Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

The development of overt hepatic encephalopathy (HE) in a patient with cirrhosis confers a damning prognosis with a 1-year mortality approaching 64%. This complex neuropsychiatric syndrome arises as a consequence of a dysfunctional gut–liver–brain axis. HE has been largely neglected over the past 30 years, with the reliance on therapies aimed at lowering ammonia production or increasing metabolism following the seminal observation that the hepatic urea cycle is the major mammalian ammonia detoxification pathway and is key in the pathogenesis of HE. The relationship with ammonia is more clear-cut in acute liver failure; but in cirrhosis, it has become apparent that inflammation is a key driver and that a disrupted microbiome resulting in gut dysbiosis, bacterial overgrowth and translocation, systemic endotoxemia and immune dysfunction may be more important drivers. Therefore, it is important to re-focus our efforts into developing therapies that modulate the disrupted microbiome or alleviating its downstream consequences.     

Hepatic encephalopathy: pathophysiology and advances in therapy.

Hepatic encephalopathy is a major neuropsychiatric complication of cirrhosis. Hepatic encephalopathy can occur in patients with fulminant liver disease without evidence of portosystemic shunting. The syndromes are distinct in acute liver failure and cirrhosis. The pathogenesis of hepatic encephalopathy probably is multifactorial, although the predominant causative agent appears to be ammonia. Prevention and treatment of hepatic encephalopathy in cirrhotic patients continues to rely on ammonia lowering strategies which include assessment of dietary protein intake and the use of lactulose, neomycin, sodium benzoate and L-ornithine-aspartate. This review provides recent information on the classification of hepatic encephalopathy, current theories for pathophysiological basis and evaluates the available therapies.     

Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis

Hepatic encephalopathy(HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liverbrain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis.Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.     

Recent insights into the pathogenesis of hepatic encephalopathy and treatments

Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric disorders related to liver failure. The development of HE can have a profound impact on mortality as well as quality of life for patients and carers. Ammonia is central in the disease process contributing to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure. Inflammation in the presence of ammonia coactively worsens HE. Inflammation can result from hyperammonemic responses, endotoxemia, innate immune dysfunction or concurrent infection. This review summarizes the current processes implicated in the pathogenesis of HE, as well as current and potential treatments. Treatments currently focus on reducing inflammation and/or blood ammonia levels and provide varying degrees of success. Optimization of current treatments and initial testing of novel therapies will provide the basis of improvement of care in the near future.     

Management of hepatic encephalopathy in patients with cirrhosis

The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.     

Helicobacter pylori infection in hepatic encephalopathy: Relationship to plasma endotoxins and blood ammonia

Background/Aim: Hepatic encephalopathy (HE) is frequently observed in patients with advanced liver disease and manifests a wide variety of neuropsychiatric signs and symptoms. Ammonia toxicity and bacterial endotoxins have been suggested as key determinants of HE onset whereas a role for Helicobacter pylori infection has not been established. We investigated the correlation between H. pylori infection and HE severity (evaluated through functional tests) in 60 outpatients with established liver cirrhosis and 20 non-cirrhotic controls. Methods: Fasting arterial blood ammonia, plasma endotoxins, and H. pylori infection status were investigated in all subjects. Results: H. pylori infection was documented in 35/60 (58%) patients and in 6/20 (30%) controls (P = 0.039). Significant differences were observed between patients with and withoutHE for age, presence of ascites, fasting arterial blood ammonia, plasma endotoxin, and H. pylori infection. Further, a significant increase in fasting arterial blood ammonia and plasma endotoxin was associated with H. pylori infection in cirrhotic patients. Last, medical treatment of H. pylori infection led to a significant decrease in HE severity and fasting arterial blood ammonia levels. Conclusion: In conclusion, we submit that H. pylori infection might, in fact, play a role in increasing the circulating levels of ammonia and endotoxins in cirrhotic patients, thus facilitating the onset of HE.     

肝性脑病发病机制的研究进展

肝性脑病(hepatic encephalopathy,HE)是肝功能严重障碍和/或门体分流术后患者发生的以代谢紊乱为基础,神经、精神症状为主要表现的综合征.其症状包括意识混乱、定向力障碍、协调能力降低,甚至昏迷.其发病机制被认为是高氨血症使脑星形胶质细胞内谷氨酰胺浓度升高、钙离子内流启动氧化应激、破坏线粒体功能,干扰能量代谢并诱发炎症反应,破坏血脑屏障使内皮细胞、脑星形胶质细胞对水通透性增加,引发脑水肿.炎症反应又反过来升高脑内氨浓度,增加其中枢神经系统毒性,而锰是参与上述过程的重要组成成分,故目前公认为高氨血症和炎症反应的协同作用导致星形胶质细胞肿胀,进而引起脑水肿导致HE.本文就HE发病机制的研究进展作一综述.     

