Micronutrient deficiency and supplements in schoolchildren and teenagers.

PURPOSE OF REVIEW: The essential micronutrients are corner stones in the functional and physical development. Early deficiency has life-long consequences. While awareness about iron deficiency is relatively high, it remains lower for other micronutrients. This review aims at reporting on recent data and attracting attention to the high prevalence of micronutrient deficiencies in school-age and adolescent individuals. RECENT FINDINGS: Iron deficiency anaemia remains highly prevalent worldwide and the most frequent deficiency but can be corrected with simple tools ranging from food fortification, nutritional intervention, and to supplements. The link between micronutrient (MN) deficiency and neurobehavioral disorders is increasingly established and is worrying even in Western countries. Paediatric individuals are prone to imbalanced diets and picky eating behaviour, and their diets may then become incomplete: the highest risk for deficiency is observed for iron, zinc and vitamin D. SUMMARY: There is not much new information, but rather confirmation of the importance of health policies. Well conducted randomized controlled trials confirm that deficiencies can be corrected efficiently including with food fortification, and result in clinical benefits. Individual complementation should be considered in children and adolescents with proven deficiency.

ESPEN practical short micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. The importance of MNs in common pathologies is recognized by recent research, with deficiencies significantly impacting the outcome. OBJECTIVE: This short version of the guideline aims to provide practical recommendations for clinical practice. METHODS: An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL for the initial guideline. The search focused on physiological data, historical evidence (for papers published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: The limited number of interventional trials prevented meta-analysis and led to a low level of evidence for most recommendations. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90 % of votes. Altogether the guideline proposes 3 general recommendations and specific recommendations for the 26 MNs. Monitoring and management strategies are proposed. CONCLUSION: This short version of the MN guideline should facilitate handling of the MNs in at-risk diseases, whilst offering practical advice on MN provision and monitoring during nutritional support.

The science of micronutrients in clinical practice - Report on the ESPEN symposium.

BACKGROUND & AIMS: The European Society for Clinical Nutrition and Metabolism published its first clinical guidelines for use of micronutrients (MNs) in 2022. A two-day web symposium was organized in November 2022 discussing how to apply the guidelines in clinical practice. The present paper reports the main findings of this symposium. METHODS: Current evidence was discussed, the first day being devoted to clarifying the biology underlying the guidelines, especially regarding the definition of deficiency, the impact of inflammation, and the roles in antioxidant defences and immunity. The second day focused on clinical situations with high prevalence of MN depletion and deficiency. RESULTS: The importance of the determination of MN status in patients at risk and diagnosis of deficiencies is still insufficiently perceived, considering the essential role of MNs in immune and antioxidant defences. Epidemiological data show that deficiencies of several MNs (iron, iodine, vitamin D) are a global problem that affects human health and well-being including immune responses such as to vaccination. Clinical conditions frequently associated with MN deficiencies were discussed including cancer, obesity with impact of bariatric surgery, diseases of the gastrointestinal tract, critical illness, and aging. In all these conditions, MN deficiency is associated with worsening of outcomes. The recurrent problem of shortage of MN products, but also lack of individual MN-products is a worldwide problem. CONCLUSION: Despite important progress in epidemiology and clinical nutrition, numerous gaps in practice persist. MN depletion and deficiency are frequently insufficiently searched for in clinical conditions, leading to inadequate treatment. The symposium concluded that more research and continued education are required to improve patient outcome.

Pitfalls in the interpretation of blood tests used to assess and monitor micronutrient nutrition status.

Assessment of micronutrient (MN) status is of particular importance in patients who require medical nutrition therapy, especially those requiring parenteral nutrition. Blood testing is generally the only tool available in clinical settings to assess MN status. However, using plasma or serum concentration faces pitfalls mainly because of the impact of inflammation that diverts the MNs from the circulating compartment. This review aims to review the blood tests that are useful and provide information about how to integrate functional markers of status to reach a clinically relevant diagnosis. Most impacted, with a significant and proportional decrease in plasma concentrations, are iron, selenium, zinc, thiamin, folic acid, cobalamin, and vitamins A, C, and D; copper is the only MN for which the plasma concentration increases. Therefore, a surrogate marker of inflammation, C-reactive protein, must always be determined simultaneously. Validated intracellular and functional tests are proposed to improve status assessment. A protocol is suggested for tests required both on commencing and during nutrition support. A timely turnaround of analysis is essential for results to be clinically useful. In some cases, the appropriate provision of MNs should be commenced before results have been obtained to confirm the clinical assessment. Laboratory tests of MN status are an area prone to misuse and misinterpretation. The appropriate use and interpretation of such tests are essential to ensure the correct management of nutrition problems.

