Risk Of Overt Hepatic Encephalopathy Research Articles

P: 38 Rifaximin Reduces the Incidence of Spontaneous Bacterial Peritonitis, Variceal Bleeding and All-cause Admissions in Patients on the Liver Transplant Waiting List

BACKGROUND: Rifaximin reduces the risk of overt hepatic encephalopathy (HE) in patients with advanced chronic liver disease (ACLD) and is associated with significant reductions in hospitalisations and 30‐day readmissions. This study examined clinical outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug. METHODS: Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment. Information collected included patient demographics, aetiology of liver disease, disease severity scoring at transplant listing, concomitant medications and medical co-morbidities. Emergency admissions whilst on the waiting list for complications of ACLD in addition to requirement for prioritisation (UKELD score ≥63), duration on the waiting list (days) and mortality on the waiting list were recorded. Univariate and multivariate regression analyses were performed on acute admission and complication data (related to sepsis, acute variceal bleeding (AVB), HE and complications of ascites) with rifaximin use as the independent variable. RESULTS: Of the 622 patients listed for transplantation, 101 were listed with HE. 66 patients were treated with rifaximin and 35 were naïve at listing. Median MELD score was similar (15 [14–16)] rifaximin-treated and 16 [14–18] rifaximin-naïve). The use of lactulose was not significantly different between groups. Patients on the waiting list treated with rifaximin had an independent association with reduced all-cause admissions (P = 0.037), episodes of spontaneous bacterial peritonitis (P = 0.008) and AVB (P = 0.026). Mean length of hospital stay was 9 (95% CI 6–12) in the rifaximin-treated group vs 14 days (95% CI 7–21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in days to readmission (adjusted effect estimate 71, 95% CI 3–140 days, P = 0.037) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89–0.93, P = 0.037). CONCLUSION: Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes on the waiting list with a significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and AVB and indicating potential beneficial impacts of rifaximin beyond HE in ACLD.

P: 70 Quality of Life Assessment May Aid in the Diagnosis of Minimal Hepatic Encephalopathy and Prediction of Overt Hepatic Encephalopathy

BACKGROUND: Minimal hepatic encephalopathy (MHE) impinges on quality of life (QoL), is associated with a high risk of overt hepatic encephalopathy (OHE) and is often treatable by simple means. Still, MHE is rarely systematically diagnosed and treated likely because dedicated psychometric tests give the impression of being resource heavy and thus scare off many clinicians. Simple, patient-administered QoL questionnaires e.g. sickness impact profile (SIP), could improve diagnostic rates. This approach was tested in a US-based study introducing SIPCHE score (formula of 4 SIP statements, gender and age). We here aim at externally validate SIPCHE score in a cirrhotic cohort using continuous reaction time (CRT) test and portosystemic hepatic encephalopathy score (PHES) for MHE diagnosis. METHODS: 110 cirrhotic patients without OHE (age 60 years, MELD 11.4, 80% blue-collar) completed cognitive testing and SIP. Abnormal CRT and/or PHES diagnosed MHE. SIP consists of 136 questions inquiring about QoL and standardized QoL scores were compared in MHE and non-MHE patients. The SIPCHE (US cut point >0) was applied and predictive values were calculated. We followed the patients for 2.7 years on average and registered OHE episodes. RESULTS: The SIPCHE was abnormal in 82/110 patients and was in agreement with the psychometric tests in 73/110 cases (66%). The SIPCHE indicated MHE in 58/71 of the patients with MHE according to 2-test psychometry (positive predictive value = 71%, sensitivity = 82%, AUUROC 0.63). The SIPCHE was false positive in 24/39 non-MHE patients (specificity 38%, NPV 53%). A normal SIPCHE did not exclude MHE in our population as 13/28 (46%) with a normal SIPCHE score had MHE according to the CRT and PSE tests. In our cohort using a cut point of >−0.40, in stead of >0, sligthly improved correct classification to 72% of patients. Only 4/28 (14%) with a normal baseline SIPCHE experienced OHE, while 29/82 (35%) with abnormal SIPCHE experienced OHE (P = 0.05). Accordingly, the SIPCHE positive predictive value for a future HE episode is this 87% (likelihood ratio 2.4). CONCLUSIONS: In conclusion, the idea of a patient-reported outcome score as an addition to standard psychometry is appealing. The US derived SIPCHE score is able to identify the majority of patients with MHE and future OHE episodes, but lacks diagnostic specificity. We suggest that development of regional SIPCHE scores could be useful. In future studies using the SIPCHE as a measure of patients-experienced effect of MHE treatment would be of interest.

