Low-grade Hepatic Encephalopathy Research Articles

The magnetic resonance imaging assessment of optic nerve sheath diameter in pediatric acute liver failure patients.

To evaluate the diagnostic value of optic nerve sheath diameter (ONSD) using brain MRI in the pretransplantation period in the pediatric acute liver failure patients, and correlate the ONSD with clinical grade of hepatic encephalopathy (HE) and MRI findings. Forty acute liver failure patients and 40 control group patients were retrospectively analyzed. The high signal intensities in T2W (T2-weighted image), FLAIR (Fluid Attenuated Inversion Recovery) and DWI (diffusion-weighted imaging) sequences were evaluated and ONSD was measured. The patients were grouped first into 5 according to their West Haven score, and HE grade 0 and grade 1 were accepted as low grade HE, HE grade 2, 3 and 4 were accepted as high grade HE. The patients were grouped to 2 according to the MRI findings as low grade and high grade MRI group. The mean value of ONSD was 6.0 ± 1.80 and 4.94 ± 1.27 in the all patients and in the control group, respectively. There was statistically significant difference between both the ONSD and the low grade-high grade HE groups (p=0.01), and between the ONSD and the low grade-high grade MRI groups (p<0.001). Although high ONSD values do not make the diagnosis of cerebral edema, it may cause suspicion in the early period. MRI can be helpful in the diagnoses of increased intracranial pressure like ultrasound. Our study is the first study to compare ONSD and MRI findings in addition to HE grades. The widespread use of MRI in children in recent years may help determine the normal range of ONSD values.

Transjugular intrahepatic portosystemic shunt for the management of symptomatic malignant pseudocirrhosis

Pseudocirrhosis is defined by radiologic changes of the liver parenchyma secondary to metastatic disease and/or cancer treatments, and portends a high rate of morbidity and mortality from sequelae of portal hypertension. Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment for portal hypertension; however, TIPS is relatively contraindicated in the setting of hepatic metastases. The study aims to determine the technical efficacy and clinical outcomes of patients undergoing TIPS for symptomatic pseudocirrhosis. Retrospective analysis of patients with hepatic malignancy who underwent TIPS between 2008 and 2020 at a single tertiary care center. Patients with imaging findings of pseudocirrhosis and without history of primary liver malignancy or confounding causes of cirrhosis were included. West Haven scores assessing hepatic encephalopathy were obtained from chart review. Technical success was defined as successful TIPS creation with reduction in the portosystemic gradient (PSG). Clinical success was defined as resolution of variceal bleeding and/or ascites. Nine patients (4 female/5 male), average (± SD) age 61.2±9.5 years with metastatic pseudocirrhosis were included for analysis. Primary malignancy was colorectal adenocarcinoma (n=5), neuroendocrine tumor (n=3), and malignant endothelial hemangioendothelioma (n=1). Average Model for End Stage Liver Disease (MELD-Na) score was 15.7±3.7. Technical success was 8/9 (89%) with average PSG reduced from 23.5±11.0 to 6.5±2.8 mmHg (P=0.001). Clinical success was 6/9 (67%). Two patients required TIPS revision after initial clinical success. Mild-moderate HE occurred in 6/9 patients post TIPS (67%), with a highest West Haven score of 2. Time from TIPS to death for acute variceal bleeding and ascites was 4.9±4.2 and 12±16.5 months, respectively. Cause of death was disease progression (n=5), variceal bleeding (n=1), or unavailable (n=2). TIPS in the setting of malignant pseudocirrhosis can be created safely with similar clinical outcomes to TIPS performed for benign disease. Rates of low-grade hepatic encephalopathy may be higher amongst patients undergoing TIPS for pseudocirrhosis.

Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta-analysis

BackgroundLow serum zinc level is associated with hepatic encephalopathy (HE), but the efficacy of zinc supplementation remains uncertain. This study aimed to investigate the effects of zinc supplementation on HE treatment in patients with cirrhosis.MethodsWe searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) and Scopus from inception to December 2018; without publication date or language restrictions. Randomized controlled trials of zinc supplementation versus placebo or other treatment for the management of HE in adult patients with cirrhosis were selected. The primary outcome was the degree of HE as assessed by clinical signs or specialized psychometric tests. The secondary outcomes included serum ammonia levels, adverse events, or the length of hospital stay and costs. We carried out a meta-analysis with random effects model and summarized continuous outcomes using standardized mean differences (SMD) or mean differences (MD) with 95% confidence intervals (95% CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of evidence for each outcome was evaluated with the Grading of Recommendations, Assessment, Development, and Evaluation approach.ResultsFour trials with 247 patients were included. In patients with cirrhosis who had mild HE (≤ grade II), the available evidence suggested that the combination treatment of zinc supplementation and lactulose over 3 to 6 months significantly improved performance in the number connection test (SMD: -0.97; 95% CI: − 1.75 to − 0.19; P = 0.01; moderate certainty), reported in three trials (n = 227). However, compared with lactulose therapy alone, additional zinc supplementation demonstrated no significant difference in the digit symbol test (SMD: 0.44; 95% CI: − 0.12 to 1.00; P = 0.12; very low certainty) or serum ammonia levels (MD: -10.86; 95% CI: − 25.73 to 4.01; P = 0.15; very low certainty), reported in two trials (n = 137). None of the included trials reported adverse events or effects on hospitalization.ConclusionsIn conclusion, a combination of zinc supplementation and lactulose over 3 to 6 months may improve the number connection test in cirrhotic patients with low grade HE, compared with lactulose only.Trial registrationPROSPERO: CRD42017080955. Registered 23 November 2017

T118. Cerebellar inhibition in hepatic encephalopathy - A transcranial magnetic stimulation study

Introduction Hepatic Encephalopathy (HE) is a frequent complication in patients suffering from liver cirrhosis. HE comprises a variety of neuropsychiatric and motor symptoms. Increased ammonia levels have been suggested as a key factor in the disease pathology. Using animal models, Cauli and colleagues reported that hyperammonemia may lead to brain area depending alteration of GABAergic neurotransmission with an increase of GABAeric tone in the cerebellum and a decrease in the cerebral cortex. Consistent with this data, recent work from our group revealed a reduced GABAergic tone in the motor cortex of patients with manifest HE using transcranial magnetic stimulation (TMS). The aim of this study is to probe how GABAergic cerebellar tone is altered in patients at different stages of HE and how this alteration is related to clinical parameters such as the critical flicker frequency and ataxia scoring. Methods 30 participants [15 patients with HE (5 minimal HE, 6 HE grade I, and 4 HE grade II) and 15 age matched healthy controls] were subjected to the following: 1- Critical flicker frequency (CFF) which is a sensitive and reliable parameter for quantification of low-grade HE in cirrhotic patients. 2- Cerebellar brain inhibition TMS paradigm (CBI): in this paradigm, a conditioning TMS pulse is applied over one hemisphere of the cerebellum followed by a test pulse over the contralateral motor cortex resulting in a motor evoked potential (MEP). In healthy subjects, the MEP is inhibited when the test stimulus is preceded by the conditioning stimulus at an interval between 5 and 7 ms through inhibition of the fascilitatory disynaptic dentato-thalamo-cortical pathway. 3- Score for assessment and rating of ataxia (SARA) to detect symptoms of cerebellar affection. Results Cerebellar inhibition at ISI 5–7 ms was significantly reduced in patients with HE compared to healthy controls. However, the magnitude of cerebellar inhibition at 7 ms increased with disease severity and correlated with SARA score and with CFF by trend. Conclusion Overall cerebellar inhibition is significantly reduced in patients with HE, suggesting affection of the dentato-thalamo-cortical pathway in this disease. However, the magnitude of cerebellar inhibition at 7 ms increases with disease severity and correlates with SARA score and with CFF by trend, supporting the hypothesis of disease stage dependent increase of GABAergic tone in the Purkinje cells. Our results are consistent with pervious animal in vitro data suggesting increased GABA-ergic tone in the cerebellum and decreased GABA-ergic tone in the motor cortex.

