Development of age-dependent micronutrient centile charts and their utility in children with chronic gastrointestinal conditions at risk of deficiencies: A proof-of-concept study.

BACKGROUND & AIMS: Interpretation of blood micronutrient levels requires age-appropriate reference intervals. This study developed age-dependent micronutrient centiles for healthy children (HC) and explored their utility in sick children. METHODS: 244 blood samples were collected from normal HC who underwent tests for acute illness. Age-dependent, centile charts were fitted for zinc, copper, magnesium and selenium in plasma and erythrocytes (RBC), and for vitamins B1, B2 and B6 in RBC. For 34 children with Crohn's disease (CrD) and 55 with coeliac disease (CoeD), Z-scores for the levels of these micronutrients were computed, using the new charts. Associations were explored between plasma and RBC micronutrient Z-scores, and in CrD with CRP and serum albumin. RESULTS: In HC, plasma zinc and selenium increased and plasma copper, magnesium and RBC vitamins B1, B2 and B6 decreased with age. In HC and in CrD, plasma and RBC Z-scores for copper, selenium and magnesium (all p < 0.001) were positively correlated, but not for zinc. In CrD, albumin was related with plasma zinc (rho = 0.62; p < 0.001) and selenium Z-scores (rho = 0.65; p < 0.001) and plasma copper Z-score with CRP (rho = 0.45; p = 0.02). A higher proportion of CrD children had low levels for B2 (21% vs 0%; p = 0.01) and B6 (18% vs 0%; p = 0.02) using the new centile charts than the local laboratory references. CONCLUSION: Age-dependent micronutrient centile charts enable tracking of micronutrient status, Z-score calculation and may prevent misdiagnosis and inappropriate treatment of deficiencies. In systemic inflammatory conditions, RBC measurements of certain micronutrients may be more reliable to use than measurements in plasma.

The effect of the systemic inflammatory response on plasma zinc and selenium adjusted for albumin.

BACKGROUND & AIM: The magnitude of systemic inflammatory response, as evidenced by C-reactive protein (CRP), is a major factor associated with lower zinc and selenium. They may also be influenced by their binding proteins, such as albumin. The aim of the present study was to examine the relationships between plasma zinc, selenium and the systemic inflammatory response in a large cohort of patients referred for nutritional screen and also to examine these relationships in patients with critical illness. METHODS: Patients referred for nutritional assessment of zinc (n = 743) and selenium (n = 833) and 114 patients with critical illness were examined. Intra-assay imprecision was <10% for these analytes. RESULTS: In the nutritional screen cohort, plasma zinc was significantly associated with CRP (rs = -0.404, p < 0.001) and albumin (rs = 0.588, p < 0.001). For each CRP category (≤10, 11-80, >80 mg/l) the zinc/albumin ratio x100 was similar (31, 33 and 32 respectively, p = 0.029). Plasma selenium was significantly associated with CRP (rs = -0.489, p < 0.001) and albumin (rs = 0.600, p < 0.001). With increasing CRP category (≤10, 11-80, >80 mg/l) the selenium/albumin ratio ×100 was lower (2.3, 2.1 and 1.8 respectively, p < 0.001). Similar relationships were also observed in the cohort of patients with critical illness. CONCLUSION: Plasma zinc was associated with both CRP and albumin. The impact of the systemic inflammatory response could be largely adjusted by albumin concentrations. Plasma selenium was associated with both CRP and albumin. The impact of the systemic inflammatory response on plasma selenium concentrations could not be reasonably adjusted by albumin concentrations.

Health Behaviours during Pregnancy in Women with Very Severe Obesity.

