Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6?h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92?±?7.79?mmol/L to 7.16?±?5.64?mmol/L (P?P?Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.     

Effect of lactulose on cerebral metabolism in patients with chronic portosystemic encephalopathy

Cerebral blood flow and cerebral metabolism were studied in six patients with moderately severe portosystemic encephalopathy before and after a 10-day course of lactulose. As a result of therapy there was a mean increase in cerebral oxygen utilization but no changes in either mean glucose consumption or in mean cerebral blood flow. It appears therefore that the abnormalities in cerebral metabolism that have been previously described in patients with hepatic encephalopathy can be improved by the oral administration of lactulose.     

Serum gamma-aminobutyric acid (GABA) levels in patients with hepatic encephalopathy

Serum levels of the potent inhibitory neurotransmitter gamma aminobutyric acid (GABA) were measured in 10 patients with chronic liver disease and hepatic encephalopathy, 11 patients with chronic liver disease and no evidence of hepatic encephalopathy, 7 patients with end-stage renal disease and 11 healthy volunteers. Serum GABA levels were elevated in all 10 patients with hepatic encephalopathy, 5/11 with liver disease and no encephalopathy and 4/7 renal disease patients. The mean serum GABA level for the encephalopathic patients (0.92 +/- 0.13 microM, mean +/- SEM) was significantly greater than the mean for liver disease patients without encephalopathy (0.48 +/- 0.05 microM, p less than 0.05), renal disease patients (0.46 +/- 0.04 microM, p less than 0.05) and healthy volunteers (0.39 +/- 0.03 microM, p less than 0.001). These results would tend to support the hypothesis that GABA may play a role in the pathogenesis of hepatic encephalopathy.     

Changes in cerebral receptors for gamma aminobutyric acid in patients with hepatic encephalopathy

If the gamma-aminobutyric acid (GABA) inhibitory neurotransmitter system plays an important role in the mediation of hepatic encephalopathy (HE) in man, changes in the status of receptors for GABA in the brain may occur in patients with HE. To test this possibility, brains were obtained at autopsy from 11 patients who had died of causes unrelated to liver disease and from 11 patients who had died with chronic liver disease. Eight of the liver disease group had overt HE at the time of death. The specific binding of GABA to synaptic membranes isolated from frontal cortex was determined. Mean specific binding of GABA for patients with cirrhosis without overt HE was similar to that for control patients. In contrast, corresponding means for patients who had mild HE (stages I-III) and for patients who had severe HE (stage IV) were 45% higher (p less than 0.05) and 43% lower, respectively, than that for control patients. The mean specific binding of GABA was significantly greater for patients with mild HE than in patients with severe HE (p less than 0.025). Scatchard plots of the GABA binding data were curvilinear and consistent with a model of GABA receptors with two independent binding sites. Computer-assisted analysis of the binding data indicated that the altered GABA binding observed in patients with HE is attributable to changes in the affinity rather than the density of both GABA receptors (increased affinities in mild HE, and decreased affinities in hepatic coma). These findings are compatible with the hypothesis that alterations in GABAergic neurotransmission are associated with and contribute to the syndrome of HE in man.     

Application of Molecular Adsorbents Recirculating System to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome

Background: Molecular Adsorbents Recirculating System (MARS) is a new promising artificial liver support therapy, the aim of this study was to assess the effectiveness of MARS to remove nitrous oxide (NO) and cytokines in severe liver failure patients with multiple organ dysfunction syndrome (MODS). Methods: Sixty single MARS treatments were performed with length of 6–24 h on 24 severe liver failure patients (18 males/6 females) with MODS. Results: The MARS therapy was associated with a significant removal of NO and certain cytokines such as TNF‐α, IL‐6, IL‐8, and INF‐γ, together with marked reduction of other non‐water‐soluble albumin bound toxins and water‐soluble toxins, these were associated with a improvement of the patients' clinical conditions including hepatic encephalopathy, deranged hemodynamic situation and as well as renal and respiratory function, thus resulted into marked decrease of Sequential Organ Failure Assessment (SOFA) score and improved outcome: nine patients were able to be discharged from the hospital or bridged to successful liver transplantation, the overall survival of 24 patients was 37.5%. Conclusion: We can confirm the positive therapeutic impact and safety to use MARS on liver failure patients with MODS associated with elevated levels of NO and cytokines.     

