Plasma Phenylalanine Concentrations Research Articles

Plasma amino acid and protein concentrations in infants fed human milk or a whey protein hydrolysate formula during the first month of life

The aim of the study was to compare growth parameters, biochemical indices of protein metabolism and plasma amino acid concentrations in infants fed either human milk (n = 12) or a whey protein hydrolysate formula (n = 13) during the first month of life. Growth and gain in skin fold thickness were similar in both groups whereas serum protein concentration was significantly decreased (57.4 +/- 3.9 versus 61.2 +/- 2.9 g/l) in the infants fed the whey hydrolysate formula. The discrepancies between the plasma amino acid pattern of the whey hydrolysate formula group and that of the human milk group lessened during the first month. Nevertheless, at a mean age of 33 days the plasma threonine concentration remained twice as high and the plasma tyrosine, phenylalanine and proline concentrations were significantly lower in the whey hydrolysate formula group than in the human milk group. Thus, compared with breast-fed infants, growth and most of the biological indices of protein metabolism were satisfactory in infants fed during the first month of life on a whey protein hydrolysate formula. Nevertheless, the decrease in total plasma protein concentration needs to be confirmed in a larger cohort of infants. In addition, further research is necessary to investigate the possible ways of reducing the hyperthreoninemia and preventing other plasma amino acid disturbances since it would be desirable to obtain plasma amino acid levels similar to those of breast-fed infants.

Plasma Phenylalanine and Tyrosine Responses to Different Nutritional Conditions (Fasting/Postprandial) in Patients With Phenylketonuria: Effect of Sample Timing

To evaluate the adequacy of dietary treatment in patients with phenylketonuria, the monitoring of plasma phenylalanine and tyrosine concentrations is of great importance. The preferable time of blood sampling in relation to the nutritional condition during the day, however, is not known. It was the aim of this study to define guidelines for the timing of blood sampling with a minimal burden for the patient. Plasma concentrations of phenylalanine and tyrosine were measured in nine patients with phenylketonuria who had no clinical evidence of tyrosine deficiency. These values were measured during the day both after a prolonged overnight fast, and before and after breakfast. Phenylalanine showed a small rise during prolonged fasting, while tyrosine decreased slightly. After an individually tailored breakfast, phenylalanine remained stable, while tyrosine showed large fluctuations. It is concluded that the patient's nutritional condition (fasting/postprandial) is not important in the evaluation of the phenylalanine intake. To detect a possible tyrosine deficiency, however, a single blood sample is not sufficient and a combination of a preprandial and postprandial blood sample on the same day is advocated.

Effects of supplemental dietary iodine on organ weights, selected blood variables and bone density in silicon-deprived and -supplemented rats

Plasma silicon (Si) concentration reportedly is influenced by thyroid status. Thus, the purpose of this experiment was to determine if excess dietary iodine (I) would alter the utilization of Si. Male weanling Sprague-Dawley rats were assigned to groups of six in a 2×2 factorially arranged experiment. Supplemented to a ground corn/casein basal diet containing 1.2 μg Si and 0.3 μg I were Si as sodium meta-silicate at 0 and 50 μg/g and I as KI at 0 and 50 μg/g diet. The rats were fed ad libitum deionized water and their respective diets for nine weeks. Plasma and brain mineral concentrations were determined by inductively coupled argon plasma atomic emission spectrometry. Plasma amino acid concentrations were determined by chromatography using fluorometric detection. Tibia bone density was determined by using Archimede's principle with weighing the bone first in air and then in water. Testes weight (wt)/body wt ratio and plasma concentrations of boron, valine and cholesterol were increased and the heart wt/body wt ratio, concentrations of iron, magnesium and zinc of brain and plasma concentrations of phenylalanine, molybdenum and copper were decreased by excess iodine. These variables were not affected by dietary Si; however, tibia bone density and plasma Si were increased by feeding 50 μg Si/g diet. Although an interaction between Si and I affected hemoglobin, hematocrit, body wt, brain wt/body wt ratio, and plasma threonine and aspartic acid concentrations, plasma Si was not affected by supplemental I. Whether plasma cholesterol and copper would be similarly affected in individuals consuming I supplements such as kelp should be examined. The finding of increased bone density supports the contention that dietary Si affects bone status in rats.

