Magdalena Araya

Risks and benefits of copper in light of new insights of copper homeostasis.

Copper is an essential micronutrient involved in a variety of biological processes indispensable to sustain life. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Potent, efficient regulatory mechanisms control copper absorption in the digestive tract and copper biliary excretion; absorption ranges between 12 and 60% in humans, depending on Cu intake, presence of other factors in the diet that may promote or inhibit its absorption and on the copper status of the individual. Current evidence suggests that copper deficiency may be more prevalent than previously thought, while copper toxicity is uncommon under customary daily life conditions. Menkes syndrome and Wilson disease are genetic conditions associated with severe copper deficiency and severe copper toxicity, respectively. Effects of milder degrees of copper deficiency and excess copper exposure are not well described, mainly due to lack of sensitive and specific indicators; serum copper concentration and ceruloplasmin are the most frequently used indicators, but they only detect rather intense changes of copper status. Of the many proteins assessed as potential markers of copper status the chaperone of Zn-Cu superoxide dismutase (CCS1) has yielded promising results; data on its performance under different conditions are needed to confirm its use as an indicator of early copper deficiency. Defining copper requirements and upper safe limits of consumption (UL) is a complex process since there are adverse health consequences from both copper deficiency and copper excess (U shape curve). The regulatory framework for risk assessment of essential trace elements introduced by the International Programme on Chemical Safety (IPCS) has proposed a homeostatic model to determine the Adequate Range of Oral Intake (AROI) of essential trace elements; the nadir of the resulting U shape curve serves to define the AROI. At this range of intake physiological mechanisms allow for normal homeostasis and basically, there are no detectable adverse effects. At present, Recommended Dietary Intakes (DRIs) and Adequate Intakes (AIs) are used to recommend copper intakes at different ages and life situations. Evidence obtained in humans and non-human primates presented here suggest that current copper UL should be re evaluated. Developing the scientific basis for a copper UL and evaluating the relevance of copper deficiency globally are future key challenges for copper researchers.

Effect of dietary nucleotide supplementation on diarrhoeal disease in infants

The effects of a nucleotide‐supplemented formula on diarrhoeal disease was studied in 141 infants (group 1) who belonged to the low socioeconomic stratum; 148 controls (group 2) received the same formula but unsupplemented. Group 1 experienced less episodes of diarrhoea (109 versus 140), including less first episodes (74 versus 102; chi‐square = 8.19, p < 0.004; odds ratio 2.01) and for a lesser number of days (807 versus 996 days); 45.0% and 31.1% of infants in groups 1 and 2, respectively, never developed episodes of diarrhoea. There were no differences in the clinical characteristics of the episodes or in the enteropathogens isolated from symptomatic or asymptomatic infants. The mechanisms through which nucleotides decrease the incidence of diarrhoeal disease in infants remain unclear.

Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition Consensus Report on Celiac Disease

Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, MD, {Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile, {Centre for Diarrheal Disease and Nutrition Research, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India, §Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Melbourne, Australia, jjDivision of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Hopital Sainte-Justine, University of Montreal, Montreal, Canada, Departments of Pediatrics, Leiden University Medical Center and Free University Medical Center, Amsterdam, the Netherlands, {{Pediatric Gastroenterology and Nutrition Unit, Ntra Sra de Candelaria Universitary Hospital School of Medicine,

How reliable and robust are current biomarkers for copper status

Cu is an essential nutrient for man, but can be toxic if intakes are too high. In sensitive populations, marginal over- or under-exposure can have detrimental effects. Malnourished children, the elderly, and pregnant or lactating females may be susceptible for Cu deficiency. Cu status and exposure in the population can currently not be easily measured, as neither plasma Cu nor plasma cuproenzymes reflect Cu status precisely. Some blood markers (such as ceruloplasmin) indicate severe Cu depletion, but do not inversely respond to Cu excess, and are not suitable to indicate marginal states. A biomarker of Cu is needed that is sensitive to small changes in Cu status, and that responds to Cu excess as well as deficiency. Such a marker will aid in monitoring Cu status in large populations, and will help to avoid chronic health effects (for example, liver damage in chronic toxicity, osteoporosis, loss of collagen stability, or increased susceptibility to infections in deficiency). The advent of high-throughput technologies has enabled us to screen for potential biomarkers in the whole proteome of a cell, not excluding markers that have no direct link to Cu. Further, this screening allows us to search for a whole group of proteins that, in combination, reflect Cu status. The present review emphasises the need to find sensitive biomarkers for Cu, examines potential markers of Cu status already available, and discusses methods to identify a novel suite of biomarkers.

