Plasma amino acid imbalance in alcoholic liver cirrhosis

Plasma amino acid concentrations and plasma glucagon and serum insulin levels were studied in male patients with compensated alcoholic and nonalcoholic liver cirrhosis. Age, nutritional status, and liver function tests were similar in both groups; none of the patients presented hepatic encephalopathy. Plasma valine and leucine concentrations were lower, and tyrosine, higher in alcoholic than nonalcoholic liver cirrhosis. As a result, the molar ratios of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) were reduced markedly in this group. Although correlation coefficients comparing BCAA/AAA ratios and KICG in alcoholic and nonalcoholic liver cirrhosis were similar, a steeper regression line was observed in alcoholics. Plasma glucagon and proline levels were significantly higher in alcoholic than nonalcoholic liver cirrhosis, the former correlated with AAA concentrations only in alcoholic liver cirrhosis, but not with BCAA levels. These results indicated that alcoholic liver cirrhosis presented a more deranged plasma amino acid pattern than nonalcoholic, and the amino acid imbalances, except for depressed BCAA and elevated proline, were derived, in part, from the hyperglucagonemia.     

Peripheral T-cell subsets in chronic type B hepatitis: correlation with biochemical and histological activities and hepatitis B e antigen/antibody status

Peripheral T-cell subsets in 77 patients with hepatitis B surface antigen (HBsAg)-positive chronic liver diseases were studied by indirect immunofluorescence using murine monoclonal antibodies against all peripheral T cells (OKT3), T-helper/inducer cells (OKT4), and T-cytoxic/suppressor cells (OKT8). OKT4/OKT8 ratios were significantly reduced in patients with hepatitis B e antigen (HBeAg)-positive chronic liver diseases, including 28 patients with chronic active hepatitis (CAH) (P less than 0.001) and 15 with chronic persistent hepatitis (CPH) (P less than 0.001). OKT4/OKT8 ratios were significantly lower in 21 HBeAg-negative patients with CAH (P less than 0.05), as compared to those of 17 normal controls, while T-cell subsets in 13 patients with HBeAg-negative CPH were essentially normal. Low OKT4/OKT8 ratios significantly correlated with HBeAg positivity (P less than 0.001) and CAH (P less than 0.05), as assessed with multiple regression. There was a significant negative correlation between OKT4/OKT8 ratios and serum glutamic-pyruvic transaminase (SGPT) levels (r = -0.37; P less than 0.01). It was concluded that in chronic hepatitis B virus infection, low OKT4/OKT8 ratios are closely related to active viral replication and more severe histological and biochemical activity.     

Plasma amino acids in four models of experimental liver injury in rats

Summary We studied the plasma amino acid profiles in four models of hepatic injury in rats. In partially hepatectomized rats (65% of liver was removed) we observed significant increase of aromatic amino acids (AAA; i.e. tyrosine and phenylalanine), taurine, aspartate, threonine, serine, asparagine, methionine, ornithine and histidine. Branched-chain amino acids (BCAA; i.e. valine, leucine and isoleucine) concentrations were unchanged. In ischemic and carbon tetrachloride acute liver damage we observed extreme elevation of most of amino acids (BCAA included) and very low concentration of arginine. In carbon tetrachloride induced liver cirrhosis we observed increased levels of AAA, aspartate, asparagine, methionine, ornithine and histidine and decrease of BCAA, threonine and cystine. BCAA/AAA ratio decreased significantly in partially hepatectomized and cirrhotic rats and was unchanged in ischemic and acute carbon tetrachloride liver damage. We conclude that a high increase of most of amino acids is characteristic of fulminant hepatic necrosis; decreased BCAA/AAA ratio is characteristic of liver cirrhosis; and decrease of BCAA/AAA ratio may not be used as an indicator of the severity of hepatic parenchymal damage.Abbreviations BCAA branched-chain amino acids (i.e. valine, leucine and isoleucine) - AAA aromatic amino acids (i.e. tyrosine and phenylalanine)     

Metabolic activation of hepatocarcinogens in chronic hepatitis B

S9 fraction pools of liver biopsy samples, collected from 129 patients in two consecutive studies, were comparatively assayed for their ability to activate aflatoxin B1 (AFB1) and a tryptophan pyrolysate product (Trp-P-2) in a miniaturized Salmonella mutagenicity test system. Metabolic activation was not affected to a significant extent by most of the monitored variability factors, such as sex, alcohol, cigarette smoking and liver histology (minimal changes, chronic persistent (CPH) or active (CAH) hepatitis, CAH steatosis, or cirrhosis). Conversely, a significant enhancement of activation was observed for AFB1 in cases of mild CAH and especially for Trp-P-2 in hepatitis B virus carriers, irrespective of their histologic diagnosis.     

