Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group.

BACKGROUND: Many patients with cystic fibrosis are malnourished at the time of diagnosis. Whether newborn screening and early treatment may prevent the development of a nutritional deficiency is not known. METHODS: We compared the nutritional status of patients with cystic fibrosis identified by neonatal screening or by standard diagnostic methods. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, we evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic-enzyme therapy, and fat-soluble vitamin supplements. RESULTS: The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs. 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head-circumference percentile (52nd, vs. 32nd in the control group; P=0.003). The early-diagnosis group also had significantly higher anthropometric indexes during the follow-up period, especially the children with pancreatic insufficiency and those who were homozygous for the deltaF508 mutation. CONCLUSIONS: Neonatal screening provides the opportunity to prevent malnutrition in infants with cystic fibrosis.

Oral supplementation with a high-fat, high-energy product improves nutritional status and alters serum lipids in patients with cystic fibrosis.

OBJECTIVE: To assess the tolerance and acceptability of a nutrition supplement in patients with cystic fibrosis (CF), to monitor changes in dietary intake, and to evaluate nutritional status. DESIGN: Subjects were their own controls for this 3-month, prospective, open study. Acceptability and tolerance questionnaires and 3-day food records were completed at baseline and monthly intervals. Compliance and nutritional status were also assessed. SETTING: This study was conducted at the University of Wisconsin Hospital and Clinics Cystic Fibrosis Center, Madison. SUBJECTS: Patients with CF older than 4 years of age were recruited during clinic or hospital visits if they met specific weight or growth criteria (n = 19). INTERVENTION: Subjects were asked to consume the supplement at a maximum of 30% their estimated daily energy requirements. MAIN OUTCOME MEASURES: Responses to acceptability ratings of and tolerance questions about the supplement were obtained along with anthropometric data and biochemical measurements of serum albumin, plasma retinol, alpha-tocopherol, and fatty acid levels. STATISTICAL ANALYSES PERFORMED: Data were analyzed using Minitab and Statistical Analysis Software. Paired and unpaired t tests and nonparametric sign tests were used, as well as regression and Pearson correlations. A significance level of .05 was used for all tests. RESULTS: All subjects tolerated the supplement, although 12 reported mild symptoms of fullness, nausea, and/or bloating, which were resolved when intake was distributed throughout the day. Mean compliance was 69% of recommended intake. Weight gain in children was strongly correlated with compliance (r = .98). Linoleic acid intake increased significantly (P = .0003) as did plasma linoleic acid in the phospholipid fraction (P = .03). CONCLUSION: The supplement studied would be a beneficial addition to the supplementation choices available to patients with CF.

Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee.

This report is a summary of a meeting convened by the Cystic Fibrosis Foundation to develop a consensus among nutrition specialists and cystic fibrosis care givers regarding optimal nutritional management of patients with cystic fibrosis. The first section of the report provides a rationale for emphasizing nutritional management of this genetic disorder. The multiple factors causing malnutrition and a negative energy balance are outlined. The second section provides guidelines for routine assessment of nutrition in these patients. Five categories of nutritional status are defined based on ideal weight for height, age, and gender. These categories are used to formulate a graded response for nutritional intervention. Recommendations are provided for routine dietary supplements, vitamin supplements, and pancreatic enzyme replacement. The primary aim of this report is to educate clinicians as to the importance of frequent assessments and early intervention.

Nutritional status of infants with cystic fibrosis associated with early diagnosis and intervention.

The purpose of this study was to characterize the nutritional status of infants diagnosed with cystic fibrosis (CF) through neonatal screening and to determine if they would achieve normal nutrition when managed with early intervention. In addition, nutrient intake was assessed to determine energy and macronutrient-consumption patterns. Evaluation of growth revealed that normal patterns could be achieved with mean energy intake values at ages 6 and 12 mo of 481 and 426 kJ/kg body wt (115 and 102 kcal/kg body wt), respectively. Biochemical assessment demonstrated low alpha-tocopherol and linoleic acid values at diagnosis in the majority of infants whereas one-third had abnormal indices of protein nutriture. Essential fatty acid deficiency was also demonstrated at diagnosis by abnormal triene-tetraene ratio values in 27% of screened infants. With predigested formula and dietary supplementation, there was improvement in all indices of nutritional status and only a low percentage of patients showed mild biochemical abnormalities at age 12 mo.