ESPEN micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE: This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". METHODS: The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION: This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.

The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease.

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma.

BACKGROUND: Alkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross-sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning. METHOD: Seventy-four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7-day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25-hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti-inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)-a validated measure of disease progression stratified by age. RESULTS: Fifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid-upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as "clinically undernourished." Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti-inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score. CONCLUSION: AKU patients are at risk of protein depletion associated with a "perfect storm" of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated.

Hypoalbuminemia: Pathogenesis and Clinical Significance.

Hypoalbuminemia is associated with inflammation. Despite being addressed repeatedly in the literature, there is still confusion regarding its pathogenesis and clinical significance. Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin. The half-life of albumin has been shown to shorten, decreasing total albumin mass. These 2 factors lead to hypoalbuminemia despite increased fractional synthesis rates in plasma. Hypoalbuminemia, therefore, results from and reflects the inflammatory state, which interferes with adequate responses to events like surgery or chemotherapy, and is associated with poor quality of life and reduced longevity. Increasing or decreasing serum albumin levels are adequate indicators, respectively, of improvement or deterioration of the clinical state. In the interstitium, albumin acts as the main extracellular scavenger, antioxidative agent, and as supplier of amino acids for cell and matrix synthesis. Albumin infusion has not been shown to diminish fluid requirements, infection rates, and mortality in the intensive care unit, which may imply that there is no body deficit or that the quality of albumin "from the shelf" is unsuitable to play scavenging and antioxidative roles. Management of hypoalbuminaemia should be based on correcting the causes of ongoing inflammation rather than infusion of albumin. After the age of 30 years, muscle mass and function slowly decrease, but this loss is accelerated by comorbidity and associated with decreasing serum albumin levels. Nutrition support cannot fully prevent, but slows down, this chain of events, especially when combined with physical exercise.

ESPEN guideline on ethical aspects of artificial nutrition and hydration.

BACKGROUND: The worldwide debate over the use of artificial nutrition and hydration remains controversial although the scientific and medical facts are unequivocal. Artificial nutrition and hydration are a medical intervention, requiring an indication, a therapeutic goal and the will (consent) of the competent patient. METHODS: The guideline was developed by an international multidisciplinary working group based on the main aspects of the Guideline on "Ethical and Legal Aspects of Artificial Nutrition" published 2013 by the German Society for Nutritional Medicine (DGEM) after conducting a review of specific current literature. The text was extended and introduced a broader view in particular on the impact of culture and religion. The results were discussed at the ESPEN Congress in Lisbon 2015 and accepted in an online survey among ESPEN members. RESULTS: The ESPEN Guideline on Ethical Aspects of Artificial Nutrition and Hydration is focused on the adult patient and provides a critical summary for physicians and caregivers. Special consideration is given to end of life issues and palliative medicine; to dementia and to specific situations like nursing care or the intensive care unit. The respect for autonomy is an important focus of the guideline as well as the careful wording to be used in the communication with patients and families. The other principles of Bioethics like beneficence, non-maleficence and justice are presented in the context of artificial nutrition and hydration. In this respect the withholding and withdrawing of artificial nutrition and/or hydration is discussed. Due to increasingly multicultural societies and the need for awareness of different values and beliefs an elaborated chapter is dedicated to cultural and religious issues and nutrition. Last but not least topics like voluntary refusal of nutrition and fluids, and forced feeding of competent persons (persons on hunger strike) is included in the guideline.

Meta-analysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition.

