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Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). Sample handling, processing, and protein intake impact ammonia levels across sites.

Objective This study was performed to investigate the role of probiotics (Clostridium butyricum combined with Bifidobacterium infantis) in the treatment of minimal hepatic encephalopathy (MHE) in patients with hepatitis B virus (HBV)-induced liver cirrhosis. Methods Sixty-seven consecutive patients with HBV-induced cirrhosis without overt hepatic encephalopathy were screened using the number connection test and digit symbol test. The patients were randomized to receive probiotics (n = 30) or no probiotics (n = 37) for 3 months. At the end of the trial, changes in cognition, intestinal microbiota, venous ammonia, and intestinal mucosal barriers were analyzed using recommended systems biology techniques. Results The patients’ cognition was significantly improved after probiotic treatment. The predominant bacteria (Clostridium cluster I and Bifidobacterium) were significantly enriched in the probiotics-treated group, while Enterococcus and Enterobacteriaceae were significantly decreased. Probiotic treatment was also associated with an obvious reduction in venous ammonia. Additionally, the parameters of the intestinal mucosal barrier were obviously improved after probiotic treatment, which might have contributed to the improved cognition and the decreased ammonia levels. Conclusion Treatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis.

Plyometric training is characterized by high-intensity exercise which is performed in short term efforts divided into sets. The purpose of the present study was twofold: first, to investigate the effects of three distinct plyometric exercise protocols, each with varying work-to-rest ratios, on muscle fatigue and recovery using an incline-plane training machine; and second, to assess the relationship between changes in lower limb muscle strength and power and the biochemical response to the three exercise variants employed. Forty-five adult males were randomly divided into 3 groups (n = 15) performing an exercise of 60 rebounds on an incline-plane training machine. The G0 group performed continuous exercise, while the G45 and G90 groups completed 4 sets of 15 repetitions, each set lasting 45 s with 45 s rest in G45 (work-to-rest ratio of 1:1) and 90 s rest in G90 (1:2 ratio). Changes in muscle torques of knee extensors and flexors, as well as blood lactate (LA) and ammonia levels, were assessed before and every 5 min for 30 min after completing the workout. The results showed significantly higher ( p  < 0.001) average power across all jumps generated during intermittent compared to continuous exercise. The greatest decrease in knee extensor strength immediately post-exercise was recorded in group G0 and the least in G90. The post-exercise time course of LA changes followed a similar pattern in all groups, while the longer the interval between sets, the faster LA returned to baseline. Intermittent exercise had a more favourable effect on muscle energy metabolism and recovery than continuous exercise, and the work-to-rest ratio of 1:2 in plyometric exercises was sufficient rest time to allow the continuation of exercise in subsequent sets at similar intensity.

Purpose Minimal hepatic encephalopathy (MHE) is common in cirrhosis, leading to cognitive impairment and eye-hand coordination (EHC) alterations. Hyperammonemia plays a key role in MHE, contributing to motor and cognitive deficits. Elevated blood ammonia levels and impaired EHC correlate with neuropsychiatric dysfunction, yet their direct impact on health-related quality of life (HRQoL) is complex. This study examines the associations between blood ammonia, EHC, and HRQoL, and the moderating influence of sex on these associations. Methods Eighty-seven cirrhotic patients (67 male) and 23 healthy volunteers (11 male), aged 44–80 years, performed the Psychometric Hepatic Encephalopathy Score (PHES) for MHE diagnosis, the Vienna Test System, bimanual and visuomotor tests, and completed the SF-36 questionnaire to measure HRQoL. Blood samples were taken to test ammonia levels. Results Results indicated a significant association between elevated blood ammonia and impaired EHC among cirrhotic patients. However, increased blood ammonia and EHC did not directly predict HRQoL. Moderated moderation analysis revealed that women with MHE showed greater sensitivity to hyperammonemia and EHC deficits in tasks requiring fine motor control and stability skills (aiming, tapping, and bimanual coordination), which were linked to lower HRQoL in both physical and mental domains. In women without MHE, alterations in linear tracking were linked to worse HRQoL. These effects were not observed in men. Conclusions The findings underscore the sex-specific impacts of MHE, with women disproportionately affected by ammonia-related motor impairments and their subsequent influence on HRQoL. These results could contribute to developing targeted strategies to improve outcomes in this vulnerable population.