Growth, nutrient intake and plasma phenylalanine and tyrosine concentrations of infants treated with phenex TM-1 amino acid modified medical food with iron

The objective of this study was to evaluate the effects of a new medical food (Phenex-1) on growth, nutrient intake and plasma phenylalanine (PHE) and tyrosine (TYR) concentrations of infants and toddlers with phenylketonuria (PKU). Ten full-term infants (5F, 5M) with classical PKU were placed on Phenex-1 as their primary protein source at a mean age of 11.8 days (range 7–20 days). Two infants received human milk and eight received proprietary infant formula as the source of PHE. Anthropometric measures were obtained by standard techniques, nutrient intakes were calculated using Amino Acid Analyzer© software, and plasma amino acids were analyzed by ion exchange chromatography. When compared to NCHS growth curves, mean head circumference and weight of subjects at birth were at the 75th percentile and greater than the 75th percentile at six months of age. Mean length was at the 75th percentile at birth and at six months of age. During the first three months of study mean PHE intake was 47 mg/kg (range 34–67 mg/kg) and mean TYR intake was 154 mg/kg (range 119–291 mg/kg). During the second three months of study mean PHE intake was 36 mg/kg (range 27–61 mg/kg) and mean TYR intake was 214 mg/kg (range 181–257 mg/kg). Mean protein intake during the study was consistently above RDAs; mean energy intake, except at month one, was below RDAs and the lowest mean value was 87% of RDA at 3 months of age. Mean plasma PHE (35 samples) during the course of the study was 258 μmol/L (range 6–1054 μmol/L) (NL 19–76 μmol/L). Twenty-three percent of samples were in the normal range; forty percent were < 121 μmol/L, 66% were < 303 μmol/L and 89% of samples were < 619 μmol/L. Mean plasma TYR was 47 μmol/L (range 16–98 μmol/L) (NL 25–148 μmol/L). Ninety-one percent of the 35 plasma TYR concentrations were in the normal range. Despite energy intakes that were below RDAs and plasma PHE that was < 121 μmol/L in 40% of the samples, Phenex-1 supported excellent growth and normal plasma TYR concentrations.

Decreased plasma proteins, increased total plasma-free amino acids, and disturbed amino acid metabolism in the hereditary severe anemia of the Belgrade laboratory (b/b) rat.

The plasma amino acid pattern has been investigated in severely anemic Belgrade laboratory (b/b) rats. Nonanemic heterozygous (b/+) or normal homozygous (+/+) rats of the same age (six weeks) were used as controls. Decreased plasma proteins, increased total free amino acid, and urea concentrations in plasma associated with increased urea and 3-methylhistidine urinary excretion were found, indicating protein and amino acid metabolic alterations in anemic b/b rats. Plasma alanine, glutamine, tyrosine, and phenylalanine concentrations were increased. The significantly reduced molar ratio between valine+leucine+isoleucine and phenylalanine+tyrosine suggested severe disturbance in the hepatic energy-producing system and derangement of hepatic energy status. Partial or complete reversal of the anemia within 3 days by red blood cell transfusion or within 3 weeks by iron treatment resulted in normalization of tyrosine, alanine, glutamine, and total amino acid concentrations in plasma, as well as of molar ratio between valine+leucine+isoleucine and phenylalanine+tyrosine. This indicated a better oxygen supply to the liver and normalization of the hepatic energy status. These findings suggest that the metabolic disturbances in the b/b rat are the consequence of hypoxia due to the severe anemia.

