Nutritional aspects of prehabilitation in adults with cirrhosis awaiting liver transplant.

Malnutrition, sarcopenia (low muscle mass), and physical frailty have gained increasing recognition in candidates for liver transplant (LT) as these conditions can impact postoperative functional capacity. Multidimensional prehabilitation programs have been proposed as a safe intervention in adults awaiting LT but the nutritional pillar of prehabilitation has been understudied. This review summarizes the nutritional recommendations for prehabilitation for individuals with cirrhosis awaiting LT. Three major aspects of nutritional prehabilitation are discussed: (1) Assess: Evaluate nutritional status and assess for malnutrition, sarcopenia, and frailty to guide the nutritional prehabilitation intervention intensity, increasing across universal, targeted, and specialist levels; (2) Intervene: Prescribe a nutritional prehabilitation intervention to meet established nutrition guidelines in cirrhosis with a targeted focus on improving nutritional status and muscle health; (3) Reassess: Follow-up based on the required intensity of nutritional care with as needed intervention adjustment. Topics covered in the review include nutritional care levels for prehabilitation, energy prescriptions across body mass index strata, detailed considerations around protein intake (amount, distribution, and quality), carbohydrate and fat intake, other nutritional considerations, and the potential role of dietary supplements and nutraceuticals. Future research is warranted to more accurately evaluate energy needs, evaluate emerging dietary supplementation strategies, and establish the role of nutraceuticals alongside food-based interventions. While the general principles of nutritional prehabilitation are ready for immediate application, future large-scale randomized controlled trials in this space will help to quantify the benefit that can be gained by transitioning the LT approach from passive "transplant waitlist time" to active "transplant preparation time."

Amino acids, ammonia, and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a decline in brain function arising due to liver insufficiency. The liver's diminished capacity to clear ammonia, and the subsequent accumulation of it, is highly implicated in pathogenesis of HE. Ammonia is endogenously generated from the catabolism of amino acids derived from dietary protein intake. Therefore, a conflict arises in cirrhosis where dietary protein intake may increase ammonia and precipitate HE, and at the same time, cirrhotic patients require high daily protein intake due to altered nutrient metabolism. A nutritional solution is needed to deliver sufficient doses of protein to patients without increasing the risk of HE. In order to address this issue, this review will discuss the catabolism of individual amino acids with a special focus on ammonia-generating steps and highlight a subset of amino acids that have the potential to generate multiple equivalents of ammonia. Following, studies investigating the effects of individual amino acids in cirrhosis on blood ammonia levels as well as development of HE will be reviewed.

Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia.

Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90 mm Hg) were induced via blood withdrawal from the femoral artery and maintained for 120 min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1 g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60 mm Hg (not 90 mm Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.

Progressive resistance training prevents loss of muscle mass and strength in bile duct-ligated rats.

BACKGROUND: Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct-ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats. METHODS: A group of BDL-rats underwent a progressive resistance training programme and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. RESULTS: BDL + exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. CONCLUSION: Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia; however, a tendency was observed.

The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis.

Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss.

Brain edema: a valid endpoint for measuring hepatic encephalopathy?

Hepatic encephalopathy (HE) is a major complication of liver failure/disease which frequently develops during the progression of end-stage liver disease. This metabolic neuropsychiatric syndrome involves a spectrum of symptoms, including cognition impairment, attention deficits and motor dysfunction which eventually can progress to coma and death. Pathologically, HE is characterized by swelling of the astrocytes which consequently leads to brain edema, a common feature found in patients with acute liver failure (ALF) as well as in cirrhotic patients suffering from HE. The pathogenic factors involved in the onset of astrocyte swelling and brain edema in HE are unresolved. However, the role of astrocyte swelling/brain edema in the development of HE remains ambiguous and therefore measuring brain edema as an endpoint to evaluate HE is questioned. The following review will determine the effect of astrocyte swelling and brain edema on neurological function, discuss the various possible techniques to measure brain edema and lastly to propose a number of neurobehavioral tests to evaluate HE.

The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.

UNLABELLED: Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. CONCLUSION: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE.

Telehealth-Delivered Program and Accompanying Patients to Enhance the Clinical Condition of Patients Throughout a Liver Transplant: Protocol for a Mixed Methods Study.