The health behaviours of pregnant women with very severe obesity are not known, though these women are at high risk of pregnancy complications. We carried out a prospective case-control study including 148 very severely obese (BMI >40 kg/m²) and 93 lean (BMI <25 kg/m²) pregnant women. Diet, physical activity, smoking, alcohol and folic acid consumption were assessed by questionnaire in early and late (16 and 28 weeks gestation) pregnancy. Circulating levels of iron, vitamin B12 and folate and other essential trace elements and minerals were measured in a subset at each time point. The findings biochemically confirmed that very severely obese women consumed diets that were energy-rich but poor in essential micronutrients. A third of all women met physical activity recommendations for pregnancy. A third of very severely obese women and two thirds of lean women took folic acid supplements prior to pregnancy. Very severely obese women were more likely to smoke but less likely to drink alcohol than lean women (all p < 0.05). Women with very severe obesity have low self-reported intakes and circulating levels of essential micronutrients in pregnancy and few follow current recommendations for pregnancy nutrition and lifestyle. These high-risk women represent a group to target for education about health behaviours prior to and during pregnancy.

The risk of copper deficiency in patients prescribed zinc supplements.

AIMS: In high doses zinc may cause copper deficiency, a diagnosis that is often missed resulting in anaemia, neutropenia and irreversible neurological symptoms. The aim of this study was to assess if zinc deficiency is erroneously diagnosed by misinterpretation of plasma zinc concentrations and whether copper deficiency is induced in patients prescribed zinc. METHODS: Casenotes of 70 patients prescribed zinc were scrutinised. Plasma concentrations of zinc, copper, C reactive protein and albumin were recorded from the laboratory database. RESULTS: 62% of patients were prescribed zinc at doses sufficient to cause copper deficiency. In 48% of the patients, plasma zinc concentrations were low as a probable result of hypoalbuminaemia or the systemic inflammatory response rather than deficiency. Awareness of copper deficiency was lacking; it was only documented as a possible side effect in one patient and plasma copper was measured in only two patients prescribed zinc. 9% of patients developed unexplained anaemia and 7% developed neurological symptoms typical of copper deficiency. CONCLUSIONS: Zinc deficiency is frequently misdiagnosed on the basis of low plasma zinc concentrations. The potential risk of copper deficiency developing in patients prescribed high doses of zinc is apparently infrequently considered. It is probable that a significant minority of patients prescribed with high doses of zinc develop iatrogenic copper deficiency.

Assessment of plasma and red cell trace element concentrations, disease severity, and outcome in patients with critical illness.

PURPOSE: The purpose of the study is to examine the value of both plasma and red cell trace element measurements when assessing nutritional status in patients with critical illness. MATERIALS AND METHODS: A total of 125 patients who were admitted to intensive care unit with evidence of systemic inflammatory response as per Bone's criteria were recruited. Venous blood samples were obtained from all on admission and, in 31 of the 125 patients, on approximately days 4 and 7. Copper, zinc, and selenium concentrations were measured in plasma and erythrocytes and results related to mortality and patient outcome measures. RESULTS: A total of 125 critically ill patients were recruited; 81 (66%) were male, the median age was 60 (range, 18-100), and the medical/surgical proportion was 55/70 (44%/56%). The median (lower and upper 2.5th percentile) Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, and length of stay and mortality were 21 (16-26), 7 (4-9) 3.7 days (1.5-11.1) and 19%, respectively. Plasma zinc and selenium concentrations were significantly lower on admission compared with reference intervals, whereas copper was increased. Normal plasma glutathione peroxidase activity suggested selenium status was adequate on admission; erythrocyte concentrations of glutathione peroxidase and trace elements were normal, suggesting adequate nutritional status 1 to 2 months before admission. Only plasma zinc and selenium were inversely associated with C-reactive protein (rs = -0.266, P = .004, rs = -0.322, P < .001, respectively). Compared with survivors, albumin (P < .001) concentrations were significantly lower in the nonsurvivor group. No significant difference of plasma selenium and zinc between survivors and nonsurvivors was found, although plasma selenium concentrations tended to be lower (P = .04). On multivariate logistic regression analysis of the significant variables, none was independently associated with mortality. CONCLUSION: The altered plasma concentrations of zinc, selenium, and copper in patients with critical illness were primarily due to the effects of the systemic inflammatory response and do not reliably indicate their status.

