Pathophysiology of hepatic encephalopathy.

Changes in various neurotransmitter systems, in blood brain barrier integrity and/or function, and in brain energy metabolism, may precipitate HE. Although a "specific cause" of HE (i.e. the presence of a well-defined toxin) has not been identified so far, the common denominator of all these changes is the presence of liver failure. The various hypotheses of the pathogenesis of HE are not mutually exclusive, but have to be integrated into the clinical syndrome of liver failure. It is conceivable that "specific causes" of HE do not exist at all. Brain function may be affected to a certain degree by the various consequences of liver failure (such as the accumulation of neuroactive compounds and of neurotoxins, changes in the metabolism of amino acids, decreased availability of energy fuels and circulatory changes), finally precipitating the syndrome of HE.     

Refractory hepatic encephalopathy in a patient with hypothyroidism: Another element in ammonia metabolism

Hepatic encephalopathy(HE) remains a diagnosis of exclusion due to the lack of specific signs and symptoms. Refractory HE is an uncommon but serious condition that requires the search of hidden precipitating events(i.e.,portosystemic shunt) and alternative diagnosis. Hypothyroidism shares clinical manifestations with HE and is usually considered within the differential diagnosis of HE. Here,we describe a patient with refractory HE who presented a large portosystemic shunt and post-ablative hypothyroidism. Her cognitive impairment,hyperammonaemia,electroencephalograph alterations,impaired neuropsychological performance,and magnetic resonance imaging and spectroscopy disturbances were highly suggestive of HE,paralleled the course of hypothyroidism and normalized after thyroid hormone replacement. There was no need for intervention over the portosystemic shunt. The case findings support that hypothyroidism may precipitate HE in cirrhotic patients by inducing hyperammonaemia and/or enhancing ammonia brain toxicity. This case led us to consider hypothyroidism not only in the differential diagnosis but also as a precipitating factor of HE.     

Pathogenetic mechanisms of hepatic encephalopathy

Hepatic encephalopathy (HE) in liver cirrhosis is a clinical manifestation of a low-grade cerebral oedema, which is exacerbated in response to ammonia and other precipitating factors. This low-grade cerebral oedema is accompanied by an increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS), which trigger multiple protein and RNA modifications, thereby affecting brain function. The action of ammonia, inflammatory cytokines, benzodiazepines and hyponatraemia integrates at the level of astrocyte swelling and oxidative stress. This explains why heterogenous clinical conditions can precipitate HE episodes. Oxidised RNA species, which are formed in response to oxidative stress, also participate in local postsynaptic protein synthesis in neurons, which is required for memory formation. Although the functional consequences of RNA oxidation in this context remain to be established, these findings bear a potential biochemical explanation for the multiple alterations of neurotransmitter receptor systems and of synaptic plasticity. Such changes may in part also underlie the pathologically altered oscillatory networks in the brain of HE patients in vivo, as detected by magnetencephalography. These disturbances of oscillatory networks, which in part are triggered by hypothalamic structures, can explain the motor and cognitive deficits in patients with HE. Current therapeutic strategies aim at the elimination of precipitating factors. The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention.     

Management of Hepatic Encephalopathy Not Responsive to First-Line Treatments

Purpose of review

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that occurs in up to 30% of patients with cirrhosis. HE may be a consequence of pure liver failure, as in patients with fulminant hepatitis, or of the combination of liver failure and portal-systemic shunting, as in patients with liver cirrhosis. Episodes of HE are usually related to precipitating events, such as infections or gastrointestinal bleeding; a minority of cirrhotic patients experienced a chronic HE, refractory to standard medical treatment. The prevention of HE recurrence, after the first episode of HE, could be obtained by the administration of prophylactic therapy with lactulose, rifaximin or a combination of both.The aim of this review is to clarify some key points in the management of cirrhotic patients with HE, not responsive to first line treatment.

Recent findings

Recent studies investigated the role of fecal microbiota transplantation in the treatment of HE with promising results, but further investigations are needed.

Summary

In a cirrhotic patient with acute cognitive impairment, the correct diagnosis of HE, after excluding other causes of neurological diseases, is mandatory for the correct management of the precipitating factors and for the treatment. In patients not responsive to standard treatment, the probable precipitating factors have not been correctly identified, multiple precipitating events are coexisting or a new precipitating event is superimposed.In some patients with recurrent HE, characterized by persistent alterations in neurological symptoms, without specific precipitants events, the presence of spontaneous or iatrogenic shunts should be investigated.

