• Hepatic encephalopathy
• Lactulose
• NCPH
• PARTO
• PSVD
• Rifaximin

• Humans
• Hepatic Encephalopathy/therapy
• Hepatic Encephalopathy/epidemiology
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/diagnosis
• Hypertension, Portal/complications
• Hypertension, Portal/epidemiology
• Hypertension, Portal/therapy
• Liver Cirrhosis
• Ammonia/blood
• Portasystemic Shunt, Surgical

Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis.

• Animals
• Hyperammonemia/chemically induced
• Ligilactobacillus salivarius
• Liver
• Mice
• Mice, Inbred C57BL
• Thioacetamide/toxicity

• National Natural Science Foundation of China

Hyperammonemia in the CNS induces irreversible damages to neurons due to ultimate cell loss. Neurite degeneration, a primary event that leads to neuronal cell death, remains less elucidated especially in hyperammonemia circumstances. Here, we found that the administration of ammonia induced neurite degeneration in cultured cerebellar granule neurons. The resulting altered neuronal morphology, rupture of neurites, and disassembly of the cytoskeleton led to cell death. Calcein and Fluo-4 staining revealed that ammonia induced intracellular calcium dysregulation. Subsequently activated calpain cleaved CRMP-2, a microtubule assembly protein. Pharmacologically inhibition of calpain, but not caspases or GSK-3, suppressed the cleavage of CRMP-2 and reversed neurite degeneration under ammonia treatment. Exposure to ammonia decreased whereas inhibition of calpain restored the amplitude and frequency of miniature excitatory postsynaptic currents. These data suggest a mechanism by which elevated ammonia level may induce neuronal dysfunction via abnormal calcium influx and calpain-dependent CRMP-2 cleavage, leading to abnormal synaptic transmission, cytoskeletal collapse, and neurite degeneration.

• CRMP-2
• ammonia
• calpain, GSK-3
• neurite degeneration

• Cerebral edema
• Cirrhosis
• Hepatic encephalopathy
• Liver failure

Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.

• acute liver failure
• brain energy metabolism
• glial reactivity
• hepatic encephalopathy
• mitochondria
• redox homeostasis

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.

To investigate the relationship between the use of proton pump inhibitors (PPIs) and HE in patients with cirrhosis.

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.

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).

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.

• Cirrhosis
• Hepatic encephalopathy
• Proton pump inhibitors
• Hepatology
• Proton pump inhibitor

• U01 AA026977 NIAAA NIH HHS

• Hepatic encephalopathy
• Hydrogen sulfide
• Inflammation

• AHE, Acute Hepatic Encephalopathy
• ALF, Acute Liver Failure
• CHE, Chronic Hepatic Encephalopathy
• CNS, Central Nervous System
• CSF, Cerebrospinal Fluid
• ECs, Endothelial Cells
• HE, Hepatic Encephalopathy
• IL, Interleukin
• LPS, Lipopolysaccharide
• MAPKs, Mitogen-Activated Protein Kinases
• NCX, Sodium-Calcium Exchanger
• NF-κB, Nuclear Factor-kappaB
• NHE, Sodium/Hydrogen Exchanger-1 or SLC9A1 (SoLute Carrier Family 9A1)
• SUR1, The Sulfonylurea Receptor 1
• TDP-43 and tau proteinopathies
• TDP-43, TAR DNA-Binding Protein, 43 kDa
• TLR, Toll-like Receptor
• TNF-α, Tumor Necrosis Factor-Alpha
• TSP-1, Thrombospondin-1
• ammonia
• hepatic encephalopathy
• inflammation
• matricellular proteins

• Ammonia
• Bile duct ligation
• Energy metabolism
• Hepatic encephalopathy
• Mitochondria
• Oxidative stress

• Animals
• Brain/metabolism
• Disease Models, Animal
• Energy Metabolism/physiology
• Hepatic Encephalopathy/metabolism
• Liver/metabolism
• Male
• Mitochondria/metabolism
• Oxidative Stress/physiology
• Rats, Wistar
• Reactive Oxygen Species/metabolism

