Neurofilament light chain but not glial fibrillary acidic protein is a potential biomarker of overt hepatic encephalopathy in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE). MATERIALS AND METHODS: We included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays. RESULTS: ICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each). CONCLUSIONS: Plasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score.

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy.

Low plasma levels of branched chain amino acids (BCAA) in liver cirrhosis are associated with hepatic encephalopathy (HE). We aimed to identify a metabolic signature of minimal hepatic encephalopathy (MHE) in malnourished cirrhotic patients and evaluate its modification with oral nutritional supplements (ONS) enriched with ß-Hydroxy-ß-methylbutyrate (HMB), a derivative of the BCAA leucine. Post hoc analysis was conducted on a double-blind placebo-controlled trial of 43 individuals with cirrhosis and malnutrition, who were randomized to receive, for 12 weeks, oral supplementation twice a day with either 220 mL of Ensure® Plus Advance (HMB group, n = 22) or with 220 mL of Ensure® Plus High Protein (HP group, n = 21). MHE evaluation was by psychometric hepatic encephalopathy score (PHES). Compared to the HP group, an HMB-specific treatment effect led to a larger increase in Val, Leu, Phe, Trp and BCAA fasting plasma levels. Both treatments increased Fischer's ratio and urea without an increase in Gln or ammonia fasting plasma levels. MHE was associated with a reduced total plasma amino acid concentration, a reduced BCAA and Fischer´s ratio, and an increased Gln/Glu ratio. HMB-enriched ONS increased Fischer´s ratio without varying Gln or ammonia plasma levels in liver cirrhosis and malnutrition, a protective amino acid profile that can help prevent MHE.

Prediction of minimal hepatic encephalopathy by using an radiomics nomogram in chronic hepatic schistosomiasis patients.

OBJECTIVE: To construct an MR-radiomics nomogram to predict minimal hepatic encephalopathy (MHE) in patients with chronic hepatic schistosomiasis (CHS). METHODS: From July 2017 to July 2020, 236 CHS patients with non-HE (n = 140) and MHE (n = 96) were retrospective collected and randomly divided into training group and testing group. Radiomics features were extracted from substantia nigra-striatum system of a brain diffusion weighted images (DWI) and combined with clinical predictors to build a radiomics nomogram for predicting MHE in CHS patients. The ROC curve was used to evaluate the predicting performance in training group and testing group. The clinical decisive curve (CDC) was used to assess the clinical net benefit of using radiomics nomogram in predicting MHE. RESULTS: Low seralbumin (P < 0.05), low platelet count (P < 0.05) and high plasma ammonia (P < 0.05) was the significant clinical predictors for MHE in CHS patients. The AUC, specificity and sensitivity of the radiomics nomogram were 0.89, 0.90 and 0.86 in the training group, and were 0.83, 0.85 and 0.75 in the training group. The CDC analysis showed clinical net benefits for the radiomics nomogram in predicting MHE. CONCLUSIONS: The radiomics nomogram combining DWI radiomics features and clinical predictors could be useful tool to predict MHE in CHS patients.

Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

INTRODUCTION: Serum biomarkers for the diagnosis of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis would be desirable. In this proof-of-concept study, we investigated the association between MHE and serum levels of neurofilament light chains (sNfL) in patients with liver cirrhosis. METHODS: sNfL were studied in patients with liver cirrhosis (with or without MHE) and controls (patients with ischemic stroke, transitory ischemic attack, and healthy individuals). MHE was diagnosed using the Psychometric Hepatic Encephalopathy Score. RESULTS: Patients with MHE showed higher sNfL than patients without MHE and controls. In multivariable analyses, higher sNfL were independently associated with the presence of MHE. sNfL had a reliable discriminative power for the detection of MHE with an area under the curve of 0.872. DISCUSSION: MHE is associated with higher sNfL.

Predictive Value of the Serum Matrix Metalloproteinase-9 Level on Hepatic Encephalopathy in Patients with Chronic Liver Disease.