Seeing is believing: a demonstration of critical fusion frequency and its multidimensional nature.

critical fusion frequency (CFF), or the flicker fusion threshold, is defined as the critical frequency above which a flickering light source appears steady to the observer (see [Fig. 1][1]). It is known to depend on a number of parameters, namely, intensity of the light source ([5][2], [15][3]),

Role of Fecal Calprotectin in Diagnosis and Follow up of Hepatic Encephalopathy

Fecal calprotectin is considered a valid marker of intestinal inflammation and its high level in patients with HE may be explained by small intestinal bacterial overgrowth. This study aimed to assess the role of fecal calprotectin in diagnosis and follow up of patients with hepatic encephalopathy. Fifteen patients with uncomplicated liver cirrhosis, 30 patients with liver cirrhosis complicated by hepatic encephalopathy (HE) and 15 healthy subjects were enrolled. All participants were subjected to: clinical examination, laboratory investigations (CBC, liver function tests, kidney functions, HBs Ag and HCV Antibody), fecal calprotectin concentration, abdominal ultrasound. Severity of HE was assessed according to West–Haven criteria. Patients with HE was managed using metronidazole and rifaximin and fecal calprotectin concentrations were reassessed. The level of fecal calprotectin is significantly higher in patients with Child-Pugh class B (116±12 mg/kg) versus that in class A (66±15 mg/kg) (p<0.01). FC concentrations showed the lowest value in the cirrhotic group (66+15 mg/kg) followed by low grade HE (195+12mg/kg) and the highest value in the high grade HE group (489+23mg/kg) (p<0.01). A significant decrease in FC concentrations occurred in HE group after receiving treatment, reaching a level of 273+42.68 mg/kg versus 364+83.12 mg/kg before rifaximin. In conclusion: Fecal calprotectin can be used in diagnosis of HE. Significant high levels of fecal calprotectin in high grade HE patients and its reduction following effective treatment could consider fecal calprotectin as a follow up marker in association with clinical signs in patients with HE.

Multicenter Analysis of Clinical Characteristics and Long-Term Outcomes of Transjugular Intrahepatic Portosystemic Shunt Procedure for MPN-Associated Portal Hypertension

The myeloproliferativeneoplasms (MPNs), polycythemia vera(PV), essential thrombocythemia(ET), and primary myelofibrosis(PMF), are clonal stem cell disorders defined by proliferation of one or more myeloid lineages and variable progression to myelofibrosisand leukemia. Portal hypertension (pHTN) occurs in 7-18% of MPN patients and portends a poor prognosis. The most common causes of MPN-associated pHTNinclude splanchnic vein thrombosis (SVT), extramedullaryhematopoiesis (EMH), and nodular regenerative hyperplasia (NRH). pHTNin MPN patients presents similarly to that in patients with cirrhosis, with refractory ascites, gastrointestinal bleeding, and hepatic encephalopathy. Transjugularintrahepatic portosystemicshunt (TIPS) insertion has been used empirically to treat refractory ascites and varicealbleeding in MPN-associated pHTN; however, little data exists on long-term outcomes of MPN patients who have undergone TIPS procedure. To assess the safety and efficacy of TIPS for treatment of pHTNin MPN, we performed a retrospective analysis of outcomes of TIPS procedure in MPN patients at three academic medical centers.Through a defined search of the electronic medical records of the participating institutions, 29 MPN patients were identified who underwent TIPS procedure forpHTNbetween 2000 and 2016. Patients with portal hypertension from causes other than MPN were excluded from the study as were patient with fewer than 6 months of follow-up. Clinical characteristics and long-term outcomes were analyzed.The mean age of the patients was 51.5 years (range 29-86 years) and 65.5% were women. PV and PV-MF were the most common MPN subtypes (58.6%), followed by MPN unclassifiable (20.7%), PMF (10.3%), and ET (10.3%) (Table 1).JAK2V617F mutation was present in all but one patient, while CALR and MPL mutations were detected in one patient each. Budd-Chiari syndrome (BCS) represented the predominant etiology of portal hypertension in 72.4% of patients. Of note, 31% of patients had a multifactorial etiology of portal hypertension. Females with PV comprised 75% of BCS presentations, whereas males with MF comprised 80% of EMH. Indications for TIPS included refractory ascites (86%), esophagealvarices (51.7%), intestinal ischemia (6.9%), and fulminant liver failure (6.9%). All patients demonstrated immediate normalization of portal pressures following TIPS insertion with a covered-uncovered stent-graft. Post-TIPS anticoagulation included warfarin (69%), low-molecular weight heparin (17.2%), andfondaparinux (17.2%). Four patients (13.8%) did not receive anticoagulation following TIPS, two of whom had knownvarices and one who had gastro-intestinal bleeding following TIPS. The majority of patients experienced complete resolution of ascites (96.2%) andvarices (93.3%). Post-TIPS complications included TIPS thrombosis (31.0%; notably these occurred despite anticoagulation), heparin-induced thrombocytopenia (20.7%), low-grade hepatic encephalopathy (20.7%), TIPS stenosis (17.2%), and mild NSTEMI (1 patient). Of the eight patients listed for liver transplant, only one patient required transplant following TIPS. One, two, and three-year overall survival post-TIPS were 96.4%, 92.5% and 85.2%, respectively.Our study represents the largest cohort to date of MPN-associated portal hypertension patients who received TIPS. Our results indicate that TIPS can be performed safely in this high-risk population and can effectively mitigate the clinical consequences of MPN-associatedpHTN. However, the risk of TIPS complications, particularly of thrombosis and hepatic encephalopathy, remains prevalent and must be balanced against the intended clinical benefits. [Display omitted] DisclosuresStein:Incyte: Membership on an entity's Board of Directors or advisory committees.

