Long-Term Carbohydrate-Containing Late-Evening Snack Significantly Improves the Ratio of Branched Chain Amino Acids to Aromatic Amino Acids in Adults with Liver Cirrhosis due to Hepatitis B.

BACKGROUND: The liver is the primary organ for amino acid metabolism, and metabolic disorder of amino acids is common in liver disease. However, the characteristics of plasma amino acid profiles in patients with HBV-related cirrhosis and the impacts of late-evening snack (LES) on cirrhosis are unclear. OBJECTIVES: To investigate the characteristics of plasma amino acid profiles in patients with HBV-related chronic hepatitis, cirrhosis, and the effects of late-evening snacks on plasma amino acid profiles. METHODS: 86 patients with HBV-related cirrhosis and eighty patients with chronic hepatitis B were included in this study. The plasma amino acid profiles were measured by the amino acid analyzer. Patients were randomly divided into two groups, of which the liver cirrhosis group was to receive daily LES (n = 43) or non-LES (n = 43) for 6 months. Plasma amino acid profiles and biochemical parameters were measured in both groups at baseline and after 1, 3, and 6 months. RESULTS: Compared to healthy controls, the plasma concentration in the liver cirrhosis group of threonine, serine, glycine, glutamine, cysteine, tyrosine, phenylalanine, arginine, and methionine increased significantly (P < 0.05), while the ratio of branched chain amino acids (BCAA) to aromatic amino acids (AAA) decreased significantly (P < 0.05). A carbohydrate-predominant LES treatment resulted in a significant increase in BCAA/AAA and decrease in the level of ammonia and glutamine compared with baseline after 6 months of supplementation (P < 0.05). Patients with Child-Pugh B and C are more responsive to changes in amino acid profiles than those with Child-Pugh A. CONCLUSIONS: The application of an LES carbohydrate module for six months in liver cirrhosis patients was associated with increased BCAA/AAA and decreased level of ammonia. Patients with Child-Pugh B and C grades were the most beneficial population.

Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal.

BACKGROUND: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown. METHODS: A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal. RESULTS: Among the metabolites analyzed, omega-6 polyunsaturated fatty acids (linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid), omega-3 polyunsaturated fatty acids (docosahexaenoic acid, docosapentaenoic acid), aromatic amino acids (phenylalanine, tyrosine, tryptophan), and intermediates of the tricarboxylic acid cycle (oxoglutaric acid, isocitric acid) were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover. CONCLUSIONS: In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts.

Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes.

Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81-0.93)). Multivariable Mendelian randomization revealed inverse association for higher log10-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04-0.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.

Amino acid profile and metabolic syndrome in a male Mediterranean population: A cross-sectional study.

BACKGROUND AND AIMS: The metabolic syndrome (MetS) refers to a cluster of clinically relevant factors that increases the risk of cardiovascular diseases and all-cause mortality. Circulating levels of several amino acids and metabolites related to one-carbon metabolism have been associated with cardiometabolic risk factors and MetS. We aimed to identify the amino acid profile that is significantly associated with MetS among an all male Mediterranean population. METHODS AND RESULTS: One hundred middle-aged men (54.6 ± 8.9 years) participated in a cross-sectional study carried out during 2011-2012. The International Diabetes Federation (IDF) criteria were used to define MetS. Fasting plasma levels of 20 common amino acids and 15 metabolites related to amino acid and one-carbon metabolism were measured using gas chromatography (GC-MS/MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS). Principal components analysis was applied. Fifty-six participants fulfilled the IDF criteria for defining MetS. Five factors were extracted from the 35 measured metabolites. The branched-chain amino acids/aromatic amino acids (BCAA/AAA) related pattern and the glutamine/glycine/serine/asparagine (Gln/Gly/Ser/Asn) related pattern were significantly associated with MetS (odds ratio, 95% confidence interval; 6.41, 2.43-16.91, and 0.47, 0.23-0.96, respectively) after adjustment for age, current smoking status, physical activity level and medical treatment for hypertension, dyslipidaemia, type 2 diabetes mellitus. Further adjustment for liver function markers (i.e. glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and γ-glutamyltransferase), and plasma adiponectin levels did not significantly affect the associations. CONCLUSION: The BCAA/AAA pattern was positively associated, while the Gln/Gly/Ser/Asn pattern was inversely associated with established cardiometabolic risk factors and MetS. Plasma adiponectin levels or markers of liver function did not significantly affect these associations.

Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner.

BACKGROUND: Obesity is associated with multiple diseases. Bariatric surgery is the most effective therapy for severe obesity that can reduce body weight and obesity-associated morbidity. The metabolic alterations associated with obesity and respective changes after bariatric surgery are incompletely understood. OBJECTIVE: We comprehensively assessed metabolic alterations associated with severe obesity and distinct bariatric procedures. DESIGN: In our longitudinal observational study, we applied a (1)H-nuclear magnetic resonance-based global, untargeted metabolomics strategy on human serum samples that were collected before and repeatedly ≤1 y after distinct bariatric procedures [i.e., a sleeve gastrectomy, proximal Roux-en Y gastric bypass (RYGB), and distal RYGB]. For comparison, we also analyzed serum samples from normal-weight and less-obese subjects who were matched for 1-y postoperative body mass index (BMI) values of the surgical groups. RESULTS: We identified a metabolomic fingerprint in obese subjects that was clearly discriminated from that of normal-weight subjects. Furthermore, we showed that bariatric surgery (sleeve gastrectomy and proximal and distal RYGB) dynamically affected this fingerprint in a procedure-dependent manner, thereby establishing new fingerprints that could be discriminated from those of BMI-matched and normal-weight control subjects. Metabolites that largely contributed to the metabolomic fingerprints of severe obesity were aromatic and branched-chain amino acids (elevated), metabolites related to energy metabolism (pyruvate and citrate; elevated), and metabolites suggested to be derived from gut microbiota (formate, methanol, and isopropanol; all elevated). CONCLUSION: Our data indicate that bariatric surgery, irrespective of the specific kind of procedure used, reverses most of the metabolic alterations associated with obesity and suggest profound changes in gut microbiome-host interactions after the surgery. This trial was registered at clinicaltrials.gov as NCT02480322.

Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy.

Hyperammonemia and severe amino acid imbalances play central role in hepatic encephalopathy (HE). In the article is demonstrated that the main source of ammonia in cirrhotic subjects is activated breakdown of glutamine (GLN) in enterocytes and the kidneys and the main source of GLN is ammonia detoxification to GLN in the brain and skeletal muscle. Branched-chain amino acids (BCAA; valine, leucine, and isoleucine) decrease due to activated GLN synthesis in muscle. Aromatic amino acids (AAA; phenylalanine, tyrosine, and tryptophan) and methionine increase due to portosystemic shunts and reduced ability of diseased liver. The effects on aminoacidemia of the following variables that may affect the course of liver disease are discussed: nutritional status, starvation, protein intake, inflammation, acute hepatocellular damage, bleeding from varices, portosystemic shunts, hepatic cancer, and renal failure. It is concluded that (1) neither ammonia nor amino acid concentrations correlate closely with the severity of liver disease; (2) BCAA/AAA ratio could be used as a good index of liver impairment and for early detection of derangements in amino acid metabolism; (3) variables potentially leading to overt encephalopathy exert substantial but uneven effects; and (4) careful monitoring of ammonia and aminoacidemia may discover important break points in the course of liver disease and indicate appropriate therapeutic approach. Of special importance might be isoleucine deficiency in bleeding from varices, arginine deficiency in sepsis, and a marked rise of GLN and ammonia levels that may appear in all events leading to HE.

T-type amino acid transporter TAT1 (Slc16a10) is essential for extracellular aromatic amino acid homeostasis control.