Muscle Alterations Are Associated With Minimal and Overt Hepatic Encephalopathy in Patients With Liver Cirrhosis.

Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications including overt hepatic encephalopathy (HE). The aim of our study was to investigate the relationship between muscle alterations and minimal HE (MHE) and their role in the risk of overt HE. Sixty-four patients with cirrhosis were administered the Psychometric Hepatic Encephalopathy Score and animal naming test to detect MHE. Computed tomography was used to analyze the skeletal muscle index and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%), and MHE in 32 (50%). Both myosteatosis (62.5% versus 12.5%, P<0.001) and sarcopenia (84% versus 31%, P<0.001) were more frequent in patients with MHE. The variables independently associated with the presence of MHE were sarcopenia, previous overt HE, and myosteatosis. Thirty-one (48%) patients developed overt HE over 16.1±13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated with the development of overt HE. Venous ammonia was significantly higher in patients with sarcopenia (62.6±17.7 versus 41.4±16.1 μg/dL, P<0.001) and in patients with myosteatosis (65.2±19.2 versus 46.7±17.1 μg/dL, P<0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared to patients without myosteatosis or sarcopenia (P<0.001). Conclusion: Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE and the risk of overt HE in patients with cirrhosis; in malnourished patients, the amelioration of nutritional status may be a goal to decrease both the prevalence of MHE and the incidence of overt HE.

Long-term effects and complications of the transjugular intrahepatic portosystemic shunt: a single-centre experience

Background and aims: Accurate estimates of the long-term risks of adverse outcomes after transjugular intrahepatic portosystemic shunt (TIPS) treatment are needed. The aim of this cohort study was to estimate the risks of stent dysfunction, variceal bleeding, refractory ascites, hepatic encephalopathy (HE), and death after TIPS treatment.Methods: We extracted data from electronic medical records of 104 consecutive TIPS patients. Gore® Viatorr® TIPS endoprostheses were used in all patients. We conducted competing risks analysis of the risk of stent dysfunction and variceal bleeding, and Kaplan–Meier estimation of overall survival.Results: The overall 1-year survival after TIPS insertion was 82% (95% confidence interval [CI]: 73–88%), and the 1-year risk of stent dysfunction was 15% (95% CI: 9–22%). In patients who had a TIPS for variceal bleeding, the 1-year risk of rebleeding was 23% (95% CI: 13–35%). In patients who had a TIPS for refractory ascites, the risk of having an unsuccessful ascites outcome 1 year after TIPS for refractory ascites was 35% (95% CI: 21–52%). Overall, the 1-year risk of overt HE was 38% (95% CI: 32–43%). The risk of experiencing any of the defined complications during the first year was 56% (95% CI: 45–66%).Conclusion: TIPS is an effective treatment for variceal bleeding and refractory ascites in most cases, but more than half of the patients experience either death, stent dysfunction, recurrence of symptoms, or overt HE within the first year after the procedure.

Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list.

SummaryBackgroundRifaximin reduces the risk of overt hepatic encephalopathy (HE) and is associated with significant reductions in hospitalisations and 30‐day readmissions.AimTo examine the outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.MethodsPatient records of those listed for liver transplantation over a 2‐year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment.ResultsOf the 622 patients listed for transplantation, 101 had HE. Sixty‐six patients were treated with rifaximin and 35 were naïve at listing. The use of concurrent lactulose was not significantly different between groups. Median MELD score was similar (15 [14‐16)] rifaximin‐treated and 16 [14‐18] rifaximin‐naïve). Patients on the waiting list treated with rifaximin had reduced all‐cause admissions, episodes of spontaneous bacterial peritonitis and variceal bleeding. Mean length of stay was 9 days (95% CI 6‐12) in the rifaximin‐treated group vs 14 (95% CI 7‐21) in the rifaximin‐naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in average days to readmission (adjusted effect estimate 71, 95% CI 3‐140 days) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89‐0.93).ConclusionRifaximin prescribed for HE in patients listed for liver transplantation improved outcomes with significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and variceal bleeding.