Association between road accidents and low-grade hepatic encephalopathy among Sri Lankan drivers with cirrhosis: a prospective case control study.

BackgroundLow-grade hepatic encephalopathy (LGHE) comprises minimal hepatic encephalopathy (MHE) and grade 1 hepatic encephalopathy. LGHE has no or minimal recognizable symptoms but has mild cognitive and psychomotor deficits. Studies in Western countries have demonstrated increased road accidents (RA) among patients with MHE. Our objective was to investigate the association between Sri Lankan LGHE phenotype and RA.Study design and methodsA prospective, case–control study was conducted in the University Medical Unit, North Colombo Teaching Hospital, Ragama Sri Lanka. Patients with cirrhosis of any aetiology, without OHE, who had been driving during previous 1 month were included. A similar number of age matched, healthy control drivers were also enrolled. Both groups were subjected to five pencil-paper based psychometric tests used to detect LGHE in cirrhotics. Self-reported RA during the previous 1 month were recorded: categorized as ‘major’ when resulted in hospitalization of the involved, ‘minor’ when there were injuries, but not serious enough for hospitalization of the involved and ‘other’ when limited to damages to vehicle or environment without injuries.ResultsAmong 55 drivers with cirrhosis and LGHE [males, median age 53 years (range 30–60)], 7 (12.7 %) reported RA compared to 6 (10.9 %) among 55 controls [males; median age 51 years (range 30–60)]. There were no ‘major’ accidents in either group. 2/55 (3.6 %) cases and 2/55 (3.6 %) controls reported ‘minor’ accidents.ConclusionThere was no increased frequency of RA among Sri Lankan drivers with LGHE compared to healthy controls. This is with the limitation of the study based only on self reported RA.

Clinical scenarios for the use of S100β as a marker of hepatic encephalopathy.

To evaluate the association between serum concentrations of S100β in patients with cirrhosis and the presence of low grade hepatic encephalopathy (HE). This was a cross-sectional study. The population was categorized into four groups healthy subjects, cirrhosis without HE, cirrhosis with covert hepatic encephalopathy (CHE) and cirrhosis with overt HE. Kruskal-Wallis, Mann Whitney's U with Bonferroni adjustment Spearman correlations and area under the ROC were used as appropriate. A total of 61 subjects were included, 46 cirrhotic patients and 15 healthy volunteers. S100β values were different among all groups, and differences remained significant between groups 1 and 2 (P < 0.001), and also between groups 2 and 3 (P = 0.016), but not between groups 3 and 4. In cirrhotic patients with HE S100β was higher than in patients without HE [0.18 (0.14-0.28) ng/mL vs 0.11 (0.06-0.14) ng/mL, P < 0.001]. There was a close correlation between serum concentrations of S100β and psychometric hepatic encephalopathy score in patients with cirrhosis without HE compared to the patients with cirrhosis with CHE (r = -0.413, P = 0.019). ROC curve analysis yielded > 0.13 ng/mL as the best cutoff value of S100β for the diagnosis of HE (sensitivity 83.3%, specificity 63.6%). Serum concentrations of S100β are higher in patients with cirrhosis than in healthy volunteers, and are further increased in the presence of hepatic encephalopathy. The results suggest that serum biomarkers such as S100β could help in the correct characterization of incipient stages of HE.

