Progression Of Hepatic Encephalopathy Research Articles

Association Of Electroencephalogram Patterns With Ammonia Levels In Hepatic Encephalopathy Patients

Objective: To find out the association between electroencephalogram (EEG) and hepatic encephalopathy.
 Methodology: This cross-sectional study included 100 patients (with the age of52.5±6.09years for males and 51.7 ± 6.10 years for females) of reported hepatic encephalopathy, visiting the medical department (indoor and OPD) at Federal Government Polyclinic Hospital, Islamabad. The study was conducted from January 2020 to May 2021. Patients who had known epileptic and structural brain lesions or strokes were excluded from the study. Statistical analysis was done using GraphPad Prism software. The significance of data (p-value or R2 value) was calculated through a two-tailed test or correlation coefficient.
 Results: All the patients in hepatic encephalopathy grade IV reported abnormal EEG representing triphasic waves and flattening of EEG pattern. There was no correlation observed between age, gender and hepatic encephalopathy grades. However, a significant correlation (R2= 0.9032) was observed between serum ammonia levels and hepatic encephalopathy grades. Elevated serum ammonia levels depicted the severity of hepatic encephalopathy. Overall, the percentage of patients with abnormal EEG increased with increasing grade of hepatic encephalopathy. It was quite intriguing to note that EEG, being the common method to diagnose hepatic encephalopathy grades, is not dependent on patients’ socio-economic status.
 Conclusion: Data concluded that serum ammonia levels are well associated with the progression of hepatic encephalopathy. Moreover, the EEG patter provides the appropriate information about the neurological abnormalities associated with the severity of hepatic encephalopathy. Hence, serum ammonia levels and EEG both should accurately be used as indicators for diagnosis and monitoring the response to the treatment of various grades of hepatic encephalopathy. Data warrant further investigations to get a better insight into hepatic encephalopathy's relationship with EEG patterns through the inclusion of molecular parameters.

The role of albumin replacement therapy in the treatment of hepatic encephalopathy in patients with liver cirrhosis

Introduction. It is often observed that decompensated liver cirrhosis is accompanied by hepatic encephalopathy. The role of violation of the structural and functional properties of albumin in the development of this pathology is currently not defined.Aim. Was to evaluate the effect of albumin replacement therapy on the clinical manifestations of hepatic encephalopathy and the severity of structural and functional changes in serum albumin.Materials and methods. The study included 28 adult patients with decompensated cirrhosis and hepatic encephalopathy divided into two comparable groups. In addition to the standard examination, the properties of the albumin molecule were evaluated using the EPR test. The dynamics of indicators was assessed in the groups of standard treatment and standard treatment + albumin. Mathematical processing was carried out in the StatTech v. 3.1.4 (developer Stattech LLC, Russia).Results and discussion. It was revealed that patients with decompensated liver cirrhosis have serious disturbances in the albumin configuration, which lead to a decrease in its functional activity. The ability to bind, transport and detoxify were impaired in the vast majority of patients. The native conformation of the molecule was abnormal in all patients. Against the background of albumin replacement therapy, these disorders are able to recover to normal values. Along with this, we found that albumin replacement therapy reduced the severity of hepatic encephalopathy to a greater extent than standard treatment.Conclusion. Violation of the structural and functional albumin properties is associated with the progression of hepatic encephalopathy in patients with liver cirrhosis. Transfusions of highly concentrated human albumin lead to the normalization of the molecule properties and the encephalopathy regression.

МОДИФИЦИРОВАННОЕ ТРАНСЪЮГУЛЯРНОЕ ВНУТРИПЕЧЕНОЧНОЕ ПОРТОСИСТЕМНОЕ ШУНТИРОВАНИЕ В СОЧЕТАНИИ С ПОСЛЕОПЕРАЦИОННОЙ АУТОГЕМОМАГНИТОТЕРАПИЕЙ

