Role of anthraquinones in Cassia occidentalis induced hepato-myo-encephalopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: The different plant parts of Cassia occidentalis Linn, (CO) such as root, leaves, seeds and pods have traditionally been used in multifarious medicines for the treatment of dysentery, diarrhea, constipation, fever, eczema, cancer and venereal diseases. MATERIALS AND METHODS: A systematic search of literature has been done in books and scientific databases like Science Direct, Pubmed, Google Scholar and Scopus etc. These sources were used to compile, analyze and review the information regarding the phytochemistry, toxicology and mechanism of toxicity of CO. The various references on this subject are cited in our review ranging from 1956 to 2019. RESULTS: Unintentional exposure of CO causes serious pathological condition in children, known as hepato-myo-encephalopathy (HME). The toxicity after CO consumption is associated with the presence of anthraquinones (AQs), a class of secondary plant metabolites. These AQs at high concentrations are known to cause detrimental effects on essential vital organs such as liver, kidney, spleen, brain, muscle and reproductive organs. The animal studies in rodent models as well as clinical investigations have clearly revealed that CO toxicity is associated with enhanced hepatotoxicity serum markers (ALT, AST, and LDH) and presence of necrotic lesions in liver. Furthermore, CO also causes vacuolization in muscle tissue and increases the level of CPK which is a prominent muscle damage marker. Apart from these target organs, CO consumption also causes neuronal damage via disturbing the levels of different proteins such as (GFAP and b-tubulin III). The mechanistic studies show that AQs present in CO have the potential to disturb the cellular homeostasis via binding to DNA, increasing the production ROS and showing inhibitory effects on essential enzymes etc. Therefore, AQs have been observed to be the primary culprit agents contributing to the toxicity of CO in children and animals. CONCLUSION: Despite its therapeutic potential, CO consumption can be detrimental if consumed in high amounts. A thorough analysis of literature reveals that AQs are the primary factors contributing to toxicity of CO seeds. Exposure to CO seeds causes HME, which is a serious life threatening condition for the malnourished children from lower strata. Multiple mechanisms are involved in the CO induced HME in patients. Lack of appropriate diagnostic measures and a poor understanding of the CO toxicity mechanism in humans and animals complicate the clinical management of CO poisoning subjects. Therefore, development of point of care diagnostic kits shall help in early diagnosis & suitable management of CO poisoning.

Babao Dan improves neurocognitive function by inhibiting inflammation in clinical minimal hepatic encephalopathy.

BACKGROUND AND PURPOSE: Inflammation has been considered a precipitating event that contributes to neurocognitive dysfunction in minimal hepatic encephalopathy (MHE). Inhibition TLR-4 related inflammation can effectively improve neurocognitive dysfunction of MHE. Our previous study showed that Babao Dan (BBD) effectively inhibited inflammation and ameliorated neurocognitive function in rats with acute hepatic encephalopathy (HE) and chronic HE. The mechanism may lie in the regulation of TLR4 signaling pathway. Therefore, this study aimed to evaluate the role of BBD in the treatment of MHE patients with cirrhosis and to elucidate the underlying mechanism by which BBD regulated TLR4 pathway to alleviate inflammation. METHODS: A randomized controlled trial (n = 62) was conducted to evaluate the clinical efficacy between BBD plus lactulose (n = 31) and lactulose alone (n = 31) in MHE patients by testing neurocognitive function (NCT-A and DST), blood ammonia, liver function (ALT, AST and TBIL) and blood inflammation (IL-1ß, IL-6 and TNF-α). Afterward, we detected NO, inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and the phosphorylation of P65, JNK, ERK as well as P38 in LPS-activated rat primary bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs), and mouse primary BMDMs/PMs/microglia/astrocytes, to investigate the underlying mechanism of BBD inhibiting inflammation through TLR4 pathway. Also, the survival rate of mice, liver function (ALT, AST), blood inflammation (IL-1ß, IL-6 and TNF-α), inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and histopathological changes in the liver, brain and lung were measured to assess the anti-inflammatory effect of BBD on neurocognitive function in endotoxin shock/endotoxemia mice. RESULTS: BBD combined with lactulose significantly ameliorated neurocognitive function by decreasing NCT-A (p＜0.001) and increasing DST (p＜0.001); inhibited systemic inflammation by decreasing IL-1ß (p＜0.001), IL-6(p＜0.001) and TNF-α (p＜0.001); reduced ammonia level (p = 0.005), and improved liver function by decreasing ALT(p = 0.043), AST(p = 0.003) and TBIL (p = 0.026) in MHE patients. Furthermore, BBD inhibited gene and protein expression of IL-1ß, IL-6 and TNF-α as well as NO in rat primary BMDMs/PMs, and mouse primary BMDMs/PMs/microglia/astrocytes in a dose-dependent manner. BBD inhibited the activation of mouse primary BMDMs/PMs/microglia/astrocytes by regulating TLR4 pathway involving the phosphorylation of P65, JNK, ERK and P38. Also, BBD reduced the mortality of mice with endotoxin shock/endotoxemia; serum levels of ALT, AST, IL-1ß, IL-6 and TNF-α; gene expression of IL-1ß, IL-6 and TNF-α in the liver, brain and lung, and tissue damage in the liver and lung. CONCLUSION: Our study provided for the first time clinical and experimental evidence supporting the use of BBD in MHE, and revealed that BBD could play a crucial role in targeting and regulating TLR4 inflammatory pathway to improve neurocognitive function in MHE patients.

