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Background: Little is yet known about zinc absorption in late pregnancy, and no information on absorption from the total diet is available., Objective: The objective was to measure the fractional absorption of zinc (FAZ) and to estimate the total quantity of absorbed zinc (TAZ) each day during the third trimester of pregnancy in poor rural southern Ethiopian women., Design: The participants (n = 17) were a convenience sample from a larger study population. The third stage of pregnancy was estimated from fundal height by the Bushulo Health Center prenatal outreach program. FAZ was determined with a dual-isotope tracer ratio technique that uses measurements of urine enrichment with zinc stable isotopes administered intravenously and orally, as an extrinsic label, with all meals in 1 d. Total dietary zinc (TDZ) was calculated from weighed diet records and Ethiopian food-composition tables supported by zinc and phytate analyses of major food items for individual meals. Plasma zinc and exchangeable zinc pool size were also estimated., Results: Mean (+/-SD) FAZ was 0.35 +/- 0.11, TDZ was 6.0 +/- 3.2 mg/d, TAZ was 2.1 +/- 1.0 mg/d, phytate intake was 1033 +/- 843 mg/d, plasma zinc was 44.1 +/- 6.0 microg/dL, and the exchangeable zinc pool size was 142 +/- 39 mg. The molar ratio of phytate to zinc was 17:1., Conclusions: Women from a poor rural population who were dependent on a moderately high-phytate diet had low TDZ and low plasma zinc concentrations in the third trimester of pregnancy. TAZ was modestly higher than that predicted but did not meet physiologic requirements.

Background: Measurement of the major variables of zinc homeostasis is an essential prerequisite for estimating human zinc requirements, which currently require a factorial approach. The data required for this approach have not been available for toddlers, whose requirements have been estimated by extrapolation from other age groups., Objective: The objective of the study was to measure key variables of zinc homeostasis in rural and small-town Chinese toddlers., Design: Zinc stable-isotope tracers were administered intravenously and orally with all meals for 1 d to 43 toddlers. Subsequent metabolic collections in the homes included duplicate diets, quantitative fecal collections, and spot urine sampling. Fractional absorption of zinc (FAZ) was measured by a dual-isotope tracer ratio technique, and endogenous fecal zinc (EFZ) was measured by an isotope dilution technique., Results: No group or sex differences were found. Therefore, results were combined for 43 toddlers aged 19-25 mo whose major food staple was white rice. Selected results (x+/- SD) were 1.86 +/- 0.55 mg total dietary Zn/d; 0.35 +/- 0.12 FAZ; 0.63 +/- 0.24 mg total absorbed Zn/d; 0.67 +/- 0.23 mg EFZ/d; and 65.0 +/- 8.3 microg plasma Zn/dL. The molar ratio of dietary phytate to zinc was 2.7:1., Conclusions: The mean intake and absorption of zinc in this population are low in comparison with estimated average dietary and physiologic requirements for zinc, and plasma zinc values are consistent with zinc deficiency. Intestinal losses of endogenous zinc exceed previous estimates for toddlers, and only modest evidence exists of conservation in response to low zinc intake and absorption.

Objective: This study was undertaken to assess the feasibility and effects of consuming either meat or iron-fortified infant cereal as the first complementary food., Methods: Eighty-eight exclusively breastfed infants were enrolled at 4 months of age and randomized to receive either pureed beef or iron-fortified infant cereal as the first complementary food, starting after 5 months and continuing until 7 months. Dietary, anthropometric, and developmental data were obtained longitudinally until 12 months, and biomarkers of zinc and iron status were measured at 9 months., Results: Mean (+/-SE) daily zinc intake from complementary foods at 7 months for infants in the meat group was 1.9 +/- 0.2 mg, whereas that of the cereal group was 0.6 +/- 0.1 mg, which is approximately 25% of the estimated average requirement. Tolerance and acceptance were comparable for the two intervention foods. Increase in head circumference from 7 to 12 months was greater for the meat group, and zinc and protein intakes were predictors of head growth. Biochemical status did not differ by feeding group, but approximately 20% of the infants had low (<60 microg/dL) plasma zinc concentrations, and 30% to 40% had low plasma ferritin concentrations (<12 microg/L). Motor and mental subscales did not differ between groups, but there was a trend for a higher behavior index at 12 months in the meat group., Conclusions: Introduction of meat as an early complementary food for exclusively breastfed infants is feasible and was associated with improved zinc intake and potential benefits. The high percentage of infants with biochemical evidence of marginal zinc and iron status suggests that additional investigations of optimal complementary feeding practices for breastfed infants in the United States are warranted.

Background: Poor bioavailability of zinc from high-phytate diets is an important contributory factor to zinc deficiency in low-income populations., Objective: The objective of this study was to determine the effect of low-phytate maize consumption on zinc absorption., Design: The participants were apparently healthy children from the Central Highlands of Guatemala. Sixty children (20 per group) were randomly assigned to be fed only the low-phytate maize or 1 of 2 control maizes, the isohybrid wild-type maize or a local maize, for a 10-wk period. During the final week, the fractional absorption of zinc for all meals was measured during 1 d with the use of zinc stable isotopes and a dual isotope ratio technique based on urine enrichment data., Results: Mean (+/-SD) phytate intakes for the low-phytate, wild-type, and local maize groups were 1536 +/- 563, 2056 +/- 517, and 2253 +/- 687 mg/d, respectively. Corresponding zinc intakes were 8.6 +/- 2.5, 8.1 +/- 2.0, and 9.7 +/- 2.6 mg/d, and the dietary phytate:zinc molar ratios were 18 +/- 5, 26 +/- 6, and 23 +/- 5. Corresponding fractional absorptions of zinc were 0.32 +/- 0.07, 0.28 +/- 0.07, and 0.29 +/- 0.06. The respective values for total absorbed zinc were 2.72 +/- 0.88, 2.30 +/- 0.96, and 2.78 +/- 1.04 mg/d. No significant differences in either the fractional absorption of zinc or total absorbed zinc were seen between the maize groups., Conclusion: Under the conditions of the present study, zinc absorption was not increased by the long-term use of low-phytate maize in children whose major dietary staple is maize.