Topicality. The transjugular intrahepatic portosystemic shunt (TIPS) is widely used in the treatment of portal hypertension. However, this procedure has several major potential complications, which include hepatic encephalopathy as well as shunt dysfunction. In this connection, the development of TIPS modifications aimed at reducing the incidence of complications after this procedure seems relevant. Purpose of the study. To study the results of a modified portal vein puncture method, depending on its variant anatomy, as well as the combined use of autohemomagnetotherapy to prevent shunt thrombosis and progression of hepatic encephalopathy during TIPS. Materials and methods. In the course of a prospective randomized controlled study in the period from 2014 to 2020, the results of treatment of 37 patients were studied. Modification of the standard TIPS procedure was performed in the main group of patients: the choice of the optimal puncture point of the portal vein was carried out on the basis of the anatomical variant of the divergence of the right anterior branch of the failures and complications. Autohemomagnetotherapy was performed in the same group after performing transjugular intrahepatic portosystemic shunting daily for 5 days. Results and discussion. It was noted that the anatomical variant of the portal vein structure affects the success of TIPS (the correlation coefficient of the variant anatomical type of portal vein branching and the occurrence of technical difficulties in the group of the standard TIPS technique R = 0.81, p = 0.000003). The proposed method of puncture of the portal vein is quite effective for the prevention of this complication. When using the modified TIPS, significantly less progression of hepatic encephalopathy was noted compared to the standard technique. The proposed method allows for the prevention of early thrombosis of shunts and recurrent bleeding from varicose veins of the esophagus and stomach. Conclusions. The proposed modified method of transjugular portosystemic shunting is effective, available and can be widely used in clinical practice.

Hepatic Encephalopathy in Patients with Liver Cirrhosis before and after TIPS

Aim. To analyze the dynamics of hepatic encephalopathy after transjugular intrahepatic portosystemic shunting (TIPS). Material and Methods. It was analyzed the results of complex survey of 52 patients who underwent TIPS. Self-expanding stents 8–10 cm, diameter of 8–10 mm and stent-graft were applied for portosystemic shunt creation. Results. The two main complications of TIPS are hepatic encephalopathy progression and shunt’s malfunction. The increased degree of portosystemic encephalopathy in 18 months postoperatively was revealed in 3 (10%) patients. Symptoms of encephalopathy were eliminated and did not effect on the patients’ life quality after discharge. Conclusion. Assessment of encephalopathy’s degree and individual therapy in each patient significantly decrease the severity of encephalopathy postoperatively followed by improved life quality

Evaluation of efficacy and safety of interferon-free “3D” regimen among patients with non-compensated cirrhosis caused by HCV genotype 1b infection

Objective:The first interferon-free regimen became available in Russia in 2015. It brought hope to HCV Gt1 patients with cirrhosis for whom interferon-based schemes found to be non-effective or contraindicated. 3D therapy was the only available etiotropic option for them. New safety data published after the start of our study significantly limited usage of this regimen among patients with non-compensated cirrhosis. The aim of this study was to evaluate efficacy and safety of the 3D interferon-free regimen among HCV Gt1b patients with non-compensated cirrhosis.Method:66 patients (26 males and 40 females) with HCV Gt1b and non-compensated cirrhosis were enrolled. All of them were treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin for 12 weeks. Ribavirin was discontinued after 4 weeks of therapy due to onset of new data on the efficacy of 3D regimen without ribavirin in Turquoise III study published in September 2015 before the change of package insert. Child-Pugh score was assessed before the start of antiviral therapy as follows: 21 patients (31,8%) – 9 points, 11 patients (16,7%) – 8 points, 34 patients (51,5%) – 7 points. The key method used to evaluate study results was modified intent-to-treat (mITT) analysis because number of analyzed patients within treatment period changed after withdrawal caused by safety reasons but followed by assessment of efficacy among patients who discontinued treatment. Per protocol (PP) method was also used in addition to mITT.Results:Aviremia after 14 days of treatment was reached among 35 out of 65 patients (53,8%), rapid virologic response – among 79,7% patients (51/64). Each patient who received full 12-week course of treatment (n=60) including those who discontinued due to safety reasons (n=3) between 14th and 30th days of therapy reached SVR12 and SVR24. Assessment of Child-Pugh score in 6 months after EOT demonstrated decrease by 3-4 points among 21 patients (33,9%) and by 1-2 points among 35 patients. 66,1% patients reached clinical improvement in MELD score. Treatment discontinuation was caused by progression of hepatic encephalopathy and/or jaundice (4 cases). Those adverse events regressed among majority of patients after discontinuation of therapy. 3 deaths were reported (bacterial endocarditis, progression of hepatic encephalopathy and bleeding from gastric ulcers) during treatment period and 1 death in follow-up period due to progression of hepatocellular carcinoma.Conclusion:3D therapy was effective in 100% patients (mITT) with HCV GT1b and non-compensated cirrhosis both among those who completed full therapy course and those who discontinued the therapy due to safety reasons. Safety analysis demonstrated that the rate of severe adverse events was comparable with natural course of HCV-infection in patients on non-compensated cirrhotic stage without antiviral treatment.