Predicting Overt Hepatic Encephalopathy for the Population With Cirrhosis

Hepatic encephalopathy (HE) is associated with poor quality of life, sharply increased mortality, repeated hospitalizations, falls, and motor vehicle accidents. HE manifests with a dynamic spectrum of severity. Overt HE is clinically obvious disorientation, even coma. Although multiple strategies are available to characterize early-stage HE, data are limited that validate these methods in predicting overt HE, many are impractical in clinical practice, and test cutoffs relevant to the average patient clinicians manage are lacking. To accurately and efficiently classify the risk of overt HE in the population with cirrhosis, novel strategies may be needed. Herein, we review the potential competing strategies for the prediction of overt HE. Conclusion: We propose refining diagnostic cutoffs for tests that are designed to define early HE, using overt HE as a gold standard and expanding prediction tools by using measures of components from the risk pathway for HE.

584 – Efficacy and Safety of Rifaximin Treatment for Reducing the Risk of Overt Hepatic Encephalopathy by Baseline Hepatic Impairment

584 – Efficacy and Safety of Rifaximin Treatment for Reducing the Risk of Overt Hepatic Encephalopathy by Baseline Hepatic Impairment

Understanding the impact of neurologic complications in patients with cirrhosis.

Patients with cirrhosis may experience neurologic complications, including hepatic encephalopathy. Hepatic encephalopathy may be classified as covert (mild symptoms (e.g. lack of awareness)) or overt (moderate to severe symptoms (e.g. confusion or coma)), and symptoms may overlap with other neurologic conditions (e.g. epilepsy, stroke). Managing hepatic encephalopathy includes identifying and treating precipitating factors (e.g. dehydration). First-line treatment for patients with overt hepatic encephalopathy is typically lactulose; to reduce the risk of overt hepatic encephalopathy recurrence, lactulose plus the nonsystemic antibiotic rifaximin is recommended. Rifaximin reduced the risk of breakthrough overt hepatic encephalopathy by 58% versus placebo over 6 months (p < 0.001; 91% of patients in each group were on concomitant lactulose). However, neither pharmacologic hepatic encephalopathy treatment nor liver transplantation may completely reverse neurologic impairment in patients with hepatic encephalopathy. Additional neurologic considerations for patients with cirrhosis include preventing falls, as well as managing sleep-related issues, hyponatremia, and cerebral edema. Thus, monitoring neurologic impairment is an important component in the management of patients with cirrhosis.

Association of serum albumin level with incidence and mortality of overt hepatic encephalopathy in cirrhosis during hospitalization.

Background:Hepatic encephalopathy (HE) is a serious complication of cirrhosis. Decreased serum albumin (ALB) level may facilitate the development of HE and accelerate the death of cirrhotic patients with HE. Recent evidence also suggests that human albumin infusion may reduce the incidence of HE and improve the outcomes of cirrhotic patients. This study aimed to explore the association of serum ALB level with the development of overt HE and HE-associated mortality during hospitalization.Methods:Cirrhotic patients admitted to our hospital between January 2010 and February 2019 were screened. Independent predictors for HE were identified by logistic regression analyses. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated. Area under curve (AUC) was calculated by receiver operator characteristic curve analyses.Results:Of the 2376 included patients with cirrhosis but without HE at admission, 113 (4.8%) developed overt HE during hospitalizations. ALB level (OR = 0.878, 95% CI = 0.834–0.924) was an independent risk factor for development of overt HE. AUC of ALB level for predicting the development of overt HE was 0.770 (95% CI = 0.752–0.787, p < 0.0001), and the best cut-off value was ⩽31.6 g/l. Of the 183 included patients with cirrhosis and overt HE at admission, 20 (10.9%) died during hospitalizations. ALB level (OR = 0.864, 95% CI = 0.771–0.967) was an independent risk factor for death from overt HE. The AUC of ALB level for predicting death from overt HE was 0.737 (95% CI = 0.667–0.799, p = 0.0001), and the best cut-off value was ⩽22.8 g/l.Conclusions:Decreased serum ALB level may be associated with higher risk of overt HE and HE-associated mortality during hospitalizations in cirrhosis.