BACKGROUND: Early diagnosis of hepatic encephalopathy (HE) in chronic liver disease (CLD) is difficult clinically. OBJECTIVE: The aim of this study was to evaluate whether serum matrix metalloproteinase-9 (MMP-9) levels could identify early HE in patients with CLD. METHODS: Serum MMP-9 levels in 1,187 patients with CLD were measured at baseline. A total of 1,187 patients with CLD were followed for a mean of 48 months (range: 4-50). The association between MMP-9 and the risk of HE was evaluated by logistic regression analysis and Cox regression analysis. RESULTS: Patients with higher serum MMP-9 levels had higher rates of HE history and HE events during follow-up (all P<0.001). The multivariate logistic regression analysis revealed that MMP-9 (OR=2.84, 95% CI 1.63-7.11, P=0.004) was independently associated with HE history, with an increased grade of aggravation on liver fibrosis at baseline. Multivariate Cox proportional hazard analysis revealed that MMP-9 (HR=2.21, 95% CI 1.09-5.02, P<0.001) was an independent predictor for HE events by sensitivity analysis. The Kaplan-Meier analysis demonstrated that patients with MMP-9 above the median value (176.2 mg/d) had a higher rate of new HE events than patients who had MMP-9 levels below the median value (P<0.001). CONCLUSIONS: Elevated serum RBP4 levels were associated with a higher risk of HE events during follow-up. These results may suggest that serum MMP-9 has good predictive value for detecting HE in patients with CLD, which provides some clinical reference value to clinicians for the early diagnosis of HE.

Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE.

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

Sociodemographic characteristics, complications requiring hospital admission and causes of in-hospital death in patients with liver cirrhosis admitted at a district hospital in Ghana.

BACKGROUND: Chronic liver diseases including liver cirrhosis are a major cause of morbidity and mortality globally. Despite the high burden of liver cirrhosis in Ghana, data on this disease is lacking. OBJECTIVE: To determine the sociodemographic characteristics, reasons for admission, and in-hospital mortality of patients with cirrhosis of the liver seen at a district hospital in Ghana. METHODS: A prospective study was conducted involving one hundred and eighty-six (186) patients admitted on the medical wards in St. Dominic hospital with liver cirrhosis from 1st January 2018 to 24th June 2020. The patient's demographic and clinical features were documented using a standardized questionnaire. Diagnostic biochemical and haematological tests as well as abdominal ultrasound scans were performed for all patients. They were followed up until death or discharge from hospital. RESULTS: One hundred and eighty-six patients (186) with a median age of 46 years were included in the study. HBV was the main etiology of liver cirrhosis (38.7%) followed closely by alcohol consumption (38.3%). In-hospital mortality was 41.3% and the most frequent cause of death was hepatic encephalopathy (68.4%). The following were associated with death; Jaundice, weight loss, elevated bilirubin, international normalized ratio (INR), creatinine, blood urea nitrogen(BUN), Child-Pugh score, model for end-stage liver disease sodium score (MELDNa), and low sodium. However, hepatic encephalopathy, MELDNa, INR and BUN were independent predictors of in-hospital mortality on logistic regression analysis. CONCLUSIONS: In-hospital mortality in cirrhotic patients was high with the leading cause of death being hepatic encephalopathy. Timely diagnosis and adequate management of hepatic encephalopathy are necessary to prevent death from liver cirrhosis.

Amelioration of Hepatic Encephalopathy Using Dunaliella salina Microalgae in Rats: Modulation of Hyperammonemia/TLR4.

Hepatic encephalopathy (HE) is a neuropsychiatric disease that is developed as a complication of both acute and chronic liver failure affecting psychomotor dysfunction, memory, and concentration. This study is aimed at evaluating the therapeutic effects of Dunaliella salina (D. salina) microalgae in thioacetamide- (TAA-) induced HE in rats. HE was induced by TAA (200 mg/kg; i.p.) for three successive days. Forty male Wister albino rats were divided into 4 groups; the first group was served as a normal, and the second group was injected with TAA and served as TAA control. The third and fourth groups were administered D. salina (100 and 200 mg/kg; p.o.), respectively, after TAA injection for 7 days. The behavioral and biochemical markers as well as histological aspects of HE were estimated. This study revealed that TAA caused behavioral changes, oxidative stress, neuroinflammation, nuclear pyknosis, and neurons degeneration. D. salina improved liver function and decreased oxidative stress and inflammatory mediator as TLR4 protein expression. Also, D. salina elevated HSP-25 and IGF-1 as well as improved brain histopathological alterations. In conclusion, D. salina exerted a therapeutic potential against HE via its antioxidant, antiinflammatory and cytoprotective effects.

Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients.

Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE. Transcriptomic analysis supports the hypothesis of alternations in the Th1/Th2 and Th17 lymphocytes cell populations as major drivers of MHE. Cluster analysis of serum molecules resulted in six groups of chemically similar compounds, suggesting that functional modules operate during the induction of MHE. Finally, the multi-omic integrative analysis suggested a relationship between cytokines CCL20, CX3CL1, CXCL13, IL-15, IL-22 and IL-6 with alteration in chemotaxis, as well as a link between long-chain unsaturated phospholipids and the increased fatty acid transport and prostaglandin production. We found altered immune pathways that may collectively contribute to the mild cognitive impairment phenotype in MHE. Our approach is able to combine extracellular and intracellular information, opening new insights to the understanding of the disease.

In vitro and in vivo Evaluation of Succinic Acid-Substituted Mesoporous Silica for Ammonia Adsorption: Potential Application in the Management of Hepatic Encephalopathy.

PURPOSE: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4 +) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4 + is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4 + levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons). METHODS: First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4 + was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH4 +, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model. RESULTS: It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4 + in the in vitro model. However, the NH4 + scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model. CONCLUSION: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.

Changes of Coenzyme A and Acetyl-Coenzyme A Concentrations in Rats after a Single-Dose Intraperitoneal Injection of Hepatotoxic Thioacetamide Are Not Consistent with Rapid Recovery.

Small biomolecules, such as coenzyme A (CoA) and acetyl coenzyme A (acetyl-CoA), play vital roles in the regulation of cellular energy metabolism. In this paper, we evaluated the delayed effect of the potent hepatotoxin thioacetamide (TAA) on the concentrations of CoA and acetyl-CoA in plasma and in different rat tissues. Administration of TAA negatively affects liver function and leads to the development of hepatic encephalopathy (HE). In our experiments, rats were administered a single intraperitoneal injection of TAA at doses of 200, 400, or 600 mg/kg. Plasma, liver, kidney, and brain samples were collected six days after the TAA administration, a period that has been suggested to allow for restoration of liver function. The concentrations of CoA and acetyl-CoA in the group of rats exposed to different doses of TAA were compared to those observed in healthy rats. The results obtained indicate that even a single administration of TAA to rats is sufficient to alter the physiological balance of CoA and acetyl-CoA in the plasma and tissues of rats for an extended period of time. The initial concentrations of CoA and acetyl-CoA were not restored even after the completion of the liver regeneration process.

Association between diabetes mellitus and hepatic encephalopathy in patients with cirrhosis.

BACKGROUND: Diabetes mellitus may lead to increased serum ammonia and systemic inflammation thereby promoting hepatic encephalopathy (HE). AIM: To investigate the potential association between diabetes mellitus/glycaemic control and the presence of covert HE as well as the development of overt HE in a prospective setting. METHODS: A total of 240 patients with liver cirrhosis were included into this prospective cohort study and followed for a median of 17 months. Covert HE was diagnosed by pathological results in the Portosystemic Hepatic Encephalopathy Score. Predictors for the presence of covert HE or the development of overt HE were analysed using logistic regression or Cox-regression models. RESULTS: At study inclusion, 65 patients (27.1%) presented with diabetes mellitus and covert HE was detected in 33.3%. Patients with diabetes mellitus had a more preserved liver function as compared to patients without diabetes mellitus (MELD 9 vs 10; P = 0.043). In regression analyses after adjustment for confounders, diabetes mellitus was independently associated with the presence of covert HE at study inclusion and the development of overt HE during follow-up. These associations were confirmed in separate propensity-score-weighted regression models. In subgroup analyses, patients with worse glycaemic control (HbA1c >= 6.5%) had a pronounced risk for covert HE (OR 2.264, 95% CI 1.002-5.118) and overt HE (HR 4.116, 95% CI 1.791-9.459). CONCLUSIONS: Diabetes mellitus may associate with higher risk for the presence of covert HE and the development of overt HE in patients with liver cirrhosis. Adequate glycaemic control may be a potential target to attenuate this important complication.

