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  1. Hepatic Encephalopathy

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    ... is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy or PSE, is a condition that ... medical care is an important factor in staying as healthy as possible. The American Liver Foundation is ...

  2. Hepatic Encephalopathy

    PubMed Central

    Bleibel, Wissam; Al-Osaimi, Abdullah M. S.

    2012-01-01

    Chronic liver disease and cirrhosis affect hundreds of millions of patients all over the world. The majority of patients with cirrhosis will eventually develop complications related to portal hypertension. One of these recurrent and difficult to treat complications is hepatic encephalopathy. Studies have indicated that overt hepatic encephalopathy affects 30 to 45% of patients with cirrhosis and a higher percentage may be affected by minimal degree of encephalopathy. All of these factors add to the impact of hepatic encephalopathy on the healthcare system and presents a major challenge to the gastroenterologist, hospitalist and primary care physician. PMID:23006457

  3. Hepatic encephalopathy.

    PubMed

    Córdoba, Juan; Mínguez, Beatriz

    2008-02-01

    Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices. PMID:18293278

  4. [Hepatic encephalopathy].

    PubMed

    Jacques, Jérémie; Carrier, Paul; Debette-Gratien, Marilyne; Sobesky, Rodolphe; Loustaud-Ratti, Véronique

    2016-01-01

    Hepatic encephalopathy is a severe complication of liver cirrhosis and is an important therapeutic challenge, with a social and economic issue. If, now, the pathophysiology is not totally understood (main role of ammonia, but a better understanding of cerebral mechanisms), the clinical presentation is well-known. Some treatments are useful (disaccharides, treatment of the trigger) but their efficiency is limited. Nevertheless, the emergence of new treatments, such as non-absorbable antibiotics (rifaximin essentially), is an interesting therapeutic tool. PMID:26597584

  5. [Hepatic encephalopathy].

    PubMed

    Córdoba, Juan; Mur, Rafael Esteban

    2014-07-01

    Hepatic encephalopathy (EH) is a severe complication of hepatic cirrhosis that is characterized by multiple neuropsychiatric manifestations. EH is usually triggered by a precipitating factor and occurs in patients with severely impaired hepatic function. Minimal EH is characterized by minor cognitive impairments that are difficult to specify but represent a risk for the patients. The primary pathophysiological mechanism of EH is considered to be an increase in blood ammonia with an impairment in the patency of the blood-brainbarrier and its metabolism to glutamine in astrocytes. The diagnosis is clinical and neuroimaging techniques can be complementary. The diagnosis of minimal EH requires specific neurocognitive tests. The clinical evaluation should be directed towards identifying the trigger. Nonabsorbable disaccharides and rifaximin constitute the treatment of choice, along with prophylaxis for new episodes. PMID:25087716

  6. [Hepatic encephalopathy].

    PubMed

    Festi, Davide; Marasco, Giovanni; Ravaioli, Federico; Colecchia, Antonio

    2016-07-01

    Hepatic encephalopathy (HE) is a common complication of liver cirrhosis and it can manifest with a broad spectrum of neuropsychiatric abnormalities of varying severity, acuity and time course with important clinical implications. According to recent guidelines, HE has been classified into different types, depending on the severity of hepatic dysfunction, the presence of porto-systemic shunts and the number of previous episodes or persistent manifestations. From a clinical point of view, HE can be recognized as unimpaired, covert (that deals with minimal and grade 1 according to the grading of mental state), and overt (that is categorized from grade 2 to grade 4). Different and only partially known pathogenic mechanisms have been identified, comprising ammonia, inflammatory cytokines, benzodiazepine-like compounds and manganese deposition. Different therapeutic strategies are available for treating HE, in particular the overt HE, since covert HE needs to be managed case by case. Recognition and treatment of precipitating factors represent fundamental part of the management. The more effective treatments, which can be performed separately or combined, are represented by non-absorbable disaccharides (lactulose and lactitol) and the topic antibiotic rifaximin; other possible therapies, mainly used in patients non responders to previous treatments, are represented by branched chain amino acids and metabolic ammonia scavengers. PMID:27571468

  7. Pathogenesis of Hepatic Encephalopathy

    PubMed Central

    Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

    2012-01-01

    Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. PMID:23316223

  8. Hepatic encephalopathy: a review.

    PubMed

    Lizardi-Cervera, Javier; Almeda, Paloma; Guevara, Luis; Uribe, Misael

    2003-01-01

    Hepatic encephalopathy (HE) is a complication that presents in as many as 28% of patients with cirrhosis, and reported up to ten years after the diagnosis of cirrhosis. Commonly, it is observed in patients with severe hepatic failure and is characterized by neuropsychiatric manifestations that can range in severity from a mild alteration in mental state to a coma; additionally, some neuromuscular symptoms can be observed. This complication of either acute or chronic hepatic disease is the result of a diminished hepatic reservoir and inability to detoxify some toxins that originate in the bowel. Today, the role of astrocytes, specifically the Alzheimer type II cells, is known to be very important in the pathogenesis of the hepatic encephalopathy, and will be reviewed later. In conclusion, the objectives of this review are: To understand the pathogenesis of hepatic encephalopathy, To recognize the precipitating factors, as well as preventive measures for the development of the hepatic encephalopathy, To describe the new classification of hepatic encephalopathy and its clinical implications, To recognize the clinical manifestations and stages of the disease, To understand the main diagnostic tests used to detect the hepatic encephalopathy, To describe the main therapeutic treatments of hepatic encephalopathy. PMID:15115963

  9. [Prevention of hepatic encephalopathy].

    PubMed

    Morillas, Rosa M; Sala, Marga; Planas, Ramon

    2014-06-01

    Hepatic encephalopathy (HE) is a frequent complication of cirrhosis which, in addition to producing a great social impact, deteriorates the quality of life of patients and is considered a sign of advanced liver disease and therefore a clinical indication for liver transplant evaluation. Patients who have had episodes of HE have a high risk of recurrence. Thus, after the HE episode resolves, it is recommended: control and prevention of precipitating factors (gastrointestinal bleeding, spontaneous bacterial peritonitis, use of diuretics with caution, avoid nervous system depressant medications), continued administration of non-absorbable disaccharides such as lactulose or lactitol, few or non-absorbable antibiotics such as rifaximin and assess the need for a liver transplant as the presence of a HE episode carries a poor prognosis in cirrhosis. PMID:24480288

  10. Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy

    PubMed Central

    Cichoż-Lach, Halina; Michalak, Agata

    2013-01-01

    Hepatic encephalopathy is a medical phenomenon that is described as a neuropsychiatric manifestation of chronic or acute liver disease that is characterized by psychomotor, intellectual and cognitive abnormalities with emotional/affective and behavioral disturbances. This article focuses on the underlying mechanisms of the condition and the differences between hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. Hepatic encephalopathy is a serious condition that can cause neurological death with brain edema and intracranial hypertension. It is assumed that approximately 60%-80% of patients with liver cirrhosis develop hepatic encephalopathy. This review explores the complex mechanisms that lead to hepatic encephalopathy. However, noncirrhotic hyperammonemic encephalopathy is not associated with hepatic diseases and has a completely different etiology. Noncirrhotic hyperammonemic encephalopathy is a severe occurrence that is connected with multiple pathogeneses. PMID:23326159

  11. Pharmacotherapy for hepatic encephalopathy.

    PubMed

    Phongsamran, Paula V; Kim, Jiwon W; Cupo Abbott, Jennifer; Rosenblatt, Angela

    2010-06-18

    Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents. Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE. However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication. Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE. However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been

  12. Diagnosis of minimal hepatic encephalopathy.

    PubMed

    Weissenborn, Karin

    2015-03-01

    Minimal hepatic encephalopathy (mHE) has significant impact upon a liver patient's daily living and health related quality of life. Therefore a majority of clinicians agree that mHE should be diagnosed and treated. The optimal means for diagnosing mHE, however, is controversial. This paper describes the currently most frequently used methods-EEG, critical flicker frequency, Continuous Reaction time Test, Inhibitory Control Test, computerized test batteries such as the Cognitive Drug Research test battery, the psychometric hepatic encephalopathy score (PHES) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)-and their pros and cons. PMID:26041959

  13. Hepatic Encephalopathy-the Old and the New.

    PubMed

    Kandiah, Prem A; Kumar, Gagan

    2016-07-01

    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. PMID:27339673

  14. Rifaximin in the treatment of hepatic encephalopathy

    PubMed Central

    Iadevaia, Maddalena Diana; Prete, Anna Del; Cesaro, Claudia; Gaeta, Laura; Zulli, Claudio; Loguercio, Carmelina

    2011-01-01

    Hepatic encephalopathy is a challenging complication in patients with advanced liver disease. It can be defined as a neuropsychiatric syndrome caused by portosystemic venous shunting, ranging from minimal to overt hepatic encephalopathy or coma. Its pathophysiology is still unclear, although increased levels of ammonia play a key role. Diagnosis of hepatic encephalopathy is currently based on specific tests evaluating the neuropsychiatric state of patients and their quality of life; the severity of hepatic encephalopathy is measured by the West Haven criteria. Treatment of hepatic encephalopathy consists of pharmacological and corrective measures, as well as nutritional interventions. Rifaximin received approval for the treatment of hepatic encephalopathy in 2010 because of its few side effects and pharmacological benefits. The aim of this work is to review the use and efficacy of rifaximin both in acute and long-term management of hepatic encephalopathy. Treatment of overt hepatic encephalopathy involves management of the acute episode as well as maintenance of remission in those patients who have previously experienced an episode, in order to improve their quality of life. The positive effect of rifaximin in reducing health care costs is also discussed. PMID:24367227

  15. Rifaximin in the treatment of hepatic encephalopathy.

    PubMed

    Iadevaia, Maddalena Diana; Prete, Anna Del; Cesaro, Claudia; Gaeta, Laura; Zulli, Claudio; Loguercio, Carmelina

    2011-01-01

    Hepatic encephalopathy is a challenging complication in patients with advanced liver disease. It can be defined as a neuropsychiatric syndrome caused by portosystemic venous shunting, ranging from minimal to overt hepatic encephalopathy or coma. Its pathophysiology is still unclear, although increased levels of ammonia play a key role. Diagnosis of hepatic encephalopathy is currently based on specific tests evaluating the neuropsychiatric state of patients and their quality of life; the severity of hepatic encephalopathy is measured by the West Haven criteria. Treatment of hepatic encephalopathy consists of pharmacological and corrective measures, as well as nutritional interventions. Rifaximin received approval for the treatment of hepatic encephalopathy in 2010 because of its few side effects and pharmacological benefits. The aim of this work is to review the use and efficacy of rifaximin both in acute and long-term management of hepatic encephalopathy. Treatment of overt hepatic encephalopathy involves management of the acute episode as well as maintenance of remission in those patients who have previously experienced an episode, in order to improve their quality of life. The positive effect of rifaximin in reducing health care costs is also discussed. PMID:24367227

  16. Management of Hepatic Encephalopathy in the Hospital

    PubMed Central

    Leise, Michael D.; Poterucha, John J.; Kamath, Patrick S.; Kim, W. Ray

    2014-01-01

    Hepatic encephalopathy (HE) develops in about 50% of patients with cirrhosis and is one of the features of decompensated cirrhosis. The inpatient incidence of HE is approximately 23,000/year and management of these patients is common for internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years. Treatment entails two phases, induction and maintenance of remission. Most cases of significant hepatic encephalopathy are precipitated by infection, gastrointestinal bleeding, medications or other culprits. All patients should be evaluated for secondary triggers of HE and treatment should be initiated with a non-absorbable disaccharide (i.e. lactulose) in most cases. Rifaximin (off-label) can be added in patients not responding to lactulose. Neomycin is a less preferable alternative to rifaximin, due to its side effect profile. Other therapies including zinc, LOLA, and branch chain amino acids can be considered for patients not responding to a disaccharide and non-absorbable antibiotic. Large portosystemic shunts may be embolized in patients with medically refractory recurrent or severe HE with otherwise well compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe hepatic encephalopathy who do not respond to medical therapy. It is critically important that patients hospitalized with significant hepatic encephalopathy continue a maintenance medication(s) at the time of dismissal to prevent further episodes. Patients with a 1st time episode of HE can be placed on lactulose and careful instruction should be provided to patient and caregiver about titration of dose to achieve 3 bowel movements per day. Patients with recurrent HE episodes despite lactulose benefit from the addition of rifaximin which decreases the frequency of recurrent HE episodes and related hospitalizations. Lastly, patients and their families should be counselled about the risk of motor vehicle accidents which

  17. Treatment of Overt Hepatic Encephalopathy.

    PubMed

    Sussman, Norman L

    2015-08-01

    Hepatic encephalopathy (HE) is defined by an altered mental status in the setting of portosystemic shunting, with or without cirrhosis. The basis of HE is probably multi-factorial, but increased ammonia delivery to the brain is thought to play a pivotal role. Medical therapies have typically focused on reducing blood ammonia concentrations. These measures are moderately effective, but further improvements will require identification of new therapeutic targets. Two medications, lactulose and rifaximin, are currently approved for the treatment of HE in the USA - new compounds are available off-label, and are in clinical trials. The presence of HE is associated with a higher risk of death in cirrhotic patients. Liver transplantation typically cures HE, but HE does not increase the MELD score, and therefore does not contribute to the likelihood of liver transplantation. PMID:26195208

  18. [Clinical importance and diagnostic methods of minimal hepatic encephalopathy].

    PubMed

    Stawicka, Agnieszka; Zbrzeźniak, Justyna; Świderska, Aleksandra; Kilisińska, Natalia; Świderska, Magdalena; Jaroszewicz, Jerzy; Flisiak, Robert

    2016-02-01

    Minimal hepatic encephalopathy (MHE) encompasses a number of neuropsychological and neurophysiological disorders in patients suffering from liver cirrhosis, who do not display abnormalities during a medical interview or physical examination. A negative influence of MHE on the quality of life of patients suffering from liver cirrhosis was confirmed, which include retardation of ability of operating motor vehicles and disruption of multiple health-related areas, as well as functioning in the society. The data on frequency of traffic offences and accidents amongst patients diagnosed with MHE in comparison to patients diagnosed with liver cirrhosis without MHE, as well as healthy persons is alarming. Those patients are unaware of their disorder and retardation of their ability to operate vehicles, therefore it is of utmost importance to define this group. The term minimal hepatic encephalopathy (formerly "subclinical" encephalopathy) erroneously suggested the unnecessity of diagnostic and therapeutic procedures in patients with liver cirrhosis. Diagnosing MHE is an important predictive factor for occurrence of overt encephalopathy - more than 50% of patients with this diagnosis develop overt encephalopathy during a period of 30 months after. Early diagnosing MHE gives a chance to implement proper treatment which can be a prevention of overt encephalopathy. Due to continuing lack of clinical research there exist no commonly agreed-upon standards for definition, diagnostics, classification and treatment of hepatic encephalopathy. This article introduces the newest findings regarding the importance of MHE, scientific recommendations and provides detailed descriptions of the most valuable diagnostic methods. PMID:27000818

  19. CLIF–SOFA score and SIRS are independent prognostic factors in patients with hepatic encephalopathy due to alcoholic liver cirrhosis

    PubMed Central

    Jeong, Jin Hee; Park, In Sung; Kim, Dong Hoon; Kim, Seong Chun; Kang, Changwoo; Lee, Soo Hoon; Kim, Tae Yun; Lee, Sang Bong

    2016-01-01

    Abstract Hepatic encephalopathy (HE) is a complication associated with worst prognosis in decompensated liver cirrhosis (LC) patients. Previous studies have identified prognostic factors for HE, and recent studies reported an association between systemic inflammatory response syndrome (SIRS) and liver disease. This study aimed to identify prognostic factors for 30-day mortality in alcoholic LC patients with HE who visited the emergency department (ED). This was a retrospective study of alcoholic LC patients with HE from January 1, 2010, to April 30, 2015. The baseline characteristics, complications of portal hypertension, laboratory values, Child–Pugh class, Model for End-stage Liver Disease (MELD) score, chronic liver failure-sequential organ failure assessment (CLIF–SOFA) score, and SIRS criteria were assessed. The presence of 2 or more SIRS criteria was considered SIRS. The primary outcomes were 30-day mortality and prognostic factors for patients with HE visiting the ED. In total, 105 patients who met the inclusion criteria were analyzed. Overall, the 30-day mortality rate was 6.7% (7 patients). Significant variables were hepatorenal syndrome, international normalized ratio, white blood cell count, total bilirubin level, MELD score CLIF–SOFA score, and SIRS in univariate analysis. CLIF–SOFA score and SIRS were the significant factors in the multivariate analysis (hazard ratio 5.56, 15.98; 95% confidence interval 1.18–26.18, 1.58–161.37; P = 0.03, P = 0.02). The mortality rates differed according to the CLIF–SOFA score (P < 0.01). The CLIF–SOFA score and SIRS in alcoholic LC patients with HE visiting the ED are independent predictors of 30-day mortality. PMID:27367990

  20. Useful Tests for Hepatic Encephalopathy in Clinical Practice

    PubMed Central

    Nabi, Eiman; Bajaj, Jasmohan S

    2014-01-01

    Hepatic encephalopathy (HE) is a serious complication of liver disease and portosystemic shunting that represents a continuum of neuropsychiatric changes and altered consciousness. It is classified as overt hepatic encephalopathy (OHE) when clinically apparent or as covert hepatic encephalopathy (CHE) in its mildest form. Progression of CHE to OHE and its impact of quality of life make its early diagnosis imperative. Several diagnostic techniques ranging from simple clinical scales to sophisticated computerized tests exist yet diagnosis remains a challenge due to the time, cost and personnel involved. Psychometric tests appear promising due to their high sensitivity and low cost but results are variable depending on age and education. The pros and cons of current diagnostic methods for overt and covert HE are reviewed along with strategy to CHE testing. PMID:24357348

  1. Gut microbiota and hepatic encephalopathy.

    PubMed

    Dhiman, Radha K

    2013-06-01

    There is a strong relationship between liver and gut; while the portal venous system receives blood from the gut, and its contents may affect liver functions, liver in turn, affects intestinal functions through bile secretion. There is robust evidence that the pathogenesis of hepatic encephalopathy (HE) is linked to alterations in gut microbiota and their by-products such as ammonia, indoles, oxindoles, endotoxins, etc. In the setting of intestinal barrier and immune dysfunction, these by-products are involved in the pathogenesis of complications of liver cirrhosis including HE and systemic inflammation plays an important role. Prebiotics, probiotics and synbiotics may exhibit efficacy in the treatment of HE by modulating the gut flora. They improve derangement in flora by decreasing the counts of pathogenic bacteria and thus improving the endotoxemia, HE and the liver disease. Current evidence suggest that the trials evaluating the role of probiotics in the treatment of HE are of not high quality and all trials had high risk of bias and high risk of random errors. Therefore, the use of probiotics for patients with HE cannot be currently recommended. Further RCTs are required. This review summarizes the main literature findings about the relationships between gut flora and HE, both in terms of the pathogenesis and the treatment of HE. PMID:23463489

  2. Clinical Neurophysiology of Hepatic Encephalopathy

    PubMed Central

    Amodio, Piero; Montagnese, Sara

    2015-01-01

    Background/Objectives Hepatic encephalopathy (HE) has relevant impact on the quality of life of patients and their caregivers and causes relevant costs because of hospitalizations and work days lost. Its quantification is important to perform adequate clinical trials on this relevant complication of cirrhosis and portal-systemic shunting. Clinical neurophysiology, which detects functional alterations of the nervous system, has been applied to the study of HE for over 60 years. This review aims at summarizing and clarifying the role of neurophysiologic techniques in the study of HE. Methods A narrative review was performed aiming at interpreting the cited papers and the techniques on the basis of their physiological and pathophysiological meaning. Results The potential role of EEG, quantified EEG, evoked potentials—both exogenous, endogenous and motor—have been clarified to the reader that may be unfamiliar with neurophysiology. Conclusions The EEG, reflecting the oscillatory changes of neural network is the preferable tool to detect and monitor HE, with the exception of its most severe stage, when EEG flattens. SSEP and MEP have indication to detect and monitor transmission alterations that are likely related to myelin changes and microedema. PMID:26041960

  3. Minimal Hepatic Encephalopathy Impairs Quality of Life

    PubMed Central

    Agrawal, Swastik; Umapathy, Sridharan; Dhiman, Radha K.

    2015-01-01

    Minimal hepatic encephalopathy (MHE) is the mildest form of the spectrum of neurocognitive impairment in cirrhosis. It is a frequent occurrence in patients of cirrhosis and is detectable only by specialized neurocognitive testing. MHE is a clinically significant disorder which impairs daily functioning, driving performance, work capability and learning ability. It also predisposes to the development of overt hepatic encephalopathy, increased falls and increased mortality. This results in impaired quality of life for the patient as well as significant social and economic burden for health providers and care givers. Early detection and treatment of MHE with ammonia lowering therapy can reverse MHE and improve quality of life. PMID:26041957

  4. Minimal hepatic encephalopathy impairs quality of life.

    PubMed

    Agrawal, Swastik; Umapathy, Sridharan; Dhiman, Radha K

    2015-03-01

    Minimal hepatic encephalopathy (MHE) is the mildest form of the spectrum of neurocognitive impairment in cirrhosis. It is a frequent occurrence in patients of cirrhosis and is detectable only by specialized neurocognitive testing. MHE is a clinically significant disorder which impairs daily functioning, driving performance, work capability and learning ability. It also predisposes to the development of overt hepatic encephalopathy, increased falls and increased mortality. This results in impaired quality of life for the patient as well as significant social and economic burden for health providers and care givers. Early detection and treatment of MHE with ammonia lowering therapy can reverse MHE and improve quality of life. PMID:26041957

  5. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials.

    PubMed

    Kullmann, F; Hollerbach, S; Holstege, A; Schölmerich, J

    1995-01-01

    Brainstem auditory (BAEPs) and somatosensory evoked potentials (SEPs) have been shown to be useful in detecting brainstem or cortical dysfunction in neurological diseases and in combination with other methods to diagnose brain death (37,38). These neurophysiological methods are simple and easy to perform. BAEPs and SEPs can even be easily recorded in intensive care units and guarantee a standardized examination. Moreover, these methods require no extensive patient cooperation and are not heavily influenced by learning effects. The role of BAEPs in the evaluation and diagnosis of hepatic encephalopathy is not clear. BAEPs are obviously strongly influenced by the etiology of liver disease and are normal in viral hepatitis, but prolonged in alcoholic liver disease, Wilson's disease or in hepatic coma (8,12). Unfortunately, BAEPs were not compared to psychometric tests. There was no clear-cut differentiation between various hepatic encephalopathy-gradings. At present, the use of BAEPs in the detection of subclinical hepatic encephalopathy cannot be recommended, whereas in comatose patients BAEPs can be useful as a prognostic marker and for follow-up examinations (12). Recently, Pozessere et al. (12) examined 13 comatose patients with advanced coma stages (Glasgow coma scale 5-10) and recorded unspecific changes in their EEG tracings. In all cases of hepatic coma and in one intoxicated patient they found prolongation of interpeak latencies. In addition, in this small study the interpeak latencies correlated well with the clinical outcome of the patients. Only two studies were performed using SEPs to detect neurophysiological alterations in hepatic encephalopathy (32,33). The design as well as the results of these studies are quite different. Despite the small number of patients (n = 10), the prolongation of late components in 50% of patients with hepatic encephalopathy stage 0 could be a promising result (32). The value of SEPs in detecting subclinical hepatic

  6. Hepatic Encephalopathy: From the Pathogenesis to the New Treatments

    PubMed Central

    Cordoba, Juan

    2014-01-01

    Hepatic encephalopathy is a frequent and serious complication of liver cirrhosis; the pathophysiology of this complication is not fully understood although great efforts have been made during the last years. There are few prospective studies on the epidemiology of this complication; however, it is known that it confers with high short-term mortality. Hepatic encephalopathy has been classified into different groups depending on the degree of hepatic dysfunction, the presence of portal-systemic shunts, and the number of episodes. Due to the large clinical spectra of overt EH and the complexity of cirrhotic patients, it is very difficult to perform quality clinical trials for assessing the efficacy of the treatments proposed. The physiopathology, clinical manifestation, and the treatment of HE is a challenge because of the multiple factors that converge and coexist in an episode of overt HE. PMID:27335836

  7. Disaccharides in the treatment of hepatic encephalopathy.

    PubMed

    Sharma, Praveen; Sharma, Barjesh Chander

    2013-06-01

    Management of hepatic encephalopathy (HE) primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and antimicrobial agents like rifaximin. The nonabsorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and minimal hepatic encephalopathy (MHE). Lactulose significantly improves cognitive function and health-related quality of life in patients with MHE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Disaccharides were found to be comparable to rifaximin in recent systemic reviews in the treatment of HE however conclusion was based on inclusion of some poor quality trials. Combination therapy of disaccharides either with rifaximin, L-ornithine L-aspartate,probiotics for the treatment of HE needs further validation in large studies. PMID:23456517

  8. NMDA receptors in hyperammonemia and hepatic encephalopathy.

    PubMed

    Llansola, Marta; Rodrigo, Regina; Monfort, Pilar; Montoliu, Carmina; Kosenko, Elena; Cauli, Omar; Piedrafita, Blanca; El Mlili, Nisrin; Felipo, Vicente

    2007-12-01

    The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy. PMID:17701332

  9. Experimental models of hepatic encephalopathy: ISHEN guidelines.

    PubMed

    Butterworth, Roger F; Norenberg, Michael D; Felipo, Vicente; Ferenci, Peter; Albrecht, Jan; Blei, Andres T

    2009-07-01

    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. PMID:19638106

  10. Using saccades to diagnose covert hepatic encephalopathy.

    PubMed

    Cunniffe, Nicholas; Munby, Henry; Chan, Shona; Saatci, Defne; Edison, Eric; Carpenter, R H S; Massey, Dunecan

    2015-06-01

    Covert Hepatic Encephalopathy (CHE), previously known as Minimal Hepatic Encephalopathy, is a subtle cognitive defect found in 30-70 % of cirrhosis patients. It has been linked to poor quality of life, impaired fitness to drive, and increased mortality: treatment is possible. Despite its clinical significance, diagnosis relies on psychometric tests that have proved unsuitable for use in a clinical setting. We investigated whether measurement of saccadic latency distributions might be a viable alternative. We collected data on 35 cirrhosis patients at Addenbrooke's Hospital, Cambridge, with no evidence of clinically overt encephalopathy, and 36 age-matched healthy controls. Performance on standard psychometric tests was evaluated to determine those patients with CHE as defined by the World Congress of Gastroenterology. We then compared visually-evoked saccades between those with CHE and those without, as well as reviewing blood test results and correlating saccadic latencies with biochemical parameters and prognostic scores. Cirrhosis patients have significantly longer median saccadic latencies than healthy controls. Those with CHE had significantly prolonged saccadic latencies when compared with those without CHE. Analysis of a cirrhosis patient's saccades can diagnose CHE with a sensitivity of 75 % and a specificity of 75 %. We concluded that analysis of a cirrhosis patient's saccadic latency distributions is a fast and objective measure that can be used as a diagnostic tool for CHE. This improved early diagnosis could direct avoidance of high-risk activities such as driving, and better inform treatment strategies. PMID:25586511

  11. [Rifaximin for hepatic encephalopathy in children. Case report].

    PubMed

    Malla, Ivone; Torres Cerino, Verónica; Villa, Andrés; Cheang, Yu; Giacove, Gisela; Pedreira, Alejandra; Silva, Marcelo

    2011-12-01

    Rifaximin is an antibiotic recently approved for the treatment of hepatic encephalopathy in adults. In children more than 12 year-old, it has been approved for travelers' diarrhea and it is also widely used in inflammatory bowel disease. We report, to our knowledge, the first case of a pediatric patient who received rifaximin for hepatic encephalopathy with good clinical outcome. PMID:22231877

  12. Resolution of Hepatic Encephalopathy Following Hepatic Artery Embolization in a Patient with Well-Differentiated Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Erinjeri, Joseph P. Deodhar, Ajita; Thornton, Raymond H.; Allen, Peter J.; Getrajdman, George I.; Brown, Karen T.; Sofocleous, Constantinos T.; Reidy, Diane L.

    2010-06-15

    Hepatic encephalopathy is considered a contraindication to hepatic artery embolization. We describe a patient with a well-differentiated neuroendocrine tumor metastatic to the liver with refractory hepatic encephalopathy and normal liver function tests. The encephalopathy was refractory to standard medical therapy with lactulose. The patient's mental status returned to baseline after three hepatic artery embolization procedures. Arteriography and ultrasound imaging before and after embolization suggest that the encephalopathy was due to arterioportal shunting causing hepatofugal portal venous flow and portosystemic shunting. In patients with a primary or metastatic well-differentiated neuroendocrine tumor whose refractory hepatic encephalopathy is due to portosystemic shunting (rather than global hepatic dysfunction secondary to tumor burden), hepatic artery embolization can be performed safely and effectively.

  13. A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy.

    PubMed

    Hashimoto, Joel G; Wiren, Kristine M; Wilhelm, Clare J

    2016-01-01

    Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model. PMID:27268733

  14. Hepatic Encephalopathy and Sleepiness: An Interesting Connection?

    PubMed Central

    Montagnese, Sara; Turco, Matteo; Amodio, Piero

    2015-01-01

    Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation. PMID:26041958

  15. Management options for minimal hepatic encephalopathy.

    PubMed

    Bajaj, Jasmohan S

    2008-12-01

    Minimal hepatic encephalopathy (MHE) is a neurocognitive dysfunction that is present in the majority of patients with cirrhosis. MHE has a characteristic cognitive profile that cannot be diagnosed clinically. This cognitive dysfunction is independent of sleep dysfunction or problems with overall intelligence. MHE has a significant impact on quality of life, the ability to function in daily life and progression to overt hepatic encephalopathy. Driving ability can be impaired in MHE and this may be a significant factor behind motor vehicle accidents. A crucial aspect of the clinical care of MHE patients is their driving history, which is often ignored during routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of the care of patients with MHE. The preserved communication skills and lack of specific signs and insight make MHE difficult to diagnose. The predominant strategies for MHE diagnosis are psychometric or neurophysiological testing. These are usually limited by financial, normative or time constraints. Studies into inhibitory control, cognitive drug research and critical flicker frequency tests are encouraging. These tests do not require a psychologist for administration and interpretation. Lactulose and probiotics have been studied for their potential use as therapies for MHE, but these are not standard-of-care practices at this time. Therapy can improve the quality of life in MHE patients but the natural history, specific diagnostic strategies and treatment options are still being investigated. PMID:19090738

  16. Management of hepatic encephalopathy in the hospital.

    PubMed

    Leise, Michael D; Poterucha, John J; Kamath, Patrick S; Kim, W Ray

    2014-02-01

    Hepatic encephalopathy (HE) develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis. With the goal of reviewing the evidence for treatment and prevention of overt hepatic encephalopathy, pubmed was searched using search terms hepatic encephalopathy AND treatment, limited to human studies from January 1, 2003, through December 1, 2013, and supplemented by key references. The inpatient incidence of HE is approximately 23,000 annually, and management of these patients is common for internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years. Treatment entails 2 phases: induction and maintenance of remission. Most cases of significant HE are precipitated by infection, gastrointestinal bleeding, medications, or other culprits. All patients should be evaluated for secondary triggers of HE, and treatment should be initiated with a nonabsorbable disaccharide (ie, lactulose) in most patients. Rifaximin (off label) can be added in patients not responding to lactulose. Neomycin is a less preferred alternative to rifaximin owing to its adverse effect profile. Other therapies, including zinc, L-ornithine-L-aspartate, and branched-chain amino acids, can be considered for patients not responding to disaccharides and nonabsorbable antibiotics. Large portosystemic shunts may be embolized in patients with medically refractory recurrent or severe HE with otherwise well-compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe HE who do not respond to medical therapy. It is critically important that patients hospitalized with significant HE continue maintenance therapy at the time of dismissal to prevent further episodes. Patients with a first-time episode of HE can be administered lactulose, and careful instructions should be provided to patients and caregivers about dose titration to achieve 3 bowel movements daily. Patients with recurrent HE episodes

  17. Pathogenesis, Diagnosis, and Treatment of Hepatic Encephalopathy

    PubMed Central

    Atluri, Dileep K; Prakash, Ravi; Mullen, Kevin D

    2011-01-01

    Hepatic encephalopathy (HE) is a neuropsychiatric disorder seen in patients with advanced liver disease or porto-systemic shunts. Based on etiology and severity of HE, the World Congress of Gastroenterology has divided HE into categories and sub-categories. Many user-friendly computer-based neuropsychiatric tests are being validated for diagnosing covert HE. Currently, emphasis is being given to view HE deficits as a continuous spectrum rather than distinct stages. Ammonia is believed to play crucial role in pathogenesis of HE via astrocyte swelling and cerebral edema. However, evidence has been building up which supports the synergistic role of oxidative stress, inflammation and neurosteroids in pathogenesis of HE. At present, treatment of HE aims at decreasing the production and intestinal absorption of ammonia. But as the role of new pathogenetic mechanisms becomes clear, many potential new treatment strategies may become available for clinician. PMID:25755319

  18. Leucine metabolism in patients with Hepatic Encephalopathy

    SciTech Connect

    McGhee, A.S.; Kassouny, M.E.; Matthews, D.E.; Millikan, W.

    1986-03-01

    A primed continuous infusion of (/sup 15/N, 1-/sup 13/C)leucine was used to determine whether increased oxidation and/or protein synthesis of leucine occurs in patients with cirrhosis. Five controls and patients were equilibrated on a metabolic balance diet (0.6 g protein per kg ideal body weight (IBW)). An additional four patients were equilibrated in the same manner with the same type of diet with a protein level of 0.75 g per kg IBW. Plasma leucine and breath CO/sub 2/ enrichments were measured by mass spectrometry. Protein synthesis and leucine metabolism were identical in controls and patients when both were fed a diet with 0.6 g protein/kg IBW. Results indicate that systemic derangements of leucine metabolism are not the cause of Hepatic Encephalopathy.

  19. Hepatic Encephalopathy: Pharmacological Therapies Targeting Ammonia.

    PubMed

    Rahimi, Robert S; Rockey, Don C

    2016-02-01

    Hepatic encephalopathy (HE) is a major complication in patients with decompensated cirrhosis, leading to higher readmission rates causing a profound burden of disease and considerable health care costs. Because ammonia is thought to play a crucial role in the pathogenesis of HE, therapies directed at reducing ammonia levels are now being aggressively developed. Ammonia scavengers such as AST-120 (spherical carbon adsorbent), glycerol phenylbutyrate, sodium phenylacetate or sodium benzoate, and ornithine phenylacetate have been used to improve HE symptoms. A new approach, bowel cleansing with polyethylene glycol 3350, appears to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt HE (at 24 hours after treatment) than lactulose. Extracorporeal devices, although now used primarily in research settings, have also been utilized in patients with refractory HE, but are not approved for clinical management. PMID:26870932

  20. Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy.