Efficacy and Safety of Rifaximin Treatment for Reducing the Risk of Overt Hepatic Encephalopathy by Baseline Hepatic Impairment

Introduction: Rifaximin is indicated for reducing the risk of overt hepatic encephalopathy (OHE) recurrence in adults. This analysis, in a population with cirrhosis, evaluated rifaximin for reducing the risk of OHE recurrence, assessed by patient baseline hepatic impairment. Methods: In a randomized, double-blind trial, adults with cirrhosis with a history of ≥2 OHE episodes during the previous 6 months, currently in HE remission (Conn score ≤1), received rifaximin 550 mg twice daily (BID) or placebo for up to 6 months.1 This post hoc analysis evaluated time to first breakthough OHE episode in patients stratified by baseline Child-Pugh class (A, B, or C). Breakthrough OHE was defined as an increase in Conn score to ≥2 or an increase in both Conn score and asterixis score of 1 grade each for patients entering with a Conn score of 0. Results: Overall, 140 (rifaximin) and 159 (placebo) patients were treated; mean age was 55.5 vs 56.8 y; 53.6% vs 67.3% of patients were male; 91.4% vs 91.2% used concomitant lactulose; and 46 vs 56 patients were classified as Child-Pugh class A at baseline, 65 vs 72 patients as class B, and 17 vs 14 patients as class C. There were no notable differences between rifaximin and placebo groups in mean number of days of treatment across baseline Child-Pugh classes. OHE breakthrough episodes were reported in 17.4% of patients in rifaximin group vs 46.4% in placebo group for Child-Pugh class A, 23.1% vs 44.4% for class B, and 29.4% vs 64.3% for class C. Treatment with rifaximin resulted in 66%, 56%, and 66% reduction in risk of breakthrough OHE vs placebo for Child-Pugh class A, B, and C, respectively: class A, hazards ratio (HR), 0.34 (95% CI, 0.15, 0.75; P=0.005); class B, HR, 0.44 (95% CI, 0.24, 0.82; P=0.007); and class C, HR, 0.34 (95% CI, 0.12, 1.04; P=0.047). Incidence of serious adverse events (SAEs) was generally similar in rifaximin vs placebo groups across classes: class A (28.3% vs 41.1%), class B (38.5% vs 36.1%), and class C (47.1% vs 50.0%). There were no apparent trends in between-group differences (rifaximin vs placebo) in types and frequencies of SAEs in each class. Conclusion: Regardless of Child-Pugh class of hepatic impairment, treatment with rifaximin 550 mg BID (plus lactulose [˜91% of patients]) significantly reduced the risk of OHE recurrence (up to 66% vs placebo [lactulose alone; ˜91%]) and was safe and well tolerated in patients with cirrhosis.

Skeletal Muscle Abnormalities Increase the Risk of Overt Hepatic Encephalopathy and Hyperammonemia in Patients With Cirrhosis