     

Hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which can develop in the course of chronic and acute liver disease. It is characterized by cognitive and motoric deficits of varying severity. HE is functional in nature, potentially reversible and is thought to reflect the clinical manifestation of a low-grade cerebral edema, which exacerbates in response to ammonia and other precipitating factors, such as electrolyte disturbances, bleeding, infections, high protein diet, diuretics and sedatives. The action of these rather heterogeneous factors integrates at the level of oxidative/nitrosative stress and astrocyte swelling, which is associated with an oxidative/nitrosative stress response in the brain with consequences for signal transduction, neurotransmission, synaptic plasticity and oscillatory networks in the brain. Manifest HE is diagnosed on the basis of clinical symptoms according to the West Haven criteria, whereas diagnosis of minimal HE requires psychometric or neurophysiological testings. Here objective and reproducible measures to assess HE severity, such as critical flicker frequency or evoked potentials are superior to paper pencil tests. Identification and treatment of precipitating factors is the mainstay of HE therapy. Also intravenous ornithine aspartate, vegetable protein, oral branched chain amino acids, lactulose enemas and liver transplantation are considered to be effective. Whereas the efficacy of oral lactulose and non-resorbable antibiotics in the treatment of an acute HE attack is under debate, the beneficial effect of lactulose and rifaximin in the secondary HE prophylaxis has recently been established.     

Evidence-based approach to management of hepatic encephalopathy in adults

Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function and represents one of the many complications of portal hypertension and decompensated liver disease. Although ammonia is clearly implicated in the pathogenesis of HE, the pathogenesis of HE is multifactorial with numerous mechanisms that results in functional impairment of neuronal cells. The initial management of HE focuses on supportive care and stabilization which includes providing appropriate nutritional support. Thereafter, focus should be on identifying and treating the precipitating factors. There are many therapeutic agents available for the management of HE, most of which are directed towards lowering the gut nitrogen load and thus the serum ammonia level. This review aims to provide an update on the conventional and emerging treatment options for HE.     

Gut microbiota and hepatic encephalopathy

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.     

Hepatic encephalopathy: An approach to its multiple pathophysiological features

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 bypass,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 order to clarify,at least partially,controversial topics.     

Higher prevalence and severity of hepatic encephalopathy in patients with HCV cirrhosis and diabetes mellitus: is presence of autonomic neuropathy the missing part of the puzzle?

Hepatic encephalopathy (HE) is a complex and variable neuropsychiatric syndrome that is seen in patients with acute and chronic liver diseases. The presence or severity of HE does not always show a strong and consistent relationship with the severity of liver disease or portal hypertension suggesting that other predisposing or precipitating factors may be involved. In this issue of the journal, it has been suggested that DM may contribute to the presence and severity of HE independent of the severity of liver disease in patients with HCV cirrhosis. This editorial examines the limitations of the study and potential mechanisms that could explain the relationship between DM with HE including the role of autonomic neuropathy.     

Hepatic encephalopathy:Lessons from preclinical studies

Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.     

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

INTRODUCTION Hepatic encephalopathy Hepatic encephalopathy (HE) is a complex neuropsy- chiatric syndrome present in patients with chronic or acute liver disease. HE covers a wide range of neuropsychiatric disturbances ranging from minimal changes in perso…     

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy

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.     

Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise

Hyponatremia (Na⁺ <135 mmol/l) is the most common electrolyte disorder. Cirrhosis represents a rather frequent cause of hyponatremia mainly due to systemic and splanchnic vasodilation resulting in decreased effective arterial blood volume, which leads to excessive non-osmotic secretion of antidiuretic hormone. However, hyponatremia of multifactorial origin may be seen in patients with liver diseases. The review focuses on the factors and pathogenetic mechanisms of decreased sodium levels other than the hemodynamic compromise of cirrhosis in patients with liver diseases. The mechanisms and causal or contributing role of pseudohyponatremia, hyperglycemia, infections, drugs and toxins as well as of endocrine disorders, renal failure and cardiac disease in patients with liver disease are meticulously discussed. Hyponatremia of multifactorial origin is frequently observed in patients with liver diseases, and special efforts should be made to delineate the underlying causative and precipitating factors as well as the risk factors of the osmotic demyelination syndrome in order to properly manage this serious electrolyte disorder and avoid treatment pitfalls.     

Application of fecal microbial transplantation in hepatic encephalopathy after transjugular intrahepatic portosystemic shunt

Rationale:Transjugular intrahepatic portosystemic shunt (TIPS) is mainly used to treat acute and chronic esophageal, gastric, and intestinal variceal bleeding and refractory ascites caused by portal hypertension. The most common complication of TIPS is the development of hepatic encephalopathy (HE). Fecal microbiota transplantation (FMT) is an emerging method for treating diseases by altering the intestinal flora. We present 2 cases of FMT that ameliorated liver function and HE after TIPS.Patient concerns:In this report, 2 patients with liver cirrhosis secondary to hepatitis B had recurrent Grade 2-3 HE after TIPS.Diagnosis:Two patients were diagnosed as having HE.Interventions:The 2 patients separately received 3 times of FMT.Outcomes:The liver function of both patients improved, the clinical symptoms were relieved, and the number of HE attacks decreased significantly after FMT.Lessons:FMT may be another effective way to treat HE, and is worthy of further research.     

