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Infusion of the branched chain amino acids in postoperative patients. Anticatabolic properties.

Postinjury metabolism is characterized by breakdown of muscle protein as substrate for energy production and gluconeogenesis and by the resultant loss of lean body mass and weight loss. The branched chain amino acids (BCAAs) which are principally oxidized by the skeletal muscle have been implicated in recent in vitro and in vivo studies as having special anticatabolic and regulating effects in skeletal muscle. We studied the anticatabolic effects of the BCAAs in 35 patients undergoing operative injury of moderate severity. In a prospective randomized and blinded manner patients were infused for five days starting immediately after surgery with either 5% dextrose or 5% dextrose with an amino acid solution containing 22, 35 or 100% BCAAs. All patients survived and there were no major postoperative complications. Mean hospital stay was 17 days for patients receiving amino acids and 19 days for patients receiving 5% dextrose only (p = ns). All three groups receiving amino acid solutions were in nitrogen equilibrium or in a slight positive nitrogen balance, while the group receiving 5% dextrose only was in a mean negative nitrogen balance of 6.6 +/- 0.6 gN/day. The differences between the three groups receiving amino acids were slight and not significant. Weight loss was 2 +/- 0.7 kg in the 5% dextrose group, 1 +/- 0.7 kg in the 22% BCAAs group, 0.5 +/- 0.5 kg in the 35% BCAAs group and the 100% BCAAs group gained 0.4 +/- 1.8 kg. Blood chemistries in the different groups and during the study period remained within normal limits except for ammonia levels rising significantly in the 5% dextrose group and SGOT levels rising in the 22% and 35% BCAA groups. With mild variations the plasma amino acid patterns in all groups were similar to the normal pattern, even in the 100% BCAAs group receiving an unbalanced amino acid solution, suggesting the complete cessation of amino acid efflux from muscle, the muscle depending solely on the exogenous supply of BCAAs to satisfy its metabolic requirements. The results suggest that early nutritional suppport in the postoperative period will result in nitrogen equilibrium and that the infusion of the three BCAAs only in the postoperative state is as effective in preventing muscle catabolism as other more balanced amino acid solutions. In the postinjury state balanced amino acid solutions rich in BCAA may prove beneficial.

Adult↗

Plasma amino acid concentrations during branched-chain amino acid infusions in stressed patients.

To determine the effect of infusing large quantities of BCAA on plasma amino acid concentrations, plasma amino acid profiles were measured in 18 stressed patients before and 48 to 96 hours after initiation of amino acid solutions enriched with or exclusively containing BCAA (15.6+, 50%, 100%). Plasma concentrations of BCAA were elevated in the 100% and 50% BCAA groups, but not in the 15.6% group. Methionine, glycine, and phenylalanine concentrations were increased in the 15.6% BCAA group: methionine and glycine were decreased in the 100% BCAA groups. In the 50% BCAA group, nonbranched-chain amino acids maintained baseline concentrations. The 50% solution best preserved nitrogen balance of the BCAA solutions. The plasma amino acid profiles of patients with maple syrup urine disease (BCAA levels 5 to 10 times normal) were compared to our patients receiving BCAA-enriched solutions. Although plasma BCAA levels were elevated in our patients, allo-isoleucine, alanine, and glutamine concentrations were normal; the amino acid abnormalities of maple syrup urine disease were not observed.

Abdomen↗

Mechanisms of activation of muscle branched-chain alpha-keto acid dehydrogenase during exercise in man.

1. Exercise leads to activation (dephosphorylation) of the branched-chain alpha-keto acid dehydrogenase (BCKADH). Here we investigate the effect of low pre-exercise muscle glycogen content and of branched-chain amino acid (BCAA) ingestion on the activity of BCKADH at rest and after 90 min of one-leg knee-extensor exercise at 65% maximal one-leg power output in five subjects. 2. Pre-exercise BCAA ingestion (308 mg BCAAs (kg body wt)-1) caused an increased muscle BCAA uptake, a higher intramuscular BCAA concentration and activation of BCKADH both at rest (9 +/- 1 versus 25 +/- 5% for the control and BCAA test, respectively) and after exercise (27 +/- 4 versus 54 +/- 7%). 3. At rest the percentage active BCKADH was not different, 6 +/- 2% versus 5 +/- 1%, in the normal and low glycogen content leg (392 +/- 21 and 147 +/- 34 mumol glycosyl units (g dry muscle)-1, respectively). The post-exercise BCKADH activity was higher in the low (46 +/- 2%) than in the normal glycogen content leg (26 +/- 2%). 4. It is concluded that: (1) the mechanism of activation by BCAA ingestion probably involves an increase of the muscle BCAA concentration; (2) BCKADH activation caused by exercise and BCAA ingestion are additive; (3) low pre-exercise muscle glycogen content augments the exercise-induced BCKADH activation without an increase in muscle BCAA concentration; and (4) the mechanism of BCKADH activation via BCAA ingestion and low muscle glycogen content are different.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

