Search

A series of reports in the 1960s highlighted nutritional copper deficiencies in infants and children recovering from malnutrition in Peru; since that time, a cascade of additional cases in premature infants, in patients receiving total parenteral nutrition, and in those receiving special diets or unmodified cow milk have been reported. The identification by Danks that Menkes syndrome, a genetically determined defect in copper absorption and utilization, is responsible for the observed clinical manifestations provided further insight into the physiopathologic effects of copper deficiency. New information on the metabolism and physiologic role of copper, plus the identification of additional copper metalloenzymes and improvement in how to determine copper status, has fueled interpretation and speculation on how and why the classic signs of copper deficiency occur, as well as on the possible effects of mild deficiencies. Also under scrutiny are potential interactions between other elements and the effects of other elements, even when given in acceptable amounts, on copper status. There should be no constraints in thinking on other possible effects of impaired copper status in humans. I review some of the history of nutritional copper deficiency in infants and children and attempt to interpret some of the clinical manifestations in light of newly acquired information. Am J Clin Nutr 1998;67(suppl): 1012S-6S.

While the recommendation is usually made that breast-fed infants with acute diarrhea continue to be breast-fed, the management of infants who usually receive formula is more controversial. The World Health Organization (WHO) recommends a formula containing cow milk in such cases, but the American Academy of Pediatrics recommends a formula free of lactose because many infants can not digest this substance. (Lactose is a sugar present to varying degrees in the milk of all mammals, including cows.) To learn more about the optimal approach to feeding infants with diarrhea, 50 male infants younger than 1 year were randomly assigned to receive 1 of 5 formulas. The formulas were: two-thirds diluted cow milk, a cow milk formula (Nanon), and three other commercially available formulas (Portagen, Pregestimil, and Prosobee). The compositions and nutrient values of the formulas are listed. All the infants had severe diarrhea for less than one week prior to admission to the hospital and were at least five percent dehydrated. They received fluids orally and intravenously; oral rehydration was continued for 72 hours unless further dehydration occurred. Fecal output, urine, vomiting, and weight were monitored. Results showed that the diluted cow milk formula was not well tolerated; 8 of the 10 patients in that group developed further dehydration or excessive diarrhea. Portagen, however, was the most effective formula. Results for infants fed the other formulas were acceptable, but the severity of diarrhea decreased the most with Portagen. This product contains no lactose and uses sodium caseinate as its protein source. The probable reasons for its advantage are discussed. In general, infants with severe diarrhea recover with fluid and electrolyte supplementation. If formulas are available, one such as Portagen is recommended. (Consumer Summary produced by Reliance Medical Information, Inc.)

An infant formula based on high protein rice flour, with added lysine and threonine, was evaluated in recovering malnourished infants. Acceptability, tolerance, and the digestibility of most major nutrients (energy 93.9 ± 0.7, fat 96.9 ± 0.3, carbohydrate 96.8 ± 0.6 of intake) were excellent. Digestibility of protein, as with all rice products, was moderately low (80.1 ± 3.3), but its high biological value made N retention equal to that from casein. Plasma-free amino acids were consistent with the low essential/total amino acids ratio found in cereals, with slower absorption, and with the possibility that leucine was the first-limiting amino acid. Absorptions of Ca, Mg, PO4, and Zn were considered satisfactory. Energy costs of weight gain and the estimated percentage N in the weight gained during 14 days were comparable to those attained with the highest quality cow's milk-derived formulas in children of similar ages and nutritional status.

The equivalent of 0.12% lysine enrichment of white wheat flour resulted in significant enhancement of its protein value for the rapidly growing human infant, as demonstrated by increased rates of weight gain and nitrogen retention, stability of serum albumin, and elevation of the molar ratio of plasma lysine when the flour was the only source of protein in the diet. Isonitrogenous and isocaloric casein diets were used as controls. Enrichment to the 0.2% level resulted in suggestive further increases in the rates of weight gain and N retention, a further elevation in the molar ratio of plasma lysine and a reduction in that of plasma threonine. Enrichment to the 0.4% level resulted in a suggestive further increase in N retention alone and in further elevation of plasma lysine and reduction of plasma threonine.Enrichment of white wheat flour with lysine to the 0.12% and possibly the 0.2% level is recommended for those areas in which this cereal serves as the main source of protein in the diet, particularly that of infants and children. The improvement in biological value to be expected is enough to make the difference between dietary protein adequacy and deficiency to the many, without adverse effects to the few who might not profit by such enrichment.