    PubMed

    Kimer, Nina; Krag, Aleksander; Gluud, Lise L

    2014-01-01

    Hepatic encephalopathy is a complex disease entity ranging from mild cognitive dysfunction to deep coma. Traditionally, treatment has focused on a reduction of ammonia through a reduced production, absorption, or clearance. Rifaximin is a nonabsorbable antibiotic, which reduces the production of ammonia by gut bacteria and, to some extent, other toxic derivatives from the gut. Clinical trials show that these effects improve episodes of hepatic encephalopathy. A large randomized trial found that rifaximin prevents recurrent episodes of hepatic encephalopathy. Most patients were treated concurrently with lactulose. Trials have varied greatly in design, outcomes, and duration of treatment regimes. Although a number of retrospective studies have indicated that long-term treatment with rifaximin is safe and possibly beneficial, high quality trials are needed to further clarify efficacy and safety of long-term treatment with rifaximin and evaluate effects of combination therapy with lactulose and branched-chain amino acids for patients with liver cirrhosis and hepatic encephalopathy. PMID:24672227

  1. Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy

    PubMed Central

    Kimer, Nina; Krag, Aleksander; Gluud, Lise L

    2014-01-01

    Hepatic encephalopathy is a complex disease entity ranging from mild cognitive dysfunction to deep coma. Traditionally, treatment has focused on a reduction of ammonia through a reduced production, absorption, or clearance. Rifaximin is a nonabsorbable antibiotic, which reduces the production of ammonia by gut bacteria and, to some extent, other toxic derivatives from the gut. Clinical trials show that these effects improve episodes of hepatic encephalopathy. A large randomized trial found that rifaximin prevents recurrent episodes of hepatic encephalopathy. Most patients were treated concurrently with lactulose. Trials have varied greatly in design, outcomes, and duration of treatment regimes. Although a number of retrospective studies have indicated that long-term treatment with rifaximin is safe and possibly beneficial, high quality trials are needed to further clarify efficacy and safety of long-term treatment with rifaximin and evaluate effects of combination therapy with lactulose and branched-chain amino acids for patients with liver cirrhosis and hepatic encephalopathy. PMID:24672227

  2. Coagulopathy and encephalopathy in a dog with acute hepatic necrosis.

    PubMed

    Strombeck, D R; Krum, S; Rogers, Q

    1976-10-15

    Disseminated intravascular coagulation developed secondary to hepatic necrosis in a 5-year-old Saint Bernard. Although the coagulopathy responded to treatment with heparin, the dog died from the combined effects of gastric hemorrhage and encephalopathy, both of which are complications of hepatic necrosis. PMID:977448

  3. Hepatic encephalopathy: An approach to its multiple pathophysiological features.

    PubMed

    Perazzo, Juan Carlos; Tallis, Silvina; Delfante, Amalia; Souto, Pablo Andrés; Lemberg, Abraham; Eizayaga, Francisco Xavier; Romay, Salvador

    2012-03-27

    Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in

  4. Hepatic encephalopathy: An approach to its multiple pathophysiological features

    PubMed Central

    Perazzo, Juan Carlos; Tallis, Silvina; Delfante, Amalia; Souto, Pablo Andrés; Lemberg, Abraham; Eizayaga, Francisco Xavier; Romay, Salvador

    2012-01-01

    Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in

  5. Sodium Benzoate for Treatment of Hepatic Encephalopathy

    PubMed Central

    Misel, Michael L.; Patton, Heather; Mendler, Michel

    2013-01-01

    Hepatic encephalopathy (HE) is a serious but usually reversible neuropsychiatric complication of cirrhosis, inborn errors of metabolism involving disorders of the urea cycle, and noncirrhotic portosystemic shunting that most commonly arises from a transjugular intrahepatic portosystemic shunting procedure. Symptoms can include alterations in cognitive function, neuromuscular activity, and consciousness, as well as sleep disorders and mood changes. HE is associated with significant morbidity and mortality and, if not properly treated, will lead to increased hospital admissions and healthcare costs. Although the standard therapies of lactulose and rifaximin (Xifaxan, Salix) are effective for most patients, these drugs may be associated with significant adverse effects and expense and, in some patients, inadequate therapeutic response. A need for adjunctive therapies exists. Drugs that target serum and tissue ammonia metabolism and elimination may be important adjuncts to drugs that reduce ammonia production and absorption from the gastrointestinal tract for patients with severe or persistent overt symptoms of HE. Sodium benzoate is an inexpensive adjunctive agent that can be used in addition to lactulose and rifaximin and may provide an option for some select patients with refractory HE who have failed to respond to standard therapies or who cannot afford them. Although sodium benzoate does not share the same adverse effect profiles of standard therapies for HE, its efficacy has not been well established. Given the significant dose-dependent sodium content of this therapy, it may not be appropriate for patients with significant fluid retention or kidney dysfunction. PMID:24711766

  6. The why and wherefore of hepatic encephalopathy.

    PubMed

    Grover, Vijay Pb; Tognarelli, Joshua M; Massie, Nicolas; Crossey, Mary Me; Cook, Nicola A; Taylor-Robinson, Simon D

    2015-01-01

    Hepatic encephalopathy is a common neuropsychiatric abnormality, which complicates the course of patients with liver disease. It was probably first described by Hippocrates over 2000 years ago, who said that "those whose madness arises from phlegm are quiet and neither shout nor make a disturbance, while those whose madness arises from bile shout, play tricks and will not keep still, but are always up to some mischief ". He was presumably describing the differences between patients with pneumonia and acute liver failure. Despite the fact that the syndrome was probably first recognized thousands of years ago, the exact pathogenesis still remains unclear. Furthermore, a precise definition of the syndrome is lacking, as are definitive methods of diagnosing this condition. It is important as both patients with cirrhosis and the general population with whom they interact may be affected as a consequence. At a minimum, the individual may be affected by impaired quality of life, impaired ability to work, and slowed reaction times, which are relevant to the population at large if affected individuals operate heavy machinery or drive a car. Pathogenic mechanisms, diagnostic tools, and treatment options are discussed. PMID:26719720

  7. The why and wherefore of hepatic encephalopathy

    PubMed Central

    Grover, Vijay PB; Tognarelli, Joshua M; Massie, Nicolas; Crossey, Mary ME; Cook, Nicola A; Taylor-Robinson, Simon D

    2015-01-01

    Hepatic encephalopathy is a common neuropsychiatric abnormality, which complicates the course of patients with liver disease. It was probably first described by Hippocrates over 2000 years ago, who said that “those whose madness arises from phlegm are quiet and neither shout nor make a disturbance, while those whose madness arises from bile shout, play tricks and will not keep still, but are always up to some mischief ”. He was presumably describing the differences between patients with pneumonia and acute liver failure. Despite the fact that the syndrome was probably first recognized thousands of years ago, the exact pathogenesis still remains unclear. Furthermore, a precise definition of the syndrome is lacking, as are definitive methods of diagnosing this condition. It is important as both patients with cirrhosis and the general population with whom they interact may be affected as a consequence. At a minimum, the individual may be affected by impaired quality of life, impaired ability to work, and slowed reaction times, which are relevant to the population at large if affected individuals operate heavy machinery or drive a car. Pathogenic mechanisms, diagnostic tools, and treatment options are discussed. PMID:26719720

  8. Transport of AMPA receptors during long-term potentiation is impaired in rats with hepatic encephalopathy.

    PubMed

    Monfort, Pilar; Piedrafita, Blanca; Felipo, Vicente

    2009-12-01

    Cognitive function is impaired in patients with hepatic encephalopathy. Learning ability is also impaired in rats with hepatic encephalopathy due to portacaval shunts. Long-term potentiation (LTP) in hippocampus, considered the basis of some forms of learning and memory, is impaired in rats with portacaval shunt. We analyzed the mechanisms by which LTP is impaired in these rats. In control rats, application of the tetanus to induce LTP increases phosphorylation of Thr286 of calcium-calmodulin dependent protein kinase II. This activates the kinase which phosphorylates the GluR1 subunit of AMPA receptors in Ser831 and induces its translocation to the post-synaptic densities. All these steps are completely prevented in rats with hepatic encephalopathy in which the tetanus does not induce phosphorylation of CaMKII or GluR1 nor translocation of this subunit to the post-synaptic membrane. This would explain the impairment in LTP in these rats. PMID:19450629

  9. Useful tests for hepatic encephalopathy in clinical practice.

    PubMed

    Nabi, Eiman; Bajaj, Jasmohan S

    2014-01-01

    Hepatic encephalopathy (HE) is a serious complication of liver disease and portosystemic shunting that represents a continuum of neuropsychiatric changes and altered consciousness. It is classified as overt HE (OHE) when clinically apparent or as covert HE (CHE) in its mildest form. Progression of CHE to OHE and its impact of quality of life make its early diagnosis imperative. Several diagnostic techniques ranging from simple clinical scales to sophisticated computerized tests exist, yet diagnosis remains a challenge, due to the time, cost, and personnel involved. Psychometric tests appear promising due to their high sensitivity and low cost, but results are variable depending on age and education. The pros and cons of current diagnostic methods for OHE and CHE are reviewed, along with strategy for CHE testing. PMID:24357348

  10. New Methods of Testing and Brain Imaging in Hepatic Encephalopathy: A Review.

    PubMed

    Edula, Raja G R; Pyrsopoulos, Nikolaos T

    2015-08-01

    The diagnosis of hepatic encephalopathy is predominantly clinical, and the tests available assist in the diagnosis only by excluding other causes. Covert hepatic encephalopathy, which is defined as abnormal performance on psychometric tests when standard neurologic examination is completely normal, has gained widespread attention in recent years due to its effect on quality of life. This review focuses on the tests available to aid in the diagnosis of this significant complication of liver disease, and discusses the complex pathophysiologic mechanisms identified through new imaging techniques and their significance toward development of new therapeutic targets for this condition. PMID:26195200

  11. Covert and Overt Hepatic Encephalopathy: Diagnosis and Management.

    PubMed

    Patidar, Kavish R; Bajaj, Jasmohan S

    2015-11-01

    Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient's quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion. PMID:26164219

  12. Gut microbiota: its role in hepatic encephalopathy.

    PubMed

    Rai, Rahul; Saraswat, Vivek A; Dhiman, Radha K

    2015-03-01

    Ammonia, a key factor in the pathogenesis of hepatic encephalopathy (HE), is predominantly derived from urea breakdown by urease producing large intestinal bacteria and from small intestine and kidneys, where the enzyme glutaminases releases ammonia from circulating glutamine. Non-culture techniques like pyrosequencing of bacterial 16S ribosomal ribonucleic acid are used to characterize fecal microbiota. Fecal microbiota in patients with cirrhosis have been shown to alter with increasing Child-Turcotte-Pugh (CTP) and Model for End stage Liver Disease (MELD) scores, and with development of covert or overt HE. Cirrhosis dysbiosis ratio (CDR), the ratio of autochthonous/good bacteria (e.g. Lachnospiraceae, Ruminococcaceae and Clostridiales) to non-autochthonous/pathogenic bacteria (e.g. Enterobacteriaceae and Streptococcaceae), is significantly higher in controls and patients with compensated cirrhosis than patients with decompensated cirrhosis. Although their stool microbiota do not differ, sigmoid colonic mucosal microbiota in liver cirrhosis patients with and without HE, are different. Linkage of pathogenic colonic mucosal bacteria with poor cognition and inflammation suggests that important processes at the mucosal interface, such as bacterial translocation and immune dysfunction, are involved in the pathogenesis of HE. Fecal microbiome composition does not change significantly when HE is treated with lactulose or when HE recurs after lactulose withdrawal. Despite improving cognition and endotoxemia as well as shifting positive correlation of pathogenic bacteria with metabolites, linked to ammonia, aromatic amino acids and oxidative stress, to a negative correlation, rifaximin changes gut microbiome composition only modestly. These observations suggest that the beneficial effects of lactulose and rifaximin could be associated with a change in microbial metabolic function as well as an improvement in dysbiosis. PMID:26041954

  13. Paroxysmal Amnesia Attacks due to Hashimoto's Encephalopathy

    PubMed Central

    Nar Senol, Pelin; Bican Demir, Aylin; Bora, Ibrahim; Bakar, Mustafa

    2016-01-01

    Hashimoto's encephalopathy is a rare disease which is thought to be autoimmune and steroid responsive. The syndrome is characterized by cognitive impairment, encephalopathy, psychiatric symptoms, and seizures associated with increased level of anti-thyroid antibodies. The exact pathophysiology underlying cerebral involvement is still lesser known. Although symptoms suggest a nonlesional encephalopathy in most of the cases, sometimes the clinical appearance can be subtle and may not respond to immunosuppressants or immunomodulatory agents. Here we report a case who presented with drowsiness and amnestic complaints associated with paroxysmal electroencephalography (EEG) abnormalities which could be treated only with an antiepileptic drug. PMID:27034679

  14. Treatment of chronic hepatic encephalopathy with levodopa 1

    PubMed Central

    Lunzer, Michael; James, I. M.; Weinman, J.; Sherlock, Sheila

    1974-01-01

    Three of six patients with chronic hepatic encephalopathy treated with levodopa showed a significant improvement. One patient was probably improved whilst the remaining two patients failed to show any benefit. Serial electroencephalography did not demonstrate significant changes. Treatment with levodopa was associated with an improvement in `speed-based' tasks as assessed by computerized psychometry. A significant rise in cerebral oxygen consumption was found during levodopa therapy. Gastrointestinal side effects were dose limiting. It is concluded that a therapeutic trial of levodopa in patients with chronic hepatic encephalopathy is indicated when the response to conventional therapy has been poor. PMID:4430473

  15. Nutritional assessment in cirrhotic patients with hepatic encephalopathy

    PubMed Central

    Romeiro, Fernando Gomes; Augusti, Laís

    2015-01-01

    Hepatic encephalopathy (HE) is one of the worst complications of liver disease and can be greatly influenced by nutritional status. Ammonia metabolism, inflammation and muscle wasting are relevant processes in HE pathophysiology. Malnutrition worsens the prognosis in HE, requiring early assessment of nutritional status of these patients. Body composition changes induced by liver disease and limitations superimposed by HE hamper the proper accomplishment of exams in this population, but evidence is growing that assessment of muscle mass and muscle function is mandatory due to the role of skeletal muscles in ammonia metabolism. In this review, we present the pathophysiological aspects involved in HE to support further discussion about advantages and drawbacks of some methods for evaluating the nutritional status of cirrhotic patients with HE, focusing on body composition. PMID:26730273

  16. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions.

    PubMed

    Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

    2016-07-15

    Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy. PMID:27377741

  17. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions

    PubMed Central

    Suraweera, Duminda; Sundaram, Vinay; Saab, Sammy

    2016-01-01

    Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy. PMID:27377741

  18. Detecting Minimal Hepatic Encephalopathy in an Endemic Country for Hepatitis B: The Role of Psychometrics and Serum IL-6

    PubMed Central

    Tsai, Chia-Fen; Chu, Chi-Jen; Huang, Yi-Hsiang; Wang, Yen-Po; Liu, Pei-Yi; Lin, Han-Chieh; Lee, Fa-Yauh; Lu, Ching-Liang

    2015-01-01

    Background & Aims It remains unknown what the prevalence of minimal hepatic encephalopathy is in Taiwan, a highly endemic country for chronic viral hepatitis infection. It is also unclear whether abnormal serum cytokine levels can be indicative of the presence of minimal hepatic encephalopathy. We aimed to standardize the tests of psychometric hepatic encephalopathy score and predictive value of proinflammatory cytokines in minimal hepatic encephalopathy in Taiwan. Methods 180 healthy subjects and 94 cirrhotic patients without a history of overt hepatic encephalopathy from a tertiary center were invited to participate in this cross-sectional study. Blood sampling for determination of serum levels of interleukin 6 and 18 and tumor necrosis factor-α was performed. Based on the normogram of psychometric hepatic encephalopathy score from healthy volunteers, patients with minimal hepatic encephalopathy were identified from the cirrhotic patients using the criterion of a psychometric hepatic encephalopathy score less than −4. Results In the healthy subjects, age and education were predictors of subtests of psychometric hepatic encephalopathy score. Minimal hepatic encephalopathy was identified in 27 (29%) cirrhotic patients. Serum interleukin 6 level (OR = 6.50, 95% CI = 1.64–25.76, P = 0.008) was predictive of the presence of minimal hepatic encephalopathy after multivariate analysis. Conclusions The psychometric hepatic encephalopathy score can be a useful tool for detecting patients with minimal hepatic encephalopathy in Taiwan and around one third of cirrhotic outpatients fulfill this diagnosis. A high serum interleukin 6 level is predictive of the presence of minimal hepatic encephalopathy. PMID:26039496

  19. Hepatic Encephalopathy Associated With Cancer or Anticancer Therapy

    PubMed Central

    Nott, Louise M.; Broadbridge, Vy T.; Price, Timothy

    2013-01-01

    ABSTRACT Hepatic encephalopathy is an uncommon cause of neurologic deterioration associated with hyperammonemia, which results from hepatic dysfunction or altered ammonia metabolism. Often overlooked, hyperammonemia may occur via any of several pathophysiological processes, and in the setting of malignancy, it is a potentially reversible cause of confusion and coma. Hepatic dysfunction as a result of malignant infiltration, chemotherapeutic toxicities, targeted anticancer therapies, reactivation hepatitis, portosystemic shunting, and transarterial chemoembolization (TACE) is discussed, and an approach to etiological diagnosis and management is outlined. PMID:23505573

  20. Post-TIPS Hepatic Encephalopathy Treated by Occlusion Balloon-Assisted Retrograde Embolization of a Coexisting Spontaneous Splenorenal Shunt

    SciTech Connect

    Shioyama, Yasukazu; Matsueda, Kiyoshi; Horihata, Koushi; Kimura, Masashi; Nishida, Norifumi; Kishi, Kazushi; Terada, Masaki; Sato, Morio; Yamada, Ryusaku

    1996-11-15

    A 51-year-old man with posthepatitis cirrhosis underwent a transjugular intrahepatic portosystemic shunt (TIPS) for bleeding of recurrent esophageal varices. The patient had a coexisting, spontaneous, splenorenal shunt. He subsequently developed hepatic encephalopathy, presumably due to excessive portosystemic shunting. Since medical management resulted in no significant improvement, the splenorenal shunt was embolized from the jugular vein approach via renal vein access during temporary balloon occlusion. Within a few days, the patient's hepatic encephalopathy resolved. Twelve months later the patient showed no recurrence of encephalopathy and had maintained a patent TIPS.

  1. Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement

    PubMed Central

    Bajaj, J. S.; Cordoba, J.; Mullen, K. D.; Amodio, P.; Shawcross, D. L.; Butterworth, R. F.; Morgan, M. Y.

    2014-01-01

    Summary Background The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. Aims To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. Methods A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. Results It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. Conclusions The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed. PMID:21306407

  2. Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy

    SciTech Connect

    Bassett, M.L.; Mullen, K.D.; Scholz, B.; Fenstermacher, J.D.; Jones, E.A. )

    1990-03-01

    Transfer of the inhibitory neurotransmitter gamma-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for gamma-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of gamma-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain gamma-aminobutyric acid uptake is increased in rabbits with stage II-III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. (3H) gamma-aminobutyric acid, (14C) butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of gamma-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of (3H) gamma-aminobutyric acid and (113mIn) transferrin were calculated using (14C) butanol as the highly extracted reference compound. The (113mIn) transferrin data were also used to correct the brain uptake index of (3H) gamma-aminobutyric acid for intravascular retention of (3H) gamma-aminobutyric acid. The methodology adopted minimized problems attributable to rapid (3H) gamma-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the uncorrected and corrected brain uptake indices of gamma-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy.

  3. Hepatic Encephalopathy: Early Diagnosis in Pediatric Patients With Cirrhosis

    PubMed Central

    DARA, Naghi; SAYYARI, Ali-Akbar; IMANZADEH, Farid

    2014-01-01

    Objective As acute liver failure (ALF) and chronic liver disease (cirrhosis) continue to increase in prevalence, we will see more cases of hepatic encephalopathy. Primary care physician are often the first to suspect it, since they are familiar with the patient’s usual physical and mental status. This serious complication typically occurs in patients with severe comorbidities and needs multidisciplinary evaluation and care. Hepatic encephalopathy should be considered in any patient with acute liver failure and cirrhosis who presents with neuropsychiatric manifestations, decrease level of consciousness (coma), change of personality, intellectual and behavioral deterioration, speech and motor dysfunction. Every cirrhotic patient may be at risk; potential precipitating factors should be addressed in regular clinic visits. The encephalopathy of liver disease may be prominent, or can be present in subtle forms, such as decline of school performance, emotional outbursts, or depression. “Subtle form” of hepatic encephalopathy may not be obvious on clinical examination, but can be detected by neurophysiologic and neuropsychiatric testing. PMID:24665321

  4. Rats with minimal hepatic encephalopathy due to portacaval shunt show differential increase of translocator protein (18 kDa) binding in different brain areas, which is not affected by chronic MAP-kinase p38 inhibition.

    PubMed

    Agusti, Ana; Dziedzic, Jennifer L; Hernandez-Rabaza, Vicente; Guilarte, Tomas R; Felipo, Vicente

    2014-12-01

    Neuroinflammation plays a main role in neurological deficits in rats with minimal hepatic encephalopathy (MHE) due to portacaval shunt (PCS). Treating PCS rats with SB239063, an inhibitor of MAP-kinase-p38, reduces microglial activation and brain inflammatory markers and restores cognitive and motor function. The translocator protein-(18-kDa) (TSPO) is considered a biomarker of neuroinflammation. TSPO is increased in brain of PCS rats and of cirrhotic patients that died in hepatic coma. Rats with MHE show strong microglial activation in cerebellum and milder in other areas when assessed by MHC-II immunohistochemistry. This work aims were assessing: 1) whether binding of TSPO ligands is selectively increased in cerebellum in PCS rats; 2) whether treatment with SB239063 reduces binding of TSPO ligands in PCS rats; 3) which cell type (microglia, astrocytes) increases TSPO expression. Quantitative autoradiography was used to assess TSPO-selective (3)H-(R)-PK11195 binding to different brain areas. TSPO expression increased differentially in PCS rats, reaching mild expression in striatum or thalamus and very high levels in cerebellum. TSPO was expressed in astrocytes and microglia. Treatment with SB239063 did not reduces (3)[H]-PK11195 binding in PCS rats. SB239063 reduces microglial activation and levels of inflammatory markers, but not binding of TSPO ligands. This indicates that SB239063-induced neuroinflammation reduction in PCS rats is not mediated by effects on TSPO. Also, enhanced TSPO expression is not always associated with cognitive or motor deficits. If enhanced TSPO expression plays a role in mechanisms leading to neurological alterations in MHE, SB239063 would interfere these mechanisms at a later step. PMID:24307181

  5. Rats with minimal hepatic encephalopathy due to portacaval shunt show differential increase of translocator protein (18 kDa) binding in different brain areas, which is not affected by chronic MAP-kinase p38 inhibition

    PubMed Central

    Agusti, Ana; Dziedzic, Jennifer L.; Hernandez-Rabaza, Vicente; Guilarte, Tomas R.; Felipo, Vicente

    2014-01-01

    Neuroinflammation plays a main role in neurological deficits in rats with minimal hepatic encephalopathy (MHE) due to portacaval shunt (PCS). Treating PCS rats with SB239063, an inhibitor of MAP-kinase-p38, reduces microglial activation and brain inflammatory markers and restores cognitive and motor function. The translocator protein-(18-kDa) (TSPO) is considered a biomarker of neuro-inflammation. TSPO is increased in brain of PCS rats and of cirrhotic patients that died in hepatic coma. Rats with MHE show strong microglial activation in cerebellum and milder in other areas when assessed by MHC-II immunohistochemistry. This work aims were assessing: 1) whether binding of TSPO ligands is selectively increased in cerebellum in PCS rats; 2) whether treatment with SB239063 reduces binding of TSPO ligands in PCS rats; 3) which cell type (microglia, astrocytes) increases TSPO expression. Quantitative autoradiography was used to assess TSPO-selective 3H-(R)-PK11195 binding to different brain areas. TSPO expression increased differentially in PCS rats, reaching mild expression in striatum or thalamus and very high levels in cerebellum. TSPO was expressed in astrocytes and microglia. Treatment with SB239063 did not reduces 3[H]-PK11195 binding in PCS rats. SB239063 reduces microglial activation and levels of inflammatory markers, but not binding of TSPO ligands. This indicates that SB239063-induced neuroinflammation reduction in PCS rats is not mediated by effects on TSPO. Also, enhanced TSPO expression is not always associated with cognitive or motor deficits. If enhanced TSPO expression plays a role in mechanisms leading to neurological alterations in MHE, SB239063 would interfere these mechanisms at a later step. PMID:24307181

  6. Nutritional support in the treatment of chronic hepatic encephalopathy.

    PubMed

    Milke García, María del Pilar

    2011-06-01

    The prevalence of under nutrition in cirrhotic patients is 61% and it usually progresses as the disease becomes more advanced. The deterioration in the nutritional status and its associated metabolic derangements has raised doubts about the benefits of severe and prolonged protein restriction as a treatment for hepatic encephalopathy. However, the practice of dietary protein restriction for patients with liver cirrhosis is deeply embedded among medical practitioners and dietitians. To date, no solid conclusions may be drawn about the benefit of protein restriction. However, the negative effects of protein restriction are clear, that is, increased protein catabolism, the release of amino acids from the muscle, and possible worsening of hepatic encephalopathy. In conclusion, chronic protein restriction causes progressive and harmful protein depletion and must be avoided. PMID:22228881

  7. Contributions of Microdialysis to New Alternative Therapeutics for Hepatic Encephalopathy

    PubMed Central

    Rivera-Espinosa, Liliana; Floriano-Sánchez, Esaú; Pedraza-Chaverrí, José; Coballase-Urrutia, Elvia; Sampieri, Aristides; Ortega-Cuellar, Daniel; Cárdenas-Rodríguez, Noemí; Carmona-Aparicio, Liliana

    2013-01-01

    Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi-permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease. PMID:23921686

  8. Hepatic encephalopathy coexists with acquired chronic hepatocerebral degeneration.

    PubMed

    Huang, Feng-Zhen; Hou, Xuan; Zhou, Tie-Qiao; Chen, Si

    2015-07-01

    Hyperkinetic extrapyramidal syndrome is the typical clinical characteristic of acquired hepatocerebral degeneration (AHD), but is usually not observed with hepatic encephalopathy (HE). We present a case of AHD coexisting with HE. Both conditions were secondary to liver cirrhosis and hepatitis C virus infection. The brain MRI showed bilateral and symmetric high T1 signal-intensity in the globus pallidus, and diffuse high signal-intensity of the hemispheric white matter on T2-FLAIR images. As we usually neglect the existence of AHD, the diagnosis is often ignored, especially when it coexists with HE. This case highlights the need to distinguish irreversible AHD from HE. PMID:26166598

  9. Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy.

    PubMed

    Cauli, Omar; Rodrigo, Regina; Llansola, Marta; Montoliu, Carmina; Monfort, Pilar; Piedrafita, Blanca; El Mlili, Nisrin; Boix, Jordi; Agustí, Ana; Felipo, Vicente

    2009-03-01

    Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons. PMID:19085094

  10. Advances in cirrhosis: Optimizing the management of hepatic encephalopathy

    PubMed Central

    Liu, Andy; Perumpail, Ryan B; Kumari, Radhika; Younossi, Zobair M; Wong, Robert J; Ahmed, Aijaz

    2015-01-01

    Hepatic encephalopathy (HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE (CHE) and overt HE (OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis. PMID:26692331

  11. Advances in cirrhosis: Optimizing the management of hepatic encephalopathy.

    PubMed

    Liu, Andy; Perumpail, Ryan B; Kumari, Radhika; Younossi, Zobair M; Wong, Robert J; Ahmed, Aijaz

    2015-12-18

    Hepatic encephalopathy (HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE (CHE) and overt HE (OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis. PMID:26692331

  12. Hepatic Encephalopathy Secondary to Intrahepatic Portosystemic Venous Shunt: Balloon-Occluded Retrograde Transvenous Embolization with n-Butyl Cyanoacrylate and Microcoils

    SciTech Connect

    Yamagami, Takuji; Nakamura, Toshiyuki; Iida, Shigeharu; Kato, Takeharu; Tanaka, Osamu; Matsushima, Shigenori; Ito, Hirotoshi; Okuyama, Chio; Ushijima, Yo; Shiga, Kensuke; Nishimura, Tsunehiko

    2002-06-15

    We report a 70-year-old woman with hepatic encephalopathy due to an intrahepatic portosystemic venous shunt that was successfully occluded by percutaneous transcatheter embolization with n-butyl cyanoacrylate and microcoils.

  13. GLUTAMINE IN THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY: THE TROJAN HORSE HYPOTHESIS REVISITED

    PubMed Central

    Rama Rao, Kakulavarapu V.; Norenberg, Michael D.

    2016-01-01

    Hepatic encephalopathy (HE) is major neuropsychiatric disorder occurring in patients with severe liver disease and ammonia is generally considered to represent the major toxin responsible for this condition. Ammonia in brain is chiefly metabolized (“detoxified”) to glutamine in astrocytes due to predominant localization of glutamine synthetase in these cells. While glutamine has long been considered innocuous, a deleterious role more recently has been attributed to this amino acid. This article reviews the mechanisms by which glutamine contributes to the pathogenesis of HE, how glutamine is transported into mitochondria and subsequently hydrolyzed leading to high levels of ammonia, the latter triggering oxidative and nitrative stress, the mitochondrial permeability transition and mitochondrial injury, a sequence of events we have collectively termed as the Trojan horse hypothesis of hepatic encephalopathy. PMID:23277414

  14. [Role of rifaximin in the treatment of hepatic encephalopathy].

    PubMed

    Sanchez-Delgado, Jordi; Miquel, Mireia

    2016-04-01

    Hepatic encephalopathy (HE) is a frequent and serious complication of liver cirrhosis. In addition to correction of the precipitating factors, the most commonly used treatments are non-absorbable disaccharides and rifaximin. Many of the recommendations are based on current clinical practice and there are few randomized controlled trials. Currently, rifaximin should be initiated during an episode of EH if, after 24-48 hours of non-absorbable disaccharide therapy, there is no clinical improvement. In recurrent EH, it is advisable to add rifaximin in patients under non-absorbable disaccharide therapy who develop a new episode. Currently, standard treatment with rifaximin for minimal EH is not recommended. Rifaximin is effective in the acute treatment of overt encephalopathy and in preventing recurrence. PMID:26545947

  15. Hepatitis E-associated encephalopathy in a renal transplant recipient

    PubMed Central

    de Vries, Marijke A; Samijn, Johnny P A; de Man, Rob; Boots, Johannes M M

    2014-01-01

    Hepatitis E virus genotype 3 is not rare in developed countries, and may cause chronic hepatitis in immunocompromised patients. This may not only lead to abnormalities in liver test and malaise, but to severe neurological symptoms as well. In this case, chronic hepatitis E infection caused encephalopathy, an atactic gait, Lhermitte's sign, incomplete bladder emptying and peripheral sensory neuropathy in a renal transplant recipient. The diagnosis was not performed until years after the onset of first symptoms and several months after the onset of neurological symptoms. If treated adequately, viral load can be reduced in over two-thirds of patients and neurological symptoms are often resolved. More widespread knowledge about this virus and its extrahepatic manifestations may lead to a quicker diagnosis, and may limit pathology. Serological screening should be added to standard pretransplant virological screening, so that, in the future, patients without antibodies could be vaccinated. PMID:24789162

  16. [Treatment of refractory hepatic encephalopathy associated with insertion of a transjugular intrahepatic portosystemic shunt through new endovascular techniques: a case report].

    PubMed

    Martínez Moreno, Belén; Bellot, Pablo; de España, Francisco; Palazón, José María; Such, José; Pérez-Mateo, Miguel

    2011-01-01

    Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt. PMID:21652116

  17. Comparative Neuroprotective Effects of Dexamethasone and Minocycline during Hepatic Encephalopathy

    PubMed Central

    Gamal, Maha; Abdel Wahab, Zainab; Eshra, Mohamed; Rashed, Laila; Sharawy, Nivin

    2014-01-01

    Objective. Encephalopathy and brain edema are serious complications of acute liver injury and may lead to rapid death of patients. The present study was designed to investigate the role of the inflammatory mediators and oxidative stress in the cytotoxic brain oedema and the neuroprotective effects of both minocycline and dexamethasone. Methods. 48 male albino rats were divided into 4 groups: control group, acute liver injury (ALI) group, minocycline pretreated ALI group, and dexamethasone pretreated ALI group. 24 hours after acute liver injury serum ammonia, liver enzymes, brain levels of heme oxygenase-1 gene, iNOS gene expression, nitrite/nitrate, and cytokines were measured. In addition, the grades of encephalopathy and brain water content were assessed. Results. ALI was associated with significant increases in all measured inflammatory mediators, oxidative stress, iNOS gene expression, and nitrite/nitrate. Both minocycline and dexamethasone significantly modulated the inflammatory changes and the oxidative/nitrosative stress associated with ALI. However, only minocycline but not dexamethasone significantly reduced the cytotoxic brain oedema. Conclusion. Both minocycline and dexamethasone could modulate inflammatory and oxidative changes observed in brain after ALI and could be novel preventative therapy for hepatic encephalopathy episodes. PMID:24693424

  18. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.

    PubMed

    Shawcross, D L; Olde Damink, S W M; Butterworth, R F; Jalan, R

    2005-09-01

    Ammonia is thought to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. Hippocrates 2500 years ago described 'encephalopathy' simply translated as 'inside head suffering.' Over 1500 papers have been written on hepatic encephalopathy since 1966, but only a minority of these actually refer to the original observation of hepatic encephalopathy and the link with ammonia made by Marcel Nencki and Ivan Pavlov in 1893 with very little acknowledgement being made to the early landmark studies which described the importance of the muscle and kidneys in maintaining ammonia homeostasis as well as the liver and gut. Furthermore, infection was recognized as being an important modulator of brain function by the ancient Greek physicians and philosophers. This review focuses upon the original experiments of Nencki and Pavlov and describes how they fit into what we understand about the pathophysiology and treatment of hepatic encephalopathy today. PMID:16167195

  19. Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure

    PubMed Central

    Chu, Chi-Jen; Hsiao, Ching-Chin; Wang, Teh-Fang; Chan, Cho-Yu; Lee, Fa-Yauh; Chang, Full-Young; Chen, Yi-Chou; Huang, Hui-Chun; Wang, Sun-Sang; Lee, Shou-Dong

    2005-01-01

    AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-α (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S. CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the

  20. The "Plateau" Phenomenon of Stepwise Extracorporeal Albumin Dialysis Bispectral Index Hepatic Encephalopathy Recovery.