Longitudinal osmotic and neurometabolic changes in young rats with chronic cholestatic liver disease.

Type C hepatic encephalopathy (type C HE) is increasingly suspected in children with chronic liver disease (CLD), and believed to underlie long-term neurocognitive difficulties. The molecular underpinnings of type C HE in both adults and children are incompletely understood. In the present study we combined the experimental advantages of in vivo high field 1H magnetic resonance spectroscopy with immunohistochemistry to follow longitudinally over 8 weeks the neurometabolic changes in the hippocampus of animals having undergone bile duct ligation as pups. Rats who develop CLD early in life displayed pronounced neurometabolic changes in the hippocampus characterized by a progressive increase in glutamine concentration which correlated with plasma ammonia levels and a rapid decrease in brain myo-inositol. Other neurometabolic findings included a decrease in other organic osmolytes (taurine, choline-containing compounds and creatine), ascorbate and glutamate. At the cellular level, we observed an increase in glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) expression in the hippocampus at 4 weeks post bile duct ligation (BDL), together with astrocytic morphological alterations. These findings differ from observations in the brain of adult rats following BDL, and are in keeping with the commonly accepted theory of age-dependent vulnerability.

High-mobility group protein B1: A predictive biomarker for hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.

BACKGROUND: The aim of the present study was to investigate whether portal level of high-mobility group protein B1 (HMGB1) is associated with hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We enrolled 127 consecutive patients who underwent TIPS and collected portal and peripheral blood samples in our department from December 2017 to May 2019. HMGB1 levels were determined using enzyme-linked immunosorbent assay kits. HMGB1 and other HE related parameters were estimated by competing risk analysis, receiver operating characteristic (ROC) analysis and Kaplan-Meier analysis. RESULTS: Patients with HE after TIPS were older (P = .019) and had higher portal HMGB1 level (P = .038) than those without. Univariate competing risk analysis: age (sHR 1.025, P = .026), hepatorenal syndrome (sHR 3.149, P = .010), model for end-of-stage liver disease (MELD) score (sHR 1.055, P = .024), prior HE (sHR 4.029, P = .0005), portal HMGB1 before TIPS (sHR 1.177, P = .001) reached statistical significance. Multivariate analysis: age (sHR 1.025, P = .037), MELD score (sHR 1.062, P = .011), prior HE (sHR 2.492, P = .030) and portal HMGB1 level before TIPS (sHR 1.217, P = .0002) were significantly different. ROC analyses and Kaplan-Meier curve showed portal HMGB1 level changes before and after TIPS (ΔHMGB1) had good predictive value in the cut-off 0.012 ng/mL (AUC = 0.748, P < .001, Sensitivity = 0.743, Specificity = 0.655). CONCLUSIONS: Portal HMGB1 may be a therapeutic target for post-TIPS HE.

Systemic Oxidative Stress Markers in Cirrhotic Patients with Hepatic Encephalopathy: Possible Connections with Systemic Ammoniemia.