Hepatic encephalopathy: Ever closer to its big bang

Hepatic encephalopathy(HE) is a neuropsychiatric disorder that commonly complicates the course of patients with liver disease. Despite the fact that the syndrome was probably first recognized hundreds of years ago, the exact pathogenesis still remains unclear. Minimal hepatic encephalopathy(MHE) is the earliest form of HE and is estimated to affect more that 75% of patients with liver cirrhosis. It is characterized by cognitive impairment predominantly attention, reactiveness and integrative function with very subtle clinical manifestations. The development of MHE is associated with worsen in driving skills, daily activities and the increase of overall mortality. Skeletal muscle has the ability to shift from ammonia producer to ammonia detoxifying organ. Due to its large size, becomes the main ammonia detoxifying organ in case of chronic liver failure and muscular glutaminesynthase becomes important due to the failing liver and brain metabolic activity. Gut is the major glutamine consumer and ammonia producer organ in the body. Hepatocellular dysfunction due to liver disease, results in an impaired clearance of ammonium and in its interorgan trafficking. Intestinal bacteria, can also represent an extra source of ammonia production and in cirrhosis, small intestinal bacterial overgrowth and symbiosis can be observed. In the study of HE, to get close to MHE is to get closer to its big bang; and from here, to travel less transited roads such as skeletal muscle and intestine, is to go even closer. The aim of this editorial is to expose this road for further and deeper work.     

Hepatic encephalopathy: from pathophysiology to treatment

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome due to hepatic dysfunction and porto-systemic shunting of the intestinal blood. Cirrhosis is the most frequent liver disease causing HE. On most occasions, HE appears due to a superimposed precipitating factor (gastrointestinal bleeding, infections, renal and electrolyte disturbances, etc.). Ammonia produced in colon by intestinal bacteria is the main toxic substance implicated in the pathogenesis of HE. Other mechanisms, such as changes in the GABA-benzodiazepine system, accumulation of manganese into the basal ganglia of the brain, changes in blood-brain barrier and neurotransmission disturbances are also present. Clinical manifestations of HE may vary widely, from minimal neurologic changes, only detected with specific tests, to deep coma. Treatment of HE should be directed to controlling the precipitating factors, as well as therapies aimed at correcting the above-mentioned pathophysiological changes, mainly reduction of blood ammonia levels. Artificial liver support systems may play a role in the future. Liver transplantation should be evaluated as a definitive therapy in all cases of HE.     

Immunogenetic Aspects of Primary Sclerosing Cholangitis: Implications for Therapeutic Strategies

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibro-obliterative inflammation of the intra- and extrahepatic bile ducts; in 70% of cases, it is associated with inflammatory bowel disease. The disease usually runs a progressive course, ultimately leading to biliary cirrhosis, hepatic failure, and sometimes cholangiocarcinoma, with a median survival of 12 yr after diagnosis. As yet, the etiology of primary sclerosing cholangitis remains unknown, although several recent studies have implicated immunogenetic factors as important pathogenic mechanisms.
Besides liver transplantation for patients with end-stage cirrhotic liver disease and endoscopic therapy for patients with dominant extrahepatic bile duct strictures, recent studies have also shown promising results of drug therapy with ursodeoxycholic acid in the treatment of PSC. The purpose of this article is to summarize our current knowledge of the immunogenetic factors in the pathogenesis of PSC and to present support for drug therapy with ursodeoxycbolic acid in the treatment of PSC. The genetic and immunological factors in the pathogenesis of PSC are outlined first, followed by a rationale of drug therapy with ursodeoxycholic acid in the treatment of PSC.     

Hepatic encephalopathy and Helicobacter pylori: a critical reappraisal

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, and plasma ammonia plays a pivotal role in its pathogenesis. Ammonia disposal in cirrhotics depend on intricately balanced enzyme and transport systems, involving liver, large and small bowel, muscle, and kidney. Recently, it has been suggested that Helicobacter pylori could contribute to hyperammonemia in cirrhotics, but conflicting data are available in the literature. This is a systematic review of experimental (animals and humans), epidemiological, case-control, and prospective studies, to evaluate the arguments in favor and against the role of H. pylori in HE pathogenesis. Although H. pylori produces ammonia in the stomach, several studies have shown that both basal ammonia levels and HE prevalence did not significantly differ between cirrhotics with and without infection. Moreover, some prospective studies have documented that both blood ammonia levels and mental status in HE cirrhotics are not significantly affected by H. pylori eradication. Even if a small sub-group of cirrhotics with both a high bacterial density and more severe hepatic impairment seems to benefit by bacterial eradication, data indicate that ammonia production in the stomach by H. pylori urease appears to be inadequate to clinically affect ammonia disposal in the majority of cirrhotic patients. Further studies are warranted in this field.     

