Micronutrients and outcome

OUTCOMES

RESEARCH

Nutrition Vol: 13, No. 9, 1997

GUEST EDITORS: SIMON ALLISON,

ANNE COBLE VOSS, PHD, RD

Manager Outcomes Research Ross Products Division Columbus, Ohio, USA

MD, FRCP

Consultant Physician Department of Medicine Queens Medical Centre Nottingham, United Kingdom

Micronutrients and Outcome ALAN

SHENKIN, PHD, FRCP, FRCPATH

From the Department of Clinical Chemistry, University of Liverpool, Liverpool, England, United Kingdom

How useful in clinical practice is the laboratory measurement of micronutrients in blood or plasma samples? Most protocols for investigation and monitoring of patients receiving nutritional support, especially intravenous nutrition (IVN) include the measurement of certain trace elements such as zinc and copper, and certain vitamins, such as folate and vitamin B,,. There are growing pressures for justification of the use of laboratory resources, especially when the measurements concerned are fairly costly. It is, therefore, timely to question the situations where measurements of micronutrients are helpful in the diagnosis of a nutritional deficiency, the extent to which these nutritional deficiencies will lead to a clinical complication, and whether any supplements indicated lead to a benefit in patient outcome. WHICH ASPECTS OF OUTCOME RELATE TO MICRONUTRIENT STATUS?

Dejciency

States

The natural history of the effects of inadequacy of most micronutrients is shown in Figure 1. By definition, if an essential nutrient is not supplied in the diet, whether by the intravenous or enteral route, for a long enough period of time, a deficiency state will develop. For all essential micronutrients, this is characterized by the development of biochemical abnormalities and also signs and symptoms characteristic of severe deficiency. The

Nutrition 13:825-828, 1997 OElsevier Science Inc. 1997 Printed in the USA. All rights reserved.

range of abnormalities, and the clinical situations in which they are most likely to occur, have been summarized in other reviews.i,2 Since it is unusual for any clinical presentation to be absolutely specific for a particular nutritional deficiency, use of appropriate laboratory tests is necessary to confirm the nature of the deficiency and its severity. For example, measurement of plasma zinc in a patient with a skin rash, plasma copper in a child with intractable hypochromic anemia, plasma selenium (or RBC glutathione peroxidase) in a patient with skeletal muscle pain and weakness, or RBC thiamine in peripheral neuropathy may all be helpful. Subclinical Dejiciency States In recent years, however, there has been much more interest in the potential consequences of a subclinical deficiency. This can be defined as a condition where micronutrient status is poor, with depleted reserves or localized tissue deficiencies, but where the classical signs of a deficiency state have not yet developed. There are many possible effects of a subclinical deficiency depending upon which tissue or organ is most susceptible. Effects on the Immune System Perhaps of most importance in relation to outcome is the effect of many micronutrients on the immune system. Virtually all have been shown to affect aspects of immunity in vitro.3 For example, zinc deficiency leads to reduced T lymphocyte

ELSEVIER

numbers, decreased responses to mitogens, decreased natural killer (NK) cell activity and reduced T cell dependent antibody production4 and selenium is necessary for phagocytosis,5 optimal function of NK cells and cytotoxic lymphocytes, and for T cells in producing interleukin (IL)-2.6 Despite this evidence demonstrating that defective immune function may occur in subclinical micronutrient deficiency states, it has only recently been shown that this can lead to clinically important consequences. A key, though rather small, study,7 was of a multitrace element and vitamin supplement in free living elderly individuals in Newfoundland and which led to a significant reduction in the episodes of infection over a l-y period. This was associated with a reduction in the frequency of low plasma concentrations of the micronutrients, and an increase in markers of immune function, including NK cell numbers, CD3 and CD4 positive T lymphocytes, and IL-2 production. Which of the various micronutrients was of most relevance in improving immune status was not clear. It is possible that one micronutrient alone may improve outcome. For many years it has been recognized that vitamin A deficiency may be an additional risk factor in complications of measles infection. A recent meta-analysis of prospective randomized controlled trials using vitamin A supplements both in children with measles, and in premature infants, showed a

0899.9007/97/$17.00 PI1 SO899-9007(97)00200-l

MICRONUTRIENTS

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healing in the absence of clinical deficiency.‘* Moreover, zinc deficiency is related to impaired wound healing, but there is controversy over the value of zinc supplements in surgical wounds, the best evidence relating to healing of cutaneous leg ulcers.‘3 The extent to which a subclinical deficiency of these or other micronutrients lead to impairment of wound healing is not known.

tissue level.9

I lnithd

depktioo

-compematlon to

inadequate supply

AND OUTCOME

ies. It is not clear which patients benefit, and especially whether the greatest effect is seen in the patients who are most depleted. In particular, data derived from population studies cannot necessarily be applied to individual patients. Moreover, the time scale of such studies suggests their relevance only for patients on longterm home nutritional support, although the effects of short-term oxidative damage are not known.