Effects of N‐acetylcysteine on cytokines in non‐acetaminophen acute liver failure: potential mechanism of improvement in transplant‐free survival

N-Acetylcysteine (NAC) improves transplant-free survival in patients with non-acetaminophen acute liver failure (ALF) when administered in early stages of hepatic encephalopathy. The mechanisms of this benefit are unknown. To determine whether NAC improves transplant-free survival in ALF by ameliorating the surge of pro-inflammatory cytokines. Serum samples were obtained from 78 participants of the randomized, ALF Study Group NAC Trial with grade 1 or 2 hepatic encephalopathy on randomization. Concentrations of ten cytokines, chosen to represent a wide array of inflammatory responses, were determined by multiplex enzyme-linked immunosorbent assay ELISA. In univariate analysis, predictors of transplant-free survival included NAC administration (P=0.012), admission bilirubin (P=0.003), international normalized ratio INR (P=0.0002), grade 1 vs. grade 2 encephalopathy (P=0.006) and lower admission interleukin (IL)-17 concentrations (P=0.011). IL-17 levels were higher in patients with grade 2 vs. grade 1 encephalopathy on randomization (P=0.007) and in those who progressed to grade 3 or grade 4 encephalopathy over the following 7days (P≤0.01). Stepwise multivariate logistic regression analysis identified only NAC administration and lower IL-17 concentrations as independent predictors of transplant-free survival. In patients with detectable IL-17 concentrations on admission, 78% of those who received NAC vs. 44% of those who received placebo had undetectable levels by day 3-5 (P=0.042), and the mean decrease in IL-17 concentrations between admission and late samples was significantly greater in patients who received NAC vs. placebo (P=0.045). N-acetylcysteine (NAC) may improve transplant-free survival in patients with non-acetaminophen ALF by ameliorating the production of IL-17, which is associated with progression of hepatic encephalopathy and poor outcome.

Altered Resting-State Brain Activity at Functional MR Imaging during the Progression of Hepatic Encephalopathy

To explore the spatial patterns of the amplitude of low-frequency fluctuation (ALFF) in patients with hepatic encephalopathy (HE) of varying severity and to correlate these fluctuations with clinical markers of HE. This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Twenty-nine patients with HE (15 with overt and 14 with minimal HE) and 17 healthy control subjects underwent resting-state functional magnetic resonance (MR) imaging. The ALFF, an index reflecting the amplitudes of spontaneous brain activity, was compared among patients with overt HE, patients with minimal HE, and control subjects with analysis of variance tests and t tests between each pair. Pearson correlation analysis was performed between the ALFF and the venous blood ammonia level and Child-Pugh score of all patients with HE. Compared with control subjects, patients with overt and minimal HE showed decreased ALFF mainly in regions within the default-mode network (DMN) and increased ALFF in the cerebellum and middle temporal gyrus. Compared with patients with minimal HE, those with overt HE showed decreased ALFF in DMN regions and increased ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Both the venous blood ammonia levels and Child-Pugh scores of individual patients with HE showed negative correlation with ALFF within some DMN regions, whereas they showed positive correlation with ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Patients with HE have diffuse abnormalities in intrinsic brain activity. The levels of decreased ALFF in the DMN and increased ALFF in the posterior insular cortex are dependent on the severity of HE, suggesting continuous impairment of the DMN and a compensatory role of the insula during the progression of HE. Resting-state functional MR imaging with ALFF analysis may be a noninvasive modality with which to detect the progression of HE.

Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.