The focus of this paper is on the application of measurements of zinc absorption in human research, especially studies designed to assess the efficacy of intervention strategies to prevent and manage zinc deficiency in populations. Emphasis is given to the measurement of quantities of zinc absorbed rather than restricting investigations to measurements of fractional absorption of zinc. This is especially important when determining absorption of zinc from the diet, whether it be the habitual diet or an intervention diet under evaluation. Moreover, measurements should encompass all meals for a minimum of one day with the exception of some pilot studies. Zinc absorption is primarily via an active saturable transport process into the enterocytes of the proximal small intestine. The relationship between quantity of zinc absorbed and the quantity ingested is best characterized by saturable binding models. When applied to human studies that have sufficient data to examine dose-response relationships, efficiency of absorption is high until approximately 50-60% maximal absorption is achieved, even with moderate phytate intakes. This also coincides approximately with the quantity of absorbed zinc necessary to meet physiologic requirements. Efficiency of absorption with intakes that exceed this level is low or very low. These observations have important practical implications for the design and interpretation of intervention studies to prevent zinc deficiency. They also suggest the potential utility of measurements of the quantity of zinc absorbed when evaluating the zinc status of populations.

Background: Dysprosium is a nonabsorbable rare earth element that has had successful application as a marker for fecal excretion of unabsorbed zinc., Objective: Our goals were 1) to evaluate the efficacy of administering dysprosium with all meals over several days as a method of determining the completeness of fecal collections, 2) to determine the similarity of gastrointestinal transit kinetics and excretion patterns of dysprosium and zinc tracer administered simultaneously over several days, and 3) to evaluate alternative methods of using the data for fecal excretion of orally administered zinc tracer and dysprosium to measure the fractional absorption of zinc., Design: 70Zn and dysprosium were administered orally with all meals for 5 consecutive days to 7 healthy, free-living adults consuming a constant diet based on habitual intake. Additional tracers, 67Zn and 68Zn, were administered intravenously. Urine and fecal samples were collected during tracer administration and for 8 d after the last dose. Isotope ratios were measured in urine and feces, and total zinc and dysprosium were measured in fecal samples., Results: The mean recovery of dysprosium was 101.3 +/- 2.4%. The zinc oral tracer and dysprosium had similar fecal excretory patterns; the correlation coefficient for 70Zn and dysprosium in fecal samples exceeded 0.99 (P < 0.0001) for each subject. Fractional zinc absorption measurements using various dysprosium methods correlated well (r > 0.95) with those from the fecal monitoring and dual-isotope-tracer ratio methods., Conclusion: Administration of dysprosium is a useful means of determining the completeness of fecal collections and of measuring zinc absorption.

Background: Zinc supplements are used extensively in medicine and research and for public health purposes in the prevention and treatment of zinc deficiency. However, little is known about the efficiency of zinc utilization after different doses., Objective: The objective was to determine the relation between dose of aqueous zinc and absorbed zinc (AZ) in healthy adults., Design: Eight healthy adults (3 men and 5 women) aged 33.8 +/- 9.8 y (x +/- SD) received 3 pairs of zinc doses (2 and 5, 10 and 15, and 20 and 30 mg) in random order in 3 phases (1 pair per phase). There was a 3-wk washout between phases. Aqueous zinc sulfate labeled with 70Zn or 68Zn was orally administered in the postabsorptive state on days 1 and 6, respectively; intravenous 67Zn was administered 1 h after the first oral zinc dose. Two urine samples were collected daily from days 3 to 15; zinc isotopic ratios were determined by inductively coupled plasma mass spectrometry. Fractional absorption of zinc (FAZ) was determined by dual-isotope-tracer ratio; AZ was calculated by multiplying FAZ by dose., Results: Mean (+/-SD) AZ values at doses of 2.2, 5.2, 10.4, 15.2, 20.3, and 30.1 mg ingested Zn were 1.6 +/- 0.4, 3.5 +/- 1.3, 7.4 +/- 1.0, 9.5 +/- 2.2, 11.0 +/- 4.4, and 11.2 +/- 2.1 mg, respectively. A saturable dose-response model, the Hill equation, was selected to model the relation of AZ to ingested zinc. Parameter estimation by nonlinear regression predicted a maximum zinc absorption of 13 mg for larger doses., Conclusions: Increases in aqueous zinc doses >20 mg result in relatively small and progressively diminishing increases in AZ postabsorptively in healthy adults.

The objectives of this study were to compare zinc homeostasis in premature infants enterally fed with either preterm infant formula or fortified human milk; to examine interrelationships of variables of zinc homeostasis; and to examine the findings in relation to estimated zinc requirements of preterm infants. Zinc homeostasis was studied in 14 infants (8 male), with mean gestational age of 31 wk and birth weight appropriate for gestational age, who were exclusively fed either preterm formula (n = 9) or own mother's milk with human milk fortifier (n = 5). Zinc stable isotopes were administered intravenously ((70)Zn) and orally as an extrinsic label ((67)Zn) over multiple feeds for determination of fractional absorption by dual isotope tracer ratio in urine; endogenous fecal zinc was determined by isotope dilution; and exchangeable zinc pool (EZP) size was estimated from linear regression of log-transformed urine (70)Zn enrichment data. Results indicated no significant differences in the variables of zinc homeostasis between the feeding groups; data for all subjects were thus combined. Mean (+/- SD) fractional absorption was 0.26 +/- 0.07; net absorbed zinc 0.43 +/- 0.25 mg/d (0.31 +/- 0.19 mg/kg/d). Mean EZP was 20 +/- 10 mg/kg, and was positively correlated with total absorbed zinc and with net absorbed zinc. Feeding type and total absorbed zinc were significantly related to daily weight gain (p = 0.003). Current zinc intakes from fortified human milk or formula are associated with acceptable weight gain, but whether the observed net zinc absorption was optimal in the human milk group cannot be definitively determined from these data.