Erythrocyte selenium concentration as a marker of selenium status.

BACKGROUND & AIMS: Plasma selenium concentration and glutathione peroxidase (GPx) activity are commonly used as markers of selenium nutritional status. However, plasma selenium concentrations fall independently of selenium status during the acute phase response and GPx is analytically problematic. The assay for erythrocyte selenium is robust and concentrations are unaffected by the systemic inflammatory response. This study was performed to investigate the validity of erythrocyte selenium measurement in assessing selenium status. METHODS: C-reactive protein (CRP), plasma and erythrocyte selenium concentrations and GPx activity were measured in 96 women from two regions of Malawi with low and high selenium dietary intakes. CRP and plasma and erythrocyte selenium was measured in 91 critically ill patients with a systemic inflammatory response. RESULTS & CONCLUSIONS: The median CRP value of all subjects from Malawi was 4.2 mg/L indicating no inflammation. The median CRP value for the critically ill patients was 126 mg/L indicating this group was inflamed. In the non-inflamed population there was a strong positive correlation (r = 0.95) between erythrocyte and plasma selenium and a strong positive correlation (r = 0.77) between erythrocyte selenium and erythrocyte GPx up to 6.10 nmol/g Hb after which maximal activity was reached. In the inflamed population, plasma selenium was low, erythrocyte selenium was normal and there was a weak correlation (r = 0.30) between selenium concentrations in plasma and erythrocytes. This demonstrates that plasma selenium is affected by the inflammatory response while erythrocyte selenium concentration is unaffected and can be used to reliably assess selenium status across a wide range of selenium intakes.

Zinc supplementation in intensive care: results of a UK survey.

PURPOSE: Our laboratory receives many routine requests for plasma zinc analysis from intensive care units (ICUs) throughout Scotland. However, such requests are inappropriate because plasma zinc concentrations fall independently of nutritional deficiency during the systemic inflammatory response and, therefore, in critically ill patients. This survey was performed to investigate how widespread this practice was and if low plasma zinc concentrations were interpreted as zinc deficiency so triggering inappropriate initiation of zinc supplementation. MATERIALS AND METHODS: A questionnaire was sent to ICUs throughout the UK; nonresponders were contacted by telephone, and the questionnaire details were recorded. The questionnaire asked if plasma zinc was routinely requested, the frequency of requests, whether patients were supplemented with zinc, and if so, the grounds for supplementation and the dose given. RESULTS: Plasma measurement of zinc was routinely performed in 18% of UK ICUs. Zinc supplementation was given in 10%, usually as a result of finding low plasma zinc concentrations. Dosages of supplementation varied widely between ICUs: from 0.4 to 135 mg zinc per day. Approximately 6% of ICUs gave very high supplements of zinc of 90 and 135 mg/d. CONCLUSIONS: The finding of a low plasma zinc concentration in Intensive Therapy Unit patients is often misinterpreted as indicating zinc deficiency and inappropriately prompts zinc supplementation. There is no evidence base to support high-dose zinc supplementation in ICU patients. This practice is justifiable only if future randomized trials demonstrate a benefit.

Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements.