Epinephrine transiently increases amino acid disappearance to lower amino acid levels in humans

Background: Infusion of epinephrine decreases plasma amino acid concentrations. However, the mechanism by which this decrement occurs is not well characterized. Methods: Epinephrine was infused (40 ng/kg/min) for 2 hours into eight normal healthy adults. The essential amino acid tracers L-[1- 13 C]leucine and L-[phenyl- 2 H 5 ]phenylalanine were infused before and during the epinephrine infusion and blood samples obtained to determine amino acid rates of appearance and disappearance from the time course of change in amino acid concentration and tracer enrichments. Results: Epinephrine infusion decreased plasma leucine and phenylalanine concentrations over a period of 30 to 90 minutes after the start of the epinephrine infusion. Epinephrine infusion induced an immediate decrement in tracer enrichments. These changes defined sharp increases in both rate of appearance and rate of disappearance. By 30 minutes of epinephrine infusion, the rate of amino acid appearance from proteolysis had returned to baseline, but the rate of amino acid disappearance remained elevated for 90 minutes before returning to baseline. It was the protracted increase in amino acid disappearance that was responsible for the lowering of plasma amino acid concentrations. After this acute response, rates of amino acid appearance and disappearance returned to normal whereas plasma amino acid levels remained suppressed. Conclusions: Epinephrine transiently affects both rates of amino acid appearance and disappearance, with the net effect being increased in amino acid disappearance. However, epinephrine lowers amino acid concentrations beyond the period that it affects kinetics. These results suggest that the effect of epinephrine on amino acid metabolism is not detrimental and that epinephrine allows amino acid metabolism to proceed normally but at lower concentrations of amino acids.

Pregnancy in Phenylketonuria

THOMPSON, GEOFFREY N.; FRANCIS, DOROTHY E. M.; KIRBY, DENISE M.; COMPTON, ROBYN Author Information

The ratio of plasma phenylalanine to other large neutral amino acids is not a risk factor for tardive dyskinesia

The ratio of the plasma concentration of phenylalanine (PA) to the sum of the plasma concentrations of other large neutral amino acids (LNAA) was calculated in 26 chronic, in-patient schizophrenics who met diagnostic criteria for tardive dyskinesia and 22 patients who did not. No difference in the PA/LNAA ratio was found between the two groups. Small positive correlations were found between age and both PA/LNAA ratio and tardive dyskinesia. Neuroleptic dose correlated negatively with both age and plasma PA/LNAA ratio. No support was found for previous reports of increased plasma PA/LNAA ratio in schizophrenic patients with tardive dyskinesia.

Pregnancy in phenylketonuria: dietary treatment aimed at normalising maternal plasma phenylalanine concentration.

The transport characteristics of the placenta, which favour higher phenylalanine concentrations in the fetus than in the mother, and regression data of head circumference at birth against phenylalanine concentration at conception in maternal phenylketonuria (PKU), suggest that treatment of maternal PKU should ideally aim to maintain plasma phenylalanine concentration within the normal range throughout pregnancy. A patient with classical PKU was treated from before conception by aiming to maintain plasma phenylalanine concentration within the range 50-150 mumol/l and tyrosine within the range 60-90 mumol/l. The diet was supplemented with phenylalanine-free amino acids (100-180 g/day) and tyrosine (0-5 g/day). Plasma amino acid concentrations were monitored weekly by amino acid analyser. Dietary phenylalanine intake ranged from 6 mg/kg/day at conception to 30 mg/kg/day at delivery. Normal weight gain and fetal growth were maintained throughout the pregnancy. A normal baby was born at term with a head circumference of 35.5 cm; at 1 year of age no abnormality is detectable. These results show that with careful monitoring and compliance it is possible, and may be advisable, to maintain plasma phenylalanine concentration within the normal range in the management of PKU pregnancy.

Effects of acute systemic hyperinsulinemia on forearm muscle proteolysis in healthy man.

To investigate the mechanism(s) of insulin-induced suppression of plasma amino acid concentration and release, we studied forearm as well as whole-body leucine and phenylalanine uptake and release during a peripheral insulin infusion in postabsorptive normal subjects using isotope-dilution methods. Before insulin, leucine and phenylalanine release exceeded uptake (P less than 0.01 and P less than 0.07, respectively). A net output of alpha-ketoisocaproate (KIC) was also observed. During insulin, arterial plasma leucine, KIC and phenylalanine concentrations decreased (P less than 0.05 or less vs. basal), despite ongoing net output of these substrates by the forearm, that persisted after correction for the mean transit time spent through the extracellular muscular space. By the end of insulin, whole-body leucine and phenylalanine concentrations and rate of appearance were decreased (P less than 0.01 vs. basal). However, release and uptake of both amino acids by the forearm were not significantly decreased vs. the preinsulin values. These data indicate that systemic hyperinsulinemia acutely decreases plasma amino acid concentrations by acting primarily at sites other than skeletal muscle.

