Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy

Oral glutamine challenge (OGC) has been found to be safe, and an altered response predicts elevated risk of overt hepatic encephalopathy (HE) in patients with minimal hepatic encephalopathy (MHE). We assessed the survival prognosis of patients with cirrhosis, but without current overt HE, who have an altered OGC and MHE. MHE was inferred using 3 neuropsychological tests. Venous ammonia concentrations were measured pre- and post-60 minutes of a 10 g oral glutamine load. The median follow-up was 25.2 months, by which time 22 patients had had bouts of overt HE and 18 had died from liver-related causes. The results in 126 patients with cirrhosis, indicated 25 with MHE and abnormal OGC response. Survival among patients who developed overt HE was 59% at 1 year and 38% at 3 years. In patients without HE, survival was 96% and 86% at 1 and 3 years, respectively (log-rank 50.9, P <.0001). The presence of MHE was not related to survival (log-rank 2.21, P =.23). Patients with MHE and abnormal OGC test had elevated mortality risk (log-rank 13.1, P =.0003). Multivariate analyses indicated Child-Pugh score (hazard ratio [HR] 1.46; 95% CI, 1.46-2.08), and MHE plus altered OGC response (HR 5.5; 95% CI, 1.81-16.6) were predictors of mortality, whether from liver-related or non-liver-related causes. In conclusion, a pathological OGC response in patients with MHE appears to be associated with lower survival rate and may prove useful in the selection of candidates for liver transplantation.     

Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis

Background: Minimal hepatic encephalopathy(MHE) is an early and reversible form of hepatic encephalopathy. The documentations on the treatment with probiotics are inconsistent. The present meta-analysis was to verify the role of probiotics in the treatment of cirrhotic patients with MHE.Data sources: Seven electronic databases were searched for relevant randomized controlled trials(RCTs)published until July 2015. The effects of probiotics on serum ammonia, endotoxin, and MHE were evaluated.Results: A total of 14 RCTs(combined n = 1132) were included in the meta-analysis. When probiotics were compared to placebo or no treatment, probiotics were more likely to reduce values in the number connection test(NCT; week 4: MD =-30.25, 95% CI:-49.85 to-10.66), improve MHE(week 4: OR = 0.18,95% CI: 0.07 to 0.47; week 12: OR = 0.15, 95% CI: 0.07 to 0.32), and prevent overt HE progression(week4: OR = 0.22, 95% CI: 0.07 to 0.67) in patients with liver cirrhosis. When probiotics was compared to lactulose, probiotics tended to reduce serum ammonia levels(week 4: MD =-0.33 μmol/L, 95% CI:-5.39 to 4.74; week 8: MD = 6.22 μmol/L, 95% CI:-24.04 to 36.48), decrease NCT(week 8: MD = 3.93, 95% CI:-0.72 to 8.58), improve MHE(week 4: OR = 0.93, 95% CI: 0.45 to 1.91; week 12: OR = 0.73, 95% CI: 0.35 to 1.51) and prevent the development of overt HE(week 4: OR = 0.96, 95% CI: 0.17 to 5.44; week 12:OR = 2.7, 95% CI: 0.50 to 14.64) in patients with liver cirrhosis. However, lactulose appears to be more effective in reducing NCT values as compared to probiotics(week 4: MD = 6.7, 95% CI: 0.58 to 12.82).Conclusion: Probiotics can decrease serum ammonia and endotoxin levels, improve MHE, and prevent overt HE development in patients with liver cirrhosis.     

Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy

BACKGROUND/AIMS: We performed the current study to assess the intestinal activity of enterocyte phosphate-activated glutaminase (PAG) in cirrhosis. METHODS: Forty-nine cirrhotic patients and 36 control subjects underwent endoscopic duodenal biopsies. Minimal hepatic encephalopathy (MHE) was evaluated using three psychometric tests. Oral glutamine challenge (OGC) was performed and MELD, Child-Pugh and the presence of esophageal varices were recorded. PAG was measured by enzymatic methods. Cerebral magnetic resonance spectroscopy was performed in 10 cirrhotics. RESULTS: PAG was found to be higher in cirrhotics than control subjects 2.4+/-1.51 vs. 0.68+/-0.57IU/mg protein (P<0.001). PAG was also increased in patients with MHE and correlated with MELD, INR, esophageal varices and serum bile acids. A negative correlation was observed between PAG activity and intra-cerebral choline/creatine ratio (r=-0.67; P=0.035) and a positive correlation with glutamine plus glutamate/creatine ratio (r=0.78; P=0.007). In multivariate analysis using backward logistic regression, presence of MHE was the only variable independently related to altered enterocyte PAG. CONCLUSIONS: Enterocyte PAG is increased in cirrhotic patients and correlates with MHE. These data support a possible role for intestinal glutaminase in the pathogenesis of hepatic encephalopathy (HE) and could be a new target for future therapies.     

Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose

Background and Aim: Development of overt hepatic encephalopathy (HE) is associated with poor prognosis in patients with cirrhosis. Lactulose is used for the treatment of HE. There is no study on the prevention of overt HE using lactulose in patients who never had HE earlier. Methods: Consecutive cirrhotic patients who never had an episode of overt HE were randomized to receive lactulose (Gp‐L) or no lactulose (Gp‐NL). All patients were assessed by psychometry (number connection test [NCT‐A and B], figure connection test if illiterate [FCT‐A and B], digit symbol test [DST], serial dot test [SDT], line tracing test [LTT]) and critical flicker frequency test (CFF) at inclusion and after 3 months. These patients were followed every month for 12 months for development of overt HE. Results: Of 250 patients screened, 120 (48%) meeting the inclusion criteria were randomized to Gp‐L (n = 60) and Gp‐NL (n = 60). Twenty (19%) of 105 patients followed for 12 months developed an episode of overt HE. Six (11%) of 55 in the lactulose (Gp‐L) group and 14 (28%) of 50 in the Gp‐NL (P = 0.02) developed overt HE. Ten (20%) of 50 patients in Gp‐NL and five (9%) of 55 patients in the Gp‐L group died, P = 0.16. Number of patients with minimal hepatic encephalopathy (MHE) were comparable in two groups at baseline (Gp‐L vs Gp‐NL, 32:36, P = 0.29). Lactulose improved MHE in 66% of patients in Gp‐L. Taking a cutoff < 38 Hz sensitivity and specificity of CFF in predicting HE were 52% and 77% at baseline and 52% and 82% at 3 months of treatment. On multivariate analysis, Child's score and presence of MHE at baseline were significantly associated with development of overt HE. Conclusions: Lactulose is effective for primary prevention of overt hepatic encephalopathy in patients with cirrhosis.     

Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy

OBJECTIVES: In patients with compensated liver cirrhosis the clinical repercussions of detecting subclinical hepatic encephalopathy (SHE) are unclear. We present a long-term follow-up study in cirrhotic patients to examine the relationship between SHE and subsequent episodes of overt hepatic encephalopathy. METHODS: A total of 63 cirrhotic patients were studied by Number Connection Test and auditory evoked potentials. We determined glutamine, ammonia, zinc, glutamate, urea, and ratio of branched chain amino acids to aromatic amino acids, and Child-Pugh classification. RESULTS: Of 63 patients, 34 (53%) exhibited SHE. Nineteen out of 63 (30%) developed overt hepatic encephalopathy during follow-up. Hepatic encephalopathy in follow-up was related to alcoholic etiology, ammonia, glutamine, zinc, ratio of branched chain amino acids to aromatic amino acids, liver function, presence of esophageal varices, and detection of SHE (84% of patients who exhibited hepatic encephalopathy in follow-up showed SHE). In Cox-regression, glutamine levels, SHE, esophageal varices, and Child-Pugh class were the independent variables related to hepatic encephalopathy in follow-up. CONCLUSIONS: SHE (defined on the basis of number connection test or auditory evoked potentials alteration) could predict a subsequent episode of overt hepatic encephalopathy. Lower glutamine levels, presence of esophageal varices, and liver dysfunction were also related to the development of overt hepatic encephalopathy.     

Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis

Background/Aims: Minimal hepatic encephalopathy (MHE) impairs health‐related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. However, not all patients respond to lactulose. We evaluated predictors of nonresponse to lactulose. Patients and methods: Consecutive 110 cirrhotic patients without HE were evaluated for MHE by psychometry, P300 auditory event‐related potential (P300ERP), venous ammonia and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry and P300ERP (>2 SD). MHE patients were treated with lactulose for 1 month. Response was defined by normalization of the abnormal test parameters (both psychometric tests and P300ERP). Results: Sixty patients (54.5%) were diagnosed as having MHE: 17/39 (44%) in Child's A, 21/42 (50%) Child's B and 22/29 (76%) in Child's C. There was a significant difference between Child's C's vs Child's A's and B's (P<0.05). Abnormal psychometric tests and abnormal P300ERP were seen in 74 (67%) and 74 (67%) patients respectively. Of 60 patients with MHE, after treatment, psychometry remained abnormal in 22 (36.6%) and P300ERP in 21 (35%) patients. CFF was<38 Hz in 34 (57%) and 11 (18%) patients, respectively, before and after treatment in MHE patients. There was a significant difference between the baseline serum sodium level (134.7±2.6 vs 131.1±2.2 mmol/L, P=0.001) and the venous ammonia level (76.6±20.7 vs 113.4±22.8 μmol/L, P=0.001) between responders vs nonresponders. Receiver operating characteristic analysis was performed to identify the cutoff for venous ammonia [cutoff 93.5 mmol/L, area under the curve (AUC) 0.892 (0.814–0.970)] and for the serum sodium level [cutoff 132.5 mmol/L, AUC 0.874 (0.779–0.998)]. Taking a cutoff of 93.5 mmol/L for ammonia patient had a sensitivity of 88.5% and a specificity of 79.4%, respectively, and a cutoff of 132.5 mmol/L for serum sodium patient had a sensitivity of 76.5% and a specificity of 88.5% for nonresponse to lactulose. On univariate analysis and multivariate analysis, serum sodium and venous ammonia were the only two parameters associated with nonresponse to lactulose. Conclusion: The prevalence of MHE was 55% and MHE improved in 57% patients with lactulose. Baseline low serum sodium and high venous ammonia were highly predictive of nonresponse to lactulose therapy.     

幽门螺杆菌感染对高氨血症和肝性脑病发病的影响

目的了解幽门螺杆菌(Hp)感染和血氨水平、肝性脑病(HE)发病的关系,并探讨根除Hp对血氨水平和HE发生的影响。方法2003年7月-2005年1月在浙江省5个地区收集肝硬化住院患者,记录患者的一般资料、数字连接试验结果、Hp感染情况、肝功能Child-Pugh分级、血氨水平和HE情况。Hp(+)患者予“奥美拉唑+克拉霉素+替硝唑”1周根除治疗,1个月后查~(14)C尿素呼气试验,并记录患者的神经精神症状和血氨水平。结果(1)共收集肝硬化住院患者457例,Hp感染率60．6%,HE发生率47．5%。检出亚临床肝性脑病(SHE)患者55例,SHE占未发生HE肝硬化患者的47．0%(55/117)。(2)Hp(+)和Hp(-)肝硬化患者血氨浓度分别为(78．4±63．6)μmoL/L和(53．8±51．4)μmol/L(P＜0．01);根除Hp后血氨显著下降至(53．5±37．7)μmol/L(P＜0．01)。Hp(+)和Hp(-)肝硬化患者HE发生率差异有统计学意义(58．5%比30．6%,P＜0．01);根除Hp后HE发生率下降至34．1%(P＜0．01)。(3)HE、SHE和肝硬化患者的Hp感染率分别为74．4%、69．1%和53．2%(P＜0．05)。三组患者的血氨水平分别为(94．5±75．6)μmol/L、(59．9±49．2)μmol/L和(47．3±33．5)μmol/L(P＜0．05)。结论Hp感染是引起肝硬化高氨血症和并发HE的重要因素,根除Hp有利于治疗和预防HE的发生。     

Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients

BACKGROUND/AIMS: The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations. METHODS: A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model. RESULTS: EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.2-4.7; class C: OR = 3.5, 95% CI = 1.6-7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR = 0.9; 95% CI = 0.5-1.5). The EEG predicted the occurrence of OHE (chi2 = 26; P < 0.001) and mortality (chi2 = 34; P < 0.001), also adjusting for Child-Pugh class by a multivariate analysis. In the patients with a Child-Pugh score of > or = 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR) = 3.3, 95% CI = 1.8-6.1) and death (HR = 3.1, 95% CI = 1.7-5.6). CONCLUSIONS: In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.     