Essential fatty acid deficiency in premature infants.

To better characterize essential fatty acid (EFA) deficiency in neonates, we assessed 63 premature infants by serial determinations of plasma fatty acids for the level of linoleic acid, the presence of an abnormal trienoic acid (5,8,11-eicosatrienoic acid [20:3 omega 9]), and the ratio of this compound to arachidonic acid, ie, the triene-tetraene ratio. The data indicated that at age 7 d, 67% of these infants had low plasma linoleic acid levels, 62% showed readily detectable 20:3 omega 9, and 44% had a high triene-tetraene ratio. Infants fed by age 2 d had a normal mean linoleate level at 7 d and none showed detectable 20:3 omega 9 by 10 d. In contrast, infants who were not fed until 7 d showed a very high incidence of abnormal fatty acid status. By maintaining a daily record of linoleate intake, we calculated from regression models that the average amount required to achieve normal fatty acid nutrition was 1.19 g.kg-1.d-1.

Mild peripheral neuropathy but biochemical chromium sufficiency during 16 months of "chromium-free" total parenteral nutrition.

A 6-yr, 4-month-old boy was started on total parenteral nutrition (TPN) because of chronic diarrhea. The TPN regimen (3 liter/day) initially included supplemented Cr (3 micrograms/day) in addition to standard components (including FreAmine III). At age 8 yr, 8 months, the serum Cr level was elevated: 3.7 ng/ml (normal 0.03-0.85). A repeat level at the same time by another commercial laboratory was also high (7.0). Cr supplementation was stopped. At age 10 yr, he was noted to have mild peripheral neuropathy although glucose tolerance was excellent (alpha-linolenic acid was undetectable in the plasma). Cr status was reevaluated in a research lab. The serum level was 1.4 ng/ml (normal 0.05-0.4). The urine chromium excretion was 1.27 micrograms/day (normal 0.22). The TPN regimen (unsupplemented with Cr) provided 4 micrograms/day. Normal Cr intake is about 60 micrograms/day with 0.4% absorption (net 0.24 microgram/day). We conclude that Cr contamination of standard PN fluid may prevent biochemical evidence of low Cr status. In addition, alpha-linolenic acid-free parenteral nutrition for 46 months was not associated with clinically significant neurological dysfunction.

Effect of choline deficiency on lung phospholipid concentrations in the rat.

Lung surfactant and nonsurfactant phospholipid concentrations were analyzed in relation to choline status in male rats fed a choline-deficient (CD) or choline-supplemented (CS) diet over an 8-d period. On the first day plasma choline concentrations were significantly lower (11.5 +/- 0.9 micron) in rats fed the CD diet than in those fed the CS diet (16.1 +/- 1.2 microM). This relationship continued for the duration of the study. Hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratios were significantly lower after d 1 of the CD diet, further decreased on d 2 (1.09 +/- 0.04) and remained low through d 8. Only on d 4 were lung surfactant PC and total phospholipid concentrations lower in rats fed the CD diet than in those fed the CS diet. The composition of surfactant, determined by the ratio of PC to total phospholipids, did not change. On both d 4 and d 8 the PC/PE ratios in the nonsurfactant fraction were lower in rats fed the CD diet than in those fed the CS diet. This shift in PC/PE ratio in the lung is similar to the PC/PE shift in the liver associated with dietary choline deficiency. The altered lung phospholipid concentrations in the nonsurfactant (residual) fraction on d 4 and d 8 suggest an adaptation in the lung's phospholipid metabolism to replenish the physiologically essential surfactant PC.

Changes in erythrocyte and plasma carnitine concentrations in preterm neonates.