Background and Aim: Skeletal muscle abnormalities, such as sarcopenia and myosteatosis are frequent complications of cirrhosis and are associated with increased morbidity and mortality. Hyperammonemia plays a significant role in the pathogenesis of hepatic encephalopathy (HE). Skeletal muscle have a significant compensatory part in detoxifying ammonia during liver disease since it houses the enzyme glutamine synthetase, an important ammonia-removing pathway during the amination of glutamate to glutamine. Therefore, we aimed to investigate whether reduced quantity and quality of muscle is associated with hyperammonemia, HE and mortality in patients with cirrhosis. Methods: A total of 677 cirrhotic patients were evaluated. Computed tomography (CT) scans were used to analyze the skeletal muscle (transverse CT image at the level of the 3rd. lumbar vertebra (L3) was selected from each scan) and sarcopenia and myosteatosis was evaluated. Overt HE was assessed clinically and ammonia blood levels were performed at the time of the muscularity assessment. Results: Sarcopenia was noted in 292 patients (43%), and 352 patients had myosteatosis (52%). A total of 225 patients (33%) had history of overt HE and 221 (of 267) patients (83%) had hyperammonemia. The prevalence of overt HE was higher in patients with sarcopenia (42% vs. 27%, P < 0.001), and myosteatosis (41% vs. 25%, P < 0.001). By multivariable regression analysis, sarcopenia and myosteatosis were independently associated with higher risk of overt HE (HR 1.89, P = 0.007, HR 1.68, P = 0.03) and hyperammonemia (HR 1.71, P = 0.006, HR 1.88, P = 0.001, respectively). Median survival was worse in patients with overt HE and sarcopenia (18 ± 4 vs. 42 ± 7 months, P = 0.01), hyperammonemia and sarcopenia (11 ± 7 vs. 38 ± 16 months, P < 0.001), and myosteatosis and hyperammonemia (19 ± 3 vs. 38 ± 20 months, P = 0.005) compared to patients without these factors. Conclusions: Cirrhotic patients with sarcopenia and myosteatosis have a higher risk of hyperammonemia and overt HE. Further, skeletal muscle abnormalities present concomitantly with HE and hyperammonemia increase the risk of mortality in these patients. The authors have none to declare.

RiMINI - the influence of rifaximin on minimal hepatic encephalopathy (MHE) and on the intestinal microbiome in patients with liver cirrhosis: study protocol for a randomized controlled trial.

BackgroundHepatic encephalopathy (HE) is a clinically significant complication of liver cirrhosis impacting on the patients’ quality of life. Minimal hepatic encephalopathy (MHE) is diagnosed by psychometric tests, found in up to 80 % of patients with liver cirrhosis and carries a high risk of progression to overt HE. Continuous therapy with rifaximin in combination with lactulose significantly reduces the risk of overt HE, recurrence of HE and HE-related hospitalizations in randomized, double-blind, placebo-controlled clinical trials. Rifaximin is approved for the therapy of overt HE in Germany. Treatment with lactulose has been shown to improve cognitive functions in patients with liver cirrhosis. Data from prospective clinical trials comparing the efficacy of rifaximin alone against a combination of rifaximin and lactulose in the treatment of MHE are scarce. Changes in the microbiome of the upper and lower gastrointestinal tract as a result of therapy with rifaximin have not yet been addressed in clinical studies.Methods and designRiMINI is a monocentric exploratory pilot study on 60 patients with MHE as assessed by critical flicker frequency (CFF). Additionally, visual evoked potentials’ (VEP) testing, electroencephalography (EEG) and psychometric testing (NCT-A) will be carried out. Patients will be randomized to treatment either with rifaximin alone (550 mg twice daily (bid) continuously for a period of 3 months) or with rifaximin (550 mg bid continuously) in combination with lactulose (30–60 ml daily) for 3 months. An esophagogastroduodenoscopy (EGD) will be performed at baseline, at the end of treatment and 6 and 12 weeks after the end of treatment to obtain gastric and duodenal biopsies and aspirates. The samples will be analyzed for their content of specific bacterial taxae by applying next generation sequencing (NGS) after rRNA isolation to identify the microbiome of the stomach and duodenum, and of the gut, in patients with liver cirrhosis and MHE before and after therapy.DiscussionDifferences of the effect of antibiotic therapy with rifaximin alone or in combination with lactulose on the clinical course of MHE are assessed.Trial registrationThe trial was registered as DRKS00006359 on March 17th 2015, with the universal trial number U1111-1163-9410 and with EudraCT2013-004414-18.

