Liver Elastography in Acute Liver Failure: A Pilot Study.

OBJECTIVES: We aimed to assess the feasibility and reliability of sequential ultrasonographic and elastographic monitoring in acute liver failure (ALF). DESIGN: Observational study. SETTING: ALF is a rare, life-threatening disease that requires intensive care admission and often liver transplant, where the accurate selection of patients is crucial. Liver elastography is a noninvasive tool that can measure hepatic stiffness, but previous results have been inconclusive in ALF. PATIENTS: Patients admitted between October 2021 and March 2023 to the Liver Intensive Therapy Unit at King's College Hospital with ALF were recruited, with healthy control (HC) individuals and acute-on-chronic liver failure (ACLF) used as controls. INTERVENTION: None. MEASUREMENTS: Average shear wave velocity was recorded with ElastPQ on the right and left liver lobes and the spleen. Portal vein flow, hepatic artery resistive index, and peak systolic velocity were also recorded. Physiologic and histologic data were used for comparison. MAIN RESULTS: Forty patients with ALF, 22 patients with ACLF, and 9 HC individuals were included in the study. At admission, liver stiffness measurement (LSM) of the right lobe was statistically different between HC individuals (5.6 ± 2 kPa), ALF (31.7 ± 17 kPa), and ACLF (76.3 ± 71 kPa) patients (ALF vs. ACLF, p = 0.0301). Spleen size and stiffness discriminated between ALF (10.4 ± 2 cm and 21.4 ± 16.6 kPa) and ACLF (14 ± 2.3 cm and 42.6 ± 26 kPa). At admission, LSM was not different between ALF patients who spontaneously survived versus patients who died or were transplanted in the following 90 days. However, the trend over the first 10 days of admission was different with a peak of LSM at day 5 in spontaneous survivors followed by reduction during the recovery phase. ALF patients with poor prognosis showed a persistently increased LSM. CONCLUSIONS: In ALF stiffness peaks at day 5 of admission with subsequent reduction in patients spontaneously surviving, showing significant difference according to the prognosis at day 7 of admission. LSM might be useful in distinguishing acute from acute-on-chronic liver failure together with spleen volume and stiffness.

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls. CONCLUSION: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. IMPACT AND IMPLICATIONS: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids.

Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

Systematic review and meta-analysis of tumour microsatellite-instability status as a predictor of response to fluorouracil-based adjuvant chemotherapy in colorectal cancer.

PURPOSE: Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours. AIMS: To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU. METHODS: A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan-Meier curves. Publication bias was assessed using funnel-plots and Egger's test. RESULTS: 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage. CONCLUSIONS: In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy.

Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). CONCLUSION: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02019784. LAY SUMMARY: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection.

Association of cardiometabolic microRNAs with COVID-19 severity and mortality.

AIMS: Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. METHODS AND RESULTS: We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. CONCLUSION: Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. METHODS: We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. RESULTS: Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. CONCLUSIONS: Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY: While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

Faecal cytokine profiling as a marker of intestinal inflammation in acutely decompensated cirrhosis.

BACKGROUND & AIMS: Gut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers. METHODS: Faeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), d-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed. RESULTS: Faecal (F) IL-1ß, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD vs. SC (q <0.01). F-IL-23 was significantly elevated in AD vs. HC (p = 0.0007). FABP2/d-lactate were significantly increased in faeces in AD vs. SC and AD vs. HC (p <0.0001) and in plasma (p = 0.0004; p = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; p <0.0001; model for end-stage liver disease 0.488; p <0.0001). FCAL correlated with plasma IL-21, IL-1ß, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC. CONCLUSIONS: FC profiling represents an innovative approach to investigating the localised intestinal cytokine micro-environment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of TH1/TH17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation. LAY SUMMARY: The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.

Leucocyte ratios are biomarkers of mortality in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.