Role of zinc supplementation in the management of chronic liver diseases: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Zinc deficiency has been associated with poor prognosis in chronic liver disease. This systematic review and meta-analysis aimed to evaluate the role of zinc supplementation in the management of chronic liver diseases. MATERIALS AND METHODS: We searched MEDLINE, LILACS, EMBASE, and Cochrane CENTRAL databases from inception to August 2018. We included randomized controlled trials evaluating adult patients with chronic liver disease of any etiology receiving zinc supplementation. Studies with other designs or evaluating chronic conditions other than liver disease were excluded. Two reviewers independently screened and extracted data from eligible studies. Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized studies. RESULTS: Of 1315 studies screened, 13 were included. Six assessed chronic hepatitis C treatment, with a relative risk of 0.83 indicating no protective effect of zinc supplementation on the improvement of sustained virological response. Three evaluated response to hepatic encephalopathy treatment, with a relative risk of 0.66 indicating a favorable effect of zinc supplementation on clinical improvement of this condition. Of four studies evaluating the management of cirrhosis, two analyzed the effect of zinc supplementation on serum albumin levels, with no statistical difference between zinc and placebo groups. CONCLUSIONS: Clinical trials assessing zinc supplementation in liver diseases do not show benefits in terms of clinical improvement or disease halting. There are possible benefits of zinc supplementation on hepatic encephalopathy, however, this is based on limited evidence. This research question is still open for evaluation in larger, well-designed, clinical trials.

Hepatic Encephalopathy and Nutrition Influences: A Narrative Review.

Hepatic encephalopathy (HE) is a potentially reversible neurocognitive condition seen in patients with advanced liver disease. The overt form of HE has been reported in up to 45% of patients with cirrhosis. This debilitating condition is associated with increased morbidity and mortality and imposes a significant burden on the caregivers and healthcare system. After providing an overview of HE epidemiology and pathophysiology, this review focuses on the interaction of HE and frailty, nutrition requirements and recommendations in cirrhotic patients with HE, and current dietary and pharmacologic options for HE treatment.

Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology.

Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.

Which of the branched-chain amino acids increases cerebral blood flow in hepatic encephalopathy? A double-blind randomized trial.

Branched-chain amino acids increase the brain perfusion of patients with hepatic encephalopathy (HE), but the amino acid and the mechanisms involved are still unknown. This study compared brain perfusion and clinical improvement during leucine or isoleucine supplementation. After randomization, 27 subjects with cirrhosis and HE received leucine or isoleucine supplements for one year. Brain single Photon Emission Computed Tomography (SPECT) and dynamic brain scintigraphy (DBS) were performed pretreatment and at 1, 8 and 12 months of supplementation. Brain perfusion was increased only in the isoleucine group at 8 months of treatment by both SPECT and DBS (p < 0.001 and p = 0.05, respectively) and by SPECT at the 12th month (p < 0.05). This was associated with hepatic encephalopathy improvement at 8 and 12 months (p = 0.008 and 0.004, respectively), which was not observed in the leucine group (p = 0.313 and 0.055, respectively). Isoleucine supplementation achieved a better impact on brain perfusion restoration in HE.

Multi-Sensory Integration Impairment in Patients with Minimal Hepatic Encephalopathy.