Effect of glucose and branched chain amino acid (BCAA) infusion on onset of liver regeneration and plasma amino acid pattern in partially hepatectomized rats

Immediately after 70% hepatectomy, rats were infused via the jugular vein with one of the following solutions: saline, 3% or 8% glucose solution, 3% BCAA solution, 8% Nutramin (17% BCAA) or 8% Nutramin enriched with BCAA (47% BCAA). Rats were killed 18, 21, 24 and 30 h after partial hepatectomy. The course of liver regeneration was assessed from incorporation of labeled thymidine into DNA and from hepatocyte mitotic activity. After partial hepatectomy a decrease of glycemia and increase of plasma phenylalanine concentrations were observed. Glucose infusion had a pronounced inhibiting effect on the onset of liver regeneration. The decreased incorporation of labeled thymidine into DNA and the decreased hepatocyte mitotic activity in glucose-infused rats were associated with higher plasma concentrations of tyrosine and phenylalanine. Parenteral administration of 3% BCAA solution and 8% Nutramin enriched with BCAA had a favourable effect on the onset of liver regeneration after partial hepatectomy compared with glucose- and Nutramin-infused groups. In BCAA-infused rats elevated levels of BCAA and decreased concentrations of tyrosine and phenylalanine were noted.

Plasma amino acid concentrations and amino acid ratios in normal adults and adults heterozygous for phenylketonuria ingesting a hamburger and milk shake meal

Plasma amino acid concentrations were measured and selected amino acid ratios were calculated in 12 normal adults and 12 adults heterozygous for phenylketonuria (PKU) ingesting a hamburger and milk shake meal providing 1 g protein/kg body wt. Plasma concentrations of all amino acids increased significantly over baseline after meal ingestion in both groups, reaching the highest mean values 3-5 h after meal ingestion. Plasma phenylalanine concentrations were significantly higher in heterozygous than in normal subjects both before and at all times after meal ingestion. The absolute increase in plasma phenylalanine concentration over baseline and the area under the plasma phenylalanine concentration-time curve were approximately twice as large in heterozygous as in normal subjects. However, the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids did not increase significantly over baseline, but rather decreased.

Effect of dietary phenylalanine on the plasma concentrations of phenylalanine, phenylethylamine and phenylacetic acid in healthy volunteers

Davis, Bruce A., Richard O'Reilly, Cindy L. Placatka, I. Alick Paterson, Peter H. Yu and David A. Durden: Effect of dietary phenylalanine on the plasma concentrations of phenylalanine, phenylethylamine and phenylacetic acid in healthy volunteers. Progr. Neuro-Psychopharmacol & Biol. Psychiat. 1991, 15 (5): 611–623. 1. 1. Phenylethylamine has been proposed as a neuromodulator in several psychiatric and other brain disorders, and its concentration and that of its major metabolite, phenylacetic acid, in plasma may prove useful as state or trait markers in diagnosis, treatment or in the elucidation of biochemical mechanisms of these disorders. 2. 2. The effect of dietary phenylalanine intake and changes in dietary phenylalanine intake on the plasma concentrations and changes in plasma concentrations, respectively, of phenylalanine, phenylethylamine and unconjugated and conjugated phenylacetic acid have been investigated. 3. 3. Dietary phenylalanine affects the concentration of plasma phenylalanine on the following day, but has no effect on phenylethylamine or phenylacetic acid concentrations. Thus single measurements per subject of phenylethylamine or phenylacetic acid do not need to take dietary factors into account. 4. 4 Changes in dietary phenylalanine (whether in absolute amount or in the proportion of phenylalanine in the diet) are significantly correlated with changes in unconjugated phenylacetic acid. Therefore, in longitudinal studies, dietary factors should be taken into account.