Critical flicker frequency for diagnosis and assessment of recovery from minimal hepatic encephalopathy in patients with cirrhosis

BACKGROUND:Minimal hepatic encephalopathy (MHE) impairs quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients.Diagnosis of MHE requires cumbersome tests.Lactulose is effective in the treatment of MHE.This study aimed to evaluate the use of critical flicker frequency (CFF) for the diagnosis of MHE in cirrhotic patients after treatment.METHODS:One hundred and ten patients were evaluated by psychometry (number connection tests A,B or figure connection tests A,B),P300 auditory eve...     

Relationship between interleukin-6 and ammonia in patients with minimal hepatic encephalopathy due to liver cirrhosis

Aim: Previous studies have shown significantly elevated levels of interleukin (IL)-6 in cirrhotic patients with minimal hepatic encephalopathy (MHE), but the relationship between circulating levels of IL-6 and ammonia is unclear. The aim of this study is to investigate the relationship between both variables in cirrhotic patients with MHE. Methods: Psychometric tests including number connection test part A (NCT-A) and digit symbol test (DST) were performed to diagnose MHE in 85 cirrhotic patients. Simultaneously, circulating levels of IL-6 and ammonia were measured. Results: Thirty-two (37.6%) cirrhotic patients were diagnosed with MHE. IL-6 and ammonia were the independent predictors of the presence of MHE (P < 0.05 for both variables). Circulating levels of IL-6 and ammonia correlated with the severity of MHE represented by results of NCT-A (r = 0.56, P < 0.05 and r = 0.39, P < 0.05, respectively) and DST (r = −0.48, P < 0.05 and r = −0.47, P < 0.05, respectively). Moreover, there was a significant correlation between circulating levels of IL-6 and those of ammonia in patients with MHE (r = 0.61, P < 0.05), and a positive additive interaction was found between IL-6 and ammonia on the presence of MHE, with a significant synergy index of 1.51 (95% confidence interval = 1.12–3.46). Conclusion: The present study demonstrates a significant correlation and a positive additive interaction between IL-6 and ammonia in cirrhotic patients with MHE, suggesting that IL-6 may have a potential synergistic relationship with ammonia in the induction of MHE.     

Risk factors for hepatic encephalopathy and mortality in cirrhosis: The role of cognitive impairment,muscle alterations and shunts

Introduction/AimMuscle alterations, portosystemic shunts (SPSS) and minimal hepatic encephalopathy (MHE) are related to hepatic encephalopathy (HE), however no studies have investigated the relative role of all these risk factors detected in the same patients. The aim of the study was to assess the prognostic impact of muscle alterations, MHE and SPSS on hepatic encephalopathy and transplant free survival.Patients/Methods114 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) to detect MHE. CT scan was used to analyze the skeletal muscle index (SMI), muscle attenuation and SPSS. The incidence of the first episode of HE and survival were estimated.ResultsPrevious HE was present in 47 patients (41%). The variables independently associated to previous HE were: sarcopenia, MHE and SPSS. 44 patients (39%) developed overt HE during 14±11 months; MHE and SPSS were the only variables significantly asociated to overt HE. During the same follow-up, 42 patients died (37%); MELD and sarcopenia were the only variables significantly asociated to transplant free survival.ConclusionsMHE, sarcopenia and SPSS are clinically relevant and should be sought for in cirrhotics. In particular, MHE and SPSS are the only risk factors significantly associated to the development of HE while MELD and sarcopenia are independently associated to overall mortality.     

Neuropsychological impairment in severe acute viral hepatitis is due to minimal hepatic encephalopathy

