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.

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.

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.

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.

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.

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.

Hepatic Encephalopathy-the Old and the New.

Hepatic encephalopathy occurs ubiquitously in all causes of advanced liver failure, however, its implications on mortality diverge and vary depending upon acuity and severity of liver failure. This associated mortality has decreased in subsets of liver failure over the last 20 years. Aside from liver transplantation, this improvement is not attributable to a single intervention but likely to a combination of practical advances in critical care management. Misconceptions surrounding many facets of hepatic encephalopathy exists due to heterogeneity in presentation, pathophysiology and outcome. This review is intended to highlight the important concepts, rationales and strategies for managing hepatic encephalopathy.

From Child-Pugh to Model for End-Stage Liver Disease: Deciding Who Needs a Liver Transplant.

This article reviews the historical evolution of the liver transplant organ allocation policy and the indications/contraindications for liver transplant, and provides an overview of the liver transplant evaluation process. The article is intended to help internists determine whether and when referral to a liver transplant center is indicated, and to help internists to counsel patients whose initial evaluation at a transplant center is pending.

[Hepatic encephalopathy ­ the acute management]. / Hepatisk encefalopati-det akuta omhändertagandet.

Hepatic encephalopathy causes significant impairment and morbidity. Hepatic encephalopathy is just one of many causes for altered mental status in patients with cirrhosis of the liver. The initial management at admission to hospital includes a search for differential diagnoses and precipitating factors. A structured description of the type, cause, time course and clinical severity is essential for achieving medically safe communication and care of the HE patient. Lactulose and correction of any precipitating factors is the basis for initial therapy. A post-discharge management which includes frequent monitoring, preventive measures as well as education of patient and caregivers may ameliorate the often very high readmission rate.

Hepatic encephalopathy for the hospitalist.

The care of patients with advanced liver disease is often complicated by episodes of acute decline in alertness and cognition, termed hepatic encephalopathy (HE). Hospitalists must be familiar with HE, as it is a common reason for hospitalization in this population and is associated with significantly increased mortality. This narrative review addresses common issues related to diagnosis and classification, precipitants, inpatient management, and transitions of care for patients with HE. The initial presentation can be variable, and HE remains a clinical diagnosis. The spectrum of HE manifestations spans from mild, subclinical cognitive deficits to overt coma. The West Haven scoring system is the most widely used classification system for HE. Various metabolic insults may precipitate HE, and providers must specifically seek to rule out infection and bleeding in cirrhotic patients presenting with altered cognition. This is consistent with the 4-pronged approach of the American Association for the Study of Liver Disease practice guidelines. Patients with HE are typically treated primarily with nonabsorbable disaccharide laxatives, often with adjunctive rifaximin. The evidence for these agents is discussed, and available support for other treatment options is presented. Management issues relevant to general hospitalists include those related to acute pain management, decisional capacity, and HE following transjugular intrahepatic portosystemic shunt placement. These issues are examined individually. Successfully transitioning patients recovering from HE to outpatient care requires open communication with multiple role players including patients, caregivers, and outpatient providers. Journal of Hospital Medicine 2016;11:591-594. © 2016 Society of Hospital Medicine.

Ammonia and Its Role in the Pathogenesis of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a commonly encountered sequela of chronic liver disease and cirrhosis with significant associated morbidity and mortality. Although ammonia is implicated in the pathogenesis of HE, the exact underlying mechanisms still remain poorly understood. Its role in the urea cycle, astrocyte swelling, and glutamine and gamma-amino-n-butyric acid systems suggests that the pathogenesis is multifaceted. Greater understanding in its underlying mechanism may offer more targeted therapeutic options in the future, and thus further research is necessary to fully understand the pathogenesis of HE.

Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity.

OBJECTIVE: To evaluate regional cerebral metabolic changes in minimal hepatic encephalopathy (MHE) patients using magnetic resonance spectroscopy (MRS) in 3T scanner. MATERIALS AND METHODS: This study comprised 30 cirrhotic patients with MHE, 29 cirrhotic patients without MHE and 30 healthy volunteers. Single-voxel proton MRS data in the anterior cingulate cortex (ACC) and basal ganglia were acquired using a 3-T scanner. The concentrations of N-acetylaspartate (NAA), mI (myo-inositol), glutamate (Glu), glutamine (Gln) and creatine (Cr) were obtained by LC-model software. Statistical analysis was performed to evaluate the differences between the three groups. RESULTS: There was a significant increase in Glu for the cirrhotic patients, particularly the MHE patients. There was an elevation of Gln in the cirrhotic patients, but not in all cirrhotic patients or controls. There was a significant decrease in mI for the cirrhotic patients, but no significant difference between the two cirrhosis groups. There was no significant difference in NAA between the three groups. CONCLUSIONS: MRS using a 3-T MR scanner could detect cerebral metabolic changes in cirrhotic patients with MHE. Glu levels were elevated in cirrhotic patients with MHE; Glu levels could be used as a sensitive indicator to evaluate the severity of MHE in patients with cirrhosis.

Bispectral index monitoring for diagnosis and assessment of severity of hepatic encephalopathy in cirrhotic patients.

BACKGROUND: Recent evidence suggests that bispectral index may aid in the diagnosis of hepatic encephalopathy. We evaluated its utility to diagnose, grade and monitor clinical course of hepatic encephalopathy in patients with cirrhosis. METHODS: 200 patients (70.5% males, mean age 39.5±9.1 years) with cirrhosis and 20 healthy controls were enrolled prospectively. Cirrhotic patients were divided into groups based on encephalopathy grades I-IV assessed by West Haven criteria; minimal encephalopathy was assessed by psychometric tests. Bispectral index was measured at baseline and after one week of lactulose therapy in patients with overt encephalopathy, and after 3 months in patients with minimal encephalopathy. RESULTS: Bispectral index scores were significantly different in patients with different grades of encephalopathy; 79.5±4.2, 67.5±4.3, 56.4±3.5, 44.8±3.9 and 85.0±4.3 respectively for grade I, II, III, IV overt and minimal hepatic encephalopathy, but similar (92.6±3.7 vs 93.75±2.8) in cirrhotics without encephalopathy and healthy controls. Bispectral scores' cut off values for minimal and overt encephalopathy grade I, II, III, IV were 90.5 and 77.5, 70.5, 60.5, 50.5, respectively. Changes in bispectral index after treatment corresponded to cut-off scores for grades of overt and minimal hepatic encephalopathy. CONCLUSIONS: Bispectral index was found to be useful in diagnosis, grading and monitoring of treatment response in cirrhotic patients with hepatic encephalopathy.

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.

[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.

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.

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.