• Cirrhosis
• MELD score
• Overt hepatic encephalopathy

• Brain
• Inborn errors
• MRI
• MRS
• Metabolic disorders

• Cirrhosis, Benzodiazepine
• Endozepine-4
• Glutamate-related neurotoxicity which in turn may alter the γ-aminobutyric acid
• Hepatic coma
• Hepatic encephalopathy
• Model for End - stage liver disease
• Peripheral benzodiazepine receptor

• Adult
• Aged
• Ammonia/blood
• Biomarkers/blood
• Case-Control Studies
• Diazepam Binding Inhibitor/blood
• Female
• Hepatic Encephalopathy/blood
• Hepatic Encephalopathy/diagnosis
• Humans
• Male
• Middle Aged
• Predictive Value of Tests
• Severity of Illness Index
• Up-Regulation

• Hepatic encephalopathy
• Malnutrition
• Protein diet

• Adult
• Aged
• Brain/diagnostic imaging
• Brain/pathology
• Brain Mapping
• Case-Control Studies
• Cerebellum/diagnostic imaging
• Cerebellum/pathology
• Female
• Hepatic Encephalopathy/complications
• Hepatic Encephalopathy/diagnostic imaging
• Hepatic Encephalopathy/mortality
• Humans
• Image Processing, Computer-Assisted
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/diagnostic imaging
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Prognosis
• Radiography
• Severity of Illness Index

• deficiency
• nutrition
• total parenteral nutrition
• zinc

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

• Astrocytes
• NADPH oxidase
• Protein tyrosine nitration
• RNA oxidation
• Zinc

• therapy
• liver cirrhosis
• evidence-based medicine

• Cohort Studies
• Forced Expiratory Volume/physiology
• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/physiopathology
• Predictive Value of Tests
• Risk Factors

• children
• cirrhosis
• hepatic encephalopathy
• lactulose

• Adult
• Anti-Infective Agents/adverse effects
• Anti-Infective Agents/therapeutic use
• Gastrointestinal Agents/adverse effects
• Gastrointestinal Agents/therapeutic use
• Hepatic Encephalopathy/drug therapy
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/physiopathology
• Hepatic Encephalopathy/therapy
• Humans
• Patient Compliance
• Practice Guidelines as Topic
• Treatment Outcome

• Astrocytes/metabolism
• Astrocytes/pathology
• Brain/metabolism
• Brain/physiopathology
• Brain Diseases, Metabolic/diagnosis
• Brain Diseases, Metabolic/etiology
• Brain Diseases, Metabolic/physiopathology
• Brain Edema/etiology
• Brain Edema/metabolism
• Brain Edema/physiopathology
• Diagnosis, Differential
• Hepatic Encephalopathy/diagnosis
• Hepatic Encephalopathy/physiopathology
• Humans
• Hyponatremia/complications
• Hyponatremia/diagnosis
• Hyponatremia/physiopathology
• Liver Failure, Acute/complications
• Liver Failure, Acute/physiopathology
• Water-Electrolyte Balance/physiology

AIM: To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension.

METHODS: Male Wistar rats were divided into sham-operated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas.

RESULTS: We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, significantly and persistent increase in this excitatory neurotransmitter activity.

CONCLUSION: The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modifies the normal function in some brain regions.

• Portal hypertension
• Glutamine synthetase
• Glutamate uptake
• Frontal cerebral cortex
• Hippocampus
• Rat

• Animals
• Astrocytes/metabolism
• Brain/metabolism
• Brain/physiopathology
• Brain Edema/genetics
• Brain Edema/metabolism
• Brain Edema/physiopathology
• Carrier Proteins/metabolism
• Hepatic Encephalopathy/genetics
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/physiopathology
• Humans
• Hyperammonemia/genetics
• Hyperammonemia/metabolism
• Hyperammonemia/physiopathology
• Oxidative Stress/physiology
• RNA/genetics
• RNA/metabolism
• Receptors, GABA-A/metabolism
• Water-Electrolyte Balance/physiology
• Zinc/metabolism

The aim of this study was to assess the effects of albumin dialysis on hepatic encephalopathy and circulating levels of amino acids in severe alcoholic hepatitis.