用人工合成的丁型肝炎病毒抗原多肽检测丁肝病毒IgM抗体及其初步应用

用人工合成的丁型肝炎病毒抗原（ＨＤＶ－Ａｇ）肽建立了检测抗ＨＤＶ－ＩｇＭ抗体的ＥＬＩＳＡ方法,本法操作简便、快速,重复性好,特异性强,与抗ＨＡＶ－ＩｇＭ、抗Ｈｋ－ＩｇＭ、抗ＨＢｓ－ＩｇＭ、抗ＨＣＶ－ＩｇＩ、抗ＣＭＶ－ＩｇＭ、抗ＲＶ－ＩｇＭ、类风湿因子（ＲＦ）及抗核抗体（ＡＮＡ）阳性血清均不起反应,且可被２－巯基乙醇阻断而不起反应。经初步临床应用,３１例正常人血清抗ＨＤＶ－ＩｇＭ全部阴性,２８例慢活肝患者检出率为３２．１％（９／２８）,１７例慢迁肝患者血清阳性率为１１．８％（２／１７）１８例肝癌和肝硬化病人血清阳性率为２２．２％（４／１８）这三组病人与正常对照者相比较均有显著性差异（Ｐ＜０．００１）。此外,抗ＨＤＶ－ＩｇＭ阳性血清的ＡＬＴ值均明显高于正常参考范围,提示在ＨＤＶ感染过程中,患者肝细胞进一步受损。实验结果证明,抗ＨＤＶ－ＩｇＭ是诊断ＨＤＶ感染的重要指标,对ＨＤＶ感染早期诊断具有重要价值。     

肝硬化与肝癌患者血浆游离氨基酸水平分析

采用高效液相色谱法分析了２５例肝硬化和１５例肝癌患者空腹血浆游离氨基酸水平的变化。结果表明,二者支链氨基酸（ＢＣＡＡ）如Ｖａｌ、Ｉｌｅ呈下降趋势,而芳香族氨基酸（ＡＡＡ）如Ｔｙｒ、Ｐｈｅ则呈上升趋势,ＢＣＡＡ／ＡＡＡ分子比值下降。丙氨酸（Ａｌａ）、蛋氨酸（Ｍｅｔ）、谷氨酰胺（Ｇｌｎ）及天门冬氨酸（Ａｓｐ）明显上升。其变化趋势二者存在差别。     

各型肝病患者红细胞内氨基酸检测的临床研究

本文对３０例正常人和１０８例各型肝病患者红细胞内氨基酸进行检测,结果显示,各型肝炎与正常人比较红细胞内氨基酸均表现不同程度的增高和降低。如正常人红细胞内１７种氨基酸的总量为３５５４．４７μｍｏｌ／Ｌ,支／芳比值３．０６±０．４０;急性肝炎总量３４２３．２５μｍｏｌ／Ｌ,支／芳比值２．４８±０．３０;慢性肝炎（轻度）总量３３２９．３３μｍｏｌ／Ｌ,支／芳比值２．３９±０．２２;慢性肝炎（中度）总量３２１９．３２μｍｏｌ／Ｌ,支／芳比值１．８３±０．４０;肝硬化总量３７６２．３３μｍｏｌ／Ｌ,支／芳比值１．３６±０．４１。     

Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury

Changes in plasma aromatic amino acids (AAA?=?phenylalanine, tryptophan, tyrosine) and branched chain amino acids (BCAA?=?isoleucine, leucine, valine) levels possibly influencing intracranial pressure (ICP) and cerebral oxygen consumption (SjvO(2)) were investigated in 19 sedated patients up to 14?days following severe traumatic brain injury (TBI). Compared to 44 healthy volunteers, jugular venous plasma BCAA were significantly decreased by 35% (p?相似文献   

Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects

Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle metabolism of ammonia and amino acids in 14 patients with cirrhosis and in 7 healthy subjects by combining [(13)N]ammonia positron emission tomography (PET) of the thigh muscle with measurements of blood flow and arteriovenous (A-V) concentrations of ammonia and amino acids. PET was used to measure the metabolism of blood-supplied ammonia and the A-V measurements were used to measure the total ammonia metabolism across the thigh muscle. After intake of BCAA, blood ammonia increased more than 30% in both groups of subjects (both P < 0.05). Muscle clearance of blood-supplied ammonia (PET) was unaffected (P = 0.75), but the metabolic removal rate (PET) increased significantly because of increased blood ammonia in both groups (all P < 0.05). The total ammonia clearance across the leg muscle (A-V) increased by more than 50% in both groups, and the flux (A-V) of ammonia increased by more than 45% (all P < 0.05). BCAA intake led to a massive glutamine release from the muscle (cirrhotic patients, P < 0.05; healthy subjects, P = 0.12). In conclusion, BCAA enhanced the intrinsic muscle metabolism of ammonia but not the metabolism of blood-supplied ammonia in both the patients with cirrhosis and in the healthy subjects.     

Tissue polypeptide antigen (TPA) modifications in hepatic cirrhosis, aggressive chronic hepatitis, persistent chronic hepatitis, and in minimal pathology

A total of 104 patients with various liver diseases were studied. Hepatic biopsy was performed and the AST, ALT and TPA in serum were measured. Higher levels of TPA, AST and ALT were found in CAH and LC, lower in CPH and MHP. High serum TPA values, usually suggesting the possibility of neoplasm, should be considered with attention. A follow-up with periodic TPA assays (in addition to AST and ALT) is suggested in patients with acute hepatitis, in order to predict further possible complications such as CAH and LC.     

研究荧光标记BCAA及AAA在大鼠体内代谢

使用DNS-Cl标记BCAA及AAA等六种氨基酸,观察这些氨基酸在大鼠小肠的吸收,血液的清除以及肝脏、肌肉、肾脏、脑等器官的摄取及排空情况。结果:小肠在30分钟开始吸收,4小时部分排空;血液在4小时开始清除,16小时清除完毕;肝脏、肌肉、肾脏、脑组织等,都在30分钟全部或部分摄取,但各器官对不同氨基酸,排空的时间不尽相同。     

Helicobacter pylori infection in patients with Hepatitis C Virus positive chronic liver diseases

BACKGROUND AND GOALS: One-third of patients with liver cirrhosis suffers from acute peptic ulcer, a disease strongly correlated with Helicobacter pylori (H. pylori) infection. We report the seroprevalence of antibodies to H. pylori in 179 patients with Hepatitis C Virus (HCV)-related chronic active hepatitis and cirrhosis. MATERIALS AND METHODS: Among patients, 135 (86 males and 49 females, mean age 51.2 +/- 13.28, range 27-77 years) had chronic active hepatitis (CAH) and 44 cirrhosis (28 males and 16 females, mean age 62.4 +/- 9.2, range 37-77 years). Serum antibodies to H. pylori were tested using a commercial enzyme immunosorbent assay. The control population consisted of 619 consecutive blood donors (523 males, 96 females, mean age 47 +/- 5.3 years, range 18-65). RESULTS: The overall prevalence of antibodies to H. pylori was 73.1% (131/179) among patients and 47% (291/619) among blood donors (p<0.0001; OR 3.08 [95%CI, 2.10-4.51]). 70.5% (24/34) of patients aged less than 40 years were seropositive for H. pylori versus 34.2% (90/263) of controls (p<0.0001; OR 4.61[95%CI, 2.0-10.85]). Among cirrhosis patients, the prevalence of antibodies to H. pylori was 79.5% (35/44) versus 47% (291/619) of controls (p<0.0001; OR 4.38 [95%CI, 1.98-9.98]). Overall seroprevalence among CAH patients was 71.1% (96/135) versus 47% (291/619) of blood donors (p<0.0001; OR 2.77 [95%CI, 1.82-4.24]). CONCLUSIONS: The high seroprevalence of antibodies to H. pylori in patients with HCV-positive liver diseases explains the elevated incidence of peptic ulcer, and warrants studies on the pathogenic role in human liver diseases of Helicobacter spp which is known to cause chronic hepatitis and hepatocellular carcinoma in mice.     