Paper-and-pencil-based psychometric tests are the gold standard for diagnosis of cognitive dysfunction in liver disease. However, they take time, can be affected by demographic factors, and lack ecological validity. This study explored multi-sensory integration ability to discriminate cognitive dysfunction in cirrhosis. Thirty-two healthy controls and 30 cirrhotic patients were recruited. The sensory integration test presents stimuli from two different modalities (e.g., image/sound) with a short time lag, and subjects judge which stimuli appeared first. Repetitive tests reveal the sensory integration capability. Performance in the sensory integration test, psychometric tests, and functional near-infrared spectroscopy for patients was compared to controls. Sensory integration capability, the perceptual threshold to discriminate the time gap between an image and sound stimulus, was significantly impaired in cirrhotic patients with minimal hepatic encephalopathy (MHE) compared to controls (p < 0.01) and non-MHE patients (p < 0.01). Sensory integration test showed good correlation with psychometric tests (NCT-A, r = 0.383, p = 0.002; NCT-B, r = 0.450, p < 0.01; DST-F, r = -0.322, p = 0.011; DST- B, r = -0.384, p = 0.002; ACPT, r = -0.467, p < 0.01). Psychometric tests were dependent on age and education level, while the sensory integration test was not affected. The sensory integration test, where a cut-off value for the perceptual threshold was 133.3ms, recognized MHE patients at 90% sensitivity and 86.5% specificity.

Oral administration of trace element magnesium significantly improving the cognition and locomotion in hepatic encephalopathy rats.

The therapeutic effects of iron, zinc and magnesium trace elements, as well as rifaximin were investigated and compared in HE rats. In this study, HE rats were treated with either ferrous sulfate (HE-Fe, 30 mg/kg/day), zinc sulfate (HE-Zn, 30 mg/kg/day), magnesium sulfate (HE-Mg, 50 mg/kg/day) or rifaximin (HE-Rf, 50 mg/kg/day), which was mixed with water and administered orally for 61 days. The Morris water maze (MWM) and open-field tests were used to evaluate cognitive and locomotor function. The blood ammonia levels before and after administration of the glutamine challenge test, manganese concentration and glutamine synthetase (GS) activity were measured. Significantly longer MWM escape latencies, less locomotor activity, higher blood ammonia levels, higher brain manganese concentrations and higher GS activity were observed in HE rats. However, HE-Mg and HE-Rf rats had significantly shorter MWM escape latencies, increased locomotor activity, lower blood ammonia, lower brain manganese concentrations and lower GS activity. Partial improvements were observed in HE-Fe and HE-Zn rats. The results indicated that oral administration of magnesium can significantly improve the cognitive and locomotor functions in HE rats by reducing the brain manganese concentration and regulating GS activity.

Do branched chain amino acids improve hepatic encephalopathy in cirrhosis? / ¿Aceleran los aminoácidos de cadena ramificada la recuperación de la encefalopatía hepática en pacientes con cirrosis?

There is controversy about the effectiveness of branched chain amino acids for treatment of hepatic encephalopathy. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 32 randomized controlled trials, of which 30 address the question of this article. We extracted results, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded branched chain amino acids might improve hepatic encephalopathy, but they probably lead to little or no effect on mortality.

Low-light-level therapy as a treatment for minimal hepatic encephalopathy: behavioural and brain assessment.

Minimal hepatic encephalopathy (MHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments involved in MHE. We studied one of its precipitating factors, portal hypertension. The purpose was to evaluate an enhancement in neuronal metabolism through low-light-level therapy (LLLT) and whether this therapy has effects on behavioural task acquisition. Rats were trained to perform a stimulus-response task using the Morris water maze. Three groups of animals were used: a SHAM (sham-operated) group (n = 7), a portal hypertension (PH) group (n = 7) and a PH + LLLT group (n = 7). The triple portal vein ligation method was used to create an animal model of the early developmental phase of HE, and then the animals were exposed to 670 + 10 nm LED light at a dose of 9 J/cm2 once a day for 7 days. The metabolic activity of the brains was studied with cytochrome c oxidase histochemistry. There were differences in behavioural performance, with an improvement in the PH + LLLT group. Energetic brain metabolism revealed significant differences between the groups in all the brain structures analysed, except the anterodorsal thalamus. At the same time, in different brain networks, the PH group showed a more complicated relationship among the structures, while the SHAM and PH + LLLT groups had similar patterns. In this study, we provide the first preliminary insights into the validity of LLLT as a possible intervention to improve memory under minimal hepatic encephalopathy conditions.

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

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.

Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis.

Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study.