BACKGROUND: Liver transplantation (LT) is indicated in patients with severe acute or chronic liver failure for which no other therapy is available. With the increasing number of LTs in recent years, liver centers worldwide must manage their patients according to their clinical situation and the expected waiting time for transplantation. The LT clinic at the Centre hospitalier de l'Université de Montréal (CHUM) is developing a new health care model across the entire continuum of pre-, peri-, and posttransplant care that features patient monitoring by an interdisciplinary team, including an accompanying patient; a digital platform to host a clinical plan; a learning program; and data collection from connected objects. OBJECTIVE: This study aims to (1) evaluate the outcomes following the implementation of a patient platform with connected devices and an accompanying patient, (2) identify implementation barriers and facilitators, (3) describe service outcomes in terms of health outcomes and the rates and nature of contact with the accompanying patient, (4) describe patient outcomes, and (5) assess the intervention's cost-effectiveness. METHODS: Six types of participants will be included in the study: (1) patients who received transplants and reached 1 year after transplantation before September 2023 (historical cohort or control group), (2) patients who will receive an LT between December 2023 and November 2024 (prospective cohort/intervention group), (3) relatives of those patients, (4) accompanying patients who have received an LT and are interested in supporting patients who will receive an LT, (5) health care professionals, and (6) decision makers. To describe the study sample and collect data to achieve all the objectives, a series of validated questionnaires, accompanying patient logbooks, transcripts of interviews and focus groups, and clinical indicators will be collected throughout the study. RESULTS: In total, 5 (steering, education, clinical-technological, nurse prescription, and accompanying patient) working committees have been established for the study. Recruitment of patients is expected to start in November 2023. All questionnaires and technological platforms have been prepared, and the clinicians, stakeholders, and accompanying patient personnel have been recruited. CONCLUSIONS: The implementation of this model in the trajectory of LT recipients at the CHUM may allow for better monitoring and health of patients undergoing transplantation, ultimately reducing the average length of hospital stay and promoting better use of medical resources. In the event of positive results, this model could be transposed to all transplant units at the CHUM and across Quebec (potentially affecting 888 patients per year) but could also be applied more widely to the monitoring of patients with other chronic diseases. The lessons learned from this project will be shared with decision makers and will serve as a model for other initiatives involving accompanying patients, connected objects, or digital platforms. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/54440.

Neurological complications post-liver transplantation: impact of nutritional status.

Nutritional status is significantly altered in patients with end-stage liver disease (cirrhosis). Malnutrition is a common complication of cirrhosis and is known to be associated with a greater risk of post-operative complications and mortality, especially following liver transplantation. Neurological complications occur frequently after transplant and the nature and extent of these complications may relate to nutritional deficits such as protein-calorie malnutrition as well as vitamin and micronutrient deficiencies. A consensus document from the International Society on Hepatic Encephalopathy and Nitrogen metabolism (ISHEN) has been established in order to address these concerns. Careful assessment of nutritional status followed by prompt treatment of nutritional deficits has the potential to impact on transplant outcome and, in particular, on post-transplant neurological disorders in patients with cirrhosis.

Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema.

A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.

Nutritional Strategies to Manage Malnutrition and Sarcopenia following Liver Transplantation: A Narrative Review.

Persisting or newly developed malnutrition and sarcopenia after liver transplant (LT) are correlated with adverse health outcomes. This narrative review aims to examine the literature regarding nutrition strategies to manage malnutrition and sarcopenia after LT. The secondary aims are to provide an overview of the effect of nutrition strategies on the incidence of infections, hospital length of stay (LOS), acute cellular rejection (ACR), and mortality after LT. Four databases were searched. A total of 25 studies, mostly of mid-high quality, were included. Six studies found a beneficial effect on nutritional parameters using branched-chain amino acids (BCAA), immunomodulating diet (IMD), or enteral nutrition (EN) whereas two studies using beta-hydroxy-beta-methylbutyrate (HMB) found a beneficial effect on muscle mass and function. Fourteen studies using pre- or pro-biotics, IMD, and EN were effective in lowering infection and six studies using IMD, BCAA or HMB reported reduced hospital LOS. Finally, four studies using HMB and vitamin D were effective in reducing ACR and one study reported reduced mortality using vitamin D after LT. In conclusion, nutritional intervention after LT has different beneficial effects on malnutrition, sarcopenia, and other advert outcomes. Additional large and well-constructed RCTs using validated tools to assess nutritional status and sarcopenia are warranted to ensure more robust conclusions.

Nutritional education strategies for patients with cirrhosis: A narrative review.

BACKGROUND: Patients with cirrhosis suffer from many complications, including malnutrition, which must be managed promptly and effectively by the healthcare team. Educating patients about their medical condition, the risk of malnutrition and other complications of cirrhosis, could contribute to optimal nutritional status, quality of life and general health. OBJECTIVE: This review provides an overview of the literature on a variety of nutritional education strategies used with patients suffering from cirrhosis. This review also identifies barriers and facilitators which impact the adherence in using these strategies. PATIENT INVOLVEMENT: A patient-partner contributed to this review by providing insights on different issues and concerns that patients with cirrhosis might ask themselves regarding nutritional education strategies. The patient-partner was also involved in the overall revision of the review. METHODS: Articles published between the years 2000-2023 focusing on nutritional education strategies in patients living with cirrhosis were identified using Google Scholar and PubMed and were screened for inclusion in the study. All selected studies were intervention studies. A quality assessment of the included studies was conducted using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Only a few nutritional education strategies in patients with cirrhosis were documented in the literature. The strategies ranged from using traditional printed materials to advanced technologies. These strategies may prove beneficial in complementing routine interventions provided by health professionals, such as registered dietitians, in their clinical practice. DISCUSSION: This narrative review clearly highlights the need for further research to elaborate and evaluate nutritional education strategies for people living with cirrhosis. PRACTICAL VALUE: Elaborating and evaluating educational strategies in nutrition for patients living with cirrhosis will be an adjuvant to health professionals and dietitians in their clinical practice by providing them, and the patients, with targeted education resources.

IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease.

Many people living with diabetes also have nonalcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating (trans-signaling) soluble receptors. We investigated whether secretion of IL-6 trans-signaling coreceptors are altered in NAFLD by diabetes and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated with use of human hepatocyte, stellate, and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed steatohepatitis and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and soluble gp130 (sgp130) secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling coreceptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes. ARTICLE HIGHLIGHTS: IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.

Renal dysfunction independently predicts muscle mass loss in patients following liver transplantation.

Background: Liver transplantation (LT) is the only curative treatment for cirrhosis. However, the presence of complications can impact outcomes following LT. Sarcopenia, or muscle mass loss, is highly prevalent in patients with cirrhosis and is associated with longer hospitalization stays and a higher infection rate post-surgery. We aimed to identify patients at higher risk of early sarcopenia post-LT. Methods: This retrospective study included 79 cirrhotic patients who underwent LT. Muscle mass was evaluated using the third lumbar spine vertebra skeletal muscle index (SMI) and sarcopenia was defined using established cut-off values. Computerized tomography (CT) scans performed within a six-month peri-operative period (three months pre- and post-LT) were included in the study. Complications and comorbidities were collected and correlated to SMI post-LT and predictive models for SMI post-LT were constructed. Results: The overall prevalence of sarcopenia was 46% and 62% before and after LT, respectively. Newly developed sarcopenia was found in 42% of patients. Post-LT sarcopenia was associated with longer hospital stays (54±37 versus 29±10 days, p = 0.002), higher number of infection (3±1 versus 1±2, p = 0.027), and greater number of complications (5±2 versus 3±2, p < 0.001) compared to absence of sarcopenia. Multivariate analyses showed that the SMI post-LT was independently associated with pre-LT renal function markers, the glomerular filtration rate (GFR) and creatinine (Model 1, GFR: ß = 0.33; 95% CI 0.04-0.17; p = 0.003; Model 2, Creatinine: ß = -0.29; 95% CI -0.10 to -0.02; p = 0.009). Conclusions: The present study highlights the potential role of renal dysfunction in the development and persistence of sarcopenia after LT.

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.

Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse.

Previous studies have demonstrated protective effects of mild hypothermia following acetaminophen (APAP)-induced acute liver failure (ALF). However, effects of this treatment in ALF due to other toxins have not yet been fully investigated. In the present study, the effects of mild hypothermia in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines were assessed in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stages of encephalopathy in parallel with AOM mice maintained mildly hypothermic (35 degrees C). AOM treatment led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels, and brain GSH/GSSG ratios as well as selective increases in expression of plasma proinflammatory cytokines. Mild hypothermia resulted in reduced hepatic damage, improvement in neurological function, normalization of glutathione levels, and selective attenuation in expression of circulating proinflammatory cytokines. These findings demonstrate that the beneficial effects of mild hypothermia in experimental AOM-induced ALF involve both antioxidant and anti-inflammatory mechanisms.

N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms.

N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.

Role of Exercise in the Management of Hepatic Encephalopathy: Experience From Animal and Human Studies.

Sarcopenia and malnutrition are common features in patients with hepatic encephalopathy. Ammonia, a factor implicated in the pathophysiology of hepatic encephalopathy, may be cleared by the muscle via the enzyme glutamine synthetase when the liver function is impaired. Hence, optimizing muscle mass in patients suffering from hepatic encephalopathy is a potential strategy to decrease ammonia levels. Exercise could be an efficient therapeutic approach to optimize muscle mass and therefore potentially reduce the risk of hepatic encephalopathy in patients with chronic liver disease. This review reports the current evidence regarding exercise and hepatic encephalopathy from animal and human studies. After defining concepts such as frailty, sarcopenia, and malnutrition, the present knowledge regarding exercise as potential therapy in cirrhotic patients with or without hepatic encephalopathy is discussed. Recommendations and future aspects are also considered.

Increased oxidative stress during hyperglycemic cerebral ischemia.

In this review, we summarize the role of hyperglycemia during cerebral ischemia. Hyperglycemia occurring during experimental and clinical stroke has been associated with increased cerebral damage. Increased oxidative stress resulting from hyperglycemia is believed to contribute to the exacerbated damage. More specifically, superoxide, nitric oxide and peroxynitrite are believed to play an important role in cerebral damage. This also involves increased recruitment of various blood cells to the ischemic zone that contribute to inflammation. We present data from our group and others that demonstrate that free radical production is increased during hyperglycemic stroke in rodents. Recent data suggest that inflammation is an important component of ischemic damage under both normo- and hyperglycemic conditions. We summarize numerous studies that indicate that a variety of antioxidant (inhibition of free radical production, scavenging of free radicals and increasing free radical degradation) and anti-inflammatory strategies decrease cerebral infarction. Finally, we compare the success of some of these strategies in clinical trials compared to the animal models.