Milks based on isolated soy protein enriched with dl-methionine are rapidly coming into common use in pediatric practice. The biological value of its protein has been measured at critical levels in the initial therapy of malnourished infants and children and during convalescence. Absorption and retention of nitrogen, as well as growth rates, were equivalent to those from modified cow's milk. Normal serum albumin levels were achieved and maintained, as were levels of fasting plasma amino acids, both indicative of dietary protein adequacy. These results confirm the enormous potential of isolated soy protein in human nutrition, particularly in the diet of those intolerant of milk proteins or lactose.

A lactose-free, medium-chain triglyceride (MCT)-casein formula (Lactose-Free Portagen) was used with success gen) the management of four children with kwashiorkor and three infants with persistent hypoalbuminemia, two of whom had associated infections. A second formula (Pregestimil), based on a casein hydrolysate and MCTs, with dextrose as the major carbohydrate, was used successfully in five infants with severe marasmus, one with kwashiorkor, and five with marasmus, severe diarrhea, and infection. The absence of lactose was of definite benefit, as was probably the MCT content. It is probable that the dextrose was of benefit to some of the sickest infants but this was not proved in these studies.

AS INTEREST increases in the worldwide problem of malnutrition in infants and preschool children, it becomes ever more apparent that the basic problem is the lack of a proper substitute for human breast milk and that the age at which infants are weaned determines the type of malnutrition encountered.1 If unlimited amounts of whole cow's milk could be made available in a safe form to the millions of undernourished children of the world, there would be little need to contemplate other substitutes. Unfortunately, the supply of this most valuable of foods is limited and difficult to increase; its cost of production places it beyond the reach of most impoverished people and the problems involved in protecting it from contamination remain an important barrier to its use in primitive environments.In recent years considerable effort is being devoted to the study of possible substitutes for milk protein, many of them

Copper deficiency was often found in severely malnourished infants rehabilitated on exclusive milk diets. Marked, persistent neutropenia was its earliest and most constant manifestation.

The utilization of proteins from a wheat flour-wheat concentrate-soy flour mixture and from a whole wheat flour-soy flour mixture were significantly limited by their digestibility, despite satisfactory biological values.The biological value of an oat flour-soy flour mixture was so high that it almost completely compensated for its own inferior digestibility, when it was compared with milk protein.

The protein of CSM, a cornmeal—soy flour-milk solids mixture now being used extensively in child feeding, has been demonstrated to have a biological value approximately two-thirds that of casein. To be the main source of protein in the diet it should provide 12% of total calories as protein. Its digestibility is relatively poor, as is that of most vegetable mixtures. Its biological value might be enhanced by methionine enrichment or by improving its digestibility.

Nitrogen-balance studies in convalescent malnourished infants and children have been used to determine the apparent biological value of the protein in a number of cottonseed flours. A “glandless” CSF proved to approximate most closely the value of milk protein. Cottonseed flour prepared by azeotropic solvent extraction was next in apparent quality and a CSF prepared by heat processing and screw-press extraction gave the poorest results. Cottonseed flour prepared in Peru by combining wet cooking and hexane extraction of a relatively low gossypol variety was no better than this last product. The “gland-less” CSF, if used as the main or only source of protein in the diets of infants and children, should provide 8–10% of calories as protein. For the solvent-extracted CSF, a minimum of 10% protein calories seems indicated and for the heat-press extracted CSF, 12% protein calories. These results indicate that both the origin of CSF and the manner of its processing have important effects on the nutritive value of its protein. They suggest that at appropriate levels, a properly processed CSF can be the main or only source of protein in the diets of infants and children. Prolonged feeding trials are necessary to confirm or deny these observations.