Ingestão proteica na encefalopatia hepática: panorama atual / Protein intake in hepatic encephalopathy: current concepts

Hepatic encephalopathy is a severe complication of cirrhosis and comprises a complexand multifactorial pathophysiology. However, ammonia exchange between different tissues still deserves attention in relation to neurological alterations. Hepatic encephalopathy treatment remains focused on the trigger factor correction and the ammonia formation. Therefore, it was believed that high-proteic diets could lead to hepatic encephalopathy through the accumulation of nitrogen compounds in the gastrointestinal tract, which could increase production and absorption of ammonia.Currently, it is known that proteic restriction is harmful to cirrhotic patients, but it isstill utilized. Malnutrition is highly prevalent among cirrhotic individuals with hepatic encephalopathy, thus indicating a nutritional risk which is clearly related to higher mortality rates. Furthermore, there is an increase in the protein needs of these patients and also a relationship between the loss of lean mass and hyperammonaemia. For these and other factors herein discussed, today's global guidelines recommend the ingestion of higher protein levels for patients with hepatic encephalopathy

A encefalopatia hepática é uma complicação grave da cirrose e envolve uma fisiopatologia complexa e multifatorial. Entretanto, a influência da amônia nos diferentes tecidos ainda merece atenção no que se refere às manifestações neuropatológicas. O tratamento da encefalopatia hepática permanece focado na correção do distúrbio desencadeante e na diminuição da formação da amônia a partir do cólon. Por conta disso, acreditava-se que dietas ricas em proteínas poderiam desencadear a encefalopatia hepática por meio do aporte de nitrogênio no trato gastrointestinal, podendo aumentar a produção e a absorção da amônia. Atualmente, sabe-se que a restrição proteica é prejudicial para portadores de cirrose, embora ainda utilizada. A desnutrição é prevalente entre indivíduos cirróticos com encefalopatia hepática, indicando um estado nutricional de risco que está nitidamente relacionado às maiores taxas de mortalidade. Além disso, há um aumento nas necessidades proteicas desses pacientes e uma relação entre a perda de massa magra e a hiperamoniemia. Com base em tais fatores, os guidelines atuais mundiais recomendam dieta hiperproteica para pacientes com encefalopatia hepática.

Hepatic encephalopathy: cause and possible management with botanicals.

Hepatic encephalopathy is a brain functional disorder, characterized by neuropsychiatric abnormalities with liver failure. High blood ammonia, causing glutamate neurotoxicity is the basic cause, finally leading to low-grade cerebral edema. Its manifestation is more likely in patients of sepsis, oxidative stress, generalized inflammation, gut mal-functioning, amoebiaesis, viral hepatitis, nervous imbalance, etc. Thus, the therapeutic goals primarily include the maintenance of proper blood supply and prevention of hypoxic condition in liver, along with management of factors responsible for high blood ammonia, oxidative stress, inflammation, and high GI- serotonin. The drugs in clinical practice include lactulose, sodium benzoate, flumazenil and rifaximin, supplementation of zinc, branched chain amino acids (BCAA), l-ornithine-l aspartate, antioxidants and iNOS inhibitors. However, herbal formulations would be of great importance as it shows multi-targeted action because it possesses a natural cocktail of secondary metabolites. It can collectively act as an antioxidant, anti-inflammatory, prebiotic, hepatoprotective and neuron-protective agents. We have briefly outlined some of these plants and also recent patents useful in the management of hepatic encephalopathy.

Elevated intracranial dopamine impairs the glutamate­nitric oxide­cyclic guanosine monophosphate pathway in cortical astrocytes in rats with minimal hepatic encephalopathy.

In a previous study by our group memory impairment in rats with minimal hepatic encephalopathy (MHE) was associated with the inhibition of the glutamate­nitric oxide­cyclic guanosine monophosphate (Glu­NO­cGMP) pathway due to elevated dopamine (DA). However, the effects of DA on the Glu­NO­cGMP 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 high­dose DA (3 mg/kg)­treated rats were increased, the co­localization of N­methyl­d­aspartate 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 high­dose DA­treated rats (P<0.01). Furthermore, NMDA­induced augmentation of the expression of NMDAR1, CaM, nNOS, sGC and cGMP localized in PCAs was decreased in MHE and DA­treated rats, as compared with the controls. Chronic exposure of cultured cerebral cortex PCAs to DA treatment induced a dose­dependent 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 NMDA­induced 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 Glu­NO­cGMP pathway localized in PCAs contributes to memory impairment in rats with MHE.

Disrupted thalamic resting-state functional connectivity in patients with minimal hepatic encephalopathy.