    PubMed

    Dahaba, Ashraf A

    2015-12-15

    The Bispectral Index™ monitor, an electroencephalographic-derived parameter, can quantify hepatic encephalopathy cerebral function recovery and differentiate between West Haven grades 1 to 4. I report a very peculiar "plateau" phenomenon of 3 clear distinct plateaus of stepwise albumin dialysis Bispectral Index hepatic encephalopathy recovery during an 8-hour Molecular Adsorbent Recirculating System™ (MARS™) liver-assist extracorporeal detoxification, manifesting in conjunction with 3 West Haven grade recoveries. In the patients, I observed recovery of cerebral function after hepatic encephalopathy as a series of plateaus with abrupt transitions between the plateaus, rather than the gradual recovery I anticipated. PMID:26657702

  1. Contemporary Understanding and Management of Overt and Covert Hepatic Encephalopathy.

    PubMed

    NeSmith, Meghan; Ahn, Joseph; Flamm, Steven L

    2016-02-01

    Hepatic encephalopathy (HE) is a major complication of liver disease that leads to significant morbidity and mortality. Caring for hospitalized patients with HE is becoming more complex, and the economic burden of HE continues to rise. Defining and diagnosing HE, particularly covert HE (CHE), remain challenging. In this article, we review new tools and those currently under development for the diagnosis of CHE and the latest advances in the acute and long-term management of overt HE (OHE) and CHE. In particular, we review the latest data on the use of lactulose and rifaximin for treatment of OHE and summarize the data on adjunctive agents such as sodium benzoate and probiotics. PMID:27182210

  2. Mapping Metabolic Brain Activity in Three Models of Hepatic Encephalopathy

    PubMed Central

    Méndez, Marta; Fidalgo, Camino; Aller, María Ángeles; Arias, Jaime; Arias, Jorge L.

    2013-01-01

    Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups. PMID:23573412

  3. Hepatic encephalopathy: effects of liver failure on brain function.

    PubMed

    Felipo, Vicente

    2013-12-01

    Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis - conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects. PMID:24149188

  4. Multimodality magnetic resonance imaging in hepatic encephalopathy: An update

    PubMed Central

    Zhang, Xiao-Dong; Zhang, Long-Jiang; Wu, Sheng-Yong; Lu, Guang-Ming

    2014-01-01

    Hepatic encephalopathy (HE) is a neuropsychiatric complication of cirrhosis or acute liver failure. Currently, HE is regarded as a continuous cognitive impairment ranging from the mildest stage, minimal HE to overt HE. Hyperammonaemia and neuroinflammation are two main underlying factors which contribute to the neurological alterations in HE. Both structural and functional impairments are found in the white mater and grey mater involved in HE. Although the investigations into HE pathophysiological mechanism are enormous, the exact pathophysiological causes underlying HE remain controversial. Multimodality magnetic resonance imaging (MRI) plays an important role in helping to understand the pathological process of HE. This paper reviews the up-to-date multimodality MRI methods and predominant findings in HE patients with a highlight of the increasingly important role of blood oxygen level dependent functional MRI. PMID:25170210

  5. Contemporary Understanding and Management of Overt and Covert Hepatic Encephalopathy

    PubMed Central

    NeSmith, Meghan; Ahn, Joseph

    2016-01-01

    Hepatic encephalopathy (HE) is a major complication of liver disease that leads to significant morbidity and mortality. Caring for hospitalized patients with HE is becoming more complex, and the economic burden of HE continues to rise. Defining and diagnosing HE, particularly covert HE (CHE), remain challenging. In this article, we review new tools and those currently under development for the diagnosis of CHE and the latest advances in the acute and long-term management of overt HE (OHE) and CHE. In particular, we review the latest data on the use of lactulose and rifaximin for treatment of OHE and summarize the data on adjunctive agents such as sodium benzoate and probiotics. PMID:27182210

  6. Prevention and treatment of hepatic encephalopathy: focusing on gut microbiota.

    PubMed

    Garcovich, Matteo; Zocco, Maria Assunta; Roccarina, Davide; Ponziani, Francesca Romana; Gasbarrini, Antonio

    2012-12-14

    The gut flora plays an important role in the pathogenesis of the complications of cirrhosis. Hepatic encephalopathy (HE) represents a broad continuum of neuropsychological dysfunction in patients with acute or chronic liver disease and/or porto-systemic shunting of blood flow and it manifests with progressive deterioration of the superior neurological functions. The pathophysiology of this disease is complex, as it involves overproduction and reduced metabolism of various neurotoxins, particularly ammonia. Management of HE is diversified and requires several steps: elimination of precipitating factors, removal of toxins, proper nutritional support, modulation of resident fecal flora and downregulation of systemic and gut-derived inflammation. This review will provide an overview of gut barrier function and the influence of gut-derived factors on HE, focusing on the role of gut microbiota in the pathogenesis of HE and the recent literature findings on its therapeutic manipulation. PMID:23239905

  7. PET and MR imaging of neuroinflammation in hepatic encephalopathy.

    PubMed

    Su, Yun Yan; Yang, Gui Fen; Lu, Guang Ming; Wu, Shawn; Zhang, Long Jiang

    2015-02-01

    Neurological or psychiatric abnormalities associated with hepatic encephalopathy (HE) range from subclinical findings to coma. HE is commonly accompanied with the accumulation of toxic substances in bloodstream. The toxicity effect of hyperammonemia on astrocyte, such as the alteration in neurotransmission, oxidative stress, astrocyte swelling, is considered as an important factor in the pathogenesis of HE. Besides, neuroinflammation has captured more attention in the process of HE, but the mechanism of neuroinflammation leading to HE remains unclear. Molecular imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting activated microglia and/ or other mediators appear to be promising noninvasive approaches to assess HE. This review focuses on novel imaging and therapy strategies of neuroinflammation in HE. PMID:25514861

  8. Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy

    PubMed Central

    Yang, Nan; Liu, He; Jiang, Yao; Zheng, Ji; Li, Dong-mei; Ji, Chao; Liu, Yan-yong; Zuo, Ping-ping

    2015-01-01

    Lactulose is known to improve cognitive function in patients with early hepatic encephalopathy; however, the underlying mechanism remains poorly understood. In the present study, we investigated the behavioral and neurochemical effects of lactulose in a rat model of early hepatic encephalopathy induced by carbon tetrachloride. Immunohistochemistry showed that lactulose treatment promoted neurogenesis and increased the number of neurons and astrocytes in the hippocampus. Moreover, lactulose-treated rats showed shorter escape latencies than model rats in the Morris water maze, indicating that lactulose improved the cognitive impairments caused by hepatic encephalopathy. The present findings suggest that lactulose effectively improves cognitive function by enhancing neuroplasticity in a rat model of early hepatic encephalopathy. PMID:26604907

  9. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy

    SciTech Connect

    Basile, A.S.; Pannell, L.; Jaouni, T.; Gammal, S.H.; Fales, H.M.; Jones, E.A.; Skolnick, P. )

    1990-07-01

    Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4- to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.

  10. Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

    PubMed Central

    Aldridge, Dominic R.; Tranah, Edward J.; Shawcross, Debbie L.

    2015-01-01

    The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. PMID:26041962

  11. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation.

    PubMed

    Aldridge, Dominic R; Tranah, Edward J; Shawcross, Debbie L

    2015-03-01

    The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. PMID:26041962

  12. Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy.

    PubMed

    Montoliu, Carmina; Gonzalez-Escamilla, Gabriel; Atienza, Mercedes; Urios, Amparo; Gonzalez, Olga; Wassel, Abdallah; Aliaga, Roberto; Giner-Duran, Remedios; Serra, Miguel A; Rodrigo, Jose M; Belloch, Vicente; Felipo, Vicente; Cantero, Jose L

    2012-07-16

    Little attention has been paid to cortical integrity in patients with minimal hepatic encephalopathy (MHE), although cognitive functions affected in early stages of liver disease are mainly allocated in different neocortical structures. Here we used cortical surface-based analysis techniques to investigate if patterns of cortical thinning accompany the mildest form of HE. To aim this goal, cortical thickness obtained from high-resolution 3T magnetic resonance imaging (MRI) was measured in patients with no MHE (NMHE), MHE, and healthy controls. Further correlation analyses were performed to examine whether scores in the critical flicker frequency (CFF) test, and blood ammonia levels accounted for the loss of cortical integrity in different stages of liver disease. Finally, we assessed group differences in volume of different subcortical regions and their potential relationships with CFF scores/blood ammonia levels. Results showed a focal thinning of the superior temporal cortex and precuneus in MHE patients when compared with NMHE and controls. Relationships between blood ammonia levels and cortical thickness of the calcarine sulcus accounted for impaired visual judgment in patients with MHE when compared to NMHE. Regression analyses between cortical thickness and CFF predicted differences between controls and the two groups of HE patients, but failed to discriminate between patients with NMHE and MHE. Taking together, these findings provide the first report of cortical thinning in MHE patients, and they yield novel insights into the neurobiological basis of cognitive impairment associated with early stages of liver diseases. PMID:22465844

  13. Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications.

    PubMed

    Montoliu, Carmina; Rodrigo, Regina; Monfort, Pilar; Llansola, Marta; Cauli, Omar; Boix, Jordi; Elmlili, Nisrin; Agusti, Ana; Felipo, Vicente

    2010-03-01

    Cyclic GMP (cGMP) modulates important cerebral processes including some forms of learning and memory. cGMP pathways are strongly altered in hyperammonemia and hepatic encephalopathy (HE). Patients with liver cirrhosis show reduced intracellular cGMP in lymphocytes, increased cGMP in plasma and increased activation of soluble guanylate cyclase by nitric oxide (NO) in lymphocytes, which correlates with minimal HE assessed by psychometric tests. Activation of soluble guanylate cyclase by NO is also increased in cerebral cortex, but reduced in cerebellum, from patients who died with HE. This opposite alteration is reproduced in vivo in rats with chronic hyperammonemia or HE. A main pathway modulating cGMP levels in brain is the glutamate-NO-cGMP pathway. The function of this pathway is impaired both in cerebellum and cortex of rats with hyperammonemia or HE. Impairment of this pathway is responsible for reduced ability to learn some types of tasks. Restoring the pathway and cGMP levels in brain restores learning ability. This may be achieved by administering phosphodiesterase inhibitors (zaprinast, sildenafil), cGMP, anti-inflammatories (ibuprofen) or antagonists of GABAA receptors (bicuculline). These data support that increasing cGMP by safe pharmacological means may be a new therapeutic approach to improve cognitive function in patients with minimal or clinical HE. PMID:20195723

  14. Evaluation of rifaximin in management of hepatic encephalopathy.

    PubMed

    Wahib, Ali A; El-Deen Salem, M Negm; Ahmed, Mostafa A; El-Dessouky, Yasser M M; El-Tiby, Diaa M; El-Mola, Khaled; El-Sayed, Abeer M

    2014-12-01

    This study evaluated the efficacy of rifaximin versus lactulose in the treatment of hepatic encephalopathy (HE). The study population included 50 patients who were diagnosed to have signs of the first to third degree HE, according to the West Haven criteria and classified into two groups. GI: included 25 patients who had HE and were treated with lactulose syrup (laxolac) 90 ml daily divided into 3 doses for 7 days. GII: included 25 patients who had HE and were treated with rifaximin 1200 mg daily divided into 3 doses for 7 days. Patients in both groups also received other measures of treatment of HE as daily enema and protein restriction. Rifaximin significantly improved various subjective and measurable components of HE including mental status, behavior, asterixis, and serum ammonia concentration. In acute HE of grade 1 to grade 3, rifaximin may be a good alternative to non-absorbable disaccharides as it is broad spectrum, non-absorbable antibiotic with rapid action and little side effects. It is better tolerated, associated with less frequent and shorter hospitalization in comparison to lactulose. PMID:25643509

  15. Severe hypoglycemic encephalopathy due to hypoallergenic formula in an infant.

    PubMed

    Ogawa, Erika; Ishige, Mika; Takahashi, Yuno; Kodama, Hiroko; Fuchigami, Tatsuo; Takahashi, Shori

    2016-08-01

    A 7-month-old girl was brought to hospital due to vomiting. Upon admission, she was in a convulsive state and stupor with extremely low blood glucose. Head computed tomography showed brain edema, and comprehensive treatment for acute encephalopathy was initiated immediately. Severe hypoglycemia, metabolic acidosis, elevation of ammonia and serum transaminases and creatine kinase suggested metabolic decompensation. Infusion of a high-glucose solution containing vitamins, biotin, and l-carnitine resolved the metabolic crisis quickly, but brain damage was irreversible. She was found to have been fed exclusively on a hypoallergenic formula (HF) for 7 months, although she was found later to be non-allergic. Evidence of inborn metabolic diseases was absent, therefore biotin deficiency and carnitine deficiency were concluded to be a consequence of reliance on a HF for a prolonged period. Health-care professionals should warn parents of the consequences of using HF. PMID:27324861

  16. Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: ibuprofen restores its motor activity.

    PubMed

    Cauli, Omar; Rodrigo, Regina; Piedrafita, Blanca; Llansola, Marta; Mansouri, Mohammad T; Felipo, Vicente

    2009-05-01

    Patients with hepatic encephalopathy show altered motor function, psychomotor slowing, and hypokinesia, which are reproduced in rats with portacaval shunts (PCS). Increased extracellular glutamate in substantia nigra pars reticulata (SNr) is responsible for hypokinesia in PCS rats. The mechanisms by which liver failure leads to increased extracellular glutamate in SNr remain unclear. Inflammation seems to act synergistically with hyperammonemia to induce neurological alterations in hepatic encephalopathy. It is therefore possible that inflammation-associated alterations may contribute to motor alterations in hepatic encephalopathy. The aim of this work was to assess whether treatment with an antiinflammatory, ibuprofen, is able to normalize extracellular glutamate in SNr and/or to improve hypokinesia in PCS rats. The amounts of the glutamate transporters GLT-1 and EAAC-1 are reduced by 26% and 32%, respectively, in SNr of PCS rats. This reduction is associated with a tenfold increase in extracellular glutamate in SNr and a reduction in motor activity. Chronic treatment with 30 mg/kg ibuprofen completely normalizes the amount of GLT-1 and EAAC-1 and significantly reduces (by 53%) extracellular glutamate in SNr of PCS rats. Moreover, ibuprofen, at 15 or 30 (but not at 5) mg/kg/day, completely eliminates hypokinesia, restoring normal motor activity. This supports the idea that inflammation is a main contributor to the induction of hypokinesia in hepatic encephalopathy. Moreover, these data point to the possible therapeutic utility of decreasing inflammation, by safe procedures, in the treatment of the motor deficits in patients with hepatic encephalopathy. PMID:19025766

  17. Persistence of Cognitive Impairment after Resolution of Overt Hepatic Encephalopathy

    PubMed Central

    Bajaj, Jasmohan S; Schubert, Christine M; Heuman, Douglas M; Wade, James B; Gibson, Douglas P; Topaz, Allyne; Saeian, Kia; Hafeezullah, Muhammad; Bell, Debulon E; Sterling, Richard K; Stravitz, R Todd; Luketic, Velimir; White, Melanie B; Sanyal, Arun J

    2010-01-01

    Background & Aims In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE). Methods Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol [DS], block design [BD], and number connection [NCT-A&B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and 1st minus 2nd halves (ΔL1–2) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotics, with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE. Results In study A, (226 cirrhotic patients) 54 had experienced OHE, 120 had minimal HE and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotics were cognitively impaired, based on results from all tests. Learning of response inhibition (ΔL1–2 ≥1), was evident in patients with minimal HE and no minimal HE, but was lost after OHE. In study B (50 additional patients who developed ≥1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r=0.5, P=0.0001), DST (r=−0.39, P=0.002) and NCT-B (r=0.33, P=0.04). In the prospective study (59 cirrhotics without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs.18 after, P=0.0003) and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing. Conclusion In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning. PMID:20178797

  18. Rifaximin therapy and hepatic encephalopathy: Pros and cons

    PubMed Central

    Zullo, Angelo; Hassan, Cesare; Ridola, Lorenzo; Lorenzetti, Roberto; Campo, Salvatore MA; Riggio, Oliviero

    2012-01-01

    Hepatic encephalopathy (HE) is the second most common major complication in cirrhotics and it significantly impacts quality of life. Therapeutic approaches for HE treatment and prevention mainly continue to rely on ammonia-lowering strategies and non-absorbable disaccharides are currently considered the cornerstone therapy. Non-absorbable antibiotics, such as neomycin and paramomycin, are effective in treatment of acute HE episodes but their prolonged use for recurrence prevention is hampered by possible side-effects. To overcome these limitations, rifaximin use has been proposed. Rifaximin has been shown to be not superior to non-absorbable disaccharides for either HE treatment or prevention, with a similar incidence of side-effects. Cirrhosis significantly increases rifaximin absorption and this could be a cause for concern. Following long-term rifaximin therapy, Clostridium difficile colitis has been observed and Candida albicans has been isolated from 20% of patients. In addition, selection of resistant mutants of both Gram-negative and -positive bacteria in the gastrointestinal tract cannot be definitely ruled out. Electrolyte alterations (sodium and potassium) have been reported during rifaximin therapy, a warning for its long-term use in cirrhotics. Moreover, a potential interference with vitamin K production should be considered which could further impair the already altered clotting status of these patients. The therapeutic cost of rifaximin is markedly higher than non-absorbable disaccharides. While waiting for further safety data, caution should be used to limit the use of rifaximin therapy for a very short-term period in selected HE cirrhotics not responding to non-absorbable disaccharides. PMID:22966484

  19. Rifaximin therapy and hepatic encephalopathy: Pros and cons.

    PubMed

    Zullo, Angelo; Hassan, Cesare; Ridola, Lorenzo; Lorenzetti, Roberto; Campo, Salvatore Ma; Riggio, Oliviero

    2012-08-01

    Hepatic encephalopathy (HE) is the second most common major complication in cirrhotics and it significantly impacts quality of life. Therapeutic approaches for HE treatment and prevention mainly continue to rely on ammonia-lowering strategies and non-absorbable disaccharides are currently considered the cornerstone therapy. Non-absorbable antibiotics, such as neomycin and paramomycin, are effective in treatment of acute HE episodes but their prolonged use for recurrence prevention is hampered by possible side-effects. To overcome these limitations, rifaximin use has been proposed. Rifaximin has been shown to be not superior to non-absorbable disaccharides for either HE treatment or prevention, with a similar incidence of side-effects. Cirrhosis significantly increases rifaximin absorption and this could be a cause for concern. Following long-term rifaximin therapy, Clostridium difficile colitis has been observed and Candida albicans has been isolated from 20% of patients. In addition, selection of resistant mutants of both Gram-negative and -positive bacteria in the gastrointestinal tract cannot be definitely ruled out. Electrolyte alterations (sodium and potassium) have been reported during rifaximin therapy, a warning for its long-term use in cirrhotics. Moreover, a potential interference with vitamin K production should be considered which could further impair the already altered clotting status of these patients. The therapeutic cost of rifaximin is markedly higher than non-absorbable disaccharides. While waiting for further safety data, caution should be used to limit the use of rifaximin therapy for a very short-term period in selected HE cirrhotics not responding to non-absorbable disaccharides. PMID:22966484

  20. Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities.

    PubMed

    Butterworth, Roger F

    2016-06-01

    Hepatic encephalopathy (HE) is a serious neuropsychiatric disorder resulting from liver failure. Symptoms of HE include mild cognitive impairment, stupor and coma. Morphological changes to neuroglia (both astrocytes and microglia) occur in HE consisting of cytotoxic brain edema (astrocyte swelling) in acute liver failure and Alzheimer type-2 astrocytosis in cirrhosis. Visual-evoked responses in animals with liver failure and HE manifest striking similarities to those in animals treated with agonists of the GABA-A receptor complex. Neurosteroids are synthesized in brain following activation of translocator protein (TSPO), a mitochondrial neuroglial cholesterol-transporter protein. TSPO sites are activated in both animal models of HE as well as in autopsied brain tissue from HE patients. Activation of TSPO sites results in increased cholesterol transport into the mitochondrion followed by stimulation of a metabolic pathway culminating in the synthesis of allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC), neurosteroids with potent positive allosteric modulatory action on the GABA-A receptor complex. Concentrations of ALLO and THDOC in brain tissue from mice with HE resulting from toxic liver injury are sufficient to induce sedation in animals of the same species and significant increases in concentrations of ALLO have been reported in autopsied brain tissue from cirrhotic patients with HE leading to the proposal that "increased GABAergic tone" in HE results from that increased brain concentrations of this neurosteroid. Agents with the potential to decrease neurosteroid synthesis and/or prevent their modulatory actions on the GABA-A receptor complex may provide novel approaches to the management and treatment of HE. Such agents include indomethacin, benzodiazepine receptor inverse agonists and a novel series of compounds known as GABA-A receptor-modulating steroid antagonists (GAMSA). PMID:26589093

  1. Current diagnosis and management of post-transjugular intrahepatic portosystemic shunt refractory hepatic encephalopathy.

    PubMed

    Pereira, Keith; Carrion, Andres F; Martin, Paul; Vaheesan, Kirubahara; Salsamendi, Jason; Doshi, Mehul; Yrizarry, Jose M

    2015-12-01

    Transjugular intrahepatic portosystemic shunt has evolved into an important option for management of complications of portal hypertension. The use of polytetrafluoroethylene covered stents enhances shunt patency. Hepatic encephalopathy (HE) remains a significant problem after TIPS placement. The approach to management of patients with refractory hepatic encephalopathy typically requires collaboration between different specialties. Patient selection for TIPS requires careful evaluation of risk factors for HE. TIPS procedure-related technical factors like stent size, attention to portosystemic pressure gradient reduction and use of adjunctive variceal embolization maybe important. Conservative medical therapy in combination with endovascular therapies often results in resolution or substantial reduction of symptoms. Liver transplantation is, however, the ultimate treatment. PMID:26332169

  2. A New-Onset Rash in the Setting of Rifaximin Treatment for Hepatic Encephalopathy

    PubMed Central

    Adebajo, Corlan; Aronsohn, Andrew; Jensen, Donald M.

    2014-01-01

    We present one of the first cases in the literature to describe an association between Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and rifaximin treatment in a patient with a recent diagnosis of alcoholic hepatitis, stage 2 hepatic encephalopathy, and no known existing allergies. Although SJS/TEN may be a rare reaction with rifaximin, it should be an important clinical consideration. PMID:26157902

  3. A New-Onset Rash in the Setting of Rifaximin Treatment for Hepatic Encephalopathy.

    PubMed

    Fritz, Cassandra D L; Adebajo, Corlan; Aronsohn, Andrew; Jensen, Donald M

    2014-10-01

    We present one of the first cases in the literature to describe an association between Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and rifaximin treatment in a patient with a recent diagnosis of alcoholic hepatitis, stage 2 hepatic encephalopathy, and no known existing allergies. Although SJS/TEN may be a rare reaction with rifaximin, it should be an important clinical consideration. PMID:26157902

  4. How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist

    PubMed Central

    Dunk, Arthur A.; Jalan, Rajiv; Kircheis, Gerald; de Knegt, Robert J.; Laleman, Wim; Ramage, John K.; Wedemeyer, Heiner; Morgan, Ian E.J.

    2016-01-01

    Introduction Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting. Symptoms include nonspecific cognitive impairment, personality changes and changes in consciousness. Overt (symptomatic) hepatic encephalopathy is a common complication of cirrhosis that is associated with a poor prognosis. Patients with hepatic encephalopathy may present to healthcare providers who do not have primary responsibility for management of patients with cirrhosis. Therefore, we developed a series of ‘consensus points’ to provide some guidance on management. Methods Using a modified ‘Delphi’ process, consensus statements were developed that summarize our recommendations for the diagnosis and management of patients with hepatic encephalopathy. Points on which full consensus could not be reached are also discussed. Results Our recommendations emphasize the role of all healthcare providers in the identification of cognitive impairment in patients with cirrhosis and provide guidance on steps that might be considered to make a diagnosis of overt hepatic encephalopathy. In addition, treatment recommendations are summarized. Minimal hepatic encephalopathy can have a significant impact on patients; however, in most circumstances identification and management of minimal hepatic encephalopathy remains the responsibility of specialists in liver diseases. Conclusion Our opinion statements aim to define the roles and responsibilities of all healthcare providers who at times care for patients with cirrhosis and hepatic encephalopathy. We suggest that these recommendations be considered further by colleagues in other disciplines and hope that future guidelines consider the management of patients with cirrhosis and with a ‘suspicion’ of cognitive impairment through to a formal diagnosis of hepatic encephalopathy. PMID:26600154

  5. Toxic encephalopathy due to colchicine--Gloriosa superba poisoning.

    PubMed

    Gooneratne, Inuka Kishara; Weeratunga, Praveen; Caldera, Manjula; Gamage, Ranjanie

    2014-10-01

    Gloriosa superba, a flowering plant widespread in South and Southeast Asia, is implicated in many cases of self-poisoning. Colchicine is concentrated in the seeds and tubers and this mediates its toxicity. We describe a 28-year-old woman who developed delayed encephalopathy after eating G superba tubers. MR scan of brain showed bilateral symmetrical T2 basal ganglia hyperintensities in the caudate and lentiform nuclei. The delay in onset of encephalopathy is attributable to a direct-effect colchicine, probably mediated through its effect on microtubular transport. PMID:24591648

  6. Research progress in hepatic encephalopathy in recent 10 years: A Web of Science-based literature analysis

    PubMed Central

    Li, Nan

    2012-01-01

    OBJECTIVE: To analyze international research trends in hepatic encephalopathy and examine the role of neuroelectrophysiology and neuroimaging in diagnosis of hepatic encephalopathy. DATA RETRIEVAL: We performed a bibliometric analysis of studies on hepatic encephalopathy published during 2002–2011 retrieved from Web of Science. SELECTION CRITERIA: Inclusion criteria: (1) peer-reviewed published articles on hepatic encephalopathy; (2) original article, review, meeting abstract, proceedings paper, book chapter, editorial material, news items, and (3) published during 2002–2011. Exclusion criteria: (1) articles that required manual searching or telephone access; (2) documents that were not published in the public domain; and (3) corrected papers from the total number of articles. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) type of publication; (3) publication by research field; (4) publication by journal; (5) publication by author; (6) publication by institution; (7) publication by country; (8) publication by institution in China; (9) most-cited papers. RESULTS: A total of 3 233 papers regarding hepatic encephalopathy were retrieved during 2002–2011. The number of papers gradually increased over the 10-year study period and was highest in 2010. Most papers appeared in journals with a focus on gastroenterology and hepatology. Among the included journals, Hepatology published the greatest number of papers regarding hepatic encephalopathy, and the published studies were highly cited. Thus, Hepatology appears to represent a key journal publishing papers on hepatic encephalopathy. Regarding distribution by country for publications on hepatic encephalopathy indexed in Web of Science during 2002–2011, the United States published highest number of papers, with China ranked ninth. As per distribution by institute for publications, the University of Montreal in Canada published the highest number of papers (n = 111). Among the Chinese institutes, Zhejiang

  7. The effects of propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension.

    PubMed

    Dunk, A A; Moore, J; Symon, A; Dickie, A; Sinclair, T S; Mowat, N A; Brunt, P W

    1988-04-01

    Beta adrenoreceptor blocking drugs have been used for the prevention of haemorrhage from oesophageal varices. However, it is possible that these agents, by virtue of their effects on hepatic blood flow, may impair liver function and precipitate hepatic encephalopathy. We have therefore studied the effect of the beta blocking drug propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension. Twenty patients were randomly assigned to receive 4 weeks treatment with propranolol or an identical-looking placebo, the former given in a dose sufficient to reduce resting pulse rate by greater than or equal to 25%. Before and after treatment patients were assessed for the severity of liver disease and the presence of encephalopathy. EEG mean cycle frequency and fasting arterial ammonia concentrations were also measured, and in order to detect latent hepatic encephalopathy, each patient underwent a battery of psychometric tests. Patients were blinded as to their treatment, as were those assessing their responses. Neither propranolol nor placebo had any significant effect on the parameters measured. On propranolol median EEG mean cycle frequency fell from 9.08 ct s-1 (range 8.63-11.0 ct s-1) to 8.73 ct s-1 (range 8.27-11.44 ct s-1), and median fasting arterial ammonia concentration fell from 66 mumol litre-1 (range 40-329 mumol litre-1) to 49 mumol litre-1 (range 37-188 mumol litre-1). Psychometric test values, while initially abnormal and suggestive of latent hepatic encephalopathy in the majority of patients, did not change significantly during the study. PMID:2979240

  8. Infusion of branched-chain enriched amino acid solution in patients with hepatic encephalopathy.

    PubMed

    Freund, H; Dienstag, J; Lehrich, J; Yoshimura, N; Bradford, R R; Rosen, H; Atamian, S; Slemmer, E; Holroyde, J; Fischer, J E

    1982-08-01

    Hospitalized patients with hepatic insufficiency often suffer from severe catabolic states and are in urgent need of nutritional support during their acute illness. Protein intolerence, however, remains a significant problem with respect to the provision of adequate nutrition, either enterally or parenterally. The following report is an anecdotal series of 63 consecutive patients in a large urban hospital treated prospectively with nutritional support using a prototype high branched-chain amino acid solution (FO80) given by technique of total parenteral nutrition by the subclavian or internal jugular route with hypertonic dextrose. Sixty-three patients, of which 42 had chronic liver disease (cirrhosis) with acute decompensation and 17 with acute hepatic injury as well as four with hepatorenal syndrome, are the subject of this report. All required intravenous nutritional support and were either intolerant to commercially available parenteral nutrition solutions or were in hepatic encephalopathy at the time they were initially seen. The cirrhotic patients had been hospitalized for a mean of 14.5 +/- 1.9 days before therapy, had a mean bilirubin of 13 mg/100 ml, and had been in coma for 4.8 +/- 0.7 days despite standard therapy. Patients with acute hepatitis had been in the hospital for 16.2 +/- 4.1 days before therapy, had a mean bilirubin of 25 mg/100 ml, and had been in coma 5.2 +/- 1.6 days before therapy. Routine tests of liver function, blood chemistries, amino acids, EEGs, and complex neurological testing including Reitan trailmaking tests were used in the evaluation of these patients. Up to 120 grams of synthetic amino acid solution with hypertonic dextrose was tolerated in these patients with improvement noted in encephalopathy of at least one grade in 87% of the patients with cirrhosis and 75% of the patients with hepatitis. Nitrogen balance was achieved when 75 to 80 grams of synthetic amino acids were administered. Survival was 45% in the cirrhotic group

  9. Early detection of hepatic encephalopathy by recording visual evoked potential (VEP).

    PubMed

    Zamir, Doron; Storch, Shimon; Kovach, Ivan; Storch, Rita; Zamir, Chen

    2002-01-01

    The visual evoked potential (VEP) record in response to a pattern stimulus is a non invasive and reliable method of detecting central and peripheral nerve system abnormalities. VEP recording have been used in animals with fulminant hepatic failure, and also in-patients with hepatic encephalopathy and acute severe hepatitis. Our aims were: a. to evaluate the potency of PVEP in assessing hepatic encephalopathy. b. to find the rate of pathologic PVEP in patients with advanced liver cirrhosis. VEP was recorded in 14 chronic liver cirrhotic patients (6 alcoholic, 6 HCV-related, 2 cryptogenic) and 14 controls. Patients with any neurologic abnormalities were excluded from the study. All patients were subjected to the Mental State Score (MSS) test, and venous blood ammonia was measured on the same day of VEP recording. In 10/14 (71%) patients some VEP recording abnormality was detected. In the cirrhotic patients, P100 latency was significantly longer (P < 0.05) than in controls. Low amplitude was observed in 8 patients compared to controls. Marked increase of N75 (3 patients) and marked increase of N145 (2 patients) were observed. Mean blood ammonia and MSS score were normal in all patients. No correlation was found between both MSS score and blood ammonia levels and the P100 delay. Five out of 10 patients with pathologic VEP developed hepatic encephalpathy during a follow-up of one year, compared to one out of 4 patients with no pathology on VEP recording. VEP recording may be a valuable tool in assessing patients with early hepatic encephalopathy and in predicting encephalopathy. PMID:12533959

  10. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy

    PubMed Central

    Hawkes, N; Thomas, G; Jurewicz, A; Williams, O; Hillier, C; McQueen, I; Shortland, G

    2001-01-01

    The clinical syndrome of encephalopathy is most often encountered in the context of decompensated liver disease and the diagnosis is usually clear cut. Non-hepatic causes of encephalopathy are rarer and tend to present to a wide range of medical specialties with variable and episodic symptoms. Delay can result in the development of potentially life threatening complications, such as seizures and coma.
Early recognition is vital. A history of similar episodes or clinical risk factors and early assessment of blood ammonia levels help establish the diagnosis. In addition to adequate supportive care, investigation of the underlying cause of the hyperammonaemia is essential and its reversal, where possible, will often result in complete recovery. Detection of an unborn error of metabolism should lead to the initiation of appropriate maintenance therapy and genetic counselling.