Evidence based medicine has preferably been based on prospective randomized controlled trials (PRCT's) and subsequent meta-analyses in many fields including nutrition and metabolism. These meta-analyses often yield convincing, contradictory or no proof of effectiveness. Consequently recommendations and guidelines of varying validity and quality have been published, often failing to convince the medical, insurance and government worlds to support nutritional care. Causes for lack of adequate proof of effectiveness are manifold. Many studies and meta-analyses lacked pathophysiological depth in design and interpretation. Study populations were not homogenous and endpoints not always clearly defined. Patients were included not at nutritional risk, unlikely to benefit from nutritional intervention. Others received nutrients in excess of requirements or tolerance due to organ failure. To include all available studies in a meta-analysis, study quality and homogeneity were only assessed on the basis of formal study design and outcome rather than on patient characteristics. Consequently, some studies showed benefit but included patients suffering harm, other studies were negative but contained patients that benefited. Recommendations did not always emphasize these shortcomings, confusing the medical and nutritional community and creating the impression that nutritional support is not beneficial. Strong reliance on meta-analyses and guidelines shifts the focus of education from studying clinical and nutritional physiology to memorizing guidelines. To prevent or improve malnutrition more physiological knowledge should be acquired to personalize nutritional practices and to more correctly value and evaluate the evidence. This also applies to the design and interpretation of PRCT's and meta-analyses.

A Call to Action to Bring Safer Parenteral Micronutrient Products to the U.S. Market.

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) started an intensive review of commercially available parenteral vitamin and trace element (TE) products in 2009. The chief findings were that adult multi-TE products currently available in the United States (U.S.) provide potentially toxic amounts of manganese, copper, and chromium, and neonatal/pediatric multi-TE products provide potentially toxic amounts of manganese and chromium. The multivitamin products appeared safe and effective; however, a separate parenteral vitamin D product is needed for those patients on standard therapy who continue to be vitamin D depleted and are unresponsive to oral supplements. The review process also extended to parenteral choline and carnitine. Although choline and carnitine are not technically vitamins or trace elements, choline is an essential nutrient in all age groups, and carnitine is an essential nutrient in infants, according to the Food and Nutrition Board of the Institute of Medicine. A parenteral choline product needs to be developed and available. Efforts are currently under way to engage the U.S. Food and Drug Administration (FDA) and the parenteral nutrient industry so A.S.P.E.N.'s recommendations can become a commercial reality.

Zinc induced damage to kidney proximal tubular cells: studies on chemical speciation leading to a mechanism of damage.

UNLABELLED: This study was carried out to investigate whether zinc can potentiate renal toxicity using monolayer cultures of kidney proximal tubular cells and if so to establish the chemical species and the mechanism involved. METHODS: Zinc was prepared as the citrate complex at pH 7.4 in phosphate buffered saline. Monolayers of kidney proximal tubular cells under standard cell culture conditions were exposed to zinc concentrations of 0, 5 10, 20, 50 and 100 µmol/L. To assess cellular damage, thiazol blue (MTT) uptake, NAG and LDH release, DAPI staining and Tunel assay were used. Cytoprotective agents: trolox, cysteine, glutathione, ascorbic acid and sodium selenite were used to investigate if the damage was reversible. RESULTS: Incubation of kidney cells with zinc citrate showed a dose related reduction in cell viability (p<0.005) associated with cellular uptake of zinc ions. After 24 h incubation with 100 µmol/L Zn citrate, NAG release was not significantly different compared to the control whereas LDH increased 3 fold. DAPI staining showed apoptotic bodies within the cells confirmed by Tunel assay using flow cytometry. Electron microscopy showed significant morphological changes including loss of brush border, vacuolated cytoplasm and condensed nuclei. Trolox almost completely (>85±5%) and sodium selenite partially recovered (40±4%) the viability of cells exposed to Zn but no protection was observed with other cytoprotectants, e.g. glutathione, cysteine or ascorbic acid. In conclusion zinc can induce damage to kidney cells by a mechanism dependent on zinc ions entering the cell, binding to the cell organelles and disrupting cellular processes rather than damage initiated by free radical and ROS production.

A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products.