BACKGROUND: In patients with cirrhosis, progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF) has been associated with poor prognosis. Differential leucocyte ratios might predict mortality in systemic inflammatory conditions. AIM: To evaluate differential leucocyte ratios as prognostic biomarkers in patients with cirrhosis. METHODS: Patients with AD and ACLF were recruited from four centres in three countries. Peripheral blood differential leucocytes were measured (three centres using flow cytometry) on hospital admission and at 48 hours. Ratios were correlated to model for end-stage liver disease (MELD), chronic liver failure-sequential organ failure (CLIF-SOFA), suspected/culture-positive bacterial infection and survival. RESULTS: Nine hundred twenty-six patients (562 (61%) male, median age 55 (25-94) years) were studied. Overall, 350 (37%) did not survive to hospital discharge. Neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) were elevated in patients with AD and ACLF who died during their hospital stay. On multivariate analysis NLR retained statistical significance independently of CLIF-SOFA or MELD. NLR >30 was associated with an 80% 90-day mortality in patients with ACLF but not AD. On sensitivity analysis for subgroups (alcohol-related liver disease and suspected sepsis), NLR and MLR retained statistically robust accuracy for the prediction of mortality. Significant predictive accuracy was only observed in centres using flow cytometry. CONCLUSION: Leucocyte ratios are simple and robust biomarkers of outcome in ACLF, which are comparable to CLIF-SOFA score but dependent on leucocyte quantification method. NLR and MLR may be used as screening tools for mortality prediction in patients with acutely deteriorating cirrhosis.

Serum MicroRNA Signatures in Recovery From Acute and Chronic Liver Injury and Selection for Liver Transplantation.

We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease.

2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia.

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo, and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis.

A 'real-world' analysis of risk factors for post liver transplant delirium and the effect on length of stay.

BACKGROUND: The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS). METHODS: All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records. RESULTS: Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure. CONCLUSION: Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. MATERIALS AND METHODS: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. RESULTS: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) µg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. CONCLUSIONS: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

L-Ornithine L-Aspartate (LOLA) for Hepatic Encephalopathy in Cirrhosis: Results of Randomized Controlled Trials and Meta-Analyses.

This manuscript represents an appraisal of the evidence in support of L-ornithine-L-aspartate (LOLA) for the management and treatment of hepatic encephalopathy (HE) in cirrhosis. Meta-analyses of randomized controlled trials (RCTs) conducted over the last two decades generally reveal evidence of benefit of LOLA in a range of clinical presentations. This included improvement of mental state grade in overt HE (OHE) assessed by West Haven criteria as well as in minimal HE (MHE) assessed by psychometric testing where the oral formulation of LOLA was determined to be particularly effective. However, concerns over study quality were noted in one meta-analysis. Nevertheless, the concomitant lowering of fasting blood ammonia was reported in all RCTs using this endpoint. Network meta-analyses showed that LOLA appears to be comparable (or superior) in efficacy to non-absorbable disaccharides or probiotics. Emerging evidence from single RCTs show efficacy of LOLA for the treatment of post-transjugular intrahepatic portosystemic shunt (TIPSS) HE as well as for secondary HE prophylaxis. These findings provide support for the use of LOLA in the treatment of HE and future trials should focus on the use of LOLA for prophylaxis.

Update on the management of acute liver failure.

PURPOSE OF REVIEW: This review describes the current intensive care management of acute liver failure (ALF) and the latest evidence for emerging therapies. RECENT FINDINGS: Mortality from ALF continues to improve and in some cases, medical therapy can negate the need for liver transplantation because of protocolized management in specialist centres. Liver transplantation remains the cornerstone of management for poor prognosis ALF. The reduced use of blood products in ALF reflects growing evidence of balanced haemostasis in severe liver disease. Prophylactic therapeutic hypothermia is no longer recommended for neuroprotection. In cases not suitable for liver transplantation, high-volume plasma exchange (HVP) has potential benefit, although further research on the optimal timing and dosing is needed. Although sepsis remains an important complication in ALF, the use of prophylactic antimicrobials is being questioned in the era of emerging bacterial resistance. SUMMARY: ICU management of ALF has improved such that liver transplantation is not required in some cases. HVP has emerged as a potential therapy for patients who may not be good liver transplantation candidates. Nevertheless in suitable patients with poor prognosis liver transplantation remains the optimal therapy.

Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/OBJECTIVES: l-Ornithine l-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its' efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE. METHODS: Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI). RESULTS: 10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10-1.69), p = 0.005), OHE (RR: 1.19, 95% CI of 1.01-1.39, test for overall effect: Z = 2.14, p = 0.03), MHE (RR: 2.15 (1.48-3.14), p < 0.0001) and for lowering of blood ammonia (MD: -17.50 µmol/l (-27.73 to (-7.26)), p = 0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE. CONCLUSION: LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.