Rifaximin: a nonsystemic rifamycin antibiotic for gastrointestinal infections

Use of nonsystemic antimicrobials with activity against enteropathogens is a promising approach for treatment of infectious diarrhea and other nonsystemic gastrointestinal infections. Rifaximin is approved by the US FDA for the treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in patients aged 12 years and older, and for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients aged 18 years or older. Rifaximin has been available in Italy since 1987 and overall is approved in 33 countries for various conditions, such as acute and chronic infections, bacterial diarrhea, HE, and pre- and postsurgical prophylaxis. There is accumulating evidence on the benefit of rifaximin for nonsystemic gastrointestinal infections. This article will serve as an update on rifaximin. The pharmacology and pharmacodynamics of rifaximin along with an updated review on the bacterial susceptibility to rifaximin will be presented. Finally, clinical trials with rifaximin for nonsystemic gastrointestinal indications will be updated.

S1839 Pharmacokinetic (PK) and Safety Analyses of a Novel Ammonia-Reducing Agent in Healthy Adults and Patients with Cirrhosis

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is associated with a poor quality of life and difficulty in driving. It has also been suggested that MHE can precede the development of overt hepatic encephalopathy (OHE). No gold standard exists to detect MHE. Therefore the prevalence of this entity varies depending on the diagnostic methods used. Aims & Methods: To assess: a) the prevalence of MHE using standard (1) and nonstandard diagnostic methods, b) the usefulness of these tests for predicting of OHE, 51 patients with liver cirrhosis and portal hypertension (29 with primary biliary cirrhosis, 22 with HCV infection) were studied. In all patients we performed seven diagnostic tests: four psychometric tests (NTC-A, NTC-B, DST, BDT), EEG, spectral EEG, P300 auditory event related potential, critical flicker frequency (CFF), proton magnetic resonance spectroscopy of the brain (1HMRS) and serum concentration of astroglial protein S100β.Patients were followed up for a period of 4 years. Results: Based on the psychometric tests, 9 out of 51 patients (17.6%, 95% CI 7-28) were diagnosed to have MHE. If the results of EEG, P300 and spectral EEG were added, the prevalence of MHE raised to 16 of 51 patients (31.3%, 95% CI 18-44). Addition one nonstandard test (CFF, 1HMRS or S100β) raised the percentage of patients suspected of MHE to above 40%. During follow up OHE developed in 14 patients but MHE in this group was earlier diagnosed using psychometric tests in only 10 patients. Twelve of 14 patients with OHE had at least one abnormal result out of the seven tests. Multiple proportional hazard regression model showed a higher risk of OHE in patients with abnormal EEG (HR 8.4, 95% CI 2.6 -27.3, p < 0.001). Other factors, including psychometric and standard and nonstandard tests, did not predict the OHE. Conclusions: 1. Diagnosis of minimal hepatic encephalopathy needs further standardization. 2. Among the seven different diagnostic methods, only EEG has a predicting value for overt hepatic encephalopathy in cirrhotic patients. Reference: 1.Ferenci P.et al: Hepatology.2002;35:716 Supported by grant MNiSzW 3PO5B03926

S1838 Usefulness of a Large Set of Tests for the Diagnosis of Hepatic Encephalopathy

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is associated with a poor quality of life and difficulty in driving. It has also been suggested that MHE can precede the development of overt hepatic encephalopathy (OHE). No gold standard exists to detect MHE. Therefore the prevalence of this entity varies depending on the diagnostic methods used. Aims & Methods: To assess: a) the prevalence of MHE using standard (1) and nonstandard diagnostic methods, b) the usefulness of these tests for predicting of OHE, 51 patients with liver cirrhosis and portal hypertension (29 with primary biliary cirrhosis, 22 with HCV infection) were studied. In all patients we performed seven diagnostic tests: four psychometric tests (NTC-A, NTC-B, DST, BDT), EEG, spectral EEG, P300 auditory event related potential, critical flicker frequency (CFF), proton magnetic resonance spectroscopy of the brain (1HMRS) and serum concentration of astroglial protein S100β.Patients were followed up for a period of 4 years. Results: Based on the psychometric tests, 9 out of 51 patients (17.6%, 95% CI 7-28) were diagnosed to have MHE. If the results of EEG, P300 and spectral EEG were added, the prevalence of MHE raised to 16 of 51 patients (31.3%, 95% CI 18-44). Addition one nonstandard test (CFF, 1HMRS or S100β) raised the percentage of patients suspected of MHE to above 40%. During follow up OHE developed in 14 patients but MHE in this group was earlier diagnosed using psychometric tests in only 10 patients. Twelve of 14 patients with OHE had at least one abnormal result out of the seven tests. Multiple proportional hazard regression model showed a higher risk of OHE in patients with abnormal EEG (HR 8.4, 95% CI 2.6 -27.3, p < 0.001). Other factors, including psychometric and standard and nonstandard tests, did not predict the OHE. Conclusions: 1. Diagnosis of minimal hepatic encephalopathy needs further standardization. 2. Among the seven different diagnostic methods, only EEG has a predicting value for overt hepatic encephalopathy in cirrhotic patients. Reference: 1.Ferenci P.et al: Hepatology.2002;35:716 Supported by grant MNiSzW 3PO5B03926