The exchangeable zinc pool (EZP) is the sum of the combined pools that exchange with zinc in the plasma within 48-72 h and is thought to be critical for zinc-dependent biological processes. The size of the EZP in adults has been found to be positively related to dietary zinc intake, daily absorbed zinc and fecal excretion of endogenous zinc. In this study, we examine data on EZP size in relation to variables of zinc homeostasis in normal infants on different feeding regimens. Data from 45 male infants who participated in one of four different studies contribute to the analysis. The feeding regimens include exclusive breastfeeding (n = 9; age, 2-5 mo); breastfeeding plus modest supplementation with cow's milk-based formula (n = 16; age, 3-4 mo); exclusive formula feeding (n = 4; age, 3-4 mo) and exclusive breastfeeding plus complementary foods (n =16; age, 7 mo). Fractional absorption was determined by fecal monitoring after oral administration of zinc-stable isotopes. Urine enrichment 4-8 d posttracer was used to determine endogenous fecal zinc (7-mo-old infants excepted) and EZP size. Univariate correlations and multivariate regression analyses were performed between EZP and age, weight, dietary zinc intake, fractional absorption, total absorbed zinc and endogenous fecal zinc. Results include no significant relationship between EZP size and age, body weight or fractional absorption but a positive relationship with daily absorbed zinc and endogenous fecal zinc excretion. We conclude that the amount of absorbed zinc is not tightly regulated, and that endogenous fecal zinc is dependent on and responsive to the zinc status of the organism.

The objective of this study was to compare the fractional zinc absorption (FAZ) and the size of the rapidly exchangeable zinc pool (EZP) after three months of iron supplementation in women consuming ferrous sulfate between meals. Twenty-one non-anemic apparently healthy women received on average 55.1 +/- 18.5 mg elemental iron per day as ferrous sulfate, and five received no supplemental iron. Fractional absorption of zinc was determined before and three days after finishing the third month of iron supplementation by using an extrinsic labeling with zinc stable isotopes and a dual isotope enrichment method in urine. EZP was determined from urine enrichment following intravenous administration of 70Zn. Results of selected zinc-related variables in the iron supplemented women were (before vs. after iron supplementation): FAZ with meal 0.22 vs. 0.24, p = .23; FAZ in fasting state 0.58 vs. 0.69, p = .005; EZP 177 mg vs. 160 mg, p = .058; plasma zinc 90.6 vs. 86.1 micrograms/dl, p = .065. The control group remained unchanged. The capacity to absorb zinc was increased three days after terminating a period of iron supplementation as compared with the pre-iron period. This may be attributable to impairment of zinc status by the iron supplements as evidenced by a trend for lower plasma zinc and EZP.

This study describes a community-based method used in rural Malawi to remove dietary phytate, an inhibitor of iron absorption, and notes an improvement in the iron status of ten children who participated in the trial. Phytate was removed by soaking maize flour in excess water with phytase and decanting the water before cooking the flour. Iron status, as measured by soluble transferrin receptor and zinc protoporphyrin, was improved but not normal.

Background: Zinc deficiency in children is an important public health concern in the developing world, and the consumption of predominantly cereal-based diets with a high phytate content may contribute to the risk. The gastrointestinal tract plays a central role in absorbing and conserving zinc, yet it has not been carefully studied in such children., Objective: This study investigated zinc homeostasis in healthy, free-living Malawian children with habitually high-phytate diets to better understand the role of the gastrointestinal tract., Design: We evaluated zinc homeostasis in 10 children aged 2-5 y who were consuming a maize-based diet (phytate:zinc molar ratio of 23:1). Zinc stable isotopes were administered orally and intravenously. The tracer and tracee were measured in urine and feces., Results: Endogenous fecal zinc was high in comparison with results for this measure in previous studies. Typical correlations seen in subjects consuming a low-phytate diet between total absorbed zinc, the size of the exchangeable zinc pool, and endogenous fecal zinc were not observed. Fractional absorption of zinc was 0.24., Conclusions: Zinc homeostasis was perturbed, particularly by large, endogenous fecal zinc losses, in this vulnerable population. The effects of interventions to improve zinc status, including dietary phytate reduction, on zinc homeostasis merit further study.

Tracer kinetic techniques based on zinc stable isotopes have a vital role in advancing knowledge of human zinc physiology and homeostasis. These techniques have demonstrated the complexity of zinc metabolism, and have been critical to estimating the size and interrelationships of those pools of zinc that exchange rapidly with zinc in plasma and which are likely to be especially important for zinc dependent biology. This paper presents findings from recent research linking a steady state compartmental model with non-steady state post-prandial sampling from the intestine, utilizing a combination of intestinal intubation/perfusion and stable isotope tracer kinetic techniques. The gastrointestinal tract has a central role in maintaining whole body zinc homeostasis. While the fractional absorption of zinc from a meal depends on the quantity of exogenous zinc and on such dietary factors as phytic acid, the fractional absorption does not appear to be dependent on the size of the rapidly exchanging pool of the host. In contrast, the quantity of endogenous zinc excreted via the intestine is positively correlated with both the amount of absorbed zinc and the zinc 'status' of the host, and thus this process has an equally critical role in maintaining zinc homeostasis. The observed alterations in zinc metabolism in some disease states can be understood in the context of known homeostatic processes. In other conditions, however, such alterations as inflammation-associated hyperzincuria and zinc redistribution, the links between homeostatic perturbation and cellular biology are yet to be explained. Thus the challenge remains for research at the whole body level to carefully characterize zinc distribution and exchange under diverse circumstances, while research at the cellular level must elucidate the regulatory processes and the factors to which they respond.

Objective: We investigated whether previous reports of reduced bone mineral density after management for childhood acute lymphoblastic leukemia (chALL) were confirmed in a more recently treated cohort., Study Design: In a cross-sectional study 75 subjects who were given the diagnosis of chALL between January 1, 1991, and December 31, 1997 (69% standard, 31% high risk), at Denver Children's Hospital and who were 11 to 82 months post-diagnosis with no history of relapse, secondary malignancy, or transplant underwent whole body areal bone mineral densitometry (BMD(A) expressed as age- and sex-standardized z scores), a food frequency questionnaire, and a weight-bearing activity survey., Results: Overall, the mean whole body BMD(A) z score was normal (+0.22 +/- 0.96). A significant positive association was found with whole body BMD(A) z score and years elapsed since the beginning of maintenance (linear regression coefficient = +0.2 Deltaz score/year; 95% CI = 0.09 to 0.3) after adjustment was done for risk status/age category, history of cranial radiation, and total days hospitalized. No association was found with high risk/older age at diagnosis, nutrient intake, chemotherapy dosage, or weight-bearing activity., Conclusion: Contrary to previous reports in which cranial radiation and longer hospitalizations were prominent components of therapy, our study suggests that more recently treated patients with chALL do not have persistent abnormalities of bone mineral density after completion of therapy.