Keywords: hyperammonaemia; encephalopathy; portosystemic venous shunt; urea cycle defect PMID:11677282

  11. Branched-chain amino acids in the treatment of chronic hepatic encephalopathy.

    PubMed Central

    Eriksson, L S; Persson, A; Wahren, J

    1982-01-01

    The therapeutic efficacy of orally administered branched-chain amino acids in patients with liver cirrhosis and chronic encephalopathy was examined in a double blind, randomised crossover study. Seven patients with manifest hepatic cirrhosis and encephalopathy of six months' duration or longer ingested 30 g branched-chain amino acids or placebo during two 14-day periods. Psychometric tests and electroencephalograms were used to evaluate cerebral function. Neither clinical observations nor psychometric testing or electroencephalogram indicated a significant difference in the patients' response to branched-chain amino acids as compared with placebo. In four patients given branched-chain amino acids for longer periods (five to 22 weeks), psychometric tests also remained unchanged. The plasma concentrations of these acids after oral intake increased significantly, demonstrating adequate absorption. Basal plasma amino acid concentrations were unchanged, however, after branched-chain amino acid therapy. No side-effects were seen, which indicates that these amino acids are well tolerated as an extra protein supply in patients with chronic hepatic encephalopathy. As compared with placebo, however, no effect of branched-chain amino acids on the encephalopathy could be detected. PMID:6749604

  12. Hypercalcemic encephalopathy due to milk alkali syndrome and injection teriparatide.

    PubMed

    Kharb, Sandeep; Gundgurthi, Abhay; Pandit, Aditi; Brar, Karninder S; Garg, M K

    2012-11-01

    An 82-year-old male, a known case of severe osteoporosis with vertebral fracture and prostatic carcinoma, was treated with gonadotropin releasing hormone analogue, calcium carbonate, cholecalciferol sachet and injection teriparatide. His diet consisted of milk and curd. He developed altered behavior and generalized weakness, and on investigation, hypercalcemia, hypokalemia, and metabolic alkalosis with low parathyroid hormone levels were detected. Injection teriparatide was stopped and he was managed with forced saline diuresis and injection zoledronic acid. He was diagnosed as a case of milk alkali syndrome in whom teriparatide and prolonged immobilization played a permissive role in the development of hypercalcemic encephalopathy. PMID:23226658

  13. Recent developments in the diagnosis and treatment of covert/minimal hepatic encephalopathy.

    PubMed

    De Rui, M; Montagnese, S; Amodio, P

    2016-04-01

    The terms minimal hepatic encephalopathy and covert hepatic encephalopathy are defined. Clinical assessment is unreliable and both require the use of diagnostic tools. Of these, psychometric tests are the most widely used. They require proper standardization and may be biased by patient cooperation or lack thereof. The measure of the critical flicker frequency and of the electroencephalogram, possibly quantified, are also useful. The alteration of any of them is not strictly parallel in size and may vary from patient to patient. When possible, the use of multiple measures might increase diagnostic reliability. These functional measures should be interpreted within the clinical/biochemical profile of the patient to exclude other disorders. A flow chart for treatment is proposed on the basis of current knowledge. PMID:26758861

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

    PubMed Central

    Duarte-Rojo, Andrés; Ruiz-Margáin, Astrid; Macias-Rodriguez, Ricardo U; Cubero, Francisco Javier; Estradas-Trujillo, José; Muñoz-Fuentes, Rosa Ma; Torre, Aldo

    2016-01-01

    AIM: To evaluate the association between serum concentrations of S100β in patients with cirrhosis and the presence of low grade hepatic encephalopathy (HE). METHODS: This was a cross-sectional study. The population was categorized into four groups healthy subjects, cirrhosis without HE, cirrhosis with covert hepatic encephalopathy (CHE) and cirrhosis with overt HE. Kruskal-Wallis, Mann Whitney’s U with Bonferroni adjustment Spearman correlations and area under the ROC were used as appropriate. RESULTS: A total of 61 subjects were included, 46 cirrhotic patients and 15 healthy volunteers. S100β values were different among all groups, and differences remained significant between groups 1 and 2 (P < 0.001), and also between groups 2 and 3 (P = 0.016), but not between groups 3 and 4. In cirrhotic patients with HE S100β was higher than in patients without HE [0.18 (0.14-0.28) ng/mL vs 0.11 (0.06-0.14) ng/mL, P < 0.001]. There was a close correlation between serum concentrations of S100β and psychometric hepatic encephalopathy score in patients with cirrhosis without HE compared to the patients with cirrhosis with CHE (r = -0.413, P = 0.019). ROC curve analysis yielded > 0.13 ng/mL as the best cutoff value of S100β for the diagnosis of HE (sensitivity 83.3%, specificity 63.6%). CONCLUSION: Serum concentrations of S100β are higher in patients with cirrhosis than in healthy volunteers, and are further increased in the presence of hepatic encephalopathy. The results suggest that serum biomarkers such as S100β could help in the correct characterization of incipient stages of HE. PMID:27158209

  15. Comparison of Rifaximin and Lactulose for the Treatment of Hepatic Encephalopathy: A Prospective Randomized Study

    PubMed Central

    Paik, Yong-Han; Han, Kwang-Hyub; Song, Kun Hoon; Kim, Myoung Hwan; Moon, Byung Soo; Ahn, Sang Hoon; Lee, Se Joon; Park, Hyo Jin; Lee, Dong Ki; Chon, Chae Yoon; Lee, Sang In; Moon, Young Myoung

    2005-01-01

    Rifaximin has been reported to be effective for the treatment of hepatic encephalopathy (HE) in Europe. However, it is unknown whether Rifaximin is effective for the treatment of HE in Koreans, therefore we conducted a open-label prospective randomized study to evaluate the efficacy of rifaximin versus lactulose in Korean patients. Fifty-four patients with liver cirrhosis and hepatic encephalopathy were enrolled. Thirty-two patients were randomized to receive rifaximin and 22 to receive lactulose both over a 7-day periods. Before and at the end of treatment, gradation of blood ammonia, flapping tremor, mental status, number connection test (NCT) were performed and estimation of HE indexes determined. Both rifaximin and lactulose were effective in the majority of patients (84.4% and 95.4%, respectively, p=0.315). Blood NH3, flapping tremor, mental status, and NCT was significantly improved by rifaximin and lactulose, and the posttreatment levels of these measures were similar for the rifaximin and lactulose-treated groups, as was the HE index (rifaximin group (10.0→4.2, p=0.000); lactulose group (11.3→5.0, p=0.000)). One patient treated with rifaximin complained of abdominal pain, which was easily controlled. There was no episode of renal function impairment in either treatment group. Rifaximin proved to be as safe and as effective as lactulose for the treatment of Korean patients with hepatic encephalopathy. PMID:15988813

  16. Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

    PubMed

    Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

    2015-09-01

    The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. PMID:25447766

  17. Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

    PubMed

    Rösche, Johannes; Sieveking, Catharina; Kampf, Christina; Benecke, Reiner

    2015-10-01

    Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy. PMID:24973231

  18. Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients.

    PubMed

    Barboza, Katherine C; Salinas, Lilian M; Sahebjam, Farhad; Jesudian, Arun B; Weisberg, Ilan L; Sigal, Samuel H

    2016-08-01

    Depression, common in chronic medical conditions, and hepatic encephalopathy (HE), a reversible neuropsychiatric syndrome due to liver dysfunction, are associated with impaired health-related quality of life (HRQOL) in cirrhosis and hepatitis C (HCV). This study investigated the impact of depression and HE on HRQOL in cirrhotic patients with HCV. A convenience sample of 43 ambulatory patients, with varying degrees of cirrhosis secondary to HCV, was prospectively enrolled in this study. Participants were assessed for any current depressive, fatigue, and daytime sleepiness symptoms and underwent a psychometric evaluation to determine the presence of HE symptoms. Participants reported current HRQOL on general health and liver disease-specific questionnaires. Diagnosis and current health status were confirmed via medical records. The associations between disease severity, depressive symptoms, HE, fatigue, and daytime sleepiness were measured. Predictors of HRQOL in this sample were determined. Depressive symptoms (70 %) and HE (77 %) were highly prevalent in this sample, with 58 % actively experiencing both conditions at the time of study participation. A significant positive association was found between depressive symptoms and HE severity (P = .05). Depressive symptoms were significantly associated with fatigue (P < .001), daytime sleepiness (P < .001), general HRQOL (P < .001), and disease-specific HRQOL (P < .001). HE was significantly associated with fatigue (P = .02), general HRQOL (P < .001), and disease-specific HRQOL (P < .001). Depressive symptoms and HE were significant predictors of reduced HRQOL (P < .001), with depressive symptoms alone accounting for 58.8 % of the variance. Depressive symptoms and HE accounted for 68.0 % of the variance. Findings suggest a possible pathophysiological link between depression and HE in cirrhosis, and potentially a wider-reaching benefit of treating minimal and overt HE than previously appreciated

  19. HCV encephalopathy - an artefact due to medical care?

    PubMed

    Weissenborn, K; Tillmann, H L

    2016-08-01

    Anti-HCV positive individuals frequently complain about chronic disabling fatigue, mood alterations and deficits in concentration and memory. Several data provide evidence that such alterations are unrelated to hepatitis C virus (HCV) viremia. Thus, merely being exposed to HCV in the past may be sufficient to trigger, but the HCV exposure itself. This commentary reviews the available data upon this topic with special reference to the paper by Lowry and colleagues published in this issue of the Journal of Viral hepatitis. We will carefully discuss scientific reasons, why HCV may be directly involved in the development of neuropsychiatric symptoms independent from ongoing detectable viremia, as suggested by epidemiological data. PMID:27225063

  20. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications.

    PubMed

    Monfort, Pilar; Cauli, Omar; Montoliu, Carmina; Rodrigo, Regina; Llansola, Marta; Piedrafita, Blanca; El Mlili, Nisrin; Boix, Jordi; Agustí, Ana; Felipo, Vicente

    2009-01-01

    Patients with liver diseases (e.g. cirrhosis) may present hepatic encephalopathy (HE), an alteration in cerebral function which is a consequence of previous failure of liver function. Patients with minimal or clinical HE present different levels of cognitive impairment. Hyperammonemia is considered a main contributor to the neurological alterations in HE. Animal models of chronic HE (e.g. rats with portacaval shunts) or of "pure" hyperammonemia also show impaired cognitive function. The studies summarized here show that the impairment of some types of cognitive function in chronic HE is due to the impaired function of the glutamate-nitric oxide-cGMP pathway in brain. Both hyperammonemia and neuroinflammation contribute to the impairment of the pathway and of cognitive function. Treatment of rats with chronic HE or hyperammonemia with inhibitors of phosphodiesterase 5 restores the function of the glutamate-nitric oxide-cGMP pathway and cGMP levels in brain as well as the ability to learn a Y maze conditional discrimination task. The same beneficial effects may be obtained by treating the rats chronically with an anti-inflammatory, ibuprofen. As the function of this pathway is also altered in brain of patients died in HE, this alteration would also contribute to cognitive impairment in patients with HE. Increasing cGMP by using inhibitors of phosphodiesterase 5 (PDE-5) or anti-inflammatories (under safe conditions) would be therefore a new therapeutic approach to improve learning and memory performance in individuals with minimal or clinical HE. PMID:19428813

  1. Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy.

    PubMed

    Jao, Tun; Schröter, Manuel; Chen, Chao-Long; Cheng, Yu-Fan; Lo, Chun-Yi Zac; Chou, Kun-Hsien; Patel, Ameera X; Lin, Wei-Che; Lin, Ching-Po; Bullmore, Edward T

    2015-11-15

    Functional properties of the brain may be associated with changes in complex brain networks. However, little is known about how properties of large-scale functional brain networks may be altered stepwise in patients with disturbance of consciousness, e.g., an encephalopathy. We used resting-state fMRI data on patients suffering from various degrees of hepatic encephalopathy (HE) to explore how topological and spatial network properties of functional brain networks changed at different cognitive and consciousness states. Severity of HE was measured clinically and by neuropsychological tests. Fifty-eight non-alcoholic liver cirrhosis patients and 62 normal controls were studied. Patients were subdivided into liver cirrhosis with no outstanding HE (NoHE, n=23), minimal HE with cognitive impairment only detectable by neuropsychological tests (MHE, n=28), and clinically overt HE (OHE, n=7). From the earliest stage, the NoHE, functional brain networks were progressively more random, less clustered, and less modular. Since the intermediate stage (MHE), increased ammonia level was accompanied by concomitant exponential decay of mean connectivity strength, especially in the primary cortical areas and midline brain structures. Finally, at the OHE stage, there were radical reorganization of the topological centrality-i.e., the relative importance-of the hubs and reorientation of functional connections between nodes. In summary, this study illustrated progressively greater abnormalities in functional brain network organization in patients with clinical and biochemical evidence of more severe hepatic encephalopathy. The early-than-expected brain network dysfunction in cirrhotic patients suggests that brain functional connectivity and network analysis may provide useful and complementary biomarkers for more aggressive and earlier intervention of hepatic encephalopathy. Moreover, the stepwise deterioration of functional brain networks in HE patients may suggest that hierarchical

  2. [Hepatitis due to herpes group viruses].

    PubMed

    Cisneros-Herreros, José M; Herrero-Romero, Marta

    2006-01-01

    In immunocompetent patients, primary infection by herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6, and Epstein-Barr virus (EBV) generally produces mild, self-limited hepatitis. Primary infection by HSV in neonates and pregnant women, and infection by VZV in hematological and bone marrow recipients can cause fulminant hepatitis without characteristic skin lesions. In liver transplant recipients, hepatitis is the most common expression of CMV infection and the related symptoms are indistinguishable from those of acute rejection. Persistent hepatitis is a manifestation of the syndrome of active chronic infection by the EBV. Fulminating hepatitis due to herpes virus can be treated effectively if therapy is started early; hence, a high degree of clinical suspicion and inclusion of herpes virus in the differential diagnosis of this syndrome is necessary. PMID:16792943

  3. Brainstem evoked response audiometry: an investigatory tool in detecting hepatic encephalopathy in decompensated chronic liver disease.

    PubMed

    Kabali, Balasubramanian; Velayutham, Gowri; Kapali, Suresh Chander

    2014-01-01

    It is estimated that globally there is a marked increase in liver disease with reports of rising morbidity and mortality, particularly in younger age groups. Brainstem auditory evoked potential (BAEP) was recorded in 60 decompensated chronic liver disease (DCLD) subjects who fulfilled the selection criteria and compared to 60 age and gender matched healthy subjects with normal liver functions. DCLD subjects were divided into two inter groups based on presence or absence of hepatic encephalopathy (HE). Group 1 comprises of 30 subjects of grade- I HE and Group 2 included 30 subjects without hepatic encephalopathy (NHE). Absolute and interpeak wave latencies were measured. Results were analysed by student independent t- test using SPSS software 11 version. Statistical significance was tested using P value. From the present study it can be concluded that the central nervous system is involved in liver cirrhosis evidenced by an abnormal BAEP latencies parameters. This shows that there may be progressive demyelination occurring along with axonal loss or dysfunction in liver cirrhosis HE. This study suggests that periodic evaluation of cirrhotic individuals to such test will help in monitoring the progress of encephalopathy. The prime goal of this study is early diagnosis and initiation of treatment before the onset of coma can reduce the fatality rate. PMID:25508308

  4. Brainstem evoked response audiometry: an investigatory tool in detecting hepatic encephalopathy in decompensated chronic liver disease.

    PubMed

    Kabali, Balasubramanian; Velayutham, Gowri; Kapali, Suresh Chander

    2014-01-01

    It is estimated that globally there is a marked increase in liver disease with reports of rising morbidity and mortality, particularly in younger age groups. Brainstem auditory evoked potential (BAEP) was recorded in 60 decompensated chronic liver disease (DCLD) subjects who fulfilled the selection criteria and compared to 60 age and gender matched healthy subjects with normal liver functions. DCLD subjects were divided into two inter groups based on presence or absence of hepatic encephalopathy (HE). Group 1 comprises of 30 subjects of grade- I HE and Group 2 included 30 subjects without hepatic encephalopathy (NHE). Absolute and interpeak wave latencies were measured. Results were analysed by student independent t- test using SPSS software 11 version. Statistical significance was tested using P value. From the present study it can be concluded that the central nervous system is involved in liver cirrhosis evidenced by an abnormal BAEP latencies parameters. This shows that there may be progressive demyelination occurring along with axonal loss or dysfunction in liver cirrhosis HE. This study suggests that periodic evaluation of cirrhotic individuals to such test will help in monitoring the progress of encephalopathy. The prime goal of this study is early diagnosis and initiation of treatment before the onset of coma can reduce the fatality rate. PMID:25464677

  5. Screening for minimal hepatic encephalopathy in patients with cirrhosis by cirrhosis-related symptoms and a history of overt hepatic encephalopathy

    PubMed Central

    Yoshimura, Emi; Ichikawa, Tatsuki; Miyaaki, Hisamitsu; Taura, Naota; Miuma, Satoshi; Shibata, Hidataka; Honda, Takuya; Takeshima, Fuminao; Nakao, Kazuhiko

    2016-01-01

    The diagnosis of minimal hepatic encephalopathy (MHE) is more difficult in comparison to the diagnosis of overt hepatic encephalopathy (OHE), as patients with MHE do not exhibit overt neurological deficits and must be diagnosed using specialized equipment. However, identifying MHE is critical for patients with cirrhosis, and a simple screening test is required. The present study aimed to evaluate the associations between MHE, clinical characteristics and questionnaire items regarding sleep disturbances and cirrhosis-related symptom score (CSS). A total of 91 patients who had cirrhosis without OHE were evaluated using various questionnaires [i.e., CSS, Epworth Sleepiness Scale, the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) and the Japanese 36-item short-form health survey (SF-36)]. MHE was diagnosed using the neuropsychological test. MHE was associated with severe liver damage, which was indicated by liver damage markers and a history of OHE. In addition, MHE was associated with the CSS, PSQI and SF-36 results. The multivariate analyses revealed that a history of OHE was the factor that was the most strongly associated with MHE. Among patients without a history of OHE, MHE was most strongly associated with CSS, although it was also associated with severe liver damage and platelet counts. A prediction score (calculated using a history of OHE and CSS) provided an area under the receiver operating characteristic curve of 0.738 and a sensitivity of 0.671 for identifying MHE. In conclusion, a history of OHE and CSS may be useful for identifying MHE in patients with cirrhosis. PMID:27446540

  6. Cortical signature of patients with HBV-related cirrhosis without overt hepatic encephalopathy: a morphometric analysis

    PubMed Central

    Wu, Xiu; Lv, Xiao-Fei; Zhang, Yu-Ling; Wu, Hua-Wang; Cai, Pei-Qiang; Qiu, Ying-Wei; Zhang, Xue-Lin; Jiang, Gui-Hua

    2015-01-01

    Previous studies have shown that patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt hepatic encephalopathy (OHE) are associated with a varying degree of cognitive dysfunction. Several resting-state functional magnetic resonance imaging (fMRI) studies have been conducted to explore the neural correlates of such cognitive deficits, whereas little effort has been made to investigate the cortical integrity in cirrhotic patients without OHE. Here, using cortical thickness, surface area and local gyrification index (lGI), this study performed a comprehensive analysis on the cortical morphometry of patients with HBV-RC without OHE (HBV-RC-NOHE) vs. matched healthy controls. Compared with healthy controls, we found significantly increased cortical thickness in the bilateral lingual and parahippocampal gyrus, right posterior cingulate cortex, precuneus, peri-calcarine sulcus and fusiform gyrus in patient with HBV-RC-NOHE, which may closely relate to be the low-grade brain edema. Cortical gyrification analysis showed significantly increased lGI in the left superior and inferior parietal cortex as well as lateral occipital cortex, which was speculated to be associated with disruptions in white matter connectivity and sub-optimal intra-cortical organization. In addition, the mean cortical thickness/lGI of the regions with structural abnormalities was shown to be negatively correlated with psychometric hepatic encephalopathy score (PHES) of the patients with HBV-RC-NOHE. These morphological changes may serve as potential markers for the preclinical diagnosis and progression of HBV-RC-NOHE. PMID:26106307

  7. Cortical signature of patients with HBV-related cirrhosis without overt hepatic encephalopathy: a morphometric analysis.

    PubMed

    Wu, Xiu; Lv, Xiao-Fei; Zhang, Yu-Ling; Wu, Hua-Wang; Cai, Pei-Qiang; Qiu, Ying-Wei; Zhang, Xue-Lin; Jiang, Gui-Hua

    2015-01-01

    Previous studies have shown that patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt hepatic encephalopathy (OHE) are associated with a varying degree of cognitive dysfunction. Several resting-state functional magnetic resonance imaging (fMRI) studies have been conducted to explore the neural correlates of such cognitive deficits, whereas little effort has been made to investigate the cortical integrity in cirrhotic patients without OHE. Here, using cortical thickness, surface area and local gyrification index (lGI), this study performed a comprehensive analysis on the cortical morphometry of patients with HBV-RC without OHE (HBV-RC-NOHE) vs. matched healthy controls. Compared with healthy controls, we found significantly increased cortical thickness in the bilateral lingual and parahippocampal gyrus, right posterior cingulate cortex, precuneus, peri-calcarine sulcus and fusiform gyrus in patient with HBV-RC-NOHE, which may closely relate to be the low-grade brain edema. Cortical gyrification analysis showed significantly increased lGI in the left superior and inferior parietal cortex as well as lateral occipital cortex, which was speculated to be associated with disruptions in white matter connectivity and sub-optimal intra-cortical organization. In addition, the mean cortical thickness/lGI of the regions with structural abnormalities was shown to be negatively correlated with psychometric hepatic encephalopathy score (PHES) of the patients with HBV-RC-NOHE. These morphological changes may serve as potential markers for the preclinical diagnosis and progression of HBV-RC-NOHE. PMID:26106307

  8. Longitudinal brain white matter alterations in minimal hepatic encephalopathy before and after liver transplantation.

    PubMed

    Lin, Wei-Che; Chou, Kun-Hsien; Chen, Chao-Long; Chen, Hsiu-Ling; Lu, Cheng-Hsien; Li, Shau-Hsuan; Huang, Chu-Chung; Lin, Ching-Po; Cheng, Yu-Fan

    2014-01-01

    Cerebral edema is the common pathogenic mechanism for cognitive impairment in minimal hepatic encephalopathy. Whether complete reversibility of brain edema, cognitive deficits, and their associated imaging can be achieved after liver transplantation remains an open question. To characterize white matter integrity before and after liver transplantation in patients with minimal hepatic encephalopathy, multiple diffusivity indices acquired via diffusion tensor imaging was applied. Twenty-eight patients and thirty age- and sex-matched healthy volunteers were included. Multiple diffusivity indices were obtained from diffusion tensor images, including mean diffusivity, fractional anisotropy, axial diffusivity and radial diffusivity. The assessment was repeated 6-12 month after transplantation. Differences in white matter integrity between groups, as well as longitudinal changes, were evaluated using tract-based spatial statistical analysis. Correlation analyses were performed to identify first scan before transplantation and interval changes among the neuropsychiatric tests, clinical laboratory tests, and diffusion tensor imaging indices. After transplantation, decreased water diffusivity without fractional anisotropy change indicating reversible cerebral edema was found in the left anterior cingulate, claustrum, postcentral gyrus, and right corpus callosum. However, a progressive decrease in fractional anisotropy and an increase in radial diffusivity suggesting demyelination were noted in temporal lobe. Improved pre-transplantation albumin levels and interval changes were associated with better recoveries of diffusion tensor imaging indices. Improvements in interval diffusion tensor imaging indices in the right postcentral gyrus were correlated with visuospatial function score correction. In conclusion, longitudinal voxel-wise analysis of multiple diffusion tensor imaging indices demonstrated different white matter changes in minimal hepatic encephalopathy patients

  9. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy.

    PubMed

    Tapper, Elliot B; Jiang, Z Gordon; Patwardhan, Vilas R

    2015-05-01

    Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the

  10. Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Patients with Recurrent Variceal Hemorrhage

    PubMed Central

    Peter, Popovič; Andrej, Zore; Katarina, Šurlan Popovič; Manca, Garbajs; Pavel, Skok

    2013-01-01

    Purpose. The purpose of this study was to determine the incidence and predictors of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) and endoscopic therapy (ET) in the elective treatment of recurrent variceal hemorrhage. Methods. Seventy patients were treated with elective TIPS and fifty-six patients with ET. Median observation time was 46.28 months in the TIPS group and 42.31 months in the ET group. Results. 30 patients (42.8%) developed clinically evident portosystemic encephalopathy in TIPS group and 20 patients (35.6%) in ET group. The difference between the groups was not statistically significant (P = 0.542; χ2 test). The incidence of new or worsening portosystemic encephalopathy was 24.3% in TIPS group and 10.7% in ET group. Multivariate analysis showed that ET treatment (P = 0.031), age of >65 years (P = 0.022), pre-existing HE (P = 0.045), and Child's class C (P = 0.051) values were independent predictors for the occurrence of HE. Conclusions. Procedure-related HE is a complication in a minority of patients treated with TIPS or ET. Patients with increased age, preexisting HE, and higher Child-Pugh score should be carefully observed after TIPS procedure because the risk of post-TIPS HE in these patients is higher. PMID:23606833

  11. Ammonia-induced senescence in cultured rat astrocytes and in human cerebral cortex in hepatic encephalopathy.

    PubMed

    Görg, Boris; Karababa, Ayse; Shafigullina, Aygul; Bidmon, Hans J; Häussinger, Dieter

    2015-01-01

    Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is due to a low-grade cerebral edema associated with oxidative/nitrosative stress. Recent reports suggest that cognitive impairment in cirrhotic patients may not resolve completely after an attack of manifest HE. As astrocyte dysfunction is central to the pathogenesis of HE and astrocytes are critically involved in synaptic plasticity, we tested for sustained impairment of astrocyte function by analyzing expression levels of senescence biomarkers in ammonia-treated cultured rat astrocytes and in postmortem brain samples from cirrhotic patients with or without HE. NH4 Cl time- and dose-dependently inhibited proliferation of cultured astrocytes by up to 45% (5 mmol/L, 72 h) and strongly increased senescence-associated β-galactosidase activity. Inhibition of astrocyte proliferation by ammonia was mediated by a l-methionine sulfoximine-, oxidative stress-, and p38(MAPK) -dependent activation of p53 associated with enhanced transcription of cell cycle inhibitory genes GADD45α and p21. Mitochondria and the nucleus were identified as sources of oxygen radical formation after prolonged NH4 Cl exposure. Concurrently, NH4 Cl (5 mmol/L) treatment inhibited both epidermal growth factor- and brain-derived neurotrophic factor (BDNF)-induced proliferation as well as BDNF-mediated astrocyte morphology changes through downregulation of the respective growth factor receptors epidermal growth factor receptor and truncated tyrosine receptor kinase B. Increased mRNA expression levels of senescence-associated genes were also found in post mortem brain samples from patients with liver cirrhosis with HE, but not in those without HE. The data suggest that ammonia toxicity and HE are associated with premature astrocyte senescence, which may impair neurotransmission and contribute to persistence of cognitive disturbances after resolution of episodes of overt HE. PMID:25092802

  12. Embolization of Portosystemic Shunts for Treatment of Medically Refractory Hepatic Encephalopathy

    PubMed Central

    Lynn, Amanda M.; Singh, Siddharth; Congly, Stephen E.; Khemani, Disha; Johnson, David H.; Wiesner, Russell H.; Kamath, Patrick S.; Andrews, James C.; Leise, Michael D.

    2016-01-01

    Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003–2015). Patient data collected included the type of HE, medications, Model for End-Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1–4 months), and longer-term (6–12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty-five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1–4 and 6–12 months, respectively. The majority (67%; 8/12) were free from HE-related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. PMID:26970243

  13. Efficacy of liver assisting in patients with hepatic encephalopathy with special focus on plasma exchange.

    PubMed

    Stenbøg, Poul; Busk, Troels; Larsen, Fin Stolze

    2013-06-01

    Severe liver injury result in development of hepatic encephalopathy (HE) and often also in brain edema that is a potentially fatal complication. HE and brain edema are correlated to the level and persistence of hyperammonemia and the presence of systemic inflammation. Treatment of HE and brain edema is based on restoring and keeping normal physiological variables including tonicity, blood gasses, lactate, temperature and vascular resistance by a wide variety of interventions. In addition liver support devices improve the stage of HE, cerebral metabolic rate for oxygen and glucose, and are used either as a bridge to liver transplantation or liver recovery in patients with fulminant hepatic failure and in patients with acute-on-chronic liver failure. This short review will mainly focus on the management and efficacy of doing plasma exchange on HE in patients with acute HE. PMID:23572273

  14. Generalized chorea due to delayed encephalopathy after acute carbon monoxide intoxication

    PubMed Central

    Sung, Yueh-Feng; Chen, Ming-Hua; Peng, Giia-Sheun; Lee, Jiunn-Tay

    2015-01-01

    Movement disorder due to delayed encephalopathy after carbon monoxide (CO) intoxication is uncommon. Generalized chorea, presenting as an initial symptom of delayed encephalopathy, is extremely rare. We describe a 60-year-old woman, who had completely recovered from acute CO poisoning, developed mental and behavioral changes, urinary incontinence and generalized chorea 2 weeks thereafter. T2-weighted brain magnetic resonance imaging showed extensive hyperintensity of the bilateral periventricular and subcortical white matter and the globus pallidus. Brain single-photon emission computed tomography (SPECT) with technetium-99 ethylene cysteine dimer showed inhomogeneous perfusion in the cerebral cortex, with decreased uptake in bilateral frontal regions. Delayed encephalopathy after acute CO intoxication was diagnosed, and the symptoms gradually improved after hyperbaric oxygen therapy (HBOT). This case report demonstrates that generalized chorea may be one of the initial presenting symptoms of delayed encephalopathy after acute CO intoxication. We hypothesize that the generalized chorea in our patient may have been caused by the subcortical white matter lesions, which most likely interrupted the basal ganglia-thalamocortical circuits and that HBOT may be the treatment of choice for such patients. PMID:25745326

  15. Generalized chorea due to delayed encephalopathy after acute carbon monoxide intoxication.

    PubMed

    Sung, Yueh-Feng; Chen, Ming-Hua; Peng, Giia-Sheun; Lee, Jiunn-Tay

    2015-01-01

    Movement disorder due to delayed encephalopathy after carbon monoxide (CO) intoxication is uncommon. Generalized chorea, presenting as an initial symptom of delayed encephalopathy, is extremely rare. We describe a 60-year-old woman, who had completely recovered from acute CO poisoning, developed mental and behavioral changes, urinary incontinence and generalized chorea 2 weeks thereafter. T2-weighted brain magnetic resonance imaging showed extensive hyperintensity of the bilateral periventricular and subcortical white matter and the globus pallidus. Brain single-photon emission computed tomography (SPECT) with technetium-99 ethylene cysteine dimer showed inhomogeneous perfusion in the cerebral cortex, with decreased uptake in bilateral frontal regions. Delayed encephalopathy after acute CO intoxication was diagnosed, and the symptoms gradually improved after hyperbaric oxygen therapy (HBOT). This case report demonstrates that generalized chorea may be one of the initial presenting symptoms of delayed encephalopathy after acute CO intoxication. We hypothesize that the generalized chorea in our patient may have been caused by the subcortical white matter lesions, which most likely interrupted the basal ganglia-thalamocortical circuits and that HBOT may be the treatment of choice for such patients. PMID:25745326

  16. Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis

    PubMed Central

    Wu, Dong; Wu, Shu-Mei; Lu, Jie; Zhou, Ying-Qun; Xu, Ling; Guo, Chuan-Yong

    2013-01-01

    Background. Many studies have found that the antibiotic rifaximin is effective for the treatment of hepatic encephalopathy. However, there is no uniform view on the efficacy and safety of rifaximin. Methods. We performed a meta-analysis through electronic searches to evaluate the efficacy and safety of rifaximin in comparison with nonabsorbable disaccharides. Results. A total of 8 randomized controlled trials including 407 patients were included. The efficacy of rifaximin was equivalent to nonabsorbable disaccharides according to the statistical data (risk ratio (RR): 1.06, 95% CI: 0.94–1.19; P = 0.34). Analysis showed that patients treated with rifaximin had better results in serum ammonia levels (weighted mean difference (WMD): −10.63, 95% CI: −30.63–9.38; P = 0.30), mental status (WMD: −0.32, 95% CI: −0.67–0.03; P = 0.07), asterixis (WMD: −0.12, 95% CI: −0.31–0.08; P = 0.23), electroencephalogram response (WMD: −0.21, 95% CI: −0.34–−0.09; P = 0.0007), and grades of portosystemic encephalopathy (WMD: −2.30, 95% CI: −2.78–−1.82; P < 0.00001), but only the last ones had statistical significance. The safety of rifaximin was better than nonabsorbable disaccharides (RR: 0.19, 95% CI: 0.10–0.34; P < 0.00001). Conclusion. Rifaximin is at least as effective as nonabsorbable disaccharides, maybe better for the treatment of hepatic encephalopathy. And the safety of rifaximin is better. PMID:23653636

  17. Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis.

    PubMed

    Wu, Dong; Wu, Shu-Mei; Lu, Jie; Zhou, Ying-Qun; Xu, Ling; Guo, Chuan-Yong

    2013-01-01

    Background. Many studies have found that the antibiotic rifaximin is effective for the treatment of hepatic encephalopathy. However, there is no uniform view on the efficacy and safety of rifaximin. Methods. We performed a meta-analysis through electronic searches to evaluate the efficacy and safety of rifaximin in comparison with nonabsorbable disaccharides. Results. A total of 8 randomized controlled trials including 407 patients were included. The efficacy of rifaximin was equivalent to nonabsorbable disaccharides according to the statistical data (risk ratio (RR): 1.06, 95% CI: 0.94-1.19; P = 0.34). Analysis showed that patients treated with rifaximin had better results in serum ammonia levels (weighted mean difference (WMD): -10.63, 95% CI: -30.63-9.38; P = 0.30), mental status (WMD: -0.32, 95% CI: -0.67-0.03; P = 0.07), asterixis (WMD: -0.12, 95% CI: -0.31-0.08; P = 0.23), electroencephalogram response (WMD: -0.21, 95% CI: -0.34--0.09; P = 0.0007), and grades of portosystemic encephalopathy (WMD: -2.30, 95% CI: -2.78--1.82; P < 0.00001), but only the last ones had statistical significance. The safety of rifaximin was better than nonabsorbable disaccharides (RR: 0.19, 95% CI: 0.10-0.34; P < 0.00001). Conclusion. Rifaximin is at least as effective as nonabsorbable disaccharides, maybe better for the treatment of hepatic encephalopathy. And the safety of rifaximin is better. PMID:23653636

  18. Embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy

    SciTech Connect

    Sakurabayashi, Shin; Sezai, Shuichi; Yamamoto, Yoshihiro; Hirano, Masanori; Oka, Hiroshi

    1997-03-15

    Purpose. To evaluate the efficacy of embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy (CRHE). Methods. Seven cirrhotic patients with CRHE refractory to medical treatment (3 men and 4 women, mean age 66 years) were studied. Five patients had splenorenal shunts, 1 had a gastrorenal shunt, and 1 had an intrahepatic portal vein-hepatic vein shunt. Shunt embolization was performed using stainless steel coils, with a percutaneous transhepatic portal vein approach in 4 patients and a transrenal vein approach in 3 patients. Results. After embolization, the shunt disappeared in 4 patients on either ultrasound pulsed Doppler monitoring or portography. Complications observed in the 7 patients were fever, transient pleural effusion, ascites, and mild esophageal varices. For 3-6 months after embolization, the 4 patients whose shunts disappeared showed minimal or no reappearance of a shunt, and had no recurrence of encephalopathy. The serum ammonia levels decreased and electroencephalograms also improved. One of the 4 patients, who developed mild esophageal varices, required no treatment. Treatment was effective in 3 of the 4 patients (75%) who underwent embolization via a transhepatic portal vein. Conclusion. Transvascular embolization of shunts improved the outcome in 4 of 7 patients. The most effective embolization was achieved via the percutaneous transhepatic portal vein approach.

