1 disease progression. AIDS 11: 613–620.[Medline]
44. Friis, H., Gomo, E., Koestel, P., Ndhlovu, P., Nyazema, N., Krarup, H. & Michaelsen, K. F. (2001) HIV and other predictors of serum beta-carotene and retinol in pregnancy: a cross-sectional study in Zimbabwe. Am. J. Clin. Nutr. 73: 1058–1065.
45. Adelekan, D. A., Adeodu, O. O. & Thurnham, D. I. (1997) Comparative effects of malaria and malnutrition on plasma concentrations of antioxidant micronutrients in children. Ann. Trop. Paediatr. 17: 223–227.[Medline]
46. Thurnham, D. I., Northrop-Clewes, C. A., Paracha, P. I. & McLoone, U. J. (1997) The possible significance of parallel changes in plasma lutein and retinol in Pakistani infants during the summer season. Br. J. Nutr. 78: 775–784.[Medline]
47. Friis, H., Kaestel, P., Nielsen, N. & Simonsen, P. E. (2002) Serum ferritin, alpha-tocopherol, beta-carotene and retinol levels in lymphatic filariasis. Trans. R. Soc. Trop. Med. Hyg. 96: 151–156.[Medline]
48. Beasley, N. M., Tomkins, A. M., Hall, A., Kihamia, C. M., Lorri, W., Nduma, B., Ghisolfi, J. & Thouvenot, J. (1999) The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania. Trop. Med. Int. Health 4: 744–750.[Medline]
49. Friis, H., Ndhlovu, P., Kaondera, K., Sandstrom, B., Michaelsen, K. F., Vennervald, B. J. & Christensen, N. O. (1996) Serum concentration of micronutrients in relation to schistosomiasis and indicators of infection: a cross-sectional study among rural Zimbabwean schoolchildren. Eur. J. Clin. Nutr. 50: 386–391.[Medline]
50. Weinberg, E. D. (1999) The role of iron in protozoan and fungal infectious diseases. J. Eukaryot. Microbiol. 46: 231–238.[Medline]
51. Gordeuk, V. R., Delanghe, J. R., Langlois, M. R. & Boelaert, J. R. (2001) Iron status and the outcome of HIV infection: an overview. J. Clin. Virol. 20: 111–115.[Medline]
52. Oppenheimer, S. J. (2001) Iron and its relation to immunity and infectious disease. J. Nutr. 131: 616S–633S.
53. Loyevsky, M., John, C., Dickens, B., Hu, V., Miller, J. H. & Gordeuk, V. R. (1999) Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators. Mol. Biochem. Parasitol. 101: 43–59.[Medline]
54. Canonne-Hergaux, F., Fleming, M. D., Levy, J. E., Gauthier, S., Ralph, T., Picard, V., Andrews, N. C. & Gros, P. (2000) The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border. Blood 96: 3964–3970.
55. Cook, J. (1999) The nutritional assessment of iron status. Arch. Latinoam. Nutr. 49: 11S–14S.[Medline]
56. Witte, D. L. (1991) Can serum ferritin be effectively interpreted in the presence of the acute-phase response? Clin. Chem. 37: 484–485.
57. Friis, H., Gomo, E., Koestel, P., Ndhlovu, P., Nyazema, N., Krarup, H. & Michaelsen, K. F. (2001) HIV and other predictors of serum folate, serum ferritin, and hemoglobin in pregnancy: a cross-sectional study in Zimbabwe. Am. J. Clin. Nutr. 73: 1066–1073.
58. Cook, J. D. (1999) The measurement of serum transferrin receptor. Am. J. Med. Sci. 318: 269–276.[Medline]
59. Verhoef, H., West, C. E., Ndeto, P., Burema, J., Beguin, Y. & Kok, F. J. (2001) Serum transferrin receptor concentration indicates increased erythropoiesis in Kenyan children with asymptomatic malaria. Am. J. Clin. Nutr. 74: 767–775.
60. van den Broek, N. R. & Letsky, E. A. (2000) Etiology of anemia in pregnancy in south Malawi. Am. J. Clin. Nutr. 72: 247S–256S.
61. Fischer, J. G., Glauert, H. P., Yin, T., Sweeney-Reeves, M. L., Larmonier, N. & Black, M. C. (2002) Moderate iron overload enhances lipid peroxidation in livers of rats, but does not affect NF-kappaB activation induced by the peroxisome proliferator, wy–14,643. J. Nutr. 132: 2525–2531.
62. Hambidge, M. & Krebs, N. (1995) Assessment of zinc status in man. Indian J. Pediatr. 62: 169–180.[Medline]
63. King, J. C., Hambidge, K. M., Westcott, J. L., Kern, D. L. & Marshall, G. (1994) Daily variation in plasma zinc concentrations in women fed meals at six-hour intervals. J. Nutr. 124: 508–516.