Extract: In nine infants suffering from protein-calorie malnutrition, significantly low values for muscle mass and cell mass which were proportional were observed. These were 1.02±0.44 kg and 2,295±693 pg, respectively (P < 0.001). The extracellular volume was disproportionally high relative to creatinine excretion before and after rehabilitation. The extracellular volume was disproportionally high relative to creatinine excretion before and after rehabilitation. The major loss of muscle mass was due to loss of cell size rather than cell number.The protein/DNA ratio was 78±18.7 (P<0.001) prior to rehabilitation and 109.6±45.1 (P<0.001) following rehabilitation. The RNA/DNA ratio was low at 0.96±0.26 (P0.001) prior to rehabilitation while after rehabilitation the value increased to 1.24±0.14 but was still less than normal (P<0.01).The levels of Mg and Zn per unit DNA were reduced in muscle prior to rehabilitation. These values were 6.6±0.7 and 35.6±15.8, respectively (P<0.001).The significantly reduced protein/DNA and RNA/DNA ratios after rehabilitation suggest either persistent alteration in mechanisms responsible for protein synthesis or a prolonged period necessary for recovery. Muscle mass of 1.67±0.64 kg was not significantly different from the normal for body length after rehabilitation.The concerntrations of water (39.96±16.99) and collagen (3.86±2.24) in adipose tissue were elevated (P<0.01), while that of fat (50.36±21.87) was low prior to rehabilitation. The noncollagen protein was constant per gram of tissue in marasmus and following rehabilitation.Speculation: Because insulin is intimately related to protein synthesis and the attainment of normall cytoplasmic growth, the persistently poor secretion of insulin during rehabilitation from malnutrition may be responsible for inadequate cytoplasmic growth.Inaulin administered judiciously during the recovery phase may accelerate recovery and insure a return to normal.

Studies in severely malnourished infants to whom a fish protein concentrate, wheat enriched with the same, or a vegetable protein mixture was given as the only source of dietary protein, reveal a marked inferiority to cow’s milk in their ability to correct hypoalbuminemia or to maintain serum albumin at the levels usually considered normal. Nevertheless, in the convalescing subject, these same proteins support growth and produce nitrogen retentions similar to those obtained with milk. The reasons for this contrast are not apparent and deserve further study.

In severe marasmus and in partially recovered malnourished infants, the retention of nitrogen is shown to depend on the total intake of calories as well as on the quantity and quality of protein ingested. If the caloric requirements are not met, protein is “wasted.” Early in the treatment of patients with hypoalbuminemia, with or without other signs of kwashiorkor, nitrogen retention is, to a great extent, independent of caloric intake but closely related to the quantity and quality of protein in the diet. After this initial period of repletion, nitrogen retention is also dependent on caloric intake.

White wheat flour enriched with lysine was the only source of protein in the diet of six convalescent malnourished infants for 3–6 months. At 8 % protein calories the equivalents of 0.1, 0.2, and 0.4% lysine enrichment were equally effective in supporting normal linear growth, weight gain, nitrogen retention, serum proteins, plasma amino acids, and liver morphology. Between 6.4 and 7.3 % protein calories there was almost certainly an advantage to 0.2 % over 0.1 % enrichment, and possibly to 0.4 over 0.2% enrichment, by the same parameters. If wheat is to be enriched with lysine in those areas where it is the main source of protein for many infants and small children, and where dilution by nonprotein calories is the rule, at least 0.2% enrichment is recommended.

Prolonged feeding trials confirm the impression gained from metabolic studies that properly processed cottonseed flours, at adequate levels, can serve as the main or only source of protein for rapidly growing infants and children.