  19. Lactitol in the treatment of chronic hepatic encephalopathy: an open comparison with lactulose.

    PubMed Central

    Lanthier, P L; Morgan, M Y

    1985-01-01

    Lactulose is currently the drug of choice for the treatment of hepatic encephalopathy. It is, however, only available as a syrup which is contaminated with other sugars. Consequently patients may express aversion to its excessively sweet taste and many experience nausea because of its hyperosmolarity. Lactitol is a disaccharide analogue of lactulose which can be produced as a pure crystalline powder with a low relative sweetness. Theoretically it should have the same therapeutic effects as lactulose but fewer side effects. Five patients with chronic hepatic encephalopathy on maintenance lactulose were monitored clinically, psychometrically, and by measurement of venous blood ammonia, electroencephalogram mean cycle frequency, and cerebral blood flow during three months treatment with lactulose and a similar period on lactitol. Lactitol was at least as efficacious as lactulose but was more acceptable because its cathartic effect was more predictable, its formulation was more convenient and its less sweet taste preferred. Lactitol is the ideal successor to lactulose for treatment of this condition. PMID:3979914

  20. Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance.

    PubMed

    Jiménez, Beatriz; Montoliu, Carmina; MacIntyre, David A; Serra, Miguel A; Wassel, Abdallah; Jover, María; Romero-Gomez, Manuel; Rodrigo, Jose M; Pineda-Lucena, Antonio; Felipo, Vicente

    2010-10-01

    Minimal hepatic encephalopathy (MHE) reduces quality of life of cirrhotic patients, predicts overt hepatic encephalopathy, and is associated with poor prognosis. We hypothesized that MHE arises once metabolic alterations derived from the liver reach a particular threshold. Our aim was to assess whether metabolic profiling of serum samples by high-field (1)H-nuclear magnetic resonance spectroscopy ((1)H NMR) and subsequent multivariate analyses would be useful to characterize metabolic perturbations associated with MHE and to identify potential metabolic biomarkers. Metabolic serum profiles from controls (n = 69) and cirrhotic patients without MHE (n = 62) and with MHE (n = 39) were acquired using high field NMR. Supervised modeling of the data provided perfect discrimination between healthy controls and cirrhotic patients and allowed the generation of a predictive model displaying strong discrimination between patients with and without MHE (R(2)Y = 0.68, Q(2)Y = 0.63). MHE patients displayed increased serum concentrations of glucose, lactate, methionine, TMAO, and glycerol, as well as decreased levels of choline, branch amino acids, alanine, glycine, acetoacetate, NAC, and lipid moieties. Serum metabonomics by (1)H NMR offers a useful approach for characterizing underlying metabolic differences between patients with and without MHE. This procedure shows great potential as a diagnostic tool of MHE as it objectively reflects measurable biochemical differences between the patient groups and may facilitate monitoring of both disease progression and effects of therapeutic treatments. PMID:20690770

  1. Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats.

    PubMed

    Ilic, Spomenko; Drmic, Domagoj; Zarkovic, Kamelija; Kolenc, Danijela; Brcic, Luka; Radic, Bozo; Djuzel, Viktor; Blagaic, Alenka Boban; Romic, Zeljko; Dzidic, Senka; Kalogjera, Livije; Seiwerth, Sven; Sikiric, Predrag

    2011-09-30

    Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 μg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 μg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen. PMID:21645505

  2. Hepatic Encephalopathy With Corticospinal Tract Involvement Demonstrated by Diffusion Tensor Tractography

    PubMed Central

    Bang, Hyun; Lee, Hye Yeon; Kim, Bo-Ram; Lee, In-Sik; Jung, Heeyoune; Koh, Seong-Eun

    2015-01-01

    A 50-year-old man with liver cirrhosis and esophageal varix for 3 years was diagnosed with hematemesis and treated for a bleeding varix. However, bleeding recurred 11 days later, and he developed drowsiness with left hemiparesis. His left upper and lower extremity muscle strengths based on the manual muscle test at the onset were grade 2/5 and 1/5, respectively. The Babinski sign was positive. His serum ammonia level was elevated to 129.9 µg/dL (normal, 20-80 µg/dL). Magnetic resonance imaging revealed restriction on diffusion and T2-hyperintensities with decreased apparent diffusion coefficient values in the bilateral frontoparietooccipital cortex. The effect was more severe in the right hemisphere and right parietooccipital cortices, which were compatible with hepatic encephalopathy. Although the patient's mental status recovered, significant left-sided weakness and sensory deficit persisted even after 6 months. Diffusion tensor tractography (DTT) performed 3 months post-onset showed decreased volume of the right corticospinal tract. We reported a patient with hepatic encephalopathy involving the corticospinal tract by DTT. PMID:25750884

  3. Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia.

    PubMed

    Iwasa, Motoh; Takei, Yoshiyuki

    2015-12-01

    Hyperammonemia is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia elicits astrocyte swelling and causes brain edema. In addition, hyponatremia, a condition frequently observed in hepatic cirrhosis, also exacerbates brain edema, potentially becoming a factor that exacerbates HE. Therefore, as a treatment strategy for HE, alleviating ammonia toxicity is essential. In addition to restricting protein intake, synthetic disaccharides such as lactulose and lactitol, probiotics that improve gut flora, and rifaximin, an antibiotic with poor bioavailability, are also administrated. Additionally, branched-chain amino acids and carnitine have also been administrated. Moreover, we investigated the current trend in the concomitant use of drugs with different mechanisms of action. In Japan, the V2 receptor antagonist tolvaptan can be administrated to hepatic cirrhosis patients with fluid retention. This drug is also useful as a countermeasure for hyponatremia in hepatic cirrhosis, and elucidating its effects in HE patients may therefore become an agenda in the future. These observations indicate that ammonia toxicity, gut flora control and low sodium control are major focuses in HE improvement and long-term prognosis. PMID:25604571

  4. Cholestatic hepatitis due to Ecballium elaterium ingestion.

    PubMed

    Bizid, Sondès; Sabbah, Mériam; Msakni, Issam; Ben Slimene, Baha; Mohamed, Ghanem; Bouali, Riadh; Ben Abdallah, Hatem; Abdelli, Nabil

    2015-10-01

    Ecballium elaterium is an herbaceous plant belonging to the Cucurbitaceae family. This plant is fairly common in the Mediterranean regions. It is frequently consumed in infusion, mixture of fruit or even in aerosol in cases of fever or flu. This plant is known for its respiratory and ocular toxicity. Hepatotoxicity has never been described in the literature. We report a case of acute cholestatic hepatitis due to Ecballium elaterium in a 39 years old patient, with no past medical history. PMID:25573494

  5. Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests

    PubMed Central

    Felipo, Vicente; Urios, Amparo; Giménez-Garzó, Carla; Cauli, Omar; Andrés-Costa, Maria-Jesús; González, Olga; Serra, Miguel A; Sánchez-González, Javier; Aliaga, Roberto; Giner-Durán, Remedios; Belloch, Vicente; Montoliu, Carmina

    2014-01-01

    AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy. METHODS: Blood flow (BF) was analyzed by arterial spin labeling (ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy (MHE). Images were collected using a 3 Tesla MR scanner (Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score (PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins (IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated. RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere (P = 0.03) and vermis (P = 0.012) and reduced in occipital lobe (P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE (P = 0.02). Bimanual coordination was impaired in patients without MHE (P = 0.05) and much more in patients with MHE (P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE (P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE (P < 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A (NCT-A), B (NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with

  6. Endovascular Management of Refractory Hepatic Encephalopathy Complication of Transjugular Intrahepatic Portosystemic Shunt (TIPS): Comprehensive Review and Clinical Practice Algorithm.

    PubMed

    Pereira, Keith; Carrion, Andres F; Salsamendi, Jason; Doshi, Mehul; Baker, Reginald; Kably, Issam

    2016-02-01

    Transjugular intrahepatic portosystemic shunt (TIPS) has evolved as an effective intervention for treatment of complications of portal hypertension. The use of polytetrafluoroethylene-covered stents have improved the patency of the shunts and diminished the incidence of TIPS dysfunction. However, TIPS-related refractory hepatic encephalopathy (rHE) poses a significant challenge. Approximately 3-7 % of patients with TIPS develop rHE. Refractory hepatic encephalopathy is defined as a recurrent or persistent encephalopathy despite appropriate medical treatment. Hepatic encephalopathy can be an extremely debilitating complication that profoundly affects quality of life. The approach to management of patients with rHE is complex and typically requires collaboration between different specialties. Liver transplantation is the ultimate treatment for rHE; however, the ongoing shortage of organ donation markedly limits this treatment option. Alternative therapies such as shunt occlusion or reduction can control symptoms and serve as a 'bridge' therapy to liver transplantation. Therefore, interventional radiologists play a key role in the management of these patients by offering a variety of endovascular techniques. The purpose of this review is to highlight some of these endovascular techniques and to develop a therapeutic algorithm that can be applied in clinical practice for the management of rHE. PMID:26285910

  7. Changing face of hepatic encephalopathy: Role of inflammation and oxidative stress

    PubMed Central

    Seyan, Amit S; Hughes, Robin D; Shawcross, Debbie L

    2010-01-01

    The face of hepatic encephalopathy (HE) is changing. This review explores how this neurocognitive disorder, which is associated with both acute and chronic liver injury, has grown to become a dynamic syndrome that spans a spectrum of neuropsychological impairment, from normal performance to coma. The central role of ammonia in the pathogenesis of HE remains incontrovertible. However, over the past 10 years, the HE community has begun to characterise the key roles of inflammation, infection, and oxidative/nitrosative stress in modulating the pathophysiological effects of ammonia on the astrocyte. This review explores the current thoughts and evidence base in this area and discusses the potential role of existing and novel therapies that might abrogate the oxidative and nitrosative stresses inflicted on the brain in patients with, or at risk of developing, HE. PMID:20632436

  8. A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy

    PubMed Central

    2013-01-01

    Background and aim Because low serum zinc levels precipitate hepatic encephalopathy, zinc supplementation is considered a potential therapeutic option. The aim of this study was to assess the effects of oral zinc supplementation in the treatment of hepatic encephalopathy. Methods For this systematic review and meta-analysis, data sources included electronic databases (CENTRAL, MEDLINE, EMBASE) and manual searching. Randomized clinical trials of adult patients diagnosed with liver cirrhosis and hepatic encephalopathy were included. The types of interventions considered were any oral zinc supplementation versus no intervention, placebo, or other interventions for the management of hepatic encephalopathy. The data were analyzed by calculating the RR for each trial and expressing the uncertainty as 95% CI. Continuous data were analyzed by calculating the standard mean differences (SMD) between groups within each trial and their 95% CI. Statistical heterogeneity was defined as a P-value > 0.10 (χ2) or I2 > 25%. Results Four trials with a total of 233 patients were included. Oral zinc supplementation was associated with a significant improvement in performance on the number connection test (SMD –0.62; 95% CI –1.12 to –0.11) reported in three trials (n = 189), but not with encephalopathy recurrence reduction (RR 0.64; 95% CI 0.26 to 1.59) reported in two trials (n = 169). Other clinically significant outcomes (mortality, liver related morbidity, quality of life) were not reported. Conclusion Oral zinc supplementation improved performance on the number connection test, but no evidence about other clinical or biochemical outcomes was available. PMID:23742732

  9. Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis

    PubMed Central

    Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

    2015-01-01

    Background Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. Aim To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Methods Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Results Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. Conclusions This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. PMID:25339518

  10. Identifying minimal hepatic encephalopathy in cirrhotic patients by measuring spontaneous brain activity.

    PubMed

    Chen, Hua-Jun; Zhang, Ling; Jiang, Long-Feng; Chen, Qiu-Feng; Li, Jun; Shi, Hai-Bin

    2016-08-01

    It has been demonstrated that minimal hepatic encephalopathy (MHE) is associated with aberrant regional intrinsic brain activity in cirrhotic patients. However, few studies have investigated whether altered intrinsic brain activity can be used as a biomarker of MHE among cirrhotic patients. In this study, 36 cirrhotic patients (with MHE, n = 16; without MHE [NHE], n = 20) underwent resting-state functional magnetic resonance imaging (fMRI). Spontaneous brain activity was measured by examining the amplitude of low-frequency fluctuations (ALFF) in the fMRI signal. MHE was diagnosed based on the Psychometric Hepatic Encephalopathy Score (PHES). A two-sample t-test was used to determine the regions of interest (ROIs) in which ALFF differed significantly between the two groups; then, ALFF values within ROIs were selected as classification features. A linear discriminative analysis was used to differentiate MHE patients from NHE patients. The leave-one-out cross-validation method was used to estimate the performance of the classifier. The classification analysis was 80.6 % accurate (81.3 % sensitivity and 80.0 % specificity) in terms of distinguishing between the two groups. Six ROIs were identified as the most discriminative features, including the bilateral medial frontal cortex/anterior cingulate cortex, posterior cingulate cortex/precuneus, left precentral and postcentral gyrus, right lingual gyrus, middle frontal gyrus, and inferior/superior parietal lobule. The ALFF values within ROIs were correlated with PHES in cirrhotic patients. Our findings suggest that altered regional brain spontaneous activity is a useful biomarker for MHE detection among cirrhotic patients. PMID:26886109

  11. The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy

    SciTech Connect

    Basile, A.S. )

    1991-02-01

    The involvement of the gamma-aminobutyric acid A(GABAA) receptor complex in the pathogenesis of hepatic encephalopathy (HE) was examined in galactosamine-treated rabbits with HE caused by fulminant hepatic failure. Radioligand binding to the constituent components of the GABAA receptor complex was unchanged in rabbits with HE. However, partially purified extracts from encephalopathic rabbit brain were approximately three times more potent in inhibiting ({sup 3}H)Ro 15-1788 binding to benzodiazepine (BZ) receptors than extracts from control rabbits. The inhibition of radioligand binding to the BZ receptor produced by these extracts was competitive and reversible and was significantly enhanced by GABA. Further purification of these extracts by high-performance liquid chromatography (HPLC) indicated that the inhibitory activity was localized in several peaks, some of which had retention times corresponding to 1,4-benzodiazepine standards. The presence of diazepam in these extracts was confirmed using mass spectroscopy. Both mass spectroscopic and radiometric techniques demonstrated that the concentration of diazepam in brain extracts from encephalopathic rabbits was approximately 4 times greater than control extracts. These findings link the presence of BZ receptor agonists to the development of a neuropathological condition, thereby providing a rational basis for the use of BZ receptor antagonists in the management of HE in man.

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

    PubMed Central

    Eltawil, Karim M; Laryea, Marie; Peltekian, Kevork; Molinari, Michele

    2012-01-01

    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. PMID:22371636

  13. Invasive intracranial pressure monitoring is a useful adjunct in the management of severe hepatic encephalopathy associated with pediatric acute liver failure

    PubMed Central

    Kamat, Pradip; Kunde, Sachin; Vos, Miriam; Vats, Atul; Heffron, Thomas; Romero, Rene; Fortenberry, James D.

    2011-01-01

    Introduction Pediatric acute liver failure (ALF) is often accompanied by hepatic encephalopathy, cerebral edema and raised intracranial pressure (ICP). Elevated ICP can be managed more effectively with intracranial monitoring, but ALF-associated coagulopathy is often considered a contraindication for invasive monitoring due to risk for intracranial bleeding. We reviewed our experience with use of early ICP monitoring in ALF in children listed for liver transplantation. Methods Retrospective review of all intubated pediatric ALF patients with Grade 3 and Grade 4 encephalopathy requiring intracranial pressure monitoring and evaluated for potential liver transplant were identified from an institutional liver transplant patient database from 1999 to 2009. Result 14 patients were identified that met inclusion criteria. Age ranged from 7 months to 20 yrs. Diagnoses of ALF were infectious (3), drug induced (7), autoimmune hepatitis (2) and indeterminate (2). Grade 3 and 4 encephalopathy was seen in 10 (71%) and 4 (29%) patients respectively. CT scans prior to ICP monitor placement showed cerebral edema in 5 (35.7%) patients. Prior to ICP monitor placement, fresh frozen plasma, Vitamin K and activated recombinant factor VIIa were given to all 14 patients with significant improvement in coagulopathy (p<.04). Initial ICP ranged from 5 – 50 cmH2O; ICP was significantly higher in patients with cerebral edema by CT (p<.05). 11/14 (78%) patients received hypertonic saline and 3 (22%) received mannitol for elevated ICP. 8 of 14 (56%) monitored patients were managed to liver transplant with 100% surviving neurologically intact. 4/14 (28%) patients had spontaneous recovery without liver transplant. 2 of 14 (14%) patients died due to multiple organ failure prior to transplant. One patient had a small 9mm intracranial hemorrhage but survived after receiving a liver transplant. No patient developed intracranial infection. Conclusion In our series of patients, ICP monitoring had a

  14. Pharmacological manipulation of cyclic GMP levels in brain restores learning ability in animal models of hepatic encephalopathy: therapeutic implications

    PubMed Central

    Rodrigo, Regina; Monfort, Pilar; Cauli, Omar; Erceg, Slaven; Felipo, Vicente

    2006-01-01

    Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function. To develop therapeutic treatments to restore cognitive function, it is important to understand the molecular mechanisms that impair cognitive function in HE. This review summarizes data showing that: (a) cognitive function and learning are impaired in patients with liver disease and in animal models of chronic liver failure or hyperammonemia; (b) the glutamate–NO–cGMP pathway modulates some forms of learning; and (c) the function of this pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients who died from HE. Learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase; (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood–brain barrier; and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate–NO–cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with HE. PMID:19412446

  15. Anomalous Gray Matter Structural Networks in Patients with Hepatitis B Virus-Related Cirrhosis without Overt Hepatic Encephalopathy

    PubMed Central

    Qiu, Ying-Wei; Cai, Pei-Qiang; Li, Jing; Jiang, Gui-Hua; Deng, Yan-Jia; Zhang, Xue-Lin; Wu, Pei-Hong; Xie, Chuan-Miao; Wen, Ge

    2015-01-01

    Background and Purpose Increasing evidence suggests that cirrhosis may affect the connectivity among different brain regions in patients before overt hepatic encephalopathy (OHE) occurs. However, there has been no study investigating the structural reorganization of these altered connections at the network level. The primary focus of this study was to investigate the abnormal topological organization of the structural network in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using structural MRI. Methods Using graph theoretical analysis, we compared the global and regional topological properties of gray matter structural networks between 28 patients with HBV-RC without OHE and 30 age-, sex- and education-matched healthy controls. The structural correlation networks were constructed for the two groups based on measures of gray matter volume. Results The brain network of the HBV-RC group exhibited a significant decrease in the clustering coefficient and reduced small-worldness at the global level across a range of network densities. Regionally, brain areas with altered nodal degree/betweenness centrality were observed predominantly in association cortices (frontal and temporal regions) (p < 0.05, uncorrected), including a significantly decreased nodal degree in the inferior temporal gyrus (p < 0.001, uncorrected). Furthermore, the HBV-RC group exhibited a loss of association hubs and the emergence of an increased number of non-association hubs compared with the healthy controls. Conclusion The results of this large-scale gray matter structural network study suggest reduced topological organization efficiency in patients with HBV-RC without OHE. Our findings provide new insight concerning the mechanisms of neurobiological reorganization in the HBV-RC brain from a network perspective. PMID:25786256

  16. Exploratory investigation on nitro- and phospho-proteome cerebellum changes in hyperammonemia and hepatic encephalopathy rat models.

    PubMed

    Brunelli, Laura; Campagna, Roberta; Airoldi, Luisa; Cauli, Omar; Llansola, Marta; Boix, Jordi; Felipo, Vicente; Pastorelli, Roberta

    2012-03-01

    Hepatic encephalopathy (HE) is a neurological disease associated with hepatic dysfunction. Current knowledge suggests that hyperammonemia, related to liver failure, is a main factor contributing to the cerebral alterations in HE and that hyperammonemia might impair signal transduction associated with post-translational modification of proteins such as tyrosine-nitration and phosphorylation. However, the molecular bases of the HE remain unclear and very little is known about the occurrence of post-translational modification on in vivo proteins. In this exploratory study we look for evidence of post-translation modifications of proteins in the cerebellum of experimental HE rat models using a proteomic approach. For the first time we showed that hyperammonemia without liver failure (HA rats) and experimental HE with liver failure due to portacaval shunt (PCS rats) lead to a reduced protein nitration in rat cerebellum, where the undernitrated proteins were involved in energy metabolism and cytoskeleton remodelling. Moreover we showed that tyrosine nitration loss of these proteins was not necessarily associated to a change in their phosphorylation state as result of the disease. Interestingly the rat cerebellum phosphoproteome was mainly perturbed in PCS rats, whereas HA rats did not shown appreciable changes in their phosphoprotein profile. Since the protein nitration level decreased similarly in the cerebellum of both HA and PCS rats, this implies that the two disease models share common effects but also present some differential signalling effects in the cerebellum of the same animals. This study highlights the interest for studying the concerted action of multiple signalling pathways in HE development. PMID:22083566

  17. Symptomatic hepatic hydrothorax successfully treated with transjugular intrahepatic portosystemic shunt (TIPS)–role of titration of portosystemic gradient reduction to avoid post-TIPS encephalopathy

    PubMed Central

    Krishnamoorthy, T L; Taneja, M; Chang, P E

    2014-01-01

    Key Clinical Message We describe a challenging case of hepatic hydrothorax secondary to nonalcoholic steatohepatitis cirrhosis. Our management involved successfully treating the hydrothorax with a transjugular intrahepatic porto-systemic shunt but having to manage the subsequent complication of hepatic encephalopathy. We conclude with a review of the available literature. PMID:25356258

  18. Covert Hepatic Encephalopathy Is Independently Associated With Poor Survival and Increased Risk of Hospitalization

    PubMed Central

    Patidar, Kavish R.; Thacker, Leroy R.; Wade, James B.; Sterling, Richard K.; Sanyal, Arun J.; Siddiqui, Mohammad S.; Matherly, Scott C.; Stravitz, R. Todd; Puri, Puneet; Luketic, Velimir A.; Fuchs, Michael; White, Melanie B.; Noble, Nicole A.; Unser, Ariel B.; Gilles, HoChong; Heuman, Douglas M.; Bajaj, Jasmohan S.

    2015-01-01

    OBJECTIVES Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE. METHODS Outpatient cirrhotics without OHE were enrolled and were administered a standard paper–pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression. RESULTS A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0±14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01–4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4–4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2–9.7) in the follow-up period. CONCLUSIONS Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks. PMID:25178701

  19. Role of local and distant functional connectivity density in the development of minimal hepatic encephalopathy

    PubMed Central

    Qi, Rongfeng; Zhang, Long Jiang; Chen, Hui Juan; Zhong, Jianhui; Luo, Song; Ke, Jun; Xu, Qiang; Kong, Xiang; Liu, Chang; Lu, Guang Ming

    2015-01-01

    The progression of functional connectivity (FC) patterns from non-hepatic encephalopathy (non-HE) to minimal HE (MHE) is not well known. This resting-state functional magnetic resonance imaging (rs-fMRI) study investigated the evolution of intrinsic FC patterns from non-HE to MHE. A total of 103 cirrhotic patients (MHE, n = 34 and non-HE, n = 69) and 103 healthy controls underwent rs-fMRI scanning. Maps of distant and local FC density (dFCD and lFCD, respectively) were compared among MHE, non-HE, and healthy control groups. Decreased lFCD in anterior cingulate cortex, pre- and postcentral gyri, cuneus, lingual gyrus, and putamen was observed in both MHE and non-HE patients relative to controls. There was no difference in lFCD between MHE and non-HE groups. The latter showed decreased dFCD in inferior parietal lobule, cuneus, and medial frontal cortex relative to controls; however, MHE patients showed decreased dFCD in frontal and parietal cortices as well as increased dFCD in thalamus and caudate head relative to control and non-HE groups. Abnormal FCD values in some regions correlated with MHE patients’ neuropsychological performance. In conclusion, lFCD and dFCD were perturbed in MHE. Impaired dFCD in regions within the cortico-striato-thalamic circuit may be more closely associated with the development of MHE. PMID:26329994

  20. Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy.

    PubMed

    Dhanda, Saurabh; Sandhir, Rajat

    2015-06-01

    The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE. PMID:25639545

  1. The effect of small intestinal bacterial overgrowth on minimal hepatic encephalopathy in patients with cirrhosis

    PubMed Central

    Feng, Yikuan; Cao, Bin; Tian, Qiang

    2015-01-01

    Introduction The aim of the study was to investigate the significance of factors associated with minimal hepatic encephalopathy (MHE) in cirrhotic patients. Material and methods Between September 2012 and August 2013, 60 cirrhotic patients, including MHE and non-MHE (NMHE) patients, were included in the study. Associated factors and clinical factors were analyzed to see if they were significantly different between MHE and non-MHE patients. Upon identifying the factors showing differences, we applied multivariate regression analysis to further decide which were the most significant ones to differentiate MHE from NMHE patients. Results There were 26 patients diagnosed with MHE and 34 with NMHE. Our results demonstrated that the prevalence rate of small intestinal bacterial overgrowth (SIBO) was highly associated with patients with MHE (65.4%, 17 out of 26), in contrast to the rate in NMHE patients (8.8%, 3 out of 34). We also found that factors including age, education level, intelligent test results, plasma albumin level and plasma ammonia levels were significantly different between MHE and NMHE patients. Ultimately, with logistic regression analysis, we found that SIBO was the most significant factor differentiating MHE patients from NMHE patients (p < 0.05). Conclusions In cirrhotic patients, SIBO was highly associated with MHE. This may further our understanding of the mechanisms of MHE and help to develop potential therapeutic interventions to treat cirrhotic patients with MHE. PMID:27279853

  2. Abnormal spontaneous brain activity in minimal hepatic encephalopathy: resting-state fMRI study

    PubMed Central

    Zhong, Wei-Jia; Zhou, Zhi-Ming; Zhao, Jian-Nong; Wu, Wei; Guo, Da-Jing

    2016-01-01

    PURPOSE We aimed to assess the abnormality of baseline spontaneous brain activity in minimal hepatic encephalopathy (MHE) by amplitude of low frequency fluctuation (ALFF) and fraction ALFF (fALFF). METHODS A total of 14 MHE patients and 14 healthy controls were included in our study. Both ALFF and fALFF of functional magnetic resonance imaging were calculated for statistical analysis. RESULTS Compared with healthy controls, patients with MHE had significantly decreased ALFF in the bilateral medial prefrontal cortex (MPFC), left superior frontal gyrus, right precentral gyrus, left opercular part of inferior frontal gyrus, left gyrus rectus, bilateral precuneus, and the posterior lobe of right cerebellum; and they had significantly decreased fALFF in the bilateral MPFC, right middle frontal gyrus, right superior temporal gyrus, and the posterior lobe of left cerebellum. CONCLUSION ALFF and fALFF changes in many brain regions demonstrate abnormality of the spontaneous neuronal activity in MHE. Especially the impairment of right precuneus and left MPFC may play a critical role in manifestation of MHE. Changes of ALFF and fALFF in the precuneus and the MPFC can be used as a potential marker for MHE. PMID:26742646

  3. Role of Magnetic Resonance in Understanding the Pathogenesis of Hepatic Encephalopathy

    PubMed Central

    Huda, A.; Gupta, R.K.; Rajakumar, N.; Thomas, M.A.

    2009-01-01

    A spectrum of neuropsychiatric abnormalities caused by portosystemic venous shunting occurs in hepatic encephalopathy (HE) patients with or without liver dysfunction. It is not completely clear how the astrocyte swelling leads to glial-neuronal dysfunction, and how the symptoms are manifested in HE. A major goal of this work is to review the current status of information available from the existing magnetic resonance (MR) modalities including MR imaging (MRI) and MR Spectroscopy (MRS) as well as other modalities in the understanding the pathogenesis of HE. First, we discuss briefly neuron-histopathology, neurotoxins, neuropsychological and neurophysiological tests. A short review on the progress with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) is then presented. In the remaining part of the manuscript, the following topics pertinent to understanding the pathogenesis of HE are discussed: MRI, diffusion tensor imaging (DTI), one-dimensional MRS based single- and multi-voxel based spectroscopic imaging techniques and two-dimensional MRS. PMID:20890387

  4. Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts.

    PubMed

    Llansola, M; Cantero, J L; Hita-Yañez, E; Mirones-Maldonado, M J; Piedrafita, B; Ahabrach, H; Errami, M; Agusti, A; Felipo, V

    2012-01-10

    Patients with liver cirrhosis show sleep disturbances. Insight into their relationship with hepatic encephalopathy (HE) can be obtained using animal models of HE. The aims of this work were to assess (1) whether rats with portacaval shunts (PCS), a model of HE, show alterations in sleep and if they are similar to those in patients with HE; (2) Whether hyperammonemia plays a role in these sleep alterations; and (3) the time course of sleep alterations in these animal models. Rats were subjected to PCS to induce HE. Another group of rats was fed an ammonium-containing diet to induce hyperammonemia. Polysomnographic recordings were acquired for 24 h and sleep architecture was analyzed in control, PCS, and hyperammonemic rats at 4, 7, and 11 weeks after surgery or diet, respectively. PCS rats show a significant reduction in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep time and increased sleep fragmentation, whereas reduced sleep occurs at 4 weeks and worsens at 7 and 11 weeks, sleep fragmentation appears at 7 weeks and worsens at 11 weeks. Hyperammonemic rats show decreased REM sleep, starting at 7 weeks and worsening at 11 weeks, with no changes in NREM sleep or sleep fragmentation. Therefore, PCS rats are a good model to study sleep alterations in HE, their mechanisms, and potential treatment. Mild hyperammonemia mainly impacts mechanisms involved in REM generation and/or maintenance but does not seem to be involved in sleep fragmentation. PMID:22108612

  5. Rifaximin: a review of its use in reducing recurrence of overt hepatic encephalopathy episodes.

    PubMed

    Scott, Lesley J

    2014-12-01

    Oral rifaximin 550 mg (Refero(®); Targaxan(®); Tixteller(®); Xifaxan(®)) twice daily, either alone or more commonly with medicines containing lactulose, is approved in several countries, including the UK, EU and USA, for use in adults with liver disease to reduce the recurrence of episodes of overt hepatic encephalopathy (HE). Rifaximin is a broad-spectrum antibacterial that acts locally in the gut to reduce intestinal flora, including ammonia-producing species, with hyperammonaemia considered to play a central role in the pathogenesis of HE. In a 6-month, multinational trial in patients with liver disease, rifaximin 550 mg twice daily (± lactulose) was an effective and well tolerated treatment for reducing the recurrence of HE episodes. At study end, rifaximin therapy significantly prolonged the time to the first breakthrough HE episode compared with placebo (± lactulose), irrespective of geographical region or baseline patient and disease characteristics. Rifaximin treatment also significantly reduced HE-related hospitalizations and improved health-related quality of life compared with placebo. Furthermore, the efficacy of rifaximin with or without lactulose in reducing the recurrence of overt HE episodes was maintained after up to 2.5 years of treatment, with no new safety signals arising during this period. This article reviews the pharmacology and therapeutic efficacy of rifaximin 550 mg twice daily in reducing the recurrence of overt HE episodes in adults with liver disease. PMID:25352391

  6. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

    PubMed

    Gluud, Lise Lotte; Dam, Gitte; Borre, Mette; Les, Iñigo; Cordoba, Juan; Marchesini, Giulio; Aagaard, Niels Kristian; Vilstrup, Hendrik

    2013-06-01

    Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions. PMID:23275147

  7. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis

    PubMed Central

    Luo, Ming; Guo, Jian-Yang; Cao, Wu-Kui

    2015-01-01

    Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrum of manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The anti-inflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE. PMID:26557005

  8. Breathomics--exhaled volatile organic compound analysis to detect hepatic encephalopathy: a pilot study.

    PubMed

    Arasaradnam, R P; McFarlane, M; Ling, K; Wurie, S; O'Connell, N; Nwokolo, C U; Bardhan, K D; Skinner, J; Savage, R S; Covington, J A

    2016-03-01

    The current diagnostic challenge with diagnosing hepatic encephalopathy (HE) is identifying those with minimal HE as opposed to the more clinically apparent covert/overt HE. Rifaximin, is an effective therapy but earlier identification and treatment of HE could prevent liver disease progression and hospitalization. Our pilot study aimed to analyse breath samples of patients with different HE grades, and controls, using a portable electronic (e) nose. 42 patients were enrolled; 22 with HE and 20 controls. Bedside breath samples were captured and analysed using an uvFAIMS machine (portable e-nose). West Haven criteria applied and MELD scores calculated. We classify HE patients from controls with a sensitivity and specificity of 0.88 (0.73-0.95) and 0.68 (0.51-0.81) respectively, AUROC 0.84 (0.75-0.93). Minimal HE was distinguishable from covert/overt HE with sensitivity of 0.79 and specificity of 0.5, AUROC 0.71 (0.57-0.84). This pilot study has highlighted the potential of breathomics to identify VOCs signatures in HE patients for diagnostic purposes. Importantly this was performed utilizing a non-invasive, portable bedside device and holds potential for future early HE diagnosis. PMID:26866470

  9. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis.

    PubMed

    Luo, Ming; Guo, Jian-Yang; Cao, Wu-Kui

    2015-11-01

    Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrum of manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The anti-inflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE. PMID:26557005

  10. Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy.