Albumin Dialysis Molecular Adsorbents Recirculating System: Impact of Dialysate Albumin Concentration on Detoxification Efficacy

Albumin dialysis with the molecular adsorbent recirculating system (MARS) or single pass albumin dialysis (SPAD) uses human serum albumin (HSA) as an addendum of the dialysate fluid. The purpose of this in vitro study was to evaluate the impact of the dialysate albumin concentration on removal efficacy. Heparinized human plasma (3 L/test) was spiked with creatinine (1000 mg/L), unconjugated bilirubin (100 mg/L), chenodeoxycholic acid (CDCA) (100 mg/L), and diazepam (3 mg/L). The MARS albumin circuit was primed with different amounts of HSA (150, 100, 60, and 40 g). The plasma, albumin, and dialysate flow rates were 200, 200, and 40 mL/min, respectively. Clearances were calculated based on repeated sampling during the experiments, which lasted 480 min. The effective HSA concentrations in the dialysate were 175, 115, 77, and 46 g/L, respectively. They decreased over treatment time to 147, 99, 63, and 41 g/L, respectively, due to surface adsorption. The plasma–HSA concentration remained unchanged over time in all experiments (average 39 g/L). The creatinine clearance was not impacted by dialysate HSA concentration. For the albumin‐bound markers a clear correlation between HSA‐concentration and clearance was demonstrated with the highest clearances for the 100 and 150 g HSA experiments. The 100 g HSA setup appeared to be the one with best cost–benefit ratio, resulting in clearances (after 1 h of treatment) of 31 mL/min creatinine, 0.3 mL/min unconjugated bilirubin, 11 mL/min CDCA, and 35 mL/min diazepam. Low albumin concentrations, such as in SPAD, result in low clearance rates for albumin‐bound substances. The optimal clearances in these experiments were reached with a priming dose of 100 g HSA.     

血浆置换对肝性脑病患者血锰水平的影响

目的探讨非生物型人工肝血浆置换疗法对肝性脑病患者血锰水平的影响及其临床意义。方法以2007年10月-2011年7月于广西医科大学第一附属医院住院的22例肝性脑病患者为研究对象,给予血浆置换治疗,根据研究对象预后不同分为好转组和恶化组。采用石墨炉原子吸收法动态测定血中锰含量,分析治疗前后及病情转变后患者血锰水平的变化情况。计量资料组间比较采用t检验,并采用Pearson相关分析。结果 22例患者治疗后血锰水平(22.6±6.9)μg/L均较治疗前(36.4±10.6)μg/L下降,差异有统计学意义(t=4.789,P=0.000)。治疗后,8例好转,14例恶化,好转组血锰水平(18.9±6.3)μg/L明显低于恶化组的血锰水平(39.2±9.8)μg/L,差异有统计学意义(t=4.816,P=0.000)。结论非生物型人工肝支持可以降低肝性脑病患者血锰水平;血锰水平可能影响慢性肝性脑病患者的病情发展。     

Plasma and cerebrospinal fluid amino acid patterns in hepatic encephalopathy

Plasma and cerebrospinal fluid amino acid levels were measured in 12 cirrhotic patients in grade 0 hepatic encephalopathy and 17 in grade 3–4 hepatic encephalopathy. In 5 of these patients amino acid determinations were performed during the evolution of the encephalopathy. No correlation was found between the degree of hepatic encephalopathy and the plasma amino acid imbalance. In the CSF of cirrhotic patients without encephalopathy, a significant increase was found in nearly all amino acids, including those known to not easily cross the blood-brain barrier; this suggests the presence of a nonspecific modification of the blood-brain barrier permeability. In patients with severe hepatic encephalopathy, the further increase only in cerebrospinal fluid aromatic amino acids and methionine levels suggests the presence of a selective stimulation of the neutral amino acid transport system across the blood-brain barrier. Finally, the good correlation between glutamine and the sum of neutral amino acids found in the cerebrospinal fluid only in the presence of encephalopathy supports the hypothesis that brain glutamine may stimulate neutral amino acid transport across the blood-brain barrier.This work was supported by grant 500.6/Contr. 70/1743 Ministry of Health, Rome, Italy.     

Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy : A double-blind study of 65 patients with cirrhosis

We studied the effects of infusion of a branched chain enriched amino acid mixture versus glucose on acute hepatic encephalopathy in patients with cirrhosis. Sixty-five patients were randomly treated with 1 g/kg per day of an amino acid mixture with 40% branched chain contents (32 patients), or isocaloric glucose (33 patients) for a maximum of 16 days. The regimens further included glucose infusion to a total of 26.5 kcal/kg per day and lactulose. The patients took part in the study for 5-6 days. In each group 17 patients woke up. In the amino acid group eleven died and four developed renal failure. In the glucose group ten died, three developed renal and two respiratory failure, and one remained encephalopathic. The coma score worsened in three of the patients who died in the amino acid group, but in all patients who died in the glucose group. The negative nitrogen balance on entry reversed in the amino acid group, but not in the glucose group. Thus, the branched chain enriched amino acid supplement did not change the prognosis for wake-up, but had other effects on the cerebral state and on nitrogen homeostasis.     

Branched-chain amino acids in the treatment of chronic hepatic encephalopathy.

