Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy.

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.

Diagnosis and management of hepatic encephalopathy.

Overt and covert hepatic encephalopathy (HE) are debilitating complications of cirrhosis. HE results in a poor quality of life for patients and their caregivers and, unless there is access to liver transplantation, the prognosis is poor. The development of overt HE is often unpredictable, and its management, particularly in the ward, remains challenging. There is an urgent need for novel approaches to treat HE. Until recently, therapies for this complication were disappointing, with frequently intolerable side effects such as diarrhoea and faecal incontinence. However, a non-absorbable antibiotic, rifaximin, * has been approved for the prevention of recurrent overt HE. It aims to reduce hospitalisation and resource use, as well as improve patients' quality of life. This article describes the practical aspects of diagnosing, classifying and managing HE. It reviews the pharmacological options for the treatment and prophylaxis of overt HE, and explores the evidence base demonstrating that rifaximin reduces the recurrence of overt HE.

Outcomes of Children With and Without Hepatic Encephalopathy From the Pediatric Acute Liver Failure Study Group.

OBJECTIVES: Hepatic encephalopathy (HE) is challenging to identify in children with acute liver failure and was not a requirement for enrollment into the Pediatric Acute Liver Failure Study Group (PALFSG). The outcomes of PALFSG participants presenting with and without HE are presented. METHODS: PALFSG participants were classified based on daily assessment of HE during the first 7 days following study enrollment: group 1-never developed HE; group 2-no HE at enrollment with subsequent HE development; and group 3-HE at study enrollment. Clinical and biochemical parameters and outcomes of death, spontaneous recovery, or liver transplantation were compared between groups. RESULTS: Data from 769 PALFSG (54% boys; median age 4.2 years; range 0-17.9 years) participants were analyzed, with 277 in group 1 (36%), 83 in group 2 (11%), and 409 in group 3 (53%). Mortality occurred in 11% of all participants and was highest among group 3 participants who demonstrated persistent grade III-IV HE (55%) or showed progression of HE (26%). Eleven (4%) group 1 participants died within 21 days of enrollment. Spontaneous recovery was highest in group 1 (79%) and lowest in group 2 (25%; P < 0.001). CONCLUSIONS: Mortality 21 days after enrollment was highest in participants enrolled with severe HE (grades III or IV) or demonstrating HE progression. Four percent of participants without recorded clinical HE in the 7 days after enrollment, however, died within 21 days. Improved assessment of neurological injury and pediatric acute liver failure prognostication schema are needed.

Challenges in diagnosing hepatic encephalopathy.

The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction.

Concise review of current concepts on nomenclature and pathophysiology of hepatic encephalopathy.

Hepatic encephalopathy is a neuropsychiatric complication of liver cirrhosis the symptoms of which may vary from imperceptible to severe, invaliding, and even lethal. Minimal hepatic encephalopathy is also important because of its tendency to impair patients' cognitive functions and quality of life. The polyetiological pathogenesis of hepatic encephalopathy is intensively studied. A general consensus exists that not only excess of ammonia but also inflammatory, oxidative, and other processes are significant in the development of hepatic encephalopathy.

[Hepatic encephalopathy: recent developments]. / Actualités diagnostiques et thérapeutiques dans le domaine de l'encéphalopathie hépatique.

Hepatic encephalopathy is a neurological syndrome occurring in patients with liver failure or in those with a large porto-systemic shunt. In cirrhotic patients, the current classification comprises covert and overt encephalopathy. Diagnosis of covert encephalopathy requires sensitive tests. Lactulose and rifaximin are the two leading therapeutic options. Rifaximin is efficacious for maintaining remission from hepatic encephalopathy. Liver transplantation should be discussed in cirrhotic patients with encephalopathy.

Acetyl-L-carnitine in hepatic encephalopathy.