High dietary phytate content that compromises zinc nutriture is thought to be a major problem among children of the developing world. Zinc stable isotope techniques permit the quantitative assessment of the effect of phytate reduction on zinc homeostasis. We tested the hypothesis that zinc absorption would be increased in Malawian children fed a reduced-phytate corn-plus-soy diet compared with a standard high phytate diet. Twenty-three children hospitalized in Blantyre, Malawi, were enrolled. Children were selected from those recovering from tuberculosis and from well children (those with minor injuries, those awaiting elective surgery or healthy siblings). Children received a diet of corn-plus-soy porridge (either low phytate or high phytate) for a period of 3-7 d and then participated in a zinc stable isotope study. The study included the administration of oral and intravenous zinc stable isotopes and 7-d collections of urine and stool. The diet was maintained throughout the duration of specimen collection. Zinc isotopic enrichments in urine and stool were measured, and zinc fractional absorption, total zinc absorption, endogenous fecal zinc, net zinc retention and size of the exchangeable zinc pool were calculated. Among the 14 children recovering from tuberculosis, dietary phytate reduction resulted in higher fractional absorption (0.41 +/- 0.14 versus 0.24 +/- 0.09, mean +/- SD, P: < 0.05) and total zinc absorption (169 +/- 55 versus 100 +/- 46 microg/(kg. d), P: < 0.05). No effect of phytate reduction was seen in the well children (n = 9). Phytate reduction did not decrease the absolute endogenous fecal zinc, but it did decrease it relative to total absorbed zinc. These preliminary results indicate that phytate reduction may be beneficial in improving zinc nutriture in groups with increased zinc requirements who consume a cereal-based diet.

A compartmental model of zinc metabolism has been developed from stable isotope tracer studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously, and the resulting enrichment was measured in plasma, erythrocytes, urine, and feces for as long as 3 wk. Data from total zinc measurements and model-independent calculations of various steady-state parameters were also modeled with the kinetic data. A structure comprised of 14 compartments and as many as 25 unknown kinetic parameters was developed to adequately model the data from each of the individual studies. The structural identifiability of the model was established using the GLOBI2 identifiability analysis software. Numerical identifiability of parameter estimates was evaluated using statistical data provided by SAAM. A majority of the model parameters was estimated with sufficient statistical certainty to be considered well determined. After the fitting of the model and data from the individual studies using SAAM/CONSAM, results were submitted to SAAM extended multiple studies analysis for aggregation into a single set of population parameters and statistics. The model was judged to be valid based on criteria described elsewhere.

Low plasma zinc concentrations have been reported in approximately 30% of young infants with cystic fibrosis identified by newborn screening. The objective of this study was to examine zinc homeostasis in this population by application of stable isotope methodology. Fifteen infants with cystic fibrosis (9 male, 6 female; 7 breast-fed, 8 formula-fed) were studied at a mean (+/-SD) age of 1.8 +/- 0.7 mo. On d 1, 70Zn was administered intravenously, and 67Zn was quantitatively administered with all human milk/formula feeds during the day. Three days later, a 3-d metabolic period was initiated, during which time intake was measured and complete urine and fecal collections were obtained. Fractional zinc absorption, total absorbed zinc, endogenous fecal zinc, and net absorbed zinc were measured; fecal fat excretion was also determined. Fractional absorption was significantly higher for the breast-fed infants (0.40 +/- 0.21) compared with the formula-fed group (0.13 +/- 0.06) (p = 0.01), but with the significantly higher dietary zinc intake of the formula-fed group, total absorbed zinc was higher for those receiving formula (p = 0.01). In 1 infants with complete zinc metabolic data, excretion of endogenous zinc was twofold greater for the formula-fed infants (p < 0.05); net absorption (mg zinc/d) was negative for both feeding groups: -0.04 +/- 0.52 for breast-fed; -0.28 +/- 0.57 for formula-fed. Endogenous fecal zinc losses correlated with fecal fat excretion (r = 0.89, n = 9, p = 0.001), suggesting interference with normal conservation of endogenously secreted zinc. These findings indicate impaired zinc homeostasis in this population and suggest an explanation for the observations of suboptimal zinc status in many young infants with cystic fibrosis prior to diagnosis and treatment.

Objectives: The purpose of this study was to examine the zinc status of young infants with cystic fibrosis before and after the initiation of pancreatic enzyme therapy., Study Design: Cross-sectional data were obtained for infants with cystic fibrosis identified by newborn screening. Plasma zinc concentrations were measured and analyzed according to enzyme use at the time of the blood draw. On a subgroup of infants, zinc concentrations were determined again after several weeks with enzyme therapy., Results: Mean (+/-SD) plasma zinc concentration for the infants studied before the initiation of enzyme therapy was 10.4 +/- 2.2 micromol/L (68.3 +/- 14.7 microgram/dL) (n = 48), which was significantly lower than the mean for those receiving enzymes for >/=2 weeks, 11.8 +/- 2. 3 micromol/L (77.1 +/- 14.9 microgram/dL) (n = 15) (P =.03). For the group not yet receiving enzymes, 29% of infants had zinc concentrations in the deficient range. Data were available before and after enzyme therapy for 30 infants and indicated a mean increase of 1.64 +/- 3.0 micromol/L (10.7 +/- 19.3 microgram/dL) (P =. 005)., Conclusions: These data suggest that many of the infants were zinc deficient at the time of diagnosis. We conclude that zinc should be included among the specific micronutrients given consideration in the management of cystic fibrosis, particularly in infants.

Zinc stable isotopes can be applied to the identification of populations at risk for zinc deficiency and to monitoring the effects of zinc intervention studies designed to improve zinc nutriture. Techniques using these isotopes can provide information on how effectively the intestine is absorbing exogenous dietary zinc and conserving endogenous zinc. They can also yield estimates of the quantity of readily exchangeable zinc in the body. Data derived from stable-isotope studies can provide extensive information on zinc status and the bioavailability of dietary zinc, allowing researchers to relate zinc intake to physiologic and pathologic conditions. Application of these techniques in longitudinal studies can provide quantitative data on the effectiveness of prevention programs such as simple community measures aimed at reducing dietary phytate and zinc fortification and supplementation programs. Further, judicious application of zinc stable-isotope techniques could make an important contribution to progress toward the eradication of zinc deficiency in infants and young children in the developing world.