Assessment of the Trace Element Status of Individuals and Populations: The Example of Zinc and Copper

This paper describes the proceedings of a workshop that was convened at the 11th International Symposium on Trace Elements in Man and Animals (TEMA-11) symposium to review recent advances concerning the assessment of the trace element status of individuals and populations, using zinc and copper as the primary examples to illustrate basic principles and recent advances in assessment methods. The workshop was initiated with a brief review of the importance of zinc nutriture for human health and a discussion of the likely common occurrence of zinc deficiency worldwide. This overview was followed by presentations on selected issues concerning the assessment of zinc status, with particular attention devoted to dietary assessment techniques, the use of isotopic tracers to assess zinc homeostasis and the relationship of these methods to biochemical indicators of zinc status. Because relatively little information is available on zinc toxicity, the discussion concerning the definition of excess intake of trace elements focused primarily on recent work concerning risk assessment of copper toxicity.

Effect of an Acidified Milk on Diarrhoea and the Carrier State in Infants of Low Socio‐Economic Stratum

ABSTRACT. The effect on diarrhoeal disease of an acidified, modified powdered cows milk infant formula (Pelargon®) was evaluated in 82 infants (Group I) for six months; 104 infants who received the same formula but non acidified, served as controls (Group II). Nutritional status remained satisfactory in both groups throughout the observation period. Some children rejected the taste of the acidified milk. The incidence of diarrhoea was lower in Group I (p<0.001). The proportion of days in which the children suffered from acute diarrhoea, and the duration of the episodes were also lower in the children given the acidified milk (p<0.001). The rate of detection of enteropathogens and the species identified were comparable in both groups. Carrier rates for bacterial enteropathogens fell over time in Group I while they rose in Group II (p<0.001). Carrier rates for enteric parasites were comparable to those expected in our setting for this age group. These results suggest that acidified milk exerts a protective effect against diarrhoeal disease.

Field trial of an infant formula containing anti-rotavirus and anti-escherichia coli milk antibodies from hyperimmunized cows

Two groups of 124 and 108 children, respectively, living in urban Santiago, Chile in low socioeconomic conditions were prospectively followed for 6 months for their incidence of diarrhea. Each cohort was divided into two subgroups receiving either a commercial milk formula or the same formula containing 1% (wt/wt) bovine milk immunoglobulin concentrate from cows hyperimmunized with human rotaviruses and the major enteropathogenic Escherichia coli (EPEC) serogroups. Neither group differed with respect to incidence of diarrhea (98 episodes in 117 treated children versus 95 episodes in 115 control children), duration and clinical symptoms of diarrhea, and weight gain. Furthermore, neither group differed with respect to isolation of rotavirus (14 and 13 isolates in treatment and control groups, respectively) and isolation of enteropathogenic E. coli (14 and 15 isolates in treatment and control groups, respectively). The treatment but not the control formula contained neutralizing antibody against all human rotavirus serotypes. Titers were comparable to human breast milk samples. All isolated EPEC serogroups were included in the vaccine used for the immunization of the cows. The treatment, but not the control formula, protected mice against a lethal challenge with an EPEC strain. In conclusion, feeding an antibody-supplemented formula had no positive effect on diarrheal diseases under the conditions of a fairly well-controlled small-scale field trial.

