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Cysteine: a conditionally essential amino acid in low-birth-weight preterm infants? ^1,2,3,4

¹ From the Department of Pediatrics, Division of Neonatology (MAR and JBvG), Mass Spectrometry Laboratory (GV), Erasmus MC-Sophia Children's Hospital, University Medical Center, Rotterdam, the Netherlands; the Department of Pediatrics, Amphia Hospital, Breda, the Netherlands (RHTvB); the Department of Pediatrics, Vlietland Hospital, Vlaardingen, the Netherlands (HMAdB); and the Department of Pediatrics, Deventer Hospital, Deventer, the Netherlands (ACMD)

² "Cyst(e)ine" is used throughout to designate any undefined combination of cysteine and cystine. The terms "cysteine" and "cystine" are used to designate the specific amino acids.

³ Supported by the Sophia Foundation for Medical Research (grant 417), the Netherlands, and the Nutricia Research Foundation, Wageningen, the Netherlands.

⁴ Reprints not available. Address correspondence to JB van Goudoever, Erasmus MC-Sophia Children's Hospital, Department of Pediatrics, Division of Neonatology, Dr Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands. E-mail: j.vangoudoever{at}erasmusmc.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Cyst(e)ine can be synthesized de novo from methionine and serine and is, therefore, a nonessential amino acid in human adults. Several studies have suggested that cyst(e)ine might be a conditionally essential amino acid in preterm infants because of biochemical immaturity. No data are available on cyst(e)ine requirements in low-birth-weight (LBW) preterm infants.

Objective: The aim was to determine cyst(e)ine requirements in LBW infants with gestational ages from 32 to 34 wk, measured 1 mo after birth with the use of the indicator amino acid oxidation technique.

Design: LBW infants were randomly assigned to 1 or 2 of the 5 formulas containing graded cystine concentrations (11, 22, 32, 43, or 65 mg cyst(e)ine/100 mL) and generous amounts of methionine. After 24-h adaptation, cyst(e)ine requirement was determined by ¹³CO₂ release from [1-¹³C]phenylalanine in expired breath. ¹³CO₂ enrichment was measured by isotopic ratio mass spectrometry.

Results: Cyst(e)ine requirement was determined in 25 LBW infants with a mean (±SD) gestational age of 33 ± 1 wk and birth weight of 1.78 ± 0.32 kg. Fractional oxidation of [1-¹³C]phenylalanine did not differ between the 5 groups.

Conclusions: There is no evidence for limited endogenous cyst(e)ine synthesis in 4-wk-old LBW preterm infants born at gestational ages from 32 to 34 wk. It is safe to conclude that the cyst(e)ine requirement is <18 mg · kg^–1 · d^–1 providing generous amounts of methionine and that cyst(e)ine is probably not a conditionally essential amino acid in fully enterally fed LBW preterm infants born at 32–34 wk.

Key Words: Amino acid requirements • indicator amino acid oxidation • nutrition

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Cyst(e)ine is a sulfur-containing amino acid that is not essential in humans. The human body synthesizes cyst(e)ine de novo from methionine, the only essential sulfur-containing amino acid, and serine. Cyst(e)ine has several important metabolic functions. First, like all other amino acids it is involved in growth and protein synthesis. Furthermore, it is a precursor for the tripeptide glutathione, an important intracellular antioxidant. Then, it is also a precursor for the production of taurine, another antioxidant, and sulfate.

Some nonessential amino acids are classified as conditionally essential. These amino acids may become temporarily essential when synthesis during rapid growth or critical illness is insufficient. Cyst(e)ine is believed to be conditionally essential in preterm infants because of biochemical immaturity of the enzyme cystathionase (EC 4.4.1.1) that is involved in cyst(e)ine synthesis (1-3). It is, therefore, important to know the exact cyst(e)ine requirement of preterm infants and also in view of the higher amino acid requirement as a result of rapid growth and development.

Different methods are used to estimate individual amino acid requirements, eg, the nitrogen balance method, growth rate, plasma amino acid patterns, and the factorial approach. The first reports on amino acid requirements in neonates were based on nitrogen balance and weight gain rate (4, 5). Nitrogen balance has several limitations (6), for instance, it requires 7–10 d to adapt to the test diet (7). Because present-day practice will not allow neonates to be maintained on either deficient or excess intakes of amino acids for a minimum of 7 d, no recent requirement studies have used this method in preterm infants.