Background: The trace metal zinc has a wide range of important physiologic roles. Indirect evidence suggests that fat malabsorption is associated with malabsorption of zinc. The objective of this study was to evaluate the effect of pancreatic enzyme replacement on zinc absorption in children and adolescents with cystic fibrosis., Methods: Subjects were four boys and four girls ranging in age from 7 to 17 years of age. All were pancreatic insufficient. Stable isotope labels, 70Zn and 67Zn, were administered orally in divided doses on consecutive days with meals. Meals were identical on the first 2 study days. Subjects were randomized to have pancreatic enzyme replacement withheld on the first or second day. All fecal samples were collected quantitatively for 10 days after label administration and were analyzed individually for total zinc and isotopic enrichment using atomic absorption spectrophotometry and fast atom bombardment mass spectrometry, respectively. Fractional absorption of zinc was calculated from cumulative fecal excretion of unabsorbed label., Results: Fractional absorption while receiving enzymes was 0.50 +/- 0.29 versus 0.38 +/- 0.24 while not taking enzymes (p = 0.05)., Conclusions: These results indicate that fractional absorption of zinc is impaired by pancreatic insufficiency in patients with cystic fibrosis, and is improved by exocrine pancreatic enzyme replacement.

Compartmental modeling is a useful tool for investigating metabolic systems and processes. We and others have applied it to the study of zinc metabolism in humans. Because existing models could not be accurately fitted to our data, we have developed a new model of human zinc metabolism based on stable isotope tracer data from studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously and the resulting enrichment measurement in plasma, erythrocytes, urine, and feces. These tracer kinetic data, along with other measured and calculated tracee and steady-state data, were used to develop the model. A single model structure composed of fourteen compartments was found to be suitable for all subjects. Model development and fitting of data and model for each subject were accomplished using the SAAM/CONSAM computer programs. The model development and fiting processes are described and exemplified using data from one of the subjects. While identifiability could not be demonstrated a priori due to the model's complexity, parameter statistics for the fitted models did show most parameters to be adequately identified a posteriori.

The needs for dietary zinc are adequately met by most fully breast-fed infants despite relatively low zinc intakes in relation to estimated requirements. The objective of this study was to use stable isotope techniques to evaluate how zinc retention is achieved in normal fully breast-fed infants. Nine male infants, aged 2-5 mo, were fed expressed human milk labeled with 70Zn over a 24-h period. Complete fecal collections were obtained for 8 d. On d 4-7, a metabolic period was initiated which included test weighing and milk sampling, to measure zinc intake, and daily urine collections. Isotopic enrichment of fecal and urine samples was determined by fast atom bombardment mass spectrometry. Results included a mean (+/- SD) dietary zinc intake of 17.8 +/- 6.6 mumol/d; fractional absorption of 0.54 +/- 0.075; and total absorbed zinc of 9.5 +/- 3.5 mumol/d. Mean endogenous fecal zinc, determined on seven infants by isotope dilution, was 4.7 +/- 2.3 mumol/d, which resulted in a mean net absorption of 4.8 +/- 3.4 mumol/d. The results of the study indicated that, for fully breast-fed infants, it is the combination of a relatively high fractional absorption and efficient conservation of intestinal endogenous zinc that results in zinc retention adequate to meet the demands of growth in the face of modest intake.

The objective of this study was to determine the concentration of Zinc (Zn), Copper (Cu) and Manganese (Mn) in hepatic tissue from extrahepatic biliary atresia (EHBA). Liver biopsy samples were obtained at time of portoenterostomy from 49 infants ages 1.1 to 20.7 months (median 2.1) with EHBA. Samples were dry ashed and analyzed by flame (Zn) or flameless (Cu and Mn) atomic absorption spectrophotometry. Hepatic Cu concentrations are physiologically elevated at birth and decline rapidly during the first 2 month of life, therefore only samples from 29 infants, ages greater than 8 weeks were considered for Cu. Concentrations (mg/kg dry weight, mean and range) were: Zn 142 (70-507), Cu 204 (19-570), Mn 9.1 (2.8-21.8) vs. literature controls in the same age range: Zn 262 (82-543), Cu 92, Mn 4.3 (3.3-11.5). No correlations were found between serum alkaline phosphatase, AST or total bilirubin and hepatic trace element concentrations, between trace element concentrations and age, or between Cu and Mn. Decreased bile flow with intrahepatic cholestasis may result in hepatic accumulation of Mn as well as Cu. The low hepatic Zn concentrations indicate the need for further study of Zn metabolism in this population.

To investigate whether a fundamental lesion in energy metabolism is a feature of cystic fibrosis, we measured total energy expenditure using the doubly labeled water technique in 19 infants with presymptomatic cystic fibrosis (0.8 to 6.6 months of age) identified through newborn screening. Total energy expenditure data collected in a cohort of healthy infants by the same method were used for comparison. Energy balance studies were additionally performed in 10 of the infants with cystic fibrosis. Total energy expenditure levels in infants with cystic fibrosis, expressed as either kilocalories per day or kilocalories per kilogram of fat free mass per day, did not differ from control levels. When expressed on the basis of body weight (in kilocalories per kilogram per day), expenditure levels in infants with cystic fibrosis were greater (p < 0.05) than control levels. No differences in expenditure were observed between those infants who were homozygous (n = 10) for the delta F508 mutation and the heterozygous infants (n = 7), regardless of how expenditure was expressed. Assessment of energy balance indicated that infants with cystic fibrosis grow at a normal rate for metabolizable energy intakes similar to those reported for healthy infants. We conclude that there are no differences in energy expenditure between infants with presymptomatic cystic fibrosis and healthy infants, once differences in body composition are taken into account. This finding indicates that the primary cystic fibrosis defect is not an energy-requiring one.