Effects on Cognitive Function

metabolic bnmun01ogical

cognitive work

capactty

I

FIG. 1. Development of micronutrient deticiency.

significant reduction in infective complications of diarrhea1 and respiratory disease.8 Recently, Berger and colleagues,9J0 from the Burns Unit in Lausanne, have conducted a series of studies of intravenous provision over the first 8 d after bum injury, of zinc, copper, and selenium in amounts calculated to meet the high cutaneous losses as a result of severe bums. It is of interest that only the plasma selenium was significantly increased by provision of the supplement. The important clinical result, however, was that provision of the supplement was associated with a reduction in the number of infectious episodes during the first 30 d after injury. This was associated with an increased number of neutrophils, but no change in lymphocyte numbers. In the patients studied to date (10 in supplemented, 10 in placebo group), this has been associated with a reduced length of stay in the Intensive Care Unit and in the Bums Unit, but not with a reduced overall stay in hospital (Berger, personal communication). This is the first study showing that trace elements may influence the outcome of severely ill patients. Interestingly, preliminary results from a trial of such supplements in multiply injured patients, in whom excessive losses do not occur, suggest no effect on outcome (Berger, personal communication), although they may modify the low T, syndrome in these patients.” Effects on Wound Healing Severe deficiency of vitamin C scurvy, with disruption of collagen sis. There is some evidence that mented vitamin C may accelerate

leads to synthesupplewound

It is also becoming apparent that some aspects of cognitive function are probably affected by micronutrient status. Thus, adolescents who have a range of micronutrient intake relative to the type of oral diet consumed, were found to respond to a multi-supplement by improvement in ability to concentrate.14 What has been lacking to date, in this type of study, has been evidence that the individuals who responded best to the supplement were those with the poorest diet, and that they had the lowest levels of micronutrients in blood or tissues. Such studies have been controversial, and moreover are difficult to replicate in the clinical environment. Nonetheless, the changes observed may be relevant, especially to the chronic sick and those who remain on artificial nutrition at home. Micronutrients

and Antioxidant

Function

Micronutrients have a range of functions to prevent oxidative damage to polyunsaturated fatty acids in cell membranes, and to DNA within all cells. Zinc, copper, and manganese are all involved in the superoxide dismutase enzymes in mitochondria and the cytoplasm, and selenium is part of the glutathione peroxidase enzyme system, which helps to dispose of hydrogen peroxide. Moreover vitamin E, vitamin A, and /3 carotene are lipophilic antioxidants in cell membrane structures, vitamin C being the major cytoplasmic antioxidant.15 There is much activity currently in studying the effects of increased supplies of various antioxidants, either singly or in combination, in an attempt to determine whether there is a clinical benefit in conditions thought to be related to excess free radical oxidative activity. Such conditions include atherosclerosis, for which there is evidence accumulating on the supplementation benefit of vitamin E,16 and neoplastic disease where some trials have been encouraging, e.g., the use of selenium in various forms of cancer,i7 although other trials either show no effect or show a poorer outcome, e.g., vitamin E and p carotene in lung cancer.‘* There are many problems in trying to apply these data to patients receiving artificial nutrition. First, trials to date have usually been large scale population stud-

HOW WELL IS MICRONUTRIENTSTATUS ASSESSED BY MEASUREMENTS IN BLOOD OR PLASMA? If some aspects of clinical outcome do relate to micronutrient status, the key question is whether laboratory tests are useful in assessing micronutrient status, and hence in determining the patients who should be supplemented. Ideally, laboratory tests should allow identification of patients with: (1) severe micronutrient depletion posing the risk of a clinically important deficiency state; (2) a depleted micronutrient status, indicative of inadequate intake or utilisation, but not yet proving a clinical risk, or (3) adequate intake leading to optimal tissue function. The key aspects of laboratory tests which need to be considered are their sensitivity and specificity in relation to the above questions. The sensitivity determines how many individuals with the condition would be classified as not having it, i.e., false-negative results. To be able to accurately classify patients as described above, the blood test would require to vary in a linear manner with changing tissue status. For plasma measurements this is most unlikely, since the plasma concentration rarely reflects directly the tissue concentration, which determines the metabolic effects. Hence, changes in plasma concentration are more likely to reflect flow between organs as part of the metabolic response to severe illness or trauma, or changes in recent intake, e.g., plasma selenium or folate. A normal concentration in plasma, therefore, does not exclude a significant reduction in whole body status. There is also a problem in relating plasma or blood concentrations to clinical complications. Most patients who do have a deficiency state also have low plasma or whole blood concentrations.Q However, a low plasma selenium or even red cell glutathione peroxidase has been widely seen in patients on long-term home parenteral nutrition but only a small proportion of such patients developed clinical signs and symptoms of selenium deficiency. I9 Why certain patients go on to develop clinical signs of

