Origin of the Recommended Intake of L-Histidine by Infants.

ABSTRACT

Background: In mid-2012, Food Standards Australia New Zealand (FSANZ) received an application to change the Australia New Zealand Food Standards Code so that the minimum L-histidine content of infant formula sold in Australia and New Zealand could be reduced from 12 to 10 mg/100kJ. Infant formula refers to breast milk substitutes that satisfy nutritional requirements of infants up to 12 months of age. L-histidine is an essential amino acid. Although there is a population nutrient recommendation regarding total protein intake for infants in Australia and New Zealand, there are no recommendations regarding intake of the essential amino acids. The 12 mg/100kJ level that was in existence in 2012 had originally been set in 2002 based on the 1985 Joint FAO/WHO/UNU Expert Consultation report (updated in 1991). This report had estimated amino acid requirements calculated from breast milk composition data from four papers. In 2007, Codex Alimentarius adopted a minimum of 10 mg/100kJ for L-histidine based on the 2005 ESPGHAN Co-ordinated International Expert Group report. The Policy Guideline on the Regulation of Infant Formula Products issued in 2011 by the Australia and New Zealand Food Regulation Ministerial Council recommends that the primary reference for the compositional requirements of infant formula and follow-on formula should be breast milk. Therefore, the FSANZ risk assessment examined which studies of breast milk composition had been included in earlier reports and whether there was more recent data that should be included. Aim: To determine if infant formula containing a minimum content of L-histidine of 10 mg/100kJ is consistent with reported levels in breast milk and will support normal growth in formula-fed infants. It is assumed that the amount of L-histidine in breast milk is adequate to meet the requirements of infants for normal growth. The review focused on infants <6 months of age because older infants would be receiving complementary foods. Methods: The studies which contributed to the average L-histidine amount in breast milk calculated in the FAO/WHO and ESPGHAN reports and similar reports from prominent bodies in Europe and the US were examined. A literature review of the cited studies and related research reporting L-histidine content of breast milk going back to 1954 was done. Because there was great variability in the units used to describe the L-histidine content of breast milk (e.g. nmol L-histidine/ml of milk, mg L-histidine/g milk, mg L-histidine/g nitrogen, g L-histidine/kg/day etc.) all values for L-histidine were converted to mg/g crude protein to allow comparison. After examining previous reports, the estimated L-histidine content in breast milk was updated by selecting studies based on criteria around sample collection, analytical methods for amino acid analysis and measurement of protein content, and reporting items (such as full and available publication in the peer-reviewed literature). To confirm whether a lower L-histidine level would support an infant’s physiological requirements, additional literature was reviewed to examine effects of formulas with different histidine concentrations on growth and plasma histidine concentration. Results: The six reports that were examined calculated the average L-histidine intake from studies of breast milk as the basis of their recommendations. The 1985 and 1991 FAO/WHO reports recommended an intake of 26 mg/g crude protein based on four studies of breast milk. None of the studies cited in these two reports were cited by the later reports, probably because they were conducted prior to the development of modern analytical techniques. The later reports used primary data from a total of 11 studies between them, but their recommendations, which ranged from 21-23 mg L-histidine/g crude protein, were obtained by averaging data from three to seven studies (see table below). Other studies were often cited in these reports but were not included when calculating the average. No reasons were given for inclusion or exclusion of studies. Ten studies met the inclusion criteria specified by FSANZ. Of these, only five had been included in calculations by one or more of the earlier reports. FSANZ calculated an unweighted mean of 24 mg L-histidine/g crude protein. Using appropriate composition data for protein, fat and carbohydrate in breast milk, this is equivalent to 10 mg Lhistidine/ 100 kJ milk. Human milk has a variable composition and depends on a range of factors including the duration of the feed and length of lactation. In the FSANZ calculation, all of the studies used convenience samples of women and reported L-histidine concentrations ranging from 18-40 mg/g crude protein. Only one study (Raiha et al. 2002) examined physiological and biochemical outcomes in infants. In combination with six additional studies examining growth patterns and plasma concentrations of amino acids in breast and formula-fed infants, FSANZ determined that formula-fed infants consuming a formula containing 10 mg L-histidine/100 kJ are comparable to breastfed infants on the basis of the physiological and biochemical outcomes examined. Conclusion: The conversion of results from different studies to a common base, combined with rounding, inevitably introduces error when deriving a mean value. There was a 2-fold range of L-histidine concentrations across the individual studies examined. FSANZ concluded that 24 mg L-histidine/g crude protein (10 mg L-histidine/100kJ) is consistent with the average composition of breast milk and would support growth. This analysis also highlights the variability of the evidence base used by bodies making recommendations for amino acid intakes by infants. Systematic literature searching with justification for inclusion or exclusion of studies does not seem to have been widely used when deriving intake recommendations for L-histidine in infants. References are given in the full report. The complete report “Supporting document 1 – Comparative Nutrition Safety Assessment” can be downloaded for free from the FSANZ website http//www.foodstandards.gov.au/code/applications/documents/A1074_SD11.pdf