Fecal Microbiota Transplantation in the Management of Mild Overt Hepatic Encephalopathy: A Case Report: Presidential Poster

Background: Hepatic encephalopathy (HE) is one of the most common complications of end stage liver cirrhosis. Although the precise pathophysiology of HE is not well defined, data suggest that ammonia (NH3) generated by the enteric bacterial flora is the critical driver of this process. The microbiota in patients with liver cirrhosis is altered compared to healthy controls, and they have more urease-producing bacteria associated with increased NH3 production. The standard of care in patients who have recurrent HE is rifaximin and/or lactulose. Although effective, many patients continue to suffer from breakthrough HE. It is possible that fecal microbiota transplantation (FMT) may overcome the limitations of probiotics in reversing dysbiosis associated with HE, leading to clinical improvement. Methods: We treated a 57 year-old man suffering from low grade persistent HE with liver cirrhosis (MELD score of 10) secondary to alcohol and hepatitis C in this pilot study. He had previously responded well to lactulose and rifaximin. His rifaximin was stopped when Health Canada ended the compassionate release program. He had chronic Grade I-II HE despite being on lactulose, limiting his daily functionings. He was given 5 weekly FMT, with the first one administered by colonoscopy and the remaining 4 by retention enema. Changes in mental status were assessed by both inhibit control test (ICT) and Stroop test. Stool samples were obtained from the patient 1 day before FMT and 1 week following each FMT. A final sample was obtained at 7 weeks following the final FMT. Microbial DNA was extracted and used for whole genome shotgun sequencing. Results: Within the first week of treatment, objective measures of reaction time, Stroop test, serum ammonia level, patient reported cognition and appetite were significantly improved. Unfortunately he missed his 2nd FMT, and these parameters deteriorated. Following further 3 weekly FMT, he continued to improve, with ICT and Stroop test scores within normal range by week 4. Table 1 summarizes the changes in ICT, Stroop test and serum NH3 levels over time in relation to FMT. No adverse events or infectious complications related to FMT administration were observed. Fig 1A and 1B demonstrated the fecal microbial changes before and after FMT.Figure 1Table 1: Changes in ICT, Stroop test and serum NH3 levels over time in relation toConclusion: This proof-of-concept, pilot case study suggests that manipulating the gut microbiome through FMT can transiently reverse intestinal dysbiosis associated with HE, resulting in temporary cognitive improvement in persistent low grade HE. In addition, microbial analysis demonstrated decreased Bacteroidaceae and Streptococcaceae following FMT, both of which have been associated with hepatic encephalopathy and urease production. This finding is promising and warrants further investigation.Figure 2

Fulminant presentation of autoimmune hepatitis: clinical features and early predictors of corticosteroid treatment failure.

Classical features of autoimmune hepatitis (AIH) may be altered during the abrupt onset of the disease. Corticosteroid therapy can be life-saving, but its use in the fulminant presentation of AIH (F-AIH) remains controversial. We aimed to assess the clinical features of patients with F-AIH and to describe the role of corticosteroids in this population. We retrospectively analyzed 154 adult patients with fulminant hepatic failure who were admitted to six liver transplantation (LT) programs. The AIH simplified criteria were used to identify patients with F-AIH. We identified 40 (26%) patients with F-AIH. Compared with other etiologies, patients with F-AIH presented a longer interval from jaundice to encephalopathy (26 vs. 16 days, P=0.02) and a lower Model for End-Stage Liver Disease (MELD) score on admission (29 vs. 33, P=0.002). Overall, 25 (62%) patients with F-AIH underwent LT, eight (20%) patients survived, and seven (18%) died without LT. Seventeen patients received corticosteroids therapy, of whom seven (41%) survived without LT. Among the treated patients, higher MELD score and encephalopathy grade of 3 or more were associated significantly with corticosteroid failure. Patients with F-AIH have a more indolent presentation compared with the non-F-AIH population. Altogether, only eight (20%) patients presenting with F-AIH survived without LT. A subset of patients with F-AIH and an initial MELD score less than 27 and low-grade hepatic encephalopathy might benefit from administration of corticosteroids.

Hepatic encephalopathy in acute-on-chronic liver failure.