The study was carried out in nine patients with severe alcoholic hepatitis and four with primary biliary cirrhosis treated with the molecular adsorbent recirculating system. Besides standard liver function tests, circulating levels of ammonia, total, branched chain and aromatic amino acids, the presence and severity of hepatic encephalopathy, and number connection test were measured before and after each treatment.

There were eight episodes of encephalopathy in patients with alcoholic hepatitis. Albumin dialysis was associated with significant improvement in encephalopathy (p = 0.02), and a decrease in total amino acid levels (2490 ± 152 μM to 2229 ± 114 μM, p < 0.001). Moreover, the Fischer's ratio, which was significantly lower in patients with alcoholic hepatitis (1.32 ± 0.08) than in controls (3.20 ± 0.16), increased by 17% after albumin dialysis (p < 0.02) because of a significant decrease in phenolic aromatic amino acids (193 ± 17 μM to 165 ± 9 μM, p = 0.04). No differences were observed in circulating ammonia. Changes in phenolic aromatic amino acids and the Fischer's ratio were more prominent in patients with encephalopathy and higher bilirubin removal. Albumin dialysis did not significantly affect the amino acid profile in the controls.

Albumin dialysis results in a significant decrease in circulating phenolic aromatic amino acids and improvement of hepatic encephalopathy in patients with severe liver failure.

• Ammonia/chemistry
• Ammonia/pharmacology
• Animals
• Animals, Newborn
• Antioxidants/metabolism
• Antioxidants/pharmacology
• Astrocytes/metabolism
• Brain/metabolism
• Brain/pathology
• Cells, Cultured
• Edema/drug therapy
• Hydrogen Peroxide/pharmacology
• NG-Nitroarginine Methyl Ester/pharmacology
• Oxidative Stress
• Phosphorylation
• Rats
• Sodium-Potassium-Chloride Symporters/metabolism
• Sodium-Potassium-Chloride Symporters/physiology
• Solute Carrier Family 12, Member 2
• Time Factors

• DK063311 NIDDK NIH HHS

• Adult
• Anisotropy
• Brain Edema/complications
• Brain Mapping
• Case-Control Studies
• Chronic Disease
• Diffusion
• Diffusion Magnetic Resonance Imaging/methods
• Female
• Humans
• Liver Failure, Acute/complications
• Male
• Middle Aged

AIM: To evaluate the effect of an intravenous bolus of mannitol in altering brain metabolites, brain water content, brain parenchyma volume, cerebrospinal fluid (CSF) volume and clinical signs in controls and in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), by comparing changes in conventional magnetic resonance imaging (MRI), in vivo proton magnetic resonance spectroscopy (PMRS) and diffusion tensor imaging (DTI) before and after its infusion.

METHODS: Five patients each with ALF and ACLF in grade 3 or 4 hepatic encephalopathy and with clinical signs of raised intracranial pressure were studied along with five healthy volunteers. After baseline MRI, an intravenous bolus of 20% mannitol solution was given over 10 min in controls as well as in patients with ALF and ACLF. Repeat MRI for the same position was acquired 30 min after completing the mannitol injection.

RESULTS: No statistically significant difference was observed between controls and patients with ALF and ACLF in metabolite ratios, DTI metrics and brain volume or CSF volume following 45 min of mannitol infusion. There was no change in clinical status at the end of post-mannitol imaging.

CONCLUSION: The osmotic effect of mannitol did not result in significant reduction of brain water content, alteration in metabolite ratios or any change in the clinical status of these patients during or within 45 min of mannitol infusion.

• Mannitol
• Acute liver failure
• Acute-on-chronic liver failure
• Proton MR spectroscopy
• Diffusion tensor imaging