Erythrocyte and plasma total, free, and acyl carnitine concentrations in 13 low birthweight, preterm infants were determined between birth and 21 days of age. Although erythrocytes contributed 73.6 +/- 4% (mean +/- SD) of total blood carnitine at birth, the contribution by day 14 declined to 42.2 +/- 14.1. Linear regression analysis showed no significant correlation between plasma and erythrocyte concentrations. At 3 wk erythrocyte total carnitine concentrations were similar to adult values, but erythrocyte acyl carnitine concentrations were markedly lower. Although a significant (p less than 0.05) positive correlation between plasma carnitine concentrations and mean daily intake from birth was found at 7, 14, and 21 days of age (r = 0.66, 0.87, and 0.88, respectively), no significant relationships between erythrocyte carnitine concentrations and carnitine intake could be demonstrated by linear regression analysis. It appears that the carnitine present in plasma and erythrocytes represents two separate pools which are influenced by different factors in preterm infants.

Correction of linoleic acid deficiency in cystic fibrosis.

To identify evidence of essential fatty acid deficiency, we screened 64 patients with cystic fibrosis by analyzing total lipid extracts from plasma. Forty-three had an abnormal linoleate (18:2) level (less than 26%). Thirteen deficient patients (aged 10-24 yr) ingested for 1 yr 7% of their total calories as linoleate derived from a daily supplement of Microlipid. Five deficient patients (aged 10-37 yr) served as controls. Plasma and erythrocyte fatty acid composition were monitored by gas chromatography of total lipid extracts seven times during the twelve month period. Prostaglandins E2 and F2 alpha and their 15 keto 13, 14 dihydrometabolite, 6-keto F1 alpha, and thromboxane B2 were measured by radioimmunoassay. Sweat tests, oxygen saturation, growth indices, clinical severity scores, compliance, and possible side effects from taking Microlipid were followed. Results showed that oral supplementation with Microlipid can significantly increase plasma and erythrocytes % 18:2. One compliant patient died during the study and had normal tissue 18:2 levels. Nine of 13 patients gained more weight while taking Microlipid than in the previous year. No significant changes in sweat electrolytes, clinical scores, or oxygen saturation were found during the study year. Prostaglandin metabolites prostaglandin E2 showed an upward trend in supplemented patients, compared to controls. Prostaglandin F2 alpha remained unchanged over 1 yr but showed a trend significantly downward over the final 6 months in supplemented patients. We conclude that linoleate deficiency can be corrected with daily Microlipid supplements and that correction may alter prostaglandin metabolism.

Tocopherol isomers in intravenous lipid emulsions and resultant plasma concentrations.

Conflicting reports exist regarding the relative tocopherol isomer content of Intralipid ranging from 99% as alpha-tocopherol to as much as 90% as gamma-tocopherol. Our direct assay of Intralipid as well as plasma levels measured in premature infants receiving Intralipid confirm the existence of a low alpha, high gamma-tocopherol content and imply the need for alpha-tocopherol supplementation in patients receiving Intralipid, particularly the relatively tocopherol-deficient premature infant. Furthermore, the observation of abnormal erythrocyte hemolysis test values despite "normal" total tocopherol plasma concentrations may be explained by high plasma levels of non-alpha, biologically less active isomers. The quantitation of tocopherol isomers helps explain this discrepancy and suggests the need for future studies of vitamin E status to employ measurements of tocopherol isomers in reporting results.

Nutrition in cystic fibrosis.

The goal of nutritional care for the CF patient should be to support normal growth and development, even if the patient has pancreatic insufficiency. By optimizing nutritional habits, using potent pancreatic enzyme supplements effectively and treating patients with appropriate micronutrient supplements, physicians should be able to prevent malnutrition and enhance the general health of cystic fibrosis patients.

Evaluation of vitamin E deficiency in children with lung disease.