Hepatic encephalopathy is a common complication of hepatic cirrhosis. The clinical diagnosis is based on two concurrent types of symptoms: impaired mental status and impaired neuromotor function. Impaired mental status is characterized by deterioration in mental status with psychomotor dysfunction, impaired memory, and increased reaction time, sensory abnormalities, poor concentration, disorientation and coma. Impaired neuromotor function include hyperreflexia, rigidity, myoclonus and asterixis. The pathogenesis of hepatic encephalopathy has not been clearly defined. The general consensus is that elevated levels of ammonia and an inflammatory response work in synergy to cause astrocyte to swell and fluid to accumulate in the brain which is thought to explain the symptoms of hepatic encephalopathy. Acetyl-L-carnitine, the short-chain ester of carnitine is endogenously produced within mitochondria and peroxisomes and is involved in the transport of acetyl-moieties across the membranes of these organelles. Acetyl-L-carnitine administration has shown the recovery of neuropsychological activities related to attention/concentration, visual scanning and tracking, psychomotor speed and mental flexibility, language short-term memory, attention, and computing ability. In fact, Acetyl-L-carnitine induces ureagenesis leading to decreased blood and brain ammonia levels. Acetyl-L-carnitine treatment decreases the severity of mental and physical fatigue, depression cognitive impairment and improves health-related quality of life. The aim of this review was to provide an explanation on the possible toxic effects of ammonia in HE and evaluate the potential clinical benefits of ALC.

Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a heterogeneous disease that develops as a result of serious liver disease, such as in fulminant hepatitis or cirrhosis, or a portosystemic shunt. It manifests as a spectrum of abnormalities involving cognition, attention, functional ability, personality and intellect. The neuropsychiatric impairment associated with HE can range from mild alteration of cognition and consciousness to coma, depending on the stage of the illness. In 1998, the World Gastroenterology Organization formed a working party to develop guidelines and recommendations for the diagnosis, grading and treatment of HE for research and practice. In this report, we discuss the various tests available for diagnosis and grading and the recommendations of the working party, which provide a framework for further studies on clinical trial methodology.

Chronic liver disease and hepatic encephalopathy: clinical profile and outcomes.

BACKGROUND: Hepatic encephalopathy (HE) is an important neuropsychiatry complication of liver disease causing significant morbidity and mortality worldwide. Efforts at improving the outcome have resulted in development of new strategies in the management given the background of new insights in the pathogenesis of this disease entity. Understanding the disease profile including precipitants as well as prognostic factors will contribute in this regard as new strategies are yet to be widely applied. The aim of this report is to document the profile of patients with HE, the precipitants, prognostic factors as well as the scope of the burden associated with it. MATERIALS AND METHODS: In this prospective study, all patients managed for HE from January to December 2008 were recruited. A questionnaire was used to extract their basic demographics, clinical features noting any possible precipitants, complications, management protocol as well as outcome. RESULTS: A total of 21 subjects (11 females and 10 males) within the age range of 16-83 years were seen during the period under review. (mean age 57.9 ± 13). There was no significant difference in the mean ages of males and females. Two patients had acute encephalopathy, while others had acute-on chronic encephalopathy. The risk factors for liver disease included significant alcohol ingestion, hepatitis B virus infection, and previous jaundice, while other complications of liver disease noted were deepening jaundice, ascites, bleeding tendencies, and renal failure. The identified precipitants for HE were sepsis 6 (29%), electrolyte inbalance 3 (14%), gastrointestinal bleed 5 (24%), drugs (5%), and possible malignant transformation 6 (29%). Focus of sepsis was bacterial peritonitis in two cases. Majority of our patients (61%) came during advanced stage of liver disease (Child-Pugh class C). Length of hospital stay ranged from 1 to 7 weeks and a mortality of 48% was observed. Predictors of mortality were a history of significant alcohol ingestion, previous blood transfusion, Hepatitis B and C infections, and severe liver dysfunction on presentation (Child-Pugh class C). CONCLUSIONS: HE is associated with a high mortality rate and this scenario is associated with a history of previous blood transfusion, Hepatitis B and C infections, and severe liver dysfunction on presentation. Measures to reduce the burden of viral Hepatitis B and C, safe blood transfusion, and responsible use of alcohol should be promoted. Screening of those at risk of encephalopathy (liver disease patients) with a psychometric test of good predictability should be part of their routine evaluation in daily practice so as to detect cases of latent encephalopathy. Intensive care facilities and necessary personnel should be provided.

Epidemiology of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a complex condition with multiple causes each with varying degrees of severity. HE negatively impacts patients' quality of life, and it is associated with significant burdens to patients and their caregivers. The prevalence of cirrhosis, the most common risk factor for HE, has steadily increased during recent years. In turn, an upsurge in the clinical and health care burdens related to HE is expected in the upcoming years. This article provides a comprehensive review of the epidemiology of HE.