The therapeutic efficacy of orally administered branched-chain amino acids in patients with liver cirrhosis and chronic encephalopathy was examined in a double blind, randomised crossover study. Seven patients with manifest hepatic cirrhosis and encephalopathy of six months' duration or longer ingested 30 g branched-chain amino acids or placebo during two 14-day periods. Psychometric tests and electroencephalograms were used to evaluate cerebral function. Neither clinical observations nor psychometric testing or electroencephalogram indicated a significant difference in the patients' response to branched-chain amino acids as compared with placebo. In four patients given branched-chain amino acids for longer periods (five to 22 weeks), psychometric tests also remained unchanged. The plasma concentrations of these acids after oral intake increased significantly, demonstrating adequate absorption. Basal plasma amino acid concentrations were unchanged, however, after branched-chain amino acid therapy. No side-effects were seen, which indicates that these amino acids are well tolerated as an extra protein supply in patients with chronic hepatic encephalopathy. As compared with placebo, however, no effect of branched-chain amino acids on the encephalopathy could be detected.     

Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis

Background: Minimal hepatic encephalopathy(MHE) is an early and reversible form of hepatic encephalopathy. The documentations on the treatment with probiotics are inconsistent. The present meta-analysis was to verify the role of probiotics in the treatment of cirrhotic patients with MHE.Data sources: Seven electronic databases were searched for relevant randomized controlled trials(RCTs)published until July 2015. The effects of probiotics on serum ammonia, endotoxin, and MHE were evaluated.Results: A total of 14 RCTs(combined n = 1132) were included in the meta-analysis. When probiotics were compared to placebo or no treatment, probiotics were more likely to reduce values in the number connection test(NCT; week 4: MD =-30.25, 95% CI:-49.85 to-10.66), improve MHE(week 4: OR = 0.18,95% CI: 0.07 to 0.47; week 12: OR = 0.15, 95% CI: 0.07 to 0.32), and prevent overt HE progression(week4: OR = 0.22, 95% CI: 0.07 to 0.67) in patients with liver cirrhosis. When probiotics was compared to lactulose, probiotics tended to reduce serum ammonia levels(week 4: MD =-0.33 μmol/L, 95% CI:-5.39 to 4.74; week 8: MD = 6.22 μmol/L, 95% CI:-24.04 to 36.48), decrease NCT(week 8: MD = 3.93, 95% CI:-0.72 to 8.58), improve MHE(week 4: OR = 0.93, 95% CI: 0.45 to 1.91; week 12: OR = 0.73, 95% CI: 0.35 to 1.51) and prevent the development of overt HE(week 4: OR = 0.96, 95% CI: 0.17 to 5.44; week 12:OR = 2.7, 95% CI: 0.50 to 14.64) in patients with liver cirrhosis. However, lactulose appears to be more effective in reducing NCT values as compared to probiotics(week 4: MD = 6.7, 95% CI: 0.58 to 12.82).Conclusion: Probiotics can decrease serum ammonia and endotoxin levels, improve MHE, and prevent overt HE development in patients with liver cirrhosis.     

糖代谢与肝性脑病关系的临床观察

目的观察肝硬化患者血糖的改变,探讨糖代谢与肝性脑病（HE）的关系。方法 2008年8月至2010年8月间在嘉定区中心医院消化内科住院的肝硬化患者60人作为肝硬化组,非肝硬化住院患者30人作为对照组。收集一般资料,观察神志,体检有无扑翼样震颤,抽血检测患者血糖,根据患者检查结果,把肝硬化患者分为无扑翼样震颤组和有扑翼样震颤组,对肝硬化组与对照组糖代谢异常发生率进行比较,根据患者血糖情况分为血糖正常组及糖代谢异常组,对两组间扑翼样震颤及HE发生率进行比较。计量资料应用t检验,率的比较应用卡方检验。结果对照组30例,肝硬化组60例中无扑翼样震颤组28例,有扑翼样震颤组32例,对照组糖代谢异常发生率13.33%,肝硬化组糖代谢异常发生率26.67%,肝硬化组患者糖代谢异常发生率高于对照组（χ2=2.058,P〈0.05）。糖代谢正常组扑翼样震颤发生率50.00%,HE发生率34.09%,糖代谢异常组扑翼样震颤发生率62.50%,HE发生率37.50%,两组间差异均无统计学意义（P〉0.05）。结论肝硬化患者存在糖代谢的紊乱,但糖代谢异常不一定易于发生HE,提示存在大脑对糖的利用障碍。     

Regional variations in cerebral proton spectroscopy in patients with chronic hepatic encephalopathy

Regional variations in proton magnetic resonance spectroscopy (MRS) were assessed in 26 patients and 14 healthy volunteers using a two dimensional chemical shift imaging technique. Patients were classified as being neuropsychiatrically unimpaired, or as having subclinical or overt chronic hepatic encephalopathy (CHE). Peak area ratios of choline (Cho), glutamine and glutamate (Glx) and N-acetylaspartate (NAA) relative to creatine (Cr) were measured. Significant reductions in mean Cho/Cr and elevations in mean Glx/Cr were observed in the patient population, which correlated with the severity of CHE. There were significant regional variations in these metabolite ratios with the mean Cho/Cr lowest in the occipital cortex and the mean Glx/Cr highest in the basal ganglia. NAA/Cr remained relatively constant in all areas of the brain analysed. The regional variation in the metabolite ratios suggests that spectral information from more than one voxel may be useful in the assessment of patients with CHE.