Zinc,iron, and peroxidation in liver tissue

In an attempt to elucidate further the mechanisms involved in alcohol-mediated liver damage and the correlation between alcohol and viruses in chronic liver lesions, we determined the levels of liver glutathione (GSH), thiobarbituric acid reactive substances (TBARS), iron (Fe), and zinc (Zn) in 31 patients with chronic viral hepatitis (CAH), 6 with alcohol-related chronic hepatitis (CALD), 6 with alcoholic cirrhosis (AC), 8 with primary biliary cirrhosis (PBC), and 10 healthy controls (C). Liver GSH was significantly lower in CALD and AC patients (p<0.005). TBARS levels were significantly higher in CAH, CALD, and PBC patients (p<0.001, <0.02, and <0.001, respectively). In CAH patients, alcohol consumption correlated inversely with GSH and directly with TBARS (p<0.05). Patients with both CAH and alcohol abuse had a further reduction in liver GSH levels (p<0.005). Tissue levels of Fe were significantly increased in CALD and AC patients with respect to controls and CAH patients, whereas no significant difference was observed in Zn. These data confirm that patients with chronic ethanol exposure reveal a depletion in liver GSH content clearly correlated with an increase in lipid peroxidation and Fe liver storage. On the other hand, these findings appear to suggest no significant change in Zn levels in chronic hepatitis.     

Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease

Background

Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD.

Methods

Hepatic fat content was measured using proton magnetic resonance spectroscopy (¹H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot.

Results

Increased branched-chain amino acid (BCAA), aromatic amino acid (AAA) and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all). Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all), whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all).

Conclusions

Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.     

Decreased serum osteocalcin levels in patients with liver cirrhosis

Serum levels of osteocalcin (OC) have been found to be a specific biochemical parameter of bone formation. We measured serum levels of osteocalcin, parathyroid hormone (PTH) and 25-hydroxyvitamin D (25(OH)D) in 49 patients with liver cirrhosis, who are known to have an increased prevalence of metabolic bone disease, and a matched control group (n = 35). Serum levels of OC were significantly decreased in the patients with liver cirrhosis when compared to control subjects (P < 0.001). Serum levels of 25(OH)D were decreased (P < 0.001), whereas no statistical difference was found between the serum levels of PTH in the patients with liver cirrhosis and those of the controls. In a subgroup of 23 patients with cirrhosis of the liver and 34 control subjects, the bone mineral content (BMC) of the non-dominant forearm was determined by single photon absorptiometry. BMC was significantly lower in the patient with liver cirrhosis than the control subjects (P < 0.04). Our data demonstrate vitamin D deficiency, decreased bone formation and a decreased BMC in patients with liver cirrhosis.     

Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis

Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.     

Effects of chronic oral branched-chain amino acid supplementation in a subpopulation of cirrhotics

Liver cirrhosis is characterized by low plasma levels of branched chain amino acids (BCAA) and high concentrations of aromatic amino acids (AAA), and this imbalance has been implicated in the pathogenesis of hepatic encephalopathy by the synthesis of altered neurotransmitters. Contrasting results on intravenous or oral BCAA efficacy and metabolic impact have already been reported, but studies reported in the literature were never longer than a few weeks. After oral administration of BCAA and a standard diet to 28 cirrhotic patients for 1 year, no modifications in plasma concentrations of BCAA could be observed up to 3 months of therapy. Our data and an accurate analysis of the current literature lead us to propose the hypothesis that in the impaired nitrogen metabolism following cirrhosis there are neither single metabolic presentations nor many perturbations, but numerous 'subpopulations' of patients who present a homogeneous pattern of alterations that may distinguish them in terms of therapeutic approach.     

Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels (P < 0.001) with hepatic venous resistin being higher than arterial levels (P < 0.001). Circulating resistin was significantly correlated with plasma TNF-alpha levels (r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production (r = -0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies (r = 0.48, P < 0.001) as well as hepatic ketone body production (r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved (P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis.     

Serum Sphingolipid Variations Associate with Hepatic Decompensation and Survival in Patients with Cirrhosis

Background

Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.

Methods

We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.

Results

We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p<0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p<0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p<0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).

Conclusions

In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.