Total branched-chain amino acids requirement in patients with maple syrup urine disease by use of indicator amino acid oxidation with L-[1-13C]phenylalanine.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by defects in the mitochondrial multienzyme complex branched-chain alpha-keto acid dehydrogenase (BCKD; EC 1.2.4.4), responsible for the oxidative decarboxylation of the branched-chain ketoacids (BCKA) derived from the branched-chain amino acids (BCAA) leucine, valine, and isoleucine. Deficiency of the enzyme results in increased concentrations of the BCAA and BCKA in body cells and fluids. The treatment of the disease is aimed at keeping the concentration of BCAA below the toxic concentrations, primarily by dietary restriction of BCAA intake. The objective of this study was to determine the total BCAA requirements of patients with classical MSUD caused by marked deficiency of BCKD by use of the indicator amino acid oxidation (IAAO) technique. Five MSUD patients from the MSUD clinic of The Hospital for Sick Children participated in the study. Each was randomly assigned to different intakes of BCAA mixture (0, 20, 30, 50, 60, 70, 90, 110, and 130 mg.kg(-1).day(-1)), in which the relative proportion of BCAA was the same as that in egg protein. Total BCAA requirement was determined by measuring the oxidation of l-[1-(13)C]phenylalanine to (13)CO(2). The mean total BCAA requirement was estimated using a two-phase linear regression crossover analysis, which showed that the mean total BCAA requirement was 45 mg.kg(-1).day(-1), with the safe level of intake (upper 95% confidence interval) at 62 mg.kg(-1).day(-1). This is the first time BCAA requirements in patients with MSUD have been determined directly.

Adolescent↗

Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans.

The disposal of a mixed meal was examined in 11 male subjects by multiple (splanchnic and femoral) catheterization combined with double-isotope technique (intravenous [2-3H]glucose plus oral U-[14C]starch). Glucose kinetics and organ substrate balance were measured basally and for 5 h after eating pizza (600 kcal) containing carbohydrates 75 g as starch, proteins 37 g, and lipids 17 g. The portal appearance of ingested carbohydrate was maximal (1.0 mmol/min) between 30 and 60 min after the meal and gradually declined thereafter, but was still incomplete at 300 min (0.46+/-0.08 mmol/min). The total amount of glucose absorbed by the gut over the 5 h of the study was 247+/-26 mmol (45+/-6 g), corresponding to 60+/-6% of the ingested starch. Net splanchnic glucose balance (-6.7+/-0.5 micromol x kg(-1) x min(-1), basal) rose by 250-300% between 30 and 60 min and then returned to baseline. Hepatic glucose production (HGP) was suppressed slightly and only tardily in response to meal ingestion (approximately 30% between 120 and 300 min). Splanchnic glucose uptake (3.7+/-0.6 micromol x kg(-1) x min(-1), basal) peaked to 9.8+/-2.0 micromol x kg(-1) x min(-1) (P<0.001) at 120 min and then returned slowly to baseline. Leg glucose uptake (34+/-5 micromol x leg(-1) x min(-1), basal) rose to 151+/-29 micromol x leg(-1) x min(-1) at 30 min (P<0.001) and remained above baseline until the end of the study, despite no increase in leg blood flow. The total amount of glucose taken up by the splanchnic area and total muscle mass was 161+/-16 mmol (29+/-3 g) and 128 mmol (23 g), respectively, which represent 39 and 30% of the ingested starch. Arterial blood lactate increased by 30% after meal ingestion. Net splanchnic lactate balance switched from a basal net uptake (3.2+/-0.6 micromol kg(-1) x min(-1) to a net output between 60 and 120 min and tended to zero thereafter. Leg lactate release (25+/-11 micromol x leg(-1) x min(-1), basal) drastically decreased postprandially. Arterial concentration of both branched-chain amino acids (BCAA) and non-branched-chain amino acids (N-BCAA) increased significantly after meal ingestion (P<0.001). The splanchnic area switched from a basal net amino acid uptake (31+/-16 and 92+/-48 micromol/min for BCAA and N-BCAA, respectively) to a net amino acid release postprandially. The net splanchnic amino acid release over 5 h was 11.3+/-4.2 mmol for BCAA and 37.8+/-9.7 mmol for N-BCAA. Basally, the net leg balance of BCAA was neutral (-3+/-5 micromol x leg(-1) x min(-1)), whereas that of N-BCAA indicated a net release (54+/-14 micromol x leg(-1) x min(-1)). After meal ingestion, there was a net leg uptake of BCAA (20+/-6 micromol x leg(-1) x min(-1)), whereas leg release of N-BCAA decreased by 50%. It is concluded that in human subjects, 1) the absorption of a natural mixed meal is still incomplete at 5 h after ingestion; 2) HGP is only marginally and tardily inhibited; 3) splanchnic and peripheral tissues contribute to the disposal of meal carbohydrate to approximately the same extent; 4) the splanchnic area transfers >30% of the ingested proteins to the systemic circulation; and 5) after meal ingestion, skeletal muscle takes up BCAA to replenish muscle protein stores.