BACKGROUND: Plasma concentrations of several trace elements and vitamins decrease because of the systemic inflammatory response. Thus, low values do not necessarily indicate deficiency. OBJECTIVE: The magnitude of this effect on plasma micronutrient concentrations was investigated to provide guidance on the interpretation of routine clinical results. DESIGN: Between 2001 and 2011, the results (2217 blood samples from 1303 patients) of routine micronutrient screens (plasma zinc, copper, selenium, and vitamins A, B-6, C, and E) and all vitamin D results (4327 blood samples from 3677 patients) were extracted from the laboratory database. C-reactive protein concentrations were measured as a marker of the severity of inflammation and categorized into 6 groups; for each group, plasma micronutrient concentrations and percentage changes were calculated. RESULTS: Except for copper and vitamin E, all plasma micronutrient concentrations decreased with increasing severities of the acute inflammatory response. For selenium and vitamins B-6 and C, this occurred with only slightly increased C-reactive protein concentrations of 5 to 10 mg/L. For each micronutrient, the change in plasma concentrations varied markedly from patient to patient. The magnitude of the effect was greatest for selenium and vitamins A, B-6, C, and D, for which the median plasma concentrations decreased by >40%. CONCLUSIONS: The clinical interpretation of plasma micronutrients can be made only with knowledge of the degree of inflammatory response. A reliable clinical interpretation can be made only if the C-reactive protein is <20 mg/L (plasma zinc), <10 mg/L (plasma selenium and vitamins A and D), or <5 mg/L (vitamins B-6 and C).

Acute inflammatory response does not affect erythrocyte concentrations of copper, zinc and selenium.

BACKGROUND & AIMS: Measuring the nutritional status of trace elements in plasma is invalidated in the presence of a systemic inflammatory response. We examined the potential of erythrocytes to assess copper, zinc and selenium status in such situations. METHODS: Venous blood samples were withdrawn pre-operatively and at 12, 24, 48, 72 and 168 h post-operatively from 11 patients (6 males and 5 females) who were admitted for elective knee arthroplasty. C-reactive protein, albumin, copper, zinc, selenium and iron were measured in plasma and erythrocytes. RESULTS: Plasma zinc and selenium concentrations fell significantly: 95% confidence intervals (CI)=-32% to -44% and -22% to -36%, respectively. Copper concentrations fell transiently and then increased significantly: CI=12-43%. No significant changes were seen in trace element concentrations in erythrocytes expressed either as a ratio of haemoglobin or iron concentration. Erythrocyte iron levels correlated significantly with haemoglobin (r=0.93). CONCLUSIONS: Plasma concentrations of copper, zinc and selenium are unreliable markers of status in patients with an acute inflammatory response. Erythrocyte concentrations of these trace elements may provide a more reliable measure in long-term studies of patients with a chronic systemic inflammatory response. Iron can be used instead of haemoglobin as the denominator when expressing erythrocyte concentrations of trace elements.

Assessment of dietary intake and trace element status in patients with ileal pouch-anal anastomosis.

PURPOSE: Panproctocolectomy and ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis and familial polyposis. The long-term nutritional consequences after pouch surgery are unknown. We have assessed the nutritional status of the essential trace elements-zinc, copper, manganese, and selenium-in patients several years (median, 10 (range, 2-15) years) after surgery. METHODS: Fifty-five patients with uncomplicated ileal pouch-anal anastomosis and 46 healthy control subjects were studied. A dietary assessment of trace element intake was undertaken by using a semiquantitative food frequency questionnaire. The patients' trace elements status for zinc, copper, manganese, and selenium was assessed by measuring their concentrations in blood. RESULTS: The dietary intake of individual trace elements was similar in both groups (all P values > 0.4). There was no significant difference in the concentrations of plasma copper, zinc, and selenium between patients and healthy control subjects (all P values > 0.07). The concentration of whole blood manganese was significantly higher (P = 0.004) in patients (median, 178.5 nmol/l; range, 59-478 nmol/l) compared with healthy control subjects (median, 140 nmol/l; range, 53-267 nmol/l). Four (7 percent) patients had manganese concentrations more than three standard deviations of the mean of control group (>255 nmol/l). CONCLUSIONS: This study shows that patients who have had uncomplicated pouch surgery have a normal dietary intake of trace elements and do not develop deficiencies in copper, zinc, manganese, and selenium. However, these patients may be at increased risk of manganese toxicity.

Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.

We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.