The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy

Factors other than elevated levels of ammonia may be implicated in hepatic encephalopathy (HE) pathophysiology, including abnormal cerebral haemodynamics. Transcranial Doppler ultrasonography (TCD) evaluates cerebrovascular structural integrity and reactivity, through pulsatility index (PI) and breath-holding index (BHI) respectively. The aim of this study was to evaluate cerebral haemodynamics by TCD in patients with compensated and decompensated cirrhosis, and patients with and without HE. We studied 90 subjects by TCD measuring PI and BHI in the middle cerebral artery: 30 with cirrhosis and no HE, 30 with cirrhosis and low-grade HE and 30 healthy subjects. Critical flicker frequency, psychometric hepatic encephalopathy score and West-Haven criteria were performed to assess MHE and HE respectively. Pulsatility index increased in decompensated cirrhotics (Child≥7) when compared with compensated cirrhotics and healthy subjects [median (IQR) 1.07 (0.95-1.21) vs 0.90 (0.83-1.05) vs 0.87 (0.78-0.96); P<0.001]. A reverse relationship was observed for BHI among the three groups [0.82 (0.45-1.11) vs 1.20 (0.82-1.52) vs 1.28 (1.06-1.68); P<0.001]. Similar findings were observed in decompensation [model for end-stage liver disease (MELD) score ≥14]. Patients with HE showed higher PI and lower BHI [1.05 (1.00-1.16) and 0.89 (0.59-1.15)], when compared with patients without HE [0.96 (0.83-1.13) and 1.00 (0.60-1.53)] or controls [0.87 (0.78-0.96) and 1.28 (1.06-1.68)] (P<0.001 for PI, and P=0.007 for BHI). In multivariate regression models, only PI predicted HE, but it was outperformed by MELD-sodium and tumour necrosis factor-alpha. These results indicate that cerebral haemodynamics are altered in patients with cirrhosis, in relation to severity of disease and HE. Findings on impaired PI and BHI suggest that structural vascular damage and loss of vascular autoregulation are implicated in the pathophysiology of HE.

Altered Effective Connectivity Network of the Basal Ganglia in Low-Grade Hepatic Encephalopathy: A Resting-State fMRI Study with Granger Causality Analysis

BackgroundThe basal ganglia often show abnormal metabolism and intracranial hemodynamics in cirrhotic patients with hepatic encephalopathy (HE). Little is known about how the basal ganglia affect other brain system and is affected by other brain regions in HE. The purpose of this study was to investigate whether the effective connectivity network associated with the basal ganglia is disturbed in HE patients by using resting-state functional magnetic resonance imaging (rs-fMRI).Methodology/Principal FindingsThirty five low-grade HE patients and thirty five age- and gender- matched healthy controls participated in the rs-fMRI scans. The effective connectivity networks associated with the globus pallidus, the primarily affected region within basal ganglia in HE, were characterized by using the Granger causality analysis and compared between HE patients and healthy controls. Pearson correlation analysis was performed between the abnormal effective connectivity and venous blood ammonia levels and neuropsychological performances of all HE patients. Compared with the healthy controls, patients with low-grade HE demonstrated mutually decreased influence between the globus pallidus and the anterior cingulate cortex (ACC), cuneus, bi-directionally increased influence between the globus pallidus and the precuneus, and either decreased or increased influence from and to the globus pallidus in many other frontal, temporal, parietal gyri, and cerebellum. Pearson correlation analyses revealed that the blood ammonia levels in HE patients negatively correlated with effective connectivity from the globus pallidus to ACC, and positively correlated with that from the globus pallidus to precuneus; and the number connectivity test scores in patients negatively correlated with the effective connectivity from the globus pallidus to ACC, and from superior frontal gyrus to globus pallidus.Conclusions/SignificanceLow-grade HE patients had disrupted effective connectivity network of basal ganglia. Our findings may help to understand the neurophysiological mechanisms underlying the HE.

Lactulose in the treatment of hepatic encephalopathy: New evidence for an old modality

See article in J. Gastroenterol. Hepatol. 2012; 27: 1329–1335.