Background and Aims: Minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis may have prognostic significance with regard to the development of clinical hepatic encephalopathy (HE) and deterioration in patient quality of life. Its prevalence in acute viral hepatitis (AVH) is not known. Patients and Methods: Consecutive 20 AVH patients (age, 29.9±7.9 years; M:F 18:2, hepatitis A:B:E: 2:16:2) without overt encephalopathy were evaluated for MHE and followed up. All patients underwent number connection tests – A and B, figure connection tests – A and B, digit symbol test and object assembly test and critical flicker frequency (CFF) at baseline and after the resolution of icterus. MHE was diagnosed if two or more psychometric tests were abnormal. Results: Prevalence of MHE (n=5) was 25%, which resolved on follow‐up during the anicteric resolution phase. Five (25%) patients had greater than two abnormal psychometry tests and four (20%) had CFF <38 Hz. CFF alone had sensitivity and specificity of 80 and 100%, respectively, in the diagnosis of MHE. There was significant difference in the performance of CFF during the icteric and resolution phase of AVH (40.6±3.4 vs 41.8±2.1 Hz, P=0.04). Arterial ammonia level were higher in patients with MHE compared with patients without MHE (88.2±23.5 vs 53.8±10.9 μmol/L, P=0.001). On univariate analysis fasting ammonia level at baseline was significantly associated with all the psychometric tests (P=0.001). None of the patients developed HE either in MHE group or in those who did not had MHE at baseline. Conclusions: MHE occurs in 25% of patients with AVH and resolves on follow up with recovery of AVH. Raised arterial ammonia during the icteric phase is associated with development of MHE.     

Advances in the Evaluation and Management of Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy (MHE) is a neurocognitive disorder that affects up to 80% of cirrhotic patients. Similar to overt hepatic encephalopathy, ammonia and oxidative stress play key roles in the pathogenesis of MHE. However, MHE is characterized by subtle deficits and psychomotor abnormalities that can only be elicited by specialized psychometric tests. Although no gold standard exists for the diagnosis, MHE remains an important entity for clinicians to recognize because of its negative impact on a patient’s health-related quality of life and association with driving impairment and vehicle accidents. MHE has also been associated with an increased rate in the development of overt hepatic encephalopathy and increased mortality; therefore, identification and treatment should not be delayed. Treatment to date has been focused on reducing serum ammonia levels with agents such as lactulose, probiotics, and synbiotics. MHE is a real and growing problem that is epidemic in cirrhosis, and increasing awareness of this condition is necessary for adequate management of these patients.     

Risk factors for Clostridium difficile infection in cirrhotic patients

BackgroundCirrhotic patients are susceptible to Clostridium difficile infection (CDI), however, the high risk factors are not clear. The present study aimed to identify the risk factors in cirrhotic patients with CDI.MethodsA total of 526 cirrhotic patients admitted to our hospital between May 2015 and October 2015 were included in this study. Stool samples were collected upon admission for the detection of CDI and toxin. CDI was monitored during the hospital stay. In total, 34 cases showed CDI. Then we analyzed the effects of age, sex, C. difficile colonization (CDC), multiple hospitalization, extended hospital stay, elevation of total bilirubin (TBIL), creatinine (Cr), Child-Pugh grade C, hepatic encephalopathy, hepatorenal syndrome, upper gastrointestinal hemorrhage, and exposure of antibiotics and proton pump inhibitor (PPI) on the CDI in cirrhotic patients.ResultsPatients in the CDI group had more frequent CDC, multiple hospitalization, and extended hospital stay compared to those in the non-C. difficile infection (NCDI) group. Patients in the CDI group had higher TBIL and Cr, and higher frequency of Child-Pugh grade C, hepatic encephalopathy, upper gastrointestinal hemorrhage compared with those in the NCDI group. Multiple logistic regression analysis indicated that age >60 years (OR=1.689; 95% CI: 1.135–3.128), multiple hospitalization (OR=3.346; 95% CI: 1.392–8.043), length of hospital stay >20 days (OR=1.564; 95% CI: 1.113–2.563), hypoproteinemia (OR=4.962; 95% CI: 2.053–11.996), CDC (OR=18.410; 95% CI: 6.898–49.136), hepatic encephalopathy (OR=1.357; 95% CI: 1.154–2.368), and exposure of antibiotics (OR=1.865; 95% CI: 1.213–2.863) and PPI (OR=3.125; 95% CI: 1.818–7.548) were risk factors of CDI.ConclusionsAge >60 years, multiple hospitalization, length of hospital stay >20 days, hypoproteinemia, CDC, hepatic encephalopathy, and exposure of antibiotics and PPI were risk factors for CDI in cirrhotic patients. These may contribute to the early diagnosis and monitoring of CDI in clinical practice.     

