Fructose aggravates copper-deficiency-induced cardiac remodeling by inhibiting SERCA2a.

OBJECTIVES: Accumulating evidence demonstrates that copper deficiency (CuD) is a risk factor for cardiovascular diseases, besides, fructose has been strongly linked to the development of cardiovascular diseases. However, how CuD or fructose causes cardiovascular diseases is not clearly delineated. The present study aims to investigate the mechanism of CuD or fructose on cardiac remodeling. METHODS: We established a model of CuD- or fructose-induced cardiac hypertrophy in 3-week-old male Sprague-Dawley (SD) rats by CuD diet supplemented with or without 30% fructose for 4 weeks. In vitro study was performed by treating cardiomyocytes with tetrathiomolydbate (TM) and fructose. Echocardiography, histology analysis, immunofluorescence, western blotting, and qPCR were performed. KEY FINDINGS: Our findings revealed that CuD caused noticeable cardiac hypertrophy either in the presence or absence of fructose supplement. Fructose exacerbated CuD-induced cardiac remodeling and intramyocardial lipid accumulation. Furthermore, we presented that the inhibition of autophagic flux caused by Ca2+ disturbance is the key mechanism by which CuD- or fructose-induced cardiac remodeling. The reduced expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in cardiomyocytes accounts for the elevated cytoplasmic Ca2+ concentration. CONCLUSIONS: Collectively, our study suggested that fructose aggravated CuD-induced cardiac remodeling through the blockade of autophagic flux via SERCA2a decreasing-induced Ca2+ imbalance.

Do Only Calcium and Vitamin D Matter? Micronutrients in the Diet of Inflammatory Bowel Diseases Patients and the Risk of Osteoporosis.

Osteoporosis is one of the most common extraintestinal complications among patients suffering from inflammatory bowel diseases. The role of vitamin D and calcium in the prevention of a decreased bone mineral density is well known, although other nutrients, including micronutrients, are also of extreme importance. Despite the fact that zinc, copper, selenium, iron, cadmium, silicon and fluorine have not been frequently discussed with regard to the prevention of osteoporosis, it is possible that a deficiency or excess of the abovementioned elements may affect bone mineralization. Additionally, the risk of malnutrition, which is common in patients with ulcerative colitis or Crohn's disease, as well as the composition of gut microbiota, may be associated with micronutrients status.

Copper Dyshomeostasis in Neurodegenerative Diseases-Therapeutic Implications.

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson's disease (WD), Menkes disease (MD), Alzheimer's disease (AD), Parkinson's disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.

The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus.

Copper is an essential metal ion that performs many physiological functions in living organisms. Deletion of Afmac1, which is a copper-responsive transcriptional activator in A. fumigatus, results in a growth defect on aspergillus minimal medium (AMM). Interestingly, we found that zinc starvation suppressed the growth defect of the Δafmac1 strain on AMM. In addition, the growth defect of the Δafmac1 strain was recovered by copper supplementation or introduction of the CtrC gene into the Δafmac1 strain. However, chelation of copper by addition of BCS to AMM failed to recover the growth defect of the Δafmac1 strain. Through Northern blot analysis, we found that zinc starvation upregulated CtrC and CtrA2, which encode membrane copper transporters. Interestingly, we found that the conserved ZafA binding motif 5'-CAA(G)GGT-3' was present in the upstream region of CtrC and CtrA2 and that mutation of the binding motif led to failure of ZafA binding to the upstream region of CtrC and upregulation of CtrC expression under zinc starvation. Furthermore, the binding activity of ZafA to the upstream region of CtrC was inversely proportional to the zinc concentration, and copper inhibited the binding of ZafA to the upstream region of CtrC under a low zinc concentration. Taken together, these results suggest that ZafA upregulates copper metabolism by binding to the ZafA binding motif in the CtrC promoter region under low zinc concentration, thus regulating copper homeostasis. Furthermore, we found that copper and zinc interact in cells to maintain metal homeostasis.

Association of Zinc and Copper Status with Cardiovascular Diseases and their Assessment Methods: A Review Study.