Upregulation of α-synuclein expression in the rat cerebellum in experimental hepatic encephalopathy

The overexpression of alpha-synuclein has been associated with neurodegenerative diseases, especially when the protein aggregates to form insoluble structures. The present study examined the effect of chronic hyperammonaemia on alpha-synuclein expression in the rat cerebellum following portacaval anastomosis (PCA). Immunohistochemical and western blot determinations were performed 1 month and 6 months after the PCA procedure. A time-dependent increase in alpha-synuclein expression was seen in the cerebellar grey matter compared with the controls. At 1 month post PCA, alpha-synuclein-immunopositive material was observed in the molecular layer, while the Purkinje cells showed weak alpha-synuclein expression, and alpha-synuclein aggregates were observed throughout the granular layer. At 6 months post PCA, alpha-synuclein expression was significantly increased compared with the controls. alpha-synuclein-immunostained astroglial cells were also found; the Bergmann glial cells showed alpha-synuclein-positive processes in the molecular layer of PCA-exposed rats, and in the granular layer, perivascular astrocytes showed intense alpha-synuclein immunoreactivity, as indicated by colocalization of alpha-synuclein with glial fibrillary acidic protein (GFAP). In addition, ubiquitin-immunoreactive inclusions were present in PCA-exposed rats, although they did not colocalize with alpha-synuclein. Western blotting performed at 6 months post PCA showed a reduction in the level of soluble alpha-synuclein compared with 1 month post PCA and the controls; this reduction was concomitant with an increase in the insoluble form of alpha-synuclein. Although the precise mechanism by which alpha-synuclein aggregates in PCA-treated rats remains unknown, the present data suggest an important role for this protein in the onset and progression of hepatic encephalopathy, probably via its expression in astroglial cells.

Progression of hepatic encephalopathy in fulminant hepatic failure and serum levels of S-100B: George Ostapowicz, Vuong Dao, UT Southwestern, Dallas, TX; Robert J Fontana, University of Michigan, Ann Arbor, MI; William Lee, UT Southwestern, Dallas, TX; Andres T Blei, Northwestern University, Chicago, IL

Progression of hepatic encephalopathy in fulminant hepatic failure and serum levels of S-100B: George Ostapowicz, Vuong Dao, UT Southwestern, Dallas, TX; Robert J Fontana, University of Michigan, Ann Arbor, MI; William Lee, UT Southwestern, Dallas, TX; Andres T Blei, Northwestern University, Chicago, IL

Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis

Background/AimsStudies in acute liver failure show correlation between evidence of a systemic inflammatory response syndrome (SIRS) and progression of hepatic encephalopathy (HE). We tested the hypothesis that SIRS mediators, such as nitric oxide and proinflammatory cytokines, may exacerbate the neuropsychological effects of hyperammonemia in cirrhosis. MethodsTen patients with cirrhosis were studied, 24–36 h after admission with clinical evidence of infection, and following its resolution. Hyperammonemia was induced by oral administration of an amino-acid (aa) solution mimicking hemoglobin composition. Inflammatory mediators, nitrate/nitrite, ammonia, aa profiles and a battery of neuropsychological tests were measured. ResultsThe hyperammonemia generated in response to the aa solution was similar prior to, and after resolution, of the inflammation (P=0.77). With treatment of the infection there were significant reductions in white blood cell count (WBC), C-reactive protein (CRP), nitrate/nitrite, interleukin-6, interleukin-1β and tumour necrosis factor α. Induced hyperammonemia resulted in significant worsening of the neuropsychological scores when patients showed evidence of SIRS but not after its resolution. ConclusionsThe significant deterioration of neuropsychological test scores following induced hyperammonemia during the inflammatory state, but not after its resolution, suggests that the inflammation and its mediators may be important in modulating the cerebral effect of ammonia in liver disease.

Infection and the progression of hepatic encephalopathy in acute liver failure

Background & Aims : Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. Methods : We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. Results : On multivariate analysis, acquisition of infection during stage I-II HE ( P < 0.01), increased leukocyte levels at admission ( P < 0.01), and decreased platelet count ( P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate ( P < 0.05) and AST levels ( P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and ≥2 components of SIRS, P < 0.05). Conclusions : This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.