A patients’ and caregivers’ perspective on hepatic encephalopathy

Awareness of previous hepatic encephalopathy (HE) and compliance with treatment can probably reduce HE recurrence. The aim of this study was to assess the degree of awareness of previous HE and its treatment in a group of cirrhotic patients and their caregivers. Thirty-five cirrhotic patients with a history of HE and their caregivers (n = 31) were enrolled. Patients underwent evaluation of HE (clinical, psychometry and electroencephalography), quality of life (SF36 questionnaire), and awareness of HE/treatment on an ad hoc questionnaire (QAE). Caregivers underwent the QAE plus the Caregiver Burden Inventory. On the day of study, 7 patients were unimpaired, 8 had minimal and 20 low-grade overt HE. Of the patients, 37% were aware of previous HE, 6% of being on treatment and 6% understood treatment effects. Of the caregivers, 48% were aware of previous HE, 6% of their relative being on treatment and 6% understood treatment effects. Significant correlations were observed between neuropsychiatric status/linear HE indices and both the patients' quality of life and the caregivers' burden. In conclusion, HE awareness was poor in both patients and caregivers, most likely in relation to insufficient/inadequate provision of information.

Abnormal baseline brain activity in low-grade hepatic encephalopathy: A resting-state fMRI study

Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neuropsychiatric diseases, but rarely in low-grade hepatic encephalopathy (HE), a common neuropsychiatric complication of liver cirrhosis. We conducted a resting-state fMRI in 19 healthy controls, 18 cirrhotic patients without HE, and 22 cirrhotic patients with low-grade HE. The amplitude of low-frequency fluctuations (ALFF) of fMRI signal was computed to measure the spontaneous neuronal activity. Several regions showing significant ALFF differences among three groups were the precuneus, occipital lobe, left frontal lobe and anterior/middle cingulate cortex, and left cerebellum posterior lobe. Compared to controls or patients without HE, patients with low-grade HE showed decreased ALFF in the precuneus and adjacent cuneus, visual cortex, and left cerebellum posterior lobe. Compared to controls, patients with low-grade HE showed higher ALFF in both cortical and subcortical regions, including the right middle cingulate gyrus, and left anterior/middle cingulate gyrus, inferior frontal gyrus, insula lobe, parahippocampal gyrus, middle temporal gyrus and lentiform nucleus; compared to patients without HE, patients with low-grade HE showed higher ALFF in the left medial frontal gyrus and anterior cingulate gyrus, bilateral superior frontal gyrus, and right middle frontal gyrus. Moreover, correlations between ALFF changes and poor neurocognitive performances were found in patients with low-grade HE. These results suggested the existence of aberrant brain activity at the baseline state in low-grade HE, which may be implicated in the neurological pathophysiology underlying HE.

Small intestinal bacterial overgrowth and delayed orocecal transit time in patients with cirrhosis and low-grade hepatic encephalopathy.

Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Gut-derived nitrogenous substances play a role in pathogenesis of HE. The present study was conducted to assess small intestinal bacterial overgrowth (SIBO) and prolonged orocecal transit time (OCTT) in cirrhosis and low-grade HE. In cross-sectional prospective study, 75 patients were divided into 3 groups: group 1 (no HE, n=31), group 2 (minimal HE, n=29), and group 3 (early/grade 1 HE, n=15). Minimal HE (MHE) was diagnosed when psychometric hepatic encephalopathy score (PHES) was ≤5. Early HE was diagnosed, according to West Haven criteria. All patients underwent glucose hydrogen breath test (GHBT) for SIBO and lactulose hydrogen breath test (LHBT) for OCTT. A total of 29 patients (38.67%) had MHE and 15 (20%) had early HE. Prevalence of MHE in Child-Turcotte-Pugh (CTP) class A, B, and C was 33.3, 38.71, and 45%, respectively, while SIBO was detected in 26 (34.67%). Prevalence of SIBO was 12.5% in CTP class A, 41.94% in CTP class B, and 50% in CTP class C. Five (16.13%) patients in no HE group had SIBO as compared to 14 (48.28%) in MHE group and 7 (46.67%) in early HE group (p=0.018). OCTT was 111.13±13.95min in patients with no HE as compared to 137.59±14.80min in patients with MHE and 150±15.12min in patients with early HE (p<0.001). OCTT was significantly prolonged in patients with SIBO (145±17.49min) than in those without SIBO (120.71±18.3min) (p<0.001). SIBO and delayed OCTT are more common with MHE and early HE in patients with cirrhosis.