Adult↗

Significance of breast carcinoma-associated antigens as a monitor of tumor burden: characterization by monoclonal antibodies.

Use of monoclonal antibodies (Mc 3 and Mc 8) prepared against human mammary-epithelial antigens of human mild fat globule membranes has enabled characterization of breast carcinoma (BC) associated antigens (BCAA), antibodies, and circulating immune complexes (CIC). For this study, BC patients were grouped on the basis of measurable tumor burden: Group I patients with no evidence of disease at sampling time; Group II patients with tumor burden less than or equal to 5 g; and Group III patients with known regional or distal metastases. In an in vitro simulation of tumor burden change, selected BC patients' sera were admixed with Mc 3 and Mc 8 at optimal concentration. CIC reduction (dissociation) for Groups I and III and increment (formation) for Group II were noted. Unlike Group I sera, Groups II and III sera required 4- to 16-fold dilution of Mc 3 and 4-fold more concentrated Mc 8 to achieve maximal CIC changes. Serum BCAA isolated by use of both Mc 3 and Mc 8 immunobead procedures showed apparent Mr 33,000 monomer, 66,000 dimer, and 95,000 trimer. When BCAA were added to BC patients' sera, autologous combinations resulted in small (7.7S) CIC for Groups I and III, and medium (9 to 12S) CIC for Group II. Conversely, allogenic combinations resulted in mainly small CIC for Group I, and intermediate CIC for Group II and Group III. Evaluation of circulating BCAA concentration by use of a three-step radioligand technique demonstrated significant discrimination between BC patients' sera (mean = 105 ng/ml) and normal control sera (less than or equal to 20 ng/ml). BCAA were found to be elevated in 31 of 46 (67%) Group I (mean = 70 ng/ml), 41 of 43 (95%) Group II (mean = 197 ng/ml), and 30 of 46 (65%) Group III (mean = 50 ng/ml) patients' sera, as compared to "background" levels in malignant melanoma and normal controls. Benign breast disease sera showed moderate BCAA increases (mean = 48 ng/ml) in 20 of 35 (57%) patients. Furthermore, serial sample determination of BCAA in 36 selected BC patients confirmed the above pattern, indicating that this assay can be used with some restriction to monitor tumor burden. Whereas in early breast carcinoma increase in BCAA concentration was concurrent with or antedated clinical objective evidence of tumor burden increase, significant decreased BCAA concentration was observed with tumor burden reduction. Overall, increased BCAA levels were associated with limited tumor burden (Group II) while decreased BCAA levels were observed with no evidence of disease (Group I) and known regional or distal metastatic advanced disease (Group III) during patients' follow-up.

Antibodies, Monoclonal↗

Tumor and host response to arginine and branched chain amino acid-enriched total parenteral nutrition. A study involving Walker 256 carcinosarcoma-bearing rats.