    PubMed

    Bustamante, J; Lores-Arnaiz, S; Tallis, S; Roselló, D M; Lago, N; Lemberg, A; Boveris, A; Perazzo, J C

    2011-08-01

    In this study, we describe the presence of apoptosis, associated with a mitochondrial dysfunction in the hippocampus of animals in an experimental model defined as minimal hepatic encephalopathy (MHE). This experimental model was studied after 10 days of induced portal vein calibrated stricture, leading to portal hypertension and to a moderate hyperammonemia, without the presence of other evident central nervous system changes. The molecular mechanisms here proposed indicate the presence of apoptotic intrinsic pathways that point to hippocampal mitochondria as an important mediator of apoptosis in this experimental model. In this model of MHE, the presence of DNA fragmentation is documented by 2.3-times increased number of TUNEL-positive cells. These findings together with a higher ratio of the Bcl-2 family members Bax/Bcl-xL in the outer mitochondrial membrane of the MHE animals together with 11% of cytochrome c release indicate the presence of apoptosis in this experimental model. A detailed analysis of the hippocampal mitochondrial physiology was performed after mitochondrial isolation. The determination of the respiratory rate in the presence of malate plus glutamate and ADP showed a 45% decrease in respiratory control in MHE animals as compared with the sham group. A marked decrease of cytochrome oxidase (complex IV of the electron transport chain) was also observed, showing 46% less activity in hippocampal mitochondria from MHE animals. In addition, mitochondria from these animals showed less ability to maintain membrane potential (ΔΨ (m)) which was 13% lower than the sham group. Light scattering experiments showed that mitochondria from MHE animals were more sensitive to swell in the presence of increased calcium concentrations as compared with the sham group. In addition, in vitro studies performed in mitochondria from sham animals showed that mitochondrial permeability transition (MPT) could be a mitochondrial mediator of the apoptotic signaling in the

  11. Clinical and Pathophysiological Characteristics of Cirrhotic Patients with Grade 1 and Minimal Hepatic Encephalopathy

    PubMed Central

    Thomsen, Karen Louise; Macnaughtan, Jane; Tritto, Giovanni; Mookerjee, Rajeshwar P.; Jalan, Rajiv

    2016-01-01

    Background and Aims EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term ‘Covert HE’ combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients. Methods Clinically-stable cirrhotic patients (n = 106) with no previous history of ‘Overt HE’ were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230±95 days. Results Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE. Conclusions The results of this study show for the first time that ‘Covert HE’ is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented. PMID:26745876

  12. Rifaximin Improves Driving Simulator Performance in a Randomized Trial of Patients with Minimal Hepatic Encephalopathy

    PubMed Central

    Bajaj, Jasmohan S; Heuman, Douglas M; Wade, James B; Gibson, Douglas P; Saeian, Kia; Wegelin, Jacob A; Hafeezullah, Muhammad; Bell, Debulon E; Sterling, Richard K; Stravitz, R. Todd; Fuchs, Michael; Luketic, Velimir; Sanyal, Arun J

    2010-01-01

    Background & Aims Patients with cirrhosis and minimal hepatic encephalopathy (MHE) have driving difficulties but the effects of therapy on driving performance have not been assessed. We evaluated whether performance on a driving simulator improves in patients with MHE following treatment with rifaximin. Methods Patients with MHE who were current drivers were randomly assigned to placebo or rifaximin groups and followed for 8 weeks (n=42). Patients underwent driving simulation (driving and navigation tasks) at the start (baseline) and end of the study. We evaluated patients’ cognitive abilities, quality-of-life (using the Sickness Impact Profile [SIP]), serum levels of ammonia, levels of inflammatory cytokines, and MELD scores. The primary outcome was percent who improved in driving performance, calculated by: total driving errors=speeding + illegal turns + collisions. Results Over the 8-week study period, patients given rifaximin made significantly greater improvements than those given placebo in avoiding total driving errors (76% vs. 31%, P=0.013), speeding (81% vs. 33%, P=0.005), and illegal turns (62% vs. 19%, P=0.01). Of patients given rifaximin, 91% improved their cognitive performance, compared with 61% of patients given placebo (P=0.01); they also made improvements in the psycho-social dimension of the SIP, compared with the placebo group (P=0.04). Adherence to the assigned drug averaged 92%. Neither group had changes in ammonia levels or MELD scores, but patients in the rifaximin group had increased levels of the anti-inflammatory cytokine interleukin-10. Conclusions Patients with MHE significantly improve driving simulator performance following treatment with rifaximin, compared with placebo. PMID:20849805

  13. The Multi-Dimensional Burden of Cirrhosis and Hepatic Encephalopathy on Patients and Caregivers

    PubMed Central

    Bajaj, Jasmohan S.; Wade, James B.; Gibson, Douglas P.; Heuman, Douglas M.; Thacker, Leroy R.; Sterling, Richard K.; Stravitz, R. Todd; Luketic, Velimir; Fuchs, Michael; White, Melanie B.; Bell, Debulon E.; Gilles, HoChong; Morton, Katherine; Noble, Nicole; Puri, Puneet; Sanyal, Arun J.

    2014-01-01

    Objectives Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers. Methods A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum = 155) and Zarit Burden Interview (ZBI)-Short Form (maximum = 48) and questionnaires for depression, anxiety, and social support. Results A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32 ± 14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%, P = 0.0001) and financial status (85 vs. 61%, P = 0.019) and posed a higher caregiver burden; PCB (75 vs. 65, P = 0.019) and ZBI (16 vs. 11, P = 0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non-veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score. Conclusions Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family unit's daily functioning and medical adherence. A multidisciplinary approach to address this burden is required. PMID:21556040

  14. Depletion of the AMPAR reserve pool impairs synaptic plasticity in a model of hepatic encephalopathy.

    PubMed

    Schroeter, Annett; Wen, Shuping; Mölders, Andrea; Erlenhardt, Nadine; Stein, Valentin; Klöcker, Nikolaj

    2015-09-01

    Hepatic encephalopathy (HE) is the most common neuropsychiatric complication of acute or chronic liver failure. Clinical symptoms include cognitive and intellectual dysfunction as well as impaired motor activity and coordination. There is general consensus that increased levels of ammonia play a central role in the pathogenesis of HE. However, it is still elusive how cognitive performance including the ability to learn and memorize information is affected by ammonia at molecular levels. In the present study, we have employed a neuroglial co-culture model, which preserves neuroglial interplay but allows for cell-type specific molecular and functional analyses, to investigate glutamatergic neurotransmission under conditions of high ammonia. Chronic exposure to ammonia significantly reduced neuronal mRNA and protein expression of AMPA-subtype glutamate receptors (AMPARs), which mediate most fast excitatory neurotransmission in the brain. Surprisingly, neurons were able to fully maintain basal glutamatergic neurotransmission as recorded by AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) even when >50% of total AMPARs were lost. However, long-lasting, activity-dependent changes in the efficacy of synaptic communication, which model the capability of the brain to learn and store information, were severely constrained. Whereas synaptic efficacy could still be depressed, an increase in synaptic strength was abolished. We conclude that neurons retain basal glutamatergic transmission at the expense of the extrasynaptic population of AMPARs, which is revealed when the extrasynaptic reserve pool is recruited in vain for synaptic potentiation. Our findings thus offer a molecular model, which might not only explain impaired synaptic plasticity in HE but also in other neurological diseases accompanied by a decrease in extrasynaptic AMPAR expression. PMID:26363416

  15. Covert hepatic encephalopathy: elevated total glutathione and absence of brain water content changes.

    PubMed

    Oeltzschner, Georg; Butz, Markus; Wickrath, Frithjof; Wittsack, Hans-Jörg; Schnitzler, Alfons

    2016-06-01

    Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy ((1)H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P < 0.001). It was further linked to Gln/Cr and mI/Cr (P < 0.01 in visual, P < 0.001 in sensorimotor) and to GABA/Cr (P < 0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P < 0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE. PMID:26563124

  16. Changes in sleep architecture and quality in minimal hepatic encephalopathy patients and relationship to psychological dysfunction

    PubMed Central

    Liu, Changyun; Zhou, Jianguang; Yang, Xuedong; Lv, Jiao; Shi, Yunxing; Zeng, Xiaohong

    2015-01-01

    Objectives: We examined changes in sleep quality and architecture in patients with minimal hepatic encephalopathy (MHE) and the impacts of sleep disruption on patient physical and psychological health. Methods: Ninety-eight MHE patients were examined by polysomnography (PSG) and the Pittsburg sleep quality inventory (PSQI). In addition, patients completed the SAS, SDS, and SCL-90 to examine the relationship between sleep quality and psychological health. Results: Mean relative durations of Stage 1 and Stage 2, sleep latency, microarousal frequency, and total sleep time (TST) were all lower in MHE patients compared to healthy controls (P<0.05 for all). Similarly, SWS and REM stage durations, REM latency, sleep maintenance rate, and sleep efficiency were lower than controls (P<0.01 for all). Mean PSQI scores were lower in MHE patients. Total SAS, SDS, and SCL-90 scores, as well as all SCL-90 subscores, were significantly higher in the MHE group (P<0.05), indicating significant psychological dysfunction. Longer SWS, longer REM, and lower microarousal frequency were associated with improved sleep quality (P<0.05), while shorter SWS and REM led to dyssomnia and daytime functional disturbance (P<0.05, P<0.01). Longer REM latency and higher microarousal frequency were associated with higher PSQI scores (P<0.05, P<0.01), while longer SWS, longer REM, and higher sleep maintenance rate were associated with lower PSQI scores (P<0.05, P<0.01). Finally, total PSQI score and sleep efficiency subscore were positively correlated with total SCL-90 and most SCL-90 subscores (P<0.05). Conclusions: MHE patients suffer from multiple subjective dyssomnias and changes in sleep architecture that are strongly correlated with psychological dysfunction. PMID:26885103

  17. Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy

    PubMed Central

    Dennis, Claude V.; Sheahan, Pamela J.; Graeber, Manuel B.; Sheedy, Donna L.; Kril, Jillian J.; Sutherland, Greg T.

    2014-01-01

    Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE (n = 9), alcoholics without HE (n = 4) and controls (n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed ‘proliferative HE’ (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain. PMID:24346482

  18. Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.

    PubMed

    Zielińska, Magdalena; Popek, Mariusz; Albrecht, Jan

    2014-01-01

    Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan. PMID:24072671

  19. Machine Learning Classification of Cirrhotic Patients with and without Minimal Hepatic Encephalopathy Based on Regional Homogeneity of Intrinsic Brain Activity

    PubMed Central

    Liu, Jun; Sun, Tao; Shen, Qun-Tai

    2016-01-01

    Machine learning-based approaches play an important role in examining functional magnetic resonance imaging (fMRI) data in a multivariate manner and extracting features predictive of group membership. This study was performed to assess the potential for measuring brain intrinsic activity to identify minimal hepatic encephalopathy (MHE) in cirrhotic patients, using the support vector machine (SVM) method. Resting-state fMRI data were acquired in 16 cirrhotic patients with MHE and 19 cirrhotic patients without MHE. The regional homogeneity (ReHo) method was used to investigate the local synchrony of intrinsic brain activity. Psychometric Hepatic Encephalopathy Score (PHES) was used to define MHE condition. SVM-classifier was then applied using leave-one-out cross-validation, to determine the discriminative ReHo-map for MHE. The discrimination map highlights a set of regions, including the prefrontal cortex, anterior cingulate cortex, anterior insular cortex, inferior parietal lobule, precentral and postcentral gyri, superior and medial temporal cortices, and middle and inferior occipital gyri. The optimized discriminative model showed total accuracy of 82.9% and sensitivity of 81.3%. Our results suggested that a combination of the SVM approach and brain intrinsic activity measurement could be helpful for detection of MHE in cirrhotic patients. PMID:26978777

  20. Differential regional responsiveness of astroglia in mild hepatic encephalopathy: An Immunohistochemical approach in bile duct ligated rat.

    PubMed

    Hiba, Omar El; Elgot, Abdeljalil; Ahboucha, Samir; Gamrani, Halima

    2016-05-01

    Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. However, the pathomechanisms of the disease remains obscure. Neuropathological studies have demonstrated a primary gliopathy in humans as well as in animal models of chronic and acute liver failure. Here, we have investigated in an animal model of mild HE: the bile duct ligated rat (BDL) at the cirrhotic stage (4 weeks after surgery), the expression of the key marker of mature astrocytes; the glial fibrillary acidic protein (GFAP) in different brain areas such as: Substantia nigra pars compacta (SNc), Ventral tegmental area (VTA), hippocampus, dorsal striatum and brain cortex by means of immunohistochemistry. The immunohistochemical study showed, in BDL compared to the operated controls (shams), a diminished astrocyte reactivity corresponding to a loss of GFAP expression within SNc, VTA, hippocampus and dorsal striatum (p<0.05),whereas in the brain cortex astrocytes appeared strongly immunoreactive with increased GFAP expression (p<0.05) as compared to shams. Our finding demonstrated differential astroglial responses which depend to the specificity of the area investigated and its particular neuronal neighboring environment, and could have possible outcomes on the diverse neuronal functions especially those observed during the different episodes of hepatic encephalopathy. PMID:26995310

  1. Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence.

    PubMed

    Flamm, Steven L

    2011-05-01

    Hepatic encephalopathy (HE) is a common problem in patients with chronic liver disease and is characterized by diminished mentation and neuromuscular abnormalities. Symptoms range from subtle cognitive changes to coma and death. Gut-derived toxins such as ammonia are thought to play a central role in the pathogenesis of HE. Treatment strategies are directed at increased elimination or reduction of gut-derived ammonia in addition to correction of dynamic conditions that provoke bouts of HE. The standard of care for treatment of acute HE is lactulose, a nonabsorbable disaccharide that is thought to increase elimination and reduce absorption of ammonia. Although lactulose seems to work in the acute setting, the rate of recurrent HE on maintenance lactulose is high. Medications have been sought that reduce the rate of recurrent HE in patients at high risk for HE but none have been identified. Rifaximin is a poorly absorbed antibiotic that is thought to reduce ammonia production by eliminating ammonia-producing colonic bacteria. Many small studies have suggested that rifaximin is effective in treating acute HE and is extremely well tolerated. This led to a randomized, placebo-controlled, multicenter, multinational trial investigating the efficacy of rifaximin over a 6-month period in reducing the risk of recurrent HE in patients at baseline, but with a history of at least two bouts of acute HE in the previous 6 months prior to enrollment. Lactulose could be administered at the discretion of the investigator. A total of 299 patients were randomized to receive rifaximin or placebo; 91% of patients in each group received lactulose. Compared with placebo, patients at high risk for recurrent HE in the rifaximin group had highly statistically significant reductions in bouts of acute HE (58%) and reductions in hospitalizations related to HE (50%) over a 6-month period. The medication was well tolerated with a side-effect profile comparable to placebo. This led to the approval

  2. Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence

    PubMed Central

    Flamm, Steven L.

    2011-01-01

    Hepatic encephalopathy (HE) is a common problem in patients with chronic liver disease and is characterized by diminished mentation and neuromuscular abnormalities. Symptoms range from subtle cognitive changes to coma and death. Gut-derived toxins such as ammonia are thought to play a central role in the pathogenesis of HE. Treatment strategies are directed at increased elimination or reduction of gut-derived ammonia in addition to correction of dynamic conditions that provoke bouts of HE. The standard of care for treatment of acute HE is lactulose, a nonabsorbable disaccharide that is thought to increase elimination and reduce absorption of ammonia. Although lactulose seems to work in the acute setting, the rate of recurrent HE on maintenance lactulose is high. Medications have been sought that reduce the rate of recurrent HE in patients at high risk for HE but none have been identified. Rifaximin is a poorly absorbed antibiotic that is thought to reduce ammonia production by eliminating ammonia-producing colonic bacteria. Many small studies have suggested that rifaximin is effective in treating acute HE and is extremely well tolerated. This led to a randomized, placebo-controlled, multicenter, multinational trial investigating the efficacy of rifaximin over a 6-month period in reducing the risk of recurrent HE in patients at baseline, but with a history of at least two bouts of acute HE in the previous 6 months prior to enrollment. Lactulose could be administered at the discretion of the investigator. A total of 299 patients were randomized to receive rifaximin or placebo; 91% of patients in each group received lactulose. Compared with placebo, patients at high risk for recurrent HE in the rifaximin group had highly statistically significant reductions in bouts of acute HE (58%) and reductions in hospitalizations related to HE (50%) over a 6-month period. The medication was well tolerated with a side-effect profile comparable to placebo. This led to the approval

  3. Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

    PubMed Central

    Bajaj, Jasmohan S.; Heuman, Douglas M.; Sanyal, Arun J.; Hylemon, Phillip B.; Sterling, Richard K.; Stravitz, R. Todd; Fuchs, Michael; Ridlon, Jason M.; Daita, Kalyani; Monteith, Pamela; Noble, Nicole A.; White, Melanie B.; Fisher, Andmorgan; Sikaroodi, Masoumeh; Rangwala, Huzefa; Gillevet, Patrick M.

    2013-01-01

    Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Methods Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. Results There was a significant improvement in cognition(six of seven tests improved,p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa

  4. 18F-DPA-714 PET Imaging for Detecting Neuroinflammation in Rats with Chronic Hepatic Encephalopathy

    PubMed Central

    Kong, Xiang; Luo, Song; Wu, Jin Rong; Wu, Shawn; De Cecco, Carlo N.; Schoepf, U. Joseph; Spandorfer, Adam J.; Wang, Chun Yan; Tian, Ying; Chen, Hui Juan; Lu, Guang Ming; Yang, Gui Fen; Zhang, Long Jiang

    2016-01-01

    Neuroinflammation is considered to be the pathogenesis of hepatic encephalopathy (HE), and imaging neuroinflammation is implicated in HE management. 11C-PK11195, a typical translocator protein (TSPO) radiotracer, is used for imaging neuroinflammation. However, it has inherent limitations, such as short half-life and limited availability. The purpose of this study was to demonstrate the efficiency of new generation TSPO radiotracer, 18F-DPA-714, in detecting and monitoring neuroinflammation of chronic HE. This study was divided into two parts. The first part compared 18F-DPA-714 and 11C-PK11195 radiotracers in ten HE induced rats [bile duct ligation (BDL) and fed hyperammonemic diet (HD)] and 6 control rats. The animal subjects underwent dynamic positron emission tomography (PET) during 2-day intervals. The 11C-PK11195 PET study showed no differences in whole brain average percent injected dose per gram (%ID/g) values at all time points (all P>0.05), while the 18F-DPA-714 PET study showed higher whole brain average %ID/g values in HE rats compared to control group rats at 900 s to 3300 s after injecting radiotracer (all P<0.05). The second part of the study evaluated the effectiveness of ibuprofen (IBU) treatment to chronic HE. Forty rats were classified into six groups, including Sham+normal saline (NS), Sham+IBU, BDL+NS, BDL+HD+NS, BDL+IBU, and BDL+HD+IBU groups. 18F-DPA-714 PET was used to image neuroinflammation. Whole and regional brain average %ID/g values, neurological features, inflammatory factors and activated microglia showed better in the IBU groups than in the NS groups (all P<0.05) and no difference was seen in the Sham groups compared to IBU groups (all P>0.05). In conclusion, this study demonstrated that 18F-DPA-714 is an ideal TPSO radiotracer for imaging neuroinflammation and monitoring anti-neuroinflammation treatment efficacy of chronic HE. PMID:27279913

  5. Erythromycin versus neomycin in the treatment of hepatic encephalopathy in cirrhosis: a randomized double-blind study

    PubMed Central

    2013-01-01

    Background Hepatic encephalopathy (HE) is a severe complication in patients with hepatic cirrhosis, which causes numerous hospital admissions and deaths. Antibiotics are the best options in HE treatment, but head-to-head comparisons between these drugs are scarce. Erythromycin combines the antimicrobial effect and prokinetic properties in the same drug, but it has never been used in HE treatment. Our aim was to evaluate the efficacy of erythromycin as an HE treatment. Methods We achieved a randomized controlled trial of adult patients with HE and hepatic cirrhosis admitted in our hospital. After randomization, the subjects received either erythromycin 250 mg or neomycin 1 g orally QID until hospital discharge or prescription of another antibiotic. All subjects were blindly evaluated every day towards quantifying clinical, neuropsychometric, hepatic and renal exams. Statistical analysis was employed to compare the groups and correlate the variables with hospitalization duration. Results 30 patients were evaluated (15 treated with each drug). At hospital admission, the groups were homogeneous, but the erythromycin group subjects achieved a shorter hospitalization stay (p = 0.032) and a more expressive reduction in alanine aminotranspherase levels (p = 0.026). Hospitalization duration was positively correlated with C reactive protein levels measured previous to (p = 0.015) and after treatment (p = 0.01). Conclusions In the sample evaluated erythromycin was associated with significant reductions in hospital stay and in alanine aminotranspherase values. Hospitalization time was positive correlated with C reactive protein levels measured before and after the treatments. PMID:23324408

  6. Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

    PubMed Central

    Felipo, Vicente

    2006-01-01

    Patients with liver disease may present hepatic enceph-alopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations, including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death. The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE. These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced, which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE. However, it is necessary to previously assess the possible secondary effects. Patients with HE may present psychomotor slowing, hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

  7. Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy.

    PubMed

    Agusti, Ana; Llansola, Marta; Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Montoliu, Carmina; Felipo, Vicente

    2016-06-01

    Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome affecting patients with liver diseases, mainly those with liver cirrhosis. The mildest form of HE is minimal HE (MHE), with mild cognitive impairment, attention deficit, psychomotor slowing and impaired visuo-motor and bimanual coordination. MHE may progress to clinical HE with worsening of the neurological alterations which may lead to reduced consciousness and, in the worse cases, may progress to coma and death. HE affects several million people in the world and is a serious health, social and economic problem. There are no specific treatments for the neurological alterations in HE. The mechanisms underlying the cognitive and motor alterations in HE are beginning to be clarified in animal models. These studies have allowed to design and test in animal models of HE new therapeutic approaches which have successfully restored cognitive and motor function in rats with HE. In this article we review the evidences showing that. PMID:26307490

  8. Reversal of Low-Grade Cerebral Edema After Lactulose/Rifaximin Therapy in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

    PubMed Central

    Rai, Rahul; Ahuja, Chirag K; Agrawal, Swastik; Kalra, Naveen; Duseja, Ajay; Khandelwal, Niranjan; Chawla, Yogesh; Dhiman, Radha K

    2015-01-01

    OBJECTIVES: Decreased magnetization transfer ratio (MTR) in the brain characterizes cerebral edema (CE) in patients with liver cirrhosis, but the role of treatment on its reversibility has not been studied in patients who have minimal hepatic encephalopathy (MHE). This study was carried to evaluate the reversibility of CE with lactulose and rifaximin treatment in patients with MHE and role of ammonia, pro-inflammatory interleukins (IL-1, IL-6) and tumor necrosis factor (TNF)-α in its pathogenesis. METHODS: Twenty-three patients with cirrhosis (14 with MHE, 9 without MHE (NMHE)) and 6 healthy controls underwent ammonia, IL-1, IL-6, TNF-α estimation, and MTR in frontal white matter (FWM), parietal white matter (PWM), internal capsule (IC), and basal ganglia (BG). RESULTS: Ammonia was significantly higher in the cirrhosis group compared with controls and in MHE compared with the NMHE group. Ammonia correlated positively with IL-1 and IL-6. MTRs in FWM, PWM, IC, and BG were significantly lower in the MHE group compared with controls and in PWM, IC, and BG compared with the NMHE group. MHE patients showed significant MTR increase in FWM, PWM, and IC with treatment. IL-6 and ammonia had significant negative and significant positive psychometric hepatic encephalopathy score (PHES) correlation with MTR in various regions. CONCLUSIONS: This study, for the first time, demonstrated the reversibility of low-grade CE with treatment in patients with MHE. Negative correlation between ammonia, IL-6 levels, and MTR and positive correlation between PHES and MTR in MHE patients suggests the role of inflammation and ammonia in the genesis of low-grade CE. PMID:26378384

  9. Obstructive jaundice due to radiation-induced hepatic duct stricture

    SciTech Connect

    Chandrasekhara, K.L.; Iyer, S.K.

    1984-10-01

    A case of obstructive jaundice due to radiation-induced hepatic duct stricture is reported. The patient received postoperative radiation for left adrenal carcinoma, seven years prior to this admission. The sequelae of hepatobiliary radiation and their management are discussed briefly.

  10. Effect of Rifaximin, Probiotics, and l-Ornithine l-Aspartate on Minimal Hepatic Encephalopathy: A Randomized Controlled Trial

    PubMed Central

    Sharma, Kapil; Pant, Sanjay; Misra, Sriprakash; Dwivedi, Manisha; Misra, Alok; Narang, Sushil; Tewari, Reshu; Bhadoria, Ajeet S.

    2014-01-01

    Background/Aims: Minimal hepatic encephalopathy (MHE) implies subtle impairment of cognitive functions in the absence of features of overt encephalopathy. We aimed to determine the prevalence of MHE in patients with liver cirrhosis and to find out the effect of rifaximin, probiotics, and l-ornithine l-aspartate (LOLA) individually in reversal of MHE by comparing it with placebo group. Patients and Methods: This study was carried out in two phases. Phase I included the recruitment of 250 apparently healthy controls and extraction of normative data utilizing three neuropsychometric tests (NPTs) and critical flicker frequency (CFF) test. Phase II consisted of screening and recruitment of patients of MHE followed by drugs trial. A total of 317 cirrhotics were screened; 111 were excluded and the remaining 206 cirrhotics were screened for MHE using NPTs and/or CFF test. Of these, 124 patients with MHE were randomized to receive LOLA (n = 31), rifaximin (n = 31), probiotics (n = 32), for 2 months and were compared with patients who were given placebo (n = 30). Results: Out of 206 cirrhotics, 124 (60.19%) had MHE. Among these 124 MHE patients, 87 (70.16%) patients had CFF <39Hz, 112 (90.32%) patients with MHE had two or more abnormal NPTs, and 75 (60.48%) patients had abnormality on both the CFF values and more than two abnormal NPTs. Intention-to-treat analysis showed the number of patients who improved after giving treatment were 67.7% (21/31), 70.9% (22/31), 50% (16/32), and 30% (9/30) for LOLA, rifaximin, probiotics, and placebo, respectively. CFF scores and improvement in psychometric tests after treatment were significantly higher (P < 0.05) for LOLA, rifaximin, and probiotics as compared with placebo group. Conclusions: Prevalence of MHE is high in patients with cirrhosis of liver. Rifaximin, LOLA, and probiotics are better than giving placebo in patients with MHE. PMID:25038208

  11. 1H nuclear magnetic resonance spectroscopy-based metabonomic study in patients with cirrhosis and hepatic encephalopathy

    PubMed Central

    Dabos, Konstantinos John; Parkinson, John Andrew; Sadler, Ian Howard; Plevris, John Nicholas; Hayes, Peter Clive

    2015-01-01

    AIM: To identify plasma metabolites used as biomarkers in order to distinguish cirrhotics from controls and encephalopathics. METHODS: A clinical study involving stable cirrhotic patients with and without overt hepatic encephalopathy was designed. A control group of healthy volunteers was used. Plasma from those patients was analysed using 1H - nuclear magnetic resonance spectroscopy. We used the Carr Purcell Meiboom Gill sequence to process the sample spectra at ambient probe temperature. We used a gated secondary irradiation field for water signal suppression. Samples were calibrated and referenced using the sodium trimethyl silyl propionate peak at 0.00 ppm. For each sample 128 transients (FID’s) were acquired into 32 K complex data points over a spectral width of 6 KHz. 30 degree pulses were applied with an acquisition time of 4.0 s in order to achieve better resolution, followed by a recovery delay of 12 s, to allow for complete relaxation and recovery of the magnetisation. A metabolic profile was created for stable cirrhotic patients without signs of overt hepatic encephalopathy and encephalopathic patients as well as healthy controls. Stepwise discriminant analysis was then used and discriminant factors were created to differentiate between the three groups. RESULTS: Eighteen stabled cirrhotic patients, eighteen patients with overt hepatic encephalopathy and seventeen healthy volunteers were recruited. Patients with cirrhosis had significantly impaired ketone body metabolism, urea synthesis and gluconeogenesis. This was demonstrated by higher concentrations of acetoacetate (0.23 ± 0.02 vs 0.05 ± 0.00, P < 0.01), and b-hydroxybutarate (0.58 ± 0.14 vs 0.08 ± 0.00, P < 0.01), lower concentrations of glutamine (0.44 ± 0.08 vs 0.63 ± 0.03, P < 0.05), histidine (0.16 ± 0.01 vs 0.36 ± 0.04, P < 0.01) and arginine (0.08 ± 0.01 vs 0.14 ± 0.02, P < 0.03) and higher concentrations of glutamate (1.36 ± 0.25 vs 0.58 ± 0.04, P < 0.01), lactate (1.53 ± 0

  12. Subarachnoid hemorrhage due to ruptured intracranial aneurysm following posterior reversible encephalopathy syndrome

    PubMed Central

    Nanba, Takamasa; Kashimura, Hiroshi; Saura, Hiroaki; Takeda, Masaru

    2016-01-01

    Although posterior reversible encephalopathy syndrome (PRES) is rarely associated with subarachnoid hemorrhage, to our knowledge, rupture of a concomitant cerebral aneurysm following PRES has not been reported. We describe a patient with atypical PRES involving the brainstem, thalamus, and periventricular white matter without cortical or subcortical edema of the parietooccipital lobe on magnetic resonance imaging, with rupture of a concomitant cerebral aneurysm. Preexisting extremely high blood pressure may trigger atypical PRES, and failure to lower blood pressure may lead to a concomitant aneurysm rupture. In the future treatment of hypertensive urgency with a recurrence of symptoms and mean arterial blood pressure >150 mmHg, it is advisable to immediately hospitalize the patient for aggressive blood pressure management, especially if PRES is suspected based on clinical and radiological features. PMID:27365964

  13. Posterior reversible encephalopathy syndrome with PLEDs-plus due to mesalamine

    PubMed Central

    Cherian, Ajith; Soumya, C. V.; Iype, Thomas; Mathew, Mini; Sandeep, P.; Thadam, Jessline K.; Chithra, P.

    2014-01-01

    A 32-year-old lady developed status epilepticus and acute visual loss while on mesalamine for Crohn's disease. Her clinical course and magnetic resonance imaging (MRI) were suggestive of posterior reversible encephalopathy syndrome (PRES). She had periodic lateralized epileptiform discharges plus (PLEDs-plus) on electroencephalogram (EEG), which responded to sodium valproate. Her vision improved from counting fingers at one-meter distance to 6/12. Though different cytotoxic drugs have been implicated as causative agents, this is the first case report of mesalamine-induced PRES. This case highlights the need for aggressive treatment of PLEDs-plus with EEG monitoring using a broad-spectrum antiepileptic drug like valproate, which has contributed to the rapid reversibility of vision in PRES subjects, and the need for a thorough drug history for etiological clues. PMID:24741259

  14. Subarachnoid hemorrhage due to ruptured intracranial aneurysm following posterior reversible encephalopathy syndrome.

    PubMed

    Nanba, Takamasa; Kashimura, Hiroshi; Saura, Hiroaki; Takeda, Masaru

    2016-01-01

    Although posterior reversible encephalopathy syndrome (PRES) is rarely associated with subarachnoid hemorrhage, to our knowledge, rupture of a concomitant cerebral aneurysm following PRES has not been reported. We describe a patient with atypical PRES involving the brainstem, thalamus, and periventricular white matter without cortical or subcortical edema of the parietooccipital lobe on magnetic resonance imaging, with rupture of a concomitant cerebral aneurysm. Preexisting extremely high blood pressure may trigger atypical PRES, and failure to lower blood pressure may lead to a concomitant aneurysm rupture. In the future treatment of hypertensive urgency with a recurrence of symptoms and mean arterial blood pressure >150 mmHg, it is advisable to immediately hospitalize the patient for aggressive blood pressure management, especially if PRES is suspected based on clinical and radiological features. PMID:27365964

  15. GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy

    PubMed Central

    Johansson, Maja; Agusti, Ana; Llansola, Marta; Montoliu, Carmina; Strömberg, Jessica; Malinina, Evgenya; Ragagnin, Gianna; Doverskog, Magnus; Bäckström, Torbjörn

    2015-01-01

    Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE. PMID:26138462

  16. GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

    PubMed

    Johansson, Maja; Agusti, Ana; Llansola, Marta; Montoliu, Carmina; Strömberg, Jessica; Malinina, Evgenya; Ragagnin, Gianna; Doverskog, Magnus; Bäckström, Torbjörn; Felipo, Vicente

    2015-09-01

    Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE. PMID:26138462

  17. Differential Impact of Hyponatremia and Hepatic Encephalopathy on Health-Related Quality of Life and Brain Metabolite Abnormalities in Cirrhosis

    PubMed Central

    Ahluwalia, Vishwadeep; Wade, James B; Thacker, Leroy; Kraft, Kenneth A; Sterling, Richard K; Stravitz, R Todd; Fuchs, Michael; Bouneva, Iliana; Puri, Puneet; Luketic, Velimir; Sanyal, Arun J; Gilles, HoChong; Heuman, Douglas M; Bajaj, Jasmohan S

    2013-01-01

    Background Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality-of-life (HRQOL) and cognition in cirrhosis. Aim To study effect of hyponatremia on cognition, HRQOL and brain MR spectroscopy (MRS) independent of HE. Methods Four cirrhotic groups(no HE/HN, HE alone, HN alone (sodium<130mEq/L),HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psycho-social and physical sub-scores) and brain MRS (myoinositol(mI) and glutamate+glutamine(Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. Results 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN and 10 HN, MELD 12, 63% Hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN:3, HN:3.5, HE:6.5,HE+HN:7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP(p<0.0001, all comparisons). Brain MRS showed lowest Glx in HN and highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE,HE+HN and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psycho-social SIP scores. Conclusions Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL. PMID:23665182

  18. Hyperammonemia and Systemic Inflammatory Response Syndrome Predicts Presence of Hepatic Encephalopathy in Dogs with Congenital Portosystemic Shunts

    PubMed Central

    Tivers, Mickey S.; Handel, Ian; Gow, Adam G.; Lipscomb, Vicky J.; Jalan, Rajiv; Mellanby, Richard J.

    2014-01-01

    Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with liver disease. The pathogenesis of he is incompletely understood although ammonia and inflammatory cytokines have been implicated as key mediators. To facilitate further mechanistic understanding of the pathogenesis of HE, a large number of animal models have been developed which often involve the surgical creation of an anastomosis between the hepatic portal vein and the caudal vena cava. One of the most common congenital abnormalities in dogs is a congenital portosystemic shunt (cpss), which closely mimics these surgical experimental models of HE. Dogs with a cPSS often have clinical signs which mimic clinical signs observed in humans with HE. Our hypothesis is that the pathogenesis of HE in dogs with a cPSS is similar to humans with HE. The aim of the study was to measure a range of clinical, haematological and biochemical parameters, which have been linked to the development of HE in humans, in dogs with a cPSS and a known HE grade. One hundred and twenty dogs with a cPSS were included in the study and multiple regression analysis of clinical, haematological and biochemical variables revealed that plasma ammonia concentrations and systemic inflammatory response syndrome scores predicted the presence of HE. Our findings further support the notion that the pathogenesis of canine and human HE share many similarities and indicate that dogs with cPSS may be an informative spontaneous model of human HE. Further investigations on dogs with cPSS may allow studies on HE to be undertaken without creating surgical models of HE thereby allowing the number of large animals used in animal experimentation to be reduced. PMID:24392080

  19. Lower values of handgrip strength and adductor pollicis muscle thickness are associated with hepatic encephalopathy manifestations in cirrhotic patients.