The parenteral multivitamin preparations that are commercially available in the United States (U.S.) meet the requirements for most patients who receive parenteral nutrition (PN). However, a separate parenteral vitamin D preparation (cholecalciferol or ergocalciferol) should be made available for treatment of patients with vitamin D deficiency unresponsive to oral vitamin D supplementation. Carnitine is commercially available and should be routinely added to neonatal PN formulations. Choline should also be routinely added to adult and pediatric PN formulations; however, a commercially available parenteral product needs to be developed. The parenteral multi-trace element (TE) preparations that are commercially available in the U.S. require significant modifications. Single-entity trace element products can be used to meet individual patient needs when the multiple-element products are inappropriate (see Summary/A.S.P.E.N. Recommendations section for details of these proposed modifications).

Randomized controlled trial of zinc and vitamin A as co-adjuvants for the treatment of pulmonary tuberculosis.

OBJECTIVE: To assess the efficacy of weekly zinc or zinc plus retinol as adjuncts for the treatment of pulmonary tuberculosis. METHODS: Double-blind, randomized, placebo-controlled trial in 350 patients >15 years old with smear-positive tuberculosis in Nigeria (ISRCTN36636609). In addition to antituberculous treatment, patients were randomly allocated to weekly supplements of zinc (90 mg), zinc plus retinol (5000 IU) or placebos for 6 months. Primary outcomes were time to sputum smear conversion and resolution of radiographic abnormalities. RESULTS: After 8 weeks of treatment, 68% had achieved sputum smear conversion, and the median conversion time was 6.5 weeks. Hazard ratios (HR, 95%CI) for sputum conversion relative to the placebo group were not significant for zinc (1.07, 0.92-1.29) or zinc plus retinol (0.89, 0.76-1.07). Significant predictors of time to sputum conversion were lung abnormality score, sputum smear grade, age and serum C-reactive protein. HIV co-infection and gender were not independent predictors of time to sputum conversion. There were no significant differences between supplement groups in clinical, radiological or laboratory outcomes at 2 months or 6 months. There were 9, 9 and 2 deaths in patients receiving zinc, zinc plus retinol or placebos, respectively. Mortality in those who received zinc (HR 1.71, 0.88-3.58) or zinc plus retinol (HR 1.54, 0.78-3.26) did not differ significantly from those who received placebos. Most deaths occurred in patients co-infected with HIV. CONCLUSIONS: Supplementation with zinc or zinc plus retinol did not lead to better outcomes than placebos, and caution is warranted regarding routine micronutrient supplementation, particularly in patients co-infected with HIV.

Randomized controlled trial: lisinopril reduces proteinuria, ammonia, and renal polypeptide tubular catabolism in patients with chronic allograft nephropathy.

BACKGROUND: Angiotensin-converting enzyme inhibitors in native nephropathies reduce proteinuria and delay progression to renal failure. Data in renal transplantation remain limited. A negative effect on glomerular filtration rate was concluded in a recent systematic review. METHODS: In this novel randomized controlled trial, 47 patients with chronic allograft nephropathy, severe renal impairment, and more than or equal to 1 g/24 hr proteinuria were randomized to lisinopril (group A) or other hypotensives (group B) for 1 year. Sodium bicarbonate was given to all patients to treat metabolic acidosis prophylactically (acidosis increases significantly with lisinopril). The annual rate of decline of graft function was measured isotopically (primary outcome) and 24 hr proteinuria, genotyping, radiolabeled polypeptide aprotinin proximal tubular catabolic studies (in group A only) as secondary outcome measurements were undertaken. RESULTS: At baseline, groups were comparable except for greater proteinuria in group A. After 1 year, the rate of decline of graft function and graft survival were comparable in both groups. Proteinuria decreased significantly in group A patients only. Lisinopril also significantly reduced radiolabeled aprotinin uptake and metabolism, plasma aldosterone, and ammonia excretion. Plasma potassium, bicarbonate, and mean arterial pressures were comparable in both groups. Patients with more than or equal to 30% reduction in proteinuria had a significant association with rs699 polymorphism in the angiotensinogen gene. CONCLUSIONS: The rate of decline of renal graft function in patients with chronic allograft nephropathy was not adversely affected by lisinopril therapy given for 1 year. Lisinopril significantly reduced proteinuria, renal proximal tubular polypeptide catabolism, plasma aldosterone, and ammonia excretion suggesting relative preservation of graft function. Treating metabolic acidosis allowed safe and prolonged use of angiotensinogen-converting enzyme inhibitors.