Community-based randomized double-blind study of gastrointestinal effects and copper exposure in drinking water

We assessed gastrointestinal effects in 1,365 adults exposed to either < 0.01 (controls), 2, 4, or 6 mg copper/L of drinking water for 2 months in a randomized, double-blind community-based study. The risk of symptoms increased with increasing Cu exposure and decreased with time. The best model by counting-process analysis included Cu concentration and sex. The risk of symptoms remained significantly higher in women than in men during weeks 1–4 for all concentrations tested; at week 1 comparison with the < 0.01-mg/L group showed that differences became significant in women at 4 mg/L [relative risk (RR) = 1.53; 95% confidence interval (CI), 1.02–2.05), and in men at 6 mg/L (RR = 1.9; 95% CI, 1.02–2.79). At week 2 for men and week 4 in women, the Cu concentration required to obtain significant differences on symptom report was > 6 mg Cu/L. We conclude that exposure to Cu in drinking water results in gastrointestinal symptoms, which are modulated by Cu concentration, time, and sex.

Celiac disease in a Chilean population carrying Amerindian traits.

Background Although clinical manifestations of celiac disease may change throughout life, clinical, histologic, immunologic, and genetic studies show that there are incomplete forms of this condition, making it difficult to define the disease at a given moment. Because there is no information published in the Latin American-Amerindian population, this study was conducted to assess relations between these parameters in Chileans with celiac disease and their first-degree relatives. Methods Sixty-two persons with confirmed celiac disease (mean age, 17.9 ± 5.1 years; 78.3% females) and 126 relatives (mean age, 27.9 ± 17.2 years; 65.1% females) were evaluated. Clinical manifestations, antiendomysial antibodies (EMAs), and human leukocyte antigen (HLA) haplotypes were studied in patients. Additionally, jejunal biopsy specimens were assessed (light microscopy) in EMA-positive (EMA+) relatives. Results Of the patients, 24.1% adhered to a strict gluten-free diet; 26% were oligosymptomatic, and none were malnourished; 45% were EMA+; 13.8% who ingested gluten were EMA-negative (EMA−); one patient consuming a strict gluten-free diet was EMA+. The DQA1*0501 allele was present in the highest frequency (48%, P < 0.0005), whereas combinations of DQ8 were predominant. Of the relatives, 4.8% were EMA+; they had a significantly higher frequency of diarrhea, weight loss, and anorexia (P < 0.03); and all had abnormal histology in biopsy specimens. Conclusions After childhood, celiac disease is oligosymptomatic and is often unrecognized by patients. Disease in 13.8% of patients and in 4.8% relatives appeared as incomplete forms of celiac disease. Predominance of DQ8 HLA haplotypes reflects the genetic Spanish-Mapuche heritage of this population.

Acute Nutritional and Intestinal Changes after Pelvic Radiation

Objective: Pelvic radiotherapy induces acute small bowel injury but its effects on nutritional status are unknown. The objective of this study was to prospectively evaluate nutritional, functional and morphologic intestinal changes, after radiotherapy. Methods: Fifteen patients were studied before and after pelvic irradiation. A clinical, nutritional and routine clinical laboratory assessment was performed. Nutritional parameters included dietary recall, subjective global assessment, anthropometric measurements (body mass index, skinfold thickness at four sites and circumferences of arm, waist and hip), hand grip strength, indirect calorimetry and Dual Energy X-ray absortiometry (DEXA). Intestinal parameters included permeabilty to sugars (assessed by lactulose and mannitol urinary excretion), intestinal transit time (measured by hydrogen breath test after ingestion of lactulose) and jejunal biopsies. Results: Thirteen patients presented diarrhea during radiation therapy. After five weeks, intestinal permeability increased, while intestinal transit time decreased. The second biopsy showed hypertrophy of villae and crypts. Simultaneously, patients lost weight at the expense of fat free mass. Resting energy expenditure was elevated prior to treatment and declined after five weeks. Changes in caloric ingestion were not significant. Conclusions: Our results indicate that pelvic radiation induces a loss of fat free mass along with intestinal morphologic and functional changes.