Cardiovascular disease (CVD) is the leading cause of mortality, morbidity, and financial losses and has a high prevalence across the world. Several studies have investigated the association between various CVD types with zinc and copper status as the essential minerals for the human body, proposing contradictory and similar results. This narrative review aimed to survey the correlations between zinc and copper status in the human body and some risk factors of CVD, as well as the assessment methods of zinc and copper status in the human body. According to the reviewed articles, zinc and copper deficiency may increase the risk of coronary heart disease, valvular regurgitation, and myocardial lesions, cardiac hypertrophy. Furthermore, it could lead to the expanded mitochondrial compartments of the heart, acute and chronic heart failure, and elevation of inflammation markers, such as interleukin-1 (IL-1) and IL-6. Two methods are primarily used for the assessment of zinc and copper in the human body, including the direct method (measurement of their concentrations) and indirect method (determining the activity of zinc- and copper-containing enzymes). Both these methods are considered reliable for the assessment of the zinc and copper levels in healthy individuals. Serum or plasma levels of these elements are also commonly used for the assessment of the correlation between zinc and copper status and CVD. But, which one is a more accurate indicator in relation to CVD is not yet clear; therefore, further studies are required in this field.

Chronic pancreatitis in farmed pigs fed excessive zinc oxide.

Most of the pigs on a farm in Aichi Prefecture, Japan had chronic diarrhea and severe wasting. The pigs had consumed 8,000 ppm zinc oxide (ZnO) as a feed additive. The pancreas of each of 4 autopsied pigs was less than half the normal size. Acinar cells were considerably decreased. Epithelial duct-like cells were increased and tested positive for cytokeratin AE1/AE3, Ki67, PGP9.5, and Sox9. Pancreatic islet cells were decreased and shrunken. The α and δ cells were relatively decreased, and their distribution was abnormal. Islet cells were positive for PGP9.5. The livers and kidneys had high accumulations of zinc (Zn; 788 µg/g and 613 µg/g, respectively). Copper was deficient in the liver, likely as a result of Zn poisoning. Our immunohistologic examination suggested that the high dose of ZnO could influence the function of islet cells in addition to that of acinar cells. Given that colistin sulfate has been banned as a feed additive in order to reduce antimicrobial use in Japan, the use of ZnO in the livestock industry is expected to increase. Zn supplementation of pig feed must be monitored to prevent Zn poisoning and contamination of soil and water.

A Case of Copper Deficiency Myeloneuropathy Precipitated by Zinc Ingestion and Bariatric Surgery.

In this report, we present a case of acquired copper deficiency which initially presented as progressive pain and numbness in the patient's lower extremities. The acquired copper deficiency is attributed to a previous bariatric surgery exacerbated by zinc toxicity. A 42-year-old female with a past medical history of type 2 diabetes mellitus, anemia, hypertension, bipolar disorder, attention deficit disorder, pulmonary embolus, fibromyalgia, migraine headaches, and chronic pain as well as a remote past surgical history of gastric bypass procedure presented with progressive pain and numbness in her lower extremities. The patient reported chronic use of zinc supplements. Clinical evaluation revealed abnormal neurologic exam consistent with a myeloneuropathy and anemia. A cervical spine MRI showed increased signal intensity primarily affecting the posterior columns from C2-C6. Laboratory studies confirmed low copper, low ceruloplasmin, and elevated zinc levels. This case is an example of acquired copper deficiency due to previous bariatric surgery exacerbated by zinc ingestion. With an increased prevalence of bariatric surgery, it is important to monitor patients postoperatively for neurologic symptoms potentially due to copper deficiency.

Increased Needs for Copper in Parenteral Nutrition for Children in the Neonatal Intensive Care Unit With an Ostomy.

BACKGROUND: Copper (Cu) is an essential trace element, with deficiency causing anemia, neutropenia, and other abnormalities. Cu is mainly absorbed in the small intestine. Patients with intestinal failure or jejunostomy have increased Cu losses and require additional Cu supplementation in parenteral nutrition (PN). The American Society for Clinical Nutrition standards for trace element recommendations in PN, including Cu, were created in 1988, and the American Society for Parenteral and Enteral Nutrition currently follows the same recommendations. METHODS: Patients admitted to the neonatal intensive care unit for surgical intervention resulting in an ostomy (ileal or jejunal) were included in this retrospective study. Patients received PN support with Cu dosed individually, rather than in a multi-trace element package. Cu and ostomy output were analyzed daily. Serum Cu was obtained 2 months postsurgical intervention. RESULTS: Out of the 7 patients enrolled, 71% had low serum Cu. Weekly mean Cu intake for all 7 patients ranged from 5.3 to 154.8 µg/kg/day from enteral and parenteral sources, with individual mean weekly Cu intake ranging from 18.9 to 74.4 µg/kg/day from surgical intervention to 2 months post-surgery. Patients' weekly ostomy outputs ranged from 0 mL/kg/day to 77.2 mL/kg/day, with individual mean weekly output ranging from 3.7 to 41.6 mL/kg/day. CONCLUSION: Providing 20 µg/kg/day of Cu in PN to neonates with ostomies is insufficient to prevent Cu deficiency. Further studies are warranted to determine an optimal dosage of parenteral Cu to prevent Cu deficiency.