Ten pre-menopausal women participated in two studies to measure the daily variations in plasma zinc when meals were fed at 6-h intervals and to determine if the response was related to shifts in serum insulin, glucose, calcium, or phosphorus concentrations. In Study 1, identical meals were fed at 6-h intervals for 2 d, and blood was sampled 8 times between each meal. In Study 2, the women fasted from 1800 h on d 1 to noon the next day, and blood was sampled hourly from 0700-1200 on d 2. The postprandial plasma zinc response was similar following all four meals and accounted for 50% of the total within subject variation in plasma zinc. A small (2-6%) increase occurred within the first 60 min; then plasma zinc declined to a low point at 4 h after the meal. This characteristic pattern was not observed during the fasting study. Serum phosphorus varied consistently after each meal with a net efflux from circulation that preceded an efflux of zinc by 2 h. The postprandial response of serum glucose and insulin were related to the postprandial plasma zinc response measured 6 h earlier; the variables were not correlated at concurrent time points. The data show that food intake is a determinant of the daily variations in plasma zinc. The net efflux of zinc from circulation following meals may reflect hepatic zinc uptake in association with an increase in postprandial liver metabolism.

Zinc is important for normal cell growth and differentiation, DNA synthesis, and gene expression. IGF-II is a fetal growth and differentiation factor whose regulation is largely unknown. To assess the effect of zinc (Zn) on fetal hepatocyte IGF-II expression and DNA synthesis, primary cultures of ovine fetal hepatocytes were studied in serum-free medium containing 1 mumol/L Zn or supplemented to 10 or 50 mumol/L Zn. Fetal hepatocyte DNA synthesis, Zn and protein content, IGF-II mRNA, and IGF binding protein production were measured. Zn concentration in medium increased slightly in unsupplemented dishes, from 1 to 1.5 mumol/L; however, Zn concentration declined by 4 and 8 mumol/L over 24 h in culture medium supplemented to contain either 10 or 50 mumol/L Zn (p < 0.05). Zn content of cell pellets increased 155 and 204% after 24 h in supplemented cultures compared with unsupplemented controls, demonstrating uptake of Zn by the liver cells. Media Zn supplementation to 10 and 50 mumol/L decreased 3H-thymidine incorporation of cells in culture by 11 and 13%, respectively, compared with 1 mumol/L Zn (p = 0.001). Addition of Zn caused a progressive 2- to 3-fold decline in the nuclear labeling index of fetal hepatocytes, whereas the labeling index of nonhepatocytes increased almost 2-fold at 50 mumol/L compared with 1 mumol/L Zn. Associated with decreased hepatocyte DNA synthesis, IGF-II mRNA abundance declined by almost 30%. IGF binding protein content of conditioned medium did not change with added Zn.(ABSTRACT TRUNCATED AT 250 WORDS)

A relatively simple technique was used to estimate the size of the combined pools of zinc with which plasma zinc exchanges within 2 d (EZP). EZP size was determined from the amount of isotope introduced into the plasma and the coefficient of the simple exponential decay function fitting enrichment data between d 3 and 9 after isotope administration. Using data from 11 healthy adults, comparisons were made of EZP size estimations using oral and intravenous isotopes (r = 0.93 using urine) and urine and plasma enrichment (r = 0.85 for intravenous). EZP size estimations from urine and plasma enrichment following intravenous isotope administration were 2.35 +/- 0.84 and 2.83 +/- 0.86 mmol, respectively (mean +/- SD, P < 0.01). EZP size correlated with habitual dietary zinc intake (partial r = 0.74, P < 0.02). Cumulative declines in EZP size in two healthy adults after 3 wk of consuming a moderately zinc-restricted diet followed by 1 wk of severe zinc restriction were 26 and 32%. These results indicated that EZP size is dependent on dietary intake. We conclude that this technique is adequate to demonstrate EZP differences that are of nutritional and physiological interest. EZP size estimates can be obtained using orally or intravenously administered isotope and using plasma or urine enrichment data.

The objectives of this study were to examine the growth pattern of healthy infants who were fed human milk exclusively for > or = 5 months and its relationship to intakes of milk, energy, and zinc. Monthly anthropometric measurements were obtained on 71 infants through 7 months of age and on 43 through 9 months. Milk zinc concentrations were determined and milk intake was measured by 3-day test weighing. Mean (+/- SD) calculated energy intake from human milk was 106 +/- 20, 79 +/- 11, 70 +/- 10, and 57 +/- 12 kcal/kg per day at 2 weeks and 3, 5, and 7 months of age, respectively; intake from milk plus solids was 70 +/- 13 kcal/kg at 7 months. Zinc intakes from human milk were 2.3 +/- 0.68, 1.0 +/- 0.43, 0.81 +/- 0.42, and 0.52 +/- 0.31 mg/day at these points. The maximum mean weight-for-age percentile for both sexes was 62 at 2 months; the mean percentile declined to 33 by 7 months and to 25 by 9 months of age. Mean length-for-age percentile declined from 43 at 2 weeks of age to 28 and 26 by 7 and 9 months of age, respectively. Energy intake at 2 weeks of age was positively associated with the weight increment from 2 weeks to 7 months of age (p = 0.003) and with a change in weight-for-age z scores from 2 weeks to 3 months of age (p = 0.028). Mean energy intakes of healthy breast-fed infants are lower through the first 7 months of life than current recommendations. Zinc intakes of breast-fed infants are likely to be adequate, on average, through 5 months of breast-feeding but subsequently are marginal without the introduction of weaning foods. Revision of standards for growth based on observations in breast-fed infants may be appropriate, but the possibility of growth-limiting nutrient deficiencies should also be investigated.

Transfusion-induced hemosiderosis is a serious and potentially life-threatening complication for some patients with sickle cell anemia. The use of high-dose intravenous deferoxamine (DFO) has become widespread in spite of a paucity of published data on safety and efficacy. We report a randomized double-blind study of the dose-response relationship of intravenous DFO in six subjects with sickle cell anemia and severe transfusion-induced hemosiderosis (serum ferritin 4100 to 14,176 ng/ml). Each subject received three different doses of intravenous DFO for 3 days each while consuming a constant diet. Total iron excretion (urine and fecal) was 91% greater at 180 mg/kg/day DFO than at 60 mg/kg/day DFO, and fecal iron excretion became a relatively larger proportion of total excretion at higher doses. Subsequent treatment for 3 months with 150 mg/kg/day DFO caused a 33% to 60% reduction in serum ferritin and demonstrable improvement in hepatic function in all patients. No toxicity was encountered, but DFO at 180 mg/kg/day was associated with a significant increase in fecal zinc excretion when compared with that observed at lower doses.