Background and objectives: Oxidative stress shows evidence of dysregulation in cirrhotic patients with hepatic encephalopathy (HE), although there are still controversies regarding the connections between oxidative stress and ammonia in these patients. The aim of this study was to evaluate the oxidative stress implication in overt HE pathogenesis of cirrhotic patients. Materials and Methods: We performed a prospective case-control study, which included 40 patients divided into two groups: group A consisted of 20 cirrhotic patients with HE and increased systemic ammoniemia, and group B consisted of 20 cirrhotic patients with HE and normal systemic ammoniemia. The control group consisted of 21 healthy subjects matched by age and sex. The activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) levels (lipid peroxidation marker), and ammoniemia were evaluated. Results: We found a significant decrease in SOD and GPx activity and also a significant increase of MDA levels in cirrhotic patients with HE as compared to the healthy age-matched control group (1.35 ± 0.08 vs. 0.90 ± 0.08 U/mL, p = 0.002; 0.093 ± 0.06 vs. 0.006 ± 0.008 U/mL, p = 0.001; and 35.94 ± 1.37 vs. 68.90 ± 5.68 nmols/mL, p = 0.0001, respectively). Additionally, we found significant correlations between the main oxidative stress markers and the levels of systemic ammonia (r = 0.452, p = 0.005). Patients from group A had a significant increase of MDA as compared with those from group B (76.93 ± 5.48 vs. 50.06 ± 5.60 nmols/mL, p = 0.019). Also, there was a compensatory increase in the activity of both antioxidant enzymes (SOD and GPx) in patients with increased systemic ammoniemia (group A), as compared to HE patients from group B. Conclusions: Our results demonstrated a significant decrease in antioxidants enzymes activities (SOD and GPx), as well as a significant increase in MDA concentrations, adding new data regarding the influence of oxidative stress in HE pathogenesis in cirrhotic patients.

The Molar Ratio of Total Branched-chain Amino Acids to Tyrosine Predicts a Digit Symbol Test Abnormality in Cirrhotic Patients.

Objective We aimed to investigate the association between the digit symbol test (DST) and clinical characteristics, including the nutritional status of liver cirrhosis patients. Methods Fifty-nine cirrhotic patients without a history of overt hepatic encephalopathy were retrospectively evaluated. We examined neuropsychological abnormalities (NPAs) using the DST. We also estimated the detailed nutritional status using the Food Frequency Questionnaire (FFQ). The patients were divided into two groups according to their DST status: patients with normal DST scores (DST-Nor group, n=45) and those with abnormal DST scores (DST-Abn group, n=14). The clinical and nutritional findings of the two groups were compared. Results Overall, 14 (23.7%) patients had a DST abnormality. There were significant differences between the two groups in serum albumin (Alb; p=0.0043), valine (Val; p=0.0016), leucine (Leu; p=0.0078), isoleucine (Ile; p=0.0022), the molar ratio of total branched-chain amino acids to tyrosine (BTR; p=0.00025), total-bilirubin (T-Bil; p=0.0071), prothrombin time (%) (PT; p=0.028), and serum sodium (Na; p=0.035). A multivariate analysis found the BTR to be the only independent predictor of a DST abnormality (hazard ratio, 9.24; p<0.031). An FFQ analysis, revealed that the nutritional findings of patients with and without a DST abnormality, were similar. Conclusion The BTR was useful for predicting the risk of NPAs, as defined by a DST abnormality. The risk of NPAs may be estimated by monitoring the BTR.

Pathophysiology of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is one of the major clinical decompensations of cirrhosis, with a high impact on health care resource utilization and cost. For an effective and comprehensive management of HE, the clinicians need to understand the pathophysiologic mechanisms of HE. This review describes the multiorgan processes involved in HE and how several HE precipitants and treatment strategies act on ammonia production, excretion, and neurotoxicity, including the impact of diabetes and use of cannabinoids. The authors also discuss the current and future role of gut microbiome, systemic/central inflammation, and various neurotransmitters for the pathogenesis and treatment of HE.

Laboratory Abnormalities of Hepatic Encephalopathy.

Currently, there is no gold standard serologic or imaging modality to detect hepatic encephalopathy (HE). It is a clinical diagnosis gathered from the history and physical. Imaging is nonspecific; however, PET and MRI have shown areas of utility, but are not widely available, cost-efficient, or necessary for diagnosis. Electroencephalogram has shown promise as it can be used in conjunction with the Portal Systemic Hepatic Encephalopathy Score test to diagnose minimal HE. Further research on these techniques would need to be performed to identify strict criteria and cutoffs for diagnosing HE as well as associated sensitivities and specificities.

Novel Therapies in Hepatic Encephalopathy.

Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.