Calcium can delay age-related macular degeneration via enhanced copper metabolism.

Secondary analyses of data from the Age-Related Eye Disease Study (AREDS) revealed that higher calcium intakes were associated with slower progression to age-related macular degeneration (AMD). Earlier, primary analyses had revealed that a supplement containing copper reduced the odds of developing AMD while lengthening life. Because ocular lesions are being reported increasingly in neuropathy from copper deficiency and because higher dietary calcium can have beneficial effects on copper metabolism, it is hypothesized that the association of calcium intakes with better vision was mediated by improved copper utilization of study participants who were eating too little copper. Nutrition surveys reveal that amounts of copper proved insufficient for men and women in controlled studies are readily available to the general population. Observations on eye anatomy of animals deficient in copper and on decreased retinal superoxide dismutase, an enzyme dependent on copper for activity, in people with AMD support this hypothesis. Eradication of AMD will require new approaches based on hypotheses that fail falsification.

[Severe hypocupremia and familial amyloid polyneuropathy]. / Hipocupremia severa y polineuropatía amiloidótica familiar por transtiretina.

INTRODUCTION: Introduction: we report a patient with transthyretin familial amyloid polyneuropathy (TTR-FAP) and severe hypocupremia. Case report: a 79-year-old male with TTR-FAP and severe malnutrition. Laboratory tests showed low serum copper (Cu) and ceruloplasmin levels, as well as low urinary Cu levels. The patient reported neither digestive symptoms nor previous gastrointestinal surgery. Liver function tests, iron metabolism, hemoglobin, leukocytes and zinc were normal. Discussion: Cu is a trace element. It is part of the cuproenzymes involved in several physiological functions. Hypocupremia can be related to genetic or acquired etiologies, including low intake, bariatric surgery, increased losses, etc. Primary clinical manifestations include hematological (anemia and leukopenia) and neurological (myelopathy, peripheral neuropathy) features. Treatment is empirical. In severe cases it may be initiated with endovenose administration, followed by oral supplementation.

INTRODUCCIÓN: Introducción: presentamos el caso de un paciente con antecedentes de polineuropatía amiloidótica familiar por transtiretina (TTR-FAP) diagnosticado de hipocupremia severa. Caso clínico: varón de 79 años afecto de TTR-FAP. Visto en consulta de nutrición por desnutrición severa. En el estudio analítico presenta cifras de cobre (Cu) sérico y ceruloplasmina bajas, con Cu en orina también bajo. No tiene clínica digestiva ni antecedentes de cirugía gastrointestinal. Las pruebas de función hepática, la ferrocinética, las cifras de Hb y leucocitos y los niveles de zinc (Zn) no presentan alteraciones relevantes. Discusión: el Cu es un oligoelemento que participa como componente de las cuproenzimas en múltiples funciones fisiológicas. Los niveles séricos bajos pueden relacionarse con causas genéticas o adquiridas, como la baja ingesta, la cirugía bariátrica, el aumento de las pérdidas, etc. Las principales manifestaciones clínicas son hematológicas (anemia, leucopenia) o neurológicas (mielopatía, neuropatía periférica). El tratamiento tiene base empírica. En los casos severos puede iniciarse con administración intravenosa, seguido de mantenimiento por vía oral.

Copper deficiency-induced bicytopenia caused by poor compliance in a paediatric patient with chronic malnutrition: A case report.

A 12-year-old boy who underwent gastric wedge resection was transferred to our hospital because of vomiting, growth failure, and weight loss in January, 2016. We tried to restore his general condition by maintaining additional nutritional supply through peripheral parenteral nutrition (PN). However, continuous vomiting, weight loss, and superior mesenteric artery syndrome persisted because of low treatment compliance. The findings of hyponatraemia and bicytopenia did not improve. Bone marrow biopsy was performed, and it revealed copper deficiency. PN with additional micronutrient agents, including copper, were administered. In particular, invasive diagnosis and treatment, and adequate education improved the treatment compliance of the child. His copper deficiency and bicytopenia improved, and his weight and dietary intake also increased. We confirmed that treatment compliance is important in paediatric patients with malnutrition. In chronic malnutrition, attention should also be paid to deficiency of micronutrients such as copper, which can lead to haematologic problems.