Hepatic encephalopathy: Ever closer to its big bang

Hepatic encephalopathy(HE) is a neuropsychiatric disorder that commonly complicates the course of patients with liver disease. Despite the fact that the syndrome was probably first recognized hundreds of years ago, the exact pathogenesis still remains unclear. Minimal hepatic encephalopathy(MHE) is the earliest form of HE and is estimated to affect more that 75% of patients with liver cirrhosis. It is characterized by cognitive impairment predominantly attention, reactiveness and integrative function with very subtle clinical manifestations. The development of MHE is associated with worsen in driving skills, daily activities and the increase of overall mortality. Skeletal muscle has the ability to shift from ammonia producer to ammonia detoxifying organ. Due to its large size, becomes the main ammonia detoxifying organ in case of chronic liver failure and muscular glutaminesynthase becomes important due to the failing liver and brain metabolic activity. Gut is the major glutamine consumer and ammonia producer organ in the body. Hepatocellular dysfunction due to liver disease, results in an impaired clearance of ammonium and in its interorgan trafficking. Intestinal bacteria, can also represent an extra source of ammonia production and in cirrhosis, small intestinal bacterial overgrowth and symbiosis can be observed. In the study of HE, to get close to MHE is to get closer to its big bang; and from here, to travel less transited roads such as skeletal muscle and intestine, is to go even closer. The aim of this editorial is to expose this road for further and deeper work.     

Effects of L-carnitine in patients with hepatic encephalopathy

AIM: To evaluate the influence of L-carnitine on mental conditions and ammonia effects on patients with hepatic encephalopathy (HE). METHODS: One hundred and fifty patients (10 patients with alcoholism, 41 patients with hepatitis virus B infection, 78 patients with hepatitis C virus infection, 21 patients with cryptogenetic cirrhosis) meeting the inclusion criteria were randomized into group A receiving a 90-d treatment with L-carnitine (2 g twice a day) or into group B receiving placebo in double blind. RESULTS: At the end of the study period, a significant decrease in NH4 fasting serum levels was found in patients with hepatic encephalopathy (P<0.05) after the treatment with levocarnitine (LC). Significant differences were also found between symbol digit modalities test and block design in patients with hepatic encephalopathy (P<0.05). CONCLUSION: Results of our study suggest an important protective effect of L-carnitine against ammonia-precipitated encephalopathy in cirrhotic patients.     

Predictors of Minimal Hepatic Encephalopathy in Patients with Cirrhosis

Background/Aim:

Minimal hepatic encephalopathy (MHE) impairs patient’s daily functioning of life. Predictors of MHE in cirrhotic patients have not been evaluated.

Patients and Methods:

A total of 200 cirrhotic patients (Child A, 74 [37%]; Child B, 72 [36%]; Child C, 54 [27%]) were evaluated by psychometry, P300 auditory event-related potential (P300ERP) and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry (>2 S.D.) and P300ERP (>2.5 S.D.). Univariate and multivariate logistic regression analyses were performed to determine the predictors of MHE.

Results:

Eighty-two (41%) patients were diagnosed to have MHE – 26/74 (35%) in Child A, 26/72 (36%) in Child B and 30/54 (56%) in Child C. Ninety-seven (48.5%) patients had abnormal psychometric tests, and 96 (48%) had prolonged P300ERP (>358 ms). Sixteen (16.5%) patients with abnormal psychometry had P300ERP < 358 ms, and 15 (14.5%) patients with normal psychometry results had P300ERP > 358 ms. One hundred and three patients had CFF value < 39 Hz with specificity of 86.6% and sensitivity of 72.9% for MHE. Model for end-stage liver disease (MELD) (17.9 ± 5.7 vs. 13.4 ± 4.2, P = 0.005), Child-Turcotte-Pugh (CTP) score (8.4 ± 2.5 vs. 7.7 ± 2.2, P = 0.02), ammonia (104.8 ± 37.9 vs. 72.5 ± 45.2 µmol/L, P = 0.001) and CFF (37.0 ± 2.8 vs. 41.0 ± 3.4 Hz, P = 0.001) were significantly higher in MHE as compared to non-MHE patients. Ninety-one (45.5%) patients had MELD > 15.5, 115 (57.5%) had CTP score > 7.5, while 93 (46.5%) had venous ammonia > 84.5 µmol/L. On univariate analysis, MELD (8.52 [95% CI, 4.46-16.26; P = 0.001]), CFF (17.34 [95% CI, 8.16-36.85; P = 0.001]) and venous ammonia (7.80 [95% CI, 4.11-14.81; P = 0.003]) were associated with MHE; while CTP score (1.51 [95% CI, 0.85-2.69; P = 0.30]) was not significant. On multivariate analysis, MELD, CFF and venous ammonia were predictive of MHE.