    PubMed

    Augusti, L; Franzoni, L C; Santos, L A A; Lima, T B; Ietsugu, M V; Koga, K H; Moriguchi, S M; Betting, L E; Caramori, C A; Silva, G F; Romeiro, F G

    2016-08-01

    Hepatic encephalopathy (HE) is a late complication of liver cirrhosis and is clearly associated with poor outcomes. Chronic liver insufficiency leads to progressive muscle wasting, impairing ammonia metabolism and thus increasing the risk for HE. Given the association between lean mass and adductor pollicis muscle thickness (APMT), it has been used to predict outcome and complications in many conditions, but not yet in cirrhotic patients. Therefore, this article aimed to study the association between HE manifestations and measures related to muscle mass and strength. This cross-sectional study included 54 cirrhotic outpatients with HE varying from subclinical to grade II according to the West-Haven criteria, who were submitted to neuropsychometric tests, electroencephalogram, brain Single Photon Emission Computed Tomography (SPECT), anthropometric measurements, handgrip strength (HGS) and dual energy X-ray absorptiometry exam (DXA). Multiple logistic regression analysis was performed to investigate the association between body composition measures and HE grade. Analysis of the area under the receiver operator characteristic (AUROC) curve revealed the values related to neurological manifestations (HE grades I and II). Reductions in APMT and HGS were associated with higher HE grades, suggesting a big impact caused by the loss of muscle mass and function on HE severity. The link between HE manifestations and anthropometric measures, namely APMT and HGS, point to a significant relation concerning skeletal muscles and the neurological impairment in this population. PMID:27131802

  20. The mind and liver test: a new approach to the diagnosis of minimal hepatic encephalopathy in resource-poor settings.

    PubMed

    Das, Saurav; Ali, Sajjadh M J; Seward, James; Venkataraman, Jayanthi

    2014-01-01

    Background and Aims. Minimal hepatic encephalopathy (MHE) is diagnosed using neuropsychometric tests or neurophysiological tests that are either inapplicable to illiterate patient population in resource-poor settings or require sophisticated and expensive equipment. The available tests assess discrete domains of mental impairment. Our aim was (a) to design a neuropsychometric test that measures all domains of mental impairment in MHE using one metric; (b) to evaluate its sensitivity, specificity, and reproducibility. Methods. The mind and liver test (MALT), a psychometric test assessing cognition, memory, and psychometric impairment, each on a scale of 20, was designed keeping in mind the requirements of a universal test. 40 cirrhotics and 36 controls were subjected to critical flicker frequency (CFF) and MALT in same sitting. ROC curve was plotted for MALT using CFF as gold standard. Bland-Altman plot was used to find test-retest agreement. Results. CFF values and MALT scores varied significantly between the cases and the controls (P < 0.05). MALT was 94% sensitive and 83% specific. Using ROC with CFF as gold standard, the AUC for diagnosis of MHE using MALT score was 0.89. Test-retest agreement was high (ICC = 0.89). Conclusion. In this pilot study, MALT proved to be highly sensitive, specific, inexpensive, and reproducible. PMID:25548682

  1. The Mind and Liver Test: A New Approach to the Diagnosis of Minimal Hepatic Encephalopathy in Resource-Poor Settings

    PubMed Central

    Ali, Sajjadh M. J.; Seward, James; Venkataraman, Jayanthi

    2014-01-01

    Background and Aims. Minimal hepatic encephalopathy (MHE) is diagnosed using neuropsychometric tests or neurophysiological tests that are either inapplicable to illiterate patient population in resource-poor settings or require sophisticated and expensive equipment. The available tests assess discrete domains of mental impairment. Our aim was (a) to design a neuropsychometric test that measures all domains of mental impairment in MHE using one metric; (b) to evaluate its sensitivity, specificity, and reproducibility. Methods. The mind and liver test (MALT), a psychometric test assessing cognition, memory, and psychometric impairment, each on a scale of 20, was designed keeping in mind the requirements of a universal test. 40 cirrhotics and 36 controls were subjected to critical flicker frequency (CFF) and MALT in same sitting. ROC curve was plotted for MALT using CFF as gold standard. Bland-Altman plot was used to find test-retest agreement. Results. CFF values and MALT scores varied significantly between the cases and the controls (P < 0.05). MALT was 94% sensitive and 83% specific. Using ROC with CFF as gold standard, the AUC for diagnosis of MHE using MALT score was 0.89. Test-retest agreement was high (ICC = 0.89). Conclusion. In this pilot study, MALT proved to be highly sensitive, specific, inexpensive, and reproducible. PMID:25548682

  2. Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy.

    PubMed

    Siotto, Mariacristina; Pasqualetti, Patrizio; Marano, Massimo; Squitti, Rosanna

    2014-10-01

    Ceruloplasmin (Cp) is a serum ferroxidase that plays an essential role in iron metabolism. It is routinely tested by immunoturbidimetric assays that quantify the concentration of the protein both in its active and inactive forms. Cp activity is generally analyzed manually; the process is time-consuming, has a limited repeatability, and is not suitable for a clinical setting. To overcome these inconveniences, we have set the automation of the o-dianisidine Cp activity assay on a Cobas Mira Plus apparatus. The automation was rapid and repeatable, and the data were provided in terms of IU/L. The assay was adapted for human sera and showed a good precision [coefficient of variation (CV) 3.7 %] and low limit of detection (LoD 11.58 IU/L). The simultaneous analysis of Cp concentration and activity in the same run allowed us to calculate the Cp-specific activity that provides a better index of the overall Cp status. To test the usefulness of this automation, we tested this assay on 104 healthy volunteers and 36 patients with Wilson's disease, hepatic encephalopathy, and chronic liver disease. Cp activity and specific activity distinguished better patients between groups with respect to Cp concentration alone, and providing support for the clinical investigation of neurological diseases in which liver failure is one of the clinical hallmarks. PMID:24663495

  3. α-Ketoglutaramate: An overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle

    PubMed Central

    Cooper, Arthur J. L.; Kuhara, Tomiko

    2013-01-01

    Glutamine metabolism is generally regarded as proceeding via glutaminase-catalyzed hydrolysis to glutamate and ammonia, followed by conversion of glutamate to α-ketoglutarate catalyzed by glutamate dehydrogenase or by a glutamate-linked aminotransferase (transaminase). However, another pathway exists for the conversion of glutamine to α-ketoglutarate that is often overlooked, but is widely distributed in nature. This pathway, referred to as the glutaminase II pathway, consists of a glutamine transaminase coupled to ω-amidase. Transamination of glutamine results in formation of the corresponding α-keto acid, namely, α-ketoglutaramate (KGM). KGM is hydrolyzed by ω-amidase to α-ketoglutarate and ammonia. The net glutaminase II reaction is: L-Glutamine + α-keto acid + H2O → α-ketoglutarate + L-amino acid + ammonia. In this mini-review the biochemical importance of the glutaminase II pathway is summarized, with emphasis on the key component KGM. Forty years ago it was noted that the concentration of KGM is increased in the cerebrospinal fluid (CSF) of patients with hepatic encephalopathy (HE) and that the level of KGM in the CSF correlates well with the degree of encephalopathy. In more recent work, we have shown that KGM is markedly elevated in the urine of patients with inborn errors of the urea cycle. It is suggested that KGM may be a useful biomarker for many hyperammonemic diseases including hepatic encephalopathy, inborn errors of the urea cycle, citrin deficiency and lysinuric protein intolerance. PMID:24234505

  4. [Recurrent posterior reversible encephalopathy due to vasospasm and cerebral hypoperfusionin in acute leukemia: a case report].

    PubMed

    Hiraide, Takuya; Matsubayashi, Tomoko; Ishigaki, Hidetoshi; Asahina, Miki; Sakaguchi, Kimiyoshi; Fukuda, Tokiko

    2015-11-01

    We report the case of a 4-year-old girl who presented with recurrent posterior reversible encephalopathy syndrome (PRES). She was diagnosed with B-precursor acute lymphocytic leukemia (ALL), and was administered remission-induction chemotherapy. On day 28 of the induction therapy, she experienced seizure and prolonged unconsciousness. Blood pressure was slightly elevated. MRI revealed cortical cytotoxic edema in the right temporal and occipital lobes. In the right occipital white matter the lesion with vasogenic edema also existed. Three days later, MRI showed vasogenic edema in subcortical white matter of the right temporal right occipital and bilateral occipital lobes. The lesions had receded with time. Since the seizure occurred, the chemotherapy had been discontinued. The episodes of seizure and prolonged consciousness recurred 22 days later. MRI revealed vasogenic edema in the right occipital lobe, and MR angiography demonstrated vessel irregularity and reduced branch visualization in the middle and posterior cerebral arteries. Arterial spin-labeling (ASL) showed hypoperfusion in both occipital lobes. It suggests that vasoconstriction and hypoperfusion could lead to recurrent PRES in this case. It is possible that ASL might be more sensitive than MRI in detecting the lesions of PRES. It should be noted that PRES might recur in leukemia. PMID:26717647

  5. Posterior Reversible Encephalopathy Syndrome due to High Dose Corticosteroids for an MS Relapse.

    PubMed

    Morrow, Sarah A; Rana, Robina; Lee, Donald; Paul, Terri; Mahon, Jeffrey L

    2015-01-01

    Increased blood pressure is a known adverse effect associated with corticosteroids but little is published regarding the risk with the high doses used in multiple sclerosis (MS). A 53-year-old female with known relapsing remitting MS presented with a new brainstem relapse. Standard of care treatment for an acute MS relapse, 1250 mg of oral prednisone for 5 days, was initiated. She developed an occipital headache and dizziness and felt generally unwell. These symptoms persisted after treatment was complete. On presentation to medical attention, her blood pressure was 199/110 mmHg, although she had no history of hypertension. MRI changes were consistent with posterior reversible encephalopathy syndrome (PRES), demonstrating abnormal T2 signal in both thalami, the posterior occipital and posterior parietal white matter with mild sulcal effacement. As her pressure normalized with medication, her symptoms resolved and the MRI changes improved. No secondary cause of hypertension was found. This is the first reported case of PRES secondary to high dose corticosteroid use for an MS relapse without a history of hypertension and with no other secondary cause of hypertension identified. This rare complication should be considered in MS patients presenting with a headache or other neurological symptoms during treatment for a relapse. PMID:26101676

  6. Solvent encephalopathy.

    PubMed Central

    King, M D; Day, R E; Oliver, J S; Lush, M; Watson, J M

    1981-01-01

    Nineteen children aged 8-14 years were admitted over a six-year period with an acute encephalopathy due to toluene intoxication. Seven had a history of euphoria and hallucinations. The remainder presented with coma (4), ataxia (3), convulsions (3), and behaviour disturbance with diplopia (2), A history of glue sniffing was elicited in 14, but in the remainder toluene assay confirmed the diagnosis. Thirteen children recovered completely; five still had psychological impairment and personality change on discharge from hospital but were lost to follow-up, and one has a persistent cerebellar ataxia one year after the acute episode, despite absence of further exposure. Toluene inhalation is an important cause of encephalopathy in children and may lead to permanent neurological damage. Diagnosis is most important if further damage due to continued abuse is to be prevented, and toluene assay is a valuable aid to diagnosis. PMID:6790121

  7. Hyaluronic Acid Levels Predict Risk of Hepatic Encephalopathy and Liver-Related Death in HIV/Viral Hepatitis Coinfected Patients

    PubMed Central

    Peters, Lars; Mocroft, Amanda; Soriano, Vincent; Rockstroh, Jürgen; Rauch, Andri; Karlsson, Anders; Knysz, Brygida; Pradier, Christian; Zilmer, Kai; Lundgren, Jens D.

    2013-01-01

    Background Whereas it is well established that various soluble biomarkers can predict level of liver fibrosis, their ability to predict liver-related clinical outcomes is less clearly established, in particular among HIV/viral hepatitis co-infected persons. We investigated plasma hyaluronic acid’s (HA) ability to predict risk of liver-related events (LRE; hepatic coma or liver-related death) in the EuroSIDA study. Methods Patients included were positive for anti-HCV and/or HBsAg with at least one available plasma sample. The earliest collected plasma sample was tested for HA (normal range 0–75 ng/mL) and levels were associated with risk of LRE. Change in HA per year of follow-up was estimated after measuring HA levels in latest sample before the LRE for those experiencing this outcome (cases) and in a random selection of one sixth of the remaining patients (controls). Results During a median of 8.2 years of follow-up, 84/1252 (6.7%) patients developed a LRE. Baseline median (IQR) HA in those without and with a LRE was 31.8 (17.2–62.6) and 221.6 ng/mL (74.9–611.3), respectively (p<0.0001). After adjustment, HA levels predicted risk of contracting a LRE; incidence rate ratios for HA levels 75–250 or ≥250 vs. <75 ng/mL were 5.22 (95% CI 2.86–9.26, p<0.0007) and 28.22 (95% CI 14.95–46.00, p<0.0001), respectively. Median HA levels increased substantially prior to developing a LRE (107.6 ng/mL, IQR 0.8 to 251.1), but remained stable for controls (1.0 ng/mL, IQR –5.1 to 8.2), (p<0.0001 comparing cases and controls), and greater increases predicted risk of a LRE in adjusted models (p<0.001). Conclusions An elevated level of plasma HA, particularly if the level further increases over time, substantially increases the risk of contracting LRE over the next five years. HA is an inexpensive, standardized and non-invasive supplement to other methods aimed at identifying HIV/viral hepatitis co-infected patients at risk of hepatic complications. PMID:23724041

  8. Diphtheria, pertussis (whooping cough), and tetanus vaccine induced recurrent seizures and acute encephalopathy in a pediatric patient: Possibly due to pertussis fraction.

    PubMed

    Patel, Mahendra K; Patel, Tejas K; Tripathi, C B

    2012-01-01

    A 5-month-old male patient developed recurrent seizures and acute encephalopathy possibly due to first dose of diphtheria, pertussis (whooping cough), and tetanus (DPT) vaccine used for routine immunization. Postreaction computed tomography (CT) scan of brain, magnetic resonance imaging (MRI) of brain, and electroencephalogram were normal. Pertussis fraction of DPT vaccine is responsible for this reaction. It is suggested that acellular pertussis vaccine should be used instead of whole cell vaccine because it is associated with lower frequency of neurological complications, such as seizures, encephalopathy, and hypotensive episodes. However, acellular pertussis-containing vaccines are currently not affordable in most developing countries. PMID:22368426

  9. Diphtheria, pertussis (whooping cough), and tetanus vaccine induced recurrent seizures and acute encephalopathy in a pediatric patient: Possibly due to pertussis fraction

    PubMed Central

    Patel, Mahendra K.; Patel, Tejas K.; Tripathi, C. B.

    2012-01-01

    A 5-month-old male patient developed recurrent seizures and acute encephalopathy possibly due to first dose of diphtheria, pertussis (whooping cough), and tetanus (DPT) vaccine used for routine immunization. Postreaction computed tomography (CT) scan of brain, magnetic resonance imaging (MRI) of brain, and electroencephalogram were normal. Pertussis fraction of DPT vaccine is responsible for this reaction. It is suggested that acellular pertussis vaccine should be used instead of whole cell vaccine because it is associated with lower frequency of neurological complications, such as seizures, encephalopathy, and hypotensive episodes. However, acellular pertussis-containing vaccines are currently not affordable in most developing countries. PMID:22368426

  10. Ephrin/Ephrin receptor expression in ammonia-treated rat astrocytes and in human cerebral cortex in hepatic encephalopathy.

    PubMed

    Sobczyk, Karmela; Jördens, Markus S; Karababa, Ayse; Görg, Boris; Häussinger, Dieter

    2015-02-01

    Hepatic encephalopathy (HE) represents a neuropsychiatric syndrome, which evolves as a consequence of a low grade cerebral edema and a concomitant oxidative/nitrosative stress response. Ephrin receptors (EphR) and their ligands (ephrins) regulate astrocytic glutamate uptake and gliotransmitter release thereby governing neurotransmission, but their role in HE and ammonia toxicity is unclear. We therefore tested effects of ammonia on expression levels of EphR/ephrin isoforms in cultured rat astrocytes and analysed underlying mechanisms. NH4Cl induced mRNA expression changes of several EphR/ephrin isoforms in a methionine sulfoximine-, NADPH oxidase- and NO synthase-dependent manner in cultured astrocytes. A prominent upregulation was noted for EphR A4 mRNA and protein in NH4Cl-treated astrocytes. NH4Cl-treatment decreased EphR A4 molecular mass to similar extent as found in astrocytes treated with the N-glycosylation inhibitor tunicamycin. Knockdown of EphR A4 by siRNA, or treating astrocytes with NH4Cl or tunicamycin abolished fibroblast growth factor-induced and EphR A4-dependent astrocyte proliferation. NH4Cl-treatment also decreased GLAST mRNA levels in cultured astrocytes. This effect was sensitive to inhibitors of NAPDH oxidase or glutamine synthetase, but was insensitive to siRNA-mediated EphR A4 knockdown. Eph/ephrin gene expression changes were also found in post mortem brain samples of cirrhotic patients without or with HE compared to controls suggesting a potential in vivo relevance of the present findings. The present study suggests that ammonia modulates EphR/ephrin signaling in astrocytes and in the brain of cirrhotic patients with HE with potential implications for deranged neurotransmission in HE. PMID:25064044

  11. Probiotic and lactulose: influence on gastrointestinal flora and pH value in minimal hepatic encephalopathy rats

    PubMed Central

    Jiang, Shu-Man; Jia, Lin; Zhang, Mei-Hua

    2015-01-01

    Aim: The present study was conducted to investigate the influence on gastrointestinal flora, counts of bifidobacteria and Enterobacterceae in colon and pH value of gastrointestinal after lactulose and probiotic treatment on rat experimental minimal hepatic encephalopathy (MHE) induced by thioactamide (TAA). Methods: MHE was induced by intraperitoneal injection of TAA. 48 male MHE models were then randomly divided into 4 groups: control group (n = 12); MHE group (n = 12) received tap water ad libitum only; lactulose group (n = 12) and probiotics group (n = 12) gavaged respectively with 8 ml/kg of lactulose and 1.5 g/kg of probiotic preparation Golden Bifid (highly concentrated combination probiotic) dissolved in 2 ml of normal saline, once a day for 8 days. The latency of Brainstem auditory evoked potentials (BAEP) I was used as objective index of MHE. Counts of gastrointestinal flora, counts of bifidobacteria and Enterobacterceae in colon and pH value of gastrointestinal were examined respectively. Results: Compared to MHE group, counts of gastrointestinal flora has greatly decreased, ratio of bifidobacteria and Enterobacterceae has greatly increased, pH value of colon has greatly descended (P < 0.05). However, there was no significant difference between lactulose group and probiotic group (P > 0.05). Both lactulose and probiotics can effectively prevent bacteria translocation and overgrowth, intensify CR, improved value of B/E, and acidify intestinal, decreased pH value of colon. Conclusion: Probiotic compound Golden Bifid is as useful as lactulose for the prevention and treatment of MHE. Probiotic therapy may be a safe, natural, well-tolerated therapy appropriate for the long-term treatment of MHE. PMID:26309689

  12. The GABAA receptor complex in hepatic encephalopathy. Autoradiographic evidence for the presence of elevated levels of a benzodiazepine receptor ligand

    SciTech Connect

    Basile, A.S.; Ostrowski, N.L.; Gammal, S.H.; Jones, E.A.; Skolnick, P. )

    1990-02-01

    Autoradiographic analysis was used to examine radioligand binding to benzodiazepine (BZ) and GABAA receptors in the brains of rabbits with hepatic encephalopathy (HE). Thin sections of whole brain from normal rabbits and rabbits with HE were mounted on slides and subdivided into two groups. One group was washed before incubation with radioligand, while the second group was not prewashed. (3H)Flunitrazepam binding to BZ receptors was decreased by 22% to 42% (p less than 0.05) in the cerebral cortex, superior and inferior colliculi, and cerebellum of unwashed sections from rabbits with HE compared to all other groups. The binding of (3H)Ro 15-1788 to unwashed sections from rabbits with HE was reduced by a similar degree (18% to 37%, p less than 0.05) in the cerebral cortex, hippocampus, superior colliculus, and cerebellar cortex. Incubation of sections with the GABA-mimetic muscimol and NaCl produced an additional decrease in (3H)flunitrazepam binding to the cortex and hippocampus (25% to 31%, p less than 0.05) in unwashed HE rabbit brain, but increased radioligand binding (27% to 71%, p less than 0.05) to several regions in control rabbits. No changes in radioligand binding to either GABAA or peripheral benzodiazepine receptors was observed between HE and control rabbit sections. These findings are consistent with previous electrophysiologic and neurochemical observations indicating no significant changes in either the function or density of GABAA or BZ receptors in this model of HE. Further, they indicate that a reversible BZ receptor ligand with agonist properties is present in the brain in HE. This substance may contribute to the enhancement of GABAergic tone observed in this syndrome.

  13. Diagnosis of infectious canine hepatitis virus (CAV-1) infection in puppies with encephalopathy.

    PubMed

    Caudell, D; Confer, A W; Fulton, R W; Berry, A; Saliki, J T; Fent, G M; Ritchey, J W

    2005-01-01

    Nine weaned Labrador Retriever puppies from a litter of 11 were presented with signs of acute central nervous system (CNS) disease that included ataxia and blindness. All puppies died. Gross examination of tissues from 2 puppies revealed regionally diffuse hemorrhages in the brain stem and swollen hemorrhagic lymph nodes. Light microscopic examination of hematoxylin and eosin-stained tissues showed numerous large, basophilic intranuclear inclusion bodies within CNS vascular endothelium and occasionally in individual hepatocytes. Immunohistochemical staining of the tissue was positive using an antibody against canine adenovirus-1. Virus isolation for infectious canine hepatitis virus was achieved using inoculated cell cultures. Polymerase chain reaction amplification of DNA from cell culture material revealed shared homology with other mammalian adenoviruses. PMID:15690952

  14. Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients

    PubMed Central

    Chen, Shu-Jie; Wang, Liang-Jing; Zhu, Qin; Cai, Jian-Ting; Chen, Tao; Si, Jian-Min

    2008-01-01

    AIM: To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy (HE), and the effect of H pylori eradication in cirrhotic patients. METHODS: From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, H pylori infection, liver impairment, blood ammonia concentration and HE. Patients with H pylori infection were given 1 wk therapy with omeprazole plus clarithromycin and tinidazole. 14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after bacterium eradication. RESULTS: Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE (SHE) was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative (n = 180) and positive (n = 277) cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 μmol/L, respectively (P < 0.01), which was significantly reduced to 53.5 ± 37.7 μmol/L after bacterium eradication (n = 126) (P < 0.01). Blood ammonia was 97.5 ± 81.0 μmol/L in H pylori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after H pylori eradication (n = 11). HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). H pylori prevalence significantly differed among cirrhotic patients with HE (74.4%), SHE (69.1%), and those without HE (53.2%) (P < 0.05). Blood ammonia level was significantly different among cirrhotic patients with HE (94.5 ± 75.6 μmol/L), SHE (59.9 ± 49.2 μmol/L), and without HE (47.3 ± 33.5 μmol/L) (P < 0.05). Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nitrogen were risk

  15. Vascular plug-assisted retrograde transvenous obliteration of portosystemic shunts for refractory hepatic encephalopathy: a case report.

    PubMed

    Park, Jonathan K; Cho, Sung-Ki; Kee, Stephen; Lee, Edward W

    2014-01-01

    While balloon-assisted retrograde transvenous obliteration (BRTO) has been used for two decades in Asia for the management of gastric variceal bleeding, it is still an emerging therapy elsewhere. Given the shunt closure brought about by the procedure, BRTO has also been used for the management of portosystemic encephalopathy with promising results. Modified versions of BRTO have been developed, including plug-assisted retrograde transvenous obliteration (PARTO), where a vascular plug is deployed within a portosystemic shunt. To our knowledge, we present the first North American case of PARTO in the setting of a large splenorenal shunt for the management of portosystemic encephalopathy. PMID:24744943

  16. [EEG manifestations in metabolic encephalopathy].

    PubMed

    Lin, Chou-Ching K

    2005-09-01

    Normal brain function depends on normal neuronal metabolism, which is closely related to systemic homeostasis of metabolites, such as glucose, electrolytes, amino acids and ammonia. "Metabolic encephalopathy" indicates diffuse brain dysfunction caused by various systemic derangements. Electroencephalogram (EEG) is widely used to evaluate metabolic encephalopathy since 1937, when Berger first observed slow brain activity induced by hypoglycemia. EEG is most useful in differentiating organic from psychiatric conditions, identifying epileptogenicity, and providing information about the degree of cortical or subcortical dysfunction. In metabolic encephalopathy, EEG evolution generally correlates well with the severity of encephalopathy. However, EEG has little specificity in differentiating etiologies in metabolic encephalopathy. For example, though triphasic waves are most frequently mentioned in hepatic encephalopathy, they can also be seen in uremic encephalopathy, or even in aged psychiatric patients treated with lithium. Spike-and-waves may appear in hyper- or hypo-glycemia, uremic encephalopathy, or vitamin deficiencies, etc. Common principles of EEG changes in metabolic encephalopathy are (1) varied degrees of slowing, (2) assorted mixtures of epileptic discharge, (3) high incidence of triphasic waves, and (4), as a rule, reversibility after treatment of underlying causes. There are some exceptions to the above descriptions in specific metabolic disorders and EEG manifestations are highly individualized. PMID:16252619

  17. Hypothyroidism Due to Hepatic Hemangioendothelioma: A Case Report

    PubMed Central

    Peltek Kendirici, Havva Nur; Yılmaz Ağladıoğlu, Sebahat; Baş, Veysel Nijat; Özdemir, Sonay; Bozkurt, Ceyhun; Aycan, Zehra

    2010-01-01

    Although hemangioendothelioma (HHE) is a commonly encountered hepatic tumor during infancy, HHE−related hypothyroidism is rare. We present a patient who developed HHE−related hypothyroidism during the neonatal period and showed marked improvement in hypothyroidism by regression of HHE. A 28−day−old boy with TSH level of 77 mIU/mL on neonatal screening and diagnosed as congenital hypothyroidism was started on L−thyroxine (L−T4) (11 μg/kg/day) therapy on the 21th day of life. On physical examination, the liver was palpable 5 cm below the right costal margin, and the thyroid gland was nonpalpable. Thyroid ultrasonography was normal. Although L−T4 dose was increased to 15 μg/kg/day, TSH was not suppressed and free T3 level remained low. HHE in both lobes of the liver was detected by abdominal ultrasonography and magnetic resonance imaging. Treatment was started with prednisolone 2 mg/kg/day and alpha−interferon 3 million U/m2/3 times per week. Thyroid dysfunction was thought to be due to type 3 iodothyronine deiodinase activity expressed by HHE. L−T4 therapy was changed to Bitiron® tablet, which includes both T4 and T3, and euthyroidism was attained within 1 month. Thyroid hormone requirement was reduced and treatment was discontinued after regression of the HHE. At the most recent visit, the patient was 21 months old and off treatment. His growth and neurological development were normal for age and he was euthyroid. HHE should be considered in cases with severe hypothyroidism resistant to high−dose thyroid hormone replacement. The treatment of HHE in combination with T4 and T3 therapy results in euthyroidism. Conflict of interest:None declared. PMID:21274327

  18. Inhibitory Control Test, Critical Flicker Frequency, and Psychometric Tests in the Diagnosis of Minimal Hepatic Encephalopathy in Cirrhosis

    PubMed Central

    Sharma, Praveen; Kumar, Ajay; Singh, Shweta; Tyagi, Pankaj; Kumar, Ashish

    2013-01-01

    Background/Aim: Minimal hepatic encephalopathy (MHE) impairs health-related quality of life and driving ability of the patient. Objective: We assessed the utility of the inhibitory control test (ICT), critical flicker frequency (CFF), and psychometry in the diagnosis of MHE. Patients and Methods: Consecutive patients with cirrhosis underwent number connection tests A and B (NCT-A, B), digit symbol test (DST), line tracing test (LTT), serial dot test (SDT), CFF, and ICT at baseline and after four hours. Fifty healthy subjects served as controls for the ICT test. Results: Fifty patients with cirrhosis (43.4 ± 10.2 yrs, M: F 42:8) underwent psychometric tests [NCT-A (48.3 ± 17.7 vs. 42.6 ± 17.3 sec, P = 0.001), NCT-B (85.7 ± 40.1 vs. 90.2 ± 37.0 sec, P = 0.18), DST (23.5 ± 9.3 vs. 23.0 ± 8.7, P = 0.45), LTT (96.6 ± 48.2 vs. 96.8 ± 46.8 sec, P = 0.92), SDT (88.0 ± 39.5 vs. 83.4 ± 37.2 sec, P = 0.02)] at baseline and after four hours. Target accuracy of ICT was lower in patients with cirrhosis compared with controls (88.4 ± 5.6 vs. 95.6 ± 2.1, P = 0.01), whereas ICT lures were higher (18.3 ± 4.2 vs 10.2 ± 2.8, P = 0.01). Patients with cirrhosis showed a reduction in lures in the second evaluation compared with the first (18.3 ± 4.2 vs. 17.1 ± 4.3, P = 0.003) but no change in target accuracy (88.4 ± 5.6 vs. 88.4 ± 5.3, P = 0.97). Control subjects did not show any change either in lures (10.2 ± 2.8 vs. 10.3 ± 2.1, P = 0.65) or target accuracy (95.6 ± 2.1 vs. 95.5 ± 2.2, P = 0.82). The sensitivity and specificity of ICT test for the diagnosis of MHE at lure rate >16.5 was 88.5 and 56%, respectively. CFF in patients with MHE (38.4 ± 1.8 vs. 38.6 ± 1.5, P = 0.3) and non MHE (40.6 ± 2.2 vs. 40.8 ± 2.2, P = 0.6) did not show any difference after four hours as in controls (41.9 ± 2.4 vs. 42.1 ± 2.0, P = 0.3). Thirty one (31%) patients preferred psychometric tests, 57 (57%) preferred CFF and only 12 (12%) preferred ICT (P = 0.001). Conclusions: ICT

  19. Elevated intracranial dopamine impairs the glutamate‑nitric oxide‑cyclic guanosine monophosphate pathway in cortical astrocytes in rats with minimal hepatic encephalopathy.

    PubMed

    Ding, Saidan; Huang, Weilong; Ye, Yiru; Yang, Jianjing; Hu, Jiangnan; Wang, Xiaobin; Liu, Leping; Lu, Qin; Lin, Yuanshao

    2014-09-01

    In a previous study by our group memory impairment in rats with minimal hepatic encephalopathy (MHE) was associated with the inhibition of the glutamate‑nitric oxide‑cyclic guanosine monophosphate (Glu‑NO‑cGMP) pathway due to elevated dopamine (DA). However, the effects of DA on the Glu‑NO‑cGMP pathway localized in primary cortical astrocytes (PCAs) had not been elucidated in rats with MHE. In the present study, it was identified that when the levels of DA in the cerebral cortex of rats with MHE and high‑dose DA (3 mg/kg)‑treated rats were increased, the co‑localization of N‑methyl‑d‑aspartate receptors subunit 1 (NMDAR1), calmodulin (CaM), nitric oxide synthase (nNOS), soluble guanylyl cyclase (sGC) and cyclic guanine monophosphate (cGMP) with the glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, all significantly decreased, in both the MHE and high‑dose DA‑treated rats (P<0.01). Furthermore, NMDA‑induced augmentation of the expression of NMDAR1, CaM, nNOS, sGC and cGMP localized in PCAs was decreased in MHE and DA‑treated rats, as compared with the controls. Chronic exposure of cultured cerebral cortex PCAs to DA treatment induced a dose‑dependent decrease in the concentration of intracellular calcium, nitrites and nitrates, the formation of cGMP and the expression of NMDAR1, CaM, nNOS and sGC/cGMP. High doses of DA (50 µM) significantly reduced NMDA‑induced augmentation of the formation of cGMP and the contents of NMDAR1, CaM, nNOS, sGC and cGMP (P<0.01). These results suggest that the suppression of DA on the Glu‑NO‑cGMP pathway localized in PCAs contributes to memory impairment in rats with MHE. PMID:25059564

  20. Elevated intracranial dopamine impairs the glutamate-nitric oxide-cyclic guanosine monophosphate pathway in cortical astrocytes in rats with minimal hepatic encephalopathy

    PubMed Central

    DING, SAIDAN; HUANG, WEILONG; YE, YIRU; YANG, JIANJING; HU, JIANGNAN; WANG, XIAOBIN; LIU, LEPING; LU, QIN; LIN, YUANSHAO

    2014-01-01

    In a previous study by our group memory impairment in rats with minimal hepatic encephalopathy (MHE) was associated with the inhibition of the glutamate-nitric oxide-cyclic guanosine monophosphate (Glu-NO-cGMP) pathway due to elevated dopamine (DA). However, the effects of DA on the Glu-NO-cGMP pathway localized in primary cortical astrocytes (PCAs) had not been elucidated in rats with MHE. In the present study, it was identified that when the levels of DA in the cerebral cortex of rats with MHE and high-dose DA (3 mg/kg)-treated rats were increased, the co-localization of N-methyl-d-aspartate receptors subunit 1 (NMDAR1), calmodulin (CaM), nitric oxide synthase (nNOS), soluble guanylyl cyclase (sGC) and cyclic guanine monophosphate (cGMP) with the glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, all significantly decreased, in both the MHE and high-dose DA-treated rats (P<0.01). Furthermore, NMDA-induced augmentation of the expression of NMDAR1, CaM, nNOS, sGC and cGMP localized in PCAs was decreased in MHE and DA-treated rats, as compared with the controls. Chronic exposure of cultured cerebral cortex PCAs to DA treatment induced a dose-dependent decrease in the concentration of intracellular calcium, nitrites and nitrates, the formation of cGMP and the expression of NMDAR1, CaM, nNOS and sGC/cGMP. High doses of DA (50 μM) significantly reduced NMDA-induced augmentation of the formation of cGMP and the contents of NMDAR1, CaM, nNOS, sGC and cGMP (P<0.01). These results suggest that the suppression of DA on the Glu-NO-cGMP pathway localized in PCAs contributes to memory impairment in rats with MHE. PMID:25059564

  1. Aberrant salience network and its functional coupling with default and executive networks in minimal hepatic encephalopathy: a resting-state fMRI study

    PubMed Central

    Chen, Hua-Jun; Chen, Qiu-Feng; Liu, Jun; Shi, Hai-Bin

    2016-01-01

    The purposes of this study are to explore functional alterations in salience network (SN) and its functional coupling with default mode (DMN) and central executive (CEN) networks in minimal hepatic encephalopathy (MHE). Twenty cirrhotic patients with MHE, 23 cirrhotic patients without MHE (NHE), and 18 controls underwent resting-state fMRI and psychometric hepatic encephalopathy score (PHES) test. Independent component analysis was performed to obtain DMN (including three subsystems: anterior, inferior-posterior, and superior-posterior DMN [a/ip/spDMN]), SN, and CEN (including three subsystems: left-ventral, right-ventral, and dorsal CEN [lv/rv/dCEN]). The intrinsic functional connectivity (iFC) within (intra-iFC) and between (inter-iFC and time-lagged inter-iFC) networks was measured. MHE patients showed decreased intra-iFC within aDMN, SN, lvCEN, and rvCEN; and decreased inter-iFC and time-lagged inter-iFC between SN and ipDMN/spDMN/lvCEN and increased inter-iFC and time-lagged inter-iFC between SN and aDMN, compared with controls. A progressive trend in connectivity alterations was found as the disease developed from NHE to MHE. The inter-iFC between ipDMN/spDMN and SN was significantly correlated with PHES score. In conclusion, an aberrant SN and its functional interaction with the DMN/CEN are core features of MHE that are associated with disease progression and may play an important role in neurocognitive dysfunction in MHE. PMID:27250065

  2. Rats with mild bile duct ligation show hepatic encephalopathy with cognitive and motor impairment in the absence of cirrhosis: effects of alcohol ingestion.