Clinical Manifestations of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) occurs in patients with acute-on-chronic liver disease. It has a wide progression of symptoms, with its initial presentation being subtle. The symptoms of HE mainly affect mental status, the musculoskeletal system, and mood/behavior. Its severity ranges from minor disturbances in sleep-wake cycle to the patient being comatose. HE is categorized based on 4 main features: the underlying disease, the severity of manifestations, the time course, and whether precipitating factors are present. The severity of the manifestations is classically identified using the West Haven Criteria. There are several other clinical tests, but they require further validation.

Experimental models of hepatic encephalopathy: ISHEN guidelines.

Objectives of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Commission were to identify well-characterized animal models of hepatic encephalopathy (HE) and to highlight areas of animal modelling of the disorder that are in need of development. Features essential to HE modelling were identified. The best-characterized animal models of HE in acute liver failure, the so-called Type A HE, were found to be the hepatic devascularized rat and the rat with thioacetamide-induced toxic liver injury. In case of chronic liver failure, surgical models in the rat involving end-to-side portacaval anastomosis or bile duct ligation were considered to best model minimal/mild (Type B) HE. Unfortunately, at this time, there are no satisfactory animal models of Type C HE resulting from end-stage alcoholic liver disease or viral hepatitis, the most common aetiologies encountered in patients. The commission highlighted the urgent need for such models and of improved models of HE in chronic liver failure in general as well as a need for models of post-transplant neuropsychiatric disorders. Studies of HE pathophysiology at the cellular and molecular level continue to benefit from in vitro and or ex vivo models involving brain slices or exposure of cultured cells (principally cultured astrocytes) to toxins such as ammonia, manganese and pro-inflammatory cytokines. More attention could be paid in the future to in vitro models involving the neurovascular unit, microglia and neuronal co-cultures in relation to HE pathogenesis.

Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft.

OBJECTIVE: The purpose of this study was to review the use of an hourglass-shaped expanded polytetrafluoroethylene (ePTFE) stent-graft to reduce transjugular intrahepatic portosystemic shunts in patients with hepatic encephalopathy refractory to conventional medical therapy. MATERIALS AND METHODS: From January 2000 through December 2008, 189 transjugular intrahepatic portosystemic shunt procedures were performed with self-expanding stent-grafts. After a mean period of 43.4 +/- 57 weeks, hepatic encephalopathy developed in 12 patients and did not respond to conventional medical therapy with lactulose, nonabsorbable antibiotics, and a protein-restricted diet. In all cases, shunt reduction was performed with an hourglass-shaped balloon-expandable ePTFE stent-graft inserted into the original shunt. RESULTS: Technically successful shunt reduction with an immediate increase in portosystemic gradient was achieved in all patients. Symptoms of hepatic encephalopathy disappeared a mean of 22.3 hours (range, 18-26 hours) after the procedure. After a mean follow-up period of 73.9 +/- 61.88 weeks, no recurrence of hepatic encephalopathy was found. One patient (8.3%) needed dilation of the hourglass-shaped stent-graft after 37 weeks because of recurrence of ascites. At the end of the study, five patients (41.6%) were alive in good clinical condition. Four patients (33.3%) died of cardiovascular failure 1, 2, 24, and 96 weeks after the corrective procedure. Eight months after the reduction procedure, one patient (8.3%) underwent orthotopic liver transplantation, which resulted in clinical improvement. Two patients (16.6%) were lost to follow-up 15.6 and 46.8 weeks after the procedure. CONCLUSION: Shunt reduction with an hourglass-shaped ePTFE balloon-expandable stent-graft seems effective in reducing shunt flow and rapidly improving the patient's clinical condition. With this technique, shunt diameter can be modified on the basis of the patient's clinical condition.

Spatial memory alterations in three models of hepatic encephalopathy.

