Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

Molecular Background of Common Dyslipidemias

The leading cause of death in the Western world continues to be coronary heart disease (CHD). At the root of the disease process is dyslipidemia an aberration in the relevant amounts of circulating blood lipids. Cholesterol builds up in the arterial wall and following rupture of these plaques, myocardial infarction or stroke can occur. Heart disease runs in families and a number of hereditary forms are known. The leading cause of adult dyslipidemia presently however is overweight and obesity. This thesis work presents an investigation of the molecular genetics of common, hereditary dyslipidemia and the tightly related condition of obesity. Familial combined hyperlipidemia (FCHL) is the most common hereditary dyslipidemia in man with an estimated population prevalence of 1-6%. This complex disease is characterized by elevated levels of serum total cholesterol, triglycerides or both and is observed in about 20% of individuals with premature CHD. Our group identified the disease to be associated with genetic variation in the USF1 transcription factor gene. USF1 has a key role in regulating other genes that control lipid and glucose metabolism as well as the inflammatory response all central processes in the progression of atherosclerosis and CHD. The first two works of this thesis aimed at understanding how these USF1 variants result in increased disease risk. Among the many, non-coding single-nucleotide polymorphisms (SNPs) that associated with the disease, one was found to have a functional effect. The risk-enhancing allele of this SNP seems to eradicate the ability of the important hormone insulin to induce the expression of USF1 in peripheral tissues. The resultant changes in the expression of numerous USF1 target genes over time probably enhance and accelerate the atherogenic processes. Dyslipidemias often represent an outcome of obesity and in the final work of this thesis we wanted to address the metabolic pathways related to acquired obesity. It is recognized that active processes in adipose tissue play an important role in the development of dyslipidemia, insulin resistance and other pathological conditions associated with obesity. To minimize the confounding effects of genetic differences present in most human studies, we investigated a rare collection of identical twins that differed significantly in the amount of body fat. In the obese, but otherwise healthy young adults, several notable changes were observed. In addition to chronic inflammation, the adipose tissue of the obese co-twins was characterized by a marked (47%) decrease in amount of mitochondrial DNA (mtDNA) a change associated with mitochondrial dysfunction. The catabolism of branched chain amino acids (BCAAs) was identified as the most down-regulated process in the obese co-twins. A concordant increase in the serum level of these insulin secretagogues was identified. This hyperaminoacidemia may provide the feed-back signal from insulin resistant adipose tissue to the pancreas to ensure an appropriately augmented secretory response. The down regulation of BCAA catabolism correlated closely with liver fat accumulation and insulin. The single most up-regulated gene (5.9 fold) in the obese co-twins was osteopontin (SPP1) a cytokine involved in macrophage recruitment to adipose tissue. SPP1 is here implicated as an important player in the development of insulin resistance. These studies of exceptional study samples provide better understanding of the underlying pathology in common dyslipidemias and other obesity associated diseases important for future improvement of intervention strategies and treatments to combat atherosclerosis and coronary heart disease.

Quantitative metabolic profiling of NMR spectral signatures of branched chain amino acids in blood serum

Branched Chain Amino Acids (BCAAs) are related to different aspects of diseases like pathogenesis, diagnosis and even prognosis. While in some diseases, levels of all the BCAAs are perturbed; in some cases, perturbation occurs in one or two while the rest remain unaltered. In case of ischemic heart disease, there is an enhanced level of plasma leucine and isoleucine but valine level remains unaltered. In `Hypervalinemia', valine is elevated in serum and urine, but not leucine and isoleucine. Therefore, identification of these metabolites and profiling of individual BCAA in a quantitative manner in body-fluid like blood plasma/serum have long been in demand. H-1 NMR resonances of the BCAAs overlap with each other which complicates quantification of individual BCAAs. Further, the situation is limited by the overlap of broad resonances of lipoprotein with the resonances of BCAAs. The widely used commercially available kits cannot differentially estimate the BCAAs. Here, we have achieved proper identification and characterization of these BCAAs in serum in a quantitative manner employing a Nuclear Magnetic Resonance-based technique namely T-2-edited Correlation Spectroscopy (COSY). This approach can easily be extended to other body fluids like bile, follicular fluids, saliva, etc.

"Je ne sais plus du tout qui je suis": The Phenomenology of Cancer in Anne Cuneo’s 'Une cuillerée de bleu'

Taking as its case study Anne Cuneo’s autopathography, Une cuillerée de bleu (1979), and supported by a phenomenological reading of the subjective realities of illness, including feelings of alienation, fragmentation, and passivity, this article considers how the experience of cancer affects the patient’s perception of her body, self, and world.

Effect of plasma insulin and branched-chain amino acids on skeletal muscle protein synthesis in fasted lambs

The increase in fractional rate of protein synthesis (K-s) in the skeletal muscle of growing rats during the transition from fasted to fed state has been explained by the synergistic action of a rise in plasma insulin and branched-chain amino acids (BCAA). Since growing lambs Also exhibit an increase in K-s with level of feed intake, the objective of the present study was to determine if this synergistic relationship between insulin and BCAA also occurs in ruminant animals. Six 30 kg fasted (72 h) lambs (8 months of age) received each of four treatments, which were based on continuous infusion into the jugular vein for 6 h of: (1) saline (155 mmol NaCl/l); (2) a mixture of BCAA (0.778 mumol leucine, 0.640 mumol isoleucine and 0.693 mumol valine/min.kg); (3) 18.7 mumol glucose/min.kg (to induce endogenous insulin secretion): (4) co-infusion of BCAA and glucose. Within each period all animals received the same isotope of phenylalanine, (Phe) as follows: (1) L-[1-C-13]Phe; (2) L-phenyl-[ring H-2(5)]-alanine; (3) L-[N-15]Phe; (4) L-[ring 2,6-H-3]Phe. Blood was sampled serially during infusions to measure plasma concentrations of insulin, glucose and amino acids, and plasma free Phe isotopic activity; biopsies were taken 6 h after the beginning of infusions to determine K-s in in. longissimus dorsi and vastus muscle. Compared with control (saline-infused) lambs, K-s was increased by an average of 40% at the end of glucose infusion, but this effect was not statistically significant in either of the muscles sampled. BCAA infusion, alone or in combination with glucose, also had no significant effect on K-s compared with control sheep. K-s was approximately 60% greater for vastus muscle than for m. longissimus dorsi (P<0.01), regardless of treatment. It is concluded that there are signals other than insulin and BCAA that are responsible for the feed-induced increase in K-s in muscle of growing ruminant animals.