At present, the factorial approach is used to define amino acid requirements in infants (8). This model is based on fetal protein accretion during normal intrauterine development. Accretion data are derived from body carcass analysis of stillborn preterm infants, some born > 100 y ago (9, 10). Not all data are suitable as reference material; gestational age and cause of death were not accurately obtained (11), and, in view of this study, cysteine content of the body was not determined. The current recommendation for cyst(e)ine requirement for preterm infants, ie, 66–95 mg · kg^–1 · d^–1, is based on the minimum and maximum amounts of each amino acid present in the amounts of human milk protein corresponding to the recommended minimum and maximum protein contents of 3.0 g/120 kcal and 4.3 g/120 kcal, respectively (8).

Because methionine is the precursor of cyst(e)ine, the methionine intake needs to be taken into account as well. The current estimated methionine requirement for preterm infants is 48–69 mg · kg^–1 · d^–1 (8). To ensure an adequate methionine intake, the study formula supplied an amount of 70 mg methionine · kg^–1 · d^–1. Shoveller et al (12) determined the total sulfur amino acid requirement in enterally fed neonatal piglets when no dietary cysteine was provided. The extrapolation from this piglet study results in a methionine intake of 84 mg · kg^–1 · d^–1 for the human neonate, which is slightly above the current recommendations (8).

The objective of the present study was to use indicator amino acid oxidation (IAAO) with [1-¹³C]phenylalanine to estimate cyst(e)ine requirements in fully enterally fed low-birth-weight (LBW) infants supplied with an adequate methionine intake. We hypothesized that cyst(e)ine is a conditionally essential amino acid for these infants.

	SUBJECTS AND METHODS

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Subjects
Subjects eligible for the study were LBW infants with gestational age (GA) between 32 and 34 wk, admitted to the neonatal department of the Amphia Hospital, Breda; Vlietland Hospital, Vlaardingen; or Deventer Hospital, Deventer (all: the Netherlands). The infants needed to be clinically stable during the study, and those with any congenital or gastrointestinal disease were excluded. All tolerated full enteral feeding and were partly fed through a nasogastric feeding tube and partly bottle-fed. The study protocol was approved by The Central Committee on Research Involving Human Subjects (CCMO) and the Erasmus MC Institutional Review Board. Written and informed consent was obtained from both parents of each subject.

Study formula
We used 5 study formulas that contained graded cyst(e)ine concentrations: 11, 22, 32, 43, and 65 mg cystine/100 mL (Xcys/Neocate; Nutricia Nederland BV, Zoetermeer, the Netherlands/SHS International, Liverpool, United Kingdom). Infants were enrolled in the study when they tolerated full enteral feeding (>150 mL · kg^–1 · d^–1). Except for the cyst(e)ine concentration, the 5 formulas did not differ in amino acid composition (Table 1), and consequently the nitrogen content increased slightly from 0.37 mg nitrogen/100 mL (formula 1) to 0.38 mg nitrogen/100 mL (formula 5). The graded cyst(e)ine concentrations of the study formulas were based on the current estimated cyst(e)ine requirement for preterm infants (8), which is 66–95 mg · kg^–1 · d^–1, and is based on the minimum and maximum amounts of each amino acid present in the amounts of human milk protein corresponding to the recommended minimum and maximum protein contents of 3.0 g/120 kcal and 4.3 g/120 kcal, respectively. We decided to test 3 cyst(e)ine intakes above and 2 cyst(e)ine intakes below the estimated cyst(e)ine requirements for formula-fed preterm infants. Methionine content was similar in all formulas and was supplied generously.

The IAAO technique uses as indicator a labeled essential amino acid that is different than the test amino acid. The indicator is independent of the different intake amounts of the test amino acid. If the test amino acid is deficient in the diet, this will limit overall protein synthesis and all other essential amino acids will be oxidized. Increasing the dietary intake of the test amino acid will linearly decrease oxidation of the indicator until requirement of the test amino acid is met. We chose [1-¹³C]phenylalanine as the indicator (13).

After 24-h adaptation, subjects received a primed (10 µmol/kg) continuous (10 µmol · kg^–1 · h^–1) enteral infusion of [¹³C]bicarbonate [sterile pyrogen free, 99 atom percent excess (APE); Cambridge Isotopes, Woburn, MA] for 2.5 h to quantify individual carbon dioxide production. We infused the tracer enterally to minimize invasiveness, which was validated by our group (14). The labeled sodium bicarbonate infusion was directly followed by a primed (30 µmol/kg) continuous (30 µmol · kg^–1 · h^–1) enteral infusion of [1-¹³C]phenylalanine (93 APE; Cambridge Isotopes) for 5 h. One hour before the start of the oxidation study, the feeding regimen was changed into continuous drip-feeding. Enterally infused tracer was mixed with the study formula and infused continuously by an infusion pump through the nasogastric tube. All infants were breathing spontaneously, and 14 infants needed supplemental oxygen by a nasal prong.