BACKGROUND AND PURPOSE: Little is known about the role of thalamus in the pathophysiology of minimal hepatic encephalopathy (MHE). The purpose of this study was to investigate whether the thalamic functional connectivity was disrupted in cirrhotic patients with MHE by using resting-state functional magnetic resonance imaging (rs-fMRI). MATERIALS AND METHODS: Twenty seven MHE patients and twenty seven age- and gender- matched healthy controls participated in the rs-fMRI scans. The functional connectivity of 11 thalamic nuclei were characterized by using a standard seed-based whole-brain correlation method and compared between MHE patients and healthy controls. Pearson correlation analysis was performed between the thalamic functional connectivity and venous blood ammonia levels/neuropsychological tests scores of patients. RESULTS: The ventral anterior nucleus (VAN) and the ventral posterior medial nucleus (VPMN) in each side of thalamus showed abnormal functional connectivities in MHE. Compared with healthy controls, MHE patients demonstrated significant decreased functional connectivity between the right/left VAN and the bilateral putamen/pallidum, inferior frontal gyri, insula, supplementary motor area, right middle frontal gyrus, medial frontal gyrus. In addition, MHE patients showed significantly decreased functional connectivity with the right/left VPMN in the bilateral middle temporal gyri (MTG), temporal lobe, and right superior temporal gyrus. The venous blood ammonia levels of MHE patients negatively correlated with the functional connectivity between the VAN and the insula. Number connecting test scores showed negative correlation with the functional connectivity between the VAN and the insula, and between the VPMN and the MTG. CONCLUSION: MHE patients had disrupted thalamic functional connectivity, which mainly located in the bilateral ventral anterior nuclei and ventral posterior medial nuclei. The decreased connectivity between thalamus and many cortices, and basal ganglia indicated reduced integrity of thalamic RSN in MHE.

Hepatic encephalopathy.

Hepatic encephalopathy is a serious and potentially fatal complication of both acute and chronic liver disease, arising as a result of hepatocellular failure, cirrhosis and/or portal-systemic shunting (Ferenci et al, 2002). It reflects a broad spectrum of neuropsychiatric abnormalities, encompassing a range of defects in psychomotor, locomotive, cognitive, emotional and behavioural functions (Prakash and Mullen, 2010). Hepatic encephalopathy is either overt or minimal. While overt hepatic encephalopathy can be diagnosed using bedside clinical tests, minimal hepatic encephalopathy is clinically invisible and requires psychometric testing to diagnose. The rising prevalence of end-stage viral hepatitis-related liver disease, coupled with the growing problem of alcoholic and non-alcoholic fatty liver disease, has significantly increased the burden of disease from cirrhosis (Mooney et al, 2007; Fleming et al, 2008), so recognition and appropriate management of the manifestations of decompensating cirrhosis (including hepatic encephalopathy) is essential. Hepatic encephalopathy has a substantial societal burden because of its impact on survival, quality of life and daily functioning, including an impaired ability to drive, leaving patients especially vulnerable to road traffic accidents (Ferenci et al, 2002; Prakash and Mullen, 2010).

Lowered frequency and impaired modulation of gamma band oscillations in a bimodal attention task are associated with reduced critical flicker frequency.

Visual attention is associated with occipital gamma band activity. While gamma band power can be modulated by attention, the frequency of gamma band activity is known to decrease with age. The present study tested the hypothesis that reduced visual attention is associated with a change in induced gamma band activity. To this end, 26 patients with liver cirrhosis and 8 healthy controls were tested. A subset of patients showed symptoms of hepatic encephalopathy (HE), a frequent neuropsychiatric complication in liver disease, which comprises a gradual increase of cognitive dysfunction including attention deficits. All participants completed a behavioral task requiring shifts of attention between simultaneously presented visual and auditory stimuli. Brain activity was recorded using magnetoencephalography (MEG). The individual critical flicker frequency (CFF) was assessed as it is known to reliably reflect the severity of HE. Results showed correlations of behavioral data and HE severity, as indexed by CFF. Individual visual gamma band peak frequencies correlated positively with the CFF (r=0.41). Only participants with normal, but not with pathological CFF values showed a modulation of gamma band power with attention. The present results suggest that CFF and attentional performance are related. Moreover, a tight relation between the CFF and occipital gamma band activity both in frequency and power is shown. Thus, the present study provides evidence that a reduced CFF in HE, a disease associated with attention deficits, is closely linked to a slowing of gamma band activity and impaired modulation of gamma band power in a bimodal attention task.

Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review.

Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful.

Nutritional support in the treatment of chronic hepatic encephalopathy.

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.