Gut ammonia production and its modulation

Systemic hyperammonemia has been largely found in patients with cirrhosis and hepatic encephalopathy, and ammonia plays a major role in the pathogenesis of hepatic encephalopathy. However, controversial points remain: a) the correlation between plasma ammonia levels and neurophysiological impairment. The lack of correlation between ammonia levels and grade of hepatic encephalopathy in some cases has been considered a weakness of the ammonia hypothesis, but new methods for ammonia measurements and the implication of systemic inflammation in the modulation of ammonia neurotoxicity could explain this gap; b) the source of ammonia production. Hyperammonemia has been considered as derived from urea breakdown by intestinal bacteria and the majority of treatments were targeted against bacteria-derived ammonia from the colon. However, some data suggest an important role for small intestine ammonia production: 1) the hyperammonemia after porto-caval shunted rats has been found similar in germ-free than in non-germ-free animals. 2) In cirrhotic patients the greatest hyperammonemia was found in portal drained viscera and derived mainly from glutamine deamination. 3) The amount of time required to increase of ammonia (less than one hour) after oral glutamine challenge supports a small intestine origin of the hyperammonemia. As the main source of ammonia in cirrhotics derives from portal drained viscera owing to glutamine deamidation, increased glutaminase activity in the intestine seems to be responsible for systemic hyperammonemia. Lastly, some genetic alterations in the glutaminase gene such as the haplotype TACC could modulate intestinal ammonia production and the risk of overt hepatic encephalopathy in cirrhotics.

Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy

Background/Aims: We assessed the usefulness of oral glutamine challenge (OGC) and minimal hepatic encephalopathy in evaluating risk of overt hepatic encephalopathy in cirrhotic patients. Methods: Minimal hepatic encephalopathy (MHE) was inferred using neuro-psychological tests. Venous ammonia concentrations were measured pre- and post-60 min (NH 3-60m) of a 10 g oral glutamine load. Receiver-operating-characteristic curve analysis indicated a pathological glutamine tolerance cut-off value of NH 3-60m >128 μg/dl. Results: In healthy control subjects ( n=10) ammonia concentrations remained unchanged but increased significantly in cirrhotic patients (from 70.41±45.2 to 127.43±78.6; P<0.001). In multiple logistic regression analysis, altered OGC was related to Child-Pugh (odds ratio, OR=7.69; 95% confidence interval, CI=1.72–33.3; P<0.01) and MHE (OR=5.45; 95% CI=1.17–25.4; P<0.05). In the follow-up 11 patients (15%) developed overt hepatic encephalopathy (HE). In multivariate analysis OGC (OR=14.5; 95% CI=1.26–126.3) and MHE (OR=1.56; 95% CI=1.02–21.9) were independently related with HE in the follow-up. Patients with MHE and altered OGC showed significantly higher risk of overt HE in the follow-up (60%) than patients without MHE and normal OGC (2.8%) (Log rank test=21.60; P<0.0001). Conclusions: A pathological OGC in patients with MHE appears to be a prognostic factor for the development of overt hepatic encephalopathy, whereas a normal OGC in patients without MHE could exclude risk of overt HE.