Breath samples were obtained with the use of the direct sampling method described by van der Schoor et al (15). In brief, a 6-French gastric tube (6 Ch Argyle; Cherwood Medical, Tullamore, Ireland) was inserted 1–1.5 cm into the nasopharynx, and end-tidal breath was taken slowly with a syringe connected at the end. Collected air was transferred into 10-mL sterile, non-silicon-coated evacuated glass tubes (Van Loenen Instruments, Zaandam, the Netherlands) and stored at room temperature until analysis. Baseline samples were obtained 15 and 5 min before starting tracer infusion. Duplicate ¹³C-enriched breath samples were collected every 30 min and every 15 min during the last 45 min of the tracer infusion.

Analytic methods and calculations
¹³CO₂ isotopic enrichment in expired air was measured by isotope ratio mass spectrometry (ABCA; Europe Scientific, Van Loenen Instruments, Leiden, the Netherlands) and expressed as APE above baseline (15). APE was plotted relative to time.

It is necessary to determine the individual carbon dioxide production to determine the rate of substrate oxidation. In general, the rate of oxidation is calculated by multiplying the isotopic enrichment of carbon dioxide in breath by the total rate of carbon dioxide excreted; the latter needs to be determined by indirect calorimetry to estimate the rate of carbon dioxide production. Alternatively, body carbon dioxide production can be determined by quantifying the excretion of ¹³CO₂ in expired air during [¹³C]sodium bicarbonate infusion, which avoids the quantification of total expired air (15).

Estimated body carbon dioxide production (in mmol · kg^–1 · h^–1) was calculated as described previously (14). The rate of fractional [1-¹³C]phenylalanine oxidation was calculated as follows:

(1)

where IE_PHE is the ¹³C isotopic enrichment in expired air during [1-¹³C]phenylalanine infusion (in APE), i_B is the infusion rate of [¹³C]bicarbonate (in µmol · kg^–1 · h^–1), i_PHE is the infusion rate of [1-¹³C]phenylalanine (in µmol · kg^–1 · h^–1), and IE_B is the ¹³C isotopic enrichment in expired air during [¹³C]bicarbonate infusion (16).

Statistical analysis
Descriptive data are expressed as mean ± SD. Steady state of ¹³CO₂ in expired breath during the [1-¹³C]phenylalanine was achieved when the linear factor of the slope was found not to be significantly different from zero (P 0.05). The cyst(e)ine requirement was determined with the IAAO method. The indicator oxidation rate is plotted against the varying dietary intakes of cyst(e)ine. The inflection or breakpoint in the indicator oxidation rate represents the physiologic requirement of cyst(e)ine (17). Data were analyzed with the use of mixed model analysis of variance in SPSS SOFTWARE (version 14.0; SPSS Inc, Chicago, IL), while encoding the patients who participated twice with the same number. Repeated measures analysis of variance was performed on primary and derived variables to assess the effects of dietary intake and of subjects. Regression analysis was performed to analyze oxidation rates. Power calculation showed that, assuming 5 formula groups with a group variance of 16, an intergroup variance of 5.5, and a power of 80%, a breakpoint should be detected with 6 subjects per group. Statistical significance was assumed at the 5% level of significance (P 0.05).

	RESULTS

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We included 25 LBW infants (12 boys, 13 girls) born at mean (±SD) GA of 33 ± 1 wk (range: 32–34 wk). They were studied at mean postmenstrual age of 36 ± 1 wk (range: 35–38 wk), ie, approximately at postnatal age 1 mo. Subject characteristics are depicted in Table 2. Five infants participated twice and received 2 different study formulas. Aiming at 6 measurements per formula, we performed a total of 30 labeled phenylalanine oxidation rate measurements in these 25 infants.

To detect any differences between the 5 groups receiving the different formulas we corrected for sex, study age, and study weight. The baseline ¹³C enrichment in expired breath did not differ between the 5 formula groups (–17.24 ± 0.56, –16.77 ± 0.62, –17.95 ± 1.38, –17.87 ± 1.01, and –17.58 ± 1.55 Pee Dee Belemnite, respectively; P = 0.67) after correction for birth weight and study weight (Table 3). Each subject reached a plateau during both [¹³C]bicarbonate and [1-¹³C]phenylalanine tracer infusions. As an illustration, the ¹³C enrichments in expired breath during the infusion of [1-¹³C]phenylalanine of 6 subjects receiving 54 mg cyst(e)ine · kg^–1 · d^–1 are shown in Figure 1.

View larger version (7K): [in this window] [in a new window]   FIGURE 1.. Mean 13C enrichments in expired breath during enteral [1-13C]-phenylalanine infusion in 6 infants receiving 54 mg cyst(e)ine · kg–1 · d–1. Data are expressed as means ± SDs. APE, atom percent excess.