Conclusion:

Prevalence of MHE in this study was 41%; and MELD > 15.5, CFF < 39 Hz and venous ammonia > 84.5 µmol/L were predictive of MHE.     

Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis

AIM: To characterize the efficacy of rifaximin in the management of hepatic encephalopathy (HE) as several randomized controlled studies have shown contradictory results on its effectiveness in comparison to other oral agents.METHODS: We performed a systematic review and random effects meta-analysis of all eligible trials identified through electronic and manual searches. Twelve randomized controlled trials met the inclusion criteria with a total of 565 patients.RESULTS: The clinical effectiveness of rifaximin was equivalent to disaccharides or other oral antibiotics [odds ratio (OR) 0.96; 95% CI: 0.94-4.08] but with a better safety profile (OR 0.27; 95% CI: 0.12-0.59). At the completion of treatment protocols, patients receiving rifaximin showed lower serum ammonia levels [weighted mean difference (WMD) = -10.65; 95% CI: -23.4-2.1; P = 0.10], better mental status (WMD = -0.24; 95% CI: -0.57-0.08; P = 0.15) and less asterixis (WMD -0.1; 95% CI -0.26-0.07; P = 0.25) without reaching statistical significance. On the other hand, other psychometric outcomes such as electroencephalographic response and grades of portosystemic encephalopathy were superior in patients treated with rifaximin in comparison to the control group (WMD = 0.21, 95% CI: -0.33-0.09, P = 0.0004; and WMD = -2.33, 95% CI: -2.68-1.98, P = 0.00001, respectively). Subgroup and sensitivity analysis did not show any significant difference in the above findings.CONCLUSION: Rifaximin appears to be at least as effective as other conventional oral agents for the treatment of HE with a better safety profile.     

Psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in China

AIM:To construct normal values for the tests of the psychometric hepatic encephalopathy score(PHES)and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy(MHE)among Chinese individuals with cirrhosis.METHODS:The five tests of PHES,number connection test-A(NCT-A),number connection test-B,serial dotting test,line tracing test and digit symbol test(DST),were administered to all enrolled subjects in a quiet room with sufficient light.Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination.Based on the nomograms of healthy volunteers,the patients were classified as having MHE when their PHES was less than-4.RESULTS:In total,146 healthy volunteers completed all the PHES tests.Age and education years were confirmed to be predictors of all five tests.In total,53patients with liver cirrhosis completed the PHES.Of the patients with liver cirrhosis,24(45.3%),22(41.5%)and 7(13.2%)had Child-Pugh grades A,B and C,respectively.MHE was diagnosed in 26 patients(49.1%).Compared with compensated cirrhotic patients(Child A),decompensated cirrhotic patients(Child B and C)had a higher proportion of MHE(65.5%vs 29.2%).No differences in age and education years were found between the MHE and non-MHE groups.NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9%and a specificity of 96.3%(AUC=0.866,K=0.735).CONCLUSION:The proportion of MHE is associated with liver function.NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.     

益生菌对轻微肝性脑病疗效的Meta分析

目的 系统评价益生菌治疗轻微肝性脑病（minimal hepatic encephalopathy,MHE）的有效性。方法 计算机检索PubMed、EMbase、Cochrane Central Register of Controlled Trials、中国知网、万方、中国生物医学文献数据库和维普数据库,检索益生菌制剂治疗MHE的随机对照试验（randomized controlled trial,RCT）,检索时限均为建库至2020年7月26日。检索美国临床试验注册平台（ClinicalTrials.gov）进行文献补充。由2名研究人员独立筛选文献、提取数据、评价纳入研究的偏倚风险,采用RevMan 5.3进行Meta分析。结果 共纳入13篇RCT,Meta分析表明益生菌治疗组在降低血氨水平（SMD=-0.79,95%CI:-1.20～-0.37,P=0.0002）、缩短数字连接试验-A型（number connection test-type A,NCT-A）反应时间（MD=-16.31,95%CI:-22.09～-10.53,P <0.001）、降低显性肝性脑病发生率（R...