The metabolic effects of total parenteral nutrition (TPN) solutions containing different profiles of individual amino acids were investigated in the rats bearing Walker 256 carcinosarcoma. The rats were subcutaneously inoculated with 10(7) tumor cells and 6 days later were continuously infused intravenously for 8 days with three different TPN solutions. The experimental and control solutions were composed of high concentrations of branched chain amino acids (BCAA) and arginine (high Arg + BCAA TPN), high concentrations of BCAA (high BCAA TPN) and regular amino acids (regular TPN), respectively, and were isonitrogenous, isocaloric, and isovolemic. Rats receiving subcutaneous injection of saline rather than tumor cells received high Arg + BCAA TPN as pair-fed controls. The flooding dose method of 14C-leucine was used for the analysis of protein synthesis. With the feeding of high Arg + BCAA TPN, the tumor-bearing rats revealed a smaller increase of tumor volume and lower tumor fractional rates of growth (Kg) and synthesis (Ks) as well as protein synthesis (PS), compared with the high BCAA TPN and regular TPN in tumor-bearing rats. There were no significant differences of Ks and PS in liver and muscle between TPN groups, whereas tumor-bearing rats infused with high Arg + BCAA TPN displayed higher levels of whole-body Ks and PS than other TPN groups in tumor-bearing rats and pair-fed nontumorous rats. Except for liver RNA content which showed a lower level in tumor-bearing rats with high Arg + BCAA TPN, no other differences of DNA and RNA contents were found in tumor, liver, and muscle of the different TPN groups. The current results indicate that individual amino acids can influence tumor growth and protein metabolism, and that arginine, in combination with BCAA, may reduce tumor growth through a reduction in protein synthesis.

Amino Acids, Branched-Chain↗

Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia.

A prospective randomized trial was conducted to determine the effects of branched chain amino acids (BCAA) as the protein component of total parenteral nutrition (TPN) on protein kinetics in patients with intraabdominal adenocarcinoma. Nine malnourished patients were given both conventional TPN containing 19 per cent BCAA (AA) and isocaloric, isonitrogenous TPN containing 50 per cent BCAA (BCAA-TPN), in random order. Both [13C]leucine and [14C]tyrosine were employed as tracers to avoid the potential bias due to the different amino acid composition of the two TPN solutions. With BCAA-TPN, leucine and tyrosine flux increased significantly from (mean +/- s.d.) 158.0 +/- 37.2 to 243.5 +/- 75.8 mumol kg-1 h-1 (P less than 0.025) and from 35.0 +/- 8.4 to 42.6 +/- 11.0 mumol kg-1 h-1 (P less than 0.05) respectively. Leucine oxidation was significantly higher on BCAA-TPN (24.1 +/- 6.3 on AA versus 68.3 +/- 37.1 mumol kg-1 h-1, P less than 0.025) while tyrosine oxidation was significantly lower (3.7 +/- 1.8 mumol kg-1 h-1 on AA versus 2.5 +/- 2.0 mumol kg-1 h-1 on BCAA-TPN, P less than 0.05). Whole body protein synthesis and breakdown was significantly higher on BCAA-TPN by the tyrosine tracer (31.3 +/- 7.3 on AA versus 40.1 +/- 9.3 mumol kg-1 h-1, P less than 0.025 and 33.0 +/- 8.4 on AA versus 41.3 +/- 11.1 mumol kg-1 h-1, P less than 0.05) respectively. Using the leucine tracers both synthesis and breakdown were increased, but not significantly, from 133.8 +/- 40.0 to 175.3 +/- 65.1 mumol kg-1 h-1 and from 127.9 +/- 33.6 to 167.7 +/- 71.2 mumol kg-1 h-1 respectively. The fractional albumin synthetic rate increased significantly on BCAA-TPN from 4.3 +/- 2.9 on AA to 8.0 +/- 5.1 per cent per day (P less than 0.05). The reduction in tyrosine oxidation, suggesting improved protein utilization, coupled with an increase in protein and albumin synthesis, strongly support a positive benefit from BCAA-TPN in cancer cachexia.

Abdominal Neoplasms↗

The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment.