The effect of copper nanoparticles and copper (II) salt on redox reactions and epigenetic changes in a rat model.

The aim of the study was to evaluate the effects of a diet containing different levels of Cu in two different chemical forms (carbonate and nanoparticles) on redox reactions and epigenetic changes in a rat model. For 4 weeks, five experimental groups (eight rats in each) were fed diets with two dosages of added Cu (standard-6.5 mg/kg or half of the standard dosage-3.25 mg/kg, and as a negative control no additional Cu in the mineral mixture) in two forms (standard-CuCO3 and copper nanoparticles). Addition of Cu nanoparticles resulted in higher Cp (ceruloplasmin) activity and LOOH (lipid peroxides) and MDA (malondialdehyde) content, as well as decrease the CAT (catalase) activity and level of PC (protein carbonyl), 3-NT (3-nitrotyrosine), 8-OHdG (8-hydroxydeoxyguanosine), GSH + GSSG (total glutathione) and DNA methylation. Reducing the dose of copper resulted in a decrease in the level of LOOH and GSH + GSSG as well as CAT activity, but increased the level of PC and methylated DNA. Based on these evidence, we concluded that addition of copper nanoparticles in the diet reduces protein oxidation and nitration as well as DNA oxidation and methylation. Lowering the level of Cu in the diet increases the oxidation of proteins and DNA methylation.

Copper and Zinc Nutritional Issues for Agricultural Animal Production.

Livestock have presented unique requirements and toxicity issues depending on the species for the various concentrations of Cu and Zn and their interactions with other nutrients especially Fe, Se, Mo, and S. Soil concentrations of these elements and their availability to crops influence the health of the crop and the amount found in vegetative tissues and seeds. Hence, many livestock issues are a result of the soils in the area where production is occurring (Loneragan et al. 1981). While water can provide minerals to animals, the amount consumed and availability are highly variable. Many discoveries about Cu were a result of low Cu concentrations and its availability due to interactions with other nutrients in the soils. Anemia, bone disorders, cardiovascular abnormalities, defective wool and hair, and infertility are signs/symptoms of Cu deficiency. Toxicity due to excess Cu is more likely to occur in sheep than other farm species. Swine are tolerant of high concentrations of dietary Cu, and it is often used as a growth stimulant in production. There are many species and physiological stages where the animal's Cu requirement is not known. Grazing animals can exhibit Zn deficiency when soils and forages contain limited concentrations of Zn. Pastures have been observed to be Zn-deficient in many parts of the world. However, non-ruminant animals usually receive adequate Zn when fed corn and soybean meal diets if there is not excessive Ca and Fe in their diets, but this is not true for rapidly growing young animals. Characteristics of a Zn deficiency include loss of appetite, reduced growth and reproduction, and impaired health of bone and skin tissues.

Trace element repletion following severe burn injury: A dose-finding cohort study.

BACKGROUND & AIMS: Major burn patients are characterized by large exudative losses of Cu, Se and Zn. Trace element (TE) repletion has been shown to improve clinical outcome. Having increased the TE doses over time, the study aimed at analysing if our repletion protocol corrected TE plasma concentrations and if the necessity for continuous renal replacement therapy (CRRT) might increase the TE needs. METHODS: Retrospective analysis of prospectively collected data in burn patients requiring intensive care (ICU) between 1999 and 2015. INCLUSION CRITERIA: Admission on day 1, full treatment, burned surface area (TBSA) ≥20% and ≥1 TE plasma determination during the stay. Four groups were constituted according to protocol changes. Period 1 (P1): 1999-2000, P2: 2001-2005, P3: 2006-2010, P4: 2011-2015. Changes consisted in increasing TE repletion doses and duration. Demographic data, daily TE intakes and weekly plasma concentrations were retrieved for the first 21 ICU-days. Data as median (IQR). RESULTS: 139 patients completed the criteria, aged 37 (28) years, burned on 35 (25) % TBSA. As a result of prescription, Cu, Se and Zn intakes increased significantly between P1 and P4, resulting in normalization of plasma Cu (16 µmol/l) since P3 and Zn (13.5 µmol/l) since P2. Median plasma Se were above reference range (1400 nmol/l) during P3 and P4. CRRT patients required higher doses of Cu for maintenance within normal ranges. CONCLUSION: This dose finding study shows that the latest repletion protocol is safe and normalizes Cu and Zn concentrations. Se doses result in supra-normal Se concentrations, suggesting prescription reduction. CRRT patients are at high risk of Cu depletion and require specific monitoring.