    PubMed

    Giménez-Garzó, Carla; Salhi, Dounia; Urios, Amparo; Ruíz-Sauri, Amparo; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2015-02-01

    Studies in animal models allow identifying mechanisms and treatments for cognitive and motor alterations in hepatic encephalopathy (HE). Liver diseases leading to HE in humans have different aetiologies (alcoholic, viral, etc.). The International Society for Hepatic Encephalopathy points out that satisfactory model for HE resulting from alcoholic cirrhosis are lacking. This work aimed to develop and characterize an animal model for HE in alcoholic liver cirrhosis. To potentiate the effects of alcohol on liver we administered it (5, 8 or 10% in drinking water) to rats showing mild liver damage induced by "mild" bile duct ligation (MBDL), obtained by sectioning 3 out of 5 bile ducts. MBDL rats show increased markers of cholestasis and liver damage, hyperammonemia and inflammation. MBDL rats also show motor in-coordination, hypokinesia, impaired learning ability in a Y maze and reduced spatial memory in the Morris water maze. Ingesting 10% ethanol does not induce relevant liver damage in control rats but potentiates liver damage in MBDL rats. In contrast, ethanol did not enhance the biochemical or neurological alterations in MBDL rats. This supports that the combination of certain levels of hyperammonemia and inflammation is enough to induce mild cognitive impairment, even in the absence of liver cirrhosis. Rats with MBDL and MBDL-OH survived more than 3 months, allowing performing long-term studies on cognitive and motor alterations and on underlying mechanisms. MBDL-OH rats are a good model to study the mechanisms of ethanol-induced liver cirrhosis and the factors making the liver susceptible to ethanol damage. PMID:24838616

  3. Clinical effects of rifaximin in patientswith hepatic encephalopathy intolerant or nonresponsive to previous lactulose treatment: An open-label, pilot study

    PubMed Central

    Sama, Claudia; Morselli-Labate, Antonio Maria; Pianta, Paolo; Lambertini, Laura; Berardi, Sonia; Martini, Gabriella

    2004-01-01

    Background: Hepatic encephalopathy (HE) is a metabolic-neurophysiologicsyndrome that occurs in patients with advanced hepatic disease. One of the main pathogenic mechanisms is represented by circulating toxins produced by the intestinal metabolism of nitrogenous compounds. The therapeutic approach to HE is mainly based on drugs that eliminate ammonia-producing bacteria. Objectives: The aim of this study was to evaluate the effects of the nonabsorbable antibiotic rifaximin in patients with HE who were intolerant or nonresponsive to treatment with an oral, nonabsorbable disaccharide (lactulose). Methods: This uncontrolled, open-label, pilot study was conducted at the University of Bologna, Bologna, Italy. Patients aged ≥ 18 years with histologically proven liver cirrhosis and HE were studied. All patients were intolerant or nonresponsive to previous treatment with lactulose. Rifaximin tablets were administered to patients at a dosage of 400 mg TID for 10 days. The portal systemic encephalopathy (PSE) index was evaluated at enrollment and at the end of the treatment period. Tolerability was assessed using hematology, biochemistry, and urinalysis and by recording adverse effects (AEs). Results: Twenty-six patients (18 men, 8 women; mean [SD] age, 55.8 [8.0] years) were enrolled (intolerants, n = 17; nonresponders, n = 9). All patients completed the study. Significant improvement was shown in most of the 5 components of the PSE index after rifaximin administration in both intolerants and nonresponders. At the end of the 10-day treatment period, the PSE index was significantly reduced in both intolerants and nonresponders. Rifaximin was well tolerated; no clinically relevant AEs were observed during the treatment period. Conclusions: This pilot study of patients with liver cirrhosis and HE who were intolerant or nonresponsive to previous treatment with an oral, nonabsorbable disaccharide suggests that treatment with rifaximin may be considered as an adjuvant or an

  4. Aberrant salience network and its functional coupling with default and executive networks in minimal hepatic encephalopathy: a resting-state fMRI study.

    PubMed

    Chen, Hua-Jun; Chen, Qiu-Feng; Liu, Jun; Shi, Hai-Bin

    2016-01-01

    The purposes of this study are to explore functional alterations in salience network (SN) and its functional coupling with default mode (DMN) and central executive (CEN) networks in minimal hepatic encephalopathy (MHE). Twenty cirrhotic patients with MHE, 23 cirrhotic patients without MHE (NHE), and 18 controls underwent resting-state fMRI and psychometric hepatic encephalopathy score (PHES) test. Independent component analysis was performed to obtain DMN (including three subsystems: anterior, inferior-posterior, and superior-posterior DMN [a/ip/spDMN]), SN, and CEN (including three subsystems: left-ventral, right-ventral, and dorsal CEN [lv/rv/dCEN]). The intrinsic functional connectivity (iFC) within (intra-iFC) and between (inter-iFC and time-lagged inter-iFC) networks was measured. MHE patients showed decreased intra-iFC within aDMN, SN, lvCEN, and rvCEN; and decreased inter-iFC and time-lagged inter-iFC between SN and ipDMN/spDMN/lvCEN and increased inter-iFC and time-lagged inter-iFC between SN and aDMN, compared with controls. A progressive trend in connectivity alterations was found as the disease developed from NHE to MHE. The inter-iFC between ipDMN/spDMN and SN was significantly correlated with PHES score. In conclusion, an aberrant SN and its functional interaction with the DMN/CEN are core features of MHE that are associated with disease progression and may play an important role in neurocognitive dysfunction in MHE. PMID:27250065

  5. Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona.

    PubMed

    Stillman, A S; Huxtable, R; Consroe, P; Kohnen, P; Smith, S

    1977-08-01

    An infant with documented hepatic veno-occlusive disease due to ingestion of pyrrolizidine alkaloids is presented. The alkaloids were ingested in the form of an herbal tea commonly used as a folk remedy among the Mexican-American population. Among these people, this herb is known as gordolobo yerba. The patient presented with acute hepatocellular disease and portal hypertension which progressed over 2 months to extensive hepatic fibrosis. Other potential causes of hepatic venous occlusion were absent. PMID:873137

  6. Approach to Clinical Syndrome of Jaundice and Encephalopathy in Tropics

    PubMed Central

    Anand, Anil C.; Garg, Hitendra K.

    2015-01-01

    A large number of patients present with jaundice and encephalopathy in tropical country like India and acute liver failure is the usual cause. Clinical presentation like ALF is also a complication of many tropical infections, and these conditions may mimic ALF but may have subtle differences from ALF. Moreover, what hepatologists see as acute liver failure in tropics is different from what is commonly described in Western Textbooks. Paracetamol overdose, which is possibly the commonest cause of ALF in UK and USA, is hardly ever seen in India. Most common etiology here is viral hepatitis (hepatitis E > hepatitis B> hepatitis A). Apart from ALF, one may also come across subacute hepatic failure (SAHF) as well as acute-on-chronic liver failure (ACLF) due to viral hepatitis. Interestingly, a host of other conditions can mimic ALF because clinical presentation in these conditions can be dominated by jaundice and encephalopathy. Malarial hepatopathy is possibly the best-known condition out of these and is not an uncommon manifestation of severe malaria. A similar presentation can also be seen in other common infections in tropics such as dengue fever, typhoid fever, leptospirosis, scrub typhus, amoebic liver abscesses, tuberculosis and other bacterial and fungal infections with or without human immunodeficiency virus (HIV) related disease. In many of these conditions, liver failure may not be underlying pathophysiology. Some pregnancy related liver diseases could also present with jaundice and encephalopathy. This review summarizes the commonly seen presentations in tropical country like India, where jaundice and encephalopathy dominate the clinical picture. PMID:26041951

  7. Toxic Encephalopathy

    PubMed Central

    Kim, Jae Woo

    2012-01-01

    This article schematically reviews the clinical features, diagnostic approaches to, and toxicological implications of toxic encephalopathy. The review will focus on the most significant occupational causes of toxic encephalopathy. Chronic toxic encephalopathy, cerebellar syndrome, parkinsonism, and vascular encephalopathy are commonly encountered clinical syndromes of toxic encephalopathy. Few neurotoxins cause patients to present with pathognomonic neurological syndromes. The symptoms and signs of toxic encephalopathy may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. Thus, the importance of good history-taking that considers exposure and a comprehensive neurological examination cannot be overemphasized in the diagnosis of toxic encephalopathy. Neuropsychological testing and neuroimaging typically play ancillary roles. The recognition of toxic encephalopathy is important because the correct diagnosis of occupational disease can prevent others (e.g., workers at the same worksite) from further harm by reducing their exposure to the toxin, and also often provides some indication of prognosis. Physicians must therefore be aware of the typical signs and symptoms of toxic encephalopathy, and close collaborations between neurologists and occupational physicians are needed to determine whether neurological disorders are related to occupational neurotoxin exposure. PMID:23251840

  8. Scintigraphic study of regenerative nodules due to fulminant hepatic failure.

    PubMed

    Watanabe, Tomohiro; Kondo, Masahiko; Hirasa, Masahiro; Shirane, Hirofumi; Okabe, Yoshihiro; Ibuki, Yasuyoshi; Tomita, Shusuke; Orino, Akio; Todo, Akio; Wakatsuki, Yoshio; Chiba, Tsutomu; Kudo, Masatoshi

    2003-01-01

    We report the case of a 25-year-old woman with fulminant hepatic failure (FHF). Liver scintigraphy using (99m)Tc-galactosyl human serum albumin (GSA) and (99m)Tc-phytate produced interesting findings; regenerative nodules appeared as nodules of increased accumulation of (99m)Tc-GSA, whereas these nodules were expressed as defects of accumulation of (99m)Tc-phytate. These scintigraphic findings suggested that the functions of hepatocytes in regenerative nodules were maintained, whereas those of Kupffer cells were impaired. Although (99m)Tc-GSA scintigraphy indicated hepatic functional reserve enough to survive, she died despite intensive therapy including plasma exchange. Based on this case, it is recommended that not only (99m)Tc-GSA scintigraphy but also (99m)Tc-phytate scintigraphy is required to evaluate the prognosis of patients with FHF. PMID:12898364

  9. [Posterior reversible encephalopathy syndrome due to hypocalcemia: a description of a case and an analysis of a pathogenic role of electrolyte disturbances].

    PubMed

    Dobrynina, L A; Kalashnikova, L A; Bakulin, I S; Kremneva, E I; Krotenkova, M V; Shamtieva, K V

    2016-01-01

    Afemale patient with recurrent posterior reversible encephalopathy syndrome, severe hypocalcemia due to extirpation of the parathyroid glands is described. The disease was characterized by the acute development of headache, seizures, cognitive and behavioral disorders, mental confusion, transitory blood pressure increasing. The vasogenic edema in the posterior parts of the brain, detected by CT at the first exacerbation,was completely regressed. The residual neurological deficit and MRI changes remained after the recurrent exacerbations. Main clinical features of PRESare explained by hypocalcemia and accompanying electrolyte disturbances.The reported case shows the necessity to study blood electrolytes in patients with PRES to clarify their pathogenic role and the necessity of drug correction. PMID:27500881

  10. Encephalopathy in an infant with infantile spasms: possible role of valproate toxicity.

    PubMed

    Sivathanu, Shobhana; Sampath, Sowmya; Veerasamy, Madhubala; Sunderkumar, Satheeshkumar

    2014-01-01

    An infant presented with global developmental delay and infantile spasms. EEG was suggestive of hypsarrhythmia. She was started on sodium valproate, clonazepam and adrenocorticotropic hormone injection. After an initial improvement the child developed vomiting, altered sensorium and increase in frequency of seizures suggestive of encephalopathy. Valproate-induced hyperammonaemia or hepatic encephalopathy was considered and the drug was withheld following which there was a dramatic improvement. Paradoxically, the liver function tests and serum ammonia were normal. However, a complete reversal of encephalopathy, on withdrawal of the drug, strongly suggested an adverse drug reaction (ADR) due to valproic acid. Marginal elevation of serum valproic acid prompted us to use the Naranjo ADR probability score to confirm the diagnosis. This case highlights the fact that valproate toxicity can manifest with normal liver function and serum ammonia levels. This is the youngest reported case with this rare form of valproate-induced encephalopathy. PMID:24810446

  11. Bacopa monnieri Extract (CDRI-08) Modulates the NMDA Receptor Subunits and nNOS-Apoptosis Axis in Cerebellum of Hepatic Encephalopathy Rats

    PubMed Central

    Mondal, Papia; Trigun, Surendra Kumar

    2015-01-01

    Hepatic encephalopathy (HE), characterized by impaired cerebellar functions during chronic liver failure (CLF), involves N-methyl-D-aspartate receptor (NMDAR) overactivation in the brain cells. Bacopa monnieri (BM) extract is a known neuroprotectant. The present paper evaluates whether BM extract is able to modulate the two NMDAR subunits (NR2A and NR2B) and its downstream mediators in cerebellum of rats with chronic liver failure (CLF), induced by administration of 50 mg/kg bw thioacetamide (TAA) i.p. for 14 days, and in the TAA group rats orally treated with 200 mg/kg bw BM extract from days 8 to 14. NR2A is known to impart neuroprotection and that of NR2B induces neuronal death during NMDAR activation. Neuronal nitric oxide synthase- (nNOS-) apoptosis pathway is known to mediate NMDAR led excitotoxicity. The level of NR2A was found to be significantly reduced with a concomitant increase of NR2B in cerebellum of the CLF rats. This was consistent with significantly enhanced nNOS expression, nitric oxide level, and reduced Bcl2/Bax ratio. Moreover, treatment with BM extract reversed the NR2A/NR2B ratio and also normalized the levels of nNOS-apoptotic factors in cerebellum of those rats. The findings suggest modulation of NR2A and NR2B expression by BM extract to prevent neurochemical alterations associated with HE. PMID:26413124

  12. Glycerol Phenylbutyrate in Patients With Cirrhosis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous Ammonia Concentration.

    PubMed

    Ghabril, Marwan; Zupanets, Igor A; Vierling, John; Mantry, Parvez; Rockey, Don; Wolf, David; O'Shea, Robert; Dickinson, Klara; Gillaspy, Heather; Norris, Catherine; Coakley, Dion F; Mokhtarani, Masoud; Scharschmidt, Bruce F

    2013-07-01

    Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6 mL (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4 (27.9) µmol/L (ULN ∼48 µmol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cmax of 144 [125] vs. 292 [224] µg/mL on 6 and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9 mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE. PMID:27121790

  13. [Cholestasic toxic hepatitis due to clopidogrel in a patient with multiple conditions].

    PubMed

    Etxeberria Lekuona, D; Méndez López, I; Mercado, M R; Oteiza, J; Arteaga, M; Jarne, V

    2016-01-01

    Clopidogrel is a thienopyridine-class antiplatelet drug commonly used in ischemic heart disease,cerebrovascular disease and peripheral artery disease.Liver toxicity due to this drug is very infrequent.We found 16 cases in the literature, and in only two of them liver biopsy was carried out. We report the case of a 78 year old patient with multiple conditions affected by severe toxic cholestatic hepatitis due to clopidogrel and the results of the liver biopsy performed. Hepatitis was resolved after discontinuing the drug.Based on the characteristics of this case and other previously published cases, we review the characteristics of toxic hepatitis due to clopidogrel and its diagnosis and treatment. PMID:27125614

  14. Diets in Encephalopathy.

    PubMed

    Abdelsayed, George G

    2015-08-01

    As many as 80% of patients with end-stage liver disease and hepatic encephalopathy have significant protein-calorie malnutrition. Because of the severe hypercatabolic state of cirrhosis, the provision of liberal amounts of carbohydrate (at least 35 to 40 kcal/kg per day), and between 1.2 and 1.6 g/kg of protein is necessary. Protein restriction is not recommended. Branched-chain amino acid supplementation and vegetable protein are associated with improved outcomes. Dietary supplementation with vitamins, minerals (with the notable exception of zinc) and probiotics should be decided on a case-by-case basis. PMID:26195204

  15. Cost-effectiveness analysis of rifaximin-α administration for the reduction of episodes of overt hepatic encephalopathy in recurrence compared with standard treatment in France

    PubMed Central

    Kabeshova, Anastasiia; Ben Hariz, Soumaia; Tsakeu, Elyonore; Benamouzig, Robert; Launois, Robert

    2016-01-01

    Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs most often in a context of acute or chronic liver disease. Despite the seriousness of the pathology, only a few treatments have been developed for improving its management. Rifaximin-α is the first treatment that has been clinically developed for overt HE (OHE) episodes. Recent results of clinical studies demonstrated its significant improvement in the health-related quality of life. The objective of the current study was to estimate the long-term cost-effectiveness of rifaximin-α used in combination with lactulose compared with lactulose monotherapy in cirrhotic patients, who have experienced at least two prior OHE events. Methods: A Markov model was used to estimate rifaximin-α cost-effectiveness, evaluating it from the perspective of all contributors as recommended by French health technology assessment guidelines. Costs were based on current French treatment practices. The transition between health states was based on the reanalysis of the rifaximin-α pivotal clinical trials RFHE3001 and RFHE3002. The main outcome of the model was cost per quality adjusted life year (QALY). Results: The results indicate that rifaximin-α is a cost-effective treatment option with an incremental cost per QALY gained of €19,187 and €18,517 over two different time horizons (2 and 5 years). The robustness of the model was studied using probabilistic sensitivity analysis. Conclusion: For the societal willingness to pay threshold of €27,000 per QALY gained, rifaximin-α in combination with lactulose is a cost-effective and affordable treatment for patients who have experienced at least two prior overt HE episodes. PMID:27366216

  16. Hepatic encephalopathy induces site-specific changes in gene expression of GluN1 subunit of NMDA receptor in rat brain.

    PubMed

    Ahmadi, Shamseddin; Poureidi, Mahsa; Rostamzadeh, Jalal

    2015-08-01

    We investigate changes in gene expression of GluN1 subunit of N-Methyl-D-Aspartate (NMDA) receptor in the prefrontal cortex (PFC), hippocampus and striatum in a rat model of hepatic encephalopathy (HE). We used male Wistar rats in which HE was induced after a common bile duct ligation (BDL). The animals were divided into three sets, and each set included three groups of control, sham operated and BDL. In the first set of animals, blood samples collected for biochemical analysis on day 21 of BDL. In the second set, changes in nociception threshold was assessed on day 21 of BDL using a hotplate test. In the third set, whole brain extracted, and the PFC, the hippocampus and the striatum in each rat were immediately dissected. We used a semi-quantitative RT-PCR method for evaluating the GluN1 gene expression. The biochemical analyses showed that plasma levels of ammonia and bilirubin in BDL rats were significantly increased compared to the sham control group on day 21 of BDL (P < 0.01). Nociception threshold was also increased in rats with BDL compared to sham group (P < 0.001). The results revealed that the GluN1 gene expression at mRNA levels in BDL group was decreased by 19 % in the PFC (P < 0.05) but increased by 82 % in the hippocampus (P < 0.01) compared to the sham control group; however, no significant change was observed in the striatum. It can be concluded that HE affects the GluN1 gene expression in rat brain with a site-specific pattern, and the PFC and hippocampus are more sensitive areas than striatum. PMID:25896221

  17. Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

    PubMed

    Felipo, Vicente; Piedrafita, Blanca; Barios, Juan A; Agustí, Ana; Ahabrach, Hanan; Romero-Vives, María; Barrio, Luis C; Rey, Beatriz; Gaztelu, Jose M; Llansola, Marta

    2015-01-01

    Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light. PMID:26203935

  18. pH-sensitive microemulsion-based gels for removal of colonic ammonia: a novel preventative oral preparation for hepatic encephalopathy in rats.

    PubMed

    Zhang, Chun-Le; Duan, Zhi-Jun; Tian, Ge; Tian, Yan; He, Gao-Hong; Bian, Teng-Fei; Jin, Xue; Sun, Xiao-Yu; Liu, Zhen; Chang, Qing-Yong

    2015-05-01

    Microemulsions with limited stability in mimetic gastrointestinal environments have previously demonstrated potential for the effective removal of ammonia from artificial colonic fluid. Specialized pH‑sensitive microemulsion‑based gels for the removal of colonic ammonia (MBG‑RCA), however, possess relative stability in the gastrointestinal (GI) tract of normal rats, indicating potential use in in vivo applications. An investigation of the effects of oral MBG‑RCA was conducted in order to evaluate the reduction of intestinal ammonia and the prevention of hepatic encephalopathy (HE) in rat models. Eighty rats were allocated into eight 4‑day treatment groups: The HE model (intraperitoneal injection of thioacetamide) group; the high‑, medium‑ and low‑dose MBG‑RCA therapeutic groups (15, 10 and 5 ml/kg MBG‑RCA, respectively); and the normal, blank, lactulose and acetic acid control groups, each of which received daily treatment administration. Oral MBG‑RCA effects were identified using behavioral monitoring observed by an infrared night vision supervisory control system, electroencephalograms, blood ammonia levels, intestinal ammonia levels, liver functionality and pathological observation. High‑ and medium‑dose oral administrations of MBG‑RCA significantly decreased the blood and intestinal ammonia levels (P<0.05), improved liver functionality and reduced the clinical manifestations of HE in rats. MBG‑RCA demonstrated high clearance of rat colonic ammonia while maintaining sufficient stability in the GI tract, indicating the potential for the development of new clinically relevant oral preparations for the prevention of HE. Additionally, such preparations are advantageous in that ammonia is eliminated without the production of potentially harmful metabolic byproducts. PMID:25591795

  19. The Influence of Finasteride on Mean and Relative Spectral Density of EEG Bands in Rat Model of Thioacetamide-Induced Hepatic Encephalopathy.

    PubMed

    Mladenović, D; Hrnčić, D; Rašić-Marković, A; Macut, Dj; Stanojlović, O

    2016-08-01

    Liver failure is associated with a neuropsychiatric syndrome, known as hepatic encephalopathy (HE). Finasteride, inhibitor of neurosteroid synthesis, may improve the course of HE. The aim of our study was to investigate the influence of finasteride on mean and relative power density of EEG bands, determined by spectral analysis, in rat model of thioacetamide-induced HE. Male Wistar rats were divided into groups: (1) control; (2) thioacetamide-treated group, TAA (900 mg/kg); (3) finasteride-treated group, FIN (150 mg/kg); and (4) group treated with finasteride (150 mg/kg) and thioacetamide (900 mg/kg), FIN + TAA. Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered during 3 subsequent days, and in FIN + TAA group FIN was administered 2 h before every dose of TAA. EEG was recorded 22-24 h after treatment and analyzed by fast Fourier transformation. While TAA did not induce significant changes in the beta band, mean and relative power in this band were significantly higher in FIN + TAA versus control group (p < 0.01). TAA caused a significant decline in mean power in alpha, theta, and delta band, and in FIN + TAA group the mean power in these bands was significantly higher compared with control. While in TAA group relative power was significantly decreased in theta (p < 0.01) and increased in delta band (p < 0.01) versus control, the opposite changes were found in FIN + TAA group: an increase in theta (p < 0.01) and a decrease in delta relative power (p < 0.01). In this study, finasteride pretreatment caused EEG changes that correspond to mild TAA-induced HE. PMID:26951455

  20. Function of opioidergic and dopaminergic antagonists on both spatial and object novelty detection deficits induced in rodent model of hepatic encephalopathy.

    PubMed

    Nasehi, Mohammad; Mafi, Fatemeh; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-10-15

    Liver disease has been known for a long time to affect brain function. We now report the function of opioidergic and dopaminergic antagonists on both spatial and object novelty detection deficits induced by hepatic encephalopathy (HE) following bile duct ligation (BDL), a model of chronic liver disease. Assessment of spatial and object novelty detection memories was carried out in the non-associative task. It consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). Both spatial and object novelty detection memories were impaired by BDL after 4 weeks. In the BDL mice, pre-test intraperitoneal administration of naloxone (μ-opioidergic receptor antagonist) at dose of 0.9mg/kg restored while sulpiride (D2-like dopamine receptor antagonist) at dose of 40mg/kg potentiated object novelty detection memory deficit. However, SCH23390 (D1-like dopamine receptor antagonist) at dose of 0.04mg/kg or sulpiride (20mg/kg) restored spatial novelty detection memory deficit. Moreover, SCH23390 or sulpiride impaired while naloxone did not alter both memories in sham-operated mice. Furthermore, subthreshold dose co-administration of dopaminergic antagonists together or each one plus naloxone did not alter both memory impairments in BDL mice, while all of three co-administration groups impaired object novelty detection and co-administration of naloxone plus sulpiride impaired spatial detection memory in sham-operated mice. In conclusion, we suggest that opioidergic and dopaminergic systems through separate pathways may contribute in memory impairments induced by BDL in the non-associative task. PMID:27401106

  1. Management of Transjugular Intrahepatic Portosystemic Shunt (TIPS)-associated Refractory Hepatic Encephalopathy by Shunt Reduction Using the Parallel Technique: Outcomes of a Retrospective Case Series

    SciTech Connect

    Cookson, Daniel T. Zaman, Zubayr; Gordon-Smith, James; Ireland, Hamish M.; Hayes, Peter C.

    2011-02-15

    Purpose: To investigate the reproducibility and technical and clinical success of the parallel technique of transjugular intrahepatic portosystemic shunt (TIPS) reduction in the management of refractory hepatic encephalopathy (HE). Materials and Methods: A 10-mm-diameter self-expanding stent graft and a 5-6-mm-diameter balloon-expandable stent were placed in parallel inside the existing TIPS in 8 patients via a dual unilateral transjugular approach. Changes in portosystemic pressure gradient and HE grade were used as primary end points. Results: TIPS reduction was technically successful in all patients. Mean {+-} standard deviation portosystemic pressure gradient before and after shunt reduction was 4.9 {+-} 3.6 mmHg (range, 0-12 mmHg) and 10.5 {+-} 3.9 mmHg (range, 6-18 mmHg). Duration of follow-up was 137 {+-} 117.8 days (range, 18-326 days). Clinical improvement of HE occurred in 5 patients (62.5%) with resolution of HE in 4 patients (50%). Single episodes of recurrent gastrointestinal hemorrhage occurred in 3 patients (37.5%). These were self-limiting in 2 cases and successfully managed in 1 case by correction of coagulopathy and blood transfusion. Two of these patients (25%) died, one each of renal failure and hepatorenal failure. Conclusion: The parallel technique of TIPS reduction is reproducible and has a high technical success rate. A dual unilateral transjugular approach is advantageous when performing this procedure. The parallel technique allows repeat bidirectional TIPS adjustment and may be of significant clinical benefit in the management of refractory HE.

  2. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  3. KCNQ2 encephalopathy

    PubMed Central

    Millichap, John J.; Park, Kristen L.; Tsuchida, Tammy; Ben-Zeev, Bruria; Carmant, Lionel; Flamini, Robert; Joshi, Nishtha; Levisohn, Paul M.; Marsh, Eric; Nangia, Srishti; Narayanan, Vinodh; Ortiz-Gonzalez, Xilma R.; Patterson, Marc C.; Pearl, Phillip L.; Porter, Brenda; Ramsey, Keri; McGinnis, Emily L.; Taglialatela, Maurizio; Tracy, Molly; Tran, Baouyen; Venkatesan, Charu; Weckhuysen, Sarah

    2016-01-01

    Objective: To advance the understanding of KCNQ2 encephalopathy genotype–phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. Methods: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype–phenotype relationships in these and 70 previously described patients. Results: The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed. Conclusions: KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in “hot spots” known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions. Classification of evidence: This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy. PMID:27602407

  4. Pulmonary and hepatic granulomatous disorders due to the inhalation of cement and mica dusts.

    PubMed Central

    Cortex Pimentel, J; Peixoto Menezes, A

    1978-01-01

    Hepatic and pulmonary granulomas were recognised in two workers exposed respectively to Portland cement and to muscovite dusts. The pulmonary lesions in the patient exposed to cement consisted of histiocytic granulomas and irregular fibrohyaline scars, and in the patient exposed to mica of a diffuse thickening of all interalveolar septa due to new formation of reticulin and collagen fibres and proliferation of fibroblasts and histiocytes. In the liver the following pathological findings were observed: focal or diffuse swelling of sinusoidal lining cells, sarcoid-type granulomas, and, in the case of mica exposure, perisinusoidal and portal tract fibrosis. Abundant inclusions of the inhaled material were identified within the pulmonary and hepatic lesions by histochemical and x-ray diffraction techniques. Images PMID:663882

  5. Hashimoto's encephalopathy.

    PubMed

    Schiess, Nicoline; Pardo, Carlos A

    2008-10-01

    Hashimoto's encephalopathy (HE) is a controversial neurological disorder that comprises a heterogenous group of neurological symptoms that manifest in patients with high titers of antithyroid antibodies. Clinical manifestations of HE may include encephalopathic features such as seizures, behavioral and psychiatric manifestations, movement disorders, and coma. Although it has been linked to cases of Hashimoto's thyroiditis or thyroid dysfunction, the most common immunological feature of HE is the presence of high titers of antithyroglobulin or anti-TPO (antimicrosomal) antibodies. At present, it is unclear whether antithyroid antibodies represent an immune epiphenomenon in a subset of patients with encephalopathic processes or they are really associated with pathogenic mechanisms of the disorder. The significance of classifying encephalopathies under the term HE will be determined in the future once the relevance of the role of antithyroid antibodies is demonstrated or dismissed by more detailed experimental and immunopathological studies. The responsiveness of HE to steroids or other therapies such as plasmapheresis supports the hypothesis that this is a disorder that involves immune pathogenic mechanisms. Further controlled studies of the use of steroids, plasmapheresis, or immunosuppressant medications are needed in the future to prove the concept of the pathogenic role of antithyroid antibodies in HE. PMID:18990131

  6. Affinities and densities of high-affinity (/sup 3/H)muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

    SciTech Connect

    Butterworth, R.F.; Lavoie, J.; Giguere, J.F.; Pomier-Layrargues, G.

    1988-09-01

    The integrity of GABA-A receptors and of central benzodiazepine receptors was evaluated in membrane preparations from prefrontal cortex and caudate nuclei obtained at autopsy from nine cirrhotic patients who died in hepatic coma and an equal number of age-matched control subjects. Histopathological studies revealed Alzheimer Type II astrocytosis in all cases in the cirrhotic group; controls were free from neurological, psychiatric or hepatic diseases. Binding to GABA-A receptors was studied using (/sup 3/H)muscimol as radioligand. The integrity of central benzodiazepine receptors was evaluated using (/sup 3/H)flunitrazepam and (/sup 3/H)Ro15-1788. Data from saturation binding assays was analyzed by Scatchard plot. No modifications of either affinities (Kd) or densities (Bmax) of (/sup 3/H)muscimol of central benzodiazepine binding sites were observed. These findings do not support recent suggestions that alterations of either high-affinity GABA or benzodiazepine receptors play a significant role in the pathogenesis of hepatic encephalopathy.

  7. Retroperitoneal Biloma due to Spontaneous Perforation of the Left Hepatic Duct

    PubMed Central

    Ishii, Kenjiro; Matsuo, Kazuhiro; Seki, Hiroaki; Yasui, Nobutaka; Sakata, Michio; Shimada, Akihiko; Matsumoto, Hidetoshi

    2016-01-01

    Patient: Male, 82 Final Diagnosis: Retroperitoneal biloma due to spontaneous perforation of the left hepatic duct Symptoms: Abdominal pain • high fever Medication: — Clinical Procedure: Emergent operation Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: Spontaneous perforation of the bile duct in adults is very rare, particularly in cases accompanied by retroperitoneal biloma. We report a patient with retroperitoneal biloma due to a spontaneous perforation of the left hepatic duct. Case Report: An 82-year-old man was admitted to our institution with abdominal pain and a high fever. He had tenderness at the epi-mesogastrium. Computed tomography showed several stones in the gall bladder and common bile duct (CBD) and a few ascites. A substantial amount of fluid had collected from the dorsal stratum of the duodenum and pancreas head to the right paracolic gutter and anterior side of the right iliopsoas. Laboratory examination revealed a high inflammation score. He underwent emergent laparotomy. Biliary fluid was revealed after the mobilization of the pancreas head, duodenum, and right side of the colon. Bile duct perforation was suspected. Therefore, we exfoliated the dorsal side of the CBD to the cranial side, and intraoperative cholangiography was performed. However, the perforation site could not be detected. Cholecystectomy and choledocholithotomy were performed. A retrograde transhepatic biliary drainage tube was inserted, and primary closure of the CBD incision site was achieved. Postoperative cholangiography revealed leakage from the left hepatic duct near the caudate branch. Conclusions: There are a few reports of spontaneous bile duct perforation cases in the literature, particularly on infants or children with congenital anomalies, but it is rare in adults. It usually causes bile peritonitis, although bile duct perforation should be considered in the differential diagnosis of spontaneous retroperitoneal fluid collection in

  8. Autoimmune encephalopathies

    PubMed Central

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

    Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID:25315420

  9. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  10. Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B

    PubMed Central

    Lee, Yoon-Suk; Kim, Byung-Kook; Lee, Ho-Jae

    2016-01-01

    In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID:27247753