To our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. Patients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (≤65 μg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. Blood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. Although this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings.

Hepatic encephalopathy (HE), a morbid ordeal affecting chronic liver disease patients always insists for the search of a rational, superior & infallible agent beyond the time-proven standards i.e., Lactulose & Rifaximin. In this RCT, we compared the efficacy of intravenous (IV) l -ornithine- l -aspartate(LOLA) versus Oral LOLA in patients with chronic liver disease(CLD) enduring overt Hepatic Encephalopathy(OHE). 40 CLD patients with OHE were randomly assigned IV or oral LOLA in a 1:1 ratio. Patients were graded for HE and monitored for serum ammonia levels from day 1 to day 5. The aim was to compare IV versus oral LOLA efficacy in HE grades improvement and its correlation with ammonia levels. The study was registered with clinical trials registry-India, CTRI/2020/12/029943. Baseline characteristics of patients in both groups were similar. The mean difference in ammonia levels from day 1 to day 5 was 55.4 ± 32.58 µmol/L in the IV LOLA group and 60.75 ± 13.82 µmol/L in the oral LOLA group (p = 0.511). Significant reductions in ammonia levels were observed from day 1 to day 5 within each group (p < 0.001). HE grade & ammonia correlated positively in both groups. LOLA, regardless of administration route, has demonstrated efficacy in OHE.

INTRODUCTION:Diet can affect ammoniagenesis in cirrhosis and hepatic encephalopathy (HE), but the impact of dietary preferences on metabolomics in cirrhosis is unclear. As most Western populations follow meat-based diets, we aimed to determine the impact of substituting a single meat-based meal with an equal protein-containing vegan/vegetarian alternative on ammonia and metabolomics in outpatients with cirrhosis on a meat-based diet.METHODS:Outpatients with cirrhosis with and without prior HE on a stable Western meat-based diet were randomized 1:1:1 into 3 groups. Patients were given a burger with 20 g protein of meat, vegan, or vegetarian. Blood for metabolomics via liquid chromatography-mass spectrometry and ammonia was drawn at baseline and hourly for 3 hours after meal while patients under observation. Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between/within groups.RESULTS:Stool microbiome composition was similar at baseline. Serum ammonia increased from baseline in the meat group but not the vegetarian or vegan group. Metabolites of branched chain and acylcarnitines decreased in the meat group compared with the non-meat groups. Alterations in lipid profile (higher sphingomyelins and lower lysophospholipids) were noted in the meat group when compared with the vegan and vegetarian groups.DISCUSSION:Substitution of a single meat-based meal with a non-meat alternatives results in lower ammoniagenesis and altered serum metabolomics centered on branched-chain amino acids, acylcarnitines, lysophospholipids, and sphingomyelins in patients with cirrhosis regardless of HE or stool microbiome. Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis.

Lactulose is effective in secondary prophylaxis of hepatic encephalopathy (HE). Probiotics improves minimal hepatic encephalopathy (MHE), which predisposes to HE. No study has been conducted on the secondary prophylaxis of HE using probiotics. Our objective was to study the effects of lactulose and probiotics for secondary prophylaxis of HE. Consecutive cirrhotic patients who had recovered from HE were randomized to receive lactulose (Gp-L, 30 ml three times per day), three capsules of probiotics (Gp-P) per day containing 112.5 billion viable lyophilized bacteria per capsule, or no therapy (Gp-N). All patients were assessed by psychometry (number connection test (NCT-A, B), figure connection test if illiterate (FCT-A, B), digit symbol test (DST), and block design test (BDT)), critical flicker frequency (CFF) test, and arterial ammonia at inclusion. The patients were followed up monthly. The primary end point was development of overt HE according to West Haven criteria or a follow-up of 12 months. Of 360 patients who recovered, 235 (65.2%) met the inclusion criteria (Gp-L, n=80; Gp-P, n=77; and Gp-N, n=78). In all, 38 patients (16.1%) were lost to follow-up and 77 patients developed HE (Gp-L, n=18; Gp-P, n=22; and Gp-N, n=37). There was a significant difference between Gp-L and Gp-N (P=0.001) and between Gp-P and Gp-N (P=0.02) but no difference between the Gp-L and Gp-P groups (P=0.349). The rate of readmission for causes other than HE (Gp-L, Gp-P, and Gp-N, 19:21:28; P=0.134) and deaths (Gp-L:Gp-P:Gp-N=13:11:16; P=0.56) in all three groups were similar. There was a high prevalence of abnormal psychometry test results (NCT-A, 71.5%; NCT-B, 69.2%; DST, 76.9%; and BDT, 85.2%), and FCT-A and -B were abnormal in 35 of 48 patients (72.7%). CFF was <38 Hz in 118 patients (50.2%). Upon multivariate analysis, recurrence of overt HE was significantly associated with two or more abnormal psychometric tests and arterial ammonia after the recovery of an episode of HE. Lactulose and probiotics are effective for secondary prophylaxis of HE in patients with cirrhosis.