Aspartame and Sucrose Produce a Similar Increase in the Plasma Phenylalanine to Large Neutral Amino Acid Ratio in Healthy Subjects

Aspartame (L-aspartyl-L-phenylalanine methyl ester) consumption has been postulated to increase brain phenylalanine levels by increasing the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids (Phe/LNAA). Dietary manipulations with carbohydrate or protein can also produce changes in the Phe/LNAA value. To compare the effects of aspartame and carbohydrate on Phe/LNAA, beverages sweetened with aspartame, sucrose, and aspartame plus sucrose, and unsweetened beverage were ingested by 8 healthy, fasted subjects in a randomized, four-way crossover design. The beverages were sweetened with an amount of aspartame (500 mg) and/or sucrose (100 g) approximately equivalent to that used to sweeten 1 liter of soft drink. The baseline-corrected plasma Phe/LNAA values did not differ significantly following ingestion of aspartame or sucrose. Following aspartame alone, the high mean ratio increased 26% over baseline 1 h after ingestion. Following sucrose alone, the high mean ratio increased 19% at 2.5 h. Sucrose increased the Phe/LNAA value due to an insulin-mediated decrease in the plasma LNAA, while aspartame increased the ratio by increasing the plasma Phe concentration. These findings indicate that similar increases in plasma Phe/LNAA occur when healthy, fasting subjects ingest amounts of equivalent sweetness of sucrose or aspartame.

Phenylalanine flux, oxidation, and conversion to tyrosine in humans studied with L-[1-13C]phenylalanine

Phenylalanine metabolism was determined in 41 studies of adult males (n = 10) consuming an energy-sufficient diet and receiving graded levels of dietary phenylalanine and excess tyrosine (40 mg.kg-1.day-1). After a dietary adaptation period to either 4.2 or 14.0 mg.kg-1.day-1 of phenylalanine; flux, plasma concentration, oxidation, and conversion to tyrosine were measured at test phenylalanine intakes of 5, 7, 10, 14, 21, 28, or 60 mg.kg-1.day-1. Oxidation was low and constant (1.3 mumol.kg-1.h-1) at intakes at or below 10 mg.kg-1.day-1 and increased linearly above this level. Conversion to tyrosine was minimal (2.1%) at these intakes. Breakpoint analysis showed the phenylalanine requirement with excess tyrosine to be 9.1 mg.kg-1.day-1. Plasma phenylalanine concentrations confirmed this estimate of requirement. Prior adaptation did not significantly affect overall flux, plasma concentration, or oxidation nor did it affect the requirement estimate. With the assumption that tyrosine can supply two-thirds of the aromatic amino acid requirement, these data suggest that the aromatic amino acid requirement should be 30 mg.kg-1.day-1 and the World Health Organization recommendation of 14 mg.kg-1.day-1 is an underestimate.

Efficiency of enteral nitrogen support in surgical patients: small peptides v non-degraded proteins.

In a prospective study, 12 intensive care patients, after abdominal surgery, received three alternate six-day courses of two enteral diets with identical nitrogen (0.3 g N/kg per day) and energy (60 kcal/kg per day) supply. The protein hydrolysate (PH) diet contained enzyme-hydrolysed casein and lactoserum (60% small peptides), while the non-degraded protein (NDP) diet contained a nitrogen source of similar amino acid composition, but in the form of non-degraded proteins. The patients were randomised to receive either PH-NDP-PH or NDP-PH-NDP. Parameters reflecting protein metabolism were assessed in the plasma, urine, and stomal effluent on days 1, 6, 12, and 18, three hours after stopping the nutrition (t0), and one hour after restarting it (t1). Comparisons of t1 and t0 values showed that 13 amino acids (including the eight essential amino acids) increased significantly with the protein hydrolysate diet, but only two increased with the non-degraded protein diet. Similarly, with protein hydrolysate, insulin-aemia at t1 was significantly higher than at t0 and correlated with plasma leucine, phenylalanine, alanine, and lysine concentrations. In addition, significant improvements in plasma albumin, transferrin, and retinol binding protein concentrations were seen with protein hydrolysate, together with a significant decrease in the plasma phenylalanine/tyrosine ratio and urinary 3-methylhistidine excretion. We conclude that in patients in intensive care after abdominal surgery enteral support containing small peptides is more effective than an equivalent diet containing whole proteins in restoring plasma amino acid and protein levels.