Implications of Manganese in Chronic Acquired Hepatocerebral Degeneration

Neurological symptoms can be one of the over-riding symptoms in patients with liver cirrhosis. Patients can present with subtle changes in mood or neurological function due to hepatic encephalopathy (HE), to more severe presentations including stupor and coma. While HE, in its severe form, can be clinically easy to diagnose, more subtle forms may be more difficult to recognize. Other neurological diseases may indeed be overlooked in the context of cirrhosis or confuse the physician regarding the diagnosis. Chronic acquired hepatocerebral degeneration (CAHD) is an uncommon problem occurring in patients with cirrhosis characterised by a Parkinsonian-like neurological presentation with damage to the brain secondary to manganese (Mn) deposition. Here we describe a case of a patient with a neurological presentation of liver disease with a review of the current CAHD literature. In conclusion, CAHD is a rare condition occurring in liver cirrhosis that should always be considered in patients with neurological manifestations of chronic liver disease.     

Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy

Benzodiazepines of natural origin (NBZDs) have been found in human blood and brains as well as in medicinal plants and foods. In plasma and brain tissue there are i.e. diazepam and nordiazepam equal to commercial drugs but there are also other benzodiazepine-like compounds termed “endozepines”, which act as agonists at the benzodiazepine receptors of central type (CBR). A synthetic pathway for the production of NBZDs has not yet been found, but it has been suggested that micro-organisms may synthesize molecules with benzodiazepine-like structures. Hence NBZDs could be of both endogenous and exogenous source and be considered as natural anxyolitic and sedative. Interestingly there are also natural compounds, such as the polypeptide Diazepam Binding Inhibitor (DBI) acting as an “inversive agonist” implicated in fair and panic disorders. It has been suggested that NBZDs may play a role in the pathogenesis of hepatic encephalopathy (HE). Multidirectional studies evaluated NBZDs levels (1) in the blood of normal subjects, of cirrhotic with or without HE and in commercial benzodiazepine consumers; (2) in the blood of cirrhotic treated or not with a non-absorbable antibiotic; (3) in several constituents of our diet. In conclusion, NBZDs increase sometime in cirrhotics with or without HE but they reach concentrations not higher than those found in commercial benzodiazepines consumers. Hence NBZDs must be considered as occasional precipitating factor of HE and benzodiazepine antagonists only symptomatic drugs. The finding that NBZDs may be in part synthesized by intestinal bacterial flora and in part constituent of our diet underlines the importance to feed cirrhotic patients with selected food.     

Hepatische Enzephalopathie

Hepatic encephalopathy (HE) is a neuropsychiatric disorder which can appear as a complication of acute or chronic liver disorders. Pathophysiologically the disorder is a clinical manifestation of a low-grade chronic cerebral edema, which leads to changes in astrocytic function with disturbances of glioneuronal communication. The findings point to a disturbance of cerebral oscillatory networks in HE that is triggered by possible neurotoxic- and hydration-sensitive, thalamic structures and results in an abnormally low-frequency and rigid thalamocortical and corticomuscular coupling. While the diagnosis of high-grade HE will be done exclusively by the clinical picture, psychometric and neurophysiological tests are necessary to diagnose the low-grade forms. Yet, the analysis of the critical flicker frequency (CFF) has been shown to be an easy and simple semi-quantitative test procedure for the quantification and follow-up of neuropsychiatric deficits in HE. The recognition and consequent treatment of the precipitating factors are the most important therapeutic measures. These are complemented by dietetic and pharmaceutical treatment..     

Hepatische Enzephalopathie

Background

Hepatic encephalopathy (HE) is a disorder of the central nervous system that may occur as a complication of acute or chronic liver disease and/or portosystemic collateral circulation, and covers a wide range of cognitive, mental and motor changes.It is diagnosed by the detection of a hepatic disorder in the absence of any other probable cause of encephalopathy.

Cause

HE is caused by a low-grade glial-edema with oxidativ-nitrosativ stress in the brain. The swelling of glial cells and oxidativ-nitrosativ stress are the final common pathway of the effect of differing HE precipitating factors.

Categorization

HE is divided into three main categories, the most common of which is HE occurring in the presence of cirrhosis. A continuous grading scheme should be preferred over categorical classification.