64. Golden, M. H. (1982) Trace elements in human nutrition. Hum. Nutr. Clin. Nutr. 36: 185–202.[Medline]
65. Isaksen, B. & Fagerhol, M. K. (2001) Calprotectin inhibits matrix metalloproteinases by sequestration of zinc. Mol. Pathol. 54: 289–292.
66. Haraguchi, Y., Sakurai, H., Hussain, S., Anner, B. M. & Hoshino, H. (1999) Inhibition of HIV–1 infection by zinc group metal compounds. Antiviral Res. 43: 123–133.[Medline]
67. Mocchegiani, E., Muzzioli, M., Gaetti, R., Veccia, S., Viticchi, C. & Scalise, G. (1999) Contribution of zinc to reduce CD4+ risk factor for ‘severe’ infection relapse in aging: parallelism with HIV. Int. J. Immunopharmacol. 21: 271–281.[Medline]
68. Brown, K. H. (1998) Effect of infections on plasma zinc concentration and implications for zinc status assessment in low-income countries. Am. J. Clin. Nutr. 68 (Suppl.), 425S–429S.[Abstract]
69. Wellinghausen, N., Kern, W. V., Jochle, W. & Kern, P. (2000) Zinc serum level in human immunodeficiency virus-infected patients in relation to immunological status. Biol. Trace Elem. Res. 73: 139–149.[Medline]
70. Roy, S. K., Tomkins, A. M., Haider, R., Behrens, R. H., Akramuzzaman, S. M., Mahalanabis, D. & Fuchs, G. J. (1999) Impact of zinc supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea. Eur. J. Clin. Nutr. 53: 529–534.[Medline]
71. Bunout, D., Petermann, M., Hirsch, S., de la Mazo, P., Suazo, M., Barrera, G. & Kauffman, R. (2000) Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition 16: 434–438.[Medline]
72. Diplock, A. T. (1993) Indexes of selenium status in human populations. Am. J. Clin. Nutr. 57: 256S–258S.
73. Beck, M. A. (1999) Selenium and host defence towards viruses. Proc. Nutr. Soc. 58: 707–711.[Medline]
74. Sammalkorpi, K., Valtonen, V., Alfthan, G., Aro, A. & Huttunen, J. (1988) Serum selenium in acute infections. Infection 16: 222–224.[Medline]
75. Baum, M. K. (1997) Shor-Posner G. Nutritional status and survival in HIV–1 disease. AIDS 11: 689–690.[Medline]
76. Constans, J., Conri, C. & Sergeant, C. (1999) Selenium and HIV infection. Nutrition 15: 719–720.[Medline]
77. Bates, C. J., Prentice, A. M. & Paul, A. A. (1994) Seasonal variations in vitamins A, C, riboflavin and folate intakes and status of pregnant and lactating women in a rural Gambian community: some possible implications. Eur. J. Clin. Nutr. 9: 660–668.
78. Periquet, B. A., Jammes, N. M., Lambert, W. E., Tricoire, J., Moussa, M. M., Garcia, J., Ghisolfi, J. & Thouvenot, J. (1995) Micronutrient levels in HIV–1-infected children. AIDS 9: 887–893.[Medline]
79. Krishna, S., Taylor, A. M., Supanaranond, W., Pukrittayakamee, S., ter Kuile, F., Tawfiq, K. M., Holloway, P. A. & White, N. J. (1999) Thiamine deficiency and malaria in adults from southeast Asia. Lancet 353: 546–549.[Medline]
80. Adelekan, D. A. & Thurnham, D. I. (1998) Glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities in riboflavin-deficient rats infected with Plasmodium berghei malaria. Br. J. Nutr. 79: 305–309.[Medline]
81. Adelekan, D. A. & Thurnham, D. I. (1990) Plasma ferritin concentrations in anemic children: relative importance of malaria, riboflavin deficiency, and other infections. Am. J. Clin. Nutr. 51: 453–456.
82. Murray, M. F. (1999) Niacin as a potential AIDS preventive factor. Med. Hypotheses 53: 375–379.[Medline]
83. Murray, M. F. & Srinivasan, A. (1995) Nicotinamide inhibits HIV–1 in both acute and chronic in vitro infection. Biochem. Biophys. Res. Commun. 210: 954–959.[Medline]
84. Plit, M. L., Theron, A. J., Fickl, H., van Rensburg, C. E., Pendel, S. & Anderson, R. (1998) Influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin C, vitamin E, beta-carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 2: 590–596.[Medline]
85. Brown, K. H., Lanata, C. F., Yuen, M. L., Peerson, J. M., Butron, B. & Lonnerdal, B. (1993) Potential magnitude of the misclassification of a population's trace element status due to infection: example from a survey of young Peruvian children. Am. J. Clin. Nutr. 58: 549–554.