The uniporter TAT1 (Slc16a10) mediates the facilitated diffusion of aromatic amino acids (AAAs) across basolateral membranes of kidney, small intestine and liver epithelial cells, and across the plasma membrane of non-epithelial cells like skeletal myocytes. Its role for body AA homeostasis has now been investigated using newly generated TAT1 (Slc16a10) defective mice (tat1(-/-)). These mice grow and reproduce normally, show no gross phenotype and no obvious neurological defect. Histological analysis did not reveal abnormalities and there is no compensatory change in any tested AA transporter mRNA. TAT1 null mice, however, display increased plasma, muscle and kidney AAA concentration under both normal and high protein diet, although this concentration remains normal in the liver. A major aromatic aminoaciduria and a smaller urinary loss of all substrates additionally transported by l-type AA antiporter Lat2-4F2hc (Slc7a8) were revealed under a high protein diet. This suggests an epithelial transport defect as also shown by the accumulation of intravenously injected (123)I-2-I-l-Phe in kidney and l-[(3)H]Phe in ex vivo everted gut sac enterocytes. Taken together, these data indicate that the uniporter TAT1 is required to equilibrate the concentration of AAAs across specific membranes. For instance, it enables hepatocytes to function as a sink that controls the extracellular AAAs concentration. Additionally, it facilitates the release of AAAs across the basolateral membrane of small intestine and proximal kidney tubule epithelial cells, thereby allowing the efflux of other neutral AAs presumably via Lat2-4F2hc.

The effect of the mode of delivery on maternal-neonatal interleukin-6, biogenic amine and their precursor amino acid concentrations.

BACKGROUND: Biogenic amine, adrenaline, noradrenaline, dopamine and 5-hydroxy-tryptamine (5-HT) levels are related to interleukin-6 (IL-6) plasma concentrations and endurance exercise. The aim of our study was to investigate the effect of the mode of delivery on maternal-neonatal IL-6, biogenic amine and their precursor amino acid levels. METHODS: Some women with normal pregnancy (n=56) were divided into two groups: group A (n=26) with normal labor and vaginal delivery, and group B (n=30) with scheduled cesarean section. Blood was obtained from the mothers at the beginning of labor and immediately after delivery (pre- vs. post-delivery), as well as from the umbilical cord (CB). Total antioxidant status (TAS) and IL-6 levels were measured with commercial kits, the precursor amino acids, tyrosine and tryptophan with tandem mass spectrometry and the biogenic amine blood levels with HPLC methods, respectively. RESULTS: TAS, IL-6, biogenic amine and their precursor amino acid blood levels were similar in the two groups of mothers pre-delivery. TAS levels were reduced, whereas the amino acids, the catecholamine, 5-HT and IL-6 levels were increased post-delivery and in the CB of group A and unaltered in group B at the same time of the study. CONCLUSIONS: During a vaginal delivery process, the low TAS, the increased levels of the studied amino acids, the catecholamines, 5-HT and IL-6 may be due to the activation of the neuroendocrine system and the participation of skeletal and uterine muscles. The mode of delivery may be taken into account when IL-6 plasma levels are evaluated as an anti-inflammatory index perinatally.

Effects of polymyxin B-immobilized fiber hemoperfusion on amino acid imbalance in septic encephalopathy.

BACKGROUND: Septic encephalopathy is a common term denoting the signs of progressing central nervous system dysfunction in septic patients. Metabolic alterations including amino acid imbalance are involved in the pathogenesis of septic encephalopathy. The aim of the present study was to determine whether the ratio of branched-chain amino acids to aromatic amino acids is altered in patients with septic encephalopathy and whether polymyxin B-immobilized fiber (PMX-F) hemoperfusion affects this balance. METHODS: 16 septic patients with encephalopathy, 10 septic patients without encephalopathy, and 20 healthy controls were included in this study. Sepsis was diagnosed according to the ACCP/SCCM Consensus Conference criteria. Plasma endotoxin levels, interleukin-6 (IL-6) levels, and amino acid ratios were measured before and after PMX-F treatment. RESULTS: Within 12 h of the onset of septic encephalopathy, plasma endotoxin and IL-6 levels were increased significantly in septic patients with encephalopathy in comparison to those in septic patients without encephalopathy (endotoxin, p < 0.05; IL-6, p < 0.01) and those in healthy controls (endotoxin; p < 0.001; IL-6, p < 0.001). The ratio of branched-chain amino acids to aromatic amino acids in septic patients with encephalopathy was decreased in comparison to the ratio in septic patients without encephalopathy (p < 0.05) and that in healthy controls (p < 0.01). PMX-F treatment reduced plasma endotoxin (p < 0.01) and IL-6 levels (p < 0.01) and increased the ratio of branched-chain amino acids to aromatic amino acids (p < 0.01). CONCLUSION: The amino acid imbalance in patients with septic encephalopathy may be a marker for the severity of the septic syndrome, and PMX-F hemoperfusion is effective in ameliorating the increased plasma endotoxin and IL-6 levels and the amino acid imbalance in these patients.