The clinical assessment of vitamin E status has traditionally depended upon measurement of tocopherol concentrations in plasma or serum, with 0.5 mg/dl being used as the lower limit of normal. This approach can be supplemented by measurement of tocopherol in erythrocytes or by evaluating their susceptibility to hemolysis in the presence of hydrogen peroxide. Data obtained during the last decade indicate that tocopherol concentrations in blood samples may be misleading, and that tocopherol-lipid ratios are more reliable indicators of vitamin E status. In our studies, small populations of healthy children have been evaluated, along with infants and children with a variety of chronic diseases. Of interest is the observation that premature infants susceptible to lung disease, who often require high levels of inspired oxygen, and children with cystic fibrosis who have chronic obstructive pulmonary disease are almost invariably below 0.5 mg tocopherol per deciliter plasma. A substantial number, however, show no abnormality in peroxide-induced erythrocyte hemolysis. Expression of the tocopherol data per gram of total lipid indicates that many children with "low" tocopherol concentrations per unit volume of plasma are not deficient in vitamin E, but rather are above 0.8 mg/g, the ratio of tocopherol to lipid previously reported as the lower limit of normal.

The occurrence and effects of human vitamin E deficiency. A study in patients with cystic fibrosis.

The role of vitamin E in human nutrition was studied by investigation of patients with cystic fibrosis (CF) and associated pancreatic insufficiency. Vitamin E status was assessed by measurement of the plasma concentration of the principal circulating isomer, alpha-tocopherol. Results of such determinations in 52 CF patients with pancreatogenic steatorrhea revealed that all were deficient in the vitamin. The extent of decreased plasma tocopherol varied markedly but correlated with indices of intestinal malabsorption, such as the serum carotene concentration and percentage of dietary fat absorbed. Supplementation with 5-10 times the recommended daily allowance of vitamin E in a water-miscible form increased the plasma alpha-tocopherol concentrations to normal in all 19 CF patients so evaluated. Studies on the effects of vitamin E deficiency focused on possible hematologic alterations. An improved technique was developed to measure erythrocyte hemolysis in vitro in the presence of hydrogen peroxide. While erythrocyte suspensions from control subjects demonstrated resistance to hemolysis during a 3-h incubation, all samples from tocopherol-deficient CF patients showed abnormal oxidant susceptibility, evidenced by greater than 5% hemoglobin release. The degree of peroxide-induced hemolysis was related to the plasma alpha-tocopherol concentration in an inverse, sigmoidal manner. The possibility of in vivo hemolysis was assessed by measuring the survival of (51)Cr-labeled erythrocytes in 19 vitamin-E deficient patients. A moderate but statistically significant decrease in the mean (51)Cr erythrocyte half-life value was found in this group. Measurement of erythrocyte survival before and after supplementation of 6 patients with vitamin E demonstrated that the shortened erythrocyte lifespan could be corrected to normal with this treatment. Other hematologic indices in deficient subjects, however, were normal and did not change upon supplementation with vitamin E. It is concluded that CF is invariably associated with vitamin E deficiency, provided that the patient in question has pancreatic achylia and is not taking supplementary doses of tocopherol. Concomitant hematologic effects consistent with mild hemolysis, but not anemia, occur and may be reversed with vitamin E therapy. Patients with CF should be given daily doses of a water-miscible form of vitamin E to correct the deficiency.

Megavitamin E supplementation in man.

To assess possible toxic and/or beneficial effects of vitamin E supplementation, a group of 28 adults voluntarily ingesting 100 to 800 IU/day of tocopherol for an average of 3 years were evaluated in this study. Half of the subjects claimed a feeling of improved health or well being, but no specific beneficial effects were noted consistently; the other half indicated no change in health status after beginning vitamin E supplements. No gross evidence of toxicity was apparent on reviewing past medical histories with the subjects. Plasma alpha-tocopherol was found to be elevated significantly in the group from 650 micrograms/100 ml (control mean) to 1,340 micrograms/100 ml; however, 25% of the values were within 2 SD of the control mean. Plasma alpha-tocopherol levels did not correlate with total daily dose but did relate to plasma triglyceride and cholesterol concentrations. Total plasma carotenoids were also significantly increased along with vitamin A levels; the former did not correlate with plasma vitamin E, whereas the latter showed a significant correlation. Laboratory screening for toxic side effects of vitamin E supplementation by performance of 20 standard clinical blood tests failed to reveal any disturbance in liver, kidney, muscle, thyroid gland, erythrocytes, leukocytes, coagulation parameters, or blood glucose. It is concluded that megavitamin E supplements in this group produced no apparent toxic side effects and that subjective claims for beneficial effects were highly variable.