Malnutrition is a major factor in the etiology, management and prognosis of persistent diarrhea in young children. Apart from inadequate energy intake, deficiencies of several specific nutrients have been implicated. Zinc is a micronutrient that appears to be of special interest, at least in some communities. Zinc deficiency has been documented in otherwise normal children. The risk of deficiency, however, is enhanced by diarrhea which is associated with variable but sometimes gross increases in zinc losses in the feces. These losses could contribute to a vicious circle, as there is now evidence that mild as well as severe zinc deficiency states can contribute to the duration and severity of diarrheal disease. During rehabilitation, impaired zinc nutriture could be responsible for slow growth, especially if the rehabilitation diet is high in phytate, a recognized inhibitor of zinc absorption. Research should be directed to a better understanding of zinc metabolism and homeostasis during diarrhea disease, to the consequences of zinc deficiency and to the benefits to be derived from zinc supplementation programs.

To evaluate the impact of early pancreatic insufficiency on growth and nutritional status in cystic fibrosis, we studied 49 infants identified by a newborn screening program. Pancreatic insufficiency, determined by increased 72-hour fecal fat excretion, was present in 59% (23/39) of infants at diagnosis (7.0 +/- 0.8 weeks; mean +/- SEM). Before initiation of pancreatic enzyme replacement, growth and nutritional status of pancreatic-insufficient (n = 16) and pancreatic-sufficient (n = 13) infants were compared. Pancreatic-insufficient infants gained less weight from birth to diagnosis (13.4 +/- 3.4 vs 22.3 +/- 4.0 gm/day; p = 0.05), had decreased triceps skin-fold thicknesses (4.5 +/- 0.3 vs 6.1 +/- 0.4 mm; p less than 0.005), and had lower blood urea nitrogen (3.07 +/- 0.42 vs 4.62 +/- 0.65 mg/dl; p = 0.02) and albumin (2.99 +/- 0.14 vs 3.54 +/- 0.14 gm/dl; p less than 0.01) levels despite higher gross calorie (154 +/- 8 vs 116 +/- 13 kcal/kg per day; p less than 0.01) and protein intakes (2.81 +/- 0.21 vs 2.14 +/- 0.33 gm/kg per day; p = 0.03). Fecal nitrogen loss was correlated with fat loss (r = 0.79; p less than 0.001). Fat malabsorption was present in 79% (30/38) and 92% (33/36) of infants tested at 6 months and 12 months of age, respectively, indicating that pancreatic insufficiency persists and increases in frequency throughout infancy. We conclude that pancreatic insufficiency is prevalent in young infants with cystic fibrosis and has a significant impact on growth and nutrition.

A child with biotin-non-responsive propionic acidaemia treated with a propiogenic amino acid-restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 fl, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9 micrograms/L), and calculated dietary selenium intake was 4.7 micrograms/day. After 4 months of selenium supplementation (50 micrograms/day) plasma selenium concentration normalized (97.7 micrograms/L) in conjunction with a reduced MCV (84.0 fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.

Concentrations of copper (Cu) and ceruloplasmin in serum were measured serially in 49 preterm infants with mean (+/- SEM) birth weights of 979 +/- 33 g and gestational ages of 28.4 +/- 0.3 weeks at three, six, nine, and 12 months postpartum. Serial radiographic studies showed 17 infants with (group A) and 32 infants without (group B) rickets or fractures. Cu and ceruloplasmin concentrations in serum also were measured in 21 healthy term infants (group C) with birth weights 3668 +/- 98 g at three, six, and 12 months postpartum. Analyses of covariance of serial changes in these serum variables--taking into account such potential covariates as differences in gestational age, birth weight, initial weight and length, changes in weight and length during the study, the duration of parenteral nutrition, and increased enteral copper intake--showed both groups of preterm infants had significantly lower concentrations of Cu in serum up to age six months and ceruloplasmin up to age three months (P less than 0.001) when compared with term infants. By one year of age, Cu and ceruloplasmin concentrations in serum in all groups had increased significantly (P less than 0.001), into the adult range, and were not significantly different among groups. These data document a maturational lag in copper metabolism in small, preterm infants. Changes in concentrations of Cu and ceruloplasmin in serum were significantly correlated (r = 0.92, P less than 0.001) but were not significantly different between preterm infants with and without rickets or fractures at each age.

The aim of this study was to determine the effect of the time and size of the last meal of the previous day on pre-breakfast 0700 hours plasma zinc concentrations. Nine healthy women were each studied on four separate occasions when the same standard meal was taken either at 1800 hours (study 1); double meal at 1800 hours (study 2); at 2400 hours (study 3); or at 1800 hours and 2400 hours (study 4). Mean differences between 1800 hours (day 1) and 0700 hours (day 2) plasma zinc (mumol/L +/- SEM) were 1.6 +/- 0.3 for study one; 0.8 +/- 0.3 for study two; 0.1 +/- 0.3 for study three and 0.0 +/- 0.2 for study four. The differences for studies two, three and four were significantly less than the difference for study one (p less than 0.05). The difference for study four was also less than the difference for study two (p less than 0.05). Changes in time and size of the meals accounted for 59% of within-subject variation in 0700 hours plasma zinc concentrations. It is concluded that pre-breakfast 0700 hours plasma zinc concentrations are affected by the time and the size of the meal(s) consumed the previous evening.

To examine the role of oxidant damage to subcellular membranes in the pathogenesis of copper hepatotoxicity, the effects of dietary copper overload and varying states of vitamin E on biochemical, histological, and ultrastructural features of rat liver were investigated. Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with either deficient, sufficient, or excessive vitamin E. Hepatic microsomes and mitochondria, isolated by differential centrifugation, showed similar enrichment and recovery among all experimental groups. Evidence of in vivo peroxidation of membrane lipids (generation of conjugated dienes and thiobarbituric acid reacting substances) was present in mitochondrial but not microsomal preparations from copper-overloaded rats. Serum aspartate aminotransferase, alanine aminotransferase, and cholylglycine (which were increased in all copper-overloaded rats), as well as mitochondrial thiobarbituric acid-reacting substances, were more elevated in vitamin E-deficient rats. In copper-overloaded rats, liver histology showed changes of acute and chronic hepatocyte injury with mild periportal fibrosis; electron microscopy showed abundant copper-containing lysosomes and dilated cristae of hepatocyte mitochondria, findings similar to those in the liver of humans with copper-overload disorders. These findings suggest that an oxidant injury to hepatocyte mitochondria may be one of the initiating factors in hepatocellular damage that leads to hepatic lesions in copper-overload states in humans.