Repeated ingestion of aspartame-sweetened beverages: Further observations in individuals heterozygous for phenylketonuria

Six adults heterozygous for phenylketonuria (PKU) ingested eight successive servings of unsweetened and aspartame (APM)-sweetened beverage at 1-hour intervals in a randomized, balanced, crossover design. In one part, the eight beverage servings were not sweetened. In the other, each of the eight beverage servings provided 600 mg of APM, a dose equivalent to the amount provided by 36 oz of an APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine concentrations 2.35 to 4.03 μmol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady-state after administration of five servings of APM-sweetened beverage and were slightly, but significantly higher than usual postprandial values for adults heterozygous for PKU. Similarly, the ratio of the plasma phenylalanine concentration to the sum of the concentration of the large neutral amino acids was significantly higher than usual postprandial values. Blood methanol and formate concentrations remained within normal limits. These data indicate that a fasting adult heterozygous for PKU could consume the equivalent of 24 12-oz servings of APM-sweetened beverage over an 8-hour period and only increase plasma phenylalanine concentration to a modest degree.

Effect of sucrose on the metabolic disposition of aspartame

Twelve normal adult subjects ingested a beverage providing 0.136 mmol aspartame/kg body wt on 2 different days. On 1 study day the beverage provided only aspartame, on the other the beverage provided both aspartame and 3.51 mmol sucrose/kg body wt. The high mean plasma phenylalanine concentrations were similar after administration of aspartame alone (158 +/- 28.9 mumol/L, mean +/- SD) and administration of aspartame plus sucrose (134 +/- 44.1 mumol/L). Evaluation of the area under the plasma concentration-time curve (AUC) for phenylalanine also showed no significant difference between groups (197 +/- 49.1 vs 182 +/- 28.3 mumol.L-1.h for aspartame alone and aspartame plus sucrose, respectively). Similarly, the high mean ratio of phenylalanine to large neutral amino acids (Phe:LNAA) in plasma did not differ significantly (0.265 +/- 0.046 for aspartame alone, 0.275 +/- 0.107 for aspartame plus sucrose). However, there was a small but significant difference between groups for the 4-h AUC values for plasma Phe:LNAA. The simultaneous ingestion of sucrose with aspartame had only minor effects on aspartame's metabolic disposition.

Neuroblastoma in a patient with dihydropteridine reductase deficiency

Tetrahydrobiopterin (BH4) deficiency is a rare cause of hyperphenylalaninaemia (HPA) and usually leads to progressive neurological deterioration despite early dietary control of plasma phenylalanine concentrations. Dihydropteridine reductase (DHPR) deficiency is the most severe cause with respect to a fatal outcome. We report a 7-year-old girl with HPA diagnosed on neonatal Guthrie screening who at the age of 6 months had cytotoxic therapy for an adrenal neuroblastoma which secreted catecholamines. When 4 years old she was found to have DHPR deficiency. Although developmentally retarded and microcephalic she has failed to develop the florid neurological features often associated with the condition.

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Indirect measurements have previously suggested that patients with classical phenylketonuria (PKU) do not convert significant amounts of phenylalanine to tyrosine. Low-dose continuous infusion techniques employing [2H5]phenylalanine and [2H2]tyrosine were used to quantitate in vivo phenylalanine hydroxylation in 10 subjects with classical phenylketonuria, 2 with hyperphenylalaninemia (HPA), and 7 controls. Plasma phenylalanine concentration ranged from 523 to 1,540 mumols/liter in PKU, 402 to 533 in HPA, and 49 to 54 in controls. Subjects with classical PKU hydroxylated mean +/- SD 4.8 +/- 2.2 mumols/kg per h (range 0.9-8.4) of phenylalanine to tyrosine and those with HPA 4.4 and 5.3, respectively. These rates were substantial in comparison with those in controls (6.3 +/- 1.6, 3.2-8.2). The significant hydroxylation in PKU and HPA subjects is likely to result from induction of activity of tyrosine hydroxylase towards phenylalanine by the greatly elevated phenylalanine concentration. The presence of such activity in PKU suggests that therapy aimed at promotion of this usually latent hydroxylating capacity may be a future alternative to dietary treatment of PKU.