In vivo effects of high phenylalanine blood levels on Na+,K+-ATPase, Mg2+-ATPase activities and biogenic amine concentrations in phenylketonuria.

OBJECTIVE: To evaluate the activities of Na+,K+-ATPase and Mg2+-ATPase in erythrocyte membranes from phenylketonuric (PKU) patients and to correlate the enzyme activities with their blood phenylalanine (Phe) levels, biogenic amines as well as with their precursors tyrosine (Tyr) and tryptophan (Try). DESIGN AND METHODS: Twenty three PKU patients were divided into group A (n = 12) on a restricted diet (Phe 1.57 +/- 0.52 mg/dL or 0.10 +/- 0.03 mM) and group B (n = 11) on a "loose" diet (Phe 24.45 +/- 1.50 mg/dL or 1.72 +/- 0.09 mM). The enzyme activities were measured spectrophotometrically, the amino acids with an automatic amino analyser and the biogenic amines with HPLC methods. RESULTS: In group B, plasma amino acids (Tyr, Try), their biogenic amines [adrenaline (A), noradrenaline (NA), dopamine (DA) and serotonin (5HT)], (Na+,K+)-ATPase and Mg2+-ATPase activities were found remarkably decreased (p < 0.001). CONCLUSIONS: High Phe and/or low NA, DA, 5HT plasma levels may indirectly inhibit the erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase in PKU patients. The observed enzyme inhibitions could be a very informative peripheral marker as regards the neurotoxic Phe brain effects.

Serial therapies oriented by surgery for large primary liver carcinoma.

OBJECTIVE: To discuss the methods and effects of serial therapies oriented by surgery in the treatment of primary large liver cancers. METHODS: From January 1993 to June 1999, 191 patients with large liver carcinoma were treated surgically. The size of tumors varied from 5.2 to 19.7 cm (mean 9.4 cm). Several types of liver resections were made in 121 patients and as a supplement, cryosurgery was carried out for the remaining 70 patients. Importable drug delivery system was instituted intraoperatively. Transcatheter arterial chemo-embolization (THP 30-60 mg, E-ADM 20-40 mg, CDDP 40-80 mg, MMC 10-20 mg, iodin oil 5-30 ml), percutaneous ethanol injection, bioimmunotherapy and traditional Chinese medicine were used pre- and post-operatively. CT angiography and CT during arterial portography were used to find satellite nodules. Early stage recurrences were predicted by AFPmRNA in peripheral blood. Child-Pugh's classification plus branch chain amino acid/aromatic amino acid ratio (BCAA/AAA) was adopted in evaluating pre-operative liver functions. RESULTS: Marked results were observed after serial treatments oriented by surgery. The 1-, 3- and 5-year survival rates in resection group were 75.8%, 45.6% and 30.4%, respectively. The 1- and 3-year survival rates in cryosurgery group were 63.2% and 37.0%. The operative mortality was 1.57%. Recurrence rates were 69.2% in AFPmRNA positive group and 33.3% in AFPmRNA negative group (P<0.05). The BCAA/AAA ratio was lower than 1.5 in two patients who died of hepatic failure after resection. CONCLUSIONS: Serial treatments with surgery as the chief modality gives satisfactory results in patients with large primary liver carcinoma. This regimen should be regarded as a main strategy to deal with large liver carcinoma. AFPmRNA in the peripheral blood, signifying a recurrence, may become a new clinical parameter. The BCAA/AAA ratio plus Child-Pugh's classification is able to evaluate more accurately liver function reserve before surgery.