Nine patients with advanced chronic obstructive pulmonary disease (COPD) and recent weight loss resulting in a state of mild malnutrition were entered into a refeeding program at a clinical research center. They were divided into two groups, one using a hospital diet and the other a hospital diet with supplementation. Both groups of patients gained significant weight. Refeeding and weight gain were associated with a significant increase in absolute lymphocyte count and with an increase in reactivity to skin test antigens after 21 days of refeeding. Few changes occurred in large numbers of additional serum measurements during the study period. These preliminary observations suggest that dietary and supplementary refeeding may improve the immune responses in patients with COPD.

Penicillamine is the drug of choice for the treatment of Wilson's disease, whatever the stage of the illness. Toxic manifestations may preclude the use of this life-saving drug in some patients and discontinuation of penicillamine therapy usually leads to death. We report our experience with Trientine in seven patients, aged 13 to 33 years, with Wilson's disease who developed toxic manifestations with penicillamine that required discontinuation of therapy. These include two with nephrosis, one with neutropenia, two with thrombocytopenia, and one each with a SLE-like and a Henoch-Schonlein-like syndrome. The patients were treated for periods from 6 weeks to 16 years with a dose of 0.5 to 2 g/day. Trientine proved to be an effective alternative copper chelating agent in the treatment of Wilson's disease in patients with penicillamine-induced neutropenia, thrombocytopenia, SLE, and nephrosis. No serious untoward side effects were noted.

Prostaglandins E1, E2 and F2 alpha were measured in duodenal secretions from two healthy, fasting male subjects. Secretions were collected by duodenal intubation prior to, and following, stimulation by secretin and cholecystokinin. Prostaglandins were measured with a radioimmunoassay technique. The ranges of concentrations found were PGE1: 2.4-110 ng/ml, PGE2: 0.004-1.51 ng/ml, and PGG2 alpha: 0.44-14.6 ng/ml.

Children with phenylketonuria (PKU) are treated with semi-synthetic diets restricted in phenylalanine. Low or phenylalanine-free formulae provide the majority of protein and energy in the diet while phenylalanine requirements are met by low-protein natural foods. Because of the restriction of natural protein sources in this diet, the study assessed the zinc and copper nutriture of treated children with PKU and correlated linear growth with zinc status. The plasma zinc of the PKU population was 66.6 +/- 3.3 micrograms/dl (mean +/- SEM). The hair zinc was 70.2 +/- 11.5 micrograms/g (mean +/- SEM). The mean plasma and hair zinc of the PKU population were significantly different (p less than 0.05) when compared to normal values of 84.2 +/- 2.9 micrograms/dl and 130.7 +/- 8.3 micrograms/g (mean +/- SEM), respectively. The dietary zinc intake of 10 PKU patients was 8.56 +/- 2.68 mg/day (mean +/- SD). No significant differences (p less than 0.123) were found when the mean zinc intake was compared with recommended dietary allowances for age of 10 mg/day. No significant correlations were found when plasma and hair zinc were plotted with height percentiles. Plasma copper of the PKU subjects (87.6 +/- 6.6 micrograms/dl, mean +/- SEM) was significantly less than that of normal young children (121.5 +/- 3.1 micrograms/dl, mean +/- SEM) despite a copper intake a 1.45 +/- 0.35 mg/day (mean +/- SD).

The chromium concentration was determined in 261 samples of breast milk collected by manual expression from forty-five American women. Cr was measured in whole, liquid milk by graphite-furnace atomic absorption spectrophotometry, using the method of standard additions. The mean Cr content of the breast milk samples was 0.30 ng/ml. The range of individual values was 0.06-1.56 ng/ml and did not change significantly with duration of lactation. The Cr content of breast milk from these American women is similar to levels reported recently in milk from Finnish women.

Food intake was calculated in 30 young children with evidence of mild zinc deficiency. In a double-blind controlled study of one year's duration, the test children (n = 15, including ten boys) received a zinc supplement (average, 4.2 mg/day), and the controls received a placebo syrup. Increases during the study period in calculated intakes of energy, protein, and nine other nutrients were attributable to the zinc supplementation. A significant treatment effect on nutrient intakes was also observed for the boys but not for the girls. Calculated daily energy intakes of the test boys increased from an initial mean of 1,280 kcal (88% Recommended Dietary Allowance [RDA] ) to a final mean of 1,880 kcal (118% RDA). Zinc deficiency should be considered in the differential diagnosis of anorexia in young children.

A retinol (15 mg), riboflavin (200 mg) and zinc (50 mg) supplement or a placebo (D-mannitol) was given to 610 Chinese farmers weekly for 13.5 months. Riboflavin, retinol, beta-carotene, tocopherol and zinc status were measured in all subjects at the start and end of the intervention and in a subsample at 2 months. Plasma vitamin C, haemoglobin and haematocrits were measured on other subsamples at the end of the supplementation period. At the start vitamin A, zinc and riboflavin status were poor. Plasma retinol and zinc concentrations were higher in men than women but the opposite was observed with respect to beta-carotene. There was no difference between the sexes for tocopherol and riboflavin. Tocopherol:cholesterol ratios suggested vitamin E status was good and vitamin C status also appeared adequate. The supplement increased plasma retinol throughout the whole period but riboflavin status improved only over the first 2 months and then remained constant. Plasma zinc increased in both treatment and placebo groups by approximately 15 to 20 per cent in men and women. Mean concentrations of retinol and tocopherol and beta-carotene (in women only) increased by approximately 20 per cent in the placebo group. It is argued that seasonal factors and/or the placebo may have been responsible for the increase in retinol and beta-carotene in the placebo group. The lack of an increase in beta-carotene in the men may have been due to their higher retinol requirements. Lastly, the increase in retinol may have been responsible for the increase in tocopherol and zinc in plasma since these nutrients increased in those whose plasma retinol increased, irrespective of treatment.