Eight males were recruited to examine the effect of branched-chain amino acid (BCAA) supplementation on exercise capacity in a glycogen-depleted state in a warm environment. Following a exercise and dietary regimen designed to reduce glycogen availability, subjects returned to the laboratory the following morning and remained seated for 2 h, before cycling to volitional exhaustion at 50% VO2 peak in a warm environment [30.0 (0.2) degrees C; mean (SD)]. Four 250 ml aliquots of a 12 g l(-1) BCAA solution or placebo were ingested at 30 min intervals prior to exercise, with an additional 150 ml consumed every 15 min throughout exercise. BCAA ingestion had no effect on exercise capacity [placebo 103.9 (26.9) min; BCAA 111.0 (29.2) min; P = 0.129). No difference in heart rate (P = 0.345), core temperature (P = 0.628), or weighted mean skin temperature (P = 0.114) was apparent between trials. Ingestion of the BCAA solution produced a marked increase in plasma BCAA immediately prior to exercise [+ 1126 (158) micromol l(-1); P < 0.001) with this difference maintained throughout. Consequently, a significant reduction in the plasma concentration ratio of free tryptophan to BCAA was observed during the BCAA trial when compared to the placebo (P < 0.001). Plasma ammonia concentration was significantly elevated during exercise throughout the BCAA trial (P < 0.001), with no change from rest apparent during the placebo trial (P = 0.608). Blood glucose (P = 0.114) and lactate (P = 0.836) concentrations were not different between trials. Ingestion of a BCAA solution prior to, and during, prolonged exercise in glycogen-depleted subjects did not influence exercise capacity in a warm environment.

Adult↗

Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus.

Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.

Journal Article↗

Acidosis, not azotemia, stimulates branched-chain, amino acid catabolism in uremic rats.

To investigate branched-chain, amino acid metabolism (BCAA) in muscle in chronic renal failure (CRF), we studied rats with moderately severe uremia (PUN 110 approximately mg/dl) and spontaneous metabolic acidosis (bicarbonate, 19 +/- 1 mEq/liter). Plasma BCAA levels in CRF compared to pair-fed control rats were approximately 15% lower and muscle valine was 93 microM lower (P less than 0.05). BCAA metabolism was measured in incubated epitrochlearis muscles using L-[1-14C]valine or L-[1-14C]leucine in the presence and absence of insulin. BCAA decarboxylation was increased (P less than 0.05) and insulin-stimulated BCAA incorporation into protein was blunted (P less than 0.05) by CRF. Since we have found that metabolic acidosis, by itself, stimulates muscle branched-chain, ketoacid dehydrogenase activity, another group of CRF and control rats was given NaHCO3 which corrected the acidosis, but not the azotemia. BCAA decarboxylation in muscle was reduced in CRF rats given NaHCO3, and this was reflected in increased plasma and muscle BCAA concentrations. We conclude that in CRF, chronic metabolic acidosis stimulates BCAA decarboxylation in skeletal muscle and this could contribute to the reduced intra- and extracellular concentrations of BCAA. Correction of acidosis should be a goal of therapy in CRF, especially when dietary regimens restrict intake of BCAA.

Acidosis↗

Direct effect of branched-chain amino acids on the growth and metabolism of cultured human hepatocellular carcinoma cells.

Little is known about the influence of amino acid imbalance by supplementation of branched-chain amino acids (BCAAs) on human hepatocellular carcinoma (HCC). We investigated the effect of various BCAA concentrations in culture medium on the growth and metabolism of two human HCC cell lines: Hep G2 and KYN-1. DNA and protein syntheses were studied by radiolabeled thymidine and leucine uptake, Amino acid concentrations in cell and medium were measured with an amino acid analyzer. Expression and excretion of transforming growth factor (TGF)-alpha and TGF-beta1 were studied by immunostaining and enzyme linked immunosorbent assay methods. The cell growth was suppressed in media with higher and lower BCAA concentrations than Dulbecco's modified Eagle's medium, and this was grossly correlated with the incorporation of [3H]thymidine into DNA and incorporation of [3H]leucine into intracellular protein. Pretreatment with 10,000 nmol/ml of BCAA did not suppress the cell growth in subsequent culture in the standard Dulbecco's modified Eagle's medium, indicating that the effect of BCAAs was not cytocidal but cytostatic and reversible. BCAA and aromatic amino acid concentrations in cells increased in parallel as the BCAA level in medium was increased, despite the fixed aromatic amino acid level. Intracellular expression and extracellular excretion of TGF-alpha were higher at BCAA concentrations of 100 and 1,000 nmol/ml than at 10 or 1,000 nmol/ml. The present finding that the in vitro growth of HCC can be suppressed by enriched BCAA levels in medium may indicate that amino acid-imbalanced therapy with enriched BCAAs is useful in the treatment of HCC.