A behavioural evaluation was carried out on three chronic models of hepatic encephalopathy: two models of type B HE, portacaval shunt (PCS) and portal hypertension (PH) and one of type C HE with cirrhosis and portal hypertension from thioacetamide intoxication (TAA). The tasks selected cover a wide range of behaviours related to: locomotion (rotarod-accelerod test), anxiety (open field and elevated plus maze) and memory (Morris water maze). The results indicate that neither locomotor activity nor anxiety was affected in our models, in comparison with their respective controls. However, this is not the case for the mnesic tasks. Hence, the PCS and TAA groups displayed a severe alteration in spatial reference memory and cannot correctly perform the Morris maze task, while this alteration is less severe in the PH group. On the contrary, the PH group revealed a deficit in spatial working memory, like the TAA group, but this does not occur in subjects with PCS. These results reveal a double dissociation in spatial reference memory and spatial working memory between the PCS and PH groups, which would be of great interest to study about cerebral causes and substrates of the alterations accompanying HE.

Independent prognostic factors in patients with liver cirrhosis.

BACKGROUND/AIMS: Evaluation of the urgency of the liver transplantation in individual patients may help to prioritize patients at risk of death. Consequently we undertook the search for independent prognostic factors in patients with liver cirrhosis. METHODOLOGY: The study group was composed of 219 patients with liver cirrhosis, treated in our Department, from 1996 to 2005. Patients' files were examined for details of physical findings, results of laboratory examinations, and patients' survival. Prognostic significance of 15 variables was analyzed. All prognostic factors which turned out to be statistically significant in univariate analysis were included in the Cox proportional hazard model. RESULTS: Child-Turcotte-Pugh (CTP) score B (p<0.001; hazard ratio (HR): 13.33), CTP score C (p<0.001; HR=7.45), presence of hepato-renal syndrome (p<0.001; HR=3.54), history of esophageal bleeding (p=0.048; HR=1.63) and presence of peripheral edema (p=0.034; HR=1.61) were found to be independently associated with survival. Model of End-stage Liver Disease score, etiology of cirrhosis, sex, ascites, bacterial spontaneous peritonitis, encephalopathy, serum creatinine concentration, INR and serum bilirubin concentration were shown to be significantly associated with patients' prognosis, however not independently. CONCLUSIONS: Analysis of presence of common clinical symptoms is crucial for evaluation of patients' prognosis.

Subnetwork mining on functional connectivity network for classification of minimal hepatic encephalopathy.

Hepatic encephalopathy (HE), as a complication of cirrhosis, is a serious brain disease, which may lead to death. Accurate diagnosis of HE and its intermediate stage, i.e., minimal HE (MHE), is very important for possibly early diagnosis and treatment. Brain connectivity network, as a simple representation of brain interaction, has been widely used for the brain disease (e.g., HE and MHE) analysis. However, those studies mainly focus on finding disease-related abnormal connectivity between brain regions, although a large number of studies have indicated that some brain diseases are usually related to local structure of brain connectivity network (i.e., subnetwork), rather than solely on some single brain regions or connectivities. Also, mining such disease-related subnetwork is a challenging task because of the complexity of brain network. To address this problem, we proposed a novel frequent-subnetwork-based method to mine disease-related subnetworks for MHE classification. Specifically, we first mine frequent subnetworks from both groups, i.e., MHE patients and non-HE (NHE) patients, respectively. Then we used the graph-kernel based method to select the most discriminative subnetworks for subsequent classification. We evaluate our proposed method on a MHE dataset with 77 cirrhosis patients, including 38 MHE patients and 39 NHE patients. The results demonstrate that our proposed method can not only obtain the improved classification performance in comparison with state-of-the-art network-based methods, but also identify disease-related subnetworks which can help us better understand the pathology of the brain diseases.

Hepatic encephalopathy: a critical current review.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.

Plasma met-enkephalin, beta-endorphin and leu-enkephalin levels in human hepatic encephalopathy.

To address the role of the opioid system in the pathogenesis of hepatic encephalopathy (HE) we measured plasma met-enkephalin, beta-endorphin and leu-enkephalin in patients with different grades of HE compared to control subjects and patients with cirrhosis. Plasma met-enkephalin levels were significantly higher in patients with cirrhosis and all grades of HE than controls. Plasma beta-endorphin levels were similar in the 3 groups. Plasma leu-enkephalin levels were significantly higher in HE grades II, III and IV than in controls, patients with cirrhosis and HE grade I patients. Our results support data on the involvement of met-enkephalin and leu-enkephalin in the pathogenesis of HE and provide a rationale for the use of opioid receptor antagonists in the treatment of HE.