Effect of gastrointestinal nematodes on serum copper and phosphorus of growing beef calves in northwestern Argentina.

The aim of this work was to study the effect of gastrointestinal nematodes (GINs) on copper (Cu) and phosphorus (P) in blood of beef cattle in two ranches (R1 and R2) located in northwestern Argentina. In 2015-2016 (R1) and 2016-2017 (R2), in each ranch, 22 weaned female calves were divided into two groups: calves treated systematically with 200 mcg/kg moxidectin every 45-50 days (TG) and untreated calves (UTG). The following parameters were measured: number of fecal eggs (epg), fecal cultures, serum Cu and P levels, and live weight gain (LWG). Differences between groups were compared using analysis of variance and Tukey test. GIN infections in both ranches were subclinical and moderate, showing the highest epg (R1 = 907 ± 754; R2 = 1049 ± 1040) by mid-winter. Epg values of TG groups were always negligible (> 93% of moxidectin efficacy). The dominant nematode genera were Cooperia and Haemonchus. The average serum Cu values (µg/dl) indicated low (R1 = 49.7 ± 18) and severe (R2 = 27.2 ± 14) deficiency. The effect of treatments was evident in both ranches from late winter, with TG showing significantly (p < 0.01) higher serum levels in winter, spring, and early autumn (R1 = 65.1, 50.9, and 60.3; R2 = 48.0, 25.7, and 22.4) than UTG (R1 = 44.3, 33.9, and 32.9; R2 = 25.5, 18.2, and 16.4). There were no differences in serum P levels between groups. LWG of TG increased significantly (p < 0.008) (27.2% in R1 and 38.6% in R2), with respect to those of UTG. This study showed a negative effect of GIN on serum Cu values in moderately infected growing calves.

Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale.

Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.

Elesclomol restores mitochondrial function in genetic models of copper deficiency.

Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.

Copper deficiency anemia: review article.

Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation, and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1 transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript. Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride. Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neurological manifestations are only partially reversible with copper supplementation.

Copper Deficiency Anemia and Neutropenia Due to Ketogenic Diet.

Copper deficiency is an uncommon cause of hematologic abnormalities in children that is often overlooked or misdiagnosed. Although cases have been reported because of malabsorption syndromes or after gastrointestinal surgeries, we report a case of copper deficiency-associated anemia and neutropenia in a child because of dietary restrictions, specifically, transitioning from a formula-based ketogenic diet to a pureed food-based ketogenic diet. On copper supplementation, the patient's anemia and neutropenia resolved. To our knowledge, this report is the first revealing copper deficiency anemia and neutropenia developing because of a ketogenic diet.

Copper Supplementation in Premature Infants With Parenteral Nutrition-Associated Cholestasis.

The aim of this study was to evaluate the effect of intermittent parenteral copper supplementation (IPC) on serum copper status and biochemical and hematological measures of copper toxicity and deficiency in premature infants with parenteral nutrition (PN)-associated cholestasis (PNAC). We performed a prospective nested observational study in premature infants with PNAC who received IPC after the development of PNAC. Infants with chromosomal disorders, TORCH (toxoplasmosis, parvovirus, syphilis, rubella, cytomegalovirus, herpes, human immunodeficiency virus) infection, metabolic disorder, and/or surgical abnormality of the hepatobiliary system were excluded. Serum copper concentrations were measured once every 2-4 weeks while receiving PN; 24 premature infants were studied. The mean gestational age (GA) of infants was 28.6 ± 4.7 weeks. On regression analysis, there was no significant association between IPC and serum copper concentration (coefficient 2.72, 95% CI: -27 to 32; P = .84) after controlling for GA, gender, and baseline copper intake before PNAC. There was no significant association of IPC with alanine and aspartate transaminases levels (hepatotoxicity) and platelet count, hematocrit, white blood cell count, and neutrophil count (measures of copper deficiency) after controlling for confounders. GA and postmenstrual age were independently and positively associated with serum copper concentration after controlling for confounders on regression analyses. Thus, IPC in premature infants with PNAC does not influence copper status and is not associated with biochemical and hematological measures of copper deficiency and/or toxicity. Serum copper concentration in premature infants with PNAC receiving IPC is determined by the degree of prematurity and postmenstrual age.