Amino Acids↗

Branched-chain amino acid requirements in school-aged children determined by indicator amino acid oxidation (IAAO).

The current WHO/FAO/UNU recommendations for BCAA requirements in school-aged children are based on nitrogen balance studies that have tended to produce lower estimates of amino acid requirements that those determined using stable isotope methodologies. The new dietary reference intake (DRI) recommendations for total BCAA requirements in children were determined using a factorial approach that included adult BCAA requirements plus the additional needs for growth. The purpose of this study was to determine directly total BCAA requirements in school children aged 6-10 y using indicator amino acid oxidation (IAAO). Five children (8.5 +/- 1.2 y) were assigned randomly to receive 7 graded intakes of total BCAA. Individual BCAA in the test diet were provided in the same proportions as those present in egg protein to minimize the potential interactive effects of individual BCAA on assessment of requirement. Total BCAA requirement was determined by measuring the oxidation of L-[1-13C] phenylalanine to 13CO2 [F13CO2 in micromol/(kg x h)], after a primed, continuous infusion of the labeled tracer and using a two-phase linear crossover regression analysis. The mean requirement and the population-safe intake level (upper limit of the 95% CI) of the total BCAA in healthy school aged children were 147 and 192 mg/(kg x d), respectively. The estimated mean requirements of the total BCAA as determined by IAAO is approximately 48% higher than the current DRI recommendations, suggesting that these recommendations may be too low to meet the needs of school-aged children.

Amino Acids, Branched-Chain↗

Branched-chain amino acids and brain function.

Branched-chain amino acids (BCAAs) influence brain function by modifying large, neutral amino acid (LNAA) transport at the blood-brain barrier. Transport is shared by several LNAAs, notably the BCAAs and the aromatic amino acids (ArAAs), and is competitive. Consequently, when plasma BCAA concentrations rise, which can occur in response to food ingestion or BCAA administration, or with the onset of certain metabolic diseases (e.g., uncontrolled diabetes), brain BCAA concentrations rise, and ArAA concentrations decline. Such effects occur acutely and chronically. Such reductions in brain ArAA concentrations have functional consequences: biochemically, they reduce the synthesis and the release of neurotransmitters derived from ArAAs, notably serotonin (from tryptophan) and catecholamines (from tyrosine and phenylalanine). The functional effects of such neurochemical changes include altered hormonal function, blood pressure, and affective state. Although the BCAAs thus have biochemical and functional effects in the brain, few attempts have been made to characterize time-course or dose-response relations for such effects. And, no studies have attempted to identify levels of BCAA intake that might produce adverse effects on the brain. The only "model" of very high BCAA exposure is a very rare genetic disorder, maple syrup urine disease, a feature of which is substantial brain dysfunction but that probably cannot serve as a useful model for excessive BCAA intake by normal individuals. Given the known biochemical and functional effects of the BCAAs, it should be a straightforward exercise to design studies to assess dose-response relations for biochemical and functional effects and, in this context, to explore for adverse effect thresholds.

Adolescent↗

Branched-chain amino acid supplementation in patients with liver diseases.

Because of their peculiar role in whole-body nitrogen metabolism and the competitive action on amino acid transport across the blood-brain barrier, branched-chain amino acids (BCAAs) have been extensively used in subjects with liver disease to preserve or to restore muscle mass and to improve hepatic encephalopathy. There are no data regarding safe limits of BCAA administration; the results appear to be better when BCAA-enriched formulas or BCAA-supplemented diets are preferred to pure BCAA formulas. Improved nitrogen retention might ameliorate the nutritional status, a prognostic index of long-term survival in cirrhosis and of short-term survival in patients undergoing surgical procedures. The effects on nutrition and ultimately on prognosis of patients with advanced cirrhosis were confirmed in a large multicenter, long-term trial where oral BCAA supplements were compared with equicaloric or equinitrogenous-equicaloric supplements (maltodextrin or lactoalbumin). Similarly, BCAA treatment improved the prognosis of patients with hepatocellular carcinoma, treated by surgical resection or chemoembolization, and of liver transplant patients. The mechanism(s) for the beneficial effects of BCAAs might be mediated by their stimulating activity on hepatocyte growth factor, favoring liver regeneration. The debate regarding the potential effectiveness of BCAAs dates back to the early 1980s. The number of patients who cannot tolerate dietary proteins in amounts sufficient to meet the higher catabolism of advanced liver disease is probably low, but BCAAs remain the sole treatment of proved efficacy in this specific setting.