Reply:

We appreciate the comments of Drs. Fujiwara and Duclos-Vallée regarding our article, “Autoimmune acute liver failure: proposed clinical and histological criteria.”1 Dr. Fujiwara reports that approximately 50% of their patient population with acute liver failure (ALF) of unclear etiology was ultimately diagnosed with autoimmune ALF (AI-ALF) on the basis of liver histology and clinical parameters, similar to findings in our series (58%). The investigators advise caution in interpreting our work regarding the heterogeneity of histological findings in liver specimens from patients with ALF. Dr. Fujiwara presents data that demonstrate no difference between the time of onset of hepatitis to time of admission or liver biopsy between patients with autoimmune hepatitis presenting as acute-onset hepatitis, chronic hepatitis, or ALF, with a large degree of overlap, supporting the clinical heterogeneity of the disease. Dr. Duclos-Vallée also raises concern about the fact that two-thirds of our liver specimens were sections from explants, whereas the remainder were transjugular needle biopsies. The lack of uniform biopsy technique, they suggest, may have influenced our results by increasing the probability of finding specific features of autoimmunity in the larger specimens obtained from an explant. We did not, however, find statistically significant differences in the prevalence of the four features of autoimmunity between specimens obtained from explanted livers and those obtained by transjugular biopsy. Dr. Duclos-Vallée also requested further correlation between patients with centrilobular necrosis and their clinical phenotype and outcomes. Patients with central perivenulitis were characterized by a longer jaundice-to-encephalopathy interval, and a poorer prognosis (higher incidence of liver transplantation). These attributes can be ascribed to a more subacute liver injury in patients with AI-ALF compared to those with other indeterminate etiologies. Perhaps due to small numbers (13 of 72 patients; 18%), those patients with exclusive centrilobular necrosis were not clinically different than those without this feature. Finally, Dr. Duclos-Vallée and colleagues raise concern about administering corticosteroids to patients with suspected AI-ALF, a major rationale for performing our study. We strongly agree with their contention that corticosteroid administration may introduce a significant risk of infection, and that no convincing evidence of efficacy exists.2 It should be noted, however, that no randomized, placebo-controlled studies have explored the efficacy of corticosteroids in patients with rigorously defined AI-ALF. In the absence of such information, we would reserve the administration of corticosteroids to patients with recent-onset AI-ALF and low-grade hepatic encephalopathy. Certainly, corticosteroids are unlikely to improve the transplant-free survival of a patient with AI-ALF late in the clinical course of the syndrome or with clinical attributes of poor outcome. R. Todd Stravitz M.D.*, Jay H. Lefkowitch M.D. , * Section of Hepatology, Virginia Commonwealth University, Richmond, VA, Department of Pathology, Columbia University, New York, NY.

Effect of L-ornithine-L-aspartate Therapy on Low-Grade Hepatic Encephalopathy in Patients with Liver Cirrhosis

Background: Minimal hepatic encephalopathy (MHE) is an abnormal condition of psychometric testing before hepatic encephalopathy (HE) condition reducing quality of life and survival rate. Impractical instrument, the psychometric hepatic encephalopathy score (PHES), has been recommended in diagnosing MHE. The new critical flicker frequency (CFF) has good precision and accuracy for diagnosing MHE. Oral L-ornithine-L-aspartate (LOLA) may increase ammonia detoxification. The aim of this study was to recognize the effect of oral LOLA on low-grade HE by investigating the mean value of CFF. Method: We included 31 patients with liver cirrhosis and low-grade HE (MHE, HE grade 1 and 2) at the outpatient clinic of hepatology, Cipto Mangunkusumo hospital between November 2009 and March 2010. It was a double-blind, randomized, placebo-controlled clinical trial. Oral LOLA was administered in a dose of 18 g/day, 3 times daily for 14 consecutive days. At the end of the study, there were 27 cirrhotic patients with CFF value < 38 Hz; 14 patients had received LOLA and 13 patients had placebo. Statistic analysis was performed by using the Mann-Whitney U test. Results: The mean value of CFF in LOLA group after treatment (39.3 Hz) was significantly different than the placebo group (36.04 Hz); (p = 0.027). Ammonia level decreased in LOLA group from 118.7 into 109.1 µ mol/L. In placebo group, it increased from 106.9 into 147.5 µ mol/L with p = 0.275 (before); p = 0.052 (after). Conclusion: Oral LOLA may improve the value of CFF and is likely to decrease blood ammonia level in patients with low-grade HE. Keywords: low-grade hepatic encephalopathy, oral LOLA, CFF improvement, ammonia detoxification