MICRONUTRIENTS

AND OUTCOME

selenium deficiency is not known. It may be however that patients require a combination of poor biochemical status, together with some further stimulus to precipitate full blown complications of selenium deficiency. It is also worth noting that a state of selenium deficiency may encourage the mutation of otherwise nonvirulent viruses to a more virulent form.20 Measurements on cellular components, e.g., whole blood thiamine, red cell folate, leukocyte zinc, are more sensitive markers of whole body status of these micronutrients, but they are more difficult to perform, and hence are relatively infrequently used in clinical practice. Although such measurements may not help in the individual patient, their use in a research context may identify groups of patients who might benefit from an increased intake.21 New methods of assessing micronutrient status may prove to be more sensitive than direct analysis of the micronutrient itself, e.g., metabolic evidence of vitamin deficiency despite normal serum vitamin concentrations has been obtained by a fall in homocysteine and methylmalonic acid concentration in serum, in response to an intramuscular supplement of vitamin B,,, B,, and folate.22 On the other hand, the specificity of biochemical measurements can be a major problem, especially in sick patients. Thus, infection or trauma, e.g., surgery, causes a rapid fall in concentration of micronutrients such as plasma zinc, iron, or vitamin C. This seems to be an obligatory response as part of the acute phase response, which does not reflect either whole body status or

827 a requirement for increased supply, just redistribution to the active organs. Interpretation of the concentration of these micronutrients in plasma is, therefore, complicated in the sick patient.23 A simultaneous measurement of an acute phase reactant such as C-reactive protein (CRP), helps to indicate whether a redistribution of these micronutrients from the plasma into cells is occurring. A fall in CRP should be associated with a rise in plasma zinc, and if this does not occur, then additional zinc may be required. This could be evidence of increased anabolism, indicating an increased zinc requirement for protein synthesis in the postcatabolic period.24 IS MEASUREMENT HELPFUL IN DETECTING EXCESS PROVISION OF MICRONUTRIENTS?

Although most attention is given to the problem of an inadequate supply of micronutrients, it is important to recognize the potential for over provision, especially by the intravenous route. All of the micronutrients provided intravenously can cause harmful effects, and for some the margin of safety is fairly small. Thus, excess selenium, copper, vitamin A, and vitamin D are all potentiahy harmful. Studies in patients receiving long-term IVN demonstrated that the intake of manganese, in adults and in infants, was too high as measured by plasma manganese or whole blood manganese.i9sz5 Only recently has it been determined that such manganese excess is related to a clinical syndrome including manganese deposition in extrapyramidal tracts causing Parkinsonian-like

symptoms.26 Plasma and blood concentrations are, therefore, helpful in minimizing the risk of excess provision, whether this is due to a miscalculation in the requirements, or to contamination of some other part of the intravenous regimen. Monitoring of blood concentrations of various trace and toxic elements during long-term artificial nutrition is, therefore, highly desirable. SUMMARY Micronutrient deficiency not only causes symptoms of severe deficiency, but may also cause more subtle effects on tissue function, including immune deficiency and oxidative damage. The duration of a deficiency state, which is necessary before such effects are clinically significant, is not known. Most biochemical tests are relatively insensitive in detecting changes in micronutrient status, although they do provide a crude index. Many tests are nonspecific, being affected by the acute phase response as well as by nutritional status. Cellular tests are more sensitive and specific than tests in plasma. When interpreted carefully in association with the knowledge of the patient’s clinical condition and nutritional intake, laboratory tests can be helpful in diagnosing deficiency states or conditions of excess provision, and in monitoring progress. Well conducted clinical trials of micronutrients in nutritional support are beginning to appear in the literature. Further studies are urgently required that relate outcome to levels of provision and biochemical indices of nutrient status.

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