Serotonin Brain Circuits with a Focus on Hepatic Encephalopathy

Despite enormous strides in our understanding of human disease, the precise mechanisms of hepatic encephalopathy (HE), a potential long-term complication of liver failure, are still unclear. Brain serotonin, a neurotransmitter with widespread distribution in the CNS, plays a role in the regulation of a wide range of physiological behaviors and functions. In addition, it has been implicated in the pathogenesis of several pathological processes, including HE. This work reviews the relationship between brain serotonergic dysfunction and hepatic encephalopathy in cirrhotic patients and experimental animals. The existing changes in the synthesis, metabolism, storage, and release of neuronal serotonin in HE point to a serotonergic synaptic deficit in this condition. Given the established role of the brain serotonergic system in the regulation of sleep, circadian rhythmicity, and locomotion, selective alterations of this system could be an important part of the neurophysiological background responsible for the behavioral changes in rats with portacaval anastomosis and may contribute to the pathogenesis of HE in cirrhotic patients. The findings that serotoninergic turnover is exquisitely and selectively sensitive to the degree of porto-systemic shunting and hyperammonemia suggest a role for serotonin in early neuropsychiatric symptoms of HE. Pharmacological manipulation of the brain serotonergic system may be beneficial in the prevention and treatment of HE in cirrhotic patients.     

Role of artificial liver support in hepatic encephalopathy

Hepatic encephalopathy (HE) refers to the reversible neuropsychiatric disorders observed in acute liver failure and as a complication of cirrhosis and/or portal hypertension. This review aims to describe the pathophysiology of HE, the rationale for the use of artificial liver support in the treatment of HE, the different concepts of artificial liver support and the results obtained. Ammonia has been considered central to its pathogenesis but recently an important role for its interaction with inflammatory responses and auto-regulation of cerebral hemodynamics has been suggested. Artificial liver support might be able to decrease ammonia and modulate inflammatory mediators and cerebral hemodynamics. Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient’s circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Clinical studies have shown that artificial liver support, especially albumin dialysis, is able to improve HE in acute and acute-on-chronic liver failure. Further studies are required to better understand the mechanism, however, artificial liver support can be added to the therapeutic bundle in treating HE.     

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

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.     

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

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.     

A systemic mechanism of increased transendothelial migration of leukocytes through the blood-brain barrier in hepatic encephalopathy

BackgroundHepatic encephalopathy (HE) is a frequent neurological complication of cirrhosis. Evidence suggests a synergic pathophysiological implication of hyperammonemia and systemic inflammation. In addition, the blood-brain barrier (BBB) permeability can be impaired in cirrhotic patients, notably in those displaying HE. We hypothesized that systemic inflammation could trigger leukocytes transendothelial migration (TEM) through the BBB in cirrhotic patients and especially those with HE.MethodsWe studied the effects of patients’ plasma on the TEM of the leukocyte U937 cell line in vitro, using a validated BBB model (hCMEC/D3 cell line). We compared TEM of U937 leukocytes across hCMEC/D3 monolayer incubated with the plasma of i) patients with cirrhosis without HE, ii) patients with cirrhosis and HE, iii) healthy controls.ResultsWe show that the plasma of cirrhotic patients with HE enhances TEM of U937 leukocytes across hCMEC/D3 BBB model. We found a correlation between U937 TEM on the one hand, the West-Haven score and ammonemia on the other one. A trend towards a correlation between U937 TEM and PS-100Beta in plasma, a marker of BBB solute's permeability increase, was also found.ConclusionThese findings suggest that circulating factors could increase leukocytes TEM in cirrhotic patients and contribute to the increased BBB permeability that has been described in cirrhotic patients with HE.     

Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) is a serious complication of liver failure. HE manifests as a series of neuropsychiatric and neuromuscular symptoms including personality changes, sleep abnormalities, asterixis and muscle rigidity progressing through stupor to coma. The pathophysiologic basis of HE remains unclear. There is general agreement that ammonia plays a key role. In recent years, it has been suggested that oxidative/nitrosative stress constitutes part of the pathophysiologic cascade in HE. Direct evidence for oxidative/nitrosative stress in the pathogenesis of HE has been demonstrated in experimental animal models of acute or chronic liver failure. However, evidence from studies in HE patients is limited. This review summarizes this evidence for a role of oxidative/nitrosative stress in relation to ammonia toxicity and to the pathogenesis of HE.     

Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study

Muscle depletion is frequently encountered in cirrhotic patients. As muscle may represents an alternative site of ammonia detoxification in liver diseases, our study was aimed at investigating whether a decrease in muscle mass or function may independently influence the prevalence of neurocognitive alterations in cirrhosis. Three-hundred consecutive hospitalized cirrhotic patients were prospectively enrolled. Liver function, a complete neurocognitive assessment for the diagnosis of clinical or subclinical hepatic encephalopathy (HE) and parameters of nutritional status and muscle function were evaluated in each patient at admission. Clinically overt HE, at admission or in the last 12 months, or a diagnosis of minimal HE were significantly higher in cirrhotic patients with muscle depletion or decreased muscle strength. The fasting venous blood ammonia concentrations were also higher in this group. Muscle depletion was an independent risk factor at multivariate analysis both for overt and minimal HE. In conclusion cirrhotic patients with muscle depletion are at higher risk of HE and the amelioration of nutritional status is a possible goal to decrease the prevalence of neurocognitive alterations in these patients.     

Microglia activation in hepatic encephalopathy in rats and humans

Astrocytes play an important role in the pathogenesis of hepatic encephalopathy (HE) and ammonia toxicity, whereas little is known about microglia and neuroinflammation under these conditions. We therefore studied the effects of ammonia on rat microglia in vitro and in vivo and analyzed markers of neuroinflammation in post mortem brain tissue from patients with cirrhosis with and without HE and non-cirrhotic controls. In cultured rat microglia, ammonia stimulated cell migration and induced oxidative stress and an up-regulation of the microglial activation marker ionized calcium-binding adaptor molecule-1 (Iba-1). Up-regulation of Iba-1 was also found in the cerebral cortex from acutely ammonia-intoxicated rats and in the cerebral cortex from patients with cirrhosis who have HE, but not from patients with cirrhosis who do not have HE. However, ammonia had no effect on microglial glutamate release, prostaglandin synthesis, and messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the proinflammatory cytokines interleukin (IL)-1α/β, tumor necrosis factor α, or IL-6, whereas in cultured astrocytes ammonia induced the release of glutamate, prostaglandins, and increased IL-1β mRNA. mRNA and protein expression of iNOS and COX-2 or mRNA expression of proinflammatory cytokines and chemokine monocyte chemoattractive protein-1 in cerebral cortex from patients with liver cirrhosis and HE were not different from those found in patients with cirrhosis who did not have HE or control patients without cirrhosis. CONCLUSION: These data suggest that microglia become activated in experimental hyperammonemia and HE in humans and may contribute to the generation of oxidative stress. However, HE in patients with liver cirrhosis is not associated with an up-regulation of inflammatory cytokines in cerebral cortex, despite microglia activation.     

Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients

BACKGROUND Liver cirrhosis is the late stage of hepatic fibrosis and is characterized by portal hypertension that can clinically lead to decompensation in the form of ascites,esophageal/gastric varices or encephalopathy. The most common sequelae associated with liver cirrhosis are neurologic and neuropsychiatric impairments labeled as hepatic encephalopathy(HE). Well established triggers for HE include infection, gastrointestinal bleeding, constipation, and medications. Alterations to the gut microbiome is one of the leading ammonia producers in the body, and therefore may make patients more susceptible to HE.AIM To investigate the relationship between the use of proton pump inhibitors(PPIs)and HE in patients with cirrhosis.METHODS This is a single center, retrospective analysis. Patients were included in the study with an admitting diagnosis of HE. The degree of HE was determined from subjective and objective portions of hospital admission notes using the West Haven Criteria. The primary outcome of the study was to evaluate the grade of HE in PPI users versus non-users at admission to the hospital and throughout their hospital course. Secondary outcomes included rate of infection,gastrointestinal bleeding within the last 12 mo, mean ammonia level, and model for end-stage liver disease scores at admission.RESULTS The HE grade at admission using the West Haven Criteria was 2.3 in the PPI group compared to 1.7 in the PPI nonuser group(P = 0.001). The average length of hospital stay in PPI group was 8.3 d compared to 6.5 d in PPI nonusers(P =0.046). Twenty-seven(31.8%) patients in the PPI user group required an Intensive Care Unit admission during their hospital course compared to 6 in the PPI nonuser group(16.7%)(P = 0.138). Finally, 10(11.8%) patients in the PPI group expired during their hospital stay compared to 1 in the PPI nonuser group(2.8%)(P = 0.220).CONCLUSION Chronic PPI use in cirrhotic patients is associated with significantly higher average West Haven Criteria for HE compared to patients that do not use PPIs.