Figure 2

View larger version (8K): [in this window] [in a new window]   FIGURE 2.. Fractional [1-13C]phenylalanine oxidation plotted against increasing cyst(e)ine intake. Data are expressed as means ± SDs. No differences could be detected between the fractional oxidation of [1-13C]-phenylalanine of the 5 different cyst(e)ine intakes (n = 6 per intake; P = 0.73).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

The current guidelines on requirements of individual amino acids for infants are based on the factorial method. To calculate the deposit of each amino acid, growth rate is assumed to be constant at 15 g · kg^–1 · d^–1 for a fetus from 900 to 2400 g and protein retention at 70% of total protein intake. Furthermore, the protein maintenance requirement in preterm infants ranges from 0.55 to 0.75 g · kg^–1 · d^–1 (20). Fetal amino acid accretion during normal intrauterine growth was determined by Widdowson (21). Cyst(e)ine accretion by the human fetus was not determined, however; thus, the requirement could not be estimated by the factorial approach.

Little is known, too, about the biosynthetic capacity of nonessential amino acids in preterm infants. In the early 1970s several investigators reported that the transsulfuration pathway might be immature in preterm infants because of limited enzyme activity of cystathionase (1-3). Some found cystathionase activity to be absent in fetal liver tissues (2, 3). Zlotkin and Anderson (1) showed that cystathionine activity was limited but not isolated to the liver and was also present in extrahepatic tissues (kidneys and adrenals). They also found in term and preterm infants that this activity increased after birth. Furthermore, Stegink and Den Besten (22) showed that plasma cysteine concentrations in adult humans fed a cystine-deficient diet intragastrically were significantly higher than in those fed the same diet intravenously. This finding suggests an important role in cyst(e)ine production for the gut and was confirmed in animal experiments. Neonatal piglets fed a cysteine-free diet enterally showed significantly higher plasma cysteine concentrations than did parenterally fed piglets (23). In addition, dietary methionine and plasma cysteine concentrations were positively correlated in enterally fed piglets but not in parenterally fed piglets.

Earlier studies that investigated whether cyst(e)ine is an essential amino acid in preterm infants were all performed during parenteral nutrition. Several of those studies reported low plasma cysteine concentrations, with or without cysteine supplementation (24-26). Pohlandt (26) observed no differences in plasma cystine concentrations between preterm infants receiving only glucose intravenously and preterm infants fed a mixture of synthetic amino acids free from cystine. In both groups cystine plasma concentrations were low, <5 µmol/L, indicating limited endogenous synthesis from methionine. Furthermore, Viña et al (25) and Miller et al (27) reported impaired cysteine metabolism in premature infants on total parenteral nutrition. All those studies indicate that limited cystathionase activity makes cyst(e)ine a conditionally essential amino acid in preterm infants. Zlotkin et al (28), nevertheless, reported that cysteine supplementation did not affect growth rate and nitrogen balance in parenterally fed term and preterm infants. It did slightly increase urinary 3-methylhistidine excretion, however, suggesting that either muscle protein catabolism or muscle mass had increased. Also Malloy et al (29) did not find an improved nitrogen balance with cysteine supplementation, although plasma-free cyst(e)ine concentration increased. Contradictorily, findings from a recent study suggest that the transsulfuration pathway produces sufficient amounts of cysteine in the parenterally fed preterm infant (30).

Our study was performed when neonates received full enteral feeding supplied with a generous amount of methionine and shows that the cyst(e)ine synthesis pathway is active and sufficient at this time. We studied the indicator oxidation during 5 h when infants were continuously fed. The standard feeding regimen of these infants in our neonatal intensive care unit dictates feeding every hour or every 2 h, depending on clinical considerations. Thus, we studied neonates under physiologic circumstances. In our view, therefore, the absence of a postabsorptive state in these preterm infants does not necessitate the study of oxidation during 24 h.

In conclusion, our findings reject our hypothesis that cyst(e)ine is a conditionally essential amino acid in 1-mo-old fully enterally fed LBW preterm infants with a mean GA of 33 wk. These findings show indirectly that activity of the enzyme cystathionase is sufficient to synthesize adequate amounts of cyst(e)ine in these infants supplied with a generous amount of dietary methionine.

	ACKNOWLEDGMENTS

 
We thank Ineke van Vliet for her support in performing the studies, Ko Hagoort for critical review of the manuscript, and Paul Mulder for statistical help. We also thank all the parents who consented for their infants to participate in this study.

The author's responsibilities were as follows—MAR: collected and analyzed the data and wrote the manuscript; RHTvB, HMAdB, and ACMD: recruited all patients; GV: analyzed the data; JBvG: designed the study and provided helpful comments on the manuscript. None of the authors had any financial or personal interest in any company or organization sponsoring the research.

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