Early metabolic adaptation in C57BL/6 mice resistant to high fat diet induced weight gain involves an activation of mitochondrial oxidative pathways

We investigated the short-term (7 days) and long-term (60 days) metabolic effect of high fat diet induced obesity (DIO) and weight gain in isogenic C57BL/6 mice and examined the specific metabolic differentiation between mice that were either strong-responders (SR), or non-responders (NR) to weight gain. Mice (n = 80) were fed a standard chow diet for 7 days prior to randomization into a high-fat (HF) (n = 56) or a low-fat (LF) (n = 24) diet group. The (1)H NMR urinary metabolic profiles of LF and HF mice were recorded 7 and 60 days after the diet switch. On the basis of the body weight gain (BWG) distribution of HF group, we identified NR mice (n = 10) and SR mice (n = 14) to DIO. Compared with LF, HF feeding increased urinary excretion of glycine conjugates of β-oxidation intermediate (hexanoylglycine), branched chain amino acid (BCAA) catabolism intermediates (isovalerylglycine, α-keto-β-methylvalerate and α-ketoisovalerate) and end-products of nicotinamide adenine dinucleotide (NAD) metabolism (N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide) suggesting up-regulation of mitochondrial oxidative pathways. In the HF group, NR mice excreted relatively more hexanoylglycine, isovalerylglycine, and fewer tricarboxylic acid (TCA) cycle intermediate (succinate) in comparison to SR mice. Thus, subtle regulation of ketogenic pathways in DIO may alleviate the saturation of the TCA cycle and mitochondrial oxidative metabolism.

Redução do MELD em paciente em lista de transplante hepático após o uso de aminoácidos de cadeia ramificada: relato de caso

Liver cirrhosis (LC) is a disease with high mortality rates and its only definitive treatment is the orthotopic liver transplantation (OLT). Unfortunately, not all patients have access to OLT and many of them end up dying on the transplant waiting list. The use of branched chain amino acids (BCAA) is widely known as an effective treatment for improving the quality of life of these patients. For the first time, in this paper we documented a great improvement of clinical and laboratorial tests of a patient treated with BCAA, which allowed him to be out of the transplant waiting list. In addition to the increase of the MELD score, the patient achieved restabilization of body weight and recovery of the quality of life registered by the SF-36 questionnaire.

The possible role of leucine in modulating glucose homeostasis under distinct catabolic conditions

Branched-chain amino acids (BCAA) (especially leucine) have been shown to activate protein synthesis pathways, decrease proteolysis and increase insulin sensitivity. Furthermore, it appears that leucine can be used as a nutritional therapy to avoid sarcopenia and skeletal muscle atrophy due to immobilization or glucocorticoid treatment. However, it is of note that all of these conditions are related to insulin resistance to varying degrees and affect different tissues, particularly skeletal muscle. Additionally, evidence from recent studies demonstrate that a combination of protein containing high levels of leucine with nutrients containing saturated fatty acids or an excess of leucine are capable of inducing insulin resistance. From this discussion, a few major questions arise. First, what is the role of a combination of macronutrients in inducing insulin resistance? Second, in insulin resistance, does leucine supplementation follow the same path observed under healthy conditions? Finally, what are the dose-dependent outcome and the latency of leucine effect under such conditions? The present article discusses these questions based on data from the literature and experiments performed by our group. (C) 2012 Elsevier Ltd. All rights reserved.

Leucine Is Essential for Attenuating Fetal Growth Restriction Caused by a Protein-Restricted Diet in Rats

Certain amino acids, such as leucine (Leu) are not only substrates for protein synthesis but also are important regulators of protein metabolism. Moreover, it is known that alterations in intrauterine growth favor the development of chronic diseases in adulthood. Therefore, we investigated the role of Leu in combination with other BCAA on effects that are induced by maternal protein restriction on fetal growth. Wistar rats were divided into 4 groups according to the diet provided during pregnancy: control (C; 20% casein); V+I [5% casein + 2% L-valine (Val) + 2% L-isoleucine (Ile)1; KYT 15% casein + 1.8% L-lysine (Lys) + 1.2% L-tyrosine (Tyr) + 1% L-threonine (Thr)1; and BCAA (5% casein + 1.8% L-Leu + 1.2% L-Val + 1% L-Ile). Maternal protein restriction reduced the growth and organ weight of the offspring of dams receiving the V+I and KYT diets compared with the C group. Supplementation with BCAA reversed this growth deficit, minimizing the difference or restoring the mass of organs and carcass fat, the liver and muscle protein, and the RNA concentrations compared with newborns in the C group (P < 0.05). These effects could be explained by the activation of the mTOR signaling pathway, because phosphorylation of 4E-BP1 in the liver of offspring of the BCAA group was greater than that in the C, V+I, and KYT groups. The present results identify a critical role for Leu in association with other BCAA in the activation of the mTOR signaling pathway for the control of altered intrauterine growth induced by a maternal low-protein diet. J. Nutr. 142: 924-930, 2012.