Diagnosis and treatment

Psychometric tests as well as the determination of the flicker frequency are established methods for the diagnosis of low-grade HE and are suitable for quantifying HE as a continuum and for evaluating its course. Here, lactulose has proven effective in the prevention of recurrent HE (secondary prevention). The administration of Rifaximin at a dose of 2 × 550 mg/d in combination with lactulose maintained remission of HE more effectively than administration of lactulose only and thereby reduced the risk of HE episodes and hospitalization. L-ornithine-L-aspartate is effective in the primary treatment of hyperammonemia-induced HE. For protein intolerant patients with chronic HE the application of L-ornithine L-aspartate or oral administration of branched-chain amino acids in combination with non-absorbable disaccharides is the treatment of choice.

     

Increased concentrations of histamine and its metabolite,tele-methylhistamine and down-regulation of histamine H3 receptor sites in autopsied brain tissue from cirrhotic patients who died in hepatic coma

BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of chronic liver disease. To determine whether changes in the central histaminergic system are a feature of human HE, we studied histamine, tele-methylhistamine, and presynaptic autoregulatory H(3) receptors in cerebral cortex and caudate-putamen obtained at autopsy from six cirrhotic patients and six appropriately matched controls. METHODS: Histamine was assayed by HPLC; tele-methylhistamine by GC-MS. H(3) receptors were studied by in vitro receptor binding using [3H]R-alpha-methylhistamine as ligand. RESULTS: In HE patients, there was a significant fourfold increase of histamine in caudate-putamen and a significant increase in all cortical regions studied. tele-Methyhistamine was also increased and the densities of histamine H(3) receptor sites were significantly decreased in patient material. CONCLUSIONS: These findings are consistent with activation of the histaminergic system in HE. Given that histamine participates in the regulation of arousal and circadian rhythmicity, they indicate that induction of central histamine mechanisms may contribute to the development of neuropsychiatric symptoms, such as sleep disturbances and altered circadian rhythms in chronic HE and suggest that pharmacological manipulation of the histaminergic system could be beneficial in the treatment of HE in chronic liver failure.     

非酒精性脂肪性肝病大鼠系统免疫及肠道免疫的变化

目的 观察在肥胖导致的非酒精性脂肪性肝病的进展过程中系统免疫及肠道免疫屏障的变化.方法 90只雄性SD大鼠均分为3组,即为正常饮食组、高糖饮食组、高脂饮食组,建立非酒精性脂肪性肝病大鼠模型,并于4、8、12周各组分别处死10只.肝脏HE染色观察肝脏脂肪变程度.鲎试验终点显色法检测门静脉血中内毒素水平.流式细胞术检测外周血单个核细胞及小肠集合淋巴结(PP结)中淋巴细胞CD4-CD8比值.结果 高糖饮食组在所有时间点内毒素水平均无显著升高,与正常饮食组差异均无统计学意义(P值均＞0.05).而高脂饮食组在8周时内毒素水平显著上升,与正常饮食组差异有统计学意义(P＜0.05).高糖饮食组与高脂饮食组在4周时外周血单个核细胞CD4/CD8显著高于正常饮食组(P值均＜0.05),至8周、12周时均显著低于正常饮食组(P值均＜0.05).PP结中CD4/CD8,高糖饮食组与高脂饮食组4、8周与外周血单个核细胞CD4/CD8变化趋势一致,12周时CD4/CD8与正常饮食组差异无统计学意义(P值均＞0.05).结论 肥胖可以抑制系统免疫及肠道免疫,肝脏可能参与调节肠道免疫.

Abstract：

Objective To study the changes of system immune and intestinal immune in the progression of non-alcoholic fatty liver disease due to obesity. Methods Ninty male SD rats were divided into control, high-sucrose and high-fat diet groups. Non-alcoholic fatty liver disease models were established by feeding with high-sucrose diet or high-fat diet and were killed at the 4th,8th and 12th weeks with 10 each for each group. The extent of liver steatosis was observed with HE staining.Portal blood endotoxin level was assessed by limulus test. The percentage of CD4+ and CD8+ cells in peripheral blood mononuclear cells (PBMC) and lymphocytes in Peyer's patches (PP) were calculated by flowcytometry. Results In comparison with control group, the endotoxin level was not elevated from the 4th week to 12th week in high-sucrose diet group, (all P values＞0.05), but was increased in high-fat diet group at the 8th week (P＜0.05). CD4/CD8 ratio in PBMC was higher in high-sucrose and higt-fat diet groups than that in control group at the 4th week (P＜0. 05) ,but was lower than that in control group at the 8th and 12th weeks (P＜0. 05). Whereas the variation of CD4/CD8 ratio in PP was consisted with that in PBMC between the high-sucrose and high-fat diet groups at the 4 th and 8 th weeks, but there was no difference when compared with control group at the 12 th week (P＞0.05).Conclusion Obesity can inhibit systematic immune and intestinal immune. The intestinal immune may be regulated by the liver.