Amino Acids, Branched-Chain↗

Branched-chain amino acid needs in children with mild-to-moderate chronic cholestatic liver disease.

Protein-energy malnutrition is prevalent in children with chronic cholestatic liver disease. Supplementation of branched-chain amino acids (BCAA) in infants and children with chronic liver disease has been associated with significant improvement in growth and nitrogen balance, suggesting that BCAA requirements are increased in chronic liver disease. The goal of the present study was to determine the total BCAA requirement in children with mild-to-moderate chronic cholestatic (MCC) liver disease using indicator amino acid oxidation (IAAO). Total BCAA requirements were determined in 6 children (6.3 +/- 3.7 y, mean +/- SD) with MCC liver disease. Children were randomly assigned to receive 7 graded intakes of total BCAA. Individual BCAA in the test diet were provided in the same proportions as those present in egg protein to minimize the potential interactive effects of individual BCAA on assessment of requirement. The total BCAA requirement was determined by measuring the oxidation of l-[1-13C] Phe to 13CO2 [F13CO2 in micromol/(kg x h)], after a primed, continuous oral administration of the tracer and using a 2-phase linear regression crossover regression analysis. The estimated mean requirement and the upper limit of the 95% CI for total BCAA establishing using the IAAO in children with MCC liver disease were 209 and 272 mg/(kg x d), respectively. Total BCAA estimated average requirements using the IAAO were significantly higher than mean requirements established previously for healthy children (P < 0.05).

Amino Acids, Branched-Chain↗

Investigations of branched-chain amino acids and their metabolites in animal models of cancer.

Many of the features of BCAA metabolism in the tumor-bearing state are similar to the other disease states that feature involuntary weight loss and skeletal muscle atrophy. These states are generally characterized by altered BCAA availability (low BCAA intakes, elevated rates of BCAA oxidation, and gluconeogenesis), which are concurrent with activation of proteolysis and suppression of protein synthesis in skeletal muscle and ultimately lead to erosion of lean tissue mass. These features in turn imply BCAA deficiency compared with whole-body requirements and are the basis of suggestions for dietary supplementation with BCAA or their metabolites. Recent studies on BCAA supplementation in cancer focus on leucine and its derivative, beta-methyl beta-hydroxybutyrate, as regulators of skeletal muscle metabolism, although their relative efficacy is unknown. However, what would otherwise be a relatively straightforward consideration of amino acid supply and demand is confounded by the presence of the tumor and its potential utilization of BCAA for its proliferative and invasive activities. Positron emission tomography with (11)C-leucine, used for in vivo tumor imaging, points to the high avidity of tumor amino acid uptake. These features have incited research in opposing directions, probing BCAA deprivation, with a view to limiting tumor growth, as well as BCAA supplementation, with a view to supporting maintenance of host lean tissue. No clear conclusion is presently available from the sum of these efforts. Animal models with relevant clinical features are essential to determine if amino acid therapy can alter the balance between the host and the tumor in a manner that favors the host overall.

Amino Acids, Branched-Chain↗

Branched-chain amino acids and immunity.

Although there has been great interest in the effects of amino acids on immune function, little is known about the impact of changes in BCAA availability on the ability of the immune system to function. Human immune cells incorporate BCAA into proteins and are able to oxidize BCAA. The immune system exists to protect the host from pathogenic invaders and from other noxious insults. Upon infection, there is a marked increase in demand for substrates by the immune system; these substrates provide energy and are the precursors for the synthesis of new cells, effector molecules, and protective molecules. Cell culture studies show that BCAA are absolutely essential for lymphocytes to synthesize protein, RNA, and DNA and to divide in response to stimulation. In mice, dietary BCAA restriction impairs several aspects of the immune function and increases the susceptibility to pathogens. Postsurgical or septic patients given BCAA intravenously showed improved immunity and this may relate to improved outcome. BCAAs are therefore absolutely essential for lymphocyte responsiveness and are necessary to support other immune cell functions. However, many aspects of BCAA and its effects on immune function have been understudied or not studied at all. More research is needed to understand the extent of the immune system's requirement for BCAA. It is likely that the essentiality of BCAA for the function of immune cells relates to protein synthesis.

Amino Acids, Branched-Chain↗