Extract: Total body water (TBW), intracellular (ICW) and extracellular (ECW) spaces, muscle mass and supporting tissue were measured in nine malnourished infants, 5–30 months of age, shortly after hospitalization, and then following 4–9 months of rehabilation. Initially all infants had server growth deficits, heights age being 4–64% (average 40%) and weight age 0–40% (average 15.6%) of chronologic age TBW ranged from 63.5 to 89.3% of body weight and ECW ranged from 38.6 to 50.6% of TBW, suggesting marked losses of cell mass and body fat with conservation of supporting tissues. Excretory levels of creatinine and hydroxproline ranged from 31 to 86 mg/24 h and from 10.3 to 28.5 mg/24 h, respectively. During rehabilitation all patients exhibited accelerated growth, height age becoming 28.6–69.1% (averange 58.8%) of chronologic age; most of the children become moderately obese. With the exception of one infant, who did not gain weight well hydroxyproline increased 45–360% over the intial values. TBW became 54.7–65% of body weight and ECW 41.8–55.9% of TBW. Proportionally smaller increase in metabolically active protoplasm, respresented by ICW, were exprienced in four infants under 11 months (average 25%, than in four of five infants over 11 months of age (average 67.5%); however; these four infants demonstrated proportionately greater gains in ECW (77 versus 36%).Determinations of blood sugar, growth hormone and insulin responses to arginine were made in five of these patients and in three additional infants. On admission, the levels of growth hormone in these infants were found to be elevated (11.5–18 ng/ml) and did not respond, to arginine injection; determination of blood sugar also showed elevated levels (119–182 mg/100 ml). One to three months later the response was usually normal. Insulin responses, initially and after partial rehabilitaion, were almost invariably blunted, with only one child, at 50 days, showing a rise to 45 ng/ml.It is apparent that growth during, recovery from malnutrition is neither a uniform process nor is it simply reinitiation of normal growth.Speculation: The apparently normal production of growth hormone and the impaired insulin, which was persistently demonstrated by these infants, along wiht the poor growth in cell mass of those under 11 months of age, suggest that gains in cell mass in the younger infant may be primarily dependent on insulin and not on growth hormone. Cartilage and other supporting tissues may continue to respond to growth hormone, despite fairly severe malnutririon.

The effect of different levels of protein and calorie intake on the weight gain of severely malnourished infants 6 to 30 months of age was studied in relation to the weight deficit. In the most severely underweight, 175 kcal/kg/day were necessary to establish an adequate rate of gain; intakes of more than 2.0 g of protein/kg/day were apparently superior to lower levels. In the less severely malnourished, progressively decreasing caloric intakes were necessary and 2.0 g of protein/kg/day or even less, evenly distributed throughout all feedings, were not inferior to higher levels, particularly if the source was milk. In the least severely under-nourished or those well advanced in their recovery, a good mixture of vegetable proteins or a mixture of wheat and fish proteins appeared to be as efficacious as milk. These results were similar in marasmic infants or in cases of marasmic kwashiorkor after diuresis — confirming previous suggestions that there is no proven advantage to levels of protein intake above the usual and that on the other hand caloric requirements are directly proportional to the severity of the malnutrition. The practical implications of this study in the planning of feeding programs are discussed.

Acceptable, inexpensive products of high biologic-value are badly needed to improve foods in underdeveloped countries. The authors evaluated a corn-soy-wheat macaroni in treating malnourished infants and report their success.

• The osmolality of an elemental formula was reduced from 627 to 338 mOsm/kg H2O by replacing dextrose with corn syrup solids, reducing the content of casein hydrolysate, and replacing a portion of the medium-chain triglycerides with corn oil. In three convalescent malnourished infants, the protein quality of the formula was compared at isonitrogenous levels with that of a casein-sucrose-vegetable oil formula and was found to be at least as high: in all three nitrogen retention was higher than during a preceding casein period, and in one of the three it was also higher than during a following casein period. The levels of postprandial plasma amino acids suggested that threonine might be the first-limiting amino acid. Four severely malnourished infants received the formula as their only food during initial rehabilitation. The formula was well tolerated and supported satisfactory weight gain, linear growth, and serum protein regeneration.(Am J Dis Child 133:795-797, 1979)