Minimal hepatic encephalopathy (MHE), the preclinical stage of overt hepatic encephalopathy (OHE), is a significant condition affecting up to 60% of cirrhotics. All MHE therapies modify gut microflora, but consensus regarding MHE treatment and long-term adherence studies is lacking. The aim was to determine the effect of probiotic supplementation in the form of a food item, probiotic yogurt, on MHE reversal and adherence. Nonalcoholic MHE cirrhotics (defined by a standard psychometric battery) were randomized with unblinded allocation to receive probiotic yogurt (with proven culture stability) or no treatment (no Rx) for 60 days in a 2:1 ratio. Quality of life (short form [SF]-36), adherence, venous ammonia, model of end-stage liver disease (MELD) scores, and inflammatory markers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6) were also measured. Outcomes were MHE reversal using blinded scoring, OHE development, and adherence. Twenty-five patients (17 yogurt, 8 no Rx; 84% Child class A) were enrolled. A significantly higher percentage of yogurt patients reversed MHE compared to no Rx patients (71%vs 0%, P= 0.003, intention-to-treat). Yogurt patients demonstrated a significant improvement in number connection test-A (NCT-A), block design test (BDT), and digit symbol test (DST) compared to baseline/no Rx group. Twenty-five percent of no Rx versus 0% of yogurt patients developed OHE during the trial. Eighty-eight percent of yogurt patients were adherent. No adverse effects or change in covariates were observed. All patients who completed the yogurt arm were agreeable to continue yogurt for 6 months if needed. This trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence.

Background/objective: A distinct suppressive effect of a whey protein (including glycomacropeptide)-enriched preload drink on subsequent food intake in comparison with a maltodextrin carbohydrate-enriched preload was demonstrated in an earlier companion study with the same female subjects; however, the potential mediators underlying the effect are unclear. The objective of this study was to investigate how the ingestion of a whey protein-enriched preload beverage affected postprandial plasma concentrations of several satiety-related gastrointestinal hormones and metabolites in comparison with a maltodextrin carbohydrate-enriched preload. Subjects/methods: Eighteen normal-weight women were studied in a single-blind, randomized block design. Blood samples were collected at various time intervals for 120 min after consumption of a test drink (300 ml, ~1300 kJ) enriched (45 g) with either maltodextrin carbohydrate or whey protein containing naturally present glycomacropeptide. Results: Plasma-active ghrelin concentrations decreased after both maltodextrin carbohydrate- and whey protein-enriched test drinks ( P <0.05). The whey protein-enriched beverage led to increased plasma concentrations of cholecystokinin (CCK) at 60 and 75 min ( P <0.05), glucagon-like peptide-1 (GLP-1) at 90 min ( P <0.001), peptide tyrosine–tyrosine (PYY) at 90 and 120 min ( P <0.01) and pancreatic polypeptide (PP) from 15 to 120 min ( P <0.05) compared with maltodextrin carbohydrate. Total amino acid, urea and ammonia plasma concentrations were also higher after whey protein compared with maltodextrin carbohydrate ingestion ( P <0.01). Conclusions: Increased plasma concentrations of some gastrointestinal hormones related to satiety, particularly PP, and of amino acids and their metabolites, may have acted either singly or together to mediate the observed satiety response to whey protein.