This article has been cited by other articles:
|
|
 |
|
  J. K. Kung'u, V. J. Wright, H. J. Haji, M. Ramsan, D. Goodman, J. M. Tielsch, Q. D. Bickle, J. G. Raynes, and R. J. Stoltzfus Adjusting for the Acute Phase Response Is Essential to Interpret Iron Status Indicators among Young Zanzibari Children Prone to Chronic Malaria and Helminth Infections J. Nutr., November 1, 2009; 139(11): 2124 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, B. Lonnerdal, S. Adu-Afarwuah, K. H Brown, C. M Chaparro, R. J Cohen, M. Domellof, O. Hernell, A. Lartey, and K. G Dewey Prevalence and predictors of iron deficiency in fully breastfed infants at 6 mo of age: comparison of data from 6 studies Am. J. Clinical Nutrition, May 1, 2009; 89(5): 1433 - 1440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. de Fatima Costa Caminha, A. da Silva Diniz, A. R. Falbo, I. K. G. de Arruda, V. B. Serva, L. L. de Albuquerque, M. M. de Freitas Lola, and G. J. Ebrahim Serum Retinol Concentrations in Hospitalized Severe Protein-energy Malnourished Children J Trop Pediatr, August 1, 2008; 54(4): 248 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C Tohill, C. M Heilig, R. S Klein, A. Rompalo, S. Cu-Uvin, E. G Piwoz, D. J Jamieson, and A. Duerr Nutritional biomarkers associated with gynecological conditions among US women with or at risk of HIV infection Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1327 - 1334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kongsbak, M. A. Wahed, H. Friis, and S. H. Thilsted Acute Phase Protein Levels, T. trichiura, and Maternal Education Are Predictors of Serum Zinc in a Cross-Sectional Study in Bangladeshi Children J. Nutr., August 1, 2006; 136(8): 2262 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Gieng and F. J. Rosales Plasma {alpha}1-Acid Glycoprotein Can Be Used to Adjust Inflammation-Induced Hyporetinolemia in Vitamin A-Sufficient, but Not Vitamin A-Deficient or -Supplemented Rats J. Nutr., July 1, 2006; 136(7): 1904 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E Cusick, J. M Tielsch, M. Ramsan, J. K Jape, S. Sazawal, R. E Black, and R. J Stoltzfus Short-term effects of vitamin A and antimalarial treatment on erythropoiesis in severely anemic Zanzibari preschool children Am. J. Clinical Nutrition, August 1, 2005; 82(2): 406 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J Haskell and K. H Brown Reply to M van Lieshout and S de Pee Am. J. Clinical Nutrition, April 1, 2005; 81(4): 945 - 946. [Full Text] [PDF]
|
|
|
|
|
|
M. J Haskell, P. Pandey, J. M Graham, J. M Peerson, R. K Shrestha, and K. H Brown Recovery from impaired dark adaptation in nightblind pregnant Nepali women who receive small daily doses of vitamin A as amaranth leaves, carrots, goat liver, vitamin A-fortified rice, or retinyl palmitate Am. J. Clinical Nutrition, February 1, 2005; 81(2): 461 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Erhardt, J. E. Estes, C. M. Pfeiffer, H. K. Biesalski, and N. E. Craft Combined Measurement of Ferritin, Soluble Transferrin Receptor, Retinol Binding Protein, and C-Reactive Protein by an Inexpensive, Sensitive, and Simple Sandwich Enzyme-Linked Immunosorbent Assay Technique J. Nutr., November 1, 2004; 134(11): 3127 - 3132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Smith, J. E. Davis-Street, J. V. Fesperman, M. D. Smith, B. L. Rice, and S. R. Zwart Nutritional Status Changes in Humans during a 14-Day Saturation Dive: The NASA Extreme Environment Mission Operations V Project J. Nutr., July 1, 2004; 134(7): 1765 - 1771. [Abstract] [Full Text]
|
|
|
|
|
|
A. A. Jackson, Z. A. Bhutta, and P. Lumbiganon Introduction J. Nutr., May 1, 2003; 133(5): 1589S - 1591. [Full Text] [PDF]
|
|
|
|
|
|
R. Romero, T. Chaiworapongsa, and J. Espinoza Micronutrients and Intrauterine Infection, Preterm Birth and the Fetal Inflammatory Response Syndrome J. Nutr., May 1, 2003; 133(5): 1668S - 1673. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
